Protocol Regen 006 20mar24 Signed

A PHASE 3 RANDOMIZED CONTROLLED STUDY OF
RENAL AUTOLOGOUS CELL THERAPY (REACT) IN

SUBJECTS WITH TYPE 2 DIABETES AND CHRONIC
KIDNEY DISEASE (REGEN-006)
Protocol Number: REGEN-006

IND Number: 16482
EudraCT Number: 2020-004293-21
Development Phase: Phase 3
Investigational Therapy Name: Renal Autologous Cell Therapy (REACT)
United States Adopted
Name/International Non- Rilparencel
proprietary Name:
Brief Description: This is a 1:1 randomized, multi-center, blinded intervention, two cohort study.
All participants will receive institutional standard of care for their type 2
diabetes and chronic kidney disease. Cohort 1 participants will have scripted
Sham procedures that mimic the sounds and activities of biopsy, injection
procedures, and evaluations as a control for Cohort 2 participants who will
have a kidney biopsy followed 14 weeks later with a REACT injection into the
biopsied kidney, then, another 12 weeks later a REACT injection into their
contralateral kidney. All participants will be followed to the global trial end
date.
Version Number: 5.0
Date of Issue: 20 March 2024
Sponsor: ProKidney
8020 Arco Corporate Dr. Ste 400
Raleigh, NC 27617
Phone: +1 (919) 294-4521
Email: info@prokidney.com
Medical Monitor: Refer to Protocol Contact Sheet.
This document is a confidential communication from ProKidney. Acceptance of this document constitutes an
agreement by the recipient(s) that no unpublished information contained herein will be published or disclosed
without prior written approval from ProKidney, except that this document may be disclosed to appropriate
Institutional Review Boards (IRBs) or Ethics Committees (EC) under the condition that they are also required
to maintain confidentiality.
Renal Autologous Cell Therapy (REACT)
Clinical Protocol REGEN-006 Version 5.0
PROTOCOL SIGNATURE PAGE

REGEN-006
PROTOCOL VERSION 5.0
By signing below, I agree to the following:

 I have received and read Protocol: “A PHASE 3 RANDOMIZED CONTROLLED
STUDY OF RENAL AUTOLOGOUS CELL THERAPY (REACT) IN SUBJECTS
WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE (REGEN-006)”.
 In my formal capacity as Investigator, I understand that my duties include ensuring the
safety of all study participants as well as conducting the study in accordance with all
stipulations of the protocol as specified in both the clinical and administrative sections,
including all statements regarding confidentiality.
 I understand that no deviation from, or changes to the Protocol will take place without
prior agreement from the Sponsor and documented approval from the Institutional
Review Board or Ethics Committee, except where necessary to eliminate an immediate
hazard(s) to the study participants.
 This study will be conducted in compliance with the protocol, in accordance with ICH
E6 Harmonised Guideline (ICH-GCP), in general agreement with the most recent
version of the Declaration of Helsinki, and in accordance with all applicable United
States and European regulations.
 I agree to ensure that all staff members at this site who are involved in the conduct of
this study understand their obligations in meeting the above commitments.
Printed Name of Investigator
Signature of Investigator Date
Aparna Sahoo
Printed Name of Sponsor’s Representative
20-Mar-2024 | 15:26 EDT
Signature of Sponsor’s Representative Date
CONFIDENTIAL Page 2 of 111 ProKidney

PROTOCOL AMENDMENT HISTORY
Table 1: Amendment History

DOCUMENT HISTORY
Clinical Protocol REGEN-006
Document Date
Amendment Version 5.0 20-Mar-2024
Amendment Version 4.0 30-Jan-2023
Amendment Version 3.0 21-Jun-2022
Amendment Version 2.0 31-Jan-2022
Amendment Version 1.1 30-Jul-2021
Original Protocol Version 1.0 05-Feb-2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union.
OVERALL RATIONALE FOR THIS AMENDMENT

Amendment 5 is a global amendment intended to improve the overall clarity, consistency, and
organization of the protocol. The eligibility criteria are modified to enrich the study population
by targeting enrollment of participants with advanced chronic kidney disease (CKD)
characterized by eGFR values of 20 to 35 mL/min/1.73 m2 and increased levels of albuminuria.
Additionally, this amendment further incorporates standard of care treatments in this study
population based on recent changes in the treatment landscape for type 2 diabetes mellitus
(T2DM) and CKD. The changes in this amendment are aimed at facilitating recruitment,
clarifying processes, procedures, and assessments described within the protocol, and thereby
enhancing overall study quality.

SUMMARY OF CHANGES IN THIS AMENDMENT

REGEN-006 Amendment 5 Summary of Changes
Brief Rationale for
Section # and Name Description of Change Change
Title Page • Addition of USAN/INN Updated for clarity
name
• Brief Description updated
Procedures in Case of Emergency • Table 1 Emergency Contact information
and Contact Information moved to Study Manual in
Emergency Contact Information deleted from protocol. order to provide updated
• Medical Monitor and CRO information to sites.
safety contact information
titled Study Administrative
Structure is removed from
Investigational Plan
Section 5.
All Sections • Section and table numbers • Sections
revised. reorganized to
• Tables (Schedule of improve protocol
Events, and Laboratory flow.
Sampling Schedule) and • Reference to time
text time periods are now periods modified
predominantly indicated in to ensure
weeks and days. “Month” consistency in
used only as an aid for timelines for
estimating long durations. procedures and
assessments.
Synopsis Synopsis with repetition of protocol Updated to streamline
body revised to a concise summary. synopsis and reduce
duplicative text.
Introduction Section 2 Paragraph 4 has specific study • Updated for
Preliminary Clinical Evidence details removed: clarity.
Section 2.1.3 • Animal data summarized
concisely.
Potential Risks • RMCL-002 results
Section 2.3.1 summarized omitting • Restructured
eGFR visit details. section to
(in Version 4 Potential Risks was highlight
Section 1.2.2) • Table 3 “Literature potential risks
Published Biopsy-Relation and summarize
Complications”, Table 4 background
Expected Incidence of information in a
AE…”, and Table 5 concise manner.
“Anticipated REACT Cell Reference tables
Complications” moved to moved to
appendices appendix for
additional context
as needed.
Objectives and Endpoints Section 3 • Formatting modified to move text Secondary and exploratory
3., 3.1, 3.2, 3.3. regarding estimands to statistics endpoints modified to
section. align with study objectives
• Key secondary composite


Brief Rationale for
endpoint reformatted into and health authority
separate secondary requests.
endpoints.
• Component of key
secondary endpoint moved
to exploratory endpoint:
Increase of UACR of at
least 30% and of at least
30 mg/g, using the random
urine microalbumin/urine
creatinine ratio sustained
for 90 days.
• Exploratory Endpoints
reduced from 22 to 6
endpoints.
Investigational Product Section 4 • Harmonized description of • Updated for
REACT Description and Formulation REACT formulation with clarity and
Section 4.1 the current IB. alignment with
other core trial
documents.
REACT Dose Calculation
Section 4.3.1 • Dose Selection Table • Updated to
revised for V5. New lower include additional
median weight (83g) dose information for
volume added to table. smaller kidney
sizes.
Methodology
Section 4.3.2 • Consolidated existing text • Streamline
into new section to directly product
follow Dose Calculation information
section
Investigational Plan Section 5 • Sponsor and vendor • Updated contact
Study Administrative Structure contact information information to be
(Version 4 Section 4.1) previously outlined in included in study
section 4.1 in Version 4 is manual outside of
removed from body text protocol to allow
and moved to study flexibility for
manual. future updates
when required.
Overall Design Section 5.1 • Target sample size • Study design

increased from 600 to 685 section updated
participants. for clarity.
• Stratification by eGFR and
SGLT2i added. • To accommodate
• Figure 1 Schema revised the changes to the
for clarity. study population
• Sections 4.2.2 in Version 4 to enrich for a
Treatment Assignment is lower eGFR
moved to Section 7.2.4 range, as well as a


Brief Rationale for
• Section 4.2.3 in Version 4 shorter follow-up
Treatment Compliance, time while
deleted as duplicative. keeping the
• Section 4.2.4 in Version 4 number of target
Study Duration are merged events the same.
into Synopsis and Section
10.3. • Stratification
factors added to
account for
modified study
population which
includes
participants with
Schedule of Events and Laboratory • Tables titled” Schedule of SGLT2 inhibitor
Sample Collection Schedule Events” and” Laboratory use and lower
Section 5.3. Sampling Schedule” target eGFR
moved from synopsis to eligibility criteria.
Section 5.3.
• Modified frequency of • Placement of
certain laboratory tables moved to
assessments, imaging, and body of protocol
other safety assessments. for ease of
reference and
proximity to
relevant text.
• Accommodate
manufacturing
and shipping
timelines.
• Assessments
modified to
facilitate safety
monitoring and
ease participant
burden.


Brief Rationale for
Study Population Section 6 Criteria renumbered and revised. • Inclusion criteria
Inclusion Criteria Section 6.1 Numbers listed below are Version 4 reorganized and
numbering. clarified for
• #3 “diabetic nephropathy” additional
replaced with” chronic guidance,
kidney disease” (now #2 in including
V5) treatments used
• #5 Maximum eGFR for for standard of
enrollment reduced from care as
50 to 35 mL/min/1.73m2 appropriate for
(V5 #2b) targeted CKD
• SGLT2i treatment added Stage 3b and 4
as #5 study population
• Maximum blood pressure with T2DM.
of 140/90 was in
exclusion, but now as • Standard of care
inclusion #4 in V5 and use treatment
of ACEI/ARB is separate clarified based on
criterion. changes in
• #9 fish oil prohibition treatment
deleted. landscape for
study population.
• Exclusion Criteria in • Exclusion criteria

Exclusion Criteria Section 6.2 Version 4 rearranged and revised and
combined into 4 subgroup reorganized to
topic headings. provide clarity.
• Blood pressure max
deleted and moved to 6.1
• Clarified that concomitant
hypertension-related CKD
is not exclusionary.
Study Interventions and Concomitant • Consolidated related text Revisions intended to
Therapies regarding concomitant provide clarity and
Section 7 therapies into a single additional guidance to
Concomitant Therapies section. Within the investigators.
Section 7.1 section, additional
guidance regarding
vaccines and handling of
specific concomitant
medications/treatments
throughout the study,
including guidance during
the peri-procedure time
period.
• Covid text in Section
1.2.1.1, 6.3.1, and 8.3.6 of
Version 4 is revised and
merged with general


Brief Rationale for
vaccine advice in Version
5
Study Visits and Interventions Two subsections added for Provides clarification
Section 7.2 additional guidance during the regarding activities related
screening process: to screening procedures.
• New subsection 7.2.2
Screen Failures
• New subsection 7.2.3
Rescreening
Post-Injection Monitoring Sham and • Replaces Version 4 Provides clarification
REACT Section 6.6 limited to regarding post-injection
Section 7.2.8, 7.2.9 REACT discharge monitoring for sham and
instructions. and describes REACT
the procedure for all
participants.
• Adds subsection 7.2.9
‘REACT/Sham Injection
Follow-up Visits’ with text
and table showing same
follow-up for both
Cohorts.
• Additional information for
follow-up visit post-
procedure included and
Table 6 added.
Long-Term Follow-up Visits • New section added to Updated to provide
Section 7.2.10 support Schedule of Event information corresponding
Table footnotes. More to newly added footnotes
details than footnote brief
information.
End-of-Study Visit • Text (formerly subsection Revised for clarity and
Section 7.2.11 6.7.1 in Version 4) revised improve fluency.
for clarity and some text
replaced with Table 7 ‘EoS
Assessment and
Surveillance Guide’.
Study Assessments and Procedures • Medical history is Revised to provide
Section 8 redefined to include all additional guidance and
Demography and Medical History malignancies, major clarity.
Section. 8.1 surgery, and all CKD-
related information. Time
limits on look-back
deleted.
Physical Examinations • Text (formerly 7.2.2 Simplified text for clarity.
Section 8.3 Version 4)
revised/replaced with:
• 8.3.1 Complete Physical
Examination
• 8.3.2 Targeted Physical


Brief Rationale for
Examination
Note: other terms to describe
various levels of exams deleted.
Clinical Laboratory Assessments • Clinical Laboratory Updated for clarity
Section 8.7 Evaluations table has been
updated.
Imaging Studies • Text (former Section 7.2.6 Updated for clarity
Section 8.8 Version 4) Imaging details
moved to study manuals.
Clarification on study
imaging requirements
updated for:
• Section 8.8.1 Renal
Ultrasound Imaging
• Section 8.8.2 Specific
Timing for Safety Renal
Ultrasound Pre/Post-
Procedure
• Section 8.8.3 Magnetic
Resonance Imaging.
Safety Assessments and Management • AE, TEAE, AESI, SAE, • Updated for
Section 9 not SAE, and SUSAR are clarity.
Safety Event Definitions defined in order.
Section 9.1
• Clarified that progression • Progression of
Reporting Adverse Events of chronic kidney disease chronic kidney
Section 9.2 (i.e. expected eGFR disease is not
reduction as captured in unanticipated in
primary efficacy this patient
endpoints) should not be population and is
reported as AE/SAE a component of
primary efficacy
endpoints.
Other Significant Adverse Events • Clarified that procedure- • Procedure

Section 9.5 related SAEs assessed as complications
causally related to related to
REACT/Sham injections injection are not
(not to REACT/Sham unanticipated.
product) will not be
reported as SUSAR
Events That Are Potential Study • Added that fatal events • Clarified that
Efficacy endpoints that are considered fatal events will
Section 9.7 possibly related or related be subject
to study drug by the standard SUSAR
Investigator, will be reporting if
subject to reporting criteria met
requirements to HAs, and
will be unblinded where


Brief Rationale for
required by local
regulations.
Safety Assessments and Management • Text sections updated to define Updated AESI definition
Section 9 AESI for the study for clarity. Also clarified
Other Significant Adverse Events Procedure-related SAEs.
Section 9.5
Statistical Methods and Planned • Target sample size • To accommodate
Analyses increased from 600 to 685. the changes to the
Section 11 • Modified the statistical study population
assumptions into the to enrich for a
determination of sample lower eGFR
size, keeping the target range, as well as a
number of events the shorter follow-up
same. time while
• Stratification by eGFR and keeping the
SGLT2i added. number of target
• Removed the Planned events the same.
Interim Analysis • To update the
• Updated the definition of statistical
baseline for safety and assumptions
efficacy analyses based on the
• Fixed a typo in the null evolving standard
and alternative hypothesis. of care
• Added Estimands. medications.
• Modified the Efficacy and • Ensure balance in
Safety planned analyses to eGFR and
align with the new SGLT2i use
secondary and exploratory across cohorts.
endpoints. • To align with
• Updated the Analysis Set ProKidney
Definitions regulatory
• Updated the analysis strategy
method for the primary • To update the
endpoint. definition to
ensure a summary
of the safety of
the Biopsy and
Injection, as well
as measure the
efficacy of
REACT.
• Updated for
accuracy.
• Add Estimands.
• Align with other
changes in the
protocol.
• To update the
pre-defined


Brief Rationale for
analysis sets
• To define the
analytical method
of the primary
endpoint in the
SAP.
All updated sections Throughout the protocol, Provide clarity and correct
administrative changes have been administrative errors.
implemented including spelling
corrections, text revisions and
relocation, as appropriate, to
improve overall fluency.

TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2

PROTOCOL AMENDMENT HISTORY .......................................................................................3
OVERALL RATIONALE FOR THIS AMENDMENT .................................................................3
SUMMARY OF CHANGES IN THIS AMENDMENT .................................................................4
LIST OF APPENDICES ................................................................................................................17
LIST OF APPENDIX TABLES ....................................................................................................17
LIST OF TABLES .........................................................................................................................18
LIST OF FIGURES .......................................................................................................................18
LIST OF ABBREVIATIONS, ACRONYMS, AND THEIR DEFINITIONS ..............................19
1 PROTOCOL SUMMARY ........................................................................................................22
1.1 Synopsis ..................................................................................................................... 22
2 INTRODUCTION .....................................................................................................................25
2.1 Chronic Kidney Disease ............................................................................................ 25
2.1.1 Background .................................................................................................... 25
2.1.2 Renal Autologous Cell Therapy .................................................................... 27
2.1.3 Preliminary Clinical Evidence Supporting 2 REACT Injections .................. 27
2.1.4 Nonclinical Evidence Supporting Two Injections ......................................... 28
2.2 Study Rationale .......................................................................................................... 28
2.3 Summary of Risks and Benefits ................................................................................ 29
2.3.1 Potential Risks ............................................................................................... 29
2.3.2 Identified Risks .............................................................................................. 29
2.3.3 Percutaneous Renal Biopsy ........................................................................... 30
2.3.4 REACT Formulation ..................................................................................... 31
2.3.5 REACT Injection into the Kidney ................................................................. 31
2.3.6 Potential Benefits ........................................................................................... 32
3 OBJECTIVES AND ENDPOINTS...........................................................................................32

3.1 Primary Objective: ..................................................................................................... 32

3.2 Secondary Objectives ................................................................................................ 32
3.3 Additional Exploratory Endpoints ............................................................................. 33
4 INVESTIGATIONAL PRODUCT ...........................................................................................33
4.1 REACT Description and Formulation ....................................................................... 33
4.2 Biopsy, Cell Culture, and Formulation ...................................................................... 34
4.2.1 Biopsy ............................................................................................................ 34
4.2.2 Formulation of REACT ................................................................................. 35
4.2.3 Investigational Product Packaging ................................................................ 35
4.2.4 Investigational Product Labeling ................................................................... 35
4.2.5 Transportation of Investigational Product ..................................................... 36
4.3 REACT Product for Injection .................................................................................... 36
4.3.1 REACT Dose Calculation.............................................................................. 36
4.3.2 Methodology .................................................................................................. 37
4.3.3 Investigational Product Accountability ......................................................... 38
4.3.4 Investigational Product Handling and Disposal ............................................ 38
4.3.5 Disposition of Stored Biopsy Specimens ...................................................... 38
5 INVESTIGATIONAL PLAN ...................................................................................................39
5.1 Overall Design ........................................................................................................... 39
5.2 Study Design .............................................................................................................. 40
5.3 Schedule of Events and Laboratory Sample Collection Schedule............................. 40
6 STUDY POPULATION............................................................................................................45
6.1 Inclusion Criteria ....................................................................................................... 45
6.2 Exclusion Criteria ...................................................................................................... 46
6.3 Lifestyle Considerations ............................................................................................ 49
6.3.1 Diet and Activity............................................................................................ 49
6.3.2 Caffeine and Tobacco .................................................................................... 50
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPIES ...................................50
7.1 Concomitant Therapies .............................................................................................. 51

7.1.1 Medications Interfering with Study Assessments.......................................... 51

7.1.2 Prohibited Therapies ...................................................................................... 51
7.1.3 Prohibited Therapies During Peri-procedure Time Period ............................ 52
7.1.4 Vaccines ......................................................................................................... 52
7.2 Study Visits and Interventions ................................................................................... 53
7.2.1 Screening ....................................................................................................... 53
7.2.2 Screen Failures............................................................................................... 53
7.2.3 Rescreening.................................................................................................... 54
7.2.4 Randomization ............................................................................................... 54
7.2.5 Pre-Biopsy ..................................................................................................... 54
7.2.6 Kidney Biopsy ............................................................................................... 54
7.2.7 REACT/Sham Injections ............................................................................... 56
7.2.8 Post Injection Monitoring Sham and REACT ............................................... 57
7.2.9 REACT/Sham Injection Follow-up Visits ..................................................... 58
7.2.10 Long-Term Follow-up Visits ....................................................................... 58
7.2.11 End-of-Study Visit ....................................................................................... 59
7.3 Participant Discontinuation of Treatment and Withdrawal from the Study .............. 60
7.4 End of Treatment ....................................................................................................... 61
7.5 Participant Completion Defined ................................................................................ 61
7.6 Study Completion Defined ........................................................................................ 61
8 STUDY ASSESSMENTS AND PROCEDURES ....................................................................61
8.1 Demography and Medical History............................................................................. 61
8.2 Vital Signs ................................................................................................................. 62
8.2.1 Vital Signs at Rest ......................................................................................... 62
8.2.2 Vital Signs During Procedures ...................................................................... 62
8.3 Physical Examinations ............................................................................................... 62
8.3.1 Complete Physical Examination .................................................................... 63
8.3.2 Targeted Physical Examinations.................................................................... 63
8.4 Electrocardiogram...................................................................................................... 63

8.5 Medications - Prior and Concomitant ........................................................................ 63

8.6 Procedures - Prior and Concomitant .......................................................................... 63
8.7 Clinical Laboratory Assessments .............................................................................. 63
8.7.1 eGFR .............................................................................................................. 65
8.7.2 Urine Collection............................................................................................. 65
8.7.3 Coagulation Status ......................................................................................... 65
8.7.4 Pregnancy Testing ......................................................................................... 65
8.8 Imaging Studies: Renal Ultrasound, Magnetic Resonance Imaging (MRI) and
Computed Tomography (CT) .................................................................................... 66
8.8.1 Renal Ultrasound Imaging ............................................................................. 66
8.8.2 Specific Timing of Safety Renal Ultrasound Post-procedures ...................... 66
8.8.3 Magnetic Resonance Imaging........................................................................ 66
8.8.4 Computerized Tomography ........................................................................... 67
9 SAFETY ASSESSMENTS AND MANAGEMENT................................................................68
9.1 Safety Event Definitions ............................................................................................ 68
9.2 Reporting Adverse Events ......................................................................................... 69
9.3 Reporting Adverse Events of Special Interest and Serious Adverse Events ............. 70
9.3.1 All AESIs and SAEs ...................................................................................... 70
9.3.2 Pregnancies .................................................................................................... 71
9.4 Reporting Serious and Unexpected Suspected Adverse Reactions ........................... 72
9.5 Other Significant Adverse Events ............................................................................. 72
9.5.1 SAEs and AEs Leading to Premature Discontinuation ................................. 72
9.5.2 Definition of AEs of Special Interest (AESI) ................................................ 72
9.6 Adverse Event Intensity and Relationship Assessment ............................................. 73
9.6.1 Intensity Scale ................................................................................................ 73
9.6.2 Relationship Causality ................................................................................... 74
9.7 Events That Are Potential Study Efficacy Endpoints ................................................ 75
9.7.1 Pre-Defined Disease-Related Primary Efficacy Endpoint Events ................. 75
9.7.2 Fatal Events ................................................................................................... 76

9.7.3 Adjudication Package .................................................................................... 76

9.8 Data Monitoring Committee ...................................................................................... 76
9.9 Endpoint Adjudication Committee ............................................................................ 77
9.10 Additional Sponsor-Specific Reporting Conventions ............................................... 77
9.10.1 Special Note on Reporting Acute Kidney Injury (AKI) .............................. 78
10 STOPPING RULES: TREATMENT, PARTICIPANTS, STUDY .........................................78
10.1 Stopping Rules for an Individual Participant............................................................. 78
10.2 Study Suspension or Termination.............................................................................. 79
10.3 Global Trial End Date ................................................................................................ 79
11 STATISTICAL METHODS AND PLANNED ANALYSES ..................................................79
11.1 Determination of Sample Size ................................................................................... 80
11.2 Determination of Baseline for Analyses .................................................................... 80
11.3 Planned Analyses ....................................................................................................... 80
11.3.1 Demographics and Other Screening Characteristics ................................... 81
11.3.2 Study Exposure (Biopsy/sham, REACT/sham Injection(s)......................... 81
11.4 Efficacy Analyses ...................................................................................................... 81
11.4.1 Primary Efficacy Endpoint Analyses........................................................... 81
11.4.2 Secondary Efficacy Endpoints Analyses ..................................................... 81
11.4.3 Exploratory Efficacy Endpoints Analyses ................................................... 82
11.5 Safety Analyses ......................................................................................................... 83
11.5.1 Adverse Events ............................................................................................ 83
11.5.2 Laboratory Evaluations ................................................................................ 83
11.5.3 Vital Signs Evaluations................................................................................ 83
11.5.4 Electrocardiogram Evaluations .................................................................... 84
11.5.5 MRI and CT Imaging................................................................................... 84
11.5.6 Renal Ultrasound Imaging Evaluations ....................................................... 84
11.6 Analysis Sets .............................................................................................................. 84
11.7 Objectives, Endpoints, and Estimands....................................................................... 85
12 ETHICAL AND REGULATORY CONSIDERATIONS ........................................................85

12.1 Good Clinical Practice ............................................................................................... 85

12.2 Delegation of Principal Investigator Responsibilities ................................................ 85
12.3 Institutional Review Board/Ethics Committee .......................................................... 85
12.4 Participant Informed Consent .................................................................................... 86
12.5 Participant Confidentiality ......................................................................................... 87
12.6 Protocol Deviations.................................................................................................... 87
13 DATA HANDLING AND RECORDKEEPING ......................................................................87
13.1 Data Collection .......................................................................................................... 87
13.2 Study Monitoring ....................................................................................................... 88
13.3 Audits and Inspections ............................................................................................... 89
13.4 Retention of Records ................................................................................................. 89
14 QUALITY CONTROL AND QUALITY ASSURANCE ........................................................89
15 FINANCIAL DISCLOSURE AND INSURANCE ..................................................................90
15.1 Financial Disclosure .................................................................................................. 90
15.2 Insurance .................................................................................................................... 90
16 PUBLICATION POLICY .........................................................................................................90
17 REFERENCES ..........................................................................................................................91
18 APPENDICES ...........................................................................................................................96
LIST OF APPENDICES
Appendix 1: Contraceptive Guidance and Collection of Pregnancy Information ........................97
Appendix 2: Tables of Potential and identified Risks ................................................................101
Appendix 3: Statistical Appendices ............................................................................................108
LIST OF APPENDIX TABLES

Table A2- 1: Literature-Published Percutaneous Kidney-Biopsy-Related Complications.........101
Table A2- 2: Expected Incidence of Adverse Events and Complications of Injection
Procedures Similar to the REACT Percutaneous Investigational Product
Injection ....................................................................................................................104
Table A2- 3: Anticipated Investigational Product (REACT) Cell Complications .....................107

Table A3- 1: REGEN-006 Objectives, Endpoints, and Estimands .............................................108
LIST OF TABLES
Table 1: Amendment History..........................................................................................................3
Table 2: Investigational Product ...................................................................................................22
Table 3: Dose Selection Table ......................................................................................................37
Table 4: Schedule of Events .........................................................................................................41
Table 5: Laboratory Sampling Schedule.......................................................................................43
Table 6: Post-Injection Follow-up Visits ......................................................................................58
Table 7: End-of-Study Assessment and Surveillance Guide ........................................................59
Table 8: Clinical Laboratory Evaluations .....................................................................................64
Table 9: Study Events, Endpoints, and Regulatory Reporting .....................................................76
Table 10: AKI CTCAE Grade Scale.............................................................................................78
Table 11: Analysis Set Definitions and Use .................................................................................84
LIST OF FIGURES
Figure 1: Study Schema ................................................................................................................24
Figure 2: Study Schema ................................................................................................................40

LIST OF ABBREVIATIONS, ACRONYMS, AND THEIR DEFINITIONS

Abbreviation or Specialist Term Explanation
ACEI Angiotensin-Converting-Enzyme Inhibitor
AE Adverse Event
ALT Alanine Aminotransaminase
ANCOVA Analysis of Covariance
aPTT Activated Partial Thromboplastin Time
ARB Angiotensin Receptor Blocker
AST Aspartate Aminotransaminase
BMI Body Mass Index
BS Biopsied Set
CBC Complete Blood Count
CI Confidence Interval
CKD Chronic Kidney Disease
CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
CRP C-Reactive Protein
CT Computed Tomography
CTCAE Common Terminology Criteria for Adverse Events
DMSO Dimethyl sulfoxide
DOT Department of Transportation (US)
DMC Data Monitoring Committee
EAC Endpoint Adjudication Committee
ECG Electrocardiogram
EC Ethics Committee
eCRF Electronic Case Report Form
EDC Electronic Data Capture
eGFR Estimated Glomerular Filtration Rate
EOS End-of-Study
EPI Epidemiology
EQ-5D-5L EuroQol 5-Dimension 5 Level survey
ESRD End-Stage Renal Disease
FDA Food and Drug Administration (US)
FSH Follicle-Stimulating Hormone
g Gram(s)
GCP Good Clinical Practice
GFR Glomerular Filtration Rate
g KWest Gram(s) of Estimated Kidney Weight
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
GTED Global Trial End Date
HA Health Authorities
HbA1c Glycosylated Hemoglobin
HBV Hepatitis B Virus


hCG Human Chorionic Gonadotropin
HCV Hepatitis C Virus
HIV Human Immunodeficiency Virus
HR Hazard Ratio
HR-QoL Health-Related Quality of Life
IATA International Air Transport Association
ICAO International Civil Aviation Organization
ICH International Council for Harmonization
I/E Inclusion/Exclusion
iPTH Intact Parathyroid Hormone
IRB Institutional Review Board
ITT Intent-to-Treat
IWRS Interactive Web Randomization System
LDH Lactate Dehydrogenase
LMWH Low molecular weight heparin
KDQOL Kidney Disease Quality of Life Survey
MedDRA Medical Dictionary for Regulatory Activities
mITT Modified Intent-to-Treat
MMRM Mixed Model Repeated Measures
MRI Magnetic Resonance Imaging
NCI National Cancer Institute
NGAL Neutrophil Gelatinase-Associated Lipocalin
NSAIDs Nonsteroidal Anti-Inflammatory Drugs
PBS Phosphate Buffered Saline
PE Physical Examination
PT Preferred Term
PT-INR Prothrombin Time-International Normalized Ratio
QA Quality Assurance
QC Quality Control
RBC Red Blood Cell
REACT Renal Autologous Cell Therapy
RNA Ribonucleic Acid
RRT Renal Replacement Therapy
SAE Serious Adverse Event
SAF Safety Analysis Set
sCr Serum Creatinine
SGLT2i Sodium glucose cotransporter 2 inhibitor
Sham (procedure, biopsy, injection) a treatment or procedure performed as a control that is similar
to a treatment or procedure under investigation but omits the
investigational item.
SOC System Organ Class
SoC Standard of Care


SOP Standard operating procedure
SRC Selected Renal Cells
SUSAR Suspect, Unexpected Serious Adverse Reaction
T2DM Type 2 Diabetes Mellitus
TB Tuberculosis
UACR Urinary Albumin/Creatinine Ratio
VIBE Volumetric Interpolated Breath-hold Examination
WBC White Blood Cell
WOCBP Women of Child-bearing Potential

1 PROTOCOL SUMMARY
1.1 Synopsis
ProKidney is currently developing REACT (rilparencel), a cell-based advanced therapy, with the
aim of improving or stabilizing renal function in participants who have Chronic Kidney Disease
(CKD) and Type 2 Diabetes Mellitus (T2DM). The current standard of care (SoC) aims to
manage and, where possible, delay disease progression. Therapeutic intervention with REACT is
intended to prevent or delay the need for renal replacement therapy (hemodialysis, peritoneal
dialysis, or transplant) which is anticipated in high-risk participants in later stages of CKD and
those with categories A1-A3 albuminuria.
The autologous REACT investigational product is a frozen formulation of culture-expanded

selected renal cells (SRC) in cryopreservation media. Table 2 describes the product, storage
conditions, and administration.
Table 2: Investigational Product

Investigational Product
Product Name REACT (Renal Autologous Cell Therapy)
Renal cells obtained from autologous kidney biopsy
tissue will be culture-expanded and SRC selected.
Selected renal cells will be formulated in a
cryopreservation solution (CryoStor Freeze Medium
Dosage Form
CS10) at a concentration of 100 × 106 cells/mL ±20%.
The aseptically prepared cell product (REACT) will be
dispensed into single-use cryovials and stored in vapor
phase liquid nitrogen (-150°C or colder) until needed.
The dose of REACT will be adjusted to 3 × 106 cells/g
KWest determined from magnetic resonance imaging
Unit Dose
(MRI) study (MRI preferred) or CT if MRI cannot be
performed
Percutaneous injection into the cortex of the biopsied
Route of Administration kidney for Dose 1 and into the contralateral kidney for
Dose 2.
Physical Description Labeled, single-use cryovial of REACT
Manufacturer ProKidney, LLC, Winston-Salem, North Carolina, USA
Full traceability of the autologous starting kidney
biopsy tissue, through manufacturing into an
investigational medicinal product, and return to
Labeling (traceability) participant, will be maintained through use of a unique
identification sequence, such as the Single European
Code Donor Identification Sequence (SEC-DIS), or
equivalent, per country specific requirements.

The Primary Objective of this study is to assess the efficacy of up to 2 REACT injections in
participants with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).
Primary and secondary efficacy assessments related to eGFR will utilize the CKD-EPI equation.
The primary endpoints are the time from first injection to the earliest of:
• At least 40% reduction in eGFR sustained for 30 days, OR
• eGFR < 15 mL/min/1.73m² sustained for 30 days and/or chronic dialysis, and/or
renal transplant, OR
• Renal or cardiovascular death.
The Secondary Objectives are to assess the efficacy and safety of up to 2 REACT injections
across a range of outcome measures.
The secondary efficacy endpoints are:

• Annualized change in eGFR
• Time from first injection to at least a 40% reduction in eGFR sustained for
30 days.
• Time from first injection to eGFR < 15 mL/min/1.73m² sustained for 30 days
and/or chronic dialysis, and/or renal transplant.
• The time from first injection to all-cause mortality.
• Changes from Baseline in patient-reported outcomes from the Kidney Disease
Quality of Life (KDQOL) and EuroQol 5-Dimension 5 Level (EQ-5D-5L)
surveys.
The Safety Endpoints are:

• Summary of AEs, such as SAEs (including fatal events), AESI and AEs leading
to discontinuation of study treatment.
This is a 1:1 randomized, multi-center, blinded intervention, two cohort study. All
participants will receive institutional standard of care for their type 2 diabetes and chronic kidney
disease. Cohort 1 participants will have scripted SHAM procedures that mimic the sounds and
activities of biopsy and injection procedures and evaluations as a control for Cohort 2
participants who will have a kidney biopsy followed 14 weeks (+28 days) later with a REACT
injection into the biopsied kidney, then, another 12 weeks (+28 days) later a REACT injection
into their contralateral kidney. All participants will be followed to the global trial end date.

The plan is to enroll approximately 685 adults who are 30 to 80 years old and have a documented
diagnosis of T2DM and CKD as the underlying cause of kidney disease (diagnosis does not have
to be confirmed by renal biopsy). The enrolled study population includes participants with (1) an
eGFR of ≥ 20 mL/min/1.73m2 and < 30 mL/min/1.73m2, without renal dialysis, AND UACR
level cannot exceed 5000 mg/g (565 mg/mmol) or (2) an eGFR of 30 to ≤ 35 mL/min/1.73m2
AND UACR of 300 to ≤ 5000 mg/g (33.9 mg/mmol to ≤565 mg/mmol).
Key exclusion criteria include Type 1 diabetes mellitus, a history of kidney or other organ
transplantation, solitary kidney, malignancies, bleeding disorders and conditions requiring
anticoagulation, and anatomical or medical contraindications to receive REACT injections.
The scientific rationale for participants to receive two REACT injections in this study is based on
data from nonclinical studies and ProKidney Phase 2 trials (RMCL-002 and REGEN-003)
suggesting that two administrations of REACT delay progression of CKD by augmenting renal
function.
The study events can be summarized in this figure.
Figure 1: Study Schema
The study participants, the specified study biostatisticians, and other study team members will be
blinded to the treatment assignment.
During Screening, participants will have a renal MRI (or CT if MRI is contraindicated or
unavailable) as part of the eligibility assessment to determine the kidney weight and volume for
REACT dosage determination (Table 3). REACT/Sham injections are conducted in the CT suite
because the injection is administered by a CT-guided approach. Renal ultrasound scans are
performed post-procedure/sham to monitor for bleeds at specified times and visits.

Participants return for a series of two visits for REACT/sham injections after the renal
biopsy/sham: 1) at 14 weeks (+28 days) after biopsy for the first REACT/sham injection; 2) at
12 weeks (+28 days) after first REACT/sham injection for their second REACT/sham injection.
The evaluation and interpretation of adverse events as study endpoints is a crucial process and
the Sponsor has developed a training plan for study sites to process adverse events for primary
efficacy endpoints for evaluation by the Endpoint Adjudication Committee (Section 9.9).
Statistical analysis of the primary efficacy endpoint will use a test of the Hazard Ratio of
REACT vs Sham Injection in a stratified Cox proportional hazard regression analysis. Secondary
endpoints will be analyzed using a stratified Cox proportional hazard regression and/or stratified
mixed effects models, as appropriate.
The Intent-to-Treat (ITT), Modified Intent-to-Treat (mITT), Safety Analysis Set (SAF), and
Biopsied Analysis Set (BS) will be used to evaluate this study.
Safety assessments will include but are not limited to adverse events, clinical laboratory
assessments, vital signs, imaging, physical exam assessments, and electrocardiogram
assessments. No hypothesis testing will be performed.
Adverse events analysis periods will be defined based on the adverse event start date:
• Pre-biopsy period: from the date of randomization to the start day of biopsy.
• Pre-injection period: from the start day of biopsy to the first REACT/sham
injection.
• Post-injection period: from the first REACT/sham injection to trial withdrawal or
completion.
In tabular format, the Objectives, Endpoints, and their Estimands (treatment conditions,
population, intercurrent events, and summary measure) are shown in Appendix Table A3- 1.
2 INTRODUCTION
2.1 Chronic Kidney Disease
2.1.1 Background
ProKidney is currently developing REACT (rilparencel), a cell-based advanced therapy, with the
aim of improving or stabilizing renal function in participants who have CKD and T2DM.
Therapeutic intervention with REACT is intended to prevent or delay the need for renal

replacement therapy (hemodialysis, peritoneal dialysis, or transplant) which is anticipated in

high-risk participants in later stages of CKD and those with categories A1-A3 albuminuria.
CKD is characterized by progressive nephropathy that without therapeutic intervention may

worsen until the patient reaches End-Stage Renal Disease (ESRD). 1 CKD is defined as reduced
kidney function, demonstrated by decreased estimated Glomerular Filtration Rate (eGFR) or
evidence of kidney damage, such as increased excretion of urinary albumin. 2 The global
prevalence of CKD is estimated to be 8% to 16%. 3
Early-stage CKD is usually asymptomatic, and, in clinical practice, CKD is most often identified
during the evaluation and management of other medical conditions. Many patients experience
CKD as part of a complex cluster of comorbidities, such as T2DM 4 and cardiovascular disease
(CVD).5 Nearly half of all cases of CKD arise from diabetes with or without hypertension. 4,5 An
increased risk of cardiovascular disease can be a complication of CKD or an independent
comorbidity associated with T2DM. 6
CKD is associated with considerable morbidity 4 and is often accompanied by adverse outcomes
owing to underlying disease states and/or risk factors such as hypertension and renovascular
disease. 7 In patients with advanced CKD (Stages 4 to 5), death from cardiovascular events has
been reported to be more common than progression to dialysis. 8,9 Moreover, although 97% of
patients with moderate to severe CKD have mostly asymptomatic Stage 3 disease, these patients
bear a 2- to 4-fold rise in cardiovascular disease risk together with a significant increase in all-
cause mortality. 5,8 Due to serious comorbidities, patients with CKD are 5 to 11 times more likely
to suffer premature death than progress to ESRD (CKD Stage 5). 10,11
CKD-associated with type 2 diabetes mellitus (T2DM) develops in approximately 40% of

patients with diabetes and is the leading cause of CKD and ESRD worldwide. 12,13 The
development of CKD-associated-T2DM is characterized by glomerular hyperfiltration,
progressive albuminuria, declining eGFR, and eventually ESRD, for those who do not suffer
premature death due to existing comorbidities. Metabolic changes associated with diabetes cause
progressive damage to the kidneys including glomerular hypertrophy, glomerulosclerosis,
tubulointerstitial inflammation, and fibrosis. Risk factors for the development of CKD-
associated-T2DM include age, sex, ethnicity, hyperglycemia, hypertension, obesity, dietary
factors, smoking, and a family history of diabetes and CKD. 13

2.1.2 Renal Autologous Cell Therapy

Renal Autologous Cell Therapy (REACT) is a cell-based advanced therapy product that is being
developed to augment renal function in participants with CKD to delay or prevent renal
replacement therapy (RRT). REACT is an autologous cell-based product composed of Selected
Renal Cells (SRC) which are naturally involved in renal repair and regeneration. 14-16 Renal cells
are selected from biopsy material obtained from a participant and expanded ex vivo to form the
active biological ingredient of the REACT product. REACT is injected back into the
participant’s renal cortex, using a percutaneous computed tomography (CT) guided non-cutting
needle injection. Engraftment of SRCs provides the molecular and mechanistic basis for
activation of endogenous renal repair mechanisms that are still active in the chronically diseased
kidney. 16,17
2.1.3 Preliminary Clinical Evidence Supporting 2 REACT Injections

The scientific rationale for participants to receive two REACT injections in this study is based on
data from nonclinical studies and ProKidney Phase 2 trials (RMCL-002 and REGEN-003).
These data indicate that the autologous renal cells in REACT delay progression of CKD by
augmenting renal structure and function. 14, 18-22 Nonclinical study BAe200 16,17 23,24 an
experimental model of diabetic nephropathy (secondary to metabolic syndrome) in ZSF-1 rats,
demonstrated that two cell injections administered approximately 4 months apart was associated
with an improved proteinuric profile following the second injection. Indeed, in other nonclinical
disease models repeat administration is more effective than single-dose therapy. 25
Importantly, the more cells that can be injected, the greater the potential improvement in renal
function. However, the total number of cells that can be delivered into a kidney at one time is
limited by the size of the kidney, as well as the inelasticity of the renal capsule. Consequently, a
second injection, in the same or contralateral kidney, provides a mechanism to administer greater
numbers of SRCs, which could enhance or prolong therapeutic effects, as observed in nonclinical
studies.
Additionally, due to the bilateral nature of CKD-associated with diabetes, delivery of REACT
into both kidneys could potentially provide additional therapeutic benefit by targeting the
dysfunction present in bilateral kidneys.
Data from participants in the Phase 2 Study RMCL-002 who received 2 injections of REACT, in
addition to standard of care medications, showed stabilization of kidney function compared to
participants who only received standard of care medications.

2.1.4 Nonclinical Evidence Supporting Two Injections

A canine Good Laboratory Practice (GLP) toxicology study (CQL001) was conducted to assess
the safety of administering REACT into both kidneys. Designed similar to the clinical studies,
study animals (n=8) had renal biopsies at 4 to 6 weeks prior to Baseline. One dose was delivered
into one kidney at Baseline and a second dose was administered into the contralateral kidney
three months later. Animals were observed for 6 months following the Baseline injection. While
control animals received PBS, study animals received REACT at a 2-fold greater dose than that
used in this clinical study.
There were no detrimental effects of 2 doses of REACT into the canine kidneys as compared to
control animals 6 months after Baseline treatment. Pathology assessments showed no REACT
safety-related (macroscopic or microscopic) findings in either the target organ (kidney) or non-
target organs examined. No treatment-related kidney findings were noted following enhanced
evaluation of 8 areas of each kidney (3 stains per area), including assessment and scoring of
150 glomeruli per kidney. All kidneys appeared normal, apart from changes related to injection
site scars. There were no signs of renal insufficiency, and no indications of decreased glomerular
filtration rate (GFR). Detailed information is provided in the Investigator’s Brochure.
2.2 Study Rationale

At present, there is no cure for CKD. The current standard of care (SoC) aims to manage and,
where possible, delay disease progression. This is implemented through management of high-
risk conditions associated with CKD (hypertension, hyperlipidemia, coronary artery disease, and
congestive heart failure) and co-morbid conditions and complications (T2DM, anemia, and
disorders of mineral and bone metabolism). For patients with ESRD, RRT either by
hemodialysis, peritoneal dialysis, or kidney transplantation, is necessary to sustain life. However,
even with costly treatments, patients with ESRD experience substantial morbidity and mortality.8
CKD not only affects a patient’s physical well-being but also their quality of life, 14,16 mental
health, 28,29 economic productivity, 30 and healthcare utilization (such as office visits,
hospitalizations, etc.). 31,32
Early detection and intervention for early-stage CKD is recommended by screening high-risk
patient populations.33 Nevertheless, early treatments have been less than optimal, resulting in a
significant unmet medical need for improved interventional strategies to manage CKD and delay
progression to ESRD. This suggests the need for development of novel therapies, such as
REACT, that target patients with later stages of CKD that are non-responsive or only partially
respond to current SoC medications.

Nonclinical studies in multiple animal models of CKD have demonstrated that SRCs injected
directly into the kidney cortex were capable of effecting a regenerative response in multiple
locations of the nephron through direct engraftment or tissue replacement, and through a putative
paracrine mechanism involving the effect of secreted factors. 16,23 In models of CKD, treatment
with SRCs stabilized and/or improved renal function decline and provided a significant survival
benefit.
2.3 Summary of Risks and Benefits

In general, the risks associated with REACT treatment can be broadly divided into three
categories; percutaneous kidney biopsy, the REACT formulation and locoregional delivery or
injection into the recipient kidney parenchyma.
2.3.1 Potential Risks

The product platform utilizes culture expansion and injection of the participant’s own
(i.e., autologous) renal cells obtained through kidney biopsy. 16,24,34,35 As a result, the risk of
cellular rejection and other immunologic responses commonly seen following allogeneic cell
transplantation is not anticipated. Other formulation-related events are uncommon (see
Section 4.1).
The risks of renal biopsy have been well characterized over the 70+ years this procedure has
been developed and used. A summary of risks associated with renal biopsy and similar
procedures to REACT injections can be found in the appendix as cited below. Literature-
published adverse events include hematoma, pain, infection, and biopsy site infections.
• Appendix Table A2- 1 displays the full list of published AEs, the reported
incidence and associated clinical trial risk mitigation steps recommended by the
Sponsor.
• Adverse Events and complications from injection procedures similar to the
REACT Investigational Product injection procedure are listed in Appendix
Table A2- 2.
2.3.2 Identified Risks

While the safety and efficacy evaluation of REACT is ongoing, the percutaneous administration
and standard renal biopsy procedures have defined clinical risks and established procedures to
manage those risks are defined in the protocol.

Warnings and precautions for a renal biopsy and the percutaneous injection procedure must be
considered with use of this product. Percutaneous small needle interventions in the kidney have a
shorter history and have shown to be safe. Secondary effects of renal bleeding have been
described and include anemia, acute kidney injury, hematoma mass effect on the parenchyma
causing hypertension, and pain. Pain post-biopsy has been reported as less than 5%, including
cutaneous puncture site, musculoskeletal, and perinephric referred sources. 36
The management and abstention from anticoagulants before, during, and after biopsy and
injections is described in Study Interventions Section 7.1.3.
2.3.3 Percutaneous Renal Biopsy

Kidney biopsy complications have decreased with the use of image guidance, predominantly
with ultrasound (or CT for difficult cases) and the use of automated biopsy core devices. Kidney
damage at the biopsy site can include vascular damage and infarction and correlates with the
canine nonclinical necropsy descriptions of renal scar formation. The severity of these changes
depends on the size and number of vessels damaged during the biopsy procedure. 37
Autologous renal cells will be obtained from an enrolled participant via a standard renal biopsy
procedure following standard medical biopsy practice 38,39 at participating clinical trial sites.
A 16-gauge tissue biopsy measuring approximately 10 mm in length removes 0.01%-0.02% of

the average total volume of the diseased kidney and usually contains only 0.001% of the total
number of glomeruli. 40 The tissue biopsy causes a small linear track through the kidney. Lesions
associated with renal biopsy are largely undetectable and observed histologically in only 5.5% of
serial kidney sections taken 1 month after biopsy. 37 Renal biopsies performed for suspected
renal parenchymal disease are of low risk and most often conducted on an outpatient basis,
however standard of care varies by country and region. 41
Kidney hematoma is the most common AE observed following routine percutaneous kidney
biopsy with a broad range of diagnosis in the literature based on type of imaging method used for
the diagnosis. CT scanning and ultrasound imaging are equally accepted as standard of care to
assess for post-biopsy hematomas to determine the degree of seriousness. Post-biopsy bleeding
requiring a blood transfusion vary by study, however large meta-analysis and regional studies
indicate a less than 5% incidence of blood product administration. The occurrence of post-biopsy
interventional radiology angiography/vessel embolization (<0.5%), nephrectomy (<0.1%) and
death (<0.1%) are low. 36,42-44 Microscopic hematuria following biopsy is present in almost all

patients with little clinical significance. Macroscopic (gross) hematuria occurs in less than 4% of
the patients 37,45 and generally resolves by 24-hour post-biopsy. 45
Less common biopsy complications include blood/clots in the bladder and hematuria,
arteriovenous fistula (1%), urine extravasation (urinoma), puncture of adjacent structures, and
conscious sedation reactions. 46-48
When performed by qualified interventional proceduralists a renal biopsy properly targeted

towards the lower pole cortex and avoiding central vessels causes limited renal damage. 49
Furthermore, the access track can be embolized with hemostatic biodegradable material to
further reduce acute or delayed risk of significant bleeding.
2.3.4 REACT Formulation

The autologous REACT investigational product is a frozen formulation of culture-expanded
selected renal cells (SRC) in cryopreservation media at a concentration of 100 × 106 cells/mL
±20%. REACT is stored at -150°C or colder until use. The media is CryoStor Freeze Medium
CS10 that contains Dimethyl Sulfoxide, and Dextran 40. The Investigator Brochure provides
additional information and rare events related to intravenous DMSO and Dextran 40. The
formulation of the investigational product is fully described in Section 4.1.
2.3.5 REACT Injection into the Kidney

A percutaneous technique with CT image guidance will be used to access the kidney for REACT
delivery. REACT will be deposited at multiple locoregional sites within the kidney cortex using
small gauge needles and a syringe-connecting tube-delivery system with minimal penetration of
the kidney capsule. Additional instructions are provided in the Sponsor Study Manuals.
The REACT injection can be safely administered as an outpatient procedure. During the
injection procedure the percutaneous needles inserted under CT guidance that are used to deliver
REACT are smaller and less traumatic to the kidney tissue. Local skin anesthesia is typically
used and conscious sedation is encouraged per site standard of care. REACT injection procedure
recovery periods may be similar to other outpatient renal procedures shown to be safe, such as
renal tumor ablations as reported by Salagierski and Salagierski. 50 Safety measures performed
during REACT treatment and recovery period to assess for potential bleeding and other adverse
events include clinical and laboratory assessment pre- and post -procedure, brief suspension of
anticoagulation medications and safety renal ultrasound during the recovery period prior to
discharge. 51-55

2.3.6 Potential Benefits

To date, clinical studies in participants with CKD and T2DM suggest that treatment with
REACT may delay or prevent RRT by stabilizing eGFR. Other potential improvements observed
with REACT treatment in earlier studies include stabilization in albuminuria (UACR), increased
kidney cortical thickness, improvement in bicarbonate and stabilization of hemoglobin levels.
The Investigator’s Brochure provides additional information.
The potential benefits of REACT will be evaluated in the current trial using events involving
eGFR targets and renal RRT (see endpoints defined in Section 3). Therefore, the potential exists
for participants in this clinical study to realize therapeutic benefit from REACT treatment,
through a possible reduction in the rate of progression of CKD (e.g. reduced, stabilized, or
improved eGFR) and/or reduced complications related to CKD (e.g. anemia, and bone-mineral
dysfunction).
3 OBJECTIVES AND ENDPOINTS

Primary and secondary efficacy assessments related to eGFR will utilize the CKD-EPI equation.
3.1 Primary Objective:

To assess the efficacy of up to 2 REACT injections in participants with type 2 diabetes mellitus
(T2DM) and chronic kidney disease (CKD).
Primary Endpoint:
The time from first injection to the earliest of:
• At least 40% reduction in eGFR sustained for 30 days, OR
• eGFR < 15 mL/min/1.73m² sustained for 30 days and/or chronic dialysis, and/or
renal transplant, OR
• Renal or cardiovascular death.
3.2 Secondary Objectives

To assess the efficacy of up to 2 REACT injections across a range of outcome measures.
Secondary Endpoints:
• Annualized change in eGFR
• Time from first injection to at least a 40% reduction in eGFR sustained for
30 days.

• Time from first injection to eGFR < 15 mL/min/1.73m² sustained for 30 days
• Changes from Baseline in patient-reported outcomes from the Kidney Disease
Quality of Life (KDQOL) and EuroQol 5-Dimension 5 Level (EQ-5D-5L)
surveys.
An independent Endpoint Adjudication Committee (EAC), blinded to treatment assignment, will

adjudicate the primary efficacy endpoint in this study. The EAC is further described in
Section 9.9.
To evaluate the safety of up to 2 REACT injections.
Safety Endpoints:
• Summary of AE, such as SAEs (including fatal events), AESI and AEs leading to
discontinuation of study treatment.
3.3 Additional Exploratory Endpoints

• Change from Baseline in calcium at 26, 52, and 78 weeks
• Change from Baseline in phosphorus at 26, 52, and 78 weeks
• Change from Baseline in parathyroid hormone at 26, 52, and 78 weeks
• Change from Baseline in potassium at 26, 52, and 78 weeks
• Change from Baseline in bicarbonate at 26, 52, and 78 weeks
• Change from Baseline in UACR at 26, 52, and 78 weeks.
Additional exploratory endpoints may be included in the statistical analysis plan.
4 INVESTIGATIONAL PRODUCT
4.1 REACT Description and Formulation
Selected Renal Cells: The autologous REACT investigational product is a frozen formulation of
Selected Renal Cells (SRC) in cryopreservation media at a concentration of 100 × 106 cells/mL
±20%. REACT is stored at -150°C or colder until use.
There were no unanticipated findings in multiple animal studies, species, and disease conditions
with administration or re-administration of syngeneic or autologous SRC to the chronically

diseased kidneys. No dose-limiting toxicities relevant to humans were identified in the in vivo
animal studies.
CryoStor Freeze Medium CS10: The only excipient added is the commercial cryoprotectant
CryoStor CS10. CryoStor CS10 is a common and widely used excipient for human cell-based
medicinal products. The excipient is cGMP manufactured with USP grade/highest-quality
components. CryoStor CS10 is pre-formulated with 10% DMSO and contains Dextran 40.
Dimethyl Sulfoxide (DMSO): DMSO is a constituent of CryoStor Freeze Medium CS10 and
has been used as a medicine and pharmacological agent in humans since the 1960s and its
current primary uses are for cell cryopreservation, treatment of interstitial cystitis, and as a
penetrating vehicle for various drugs.
A recent systematic study investigating the adverse effects associated with DMSO found that
most adverse reactions are transient and mild. 56 DMSO was safe to use in small doses. Gastro-
intestinal and skin reactions were the most common reported adverse reactions to DMSO.
In practice, it is commonly recommended to limit exposure of DMSO to 1g DMSO/kg body

weight/day by intravenous delivery (IV). 57 For context, the DMSO content in the REACT final
product formulation is ~79-fold lower than the commonly recommended intravenous DMSO
limit and ~40-fold lower than a calculated DMSO limit for kidney exposure. To mitigate the risk
of reactions to DMSO, participants with known severe reaction or hypersensitivity to DMSO will
be excluded from study.
Dextran 40: Dextran 40 is a constituent of CryoStor Freeze Medium CS10 used to formulate the
final REACT product. Severe anaphylactoid reactions have been reported with Dextran infusion.
In a review of Dextran infusion reactions reported to the Food and Drug Administration (FDA)
Adverse Event Reporting System between 1969 and 2004, 58 90 events classified as severe
anaphylactoid over the 37-year period. Although extremely infrequent, concern for consideration
of the possibility of a Dextran 40 reaction can be mitigated by the use of Dextran 1 pre-
treatment, hydrocortisone, or other corticosteroid premedication, in addition to antihistamine.
4.2 Biopsy, Cell Culture, and Formulation

4.2.1 Biopsy
The biopsy material is collected using standard sterile techniques and image guidance to access
the left or right kidney cortex. The lower pole is the optimal biopsy location but is at the
discretion of the Proceduralist. A minimum of 2 cores using a 16-gauge automated biopsy device

or 4 cores using an 18-gauge automated biopsy device must be collected to provide sufficient
material for the manufacture of REACT.
Renal cells are isolated from the biopsied kidney tissue by enzymatic digestion and are expanded
using standard cell culture techniques over the course of several weeks. The desired population
of renal cells are selected by density gradient separation of the expanded cells which yields the
SRC population of REACT.
The REACT manufacturing process is designed to deliver the participant specific autologous
product in approximately fourteen (14) weeks from participant biopsy to product injection.
4.2.2 Formulation of REACT

The active substance is the expanded SRC. Just prior to formulation, the cells are washed with
Dulbecco’s Phosphate Buffered Saline (PBS) to remove process residuals and the cells are
pelleted.
The excipient is CryoStor Freeze Medium CS10. It is a commercially available GMP

manufactured cryoprotectant solution. It is added neat to the washed SRC pellet to resuspend and
formulate the final product at a concentration of 100 × 106 SRC/mL ±20%. The precise volume
of CS10 contained in the 10.0 mL cryovial is variable since it is based on a calculation needed to
obtain an SRC concentration of 100 × 106 SRC/mL ±20%. The maximum dosing volume for
injection is 8.0 mL.
4.2.3 Investigational Product Packaging

The final formulated product is dispensed aseptically into a cyclo-olefin copolymer cryovial with
a plastic elastomer closure. The maximum dosing volume is 8.0 mL/injection, however the
specific fill volume of a cryovial is dependent on the required dose volume as determined by the
participant’s estimated kidney weight. REACT product has been formulated for storage in vapor
phase liquid nitrogen (-150°C or colder) until needed.
4.2.4 Investigational Product Labeling

The REACT product is participant specific.
It is made from expanded autologous SRC obtained from each individual participant’s kidney
biopsy. Each package containing the REACT product is labeled: “FOR AUTOLOGOUS USE
ONLY” and “Investigational Use ONLY”. For each country participating in the study, labels will

comply with the relevant labeling requirements for investigational products in that country. To
ensure full traceability of the autologous starting kidney biopsy tissue, through manufacturing
into an investigational medicinal product, and return to the same participant, a unique
identification sequence will be used, such as the Single European Code Donor Identification
Sequence (SEC-DIS), or equivalent, per country specific requirements.
4.2.5 Transportation of Investigational Product

Biopsy material collected at each study site must be handled and packaged in Sponsor-provided
containers according to Sponsor instructions, then labeled and placed in shipping containers
compliant with all relevant governmental, transportation regulations, and according to individual
carrier guidelines.
REACT final investigational product, prepared, labeled, and packaged as described above must
be kept in vapor phase liquid nitrogen (at -150ºC or colder) until needed. Upon site request,
REACT product will be sent from the ProKidney manufacturing facility to the clinical site.
Shipping containers will have temperature monitors to ensure product integrity at the required
temperature between the manufacturing facility and the clinical site.
4.3 REACT Product for Injection

4.3.1 REACT Dose Calculation
6
The dose of REACT for participants in previous clinical studies was 3 × 10 SRC/g estimated
kidney weight (g KWest). Similarly, in this study, each REACT injection will contain 3 ×
10 cells/g KWest. As the concentration of SRC is approximately 100 × 10 cells /mL of REACT,
6 6
the approximate dosing volume will be 3.0 mL for each 100 g of kidney weight.
The dose of REACT will be based on kidney volume calculated from the results of the renal
imaging study performed during the Screening Visit. The volume of REACT to be administered
will be determined by renal imaging [magnetic resonance imaging (MRI) volumetric 3D
evaluation is preferred. However, CT is an acceptable imaging method if MRI is contraindicated
or unavailable].
As a conservative approach, the REACT dose is calculated using a conversion of 1 g equals

1.0 mL. This ensures that participants will not receive REACT doses higher than those
previously tested in animal studies.
Examples of dosing volumes based on estimated kidney weight are shown in Table 3.

Table 3: Dose Selection Table

Estimated Kidney Weight (g KWest) * Selected Renal Cells
REACT Dosing Volume
Delivered (Number of
Median Weight (g) Weight Range (g) (mL)
Cells x106
83 76 - 92 2.5 250 x 106
100 93 - 108 3 300 x106
117 109 - 125 3.5 350 x 106
133 126 - 141 4 400 x 106
150 142 - 158 4.5 450 x 106
167 159 - 175 5 500 x 106
183 176 - 191 5.5 550 x 106
200 192 - 208 6 600 x 106
217 209 - 225 6.5 650 x 106
233 226 - 241 7 700 x 106
250 242 - 258 7.5 750 x 106
--- >259 8 800 x 106
g = grams, mL = milliliters
*Kidney volume in cm3 will be estimated by a blinded central imaging reader based on the results of an MRI
imaging study using 3-D analysis of kidney volume during Screening. If a participant cannot undergo MRI, then
computed tomography (CT) will be substituted to obtain kidney volume at Screening. For dosing calculations, a
kidney volume of 1 cm3 is equivalent to 1 g KWest.
4.3.2 Methodology
The REACT drug product is a cryopreserved suspension of autologous SRC formulated in a
cryopreservation solution that has been aseptically dispensed into sterile single-use cryovials.
REACT is stored in vapor phase liquid nitrogen (–150°C or colder) until needed. Immediately
prior to use at the clinical site the product is removed from the liquid nitrogen shipping
container, thawed before the procedure for approximately 20 minutes according to the
Sponsor Study Manuals and the cell suspension is injected into the recipient’s kidney with no
further manipulations. Table 2 presents an overview of the investigational product. Refer to the
Investigator’s Brochure for a detailed description of SRC and REACT as well as the
manufacturing process.
The Sponsor Study Manual describes the methods for injecting REACT.
The first REACT injection will be into the biopsied kidney of eligible participants using an
image guided percutaneous approach. The percutaneous method uses techniques similar to those
utilized in targeted renal procedures such as focal mass biopsy or aspiration and renal tumor
ablations.

The second injection will be given 12 weeks (+28 days) later into the contralateral kidney using
the same percutaneous approach. Proceduralists should try to avoid the same tracks, trajectory,
location of prior renal biopsies and REACT injections.
For details of the storage and disposal of renal cells not used to manufacture REACT product, see
Section 4.3.5.
4.3.3 Investigational Product Accountability

Investigational product accountability and traceability are the responsibility of the Investigator
once it is received at the site. However, this responsibility may be delegated to a suitably
qualified individual who has had appropriate study-specific training and whose name is listed on
the Delegation of Responsibility Log for this task.
Detailed records will be maintained to allow for accurate accountability of the investigational
product in accordance with applicable Sponsor and clinical site procedures. These records will
include details about the transfer of renal biopsy material from the clinical site to the Sponsor,
transfer of REACT investigational product from the Sponsor to the clinical site, internal site
transfers, injection of investigational product to autologous participants, the number of stored
specimens remaining with the Sponsor, and disposal of unused biopsy materials.
4.3.4 Investigational Product Handling and Disposal

Though participants are screened and tested for HIV, HBV, HCV, and syphilis, the transmission
of other blood-borne pathogens can occur through contact with contaminated needles, blood,
and blood products. Therefore, appropriate blood and secretion precautions must be followed by
all personnel in the shipping and handling of all specimens for this study, as currently
recommended by the Centers for Disease Control and Prevention and the National Institutes of
Health for clinical sites in the US and as per local and country guidelines for clinical sites outside
the United States. All steps of biopsy through REACT injection require strict custody and sample
identity documentation.
All materials containing REACT investigational product will be treated and disposed of as
hazardous waste in accordance with governing regulations and clinical site procedures.
4.3.5 Disposition of Stored Biopsy Specimens

Renal cells isolated from biopsy material will be stored in the vapor phase of a liquid nitrogen
freezer at the Sponsor’s facility. Packaged REACT product will be received by the study site and

only Investigators or suitably qualified individuals who have received appropriate study-specific
training and whose names are listed on the Delegation of Responsibility Log will have access to
the investigational medicinal product.
Renal cells that may have been frozen but not used to manufacture REACT will remain in
the vapor phase of a liquid nitrogen freezer at the Sponsor’s facility until the global trial end date
(GTED). At that time, if the participant has provided written consent, these renal cells will be
stored in the vapor phase of a liquid nitrogen freezer for a maximum of 10 years post GTED.
During the informed consent process, each participant must provide written consent for the
extended storage and future use of autologous cells not used for REACT. If a participant
consents to the future use of the cells, the Sponsor will only use the cells after all REACT
injections have been completed for the participant. In addition, participants may decide at any
point during the study, or upon study completion, not to have their unused renal cells stored. In
this case, the Sponsor will destroy all known remaining samples attributed to that participant
after their injections are complete. All requests for the destruction of samples must be made in
writing to the Sponsor.
5 INVESTIGATIONAL PLAN
5.1 Overall Design
The target sample size is approximately 685 participants for this multi-center, prospective,
blinded, scripted sham-controlled, interventional study. Participants who complete the Screening
procedures and satisfy all inclusion criteria and none of the exclusion criteria for enrollment will
be randomized 1:1 to Cohort 1 or Cohort 2, stratified by eGFR and SGLT2i use at Screening,
and be either sham-treated or treated with REACT investigational product. Both Cohorts will
follow the same visit and examination schedule. The target study population is adults with CKD
and T2DM with entry eGFR of 20 to 35 mL/min/1.73m2, dependent on albuminuria level,
currently receiving standard of care treatment, and at risk for progressive renal function decline.
Participants randomized to Cohort 1 will experience a sham biopsy, a sham ‘REACT’

injection 14 weeks (+28 days) later intended for the ‘sham-biopsied’ kidney, followed another
12 weeks (+28 days) later by a second sham ‘REACT’ injection intended for the contralateral
(non-biopsied) kidney.
Participants randomized to Cohort 2 will have a renal biopsy, a REACT injection 14 weeks
(+28 days) later into the biopsied kidney, followed another 12 weeks (+28 days) later by a
REACT injection into the contralateral (non-biopsied) kidney.

Participants in Cohort 1 and Cohort 2 should continue to receive institutional standard of care
as per local and global clinical practice guidelines (see Section 6.3).
All participants will be followed until the Global Trial End Date (GTED) as determined by the
Sponsor.
5.2 Study Design

Figure 2 illustrates the study steps during the course of the study. Similarities in the management
of participants are maintained throughout the study to ensure the integrity of the blind.
Figure 2: Study Schema
5.3 Schedule of Events and Laboratory Sample Collection Schedule

The REGEN-006 Schedule of Events Table (Table 4) and the Laboratory Sampling Schedule
(Table 5) are presented on the following pages.

Table 4: Schedule of Events

Renal Biopsy/ First REACT/Sham Injection and Second REACT/Sham Injection and Long-Term End of
Study Periods Screening a
Sham Biopsy c Follow-Up c Follow-Up c Follow-Up d Study
Visit Number - 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 thru 22+ EOS e
Day of Biopsyc
2nd Injection c
1st Injection c
Beginning at
2nd Injection
2nd Injection
2nd Injection
2nd Injection
until GTED
1st Injection
1st Injection
1st Injection
1st Injection
1st Injection
Pre-Biopsy
Biopsy + 1
+ 14 Days
+ 28 Days
+ 14 Days
+ 28 Days
Injection
Week 26
+ 7 Days
+ 7 Days
+ 1 Day
+ 1 Day
Pre 2nd
GTED
Visit
Pre-
Day
Visit Events -
Long-Term Follow-up visits begin 26 weeks after the 1st Injection
Week 26, 39, 52, 65,

before 2nd Injection
before 1st Injection
78, 91, 104 then

every 12 weeks
Preparation and Shipment of REACT Product b
Randomization
Day -14 to Day -7
Day -14 to Day -7
Day -14 to Day -7

14 weeks post-
12 weeks after
14 days post-
1st Injection
before Biopsy
60 Days
Week 1
Week 2
Week 4
Biopsy
12 weeks between 1st and 2nd Injection b

Approximate
Day 1
Day 2
- - - - -
Timeframe -
Randomization
(Visit Windows) (+5 D) (+14 D) (+28 D) (+3 D) (±3 D) (±7 D) (+28 D) (+3 D) (±3 D) (±7 D) (±7 D)
Informed Consent f X - - - - - - - - - - - - - - - - -
Verify I/E Criteria X - - - - - - - - - - - - - - - - -
Demographic Data X - - - - - - - - - - - - - - - - -
Medical History X - - - - - - - - - - - - - - - - -
Review Medications
X X X X X X X X X X X X X X X X X X
and Procedures
Review Adverse
- X X X X X X X X X X X X X X X X X
Events
Physical Exam g
X X X X X X X X X X
Vital Signs X X Xh X X Xh X X X X X Xh X X X X X X
12-lead ECG X - - - X - - - - - X - - - - - Xn X
Blood and Urine
X X X i
X X X i
X X X X X X i
X X X X X X
Collections i, j
Renal MRI X k
- - - - - - - - - - - - - - - X l
Xm
Safety Renal Doppler
- X Xc X X Xc X X X X Xc X X X - - -
Ultrasound
Biopsy/Sham Biopsy - - X c
- - - - - - - - - - - - - - -
CT-guided
REACT/Sham - - - - - Xc - - - - - Xc - - - - - -
Injection
KDQOL & EQ-5D-5L - X - - X - - - - - X - - - - - X X
Abbreviations: CT (Computed Tomography: ECG (electrocardiogram); EOS (End-of-Study Visit); EQ5D-5L (EuroQol 5-Dimension 5-Level Questionnaire); D (Days); I/E (inclusion/exclusion); KDQOL (Kidney
Disease Quality of Life Questionnaire); GTED (Global Trial End Date); MRI (magnetic resonance imaging).
See table footnotes on the following page.

Schedule of Events Footnotes:

a. The screening window may be extended for up to 5 days (See Section 7.2.1).
b. The first REACT/Sham injection is to be administered 14 weeks (+28 days) after the biopsy/sham biopsy procedure, and the second REACT/Sham injection
12 weeks (+28 days) after the first injection.
c. For participants who discontinue treatment early, only pre-procedure assessments will be conducted, and post-procedure follow-up visits will be skipped.
See Section 7.3.
d. Long-Term Follow-up visits begin 26 weeks after the first injection.
e. EOS visit will be conducted within 4 weeks of the global trial end date announced by the Sponsor, or when the participant withdraws from the study early for
any reason.
f. Informed Consent Form must be signed and dated prior to any Screening or subsequent study-specific procedures.
g. A complete physical exam is conducted at Screening, pre-procedure visits (Visits 1, 4 and 10), and at the EOS visit. Targeted physical exams are conducted
at all other visits (Section 8.3).
h. On procedure days (Visits 2,5, and 11), vitals will be measured at regular intervals during the procedure (Section 8.2.2); additional information is outlined in
the Study Manual.
i. Blood and urine collections are detailed in Section 7. On procedure days, selected labs will be obtained pre- and post-procedure. If fasting status is
prolonged for the procedures and participant has a history of labile glucose levels, consider glucose monitoring during peri-procedure care period.
j. If a study endpoint threshold for change in eGFR is met, a confirmatory sample will be obtained approximately 30 days later.
k. MRI without contrast to obtain kidney size and volume should be scheduled after the participant’s initial Screening laboratory test results are anticipated, and
imaging results and central laboratory MRI measurements must be available before randomization for Proceduralist review. For participants who cannot get
an MRI, a non-contrast CT will be substituted.
l. Subsequent MRI (or CT for participants who cannot get an MRI) will be conducted at Month 12 post 1st Injection (Visit 18) and then yearly until GTED.
Imaging modality should remain constant throughout the study.
m. MRI/CT will be conducted at EOS Visit if not conducted within the previous 6 months (26 weeks).
n. During the Long-Term Follow-up period the ECG should be conducted at the Month 6 post 1st Injection (Visit 16), Month 12 (Visit 18) and then yearly until
GTED. Additional ECGs may be performed at the Investigator’s discretion.

Table 5: Laboratory Sampling Schedule

Long-
First REACT/Sham Injection and Second REACT/Sham Injection and
Study Periods Screening Renal Biopsy/ Term End of
Follow-Up a Follow-Up a
Sham Biopsy a Follow-Up Study
Visit Number - 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 thru 22+ EOS
Day of Biopsy
Beginning at
2nd Injection
2nd Injection
2nd Injection
2nd Injection
2nd Injection
2nd Injection
until GTED
1st Injection
1st Injection
1st Injection
1st Injection
1st Injection
Pre-Biopsy
Biopsy + 1
+ 14 Days
+ 28 Days
+ 14 Days
+28 Days
Injection
+ 7 Days
Week 26
+ 1 Day
+ 1 Day
+ 7 Day
Pre 1st
GTED
Visit
Pre-
Day
Visit Events -
Long-Term Follow-up visits begin 26 weeks after the 1st Injection
Week 26, 39, 52,

before 2nd Injection
12 weeks after
Randomization
Day -14 to Day -7
Day -14 to Day -7

14 weeks post-
65, 78, 91, 104

1st Injection
before Biopsy
then every
pre-Injection
12 weeks
Preparation and Shipment of REACT Product
60 Days
14 days
Week 1
Week 2
Week 4
Day -14 to
Biopsy
Approximate
Day 1
Day 2
post-
Day -7
- - - - - -
Timeframe
12 weeks between 1st and 2nd Injection

(Visit Windows) (+5 D) (+14 D) (+28 D) (+3 D) (±3 D) (±7 D) (+28 D) (+3 D) (±3 D) (±7 D) (±7 D)
Randomization
Chemistry, electrolytes, CRP,

X X - - X - - X X X X - - X X X X X
cystatin C
β2-microglobulin - X - - X - - X X X X - - X X X X X
Renal Panel b - - Xc X - Xc X - - - - Xc X - - - - -
HbA1C X X - - X - - - - - X - - - - - X X
iPTH X X - - X - - - - - X - - - - - X X
Fasting Lipid Profile d - X - - - - - - - - - - - - - X -
CBC X X Xc X X Xc X X X X X Xc X X X X X X
Hgb/HCT (local) e - - Xc X - Xc X - - - - Xc X - - - - -
aPTT/PT/INR X X X - X X - - - - X X - - - - - -
FSH f X - - - - - - - - - - - - - - - -
Serum hCG g X X - - X - -- -- -- -- X - -- - - - - -
Infection Screen h X - - - - - - - - - - - - - - - -
Research samples i - X - - X Xc X X X X Xc X X X - Xi -
Urine assessments - - - - - - - - - -- - - - - - - - -
Urine pregnancy g (dipstick) - - X - - X - - X - X - - - X X X
Drug Screen X - - - - - - - - - -- - - - - - - -
Urine Dipstick j (optional) - - Xc X Xc X - - - - Xc X - - - - -
Urinalysis (central) k X X Xc X X Xc X X X X X Xc X X X X X X
Urine culture (central) l - X - - X - - - - - X - - - - - - -
Urine albumin, urine creatinine X X - - X - - - - X X - - - - X X X
Urine NGAL, β-2 microglobulin - X - - X X X - - X X X X - - X X X
Research samples i - X - - X Xc X X X - X Xc X X X - Xi -
Abbreviations: aPTT (Activated Partial Thromboplastin Time); CBC (Complete Blood Count): CRP (C-reactive protein); D (Day): EOS (End-of-Study); FSH (Follicle-Stimulating Hormone); GTED (Global Trial End Date);
HbA1c (glycosylated hemoglobin); hCG (Human Chorionic Gonadotropin); Hgb (Hemoglobin); HCT (Hematocrit): NGAL (Neutrophil Gelatinase-Associated Lipocalin); iPTH (intact Parathyroid Hormone); PT-INR
(Prothrombin Time-International Normalized Ratio); REACT (Renal Autologous Cell Therapy). See table footnotes on the following page.

General note: Additional laboratory sampling requirements and sampling details are in Table 8.
Laboratory Sampling Schedule Footnotes

a. For participants who discontinue treatment early, only pre-procedure assessments will be performed, and post-procedure follow-up visits will be skipped.
See Section 7.3.
b. Renal panel is a subset of chemistry (See Table 8).
c. At Visit 2 (Day of Biopsy), Visit 5 (1st REACT Injection) and Visit 11 (2nd REACT Injection), specified blood and urine tests will be collected pre- and
post- procedure. All other tests for these visits will be collected pre-procedure.
d. Blood for lipids should be collected ideally in the morning while the participant has fasted for at least 8 hours. If a morning collection is not possible, any
approximate 8 hour fasting time period is acceptable. Obtain lipid assessments at Visit 1, Visit 17 (Month 9) and then annually.
e. Hemoglobin/hematocrit will be obtained at site’s local laboratory pre- and post-procedures in order for immediate availability of results to inform clinical
care. Samples must also be sent to the central laboratory. The Day +1 local test may be omitted if pre- and post-procedure samples do not indicate a clinical
concern.
f. If the FSH result at Screening confirms the participant is not of child-bearing potential in the appropriate clinical context, pregnancy testing is not required to
be conducted throughout the study.
g. In women of child-bearing potential, serum hCG test will be performed by the central laboratory at Screening, Pre-Biopsy Visit 1, Pre-1st-Injection Visit 4,
and Pre 2nd Injection Visit 10. At all other specified visits, the clinic will perform a urine pregnancy test using the central lab provided dipstick and if
positive, a serum hCG test will be performed by the central laboratory.
h. The Infection screen includes HIV, HBV, HCV, and syphilis.
i. Optional research samples (serum/plasma and urine) will be collected, processed and shipped for storage for future research related to kidney disease,
including the evaluation of novel biomarkers (Section 8.7). During the Long-term follow-up period, these samples will be collected every 6 months starting
at Month 6 until Month 24 and then annually.
j. Site may perform an optional urine dipstick assessment if needed per investigator discretion, using the central lab provided dipsticks at specified visits and at
any other visits at the Investigator’s discretion.
k. Reflex microscopy will be performed by central lab as appropriate.
l. An optional urine culture may be obtained at any other visit, at the Investigator’s discretion.

6 STUDY POPULATION
All eligibility criteria must be met for enrolling participants in this study as listed below. If there
is a question regarding these criteria, the Investigator must consult with the appropriate Sponsor
Representative and resolve any issues before enrolling a participant in the study. Waivers are not
permitted.
All clinical laboratory eligibility criteria must be based on reports from the central laboratory
selected for this study. Re-testing of laboratory values is permitted once during the Screening
period.
6.1 Inclusion Criteria

1. Man or woman (according to their reproductive organs and functions assigned at birth)
30 to 80 years of age on the date of informed consent.
2. Documented diagnosis of type 2 diabetes mellitus (T2DM) and chronic kidney disease as
the underlying cause of kidney disease (diagnosis does not have to be confirmed by renal
biopsy)
a. eGFR of at least 20 mL/min/1.73m2 and < 30 mL/min/1.73m2, not requiring renal
dialysis. UACR level cannot exceed 5000 mg/g (565 mg/mmol).
or
b. eGFR of 30 to ≤ 35 mL/min/1.73m2 AND UACR of 300 to ≤ 5000 mg/g (33.9

mg/mmol to ≤ 565 mg/mmol).
3. Serum glycosylated hemoglobin (HbA1c) of 9.5% or lower at Screening.

4. Systolic blood pressure of ≤ 140 mm Hg and diastolic blood pressure of ≤ 90 mm Hg at
Screening (based on the average of 3 measurements obtained while seated) and
maintained during the screening period until randomization.
Note: Participants who present with higher blood pressure measurements of up to
150/100 mm Hg may return to the clinic for another blood pressure check by Screening
Week 3. If the blood pressure is ≤ 140/90 mm Hg (based on the average of 3 measures
obtained while seated) at the subsequent screening visit, the participant may continue
with screening activities. Changes in medications are to be recorded in the appropriate
eCRF.
5. All participants should be considered for treatment with a sodium glucose cotransporter
2 inhibitor (SGLT2i) according to standard of care per local practice guidelines and label
when medically and economically feasible. The reason for a participant NOT receiving

SGLT2i therapy at the time of enrollment should be documented in the appropriate

eCRF.
Note: A stable treatment dose of the SGLT2i is required for at least 4 weeks prior to
randomization with the intention to maintain the dose throughout the entire study period.
(See Section 7.1 for additional guidance about Concomitant Therapies)
6. On a clinically relevant and stable dose of an angiotensin converting-enzyme inhibitor
(ACEI) OR an angiotensin receptor blocker (ARB), unless not tolerated or
contraindicated. The dose must be stable for at least 4 weeks prior to randomization and
is anticipated to remain stable for the duration of trial participation. For participants not
on an ACEI or ARB, the investigator must document the reason for contraindication or
intolerance to ACEI or ARB treatment. (See Section 7.1 for additional guidance)
7. Participant agrees, and in the judgement of the Investigator, is able to refrain from using
therapies that may increase bleeding risk during the period beginning 7 days before
through 7 days after the renal biopsy/sham biopsy and 7 days before through 7 days after
each REACT/sham injection(s), including but not limited to:
• Nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen and naproxen
• Aspirin (all dose ranges)
• Platelet aggregation inhibitors (PAIs) such as clopidogrel, prasugrel, and
dipyridamole
• Factor Xa inhibitors
• Warfarin
• Heparin products
• Other anticoagulation.
Note: See Section 7.1.3 for additional information about anticoagulants
8. Participant is willing and able to cooperate with all aspects of the protocol.
9. Participant is willing and able to provide signed informed consent.
6.2 Exclusion Criteria

A participant who satisfies any exclusion criterion listed below is not eligible to participate in
this study.
Co-existing or Prior Medical Conditions

1. History of type 1 diabetes mellitus.
2. History of kidney or other organ transplantation (corneal transplants are not an
exclusion), solitary kidney, recurrent complicated urinary tract infections or complicated

kidney stones. Urinary tract infections identified prior to renal biopsy or injection should
be resolved prior to procedures.
3. The participant has any other known underlying cause of kidney disease, including but
not limited to: Autosomal dominant and recessive polycystic kidney disease, primary
focal segmental glomerulosclerosis, vasculitis related CKD, IgA nephropathy and other
immune modulated nephropathies, drug-induced CKD or other types of CKD or anatomic
variants as determined by the Investigator or Sponsor that would interfere with biopsy
and REACT injection procedure or confound study assessments.
Participants with concomitant hypertension-related CKD may be enrolled in the study.
Note: Anatomic abnormalities and benign conditions are not exclusionary if the kidney
has accessible renal cortex for biopsy and injection procedures and meets the criteria to
receive the REACT injection. Unique situations should be discussed with the study
medical monitor.
4. History of acute kidney injury within 3 months prior to the Screening Visit.
5. Myocardial infarction, unstable angina, revascularization procedure (e.g. stent or bypass
graft surgery), or cerebrovascular accident within 12 weeks before randomization, or a
revascularization procedure is planned during the trial.
6. Current or history of heart failure of New York Heart Association (NYHA) Class IV
cardiac disease.
7. History of malignancy within the past 3 years prior to Screening, except for basal cell
and/or squamous cell carcinomas of the skin with apparent successful curative therapy,
carcinoma of the cervix in situ, or a malignancy that in the opinion of the Investigator,
along with agreement from the Medical Monitor, is considered treated with no evidence
of disease and at minimal risk of recurrence.
8. Documented clinically significant liver disease, including acute or chronic hepatitis B or
hepatitis C.
Note: At the discretion of the Investigator, a participant who gives a history of a treated
and cured Hepatitis C infection may be screened with a test for viral ribonucleic acid
(RNA), and if a cure is demonstrated, the participant may be enrolled.
9. Known infection with Human Immunodeficiency Virus, active syphilis, or other
unresolved active genitourinary infection, or active tuberculosis requiring treatment at
Screening.
10. Immunocompromised condition or condition requiring chronic immunosuppressive
agents, including individuals treated for chronic glomerulonephritis, within 3 months of
signing ICF.
Note: Inhaled corticosteroids, chronic low-dose corticosteroids (less than or equal to
7.5 mg prednisone equivalent per day), and brief pulsed corticosteroids for intermittent
symptoms (e.g., asthma) are permitted.

11. Has had a recent bleeding event (e.g., gastrointestinal, pulmonary, renal/hematuria) or
thromboembolism (less than 12 weeks prior to randomization). Or a known bleeding
disorder(s) or increased risk of either thromboembolism or bleeding, or recurrent events
of bleeding or thromboembolism (e.g., venous thromboembolism, deep venous
thrombosis, pulmonary embolism) as well as pre-existing or predisposing bleeding or
hypercoagulable conditions.
Clinical and Diagnostic Parameters
12. ECG findings within 12 weeks before randomization that would require urgent diagnostic
evaluation or intervention (e.g., new clinically important arrhythmia or conduction
disturbance).
13. Renal imaging reveals contraindications for undergoing biopsy or REACT injection
procedures, in the judgement of the Proceduralist who will perform the procedure or
Sponsor. Deciding factors may include kidney location, interposed abdominal organs
between skin and kidney, kidney size and depth (e.g. if kidney access is greater than 15
cm from skin to capsular area), kidney cysts that prevent REACT deposits, obstructed
collecting system, unexplained hydronephrosis or anatomic variations prohibiting a safe
biopsy and REACT injection into the cortex.
14. Kidney volume less than 76 grams (g KWest). The Proceduralist must review the
Screening MRI or CT scan and kidney volumes prior to randomization for technical
feasibility and safety of kidney biopsy and REACT injection procedures into both
kidneys.
15. Any of the following central laboratory values during Screening:
a. Hemoglobin levels less than 10 g/dL prior to randomization. Treatment for CKD
related anemia may be initiated and hemoglobin levels may be repeated once
during Screening.
b. Platelets <100 x 103/µL
c. Activated partial thromboplastin time (aPTT) above the upper limit of normal
defined by the central laboratory
d. International normalized ratio (INR) ≥ 1.5
e. Alanine aminotransferase [ALT] or aspartate aminotransferase [AST] greater than
3 times the upper limit of normal
f. Positive test for Human Immunodeficiency Virus antibodies, Hepatitis B surface
antigen, Hepatitis C antibodies, or syphilis infection.
Concomitant Therapies or Known Treatment Intolerance
16. Maintained on any anticoagulant agents, including fractionated heparin preparations,
Coumadin® (warfarin), Factor Xa inhibitors, aspirin or direct thrombin inhibitors that
cannot be suspended for 7 days before and 7 days after biopsy or injections.

17. Known allergy or contraindication(s) or has experienced severe systemic reaction(s) to

kanamycin/structurally similar aminoglycoside antibiotic(s), which may be a
manufacturing process residual, or has a known hypersensitivity to dimethyl sulfoxide.
18. History of anaphylactic or severe systemic reaction(s) to blood transfusions, Dextran 40,
or bovine products, or contraindication(s) to above products due to medical reasons or
participant preference.
19. History of severe systemic reaction(s) or any contraindication to local anesthetics or
sedatives.
20. Use of an investigational product or device within 12 weeks (~3 months) prior to
Randomization.
Note: Study enrollment may be discussed with the Medical Monitor for unique
circumstances that do not require ongoing treatment and systemic impact of an
investigational product/device is not anticipated.
21. Participants who have previously received treatment with REACT.
General Exclusions
22. The female participant is pregnant, lactating (breast feeding), or planning a pregnancy
during the course of the study. Or the female participant is of child-bearing potential and
is not using, or is unwilling to continue using, a highly effective method(s) of birth
control throughout the duration of the study.
Note: A highly effective method of birth control is defined as one that results in a low
failure rate (i.e., less than one percent per year) when used consistently and correctly,
such as implants, injectables, combined oral contraceptives, some intrauterine devices,
sexual abstinence, or a vasectomized partner. See Appendix 1.
23. History of alcohol and/or drug abuse that, in the judgement of the Investigator or
Sponsor, would impair the participant’s ability to comply with the protocol.
24. Participant’s health status would, in the judgement of the Investigator, be jeopardized by
participating in the study.
6.3 Lifestyle Considerations

6.3.1 Diet and Activity
Dietary restrictions may apply to the recruited population due to existing comorbidities and will
be at the discretion and management of the Investigator. Specific instructions regarding fasting
and medication adjustments may be provided by the Investigator or Proceduralist, as applicable.
Participants will be provided with educational material targeted to optimize diabetes and CKD
management.

If fasting status is prolonged and participant has a history of labile glucose levels, consider
glucose monitoring during peri-procedure care period.
6.3.2 Caffeine and Tobacco

Participants should be encouraged avoid caffeine and tobacco products (including nicotine
containing products) for at least 1 hour prior to study visits, particularly prior to blood pressure
measurements.
7 STUDY INTERVENTION(S) AND CONCOMITANT THERAPIES

The procedures for the successful conduct of this study and the collection of participant safety
and efficacy data are shown in the Schedule of Events (Table 4) and Laboratory Schedule
(Table 5). Stopping rules, procedures for treatment discontinuation, study suspensions, and end-
of-study are in Section 10, Section 7.2.11, Section 7.3 and Table 7.
Cohort 1 and Cohort 2 will undergo similar management and assessments as outlined in the
study design schema (Figure 2), the Schedule of Events (Table 4), and Laboratory Schedule
(Table 5). In general, the following steps apply to both Cohort 1 and Cohort 2:
• Participants will receive up to 2 REACT injections or 2 sham injections.
• The first REACT injection or the first sham injection procedure will be 14 weeks
(+28 Days) after the kidney biopsy or sham biopsy procedure.
• 7 to 14 days before each injection procedure (REACT or sham), every participant
will have a pre-injection visit (Visit 4 and Visit 10) for pre-procedure
assessments.
• The Medical Monitor must be consulted if visit windows for injections cannot be
maintained for any reason.
• To ensure the blind is maintained for all participants in Cohort 1 and Cohort 2, the
participants will follow all clinical assessments as described in Table 4.
• If a participant discontinues treatment prior to the first or second REACT or sham
injection, only pre-procedure assessments will be performed for the respective
visit as outlined in Table 4. The REACT or sham injection procedure and safety
renal ultrasound will not be performed, and post-injection visits Day +1, Day +7,
Day +14, and Day +28 are skipped.
• Optimize glucose control during the peri-procedure time period including glucose
monitoring as needed.

• Local urinalyses are optional during the peri-procedure period. Prophylactic

antibiotics may be given per Investigator discretion. Central laboratory urinalyses
are performed as part of the pre-procedure assessment.
7.1 Concomitant Therapies

The use of concomitant treatments, including prescription medications, conscious sedation, over
the counter medications, and vaccinations, are to be recorded in the appropriate eCRF along with
the reason the medication is taken.
The following medications should be kept at stable doses throughout the study, including during
the screening period as applicable, except for cases of toxicity or intolerance related to the
treatment. In the case of toxicity/intolerance, the medication may be decreased or discontinued
and should be recorded in the appropriate eCRF.
• Angiotensin converting-enzyme inhibitor
• Angiotensin receptor blocker
• Sodium glucose cotransporter 2 inhibitor
• Mineralocorticoid receptor antagonist.
7.1.1 Medications Interfering with Study Assessments

Medications that are known to interfere with serum creatinine measurements should be avoided
during the study. Examples of these types of medications include:
• trimethoprim
• dronedarone
• cimetidine.
If such medications are required based on medical necessity, then the circumstance should be
discussed with the Medical Monitor and documented within the eCRF.
Other treatments that potentially may confound the efficacy or safety assessments should be
discussed with the study medical monitor before initiation, when possible.
7.1.2 Prohibited Therapies

Participants should be instructed to consult with the Investigator when initiating any new
medications, including over-the-counter products, to capture potentially prohibited treatments.

Investigational drugs and investigational treatments other than REACT are prohibited during the
course of the study as outlined in the exclusion criteria (Section 6.2). Investigational drugs or
devices are defined as products that have not been approved for use by the FDA or other health
authorities.
7.1.3 Prohibited Therapies During Peri-procedure Time Period

All medications that may impact bleeding risk such as those listed below, must be suspended
during the 15-day period beginning 7 days prior through 7 days following biopsy/sham-biopsy
and each REACT injection/sham injection:
• Warfarin
• Low molecular weight heparin [LMWH] such as Lovenox (enoxaparin)
• Factor Xa inhibitors and other novel oral anticoagulants
• Platelet aggregation inhibitors [PAIs)] such as clopidogrel, prasugrel, and
dipyridamole
• Nonsteroidal anti-inflammatory drugs [NSAIDS] including ibuprofen
• Aspirin
• Supplements, including herbal treatments, that increase bleeding risk.
Coagulation parameters are obtained before the biopsy and each injection/sham intervention per
the protocol study visit schedule. Required parameters include aPTT, prothrombin time, INR,
platelets, hemoglobin, and hematocrit.
The Sponsor does not endorse anticoagulation bridging protocols for any medical condition.
7.1.4 Vaccines
Participants should be up-to-date on appropriate vaccinations prior to Screening per routine local
medical guidelines. If vaccinations must be administered during the study period, the following
vaccination guidance should be followed:
• Live vaccines are not permitted from randomization and until at least 52 weeks
after the last REACT/sham injection.
• Inactivated vaccines, including RNA vaccines, are permitted during the study.
However, inactivated vaccinations should not be administered within 14 days
before through 14 days after the kidney biopsy/sham biopsy and the
REACT/sham injections.

Vaccinations during the study are concomitant therapies and should be documented in the
participants’ eCRF.
7.2 Study Visits and Interventions

The schedules of clinical assessments and procedures to be performed during the study are
displayed in the Schedule of Events (Table 4). The schedules of sample collection and clinical
laboratory evaluations planned for the study are displayed in the laboratory schedule of events
(Table 5). Before conducting any study-specific assessments or procedures (including
Screening), the participant must provide written informed consent in accordance with the
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and
21 CFR Part 50.
7.2.1 Screening
Participants who have provided written consent and satisfy the eligibility criteria may be enrolled
into the study. Screening assessments are outlined in the SoE and include a complete physical
examination, measurement of vital signs, electrocardiogram (ECG), renal imaging, and
laboratory assessments as defined in Section 8. All Screening assessments should be completed
within a timeframe that will allow for randomization within 60 days of the participant signing the
Informed Consent Form. The Screening period may be extended up to 5 days.
An MRI study without contrast will be performed during the Screening visit to determine kidney
size and volume. If a participant cannot undergo MRI (preferred) then CT may be substituted to
obtain kidney size and volume. A local diagnostic imaging report should be reviewed with the
Proceduralist for exclusion criterion related to renal imaging and contraindications for
undergoing a biopsy and REACT injection procedure. Additionally, the Proceduralist should
review the results of the kidney volume reported by the central imaging reader prior to
randomization.
The renal imaging modality used to determine kidney size and volume for a participant during
Screening should be used for all other scheduled imaging events throughout the study.
7.2.2 Screen Failures

Screen failures are defined as participants who consent to participate in the study but are not
subsequently randomized to a treatment. A minimum set of screen failure information is
required to ensure transparent reporting and responding to queries from regulatory authorities.
This information will be collected in the eCRF.

7.2.3 Rescreening
A participant who is considered a screen failure may be rescreened once. If the Investigator has
any questions concerning the appropriateness of rescreening a participant, then the Investigator
should contact the Medical Monitor.
A participant who is rescreened must be re-consented and a new unique participant number must
be assigned. If the previous protocol-specific imaging study was successfully completed within
24 weeks of the Rescreening, the imaging study does not need to be repeated.
7.2.4 Randomization
Sites will randomize the participant via an Interactive Web Randomization System (IWRS)
within the Electronic Data Capture (EDC) System. Randomization will be stratified by SGLT2i
use and eGFR at Screening to achieve a balanced distribution in Cohort 1 and Cohort 2 among
the identified stratification factors. Permuted block size is defined by the randomization plan.
Randomization is set to occur after all Screening assessments have been successfully completed
and the participant is confirmed eligible.
7.2.5 Pre-Biopsy
Participants will report to the clinic 7 to 14 days prior to undergoing renal biopsy or sham biopsy
for pre-biopsy assessments including a targeted physical examination, measurement of vital
signs, and laboratory tests. For details of all assessments performed at the Pre-Biopsy Visit
(Visit 1), see Table 4.
Laboratory tests for hemoglobin and hematocrit will be conducted and resulted locally at Visit 1
to inform clinical care.
7.2.6 Kidney Biopsy

The Day of Biopsy Visit (Visit 2) should be scheduled 2 weeks (+14 days) after Randomization.
If, for whatever reason, the biopsy cannot be conducted within 8 weeks of randomization, then
the Investigator and Medical Monitor should discuss and agree upon the need for repeating any
of the Screening or Pre-Biopsy Visit assessments such as laboratory tests, physical exam, ECG,
or kidney imaging study prior to the Day of Biopsy Visit.
If fasting status is prolonged for the procedures and participant has a history of labile glucose
levels, consider glucose monitoring during peri-procedure care period.

If a participant discontinues treatment prior to the biopsy/sham biopsy, only pre-procedure

assessments will be performed (Table 4). The biopsy or sham biopsy procedure and safety renal
ultrasound will not be performed, and the Biopsy +1 Day visit is skipped.
7.2.6.1 Sham Percutaneous Kidney Biopsy for Cohort 1

The scripted sham biopsy in this trial omits manipulation of the kidneys, no biopsy is performed,
and no needles touch the kidney. The sham kidney biopsy will be conducted mimicking a real
kidney biopsy to ensure the blinding of participants. The use of conscious sedation is encouraged
to maintain the blind and should approximate the standard of care used for a renal biopsy. The
decision to use sedation will be at the proceduralist’s discretion. To ensure the blind is
maintained between participants in Cohort 1 and 2, the participants in both cohorts will follow all
clinical assessments as described in the Schedule of Events.
The total time for the scripted sham kidney biopsy procedure for Cohort 1 participants should
approximate the site standard for a routine kidney biopsy for the intervention treatment Cohort 2,
with a similar time spent in the procedure area or suite and post-biopsy observation. The
proceduralist and team members present during the procedure will maintain participant blinding.
The participant will be placed into a comfortable position on the CT table or ultrasound bed for
the ultrasound or CT guided biopsy. Local skin anesthetic will be given and there will be a small
skin nick at the scripted sham biopsy site. The biopsy collection will be simulated with the
clicking of a biopsy gun out of view of the participant and outside the participant’s body. The
biopsy needle will NOT be inserted, and no tissue sample will be collected from the participant.
If CT imaging is used for the sham biopsy, CT will be simulated with the participant moving in
and out of the scanner and verbal instruction by the CT technologists. However, there will be no
radiation exposure and no images will be obtained.
A script will be provided to guide the team in verbal and mechanical conduct during the
procedure to ensure the scripted sham biopsy procedure closely mimics the actual kidney biopsy
(see Sponsor Study Manuals).
Renal imaging is required post-procedure similar to Cohort 2 as described in the Sponsor Study
Manuals.

7.2.6.2 Percutaneous Kidney Biopsy for Cohort 2

Participants in Cohort 2 will undergo a kidney biopsy. A minimum of 2 biopsy cores, each
measuring 1.5 cm in length, collected using a 16-gauge biopsy device, or 4 biopsy cores, with
each measuring 1.5 cm in length, collected using an 18-gauge biopsy device under sterile
conditions from each enrolled participant are sent to the Sponsor using the refrigerated shipping
container provided by the Sponsor and according to procedures detailed in the
Sponsor Study Manuals. One additional biopsy core may be obtained for local renal pathology at
the discretion of the Principal Investigator and if determined to be safe by the Proceduralist. The
use of conscious sedation is encouraged to maintain the blind and should match the use of
sedation during sham kidney biopsies for Cohort 1 participants. The decision to use sedation will
be at the proceduralist’s discretion. A safety renal ultrasound is required post-procedure to
monitor for possible subclinical AEs (e.g., swelling, fluid accumulation, hematoma) as described
in the Sponsor Study Manuals.
7.2.6.3 Post Biopsy

Participants in both cohorts will be monitored post procedure for a minimum of 6 hours, but
longer observation periods are acceptable and at the discretion of the Investigator or per the local
Standard of Care. During this recovery period, vital signs, laboratory assessments, and a renal
safety ultrasound will be performed (Sponsor Study Manual and Table 4) in addition to local
standard of care. Participants who do not experience complications may be discharged the same
day or later at the discretion of the Investigator or Proceduralist, and consistent with site and
country standard practice. If procedure-related AEs occur following biopsy or sham biopsy,
participant monitoring should be consistent with the clinical assessment and time of discharge at
the Investigator’s discretion after the AE has resolved or remains stable.
7.2.6.4 Post Biopsy +1 Day

The day following biopsy/sham biopsy, participants return to the study site for follow-up
assessments including a safety renal ultrasound examination (See Section 8.8.1), vital signs, and
protocol-scheduled laboratory assessments.
7.2.7 REACT/Sham Injections

7.2.7.1 Sham Percutaneous Injections – Cohort 1
The sham procedures in this trial omit the investigational product (REACT) and do not involve
manipulation of the kidneys.

Two scripted sham REACT injections are planned. The first scripted sham injection will be
performed on the same side as the scripted sham biopsy. The second scripted sham injection will
be performed on the contralateral side. Each scripted sham injection will be performed in a
similar manner. The total time for the scripted sham REACT injection procedure will
approximate the time for a REACT injection. The use of conscious sedation based on site
standard of care in Cohort 1 participants is permitted. Efforts should be made to use conscious
sedation consistently during both the first and second injection visit.
CT imaging will be simulated with the participant moving in and out of the scanner and verbal
instruction by the CT technologists. However, there will be no radiation exposure and no images
will be obtained.
The Proceduralist and team members present during the procedure will maintain participant
blinding. A script will be provided to guide the team in verbal and mechanical conduct during
the procedure (see Sponsor Study Manuals).
A safety renal ultrasound is performed during the recovery period similar to Cohort 2 as
described in the Sponsor Study Manuals.
7.2.7.2 Percutaneous REACT Injections – Cohort 2

The participant will be injected with autologous REACT using a percutaneous CT-guided
approach as described in the Sponsor Study Manuals. The first injection will be into the biopsied
kidney. The second injection into the non-biopsied contralateral kidney. The Proceduralist
should avoid the same tracks, trajectory, and location of prior renal biopsies and REACT
injections.
Renal imaging will be performed shortly after the procedure to monitor for possible subclinical
AEs (e.g., swelling, fluid accumulation, hematoma) as described in Section 8.8.1 and the
Sponsor Study Manuals.
7.2.8 Post Injection Monitoring Sham and REACT

Participants in both cohorts will be monitored post procedure for a minimum of 4 hours. Vital
signs, laboratory assessments, and a safety renal ultrasound will be performed in addition to local
standard of care as described in the Sponsor Study Manuals, the Schedule of Events (Table 4)
and Laboratory Sampling Schedule (Table 5).

Participants who do not experience complications may be discharged the same day or later at the
discretion of the Investigator or Proceduralist. If procedure-related AEs occur following
REACT/sham injection, participant monitoring should be consistent with the clinical AE
assessment and time of discharge at the Investigator’s discretion after the AE has resolved or
remains stable.
7.2.9 REACT/Sham Injection Follow-up Visits

Following administration of the first REACT/sham injection at Visit 5, and the second
REACT/sham Injection at Visit 11, all participants in Cohort 1 and Cohort 2 will return to the
clinic for these follow-up visits:
Table 6: Post-Injection Follow-up Visits

After 1st REACT or Sham Injection at Visit 5
Visit 6: 1st injection + 1 Day
Visit 7: 1st injection +7 Days
After 2nd REACT or Sham Injection at Visit 11
Visit 12: 2nd injection +1 Day
Visit 13: 2nd injection +7 Days
Visit 14: 2nd injection +14 Days
Visit 15: 2nd Injection +28 Days
Safety renal ultrasound examinations will be performed to monitor for possible subclinical AEs
(e.g., swelling, fluid accumulation, hematoma) as outlined in Table 4 and Section 8.8.1.
7.2.10 Long-Term Follow-up Visits

Participants will return to the clinic for Long-term Follow-up Visits starting at Visit 16 and
return approximately every 12 weeks until GTED (Table 4 and Table 5).
If a participant is unable to attend an in-clinic visit, follow-up may be obtained by telephone call,
other means of virtual contact, or home visit, if appropriate. Any procedures listed in the
Schedule of Events that are not completed will be documented as protocol deviations. For remote
visits, local laboratory results have some conditional uses:
• Clinical laboratory evaluations are permitted to be completed by a local
laboratory but will not be collected by the Sponsor for inclusion in efficacy
analyses.

• Clinically significant laboratory results obtained locally should be repeated

through the central laboratory, including any local laboratory result that would be
considered an “event” under an endpoint.
• Only the central laboratory result will be used in data analyses.
If a participant meets a laboratory component of an endpoint (identified via central laboratory),

confirmation via central laboratory testing at an unscheduled visit at least 30 days after the initial
event occurs for eGFR. The unscheduled visit will collect assessments needed to confirm the
endpoint has been met.
An unscheduled visit may be scheduled to collect safety or efficacy assessments as needed.
7.2.11 End-of-Study Visit

The intent of the end-of-study visit is to capture available efficacy and safety data prior to a
participant completing the study after notification of the GTED or withdrawing early from the
study. Participants are expected to complete EOS assessments as outlined in the SoE in Table 4.
Participants who discontinue study treatment early should attend protocol scheduled visits until
GTED unless they have fully withdrawn from the study.
Participants who remain on-study at the time of GTED notification should preferably complete
EOS visits within 4 weeks of the GTED. The table below describes the timing and imaging
requirements for the EOS visit for completed/partially completed REACT/Sham injections and
withdrawn participants. For participants who discontinue treatment without withdrawing from
the study, refer to Section 7.3.
Table 7: End-of-Study Assessment and Surveillance Guide

Participant Status After End-of-Study (EOS) Visit
Randomization Timing Imaging Guidance a
Completed 1 or 2
EOS visit preferably within 4 Obtain MRI if more than 26 weeks since
REACT/Sham injections and
weeks before the GTED last protocol-specified MRI/imaging.
followed until GTED
Completed 1 or 2
REACT/Sham injections but not EOS visit within 4 weeks of Obtain MRI if more than 26 weeks since
all follow-up visits and withdrawal last protocol-specified MRI/imaging.
withdrawn from study
Withdrawn from study EOS visit within 2 weeks of
No imaging required
BEFORE renal biopsy withdrawal

Participant Status After End-of-Study (EOS) Visit

Randomization Timing Imaging Guidance a
Withdrawn from study
MRI only if judged necessary to provide
AFTER renal biopsy but EOS visit within 2 weeks of
critical safety information for participant
BEFORE any REACT/Sham withdrawal
care
injection(s)
a. MRI is preferable over CT scan when possible. Mode of imaging chosen for the participant should remain
consistent throughout the study.
For participants with any ongoing safety events, investigators should encourage participants to
remain on the study until resolution or stabilization of the event, particularly in the case of
serious events, before completing an EOS when possible.
7.3 Participant Discontinuation of Treatment and Withdrawal from the Study

Participants may discontinue treatment voluntarily, without withdrawing from the study, at any
time post randomization and should be encouraged to continue all subsequent visits for safety
and efficacy.
If an Investigator or the Sponsor decides to discontinue a participant from study treatment early
(see Section 10.1), the rationale for discontinuation from treatment should be documented. If a
participant voluntarily discontinues from treatment, the reason(s) should be documented.
Participants may be discontinued from treatment any time during the study, including:
• After randomization and prior to biopsy/sham biopsy
• After biopsy/sham biopsy and prior to first REACT/Sham injection
• After first REACT/Sham injection and prior to second REACT/Sham injection.
A participant discontinued from treatment will continue with study visits through the GTED and
complete the end-of-study visit as described in Section 7, Table 7 and Section 7.2.11.
The Investigator may withdraw a participant from the study if it is determined that continuing in
the study is no longer in the best interest of the participant. The Investigator is encouraged to
consult with the Medical Monitor/Sponsor prior to withdrawing a participant from the study. If a
participant is withdrawn from the study, EOS assessments should be conducted at the last visit
(Section 7.2.11).

7.4 End of Treatment

A Participant’s End of Treatment is defined as having received:
• Two REACT / Sham injections
• One REACT / Sham injection for a participant who has discontinued treatment.
All participants, including those who have discontinued treatment, should be followed through
GTED for continued collection of efficacy and safety assessments.
7.5 Participant Completion Defined

A participant will be considered as having completed the study, if the participant is followed
until after the Sponsor announces the projected GTED and completes the EOS visit. Sites should
schedule the EOS visit as soon as possible after being notified of the projected Global Trial End
Date (GTED) and preferably up to 4 weeks before the GTED.
7.6 Study Completion Defined

The end of the study is defined as the time when the Sponsor announces GTED.
8 STUDY ASSESSMENTS AND PROCEDURES

8.1 Demography and Medical History
Demographic characteristics will be obtained for each participant at the Screening Visit.
At Screening, record all clinical events that have occurred prior to randomization as medical
history including all CKD -related medical history, major surgeries, and all other significant
medical history. Also record all chronic conditions (for example, diabetes, hypertension, asthma)
and onset dates.
Record all malignancies.
Throughout the study, medical conditions that are still ongoing must be regularly updated in the
eCRF.

8.2 Vital Signs

8.2.1 Vital Signs at Rest
Vital signs to be measured include:
• resting systolic/diastolic blood pressure*
• heart rate
• respiration rate
• body temperature**
• body weight**
• height (once at Screening).
*Blood pressure will be measured after the participant has been seated for a minimum of
5 minutes. Three blood pressure measurements will be taken and entered into the eCRF. The
average of the 3 measurements (for systolic and diastolic pressure) will be used to satisfy entry
criteria at Screening.
**Body temperature and weight are not required measurements in the post-procedure time
period.
8.2.2 Vital Signs During Procedures

At regular intervals throughout the study procedures vital signs to be measured include:
• blood pressure
• heart rate
• respiration rate
• oxygen saturation
• body temperature (1X).
These values must be entered into eCRF at regular intervals during the entire procedure time
period and frequently during the actual REACT/Sham injection (see Sponsor Study Manuals).
The body temperature does not need to be recorded throughout the procedure but should be
documented once.
8.3 Physical Examinations

The Investigator or designee will perform the physical examinations as specified in the Schedule
of Events Table 4.

Virtual visits do not require a physical examination.
8.3.1 Complete Physical Examination

The complete physical examination should include, at a minimum, the following body systems:
general appearance, cardiovascular, respiratory, gastrointestinal, neurologic, and dermatologic.
8.3.2 Targeted Physical Examinations

Targeted physical examination(s) should be performed as indicated in the Schedule of Events
table. At a minimum, a targeted exam should include cardiovascular and respiratory systems;
other systems should be included as appropriate. If clinically indicated, a complete physical
examination may be performed.
An unscheduled targeted examination may be performed as needed, for example, to assess an

adverse event.
8.4 Electrocardiogram
A 12-lead ECG will be recorded after the participant has been resting on their back. ECG
recordings completed at visits will be assessed by the Investigator and the results entered into the
eCRF.
8.5 Medications - Prior and Concomitant

At Screening, record all medications taken by the participant from 3 months prior to Screening.
Record and update all concomitant medications (including conscious sedation medications) and
dosage changes in the eCRF at every study visit.
Record any medications used to treat any AE in the eCRF.
8.6 Procedures - Prior and Concomitant

All significant procedures during the study will be recorded in the eCRF.
8.7 Clinical Laboratory Assessments

Analyses will be conducted by a central laboratory, except as noted. The details of the laboratory
assessments for collection during the study is shown in Table 8. Additional information is in the

Sponsor Study Manual. The schedules of all study events and laboratory sample collections are
shown in Table 4 and Table 5.
Research samples will also be collected per the laboratory schedule of events. Participants must
provide consent to the collection and the use of their samples for future research related to
kidney disease, including the evaluation of novel biomarkers, which is exploratory and will be
reported separately. These research samples will be destroyed 10 years after the GTED.
Table 8: Clinical Laboratory Evaluations

Chemistry Hematology Urine Assessments
• Alkaline phosphatase • Complete blood count • Albumin**
• Alanine aminotransferase (CBC) includes: • Creatinine**
(ALT) WBC, platelet count, • NGAL
• Aspartate aminotransferase Hgb, HCT, RBC count • β2-Microglobulin
(AST and red cell indices • Urine
• Bilirubin (MCHC, MCV, etc.), albumin:creatinine
• Gamma-glutamyl lymphocytes, ratio (UACR)
transpeptidase (GGT) leucocyte, eosinophil, • Urinalysis with reflex
• Lactate dehydrogenase (LDH) macrophage and microscopy
• Blood urea nitrogen (BUN)* plasma cell percent • Urine culture
and counts
• Creatinine* • Urinalysis dipstick
• eGFR (calculated)* Pregnancy • Urine pregnancy
• Glucose* • Serum hCG (women dipstick (women of
• Calcium* of child-bearing child-bearing
• Phosphorus* potential) potential)
• Albumin* • FSH (females only at
• Uric acid screening)
• Creatine kinase Coagulation Status Urine Drug Screen
• Activated Partial • Amphetamine
Thromboplastin Time • Barbiturates
(aPTT) • Benzodiazepines
• Prothrombin Time • Cocaine
(PT) • Opiates
• International • Tetrahydrocannabinol
Normalized Ratio • Phencyclidine
(INR) • Methadone
Electrolyte Fasted Lipid Panel • Propoxyphene
• Sodium* • Cholesterol
• Potassium* • Ligh density
• Bicarbonate* lipoprotein (LDL)
• Chloride* • High density
• Magnesium lipoprotein (HDL)
• Anion Gap (calculated) • Triglycerides
• LDL:HDL ratio
(calculated)

Other Assays Infection Screen

• β2-Microglobulin • Hepatitis B Virus
• Cystatin C (HBV)
• c-Reactive protein (CRP) • Hepatitis C Virus
• HbA1c (HCV)
• intact Parathyroid Hormone • Human
(iPTH) Immunodeficiency
Virus (HIV)
• Syphilis
Refer to the Sponsor Study Manuals for more information.
*Parameters included in Renal Panel
**urine albumin and creatinine will be used to calculate albumin:creatinine ratio (UACR)
Abbreviations: FSH (Follicle-Stimulating Hormone); HbA1c (glycosylated hemoglobin); hCG (Human Chorionic
Gonadotropin); NGAL (Neutrophil Gelatinase-Associated Lipocalin)
8.7.1 eGFR
The estimated glomerular filtration rate will be calculated using the 2009 CKD-EPI serum
creatinine equation and analyzed by the central laboratory. 59
8.7.2 Urine Collection

The schedule for collecting urine samples is listed in Table 4. First morning void urine samples
should be collected for UACR assessments when possible. Otherwise, urine samples may be
collected at the site for other assessments when possible.
Microscopic analysis will be performed by the central laboratory for any abnormal urinalysis. A
urine culture will be performed by the central laboratory at pre-procedure visits. An optional
urine culture may be obtained at any other visit, at the Investigator’s discretion.
8.7.3 Coagulation Status

Hemorrhage following biopsy and REACT injection is a known and foreseeable risk to
participants in this study. Therefore, hemoglobin and hematocrit will be measured before and
after each procedure per Table 4. Other bleeding parameters (e.g., aPTT, PT-INR, platelets) will
also be measured during the peri-procedure time periods of the study.
8.7.4 Pregnancy Testing

Requirements for pregnancy testing (serum or urine) are outlined in Table 5 and Table 8. Any
identified pregnancy after randomization must be reported to the Sponsor and further
REACT/sham injections cannot be administered. See Section 9.3.2 for additional details.

Postmenopausal women with a confirmatory follicle-stimulating hormone (FSH) test do not have
to undergo pregnancy testing throughout the study.
Refer to Section 9.1 and Section 9.3.2 for additional details on pregnancy reporting.
8.8 Imaging Studies: Renal Ultrasound, Magnetic Resonance Imaging (MRI) and
Computed Tomography (CT)
8.8.1 Renal Ultrasound Imaging
Renal Ultrasound at time of Biopsy: The kidney biopsy is commonly performed with
ultrasound guidance by the Proceduralist. Additional guidance is provided in the Sponsor Study
Manuals.
Safety Renal Ultrasound: Safety renal ultrasounds are performed as specified in Table 4. The
safety renal ultrasound study includes morphologic information such as kidney size
(longitudinal, transverse AP and lateral dimensions) and doppler measurements such as vessel
velocities, resistive indices, and evaluation for vascular abnormalities. Findings and
measurements will be on the visit eCRF. The imaging studies must be reviewed by the
Proceduralists after each examination including prior to participant discharge.
8.8.2 Specific Timing of Safety Renal Ultrasound Post-procedures

Safety renal ultrasound is required for safety monitoring post-procedure to evaluate for
symptomatic or subclinical AEs, including identification of renal hematomas. Safety renal
ultrasounds should be performed on day of procedures for both cohorts as follows:
• Day of Biopsy at least four hours after the biopsy/sham biopsy
• Day of Injections at least 2 hours after the REACT/Sham injection procedure.
Note: Hematomas or AEs are only expected in the treatment cohort but ultrasound is required in
the scripted sham to maintain the blind.
An ultrasound may be conducted at other times, in the judgement of the Investigator or

Proceduralist, if needed for additional safety evaluation(s) and follow-up of acute changes in the
kidney.
8.8.3 Magnetic Resonance Imaging

An MRI study without contrast will be performed during the study according to the Image
Acquisition Guide and sent to a blinded central imaging reader to determine kidney size, cortical

thickness, and volume. MRI will be performed without injection of contrast agent to avoid
potential nephrotoxicity.
MRI imaging will be performed at Screening to determine kidney volume (by central imaging
reader). A local diagnostic MRI interpretation is required to assess for renal cysts or other masses
and identify adjacent viscera and lungs.
Special Circumstances
Scheduling of MRI or substitute CT: It is recommended to schedule examinations early in the
screening process to account for central imaging reader turnaround times and possible delays due
to rescanning participants with inadequate imaging or the evaluation of indeterminate masses.
Indeterminate Masses: Kidney cysts and solid tumors are common in the CKD population and
the local diagnostic interpretations require review prior to randomization. All indeterminate
renal masses identified on the initial screening MRI or CT require further imaging evaluation
prior to randomization, biopsy, or scripted sham procedure at the direction of the Investigator.
The evaluations may include consultation with MRI imagers for additional scans or urology.
MRI and CT Consistency: The imaging modality (CT or MRI) should be the same from visit to
visit to maintain reporting consistency. The Study Medical Monitor is to be consulted before
selecting CT as a substitute for MRI.
Note: To minimize the risk of inter- and intra- participant variation in MRI, CT imaging,
minimum scanning parameters will be provided to each site to comply with the central imaging
requirements.
8.8.4 Computerized Tomography

Computerized tomography (CT) is used for image guided procedures and may be a substitute for
MRI. All CTs will be completed non-contrast.
CT Substitute for MRI Volumes: CT may be substituted for the MRI when unavailable,
contraindicated, or cannot be performed for other reasons. CT without contrast will be performed
during the study and sent to a blinded central imaging reader to determine kidney size and
volume. A local diagnostic CT interpretation is required to assess for renal cysts or other masses,
and to identify adjacent viscera and lungs.

CT Guidance During Injections: CT scanning is utilized during all the injection procedures.
The REACT injections in Cohort 2 require precise placement of small injection needles into a
narrow target area in the renal cortex. CT also provides real-time assessment of the needle
pathway from the skin to the kidney and if any bleeding complications develop. Since all
REACT injections in Cohort 2 are necessary with CT, all sham procedures in Cohort 1 must be
set up to appear and sound the same as Cohort 2. However, during the sham procedure no real
CT scanning occurs and there is no radiation exposure.
CT Guidance During Renal Biopsies: Biopsies are performed with ultrasound or CT guidance
and the imaging choice is at the discretion of the Proceduralists. Common reasons for CT
guidance are participant BMI, suboptimal kidney visualization with ultrasound or anatomic
variations.
9 SAFETY ASSESSMENTS AND MANAGEMENT

9.1 Safety Event Definitions
An Adverse Event (AE) is any untoward medical occurrence associated with the use of drug in
humans, whether or not considered drug related that occurs following randomization.
A Treatment-Emergent Adverse Event (TEAE) is defined as any AE that started or worsened

in intensity on or after the start day of first REACT/Sham injection through the end of study.
An Adverse Event of Special Interest (AESI) (serious or non-serious) is one of scientific and
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and
rapid communication by the Investigator to the Sponsor may be appropriate. AESI definition for
this study can be found in Section 9.5.
A Serious Adverse Event (SAE) is an undesirable medical event meeting one or more of the
following criteria:
• results in death
• is immediately life-threatening
• requires in-patient hospitalization or prolongs an existing hospitalization that
deviates from international standard of care or practice
Note: In general, hospitalization signifies that the patient was admitted (usually involving
at least an overnight stay) to the hospital or emergency ward for observation and/or
treatment that would not have been appropriate in the physician’s office or outpatient
setting. Complications that occur during hospitalization are AEs. If a complication

prolongs hospitalization or fulfills any other serious criteria, the AE is serious. When in
doubt as to whether “hospitalization” occurred, or was necessary, the AE should be
considered serious.
• results in a persistent or significant disability of incapacity
• results in a congenital abnormality or birth defect
• is an important medical event that may jeopardize the participant or may require
medical intervention to prevent one of the above criteria.
The following are NOT considered SAEs:

• Hospitalization for elective treatment of a pre-existing condition that did not
worsen from Baseline
• Hospitalization for social/convenience considerations
• Surgery or procedure planned before consenting into the study, or a procedure to
treat or explore a non-worsened pre-existing condition (e.g., elective knee
replacement, routine coronary angiogram without intervention, elective bariatric
surgery); the non-worsening of the pre-existing condition must be documented in
the source documents and the eCRF.
A Suspected Unexpected Serious Adverse Reaction (SUSAR) refers to an adverse event in a

clinical trial whose nature and severity, as assessed by the Sponsor and/or the Investigator based
on applicable product information, as being unexpected (see Investigator’s Brochure), serious,
and as having a reasonable possibility of a causal relationship with the investigational medicinal
product.
9.2 Reporting Adverse Events

The Investigator is responsible for ensuring that all observed adverse events (AEs) are reported
and documented appropriately, including those reported by the participant and clinically
significant findings noted via clinical laboratory reports, imaging reports, consult notes, survey
instruments, hospitalization records and other data collection tools.
The guidance below should be followed when reporting adverse events:

• AEs will be reported using standard medical terminology whenever possible.
• A clinically significant change in laboratory values or vital signs should be
reported as an AE or SAE if seriousness criteria is met.

• A decline in eGFR is an expected event in this study population. Therefore, only

reduction in eGFR values that are unexpected (e.g. acute kidney injury) should be
reported as an AE/SAE.
All AEs should be entered in the AE eCRF of the EDC. For all AEs, the Investigator will record
the start date, stop date, intensity of each reportable event, the Investigator’s judgement of the
relationship to the study procedure (biopsy/Sham, or REACT/Sham injection) or investigational
product, action taken, severity (if applicable), and whether the event resulted in discontinuation
of treatment or withdrawal from the study. Follow-up information on any AE may be requested
by the Sponsor or its designee.
Adverse Events that occur from the time of randomization and through the end of study should
be recorded in the AE eCRF.
• A pre-existing medical condition is a clinical condition (including a condition
being treated) that is diagnosed and documented (in the medical history CRF) as
part of the participant’s medical history before the participant is randomized. Pre-
existing conditions that are stable and unchanged should not be considered
adverse events.
• Unscheduled visits may be conducted at any time during the study as judged
necessary by the Investigator to assess and conduct follow-up for an AE.
Evaluations and procedures to be performed at unscheduled visits will be at the
Investigator’s discretion in consultation with the Sponsor.
• All AEs should be followed until the AE is considered resolved/stabilized.
The clinical judgement of the Investigator, in consultation with the Medical Monitor and
Sponsor, will determine whether a participant should be discontinued from treatment due to an
AE.
9.3 Reporting Adverse Events of Special Interest and Serious Adverse Events
9.3.1 All AESIs and SAEs
All AESIs and SAEs must be promptly reported by the Investigator to the Sponsor, or designee,
within 24 hours from the time when the Investigator first becomes aware of the event. All AESIs
and SAEs must be reported, in the AE eCRF in the EDC whether or not they are considered
causally related to the study procedure or investigational product. Back-up paper AESI and SAE
report forms (provided by the Sponsor, or its designee to each clinical site) should be used in the

event that the EDC is down. Once the EDC is available, the site will be responsible for adding
AESI/SAE details.
The information collected in the AE eCRF must include the participant number, a narrative
description of the event, and an assessment by the Investigator (or designee as appropriate) as to
the intensity of the event and relatedness to the investigational product and procedures. The
Investigator must complete, sign and date the SAE pages, and verify the accuracy of the
information recorded against the corresponding source documents. Follow-up information on the
AESI and/or SAE may be requested by the Sponsor or its designee. Follow-up information on
AESIs and SAEs should also be entered into the EDC in the AE eCRF.
The reporting process for all death events and pre-defined disease specific laboratory values and
events that are potentially endpoint can be found in Section 9.7.
All SAEs that have not resolved by the end of the study, or that have not resolved after a
reasonable time following the discontinuation of treatment, must be followed until any of the
following occurs:
• The event resolves
• The event stabilizes
• The event returns to Baseline if a Baseline value is available
• It becomes unlikely that any additional information can be obtained (participant
or health care practitioner inability to provide additional information, lost to
follow-up after demonstration of due diligence with follow-up efforts).
9.3.2 Pregnancies
Pregnancy is neither an AE nor an SAE, unless a complication relating to the pregnancy occurs.
If a pregnancy complication meets the seriousness criteria, it should be reported as an SAE (i.e.
all reports of congenital abnormalities/birth defects are SAEs). Spontaneous miscarriages should
be reported and handled as SAEs (Section 9.3). However, elective abortions without
complications should not be handled as AEs.
All pregnancies experienced by female participants or female partners of male participants

enrolled in this study are to be reported in the same time frame as AESIs and SAEs using the
Pregnancy Form of the eCRF. Back-up paper pregnancy report forms (provided by the Sponsor,
or its designee to each clinical site) should be used in the event that the EDC is down. Once the
EDC is available, the site will be responsible for adding pregnancy details.

The course of all pregnancies, including perinatal and neonatal outcome, regardless of whether
the participant has discontinued treatment or withdrawn from the study, will be followed until
resolution, including follow-up of the health status of the newborn to a minimum of 6 weeks of
age.
Contact information for reporting pregnancies in all countries can be found in the site study
reference manual.
9.4 Reporting Serious and Unexpected Suspected Adverse Reactions
If there are serious, and unexpected suspected adverse reactions (SUSARs) associated with the
use of the investigational product, the Sponsor, or its designee, will notify the FDA and other
regulatory authorities, and all participating Investigators on an expedited basis and in accordance
with applicable regulations. It is the responsibility of the Investigator to promptly notify the
IRB/EC and other appropriate institutional regulatory bodies of all unexpected serious adverse
drug reactions involving risk to participants.
9.5 Other Significant Adverse Events

9.5.1 SAEs and AEs Leading to Premature Discontinuation
Significant events of particular clinical importance include SAEs and AEs leading to premature
discontinuation of participants from the study. These events will be recorded in the participants’
medical records as well as the AE CRF (as applicable) provided by the Sponsor or its designee.
Narratives of these events may be prepared for inclusion in the Clinical Study Report.
9.5.2 Definition of AEs of Special Interest (AESI)

AEs of Special Interest (AESI) are any Investigator assessed percutaneous kidney biopsy/sham
biopsy and percutaneous REACT/Sham injection procedure-related events. Information related
to AESIs should be specifically collected from the time a participant enters the clinical facility
and is under the care of the clinical research team for the percutaneous kidney biopsy or
percutaneous REACT injection procedures. AESIs include pre-, peri- and post procedure events,
reported at the discretion of the Principal Investigator. Acute AESIs typically occur prior to
discharge from the clinical facility. Other AESIs may be identified and reported during routine
follow-up visits. Participants should be carefully monitored for the occurrence of potential
AESIs.
Procedure-related SAEs assessed as causally related to REACT/Sham injections (not to

REACT/Sham product) will not be reported as a SUSAR since procedure complications are not
unanticipated. The events are routinely monitored as part of benefit/risk assessment.

Please see below for common AESI examples:
9.5.2.1 Procedure-Related Pain

If the participant experiences pain following the biopsy or REACT injection, management will
be determined per site standard of care and based upon clinical assessment. More severe pain in
the flank or abdomen requires ultrasonography to exclude significant perirenal hemorrhage. If
severe pain occurs, administration of opiates may be necessary. If analgesic doses higher than the
maximum authorized dose are required to alleviate pain, then the Investigator must perform
additional clinical evaluations to ascertain the probable cause(s) of excessive pain.
9.5.2.2 Post-Procedure Hemorrhage And Hematuria

Following renal biopsy and REACT injection procedures, participants undergo regular
hemoglobin and blood pressure monitoring. Participants will be confined to bed rest and
monitored for maintenance of normal coagulation indices. If bleeding occurs and the participant
is hypotensive despite bed rest, a blood transfusion may be considered. In rare cases, renal
angiography may be performed to identify the source of bleeding and vessel embolization can be
performed during the same procedure to manage bleeding. Hematuria from renal bleeding into
the collecting system may also occur as a result of the interventions and managed as appropriate
for signs and symptoms.
9.5.2.3 Other Procedure-Related Complications

In very rare cases, other organs (such as liver, gallbladder, and lungs) may be penetrated during
the biopsy and REACT injection procedures. In these cases, appropriate treatment and follow-up
may be discussed with consulting surgeons.
9.5.2.4 Post-Procedure Death

Deaths resulting from renal biopsies occur in <0.01% of participants. Participants who have
increased risk for bleeding and other complications are excluded from this study as outlined in
the eligibility criteria.
9.6 Adverse Event Intensity and Relationship Assessment

9.6.1 Intensity Scale
Intensity will be assessed by the Investigator using the US National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

(refer to
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf).
If the AE is not included in the CTCAE, then the Investigator will determine the intensity of the
AE according to the following criteria:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL).
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADL.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
If the Grade changes within a day, the maximum Grade should be recorded.
It is important to distinguish between seriousness and Grade of AEs. Severity is a measure of

intensity (Grade) whereas seriousness is defined by the criteria under Section 9.1. Therefore, a
high intensity AE may not necessarily meet the criteria for seriousness.
9.6.2 Relationship Causality

The Investigator must assess the relationship between study treatment and occurrence of each
AE/SAE. The Investigator should judge whether there is a reasonable possibility that the AE may
have been caused by the study procedure or investigational product.
Adverse events related to the study procedure will be further assessed as due to:
• Needle insertion process at the time of biopsy or injection or skin nick during
sham procedures or
• Events associated with the procedure include but not limited to, conscious
sedation, allergic reactions, participant transfer to or from the CT scanner or
procedure bed.

Definitions of relatedness categories are:
Not Related: Exposure to the study treatment or investigational product did not occur, or the
occurrence of the AE is not reasonably related in time, or the AE is considered unlikely to be
related to the study treatment or investigational product.
Unlikely Related: Exposure to the study treatment or investigational product and the AE were
not closely related in time, and/or the AE could be explained more consistently by causes other
than exposure to the study treatment or investigational product.
Possibly Related: Exposure to the study treatment or investigational product and the AE were
reasonably related in time, and the AE could be explained equally well by causes other than
exposure to the study treatment or investigational product.
Related: The study treatment or investigational product and the AE were reasonably related in
time, and the AE was more likely explained by exposure to the study treatment product than by
other causes, or the study treatment product was the most likely cause of the AE.
For the purpose of safety analyses, all AEs judged by the Investigator to be “possibly related” or
“related” will be considered treatment-related AEs.
9.7 Events That Are Potential Study Efficacy Endpoints

9.7.1 Pre-Defined Disease-Related Primary Efficacy Endpoint Events
The pre-defined disease-related primary efficacy endpoint events (except death; see Table 9) will
not be entered into EDC (eCRF) or subject to SUSAR reporting because they are not
unanticipated in this study population. To protect the integrity of the trial, these endpoint events
(except death) will not be unblinded or reported to either Health Authorities (HAs) or
investigators as safety reports unless otherwise requested by HAs or Ethics Committees. After
study completion, these events will be included in the final analysis which will be unblinded and
submitted to HAs with the study report.

Table 9: Study Events, Endpoints, and Regulatory Reporting

Primary Efficacy Endpoints Subject to Regulatory Reporting of AE/SAE
At least 40% reduction in eGFR sustained for
Should not be reported as AE/SAE
30 days
eGFR < 15ml/min/1.73m2 sustained for 30 days Should not be reported as AE/SAE
Dialysis is a procedure not AE/SAE. AE/SAE leading
Chronic dialysis to dialysis other than above endpoints will be reported
as AE/SAE.
Renal transplant is a procedure not AE/SAE. AE/SAE
Renal transplant leading to renal transplant other than above endpoints
will be reported as AE/SAE.
All deaths will be reported as SAE, and subject to
Renal or cardiovascular death. regulatory reporting if SUSAR criteria is met.
Reporting will not wait for EAC adjudication.
9.7.2 Fatal Events

All deaths (including renal and cardiovascular death) should be handled as follows:
The Investigator must report all fatal events in the AE page of eCRF to the Sponsor within
24 hours of knowledge of the event.
Fatal events that are considered possibly related or related to investigational product by the
Investigator, will be subject to reporting requirements to HAs, and will be unblinded where
required by local regulations. The number of fatal SUSAR events which are also efficacy
endpoints are expected to be low. The unblinding of these cases will not jeopardize the integrity
of the trial. Such events will be reported to Investigators in the same manner as fatal SUSARs as
required by local regulations.
9.7.3 Adjudication Package

Investigators are required to submit a specific package of information on all such possible events
(including deaths) for adjudication (see 9.12); details on assembly and submission of
adjudication packages are listed in the Adjudication Manual.
9.8 Data Monitoring Committee

A Data Monitoring Committee (DMC) will be chartered to ensure the safety of participants
enrolled in this study, especially as it relates to unexpected investigational product-related
events. Details regarding the committee members, roles and responsibilities, and procedures will
be outlined in the charter. The DMC will function independently, and its members will have no
other engagement with the Sponsor.

9.9 Endpoint Adjudication Committee

An independent Endpoint Adjudication Committee (EAC) will be chartered to adjudicate the
primary efficacy endpoints. The EAC is composed of external specialists who will review and
adjudicate the primary efficacy endpoints experienced by study participants. The EAC members,
responsibilities, and procedures will be outlined in a charter. Events potentially meeting the
primary endpoint will be adjudicated. Additional events for adjudication may be added to the
charter.
Investigators are expected to report any event that they assess as potentially being a component
of the primary endpoints and any additional endpoints in the charter that require
adjudication. Potential endpoints may also be identified by the Sponsor and/or CRO.
If any eGFR or other laboratory value obtained through a local laboratory potentially meets
adjudication requirements, the laboratory test should be confirmed by repeat central laboratory
measure 30 days for eGFR.
The EAC will assess these events according to the committee’s charter and will independently
classify the events while blinded to treatment assignment.
9.10 Additional Sponsor-Specific Reporting Conventions

In general, Investigators should report diagnoses as the verbatim term/adverse event term within
the adverse event case report form or paper SAE report form. In all instances, the most specific
medical term befitting the medical diagnosis of a clinical entity should be reported on the eCRF
form. For example, if a participant experienced ventricular tachycardia, then “ventricular
tachycardia” should be reported on the eCRF entry/AE report form. It would not be appropriate
to enter separate events of arrhythmia, tachycardia, and ventricular tachycardia on the eCRF.
Another example is hematoma, post-procedural hematoma and subcapsular hematoma should be
consolidated under the verbatim “subcapsular hematoma”. While it is ultimately medical
judgement, safety reporting and aggregate signal analysis hinge on representing a medical entity
with the single best, most specific MedDRA code available.
Upon commencement/initiation of dialysis, dialysis should be reported to the Sponsor (or

designee) via the dialysis eCRF within the EDC. Dialysis is a procedure and should not be
reported as a SAE; rather the rationale for dialysis should be reported as a SAE if the reason for
initiating dialysis is not related to one of the pre-defined disease efficacy endpoints (Table 9)
(i.e., Dialysis was commenced for fluid overload, fluid overload should be reported as a SAE and
dialysis should be recorded on the dialysis eCRF page).

Renal transplantation is a medical/surgical intervention and should not be reported as an SAE.

However, the rationale for the transplant should always be reported as a SAE if not one of the
pre-defined disease efficacy endpoints (see Table 9). Details for the renal transplantation should
be captured in the EDC on the transplant eCRF page.
In general, procedures should not be reported as SAEs. However, if the rationale for the
procedure is unknown the procedure itself should be reported as default. Investigational sites
should make all efforts to acquire necessary information for SAE reporting.
9.10.1 Special Note on Reporting Acute Kidney Injury (AKI)

CTCAE v5 defines AKI as a disorder characterized by the acute loss of renal function (within
2 weeks) and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney
damage) and post-renal causes (ureteral or bladder outflow obstruction). The grading of severity
of AKI has evolved and CTCAE v5 reports all AKI at grade 3 and above (no grade 1 or 2) as
follows:
Table 10: AKI CTCAE Grade Scale

Grade 1 -
Grade 2 -
Grade 3 Hospitalization indicated
Life threatening consequences:
Grade 4
dialysis indicated
Grade 5 Death
CTCAE V 5
For this study, please capture AKI events according the CTCAE v5 grading as noted above.
10 STOPPING RULES: TREATMENT, PARTICIPANTS, STUDY

10.1 Stopping Rules for an Individual Participant
The Investigator, DMC, and Sponsor may discontinue treatment for any participant for any AE,
laboratory abnormality, intercurrent illness, other medical condition, or situation whereby
continued treatment would not be in the best interest of the participant. However, participants
should be encouraged to continue all subsequent visits for safety and efficacy evaluations.
If any of the following events occur at a site, no additional participants at that site can receive
REACT injections until review by the DMC has been completed for the clinical site in question:

• An SAE that is rated as life-threatening and, in the judgement of the Investigator,

is related to REACT or study procedures.
• Death of an enrolled participant deemed related to REACT product or REACT
Injection Procedure.
• Similar SAEs in more than one participant at a site that are related to REACT, in
the judgement of the Principal Investigator.
10.2 Study Suspension or Termination

The Sponsor or designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies
have been collected and a study-site closure visit has been performed.
For site termination:

• Failure of the investigator to comply with the protocol, the requirements of the
IRB/EC or local health authorities, the sponsor’s procedures, or GCP guidelines.
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of
participants.
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the
Investigators, the ECs/IRBs, of the reason for termination or suspension The Investigator shall
promptly inform the participant and should ensure appropriate participant therapy and/or
follow-up.
10.3 Global Trial End Date

The Global Trial End Date (GTED) will be set by the Sponsor once 122 Primary Endpoint events
have occurred.
11 STATISTICAL METHODS AND PLANNED ANALYSES

A general description of the statistical methods to be used to analyze the efficacy and safety data
is outlined below. All efficacy and safety analyses will be performed using laboratory data
collected from the Central Laboratory, and no local results will be summarized. Specific details
will be provided in the Statistical Analysis Plan (SAP).

11.1 Determination of Sample Size

The sample size of approximately 685 participants was selected based on considerations for
powering the primary endpoint and assuming 9.5% of participants drop out. Participants will be
randomized 1:1 to Cohort 1 (sham) and Cohort 2 (REACT), stratified for eGFR
(< 25 vs ≥ 25 mL/min/1.73m²) and SGLT2i use (yes vs no) at Screening, using a permuted block
design.
This sample size with 122 events at the final analysis will have at least 80% power to detect a
difference in the primary endpoint assuming an actual hazard ratio of 0.60 and a log-rank test at a
one-sided statistical significance level of 2.5%. Moreover, this assumes non-uniform accrual
accounting for a study start-up ramp up period and the annual incidence of 13% in the SHAM
cohort. The software PASS Version 23.0.2 was applied for the sample size computations.
Sample size-re-estimation may be performed to reassess the sample size in case of an
underestimated variability postulated at the design stage in a blinded, non-binary futility test.
11.2 Determination of Baseline for Analyses

For efficacy analyses: Baseline will be defined as the last non-missing measurement taken prior
to the first REACT/Sham injection procedure excluding Biopsy+1 Day.
For safety analyses of biopsy/sham Baseline will be defined as the last non-missing
measurement taken prior to the biopsy/sham biopsy procedure.
For safety analyses of injection/sham: Baseline will be re-baselined and defined as the last
non-missing measurement taken prior to first REACT/Sham injection procedure excluding
Biopsy+1 Day.
11.3 Planned Analyses

Only a final analysis of the Primary Efficacy Endpoint and the Secondary Efficacy Endpoints is
planned for this study. An interim analysis will not be performed.
The primary analysis will occur when a minimum of 122 primary efficacy endpoints have been
accrued from the total participant population comprised of Cohort 1 and Cohort 2.

The null and alternative hypothesis to be tested at the final analysis is:
H0i: ∆HRi = 1 vs. Hai: ∆HRi < 1
for i =1, where ∆HRi denotes the hazard ratio for the primary efficacy endpoint between the
REACT and SHAM cohorts and the hypotheses H1 = (H01, Ha1) is associated with the treatment
comparisons on the primary efficacy endpoint.
A multi-testing procedure to control the type I error will be defined in the SAP.
11.3.1 Demographics and Other Screening Characteristics

Demographic and other screening characteristics will be summarized via number of participants,
mean, standard deviation, median, minimum, and maximum, as well as Q1, Q3 where
applicable, for the continuous variables as well as the frequency and percentage for categorical
variables.
11.3.2 Study Exposure (Biopsy/sham, REACT/sham Injection(s)

The number of participants who received a biopsy/sham biopsy, total number of REACT/Sham
injections received, and the total volume of REACT injected will be summarized.
11.4 Efficacy Analyses

11.4.1 Primary Efficacy Endpoint Analyses
The primary efficacy endpoint analysis will be a test of the Hazard Ratio (HR) of REACT vs.
sham injections in a stratified Cox proportional hazards regression analysis (defined in
Section 3).
The model will contain cohort and stratification factors as covariates. Other covariates may be
considered, as appropriate. The proportional hazards assumption will be verified. Further details
will be specified in the statistical analysis plan.
11.4.2 Secondary Efficacy Endpoints Analyses

The secondary efficacy endpoint analyses will include:
Annualized Change in eGFR: The change in annualized eGFR between the REACT and sham
injections are estimated using a class of mixed effects model based on a single slope after

receiving the 1st injection adjusting for stratification factors and other covariates, as
appropriate.60 To account for between participant variability in eGFR trajectories, random slopes
and intercepts will be included. Further details will be specified in the statistical analysis plan.
Additional Time to Event Analyses: The following time-to-event endpoints below will be
analyzed in a similar fashion to the primary efficacy analysis.
• The time from first injection to at least 40% reduction in eGFR, sustained for 30
days.
• The time from first injection to eGFR < 15 mL/min/1.73m² sustained for 30 days
Changes from Baseline in Patient-Reported Outcomes from the Kidney Disease Quality of Life
(KDQOL) and EuroQol 5-Dimension 5 Level (EQ-5D-5L) Surveys:
The KDQOL-SF™ 36 item survey is a validated health-related quality-of-life instrument relevant
to participants with kidney disease. These subscales will be used in this clinical study: 1) SF-12
measure of physical and mental functioning, 2) Burden of Kidney Disease, 3) Symptoms and
Problems, 4) Effects of Kidney Disease on Daily Life.
The EQ-5D-5L instrument assesses 5 dimensions: mobility, self-care, usual activities,

pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems,
slight problems, moderate problems, severe problems, and extreme problems) that reflect
increasing levels of difficulty. The participant will be asked to indicate his/her current health
state by selecting the most appropriate level in each of the 5 dimensions. The EQ-5D-5L
instrument also includes a visual analog scale, where the participant will be asked to rate their
current health status on a scale of 0 to 100, with 0 being the worst imaginable health state and
100 being the best imaginable health state. 61
• Observed values and changes from baseline in each score will be summarized by
cohort and visit using descriptive statistics. The treatment effect will be estimated
using data from each scheduled time point. This will be fit using a mixed effect
model for repeated measures, with terms for cohort, visit, and stratification factors
as covariates. Further details will be specified in the statistical analysis plan.
11.4.3 Exploratory Efficacy Endpoints Analyses

The exploratory endpoints are listed in Section 3.3 and their analyses are in the SAP.

11.5 Safety Analyses

Safety assessments will include but are not limited to adverse events, clinical laboratory
assessments, vital signs, imaging, physical exam assessments, and electrocardiogram
assessments. No hypothesis testing will be performed.
11.5.1 Adverse Events

Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
version 26.1 (or later) by System Organ Class (SOC) and Preferred Term (PT). Adverse events
will be graded using NCI CTCAE version 5.0 or later. If the AE is not included in the CTCAE,
then the Investigator will determine the intensity of the AE.
Adverse events analysis periods will be defined based on the adverse event start date:
• Pre-biopsy period: from the date of randomization to the start day of
biopsy/sham biopsy.
• Pre-injection period: from the start day of biopsy/sham biopsy to the first
REACT/Sham injection.
• Post-injection period: from the first REACT/Sham injection to trial withdrawal
or completion.
The incidence of AEs and TEAEs will be calculated in terms of the total number of participants
(frequency counts and percentages) by cohort. Overall, AE summaries may be presented by SOC
and PT or PT alone. Additional summaries will include, but are not limited to, AEs by
relationship, AEs by intensity, AEs leading to discontinuation, SAEs, and deaths. Further details
will be specified in the statistical analysis plan.
11.5.2 Laboratory Evaluations

Observed values and change from baseline laboratory assessments will be summarized by cohort
and visit by number of participants, mean, standard deviation, median, minimum, and maximum
for the continuous variables as well as frequency and percentages for the categorical variables.
Clinically significant laboratory abnormalities will be presented by cohort in shift tables using
the same analysis periods defined for AEs.
11.5.3 Vital Signs Evaluations

Descriptive statistics will be used to summarize vital sign parameters (Weight (kg), derived BMI
(kg/m2), Heart Rate (bpm), Respiratory Rate, Oxygen Saturation, Pain Scale, Body Temperature
(⸰C), Systolic Blood Pressure (mmHg), and Diastolic Blood Pressure (mmHg)) at baseline and

each post-baseline visit, including post procedure assessments (excluding temperature), and
change from baseline to each post-baseline visit by cohort. Three blood pressure measurements
for systolic and diastolic pressure will be taken and the average of the 3 measurements will be
summarized.
11.5.4 Electrocardiogram Evaluations

Descriptive statistics will be used to summarize electrocardiogram parameters (HR (bpm), PR
(PQ) Interval (msec), RR interval (msec), QRS Interval (msec), QT Interval (msec), QTc Interval
(msec), QTcF Interval (msec)), at baseline and each post-baseline visit, and change from baseline
to each post-baseline visit by cohort. Overall interpretation will also be summarized by study
visit.
11.5.5 MRI and CT Imaging

The actual change from baseline values for measurements of cortical thickness, and volume for
each kidney will be summarized descriptively at each time point.
11.5.6 Renal Ultrasound Imaging Evaluations

The number and percentage of participants with abnormalities present on the safety ultrasound
will be summarized by cohort and visit.
11.6 Analysis Sets

The Intent-to-Treat (ITT), Modified Intent-to-Treat (mITT), Safety Analysis Set (SAF), and
Biopsied Analysis Set (BS) will be used to evaluate this study.
Efficacy analyses may be conducted using both the ITT and mITT analysis sets, if different.
Safety analyses may be conducted using both the SAF and BS analysis sets. Further details
regarding the plan for the comprehensive analysis of REACT will be provided in the SAP.
Table 11: Analysis Set Definitions and Use

Analysis Set Definition How Analyzed Use
The ITT is all participants randomized, According to Efficacy analyses –
Intent-to-Treat
participants who discontinue study prior to randomized As the main
(ITT)
biopsy/sham biopsy will be excluded. treatment assigned efficacy analysis set
Modified According to
The mITT is all participants randomized who have
Intent-to-Treat randomized Efficacy analyses
received at least 1 REACT or sham injection.
(mITT) treatment assigned

Analysis Set Definition How Analyzed Use

Safety
The SAF is all participants randomized who have According to actual
Analysis Set Safety analyses
received at least 1 REACT or sham injection. treatment received
(SAF)
Biopsied
The BS is all participants randomized who had a According to actual
Analysis Set Safety analyses
biopsy or sham biopsy. treatment received
(BS)
11.7 Objectives, Endpoints, and Estimands

In tabular format, the Objectives, Endpoints, and their Estimands (treatment conditions,
population, intercurrent events, and summary measure) are shown in Appendix Table A3- 1.
See Section Primary Estimand and Section Primary Main Estimator Sensitivity Analyses for
estimand discussions and rationales.
12 ETHICAL AND REGULATORY CONSIDERATIONS

12.1 Good Clinical Practice
This study will be conducted in compliance with the protocol, in accordance with the ICH E6
Harmonised Guideline (ICH-GCP), in general agreement with the most recent version of the
Declaration of Helsinki, and in accordance with all applicable national competent authorities and
their governing regulations.
12.2 Delegation of Principal Investigator Responsibilities

The Investigator will ensure that all persons assisting with the study are adequately informed
about GCP requirements, the protocol, any amendments to the protocol, the study treatments as
well as their study-related duties and functions. The Investigator will maintain a list providing
the names, positions, signatures, and initials of sub-Investigators as well as other appropriately
qualified personnel, including those authorized to make entries and corrections on the eCRF.
12.3 Institutional Review Board/Ethics Committee

The final study protocol, Investigator’s Brochure, participant Informed Consent Form,
participant recruitment materials (if applicable), and patient-reported questionnaires/surveys (if
applicable), including respective version dates, must be approved, or given a favorable opinion
in writing by an IRB/EC as appropriate. A copy of the written approval must be provided to the
Sponsor. This documentation should clearly mention the approval/favorable opinion of the
protocol, the participant Informed Consent Form, participant recruitment materials (if
applicable), and patient-reported questionnaires/surveys (if applicable) along with the
respective version dates. The written approval and a list of current membership, or Department

of Health and Human Services Assurance Number, or letter from the IRB/EC stating that the
membership list is on file, must be provided to the Sponsor prior to the release of clinical study
supplies to the investigational site and commencement of the study. If any member of the
IRB/EC has direct participation in this clinical study, written notification regarding his or her
abstinence from voting must also be obtained.
The Investigator must inform the IRB/EC of any amendment to the protocol, provide updates
about the ongoing study at intervals (at least annually) specified by the respective IRB/EC, and
submit final study reports to the IRB/EC. In addition, the IRB/EC must approve all advertising
used to recruit participants for the study along with any written information to be provided to
participants (e.g., diaries, calendars, patient-reported surveys) and updates to the Informed
Consent Form.
It is the Investigator’s responsibility to notify the IRB/EC of all SAEs that occur at his or her site.
The Sponsor is responsible for notifying the relevant regulatory authorities of certain safety
events, including unexpected, serious, drug-related adverse reactions that occur during the
clinical study. The Investigator is responsible for notifying its IRB/EC of these unanticipated
SAEs.
Initial IRB/EC approval, and all materials approved by the IRB/EC for this study including the
participant consent form and recruitment materials must be maintained by the Investigator and
made available for inspection.
12.4 Participant Informed Consent

Informed consent is a process that is initiated prior to the individual’s agreeing to participate in
the study and continuing throughout the individual’s study participation. The Investigator will
ensure that potential participants (and their families) are given full and adequate oral and written
information about the nature, purpose, possible risk(s) and benefit(s) of the study. IRB/EC-
approved consent forms explaining study procedures and the investigational product(s)and/ or
intervention(s) will be provided. The Investigator will explain the research study and answer any
questions that may arise. Potential participants should have sufficient time to discuss the study,
ask questions, and process the information during the consent process before deciding whether or
not to participate.
The rights and welfare of potential participants will be protected by emphasizing that the quality
of their medical care will not be adversely affected should they decide not to participate in the
research study. Those individuals who agree to enroll must sign and date the current version of

the Informed Consent Form prior to starting any study-related procedures, including Screening.
Participants may withdraw consent at any time throughout the course of the clinical study
without penalty or prejudice toward future medical care.
The acquisition of informed consent will be documented in the participant’s medical records, as
required by 21 CFR 312.62 / ICH E6. The Informed Consent Form will be signed and personally
dated by the participant and the person who conducted the informed consent discussion. A copy
of the signed Informed Consent Form must be given to the participant while the original, signed
Informed Consent Form must be retained by the Investigator in the Investigator Site File.
12.5 Participant Confidentiality

Individual participant medical information obtained as a result of this study is considered
confidential. Only after the participant approves, may such confidential medical information be
given to his/her physician or to other appropriate medical personnel responsible for the
participant’s well-being. The Sponsor affirms the participant’s right to protection against
invasion of privacy. Only a participant identification number and/or initials (where allowed by
local or national regulations) will identify participant data retrieved by the Sponsor. However,
the Investigator is required to allow the Sponsor, its designated representative(s), the IRB/EC,
and when necessary, representatives of the regulatory health authorities to review and/or to copy
any medical records relevant to the study.
12.6 Protocol Deviations

A protocol deviation is any non-compliance with the protocol or GCP requirements. The non-
compliance may be attributed to the participant, the Investigator, or the site staff. All protocol
deviations will be documented and reported by the monitor during the course of the study as
described in the Protocol Deviation Plan. The CRO and/or Sponsor will work with the site to
develop and implement any corrective actions to address protocol deviations, as appropriate.
Note: serious breaches of the protocol that are likely to significantly affect the safety of a
participant or the integrity of the data generated must be reported to the Sponsor, IRB/EC, and
applicable regulatory authorities.
13 DATA HANDLING AND RECORDKEEPING

13.1 Data Collection
The Sponsor or its designee will provide the clinical sites with access to CRFs managed within
the EDC for each participant. An eCRF must be completed for every participant who provides
written, informed consent and has undergone at least one protocol-specified, study-specific

assessment. Case report form completion instructions are provided to the site. The Investigator or
designated representative should complete the eCRFs as soon as possible after the information
has been documented in the participant source materials. The Investigator is responsible for
ensuring the accuracy, completeness, and timeliness of the data reported in a participant’s eCRF.
Source documentation supporting the eCRF data should indicate the participant’s participation in
the study and document the dates and details of study procedures, AEs, participant status, and
any other study-related relevant information.
When a participant completes the study, the Investigator must review and sign the eCRF
indicating that he/she has reviewed the completed eCRF and pertinent clinical data for that
participant and that, to the best of his/her knowledge, all data recorded in the eCRF accurately
reflect the participant’s clinical performance in the study.
All clinical study information is recorded, processed, handled, and stored by the Sponsor and or
designated vendors, in such a way that it can be accurately reported, interpreted, and verified
while the confidentiality of records and the personal data of the participants remain protected in
accordance with the applicable law on personal data protection. Appropriate technical and
organizational measures have been implemented to protect information and personal data
processed against unauthorized or unlawful access, disclosure, dissemination, alteration, or
destruction or accidental loss. Data collection on participants does include basic demographic
information such as age, gender, ethnicity, and existing comorbidities for the purposes of
identification of any imbalance between cohorts after randomization as well as for monitoring
for any desirable or undesirable product effects within sub-groups of the study population.
13.2 Study Monitoring

The Monitor will perform source data verification, including a comparison of the data in the
eCRF with the participant’s medical records at the hospital or clinic, and other records relevant
to the study. Source data verification requires direct access to all original records for each
participant. The review of medical records will be performed in a manner that ensures participant
confidentiality.
In addition, the Sponsor or its designee will be allowed to conduct site visits to the
investigational facilities for the purpose of monitoring any aspect of the study. The Investigator
agrees to allow the monitor to inspect the investigational product storage area, investigational
product records, participant charts, study source documents, and other records relative to study
conduct.

13.3 Audits and Inspections

The purpose of an audit or inspection by the Sponsor, regulatory authorities, the IRB/EC, or
other appropriate institutional bodies is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and the
data were recorded, analyzed, and accurately reported, in accordance with the protocol, ICH-
GCP, and any applicable regulatory requirements. The Investigator and the site/institution must
provide support at all times for on-site audits or inspections by providing direct access to all
source documents, eCRFs, and other study documentation. The Investigator must notify the
Sponsor or its designee immediately if contacted by a regulatory agency about an inspection.
Regulatory authorities and the IRB/EC may request access to all source documents for on-site
inspection. Likewise, the Sponsor or designee may conduct a quality assurance audit to ensure
compliance with GCP and all applicable regulatory requirements.
13.4 Retention of Records

The Investigator agrees to keep records and those documents that include (but are not limited to):
the identification of all consented participants; medical records; study-specific source
documents; source worksheets; all original signed and dated Informed Consent Forms; records of
any body fluids or tissue samples retained; query responses; and detailed records of
investigational product accountability to enable evaluations or audits from regulatory authorities,
the Sponsor, or its designees.
These documents are to be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of
clinical development of the investigational therapy, or a longer document retention timeframe,
according to country specific requirements and investigator agrees to keep these records as
applicable. If the Investigator cannot meet this obligation, he/she must ask the Sponsor for
permission to make alternative arrangements; details of these arrangements should be
documented. If the Investigator withdraws from the responsibility of retaining the study records,
custody must be transferred to a person willing to accept the responsibility. The Sponsor must be
notified in writing if a custodial change occurs.
14 QUALITY CONTROL AND QUALITY ASSURANCE

Independent quality control (QC) and clinical quality assurance (QA) systems are implemented
and maintained using written SOPs to ensure that the study is conducted, and data are generated,

documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the
applicable regulatory requirements.
15 FINANCIAL DISCLOSURE AND INSURANCE

15.1 Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial
information as requested to allow the Sponsor to submit complete and accurate financial
certification or disclosure statements to the appropriate regulatory authorities. Investigators are
responsible for providing information on financial interests during the course of the study and for
1 year after completion of the study.
15.2 Insurance
The Sponsor has obtained liability insurance, which covers this study as required by local law
and/or national regulations and/or ICH guidelines, whichever is applicable. The terms of the
insurance will be kept in the study files.
16 PUBLICATION POLICY
All information regarding the investigational therapy is the confidential property of the Sponsor.
The Investigator agrees to use this information to conduct the study and will not use it for other
purposes without written approval from the Sponsor. It is understood that there is an obligation
to provide the Sponsor with complete data obtained during the study. The Sponsor retains full
rights over any invention, discovery, or innovation, patentable or not, that may occur during the
conduct of the clinical study.
It is anticipated that the results of this study will be presented at scientific meeting(s) and/or
published in a peer-reviewed journal(s). A Publications Committee, composed of Sponsor
selected Investigators participating in the study and representatives from the Sponsor, will
oversee the publication and presentation of study results, which will reflect the experience of all
participating clinical sites.
The International Committee of Medical Journal Editors has adopted a trials-registration policy
requiring that all clinical studies be registered in a public database (such as ClinicalTrials.gov
and clinicaltrialsregister.eu) as a condition for publication in member journals. It is the
responsibility of the Sponsor to register this study in an acceptable clinical trial registry on or
before the onset of participant enrollment.

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Kid Intl Reports. 2021. https://doi.org/10.1016/j.ekir.2021.06.014.

18 APPENDICES

Appendix 1: Contraceptive Guidance and Collection of Pregnancy Information
1 WOMAN OF CHILD-BEARING POTENTIAL (WOCBP)

A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
2 WOMEN IN THE FOLLOWING CATEGORIES ARE NOT CONSIDERED WOCBP

1. Premenarchal
2. Premenopausal female with one of the following:
a. Documented hysterectomy.
b. Documented bilateral salpingectomy.
c. Documented bilateral oophorectomy.
d. Note: Documentation can come from the study center personnel’s: review of the
participant’s medical records, medical examination, or medical history interview.
3. Postmenopausal female:
a. A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle-stimulating hormone (FSH) level in the
postmenopausal range may be used to confirm a postmenopausal state in women not
using hormonal contraception or hormonal replacement therapy (HRT). However, in
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
b. Females on HRT and whose menopausal status is in doubt will be required to use one
of the non-estrogen hormonal highly effective contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before study enrollment.
3 CONTRACEPTION GUIDANCE
3.1 Male Participants
Male participants with female partners of child-bearing potential are eligible to participate if they
agree to ONE of the following for the duration of the study.
1. Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent
on a long-term and persistent basis) and agree to remain abstinent.
2. Agree to use a male condom plus partner use of a contraceptive method with a failure rate of
<1% per year as described in the table below when having penile-vaginal intercourse with a
woman of child-bearing potential who is not currently pregnant.

• In addition, male participants must refrain from donating sperm throughout the
duration of the study.
• Male participants with a pregnant or breastfeeding partner must agree to remain
abstinent from penile-vaginal intercourse or use a male condom during each
episode of penile penetration throughout the duration of the study.
3.2 Female Participants

Female participants of child-bearing potential are eligible to participate if they agree to use a
highly effective method of contraception consistently and correctly as described in the table
below.
4 HIGHLY EFFECTIVE CONTRACEPTIVE METHODS

Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb
• Oral.
• Intravaginal.
• Transdermal.
Progestogen only hormonal contraception associated with inhibition of ovulation
• Oral.
• Injectable.
Highly Effective Methods That Are User Independent a
Implantable progestogen only hormonal contraception associated with inhibition of ovulation b
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Bilateral tubal occlusion.
Vasectomized Partner
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly
effective method of contraception should be used.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-vaginal
intercourse as their usual and preferred lifestyle (abstinent on a long-term and persistent basis) and agree to
remain abstinent.
NOTES:
a. Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent
with local regulations regarding the use of contraceptive methods for participants participating in clinical
studies.
b. For females of child-bearing potential, a highly effective method of contraception should be utilized
throughout the duration of the study.

5 PREGNANCY TESTING
• WOCBP should only be included after a negative highly sensitive urine pregnancy
test.
• Additional pregnancy testing should be performed at times specified in the schedule
of assessments.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is
otherwise suspected.
• Pregnancy testing will be performed at the site using a test-strip and if positive, a
confirmatory hCG test will be performed by a certified laboratory. If site practices do
not accept the results of a test-strip, a urine sample will be analyzed by the central
laboratory.
6 COLLECTION OF PREGNANCY INFORMATION

6.1 Male Participants with Partners who Become Pregnant
• The Investigator will attempt to collect pregnancy information on any male
participant’s female partner who becomes pregnant while the male participant is in
this study. This applies only to male participants who receive REACT.
• After obtaining the necessary signed informed consent from the pregnant female
partner directly, the Investigator will record pregnancy information on the appropriate
form and submit it to the Sponsor within 24 hours of learning of the partner’s
pregnancy. The female partner will also be followed to determine the outcome of the
pregnancy. Information on the status of the mother and child will be forwarded to the
Sponsor. Any termination of the pregnancy will be reported regardless of fetal status
(presence or absence of anomalies) or indication for the procedure.
6.2 Female Participants who Become Pregnant

• The Investigator will collect pregnancy information on any female participant who
becomes pregnant while participating in this study. Information will be recorded on
the appropriate form and submitted to the Sponsor within 24 hours of learning of a
participant’s pregnancy. The participant will be followed to determine the outcome of
the pregnancy. The Investigator will collect follow-up information on the participant
and the neonate and the information will be forwarded to the Sponsor. Any
termination of pregnancy will be reported, regardless of fetal status (presence or
absence of anomalies) or indication for the procedure.

• While pregnancy itself is not considered to be an AE or SAE, any pregnancy

complication or elective termination of a pregnancy will be reported as an AE or
SAE. A spontaneous abortion is always considered to be an SAE and will be reported
as such.
• Any post-study pregnancy related SAE considered reasonably related to the study
treatment by the Investigator will be reported to the Sponsor as described in
Section 9.3.2. While the Investigator is not obligated to actively seek this information
in former participants, he or she may learn of an SAE through spontaneous reporting.
• Any female participant who becomes pregnant while participating in the study will
discontinue study treatment or be withdrawn from the study.

Appendix 2: Tables of Potential and identified Risks

Table A2- 1: Literature-Published Percutaneous Kidney-Biopsy-Related Complications
Literature - Published Reported/Expected
Adverse Event Incidence Risk Mitigation
Hematoma Study Target <10% -Clinical and Laboratory assessment
-Perinephric Ranges reported: -Assessment of coagulation laboratory values and
-Subcapsular 4.3%-17% 36, 62,63 CKD bleeding risks
-Intra-parenchymal -Real-time Image guided biopsy (Ultrasound or
-Retroperitoneal CT when indicated per proceduralist)
-Automated core needle biopsy device
-16- or 18-gauge device (largest gauges required)
-Post biopsy tract embolization (when indicated)
-Post procedure observation and 24 hr. follow-up
assessment
-Immediate post biopsy and follow-up renal
ultrasound evaluation during observation period
- Proceduralist Simulation video training with
credentialing, Sponsor Study Manuals, and 24/7
Interventional Proceduralist Network.
Blood transfusion <5% 44,51 -Inclusion/Exclusion Criteria Screening for
incapacitating comorbidities
-Clinical and Laboratory assessment
-Real-time Image guided biopsy (Ultrasound or
CT)
-Automated core needle biopsy device
-16- or 18-gauge automated biopsy device
-Post biopsy tract embolization (if indicated)
-Post procedure observation and 24 hr. follow-up
assessment
-Post procedure CBC
-Immediate post biopsy and delayed renal
ultrasound evaluation prior to discharge
-Proceduralist Simulation video training and
credentialing, training manual, 24/7 Interventional
Proceduralist Network.
Radiologic Intervention <0.5% 42,44 See blood transfusion.
Nephrectomy <0.1% 42,44 See blood transfusion.
Death <0.1% 36, 42, 63-65 See blood transfusion.
Cystoscopy <1% Post procedure CBC, urinalysis, renal ultrasound,
bladder ultrasound.
Hematuria <4% Post procedure urinalysis.


Hospital admission or <1% Post procedure observation and Post Biopsy Day 1
readmission clinic visit assessments will determine the need for
further tests, treatment(s) and hospitalization.
Pain* <5% 36 Post procedure observation and pain
-Nerve injury assessment/management and 24 hr. follow-up
-Flank and back assessment
-Referred to shoulder, abdomen * Pain is subjective and determined by visual or
and groin numeric measurements. Studies report pain
-Local pain at skin site estimates from 1-12% 36 and dependent on
subgroup analysis.
Infection <1% 24 hr. and follow-up clinic assessment.
-Retroperitoneal
-Pyelonephritis
-Subcutaneous
Puncture of adjacent structures <1 % Real-time imaging observation during biopsy.
Arterio-venous fistula <1% 46 Immediate post-biopsy and delayed renal
ultrasound evaluation.
Biopsy site complications <1% -Standard sterile skin preparation and draping
-Cutaneous bleeding techniques.
-Delayed bruising -Pre- and post-biopsy assessment and follow-up.
-Local infection
Intravenous line(s) <5% -Standard sterile skin preparation and IV-line
-IV infiltration insertion
-Infection -Pre- and post-biopsy assessment and follow-up.
-Phlebitis
-Bruising/swelling
Bladder symptoms Minor <5% Pre- and post-biopsy assessment and follow-up.
-Urinary retention Major <1% see
-Dysuria cystoscopy
GI Symptoms <1% Pre- and post-biopsy assessment and follow-up.
-Abdominal pain
-Nausea/vomiting
-Diarrhea
-Constipation
Cardiac Symptoms <1% Pre- and post-biopsy assessment and follow-up.
-Chest pain
-Arrythmia
-Bradycardia/Tachycardia
-Shortness of breath
-Peripheral edema
-Hypertension
-Hypotension


Cerebrovascular Symptoms <1% Pre- and post-biopsy assessment and follow-up.
-Strokes
-Transient ischemia
-Headaches
Pulmonary Symptoms Pneumothorax <1% Pre- and post-biopsy assessment and follow-up.
-Pneumothorax (ACR/SIR) 46
-Wheezing
-Cough
-Pneumonia
Other Miscellaneous <1% Post procedure observation and Post Biopsy Day 1
-Fever clinic visit.
-Falls
-Light-headedness
Local Anesthetic, Allergic reactions: none -Local anesthetic and moderation sedation
Intravenous moderate sedation, to date in Phase II medication allergy history and prior experiences
and general anesthesia Sedation reactions: None -Amount of anesthetic per body weight limit
to date in Phase II -Minimal sedation provided for participant comfort
General Anesthesia and to limit motion during cell injection
reactions: None to date in Post procedure observation for delayed sedation
Phase II effects.
-Anesthesia risks are multifactorial and dependent
on ASA class and assessment.

Table A2- 2: Expected Incidence of Adverse Events and Complications of Injection

Procedures Similar to the REACT Percutaneous Investigational Product Injection
Adverse Events in Similar Reported/Expected
Procedures Incidence Risk Mitigation
Hematoma Target <10% - Clinical and Laboratory assessment
-Perinephric Ranges reported: - Assessment of coagulation laboratory values and CKD
-Subcapsular 1.1 - 17% 36, 39, 63, 66 bleeding risks
-Intra-parenchymal - Real-time CT guided injection with intra-injection
-Retroperitoneal intermittent imaging and end of exam CT scan through
bilateral kidneys.
- Small-gauge outer guide needle
- Small-gauge inner atraumatic injection needle
- Slow injection rate, 1 mL/min
- Post procedure observation and follow-up renal
ultrasound evaluation prior to discharge and 24 hr. in-
clinic follow-up assessment and renal ultrasound
evaluation
- Post-procedure CBC and urinalysis
- Proceduralist Simulation video training with
credentialing, training manual guide, and 24/7
Interventional Proceduralist Network.
Blood transfusion <5% 36, 44 - Inclusion/Exclusion Criteria Screening for
incapacitating comorbidities
- Clinical and Laboratory assessment
- Real-time Image guided CT IP injection
- Post injection tract embolization (if indicated)
- Post procedure observation and follow-up renal
ultrasound evaluation prior to discharge and 24 hr. in-
clinic follow-up assessment and renal ultrasound
evaluation
- Post procedure CBC and urinalysis
- Immediate post injection CT and delayed renal
ultrasound evaluation
-Proceduralist Simulation video training and
credentialing, training manual, 24/7 Interventional
Proceduralist Network.
Radiologic Intervention <0.5% 42,44 See blood transfusion.
Nephrectomy <0.1% 42,44 See blood transfusion.
Death <0.1%% 36, 42, 63-65 See blood transfusion.
IP (REACT) extravasation <5% (predicted) -Intermittent real-time CT imaging during and post each
-extracapsular capsule puncture and cell injection deposit
-intra-arterial -Slow injection rate, 1 mL/min
-intra-venous -Renal ultrasound during post-injection recovery and
-urinary collecting system 24 hr. clinic follow-up.


Cystoscopy <1% Post procedure CBC, urinalysis, renal ultrasound,
bladder ultrasound.
Hematuria <4% Post procedure urinalysis. Post procedure observation
and assessment/management and 24 hr. and Post
Injection Day 1-28 follow-up assessments.
Hospital admission or <1% Post procedure observation period and Post Injection
readmission Day 1 clinic visit will determine whether further
treatment(s) or hospitalization is necessary.
Pain* <5% 36 Post procedure observation and pain
-Nerve injury assessment/management and 24 hr. follow-up
-Flank and back assessment
-Referred to shoulder, * Pain is subjective and determined by visual or numeric
abdomen and groin measurements. Studies report pain estimates from 1-
-Local pain at skin site 12% 36 and dependent on subgroup analysis.
Infection <1% 24 hr. and 7-28 day follow-up clinic assessments.
-Retroperitoneal
-Pyelonephritis
-Subcutaneous
Puncture of adjacent <1 % Real-time CT imaging observation during and
structures post-injection.
Arterio-venous fistula <1% 65 Immediate post-injection CT scan and delayed renal
ultrasound evaluation during observation
24 hr. and 7-28 day follow-up clinic assessments
including 24 hr. ultrasound evaluation.
Biopsy site complications <1% Standard sterile skin preparation and draping techniques
-Cutaneous bleeding Pre- and post-injection assessment and follow-up
-Delayed bruising 24 hr. and 7-28 day follow-up clinic assessments.
-Local infection
Intravenous line(s) <5% Standard sterile skin preparation and IV-line insertion
-IV infiltration Pre- and post-injection assessment and follow-up
-Infection 24 hr. and 7-28 day follow-up clinic assessments.
-Phlebitis
-Bruising/swelling
Bladder symptoms Minor <5% Pre- and post-injection assessment and follow-up
-Urinary retention Major <1% see 24 hr. and 7-28 day follow-up clinic assessments.
-Dysuria cystoscopy
GI Symptoms <1% Pre- and post-injection assessment and follow-up
-Abdominal pain 24 hr. and 7-28 day follow-up clinic assessments.
-Nausea/vomiting
-Diarrhea
-Constipation
Cardiac Symptoms <5% Pre- and post-injection assessment and follow-up


-Chest pain 24 hr. and 7-28 day follow-up clinic assessments.
-Arrythmia
-Bradycardia/Tachycardia
-Peripheral edema
-Hypertension
-Hypotension
Cerebrovascular Symptoms <1% Pre- and post-injection assessment and follow-up
-Strokes 24 hr. and 7-28 day follow-up clinic assessments.
-Transient ischemia
-Headaches
Pulmonary Symptoms Pneumothorax <1% Pre- and post-injection assessment and follow-up
-Pneumothorax (ACR/SIR) 48 24 hr. and 7-28 day follow-up clinic assessments.
-Wheezing
-Cough
-Pneumonia
Other Miscellaneous <1% 24 hr. and 7-28 day follow-up clinic assessments.
-Fever
-Falls
-Light-headedness
Local Anesthetic Allergic reactions: none -Local anesthetic and moderation sedation medication
Intravenous moderate to date in Phase II allergy history and prior experiences
sedation and general Sedation reactions: -Amount of anesthetic per body weight limit
anesthesia none to date in Phase II -Minimal sedation provided for participant comfort and
General Anesthesia to limit motion during cell injection
reactions: None to date -Post procedure observation for delayed sedation effects
in Phase II -Anesthesia risks are multifactorial and dependent on
ASA class and assessment.

Table A2- 3: Anticipated Investigational Product (REACT) Cell Complications

Anticipated Adverse Event Reported/Expected Incidence Risk Mitigation
Acute cell immunologic reaction • No definite causation • Vital sign monitoring
reported to date. during cell injection
• Incidence is unknown and • Slow injection rate and
attribute <1%. documentation of injection
• No definite cell adverse time
causation in multiple • CT scan at completion of
Phase I and II trials. each cell deposit and at end
• SUSAR event 1.5 hrs. of procedure
post injection concluded: • Post procedure observation
unlikely cell causation. and
assessment/management
and 24 hr. and Day 7-28
follow-up assessments
• Cell inflammatory markers.
Acute cell expansion in kidney • No obvious morphologic CT scan at completion of each cell
• Kidney tissue expansion changes identified during deposit and at end of procedure.
• Kidney capsule expansion CT scan following
injection.
• Transient asymptomatic
decreased blood pressure
observed at time of
injection with return to
normal pressure.
Allergic reaction Potential reaction to DMSO, • Allergy history
Dextran 40, aminoglycosides • Acute allergy assessment
and triage.
Latent cell changes Expect low potential risk for Renal MRI assessment during
tumorigenicity clinical trial start to end of study.
Renal vascular event, renal fibrosis Two SUSARs have been reported • Proceduralists are to avoid
or scarring, loss of glomerular indicating a potential for a renal areas previously biopsied or
filtration rate vascular event after the second REACT injection
interventions for
injection of REACT product. One
supplemental injections in
was associated with renal fibrosis the same kidney.
and loss of eGFR • Monitor for pain, nausea
and other symptoms of
acute renal infarct after
REACT injections.

Appendix 3: Statistical Appendices

Table A3- 1: REGEN-006 Objectives, Endpoints, and Estimands
REGEN-006 Estimand
Objective Treatment Conditions Population Endpoint Intercurrent Events Summary Measure
Primary Efficacy Up to 2 REACT injections Participants ages 30 to The time from first The primary endpoint The hazard ratio (HR)
Objective: given 12 weeks (+28 days) 85 with clinical injection to the earliest of: uses the composite for the outcome above
To assess the efficacy of apart and delivered diagnosis of type 2 • At least 40% strategy to identify the (time-to-event) for
up to 2 REACT injections percutaneously into diabetes mellitus and reduction in intercurrent event (Renal REACT vs.
in participants with type 2 biopsied and non-biopsied CKD. eGFR, sustained Replacement Therapy sham injections.
diabetes mellitus (T2DM) contralateral kidneys or 2 for 30 days or (chronic dialysis and/or
and chronic kidney scripted sham injections • eGFR <15 renal transplant), or
disease. following sham biopsy. mL/min/1.73m² Renal or Cardiovascular
sustained for 30 Death) as an important
days and/or clinical event that
chronic dialysis, informs the effectiveness
and/or renal of the treatment.
transplant or Participants will be
• Renal or considered to have met
cardiovascular the endpoint/have an
death. event at time of a renal
replacement therapy or a
renal or cardiovascular
death, whichever comes
first. Further details will
be found in the statistical
analysis plan.
Secondary Efficacy Up to 2 REACT injections Participants ages 30 to Annualized Change in All information after The difference in
Objective: given 12 weeks (+28 days) 85 years with clinical eGFR. renal replacement annualized change in
To assess the efficacy of apart and delivered diagnosis of type 2 therapy (chronic dialysis eGFR between the
up to 2 REACT injections percutaneously into diabetes mellitus and and/or renal transplant) REACT and sham
in participants with type 2 biopsied and non-biopsied CKD. will be censored, using injections with
diabetes mellitus (T2DM) contralateral kidneys or 2 the intercurrent event corresponding two-
and chronic kidney disease scripted sham injections strategy while on sided 95% CI.
across a range of outcome following sham biopsy. treatment. Further
measures. details will be found in
the statistical analysis
plan.

REGEN-006 Estimand
Up to 2 REACT injections Participants ages 30 to The time from first All information after The hazard ratio for
given 12 weeks (+28 days) 85 years with clinical injection to at renal replacement the outcome above
apart and delivered diagnosis of type 2 least 40% reduction in therapy (chronic dialysis (time-to-event) for
percutaneously into diabetes mellitus and eGFR, sustained for 30 and/or renal transplant) REACT vs. sham
biopsied and non-biopsied CKD. days. will be censored, using injections.
contralateral kidneys or 2 the intercurrent event
scripted sham injections strategy while on
following sham biopsy. treatment. Further
details will be found in
plan.
Up to 2 REACT injections Participants ages 30 to The time from first All information after the The hazard ratio for
given 12 weeks (+28 days) 85 years with clinical injection to eGFR intercurrent event, renal the outcome above
apart and delivered diagnosis of type 2 <15 mL/min/1.73m² replacement therapy (time-to-event) for
percutaneously into diabetes mellitus and sustained for 30 days (chronic dialysis and/or REACT vs. sham
biopsied and non-biopsied CKD. and/or chronic dialysis, renal transplant) will be injections.
contralateral kidneys or 2 and/or renal transplant. censored, using the
scripted sham injections intercurrent event
following sham biopsy. strategy while on
treatment. Further
plan.
Up to 2 REACT injections Participants ages 30 to The time from first All available data will be The hazard ratio for
given 12 weeks (+28 days) 85 years with clinical injection all-cause used without adjustment the outcome above
apart and delivered diagnosis of type 2 mortality. for IEs per handling of (time-to-event) for
percutaneously into diabetes mellitus and the treatment policy REACT vs. sham
biopsied and non-biopsied CKD. strategy. injections.
contralateral kidneys or 2
scripted sham injections
following sham biopsy.
Up to 2 REACT injections Participants ages 30 to Changes from baseline in All information after the Comparison of
given 12 weeks (+28 days) 85 years with clinical patient reported outcomes intercurrent event, renal average change from
apart and delivered diagnosis of type 2 from the Kidney replacement therapy baseline between the
percutaneously into (chronic dialysis and/or

REGEN-006 Estimand
biopsied and non-biopsied diabetes mellitus and Disease Quality of Life renal transplant) will be REACT and sham
contralateral kidneys or 2 CKD. (KDQOL) and EuroQol censored, using the injections.
scripted sham injections 5-Dimension 5 Level intercurrent event
following sham biopsy. (EQ-5D-5L) surveys. strategy while on
treatment. Further
plan.
Safety Objective: Up to 2 REACT injections Participants ages 30 to Summary of Adverse All available data will be For each cohort,
To evaluate the safety of given 12 weeks (+28 days) 85 years with clinical Events, such as Serious used without adjustment number and
up to 2 REACT injections apart and delivered diagnosis of type 2 Adverse Events, AESI, for IEs per handling of percentage of
in participants with type 2 percutaneously into diabetes mellitus and and Adverse Events the treatment policy participants
diabetes mellitus (T2DM) biopsied and non-biopsied CKD. leading to discontinuation strategy. experiencing
and chronic kidney contralateral kidneys or of study treatment. Treatment Emergent
disease. 2 scripted sham injections Adverse Events,
following sham biopsy. Serious Adverse
Events, and Adverse
Events Leading to
Discontinuation of
Treatment
summarized overall
and by System
Organ Class (SOC)
and Preferred Term
(PT).

Primary Estimand
Our main estimator for the primary analysis uses the composite strategy to address the
intercurrent event of renal replacement therapy (chronic dialysis and/or renal transplant) or renal
or cardiovascular related death. Renal replacement therapy and renal or cardiovascular related
deaths are important clinical events that may inform the effectiveness of the treatment. Disease
progression and other undesired outcomes of chronic kidney disease are incorporated into the
composite endpoint.
Currently, the protocol inclusion criteria allows participants to enroll in the study if on a
clinically relevant and stable dose of angiotensin converting-enzyme inhibitor (ACEi) or an
angiotensin receptor blocker (ARB), as well as sodium glucose cotransporter 2 inhibitor
(SGLT2i) according to local standard of care and when economically and medically feasible.
Initiation, change in dose, or discontinuation of ACEi, ARB, and/or SGLT2i is an intercurrent
event, and the handling strategy assumes treatment policy. It is assumed that there will be equal
treatment effect between cohorts. However, to test this assumption, we intend to do a sensitivity
analysis. Additional details will be found in the statistical analysis plan.
Primary Main Estimator Sensitivity Analyses

A sensitivity analysis, in addition to the main analysis, will be performed for the primary
estimand strategy of the primary estimand due to the increased usage of ACEi, ARB and/or
SGLT2i in the standard of care of participants with chronic kidney disease over the duration of
the study, All participants who increase dosage of ACEi, ARB and/or SGLT2i after time of
randomization or start/stop a new ACEi, ARB and/or SGLT2i medication while on study after
randomization, will be censored at time of initiation or stop of a new ACEi, ARB and/or SGLT2i
or dose increase. All drugs in the drug class ACEi, ARB, and/or SGLT2i including future
approved drugs. Additional details will be included in the statistical analysis plan.

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A PHASE 3 RANDOMIZED CONTROLLED STUDY OF

RENAL AUTOLOGOUS CELL THERAPY (REACT) IN

Protocol Number: REGEN-006

PROTOCOL SIGNATURE PAGE

By signing below, I agree to the following:

Printed Name of Investigator

Signature of Investigator Date

20-Mar-2024 | 15:26 EDT

Signature of Sponsor’s Representative Date

CONFIDENTIAL Page 2 of 111 ProKidney

PROTOCOL AMENDMENT HISTORY

Table 1: Amendment History

OVERALL RATIONALE FOR THIS AMENDMENT

CONFIDENTIAL Page 3 of 111 ProKidney

SUMMARY OF CHANGES IN THIS AMENDMENT

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REGEN-006 Amendment 5 Summary of Changes

Overall Design Section 5.1 • Target sample size • Study design

CONFIDENTIAL Page 5 of 111 ProKidney

REGEN-006 Amendment 5 Summary of Changes

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REGEN-006 Amendment 5 Summary of Changes

• Exclusion Criteria in • Exclusion criteria

CONFIDENTIAL Page 7 of 111 ProKidney

REGEN-006 Amendment 5 Summary of Changes

CONFIDENTIAL Page 8 of 111 ProKidney

REGEN-006 Amendment 5 Summary of Changes

Other Significant Adverse Events • Clarified that procedure- • Procedure

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REGEN-006 Amendment 5 Summary of Changes

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REGEN-006 Amendment 5 Summary of Changes

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PROTOCOL SIGNATURE PAGE .................................................................................................2

CONFIDENTIAL Page 12 of 111 ProKidney

3.1 Primary Objective: ..................................................................................................... 32

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7.1.1 Medications Interfering with Study Assessments.......................................... 51

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8.5 Medications - Prior and Concomitant ........................................................................ 63

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9.7.3 Adjudication Package .................................................................................... 76

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12.1 Good Clinical Practice ............................................................................................... 85

LIST OF APPENDIX TABLES

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Table A3- 1: REGEN-006 Objectives, Endpoints, and Estimands .............................................108

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LIST OF ABBREVIATIONS, ACRONYMS, AND THEIR DEFINITIONS

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Abbreviation or Specialist Term Explanation

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Abbreviation or Specialist Term Explanation

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The autologous REACT investigational product is a frozen formulation of culture-expanded

Table 2: Investigational Product

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The secondary efficacy endpoints are:

The Safety Endpoints are:

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The study events can be summarized in this figure.

Figure 1: Study Schema

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