Medic Shoes - Clinic Report - 25/10/2020

Medic Shoe Ltd.
CLINICAL STUDY REPORT
A Phase 3 study to assess the efficacy and safety

of Medic Shoes in patients with neuropathic pain
associated with diabetes mellitus
Protocol MS1
Version 1.0
Date 20 September 2018
Report Version: 01
Date: 25 October 2020
CONFIDENTIAL
Signature Date
Sponsor
Name: Medic Shoe Ltd.
Address: 41 Gordon st.

City: Tel Aviv
Country: Israel
Tel: 050-6789938
Fax: 03-5292222
Principal Investigator
Name: Professor Julio Wainstein
Center01: Wolfson Medical Center

City: Holon
Center02: Diabetic Medical Center
City: Tel Aviv
Country: Israel
Tel: 03-6900333
Fax: 03-6475662
Study CRO, Author and study

Statistician:
GCP Clinical Studies
Tse’ela Schwartz
City: Rosh Ha’ayin
Country: Israel
Tel: 03-9002022
Fax: 03-9027138
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Stattistical Analysis Report Protocol: MS-1
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A Phase 3 study to assess the efficacy and safety of Medic Shoes in patients with
Protocol Title neuropathic pain associated with diabetes mellitus
Protocol No. MS1
Version 1: 20 September 2018

Protocol date
Study Phase Phase 3
Medic Shoes Ltd.

Sponsor
41 Gordon st. Tel Aviv, Israel
Medic Shoes Ltd.

Product
Manufacturer 41 Gordon st. Tel Aviv, Israel
GCP Clinical Studies Ltd.

CRO
22 Hamelacha st. Rosh Ha’Ayin, Israel
GCP Clinical Studies Ltd.

Data
Management 22 Hamelacha st. Rosh Ha’Ayin, Israel
and Statistics
Site no. 01 Diabetes Medical Center, Tel Aviv Prof. Julio Wainstein
Principal
Investigators Site no. 02 Wolfson Medical Center, Holon Prof. Julio Wainstein
(PIs)and (Replaced Dr. Yosefa Bar Dayan
Centers on 2.-Nov-2020)
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1 Summary
1.1 Title of Clinical Investigation

A Phase 3 study to assess the efficacy and safety of Medic Shoes in patients with
neuropathic pain associated with diabetes mellitus
1.2 The Purpose of the Clinical Investigation

To assess the efficacy and safety of the Medic Shoes in improving subjective and
objective parameters in patients with diabetic peripheral neuropathy.
1.2.1 Primary Endpoint

Change from the baseline week (day-7 to day 1) to week 4 (day 23-30) in the weekly
average daily pain intensity as measured on a 11-point numerical pain scale (NPS)
1.2.2 Secondary Performance Endpoint

1. Change from the baseline week (day-7 to day 1) to week 4 (day 23-30) in the
weekly maximum daily pain intensity as measured on a 11-point numerical pain scale
(NPS)
2. Changes from baseline week (day-7 to day 1) to week 12 (day 83-90) in the weekly
average and maximum daily pain intensity as measured on a 11-point numerical pain
scale (NPS)
3.Changes in DN4 criteria from end of baseline day 1 to day 30 and day 90
4. Changes from end of baseline day 1 to day 30 and day 90 in Short-Form McGill
Pain Questionnaire (SF-MPQ) score.
5. Changes from baseline week (day -7 to day 1) to week 4(day 23-30) and week 12
(day 83-90) in the weekly average daily sleep interference score.
6. Changes from baseline week (day -7 to day 1) to week 4(day 23-30) and week 12
(days 83-90) in weekly consumption of rescue analgesics (i.e. number of paracetamol
500mg tablets taken per week)
7. Changes in blood pressure in hypertensive subjects from baseline day 1 to day 30
and day 90
8. Changes in blood pressure taken before and after 15 min use of Medic Shoes on
day 1 (visit 2) and day 30 (visit 4).
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9. Change in HbA1c from screening (day -7) to day 30 and day 90
1.2.3 Secondary Safety Endpoint

The safety endpoints are serious adverse events (SAEs) and adverse events (AEs)
related to treatment with the Medic Shoe.
1.3 Description of the Population
Type 1 and 2 diabetic subjects over the age of 18 with symptoms attributable to
diabetic neuropathy
 Foot pain at rest
 Foot pain on activity
 Nocturnal feet pain
 Burning sensations
 Cold feet
 History of recurrent ulcers, wounds, minor injuries–delay in healing Subjects
with current wounds at screening will be excluded
1.3.1 Inclusion Criteria
A subject was eligible to participate in the study if he/she met all the following
criteria:
Screening Inclusion Criteria
1. Adult (> 18 years old) male or female.
2. Known diabetes mellitus Type 1 or Type 2 for at least 12 months
3. Evidence of diabetic peripheral neuropathy. The subject on evaluation of the
DN4 questionnaire should have 4 or more items positive among the 10 items to
enter the study.
4. Presence of ongoing pain due to DPN for at least 3 months.
5. Average DPN pain intensity of 4 to 9 as measured on a 11-point numerical pain
scale (NPS) at screening visit Day -7. (according to last week)
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6. Signed written informed consent and willing to comply with the study
requirements.
Day 1 Inclusion Criteria

As above
Average of 4 to 9 in the weekly average daily pain intensity as measured on a 11-
point numerical pain scale (NPS) from Day -7 to day 1.
1.3.2 Exclusion criteria
A subject was not included in the study if he/she met any of the following criteria:
Exclusion Criteria
1. Active foot infection
2. Open ulcer in shoe area
3. History of amputation
4. Subjects with unstable or life-threatening conditions
5. History of malignancy during the last year
6. Active Charcot arthropathy
7. Impaired cognitive function –unable to sign informed consent
8. History of drug or alcohol abuse
9. Subject currently enrolled or has not yet completed other investigational device
or drug study or subject is receiving other investigational agents.
10. Other medical conditions including laboratory abnormalities that places subject
at risk based on Investigators judgements
11. Pregnancy or lactating or planning pregnancy during the study
1.3.3 Sample Size
This was a single arm study to assess the ability of the Medic Shoe to improve foot
symptoms. The primary efficacy endpoint was the change from Baseline week (day -
7 to day 1) to week 4 (day 23-30) in the weekly average daily pain intensity as
measured on an 11- point numerical pain scale (NPS). In previous studies with the
Medic shoe pain scores were not assessed but change in foot symptoms by a
questionnaire and changes in total peripheral resistance. Also, change in sleep
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pattern, blood pressure changes and other cardiac function parameters have been
assessed but not pain score. Consequently, we chose a sample of N=60 aiming to
optimize clinical and statistical considerations for this preliminary estimation.
Based on the reference by John Farrar (John T. Farrar et al. 2001) that on average, a
reduction of approximately two points in the NPS represents a clinically important
difference, a total of 60 subjects with 2 points reduction, standard deviation (SD)
between 1 to 5, alpha of 0.05 The study will provide the power between 86% to
almost 100%.
1.4 Clinical Investigation Methods
1.4.1 Methods of study
This was a single-arm, open-label, study to be conducted at two centres in Israel.

60 subjects with foot symptoms attributable to diabetic peripheral neuropathy
intended to be screened and enrolled at Visit 1 (Day -7). In fact, 58 subjects were
enrolled. Enrolment was terminated by the Sponsor prior to completion of 60
subjects’ enrolment due to low rate of enrolment of subjects and the 12 months
completion as planned for recruitment period. Activities were performed as
described in the Table of Assessment (section 9.1 in the protocol):
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Table of Assessment:
Day -7 Day 1 Day 15 Day 30 Day 90
Screening/ Enrollment Telephonic Follow End of
& Run in Contact up/end study
period of study6
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

Informed consent 1 x
Inclusion/Exclusion x x
Medical History 2 x x
Full examination x x
Including
neurological –
motor, sensory,
reflexes
Blood pressure x x3 x3 x
ECG x
DN4 x x x x
Short-Form McGill x x x
Pain Questionnaire
(SF-MPQ) score.
HbA1c x x x
Pregnancy test in x
WOCBP
NPS 5 x x x x
And sleep
interference score
Medic Shoe x4 x x
supplied
Review of diary 5 x x x
Adverse events x x x x
Rescue Medication x x x x
Technical issues x x x x
The protocol allows a window period of +/- 2 days for visits days 1 /15/ 30 / 90
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Informed consent to be signed before any screening procedures initiated
2
Medical history will include diabetic management, current medication, symptoms associated with
neuropathy, quality of sleep
3
BP will be measured before (after a 5-minute rest period) and after shoe use while patient is in
supine state on day 1 and day 30
4
Medic shoe will be provided at screening with instructions to wear for 15 min in the morning after
rising and 15 min at night before going to bed. The subjects will be instructed to turn both shoes on
(green light will be turned on) Remote control to activate vibration will only be supplied at visit 2, day
1. First treatment will be given for 15 min at the clinic.
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Review of diary (Attachment 3) Average and maximum daily pain intensity as measured on an 11-
point numerical pain scale NPS to be recorded every evening for the first thirty days and weekly
(weekly average) if subject continues until day 82.
 Subjects continuing until day 90 will in addition record daily average and maximum daily pain scores
for week 12 (day 83-90).
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 Sleep interference based on a 11-point numerical scale will be recorded every morning for thirty
days and weekly (weekly average) if subject continues until 82 days;
 Subjects continuing until day 90 will in addition record daily sleep interference for week 12 (day 83-
90)
 Rescue analgesic use for first thirty days and during week 12 (days 83 – 90)
 Compliance use for first thirty days and during week 12 (days 83-90)
 Adverse events experienced during total study period (day -7 to day 90)
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Subjects wishing to continue with shoe use will return on day 90. Subjects wishing to discontinue
will have final visit
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Subjects signed informed consent and met inclusion/exclusion criteria underwent a
full medical history and examination including blood pressure measurement, heart
rate and ECG. A full neurological assessment was performed, testing motor,
sensation and reflexes.
DN4 criteria assessment were performed to estimate the probability of neuropathic
pain.
Average DPN pain intensity on a 11-point numerical pain scale (NPS) according to
last week was performed. This was required to be between 4 and 9.
HbA1c was measured. A pregnancy test was performed on women child birth
potential (WOCBP).
Medic Shoes appropriate size was supplied with instructions to wear for 15 min twice
daily on awakening and at bedtime. The subjects were instructed to turn both shoes
on (green light was turned on). Remote control was not supplied to activate vibration
during the first week.
During the one week run –in period subjects were provided with diary to record the
following. If the subject was enrolled at Day 1 diary completion continues as also
indicated below until day 30.
 Average and maximum daily pain intensity as measured on an 11-point numerical

pain scale NPS to be recorded every evening.
 Sleep interference based on a 11-point numerical scale to be recorded every
morning.
 Rescue analgesic use.
 Compliance
 Adverse events experienced
At day 1 +/- 2 Subjects met criteria for median pain severity (4 to 9) in the weekly
average daily pain intensity on an 11-point numerical pain scale NPS were enrolled
and issued with the remote control for the Medic Shoes to use at home.
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First treatment was given for 15 min at the clinic. BP was measured before (after a 5-
minute rest period) and after shoe use while patient was in supine state.
Shoes were used for 15 minutes twice daily for 30 days. 15 min in the morning after
rising and 15 min at night before going to bed.
Short-Form McGill Pain Questionnaire (SF-MPQ) score was completed.
DN4 criteria was repeated.
Subjects continued diary completion as detailed above.
Telephonic contact was made at day 15 to ensure compliance and to see if any adverse
events or technical difficulties.
Subjects were followed up at day 30 to assess compliance with Medic Shoe use,
changes in pain intensity and sleep quality.
DN4 criteria was assessed at day 30.
Blood was taken to measure HbA1c. Subjects were instructed not to use the shoe on
the morning of the visit and to bring the shoes and diaries with them. Blood pressure
in the supine position before (after 5 minutes rest) and after 15 minutes shoe use was
also assessed.
Adverse events and rescue medication taken were reviewed.
Based on doctor and subject decision ongoing treatment continued after day 30.
If Medic Shoe use was not to be continued –this was the end of study visits.
From that point, diary was completed on a weekly basis. Average and maximum daily
pain intensity as measured on a 11-point numerical pain scale NPS was recorded
weekly (weekly average) in the evening until day 82. Sleep interference based on a 11-
point numerical scale was recorded every morning for thirty days and weekly (weekly
average) if subject continued until 82 days. Average and maximum daily pain scores
and sleep interference scores were in addition recorded daily for week 12 (day 83-90)
Adverse events and compliance were also recorded daily until Day 30 and again during
week 12 (days 83-90)
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Subjects continued with Medic shoes had a final visit on day 90 to assess compliance
with Medic Shoe use, changes in pain intensity and sleep quality.
Changes in HbA1c and blood pressure were also assessed.
Adverse events and rescue medication used were reviewed.
DN4 was assessed.
Post study use of shoes was on decision of subject and investigator.
1.5 Investigational Study Device

Description of device and use instructions were included in the User Guide which
was supplied to all subjects. Medic Shoe is a shoe, providing massage together with
acupressure and reflexology functions.
Medic Shoes were developed in accordance with the principles of reflexology. Raised
areas within the shoe exert pressure on specific points of the foot, and a vibration
mechanism in the shoes can also be activated by remote control. Two mechanisms,
located at the front and back of each shoe, generate vibrations at two levels of
intensity, which can be adjusted for personal comfort. Treatment with vibration
increases the circulation (probably by a vasodilatory effect) and has been medically
proven to relieve pain, as well as sensations of tingling and numbness.
The device is fully remotely operated and controlled.
The device is charged when not in use. The shoe is unplugged from an electrical
source before use. The speed and site of action (front or rear) can be adjusted.
The presumed mode of action is pain relief of diabetic neuropathy. The shoe also has
an effect in improving peripheral circulation probably by vasodilatory effect
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Pic. 1 The Medic Shoes
1.6 Study Arms
This is a non-comparative single arm study.
1.7 Study Duration

Subjects had been enrolled over a 12-month period.
Each patient follow up period had been 30 or 90 days.
1.8 Data Analysis and Statistical Methods
Safety Analysis Set
The safety analysis set consisted of all subjects who used the Medic Shoes with
vibration at least once even if for less than 15 minutes of use.
Primary Efficacy Analysis Set
The primary efficacy analysis set was based on the intent to treat (ITT) cohort. All
subjects who used the Medic shoe at least once and had at least one assessment of
the primary efficacy endpoint post first use (with vibration, Day 1).
Secondary Efficacy Analysis Set
The secondary efficacy analysis set was based on the per protocol (PP) cohort.
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Subjects who met inclusion and inclusion criteria and fulfilled the study protocol
requirements in terms of device use (i.e. A fully compliant subject was regarded as use
of shoes 12 times per week) and collection of primary efficacy data and without major
deviations that may affect study results.
For all analyses, patients not having a valid post-device use (with vibration) value for
a particular endpoint will be excluded from the relevant analysis.
1.8.1 Statistical Analysis

1.8.1.1 Descriptive Statistics
For categorical variables summary, tables are provided giving sample size (N), absolute
and relative frequency.
For continuous variables summary, tables are provided giving the sample size (N),
mean, standard deviation, median and range (minimum and maximum).
1.8.1.2 Primary Endpoint.
The primary endpoint is the change from the baseline week (day -7 to day 1) to week
4 (day 23-30) in the weekly average daily pain intensity as measured on an 11-point (0
to 10) Numerical Pain Score (NPS).
The changes are the difference between the 2 visits. To test significance of the change,
the paired t-test would have been used. However, the change did not conform to
Normal theory so the Wilcoxon Sign-rank Test was applied.
1.8.1.3 Secondary Endpoints

For all Secondary endpoints (changes between 2 visits or more) the changes are the
different between the visits. To test significance of the change, the paired t-test was
to be used if data conformed to Normal theory. If data did not conform to Normal
theory, the Wilcoxon Sign-rank Test was to be applied.
A p-value of less than 5% (0.05) was considered statistically significant.

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The Last Observation Carried Forward (LOCF) method was used for all subjects who
withdrew during the study from any reason and who had at least one primary efficacy
assessment post device use (with vibration).
1.8.1.4 Safety
The safety analysis was descriptive and narrative in nature, with SAEs and related AEs
tabulated by body system, preferred term, severity and relation to procedure.
2 Results
2.1 Clinical Investigation initial date
Ministry of Health (MoH) study approval: NA
Diabetic Medical Center, DMC, (site #01) Ethical committee (EC) study approval:
10- February-2019
Wolfson Medical Center (Site #02) EC study approval:
16-January-2019
First Patient First Visit (FPFV): 06-March-2019 (Subject 02-001)
2.2 Clinical Investigation completion date
Last Patient Last Visit (LPLV): 26-April-2020 (Subject 01-030)
Last study Visit (LSV): 26-April-2020 (Subject 01-030)
2.3 The Disposal of Subjects and Investigational Device

Fifty-eight (58) subjects were screened for the study and assessed at screening visit.
By visit 2, Baseline visit, eleven (11) subjects were found to be screen/Run-in failures;
Five (n=5) of them did not comply with inclusion/exclusion criteria at visit 2.
Three (n=3) subjects withdrew their consent following the run-in week and by visit 2.
Two (n=2) subjects experienced unrelated AE/SAE that led to exclusion by visit 2.
One (n=1) subject had been withdrawn from the study due to low compliance during
the run-in week and by visit 2.
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Except for these 11 screen/run-in failures subjects all other 47 subjects received the
remote control of the shoes to continue to the primary endpoint period, follow up
(FU) of 30 days.
[Note: Site staff were allowed to provide the remote also to subjects that were
excluded following visit 2. A total of 49 remotes were dispensed; 47 to eligible
subjects and 2 to screen failures (subjects: 01-020, 02-025)].
Forty-Two (42) subjects, out of 47 that continued to day 30, came to visit 4; Day 30
(primary endpoint timepoint).
Five (5) subjects, out of 47, did not come to visit 4 due to different reasons; 3 due to
AE (subjects: 01-014, 02-012, 02-016), 1 due to no compliance (Subject 02-009), 1
due to Investigator decision (subject 01-010). Therefore, there is no data of the daily
average pain using NPS during weeks 1-4 for these 5 subjects.
Forty (40) subjects, out of 47 reported the week 4 weekly AVERAGE daily pain
intensity measured using NPS as required for the primary end-point.
Figure 1 presents the study subjects disposition and table 1 presents the screen
failures subjects with the reason for failure.
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Figure 1:
Enrolled
N=58
Screen Failures Eligible subjects that

N=11 received shoes remote
control (“Randomized”)
Inclusion/Exclusion issues; N=5 N=47
Withdrew consent at Baseline visit;
N=3
Experienced unrelated AE/SAE by
Baseline visit; N=2
Low compliance during Run-in; N=1
Early Termination
N=5
Adverse event; N=3
No compliance; N=1
Inv. Decision; N=1
Completed 30 days of FU
N=42 (Per protocol; n=33)
Continued to 90
Days FUL; N=10
Completed 90 days of FU
N=10
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Table 1: Screen Failures reasons
Subject ID Reason for Screen Failure
Excluded
Following
01-019
Screening and
Baseline visits Withdrew Consent. Did not arrive to Visit 2
Inclusion #5: Average of 4 to 9 in the weekly average daily

01-020 pain intensity as measured on an 11-point numerical pain
scale (NPS) from Day (-7) to Day 1 (last week) = No
01-023 SAE, not device related
02-004 Low Compliance during Run-in
02-011 Withdrew Consent. Did not arrive to Visit 2
Inclusion #4: Presence of ongoing pain due to DPN for at

least 3 months= No
02-020 Inclusion #5: Average of 4 to 9 in the weekly average daily
pain intensity as measured on an 11-point numerical pain

least 3 months= No
Inclusion #5: Average of 4 to 9 in the weekly average daily

02-024 pain intensity as measured on an 11-point numerical pain

least 3 months= No
02-026 AE, not device related
02-028 Withdrew Consent. Did not arrive to Visit 2
Total N 11 11
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2.4 Subjects’ Demographics
2.4.1 Ethnicity Age and Gender

All subjects (58) were Caucasian; 38 Males and 20 women, all post-menopausal.
The mean age was 67.0 ± 9.2 (range: 42.7 to 87.1)
2.4.2 Concomitant Medication
As part of the screening visit and during the study, subjects were asked to report of
any concomitant medication received on screening date (or started prior) and from
screening date to the end of the study. Table 2 present the concomitant medications
(CM) according to the WHO-ATC (World Health Organization – Anatomical
Therapeutic Chemical) dictionary version ATC/DDD Index 2020.
The Table does not include data from screen failures:
Table 2: Concomitant Medication

Number
of
Group Medication patients
AGENTS ACTING ON THE RENIN- CANDESARTAN 5
ANGIOTENSIN SYSTEM
CILAZAPRIL 3
CILAZAPRIL AND 1
DIURETICS
ENALAPRIL 6
ENALAPRIL AND 1
LERCANIDIPINE
LOSARTAN 5
RAMIPRIL 7
RAMIPRIL AND DIURETICS 3
VALSARTAN 2
VALSARTAN AND 2
AMLODIPINE
VALSARTAN AND 4
DIURETICS
Total 39
ANALGESICS CANNABIS SATIVA 3
CODEINE AND OTHER 4
NON-OPIOID ANALGESICS
DULOXETINE 9
GABAPENTIN 5
METAMIZOLE SODIUM 13
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OXYCODONE AND 1
NALOXONE
PARACETAMOL 4
PREGABALIN 7
Total 46
ANTIANEMIC PREPARATIONS CYANOCOBALAMIN 3
FOLIC ACID 1
IRON AND ASCORBIC ACID 1
IRON, MULTIVITAMINS 1
AND FOLIC ACID
Total 6
ANTIDIARRHEALS, INTESTINAL SULFASALAZINE 1
ANTIINFLAMMATORY/ANTIINFECTIVE
AGENTS Total 1
ANTIGOUT PREPARATIONS ALLOPURINOL 1
Total 1
ANTIHYPERTENSIVES CLONIDINE 1
DOXAZOSIN 1
Total 2
ANTIINFLAMMATORY AND DICLOFENAC 2
ANTIRHEUMATIC PRODUCTS
ETORICOXIB 2
GLUCOSAMINE 1
IBUPROFEN 2
NAPROXEN 1
Total 8
ANTITHROMBOTIC AGENTS ACETYLSALICYLIC ACID 22
APIXABAN 4
CLOPIDOGREL 9
Total 35
BETA BLOCKING AGENTS ATENOLOL 3
BISOPROLOL 18
CARVEDILOL 1
Total 22
CALCIUM CHANNEL BLOCKERS AMLODIPINE 7
LERCANIDIPINE 7
Total 14
CARDIAC THERAPY ISOSORBIDE 2
MONONITRATE
PROPAFENONE 1
Total 3
DIGESTIVES, INCL. ENZYMES PANCREATIN 1
Total 1
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DIURETICS FUROSEMIDE 1
HYDROCHLOROTHIAZIDE 2
SPIRONOLACTONE 3
Total 6
DRUGS FOR ACID RELATED ESOMEPRAZOLE 8
DISORDERS
LANSOPRAZOLE 3
OMEPRAZOLE 5
PANTOPRAZOLE 3
Total 19
DRUGS FOR CONSTIPATION BISACODYL 1
MACROGOL 2
Total 3
DRUGS FOR OBSTRUCTIVE AIRWAY SALBUTAMOL 1
DISEASE Total 1
DRUGS FOR OBSTRUCTIVE AIRWAY FORMOTEROL AND 1
DISEASES BUDESONIDE
IPRATROPIUM 1
SALBUTAMOL 1
Total 3
DRUGS FOR TREATMENT OF BONE ALENDRONIC ACID AND 1
DISEASES COLECALCIFEROL
Total 1
DRUGS USED IN DIABETES ACARBOSE 1
DAPAGLIFLOZIN 5
DULAGLUTIDE 5
EMPAGLIFLOZIN 11
GLIBENCLAMIDE 1
GLIMEPIRIDE 4
GLIPIZIDE 1
INSULIN 1
INSULIN ASPART 8
INSULIN ASPART 1
INSULIN DEGLUDEC 3
INSULIN DEGLUDEC AND 5
LIRAGLUTIDE
INSULIN GLARGINE 18
INSULIN GLULISINE 1
INSULIN LISPRO 2
LINAGLIPTIN 1
LINAGLIPTIN AND 2
EMPAGLIFLOZIN
LIRAGLUTIDE 11
METFORMIN 30
METFORMIN AND 2
DAPAGLIFLOZIN
METFORMIN AND 4
EMPAGLIFLOZIN
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METFORMIN AND 7
SITAGLIPTIN
METFORMIN AND 2
VILDAGLIPTIN
REPAGLINIDE 5
SEMAGLUTIDE 2
SITAGLIPTIN 1
Total 134
EMOLLIENTS AND PROTECTIVES LACTIC ACID AND UREA 1
Total 1
ENDOCRINE THERAPY EXEMESTANE 1
Total 1
LIPID MODIFYING AGENTS ATORVASTATIN 12
ATORVASTATIN AND 3
EZETIMIBE
BEZAFIBRATE 6
EVOLOCUMAB 1
EZETIMIBE 7
ROSUVASTATIN 10
SIMVASTATIN 5
Total 44
MINERAL SUPPLEMENTS CALCIUM AND 1
COLECALCIFEROL
CALCIUM CARBONATE 1
MAGNESIUM 3
MAGNESIUM CITRATE 1
Total 6
MUSCLE RELAXANTS ORPHENADRINE, 3
COMBINATIONS
Total 3
OPHTHALMOLOGICALS CICLOSPORIN 1
LATANOPROST 1
TIMOLOL, COMBINATIONS 2
Total 4
OTHER ALIMENTARY TRACT AND THIOCTIC ACID 3
METABOLISM PRODUCTS Total 3
PERIPHERAL VASODILATORS PENTOXIFYLLINE 2
Total 2
PSYCHOANALEPTICS ESCITALOPRAM 2
LAMOTRIGINE 1
Total 3
PSYCHOLEPTICS BROTIZOLAM 3
CLONAZEPAM 1
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LORAZEPAM 2
OXAZEPAM 2
VENLAFAXINE 1
ZOLPIDEM 2
Total 11
SEX HORMONES AND MODULATORS NORETHISTERONE AND 1
OF THE GENITAL SYSTEM ETHINYLESTRADIOL
TESTOSTERONE 1
Total 2
STOMATOLOGICAL PREPARATIONS CHLORHEXIDINE 1
TRIAMCINOLONE 1
Total 2
THYROID THERAPY LEVOTHYROXINE SODIUM 1
Total 1
TOPICAL PRODUCTS FOR JOINT VARIOUS 1
AND MUSCULAR PAIN
Total 1
UROLOGICALS ALFUZOSIN 2
MIRABEGRON 1
SILDENAFIL 1
SOLIFENACIN 1
TADALAFIL 2
TAMSULOSIN 3
TAMSULOSIN AND 3
DUTASTERIDE
TROSPIUM 1
VARDENAFIL 1
Total 15
VITAMINS COLECALCIFEROL 10
CYANOCOBALAMIN, 6
PYRIDOXINE
HYDROCHLORIDE AND
THIAMINE
HYDROCHLORIDE
TOCOPHEROL 1
Total 17
2.4.3 Medical History

Table 3 presents the medical history of the subjects enrolled to the study. 476 terms
of medical history were reported by 58 subjects and were coded using the MedDRA
version 23.0 by System Organ Class (SOC) and preferred term. Diabetes Mellitus type
I/II is not included in the table.
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Table 3: Medical History
SOC N
Blood and lymphatic system disorders Anaemia 5
Total 5
Cardiac disorders Acute myocardial infarction 2
Angina pectoris 5
Arteriosclerosis coronary artery 1
Atrial fibrillation 4
Bundle branch block right 1
Cardiac failure 1
Cardiomyopathy 1
Diastolic dysfunction 1
Left atrial dilatation 1
Myocardial infarction 1
Myocardial ischaemia 13
Ventricular extrasystoles 1
Total 32
Congenital, familial and genetic Dandy-Walker syndrome 1
disorders
Ectopic kidney 1
Strabismus congenital 1
Total 3
Ear and labyrinth disorders Deafness 3
Vertigo 2
Total 5
Endocrine disorders Goitre 2
Hyperthyroidism 1
Hypothyroidism 3
Primary hyperaldosteronism 1
Thyroid mass 1
Thyroiditis 1
Total 9
Eye disorders Blindness 1
Cataract 6
Diabetic retinopathy 4
Glaucoma 5
Hypermetropia 2
Optic disc disorder 1
Retinal detachment 2
Retinopathy 2
Total 23
Gastrointestinal disorders Constipation 2
Diaphragmatic hernia 3
Diarrhoea 1
Diverticulum intestinal 1
Duodenal ulcer 3
Dyspepsia 1
Gastric polyps 1
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SOC N
Gastritis 1
Gastritis erosive 1
Gastroesophageal reflux disease 8
Hiatus hernia 2
Impaired gastric emptying 1
Irritable bowel syndrome 2
Large intestine polyp 2
Oesophageal polyp 1
Oesophagitis 2
Rectal haemorrhage 1
Total 33
General disorders and administration Gait disturbance 1
site conditions Hernia 1
Total 2
Hepatobiliary disorders Cholelithiasis 1
Hepatic cirrhosis 1
Hepatic cyst 1
Hepatic steatosis 8
Total 11
Infections and infestations Fungal skin infection 1
Hepatitis B 1
Myelitis 1
Total 3
Injury, poisoning and procedural Facial bones fracture 1
complications
Foot fracture 1
Humerus fracture 2
Radius fracture 2
Tibia fracture 1
Traumatic arthropathy 1
Total 8
Investigations Arthroscopic surgery 1
Arthroscopy 2
Colonoscopy 1
Total 4
Metabolism and nutrition disorders Dyslipidaemia 12
Gout 2
Hypercholesterolaemia 5
Hyperlipidaemia 25
Hypertriglyceridaemia 2
Hyperuricaemia 1
Iron deficiency 1
Lipid metabolism disorder 1
Obesity 18
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SOC N
Vitamin B12 deficiency 3
Vitamin D deficiency 5
Total 75
Musculoskeletal and connective Arthralgia 1

tissue disorders
Back pain 6
Bone cyst 1
Bone hypertrophy 1
Fibromyalgia 2
Flank pain 1
Gouty arthritis 1
Intervertebral disc disorder 2
Intervertebral disc displacement 1
Intervertebral disc protrusion 2
Muscle spasms 1
Osteoarthritis 6
Osteopenia 2
Osteoporosis 6
Periarthritis 1
Spinal osteoarthritis 6
Spinal stenosis 5
Trigger finger 1
Total 46
Neoplasms benign, malignant and Basal cell carcinoma 2

unspecified (incl cysts and polyps)
Breast cancer 2
Haemangioma of liver 1
Laryngeal neoplasm 1
Lipoma 1
Malignant melanoma 3
Prolactin-producing pituitary tumour 1
Prostate cancer 2
Total 13
Nervous system disorders Carotid artery occlusion 1

Carotid artery stenosis 2
Carpal tunnel syndrome 3
Cerebral infarction 1
Cerebrovascular accident 6
Diabetic neuropathy 13
Epilepsy 1
Neuralgia 1
Neuropathy peripheral 3
Polyneuropathy 1
Quadrantanopia 1
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SOC N
Radiculopathy 1
Transient ischaemic attack 1
Total 35
Psychiatric disorders Affective disorder 1
Anxiety 4
Depression 5
Insomnia 4
Mania 1
Total 15
Renal and urinary disorders Chronic kidney disease 3
Diabetic nephropathy 2
Microalbuminuria 3
Nephrolithiasis 1
Proteinuria 2
Urinary incontinence 1
Total 12
Reproductive system and breast Benign prostatic hyperplasia 9
disorders
Erectile dysfunction 2
Sexual dysfunction 1
Total 12
Respiratory, thoracic and mediastinal Asthma 4
disorders
Chronic obstructive pulmonary disease 4
Nasal septum deviation 1
Pulmonary embolism 1
Pulmonary hypertension 1
Pulmonary oedema 1
Sleep apnoea syndrome 7
Total 19
Skin and subcutaneous tissue Stasis dermatitis 1

disorders Total 1
Social circumstances Ex-tobacco user 1
Total 1
Surgical and medical procedures Appendicectomy 2
Cardiac pacemaker insertion 1

Cataract operation 1
Chemotherapy 1
Cholecystectomy 1
Coronary angioplasty 3
Coronary artery bypass 1
Gastrectomy 2
Gastroplasty 1
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SOC N
Hysterectomy 1
Inguinal hernia repair 1
Knee arthroplasty 6
Meniscus removal 1
Percutaneous coronary intervention 10
Plasmapheresis 1
Prostatectomy 1
Radical prostatectomy 1
Spinal laminectomy 1
Stent placement 1
Thyroidectomy 1
Tumour excision 1
Total 39
Vascular disorders Aortic aneurysm 1

Aortic stenosis 1
Deep vein thrombosis 1
Hypertension 46
Peripheral vascular disorder 2
Varicose vein 2
Total 53
Total 459
2.5 Clinical Parameters

The following examinations and tests were performed on the study subjects at
screening and/or at Baseline visits and part of the tests were repeated at Day 30 to
assess improvement. Tests were performed also at Day 90 to subjects who
continued to the 90 days FU.
A descriptive statistic of the following parameters reported at screening visit is
presented for the 47 intention to treat subjects who passed successfully the run-in
week.
Diabetes Medical History:
Diabetes Type: 46 with type 2 DM and 1 with type 1 DM
Number of years since Diabetes diagnosed: 18.4 ± 8.4 years
Number of years since Neuropathy diagnosed: 7.3 ± 5.3 years
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Level pf Neuropathy:
Frequency Percent
Valid Autonomic 1 2.1
Peripheral motor 5 10.6
Peripheral Sensory 41 87.2
Total 47 100.0
Diabetes complications:
Retinopathy-10 Rt, 11 Lt
Nephropathy-13 subjects
Coronary Artery Disease-12 subjects
Peripheral Vascular Disease-5 subjects
Symptoms of possible Diabetic foot pathology:
All subjects reported at least 2 of the following-
Pain in the feet, Tingling, Numbness, Burning, Cold, Weakness, Loss of Sensation,
Pain wakes at night, Symptoms worse on walking, Recurrent injuries, wounds, ulcers
Numerical Pain Scale score:
Average DPN pain intensity as measured on a 11-point numerical pain scale (NPS)
according to 1 week prior to screening was 7.02 ± 1.30
Recent HbA1c (%) (prior to screening): 7.90 ± 1.01 (n=41)
HbA1c (%) at screening: 7.64 ± 1.17 (n=46)
History of Sleep Disorder:
Average of number of hours subjects sleep at night; 5.77 ± 1.24 hours
Average of number of arousals during the night; 2.20 ± 1.40
Subjects reported tiredness during the day: 37
Hypertension History: 35 Hypertensive subjects
Anthropometrics:
Weight (kg): 87.80 ± 14.00
Height (cm): 170.13 ± 8.79
Vital Signs:
Blood Pressure (mmHg): Systolic;140.08 ± 14.58 Diastolic; 75.61 ± 9.16
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Pulse (beats/min): 76.97 ± 11.16
Temperature (°C): 36.57 ± 0.28
Physical examination: Was checked for all body systems, some minor abnormalities
were reported.
ECG: 5 Abnormalities reported at Screening and 13 reported at Day 30
Feet Examination:
Pedal Pulses- Screening; Reported 40 at Lt. leg, 42 at Rt. Leg. Week 4; Reported 38 at
Lt. Leg, 37 at Rt. Leg
Deformities- Reported at 2 subjects at screening and only 1 subject at week 4.
No Evidence of previous infection and/or ulceration was reported
Neurological Feet Assessment
neurological abnormalities observed during examination of either legs were

reported at 33 subjects at screening and 26 subjects at week 4
DN4 Questionnaire
Average total score: 6.02 ± 1.34
Statistical tables of all these parameters are presented in section 2.7 “Analysis” as
the results of primary and secondary endpoints
2.6 CIP compliance

Seventy-Four (74) protocol deviations reported by the sites during the study;
20 subjects reported missing treatments between visit 2 (Baseline) and visit 4 (30
days). Number of missing treatments was between 8 to 56 times (on average 14
times). The reasons for missing treatments were:
Technical issues with device (reported as Device Deficiency), subjects’ forgetfulness,
adverse events and user error.
To note that it was allowed to miss 2 treatments per week, on average, however, a
Deviation was completed also for the allowed numbers.
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One (1) enrolment of subject outside inclusion/exclusion reported. Subject (02-020)
was enrolled to the run-in period although his screening DPN was less than 4. The
subject did not continue to the primary endpoint period and was excluded following
visit 2 since the same inclusion (DPN level) was not met per protocol requirement.
Other deviations reported; Diaries partially not completed (5 cases), out of window
visits (35 cases) and tests required in the protocol were not done (8 cases)
2.7 Analysis
2.7.1 Primary endpoint analysis
The primary effectiveness endpoint of the study was the Change from the baseline
week (day-7 to day 1) to week 4 (day 23-30) in the weekly average daily pain
intensity as measured on a 11-point (0 to 10) numerical pain scale (NPS)
2.7.1.1 Statistical Methods

The change is the difference between the weekly average daily pain intensity
measured during the Run-in week, reported at visit 2 and the weekly average daily
pain intensity reported at visit 4 for week 4.
The Kolmogorov -Smirnov method was used to confirm or reject normal theory for
the change. The test obtained significance (p=0.04) so the null hypothesis for normal
distribution was rejected and therefore the Wilcoxon rank test was used to assess
change significance.
2.7.1.2 Primary endpoint result

2.7.1.2.1 Primary Analysis Set- Intention to Treat Set
For the intention-to-treat (ITT) analysis, data of 42 subjects were included. All subjects
signed the written ICF, used at least once the Medic shoe and had at least one
assessment of the primary efficacy endpoint post first use (with vibration, Day 1).
For the primary endpoint, the Last Observation Carried Forward (LOCF) method was
used for 2 subjects whose week 4 data was missing. The subjects had withdrawn
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during the study and had at least one primary efficacy assessment post device use
(with vibration).
The mean weekly average daily pain intensity measured using the NPS at baseline
was 6.13 ± 1.30 points
The mean weekly average daily pain intensity measured using the NPS at week 4 was
4.57 ± 2.20 points
A decrease of 1.55 ± 1.90 points was obtained. The decrease was significant; p-
value<0.0001
2.7.1.2.2 Secondary Analysis Set- Per Protocol

33 Subjects who met inclusion and inclusion criteria and fulfilled the study protocol
deviations that may affect study results were included.
The following subjects were excluded from the PP analysis in addition to the subjects
who were excluded for the ITT cohort: 01-003, 01-007, 01-008, 01-011, 01-012, 01-
024, 02-007, 02-008, 02-015.
the change. The test obtained non significance (p=0.06) so the null hypothesis for
normal distribution was not rejected and therefore the paired t-test was used to
assess change significance.
The mean weekly average daily pain intensity measured using the NPS at baseline
The mean weekly average daily pain intensity measured using the NPS at week 4 was
4.56 ± 2.22 points
A decrease of 1.55 ± 2.00 points was obtained. The decrease was significance.
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Paired t-test p-value <0.0001.
2.7.2 Secondary Endpoint analysis
Nine secondary performance endpoints of the study were analysed.

The Intention to Treat (ITT) cohort will be presented first for all endpoints and then
the Per Protocol cohort
2.7.2.1 Intention to Treat (ITT) Cohort
1) Change from the baseline week (day-7 to day 1) to week 4 (day 23-30) in the
weekly maximum daily pain intensity as measured on a 11-point numerical pain
scale (NPS)
The change is the difference between the weekly maximal daily pain intensity
measured during the Run-in week, reported at visit 2 and the weekly maximal daily
the change. The test obtained non- significance (p=0.2) so the null hypothesis for
Forty-two (42) subjects had the weekly maximal daily pain intensity result (LOCF was
used for 2 subjects).
The mean weekly maximal daily pain intensity measured using the NPS at baseline
The mean weekly maximal daily pain intensity measured using the NPS at week 4
A decrease of 1.90 ± 2.26 points was obtained. The decrease was significance; p-
value <0.0001
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2) Changes from baseline week (day-7 to day 1) to week 12 (day 83-90) in the
weekly average and maximum daily pain intensity as measured on a 11-point
numerical pain scale (NPS)
Ten (10) subjects continued to 12 weeks of follow up. Only 9 of them completed the
whole 12 weeks FU period. One subject did not provide his follow-up diary as he lost
it, so the data of 8 subjects is presented for the 12 months FU analysis.
The change from Baseline to week 12 in the average and Maximum daily pain had
shown a non -significant decrease.
The average daily pain intensity decrease was 1.01 ± 1.68 (p=0.12) (5.54 points at
baseline to 4.53 points at week 12)
The maximum daily pain intensity decrease was 0.60 ± 1.55 (p=0.30) (6.46 points at
baseline to 5.86 points at week 12)
3) Changes from end of baseline day 1 to day 30 and day 90 in Short-Form McGill
The Short-Form McGill Pain Questionnaire was provided to the patients at Day 1,
Week 4 (primary endpoint) and week 12. The form is constructed of 3 sections.
Section A: 15 questions described patients feeling of pain graded from 0 (None) to 3
(Severe); total of 4 grades.
Section B: A line represents pain of increasing intensity from “no pain” to “worst
possible pain”. The patient should have placed a vertical line (|) across the line in the
position that best describes his pain during the past 7 days. Then, the investigator
used a ruler to measure and score the line from 0 to 100 mm.
Section C: Present of pain intensity from “No Pain” to “Excruciating”; total of 6
grades 0-5.
Results:
Section A- The sum of the 15 questions grade was calculated at Baseline, Week 4
and week 12. The change between baseline and each of the visits was calculated.
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A significant decrease was obtained between baseline and week 4; 3.10 ± 8.80 points
(absolute value; 17.45 points at baseline and 14.36 points at week 4), p=0.03, n=42.
A non-significant decrease 2.90 ± 11.86 points was obtained after 12 weeks
Section B-
The change variability from Baseline to week 4 and week 12 was wide. Therefore, a
non- significant decrease was obtained at both FU visits (Week 4; D30 and week 12;
D90). The average decrease standard deviation minimum maximum and p-value are
presented in table 4 for each visit.
Table 4: Investigator pain score by ruler (mm) from Baseline to Day 30 and Day 90
N Minimum Maximum Mean Std. Deviation p-Value (Sig.)
Ruler_BL_D30 42 -76 65 -7.18 35.505 0.34*

Ruler_BL_D90 10 -72 69 -6.46 40.738 0.44*
*Not Significant
Section C-
Pain intensity showed significant improvement (decrease) both at week 4 and at
week 12 in a non-parametric test (Wilcoxon). The average decrease standard
deviation minimum maximum and p-value are presented in table 5 for each visit
Table 5: Pain Intensity Change from Baseline to Day 30 and Day 90

Pain_Intens_BL_D30 42 -5 2 -1.50 1.43 <0.0001

Pain_Intens_BL_D90 10 -5 0 -1.40 1.43 0.01
4) Changes in DN4 criteria from end of baseline day 1 to day 30 and day 90.
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DN4 questionnaire was completed in an interview with the patient by the physician
on pain characteristics. The total score is 10. It was expected to see a significant
decrease following treatment.
A significant decrease of 1.38 ± 1.79 points was obtained in DN4 from Baseline (Day
1) to Day 30 (week 4, n=42). 5.90 points at Baseline to 4.52 points at week 4,
P<0.0001, non-parametric test. Total Score decreased at 27 subjects and increased
at 3 subjects, 12 subjects had no change.
A non-significant decrease was obtained after 12 weeks, 0.80 ± 1.40 (p=0.10, n=10).
5.00 points at Baseline to 4.20 points at week 12
5) Changes from baseline week (day -7 to day 1) to week 4(day 23-30) and week
12 (day 83-90) in the weekly average daily sleep interference score.
Data of daily sleep interreference from baseline to week 4 was received from 42
subjects. A significant decrease of 0.87 ± 2.50 (p=0.009) points was obtained . 4.67
points at baseline to 3.80 points at week 4, n=42.
subjects. A non-significant decrease of 0.90 ± 1.44 (p=0.12) was obtained . 5.09 points
at baseline to 4.19 points at week 12, n=10.
6) Changes from baseline week (day -7 to day 1) to week 4(day 23-30) and week 12
(days 83-90) in weekly consumption of rescue analgesics (i.e. number of
paracetamol 500mg tablets taken per week)
Data of rescue analgesics were asked to be recorded by the subjects in their diaries.
However, the data was not recorded properly and the study coordinators could not
record informative data in the CRF as required. Subjects who used paracetamol
reported dose of 500mg “as needed”.
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7) Changes in blood pressure in hypertensive subjects from baseline day 1 to day
30 and day 90
At day 1 visit (Baseline) and Day 30, blood pressure was measured in the supine
position before (after 5 minutes rest) and after 15 minutes shoe use in the clinic.
At day 90 blood pressure was assessed once in the clinic during the visit.
The measurements used to compute the change in blood pressure from baseline day
1 to day 30 were the measurement before shoe use in the clinic at baseline and the
measurement after shoe use in the clinic at day 30.
The measurements obtained showed no change. The paired t-test was used to assess
significance.
Table 6 presents the measurements changes (and absolute measurements at each
time point in brackets) for Hypertensive subjects only.
Hypertensive subjects were defined by the investigator in a separate yes/no
question in the CRF and based on the subject’s medical history.
A total of 30 subjects were defined as hypertensive within the ITT cohort.
Results are presented for the Systolic blood pressure (BP) and Diastolic BP
separately.
Table 6: Changes in blood pressure in hypertensive subjects from baseline day 1 to day 30
N Minimum Maximum Mean Std. Deviation p-value
Change from BL to 30 -29.00 30.00 1.53 15.09 0.58

D30 Systolic BP (138.20, 139.73)
Change from BL to 30 -18.00 16.00 -0.63 8.39 0.68
D30 Diastolic BP (77.77, 77.13)
*Not Significant
Only 4 Hypertensive subjects reached day 90 visit. Therefore, statistical tests were
not done. The following table presents the BP data of the 4 subjects
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Table 7: Blood pressure in hypertensive subjects at baseline day 1 to day 90 and change per subject
BL Systolic D90 Systolic BL Diastolic D90 Diastolic Change BL to Change BL to

BP BP BP BP D90 Systolic BP D90 Diastolic BP
135 107 67 57 -28.0 -10.0
140 132 83 79 -8.0 -4.0
147 163 76 70 16.0 -6.0
117 137 82 85 20.0 3.0
Total N 4 4 4 4 4 4
8) Changes in blood pressure taken before and after 15 min use of Medic Shoes on
At day 1 visit (Baseline) and Day 30 blood pressure was measured in the supine
The following table presents the changes between the measurements before and
after the shoes’ use at Baseline and Day 30.
No significant changes were obtained
Table 8: Changes in blood pressure taken before and after 15 min use of Medic Shoes on day 1 and day
30.
BL Systolic BP Change 47 -26.0 36.0 0.3 10.82 0.85*

Before to after shoe use (135.5, 135.8)
BL Diastolic BP Change 47 -31.0 21.0 -0.7 7.82 0.54*
D30 Systolic BP Change 42 -21.0 24.0 0.4 8.74 0.77*
D30 Diastolic BP Change 42 -12.0 16.0 0.1 5.64 0.96*
*Not Significant
9) Change in HbA1c from screening (day -7) to day 30 and day 90

A non-significant change was obtained from HbA1c (Units-%) at screening to HbA1c
at day 30 and day 90.
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Week 4 (n=42): A decrease of 0.007 ± 0.56 (p=0.24, non-parametric test. HbA1c
increased at 25 subjects and decreased at 16 subjects, 1 no change).
HbA1c at baseline: 7.63 ± 1.19 HbA1c at week 4: 7.63 ± 1.00
Week 12 (n=7): An increase of 0.48 ± 0.65. HbA1c at baseline: 7.34 ± 0.81 HbA1c at
week 12: 7.82 ± 0.70
2.7.2.2 Per Protocol (PP) Cohort
33 Subjects who met inclusion and inclusion criteria and fulfilled the study protocol
deviations that may affect study results were included in the week 4 analysis. As for
week 12, there is no change in number of patients between the ITT cohort and the PP
cohort. Therefore, secondary endpoint for the PP cohort will be presented in this
section only for the week 4 (Day 30) analysis.
1) Change from the baseline week (day-7 to day 1) to week 4 (day 23-30) in the
weekly maximum daily pain intensity as measured on a 11-point numerical pain
scale (NPS)
The change is the difference between the weekly maximal daily pain intensity
measured during the Run-in week, reported at visit 2 and the weekly maximal daily
the change. The test obtained non- significance (p=0.2) so the null hypothesis for
The mean weekly maximal daily pain intensity measured using the NPS at baseline
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The mean weekly maximal daily pain intensity measured using the NPS at week 4
A decrease of 1.77 ± 2.29 points was obtained. The decrease was significance; p-
value <0.0001
2) Changes from baseline week (day-7 to day 1) to week 12 (day 83-90) in the
weekly average and maximum daily pain intensity as measured on a 11-point
numerical pain scale (NPS)
Same results as for the ITT cohort.
3) Changes from end of baseline day 1 to day 30 and day 90 in Short-Form McGill
The Short-Form McGill Pain Questionnaire was provided to the patients at Day 1,
Week 4 (primary endpoint) and week 12. The form is constructed of 3 sections.
Section A: 15 questions described patients feeling of pain graded from 0 (None) to 3
(Severe).
Section B: A line represents pain of increasing intensity from “no pain” to “worst
possible pain”. The patient was required to place a vertical line (|) across the line in
the position that best describes his pain during the past 7 days. The investigator then
used a ruler to measure and score the line from 0 to 100 mm.
Section C: Present of pain intensity from No Pain to Excruciating (total of 6 grades 0-
5)
Results:
Section A- The sum of the 15 questions grade was calculated at Baseline, Week 4
and week 12. The change between baseline and week 4 was calculated.
A significant decrease was obtained between baseline and week 4; 3.45 ± 8.50 points
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Section B-
The change variability from Baseline to week 4 was wide. Therefore, a non-
significant decrease was obtained at both FU visits (Week 4; D30 and week 12; D90).
The average decrease standard deviation minimum maximum and p-value are
presented in table 9 for each visit.
Table 9: Investigator pain score by ruler (mm) from Baseline to Day 30

Ruler_BL_D30 33 -76 65 -9.66 37.361 0.15*
*Not Significant
Section C-
Pain intensity showed significant improvement (decrease) at week 4 in a non-
parametric test (Wilcoxon). The average decrease standard deviation minimum
maximum and p-value are presented in table 10 for each visit. Most of the patients
reported improvement (26) and the rest (7) no change.
Table 10: Pain Intensity Change from Baseline to Day 30

Pain Intensity BL toD30 33 -5 0 -1.79 1.317 <0.0001
4) Changes in DN4 criteria from end of baseline day 1 to day 30.

DN4 questionnaire was completed in an interview with the patient by the physician
on pain characteristics. The total score is 10. It was expected to see a significant
decrease following treatment.
A significant decrease of 1.39 ± 1.94 points was obtained in DN4 from Baseline (Day
1) to Day 30 (week 4, n=33). 5.91 points at Baseline to 4.52 points at week 4,
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P<0.0001, non-parametric test. Total Score decreased at 20 subjects and increased
at 3 subjects, 10 no change.
5) Changes from baseline week (day -7 to day 1) to week 4(day 23-30) in the
weekly average daily sleep interference score.
subjects. A significant decrease of 0.82 ± 2.23 (p=0.01) was obtained . 4.68 points at
baseline to 3.86 points at week 4, n=33.
6) Changes from baseline week (day -7 to day 1) to week 4(day 23-30) and week 12
(days 83-90) in weekly consumption of rescue analgesics (i.e. number of
paracetamol 500mg tablets taken per week)
Data of rescue analgesics were asked to be recorded by the subjects in their diaries.
However, the data was not recorded properly and the study coordinators could not
record informative data in the CRF as required. Subjects who used paracetamol
reported dose of 500mg “as needed”.
7) Changes in blood pressure in hypertensive subjects from baseline day 1 to day

30
At day 1 visit (Baseline) and Day 30, blood pressure was measured in the supine
The measurements used to compute the change in blood pressure from baseline day
1 to day 30 were the measurement before shoe use in the clinic at baseline and the
measurement after shoe use in the clinic at day 30.
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The measurements obtained showed no change. The paired t-test was used to assess
significance.
Table 11 presents the measurements changes (and absolute measurements at each
time point in brackets) for Hypertensive subjects only.
Hypertensive subjects were defined by the investigator in a separate yes/no
question in the CRF and based on the subject’s medical history.
A total of 2 subjects were defined as hypertensive within the PP cohort.
Results are presented for the Systolic blood pressure (BP) and Diastolic BP
separately.
Only 3 Hypertensive subjects reached day 90 visit. Therefore, statistical tests were
not done.
Table 11: Changes in blood pressure in hypertensive subjects from baseline day 1 to day 30
Change_BL_D30_SysBP 23 -29.00 30.00 0.39 15.15 0.90*

(139.48, 139.87)
Change_BL_D30_DiaBP 23 -18.00 15.00 -1.21 8.32 0.49*
(78.65, 77.43)
*Not Significant
8) Changes in blood pressure taken before and after 15 min use of Medic Shoes on
At day 1 visit (Baseline) and Day 30 blood pressure was measured in the supine
The following table presents the changes between the measurements before and
after the shoes’ use at Baseline and Day 30 for all subjects (not only Hypertensive).
No significant changes were obtained
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Table 12: Changes in blood pressure taken before and after 15 min use of Medic Shoes on day 1 and
day 30.
N Minimum Maximum Mean Std. Deviation P-Value
BL Systolic BP Change 41 -26.00 36.00 0.43 11.27 0.80*

BL Diastolic BP Change 41 -31.00 21.00 -0.56 7.75 0.65*
D30 Systolic BP Change 33 -21.00 24.00 -0.09 9.69 0.96*
D30 Diastolic BP Change 33 -12.00 16.00 -0.69 5.79 0.50*
*Not Significant
9) Change in HbA1c from screening (day -7) to day 30 and day 90

A non-significant change was obtained from HbA1c (Units-%) at screening to HbA1c
at day 30.
Week 4 (n=33): A decrease of 0.02 ± 0.57 (p=0.13, non-parametric test. HbA1c
increased at 20 subjects and decreased at 12 subjects, 1 subject had no change).
2.7.3 Safety Analysis

The safety endpoints are serious adverse events (SAEs) and adverse events (AEs)
related to treatment with the Medic Shoe.
All adverse events (AE) and all serious adverse events (SAE) were accurately
recorded on the Adverse Event/Serious Adverse Event page(s) of the CRF. The
investigator carefully evaluated the seriousness, severity, duration, and causality of
adverse events and document the following on the CRF:
 Severity. The following grading scale will be used: Mild (Grade 1), Moderate
(Grade 2), Severe (Grade 3)
 Duration of the event. The date of onset, duration of the event, method used to
treat the AE, and the outcome of the AE should be noted.
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 Relationship to study device: Related or unrelated
Any death, serious adverse event (SAE), Unexpected Serious Adverse Device Effect
(USADE) occurring in a subject while using the device or within 30 days of use, even
though the event may not appear to be related to device, was promptly reported
(within 24 hours) by telephone, fax, or e-mail to the sponsor’s designee, Stephen
Levenstein, MD from GCP Clinical Studies in Rosh Ha’Ayin.
2.7.3.1 Safety Analysis Set and results
The safety analysis set is consisted of all subjects who used the Medic Shoes with
vibration at least once even less than 15 minutes of use.
The safety analyses are descriptive and narrative in nature, with SAEs and related AEs
tabulated by body system, preferred term, severity and relation to procedure.
Frequency counts are presented.
A total of 23 events reported by 17 subjects.
The SAEs and related AEs are bolded in table 13.
Three (3) Definitely/possibly related events were reported; Erythema, Pain in
extremity and Telangiectasia.
One (1) subject reported of worsening in neuropathic pains (Neuralgia) unknown if
related to the device.
Two (2) unrelated SAEs reported. One led to a death; drowning. The other led to
hospitalization prolongation; Abdominal hernia repair
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Table 13: Adverse Events
Related to
Study
AE serious Device SOC Preferred Term N
No Definitely Skin and subcutaneous tissue disorders Erythema 1
Total 1
Possibly Musculoskeletal and connective tissue disorders Pain in extremity 1
Skin and subcutaneous tissue disorders Telangiectasia 1
Total 2
Unknown Nervous system disorders Neuralgia 3

Total 3
Unrelated Gastrointestinal disorders Aphthous ulcer 1
Diarrhoea 1
General disorders and administration site conditions Medical device 1
pain
Peripheral 1
swelling
Pyrexia 1
Infections and infestations Influenza 1
Injury, poisoning and procedural complications Ligament sprain 1
Musculoskeletal and connective tissue disorders Back pain 1

Pain in extremity 2
Neoplasms benign, malignant and unspecified (incl Neoplasm 1
cysts and polyps) malignant
Nervous system disorders Dizziness 1
Neuralgia 1
Surgical and medical procedures Carpal tunnel 1
decompression
Dental 1
implantation
Total 15
Yes Unrelated General disorders and administration site Drowning 1

conditions
Surgical and medical procedures Abdominal 1
hernia repair
Total 2
Total 23
Severity: 16 of the events reported as mild, 5 as moderate and 2 as severe (the

SAEs).
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Action taken: 13 cases needed no action, 5 drug therapy and 5 discontinued in
the study
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2.7.4 Device deficiencies
Device Deficiency was reported by the patients during the study. Most of the
complaints were charging issues, shoes not working. The complaints were reported
to the Sponsor who immediately changed the shoes. An internal analysis was done
by the company and it was decided to provide a spare pair of shoes to each patient
to avoid treatment non-compliance due to technical issues.
Table 14: Device Deficiency Report
Deficiency type Device Deficiency Details
Other 1 The shoes size was smaller than the subject needed.
2 The upper seam in the shoe pressed on the patient's foot. because of
that the subject felt uncomfortable with the shoes, probably since they
were too small for him.
3 The upper seam in the shoe is pressed on the patient's foot. because of
that the subject felt uncomfortable with the shoes, probably since they
were too small for him.
Total 3
Technical problem 1 The patient's shoes broke down
2 Just one shoe is working
3 The patient did not perform the treatment on one foot 8 times because
his left shoe didn't work
4 The left shoe stops in the middle of the treatment and needs to be
restarted again.
5 The shoe did not work
6 Shoes not working. Glowing red light
7 Shoes not working. Glowing red light
8 The patient's right shoe stops working after a few seconds despite
being loaded
9 The charger cable is not working properly. In addition, sometimes the
shoes were turned off in the middle of treatment and had to be re-lit.
10 The shoes stopped working after 2-3 minutes of operation even though
they were fully charged
11 The shoes stopped working after 1 minute
12 one shoe can not be charged
13 difficulty to charge left shoe
14 the high vibration both shoes did not work
15 both shoes do not work
16 charging problem
17 the left shoe stops working after 7 minutes of treatment
18 1.charging problem. 2.The left shoe stops after 7 minutes
19 1.charging problem (left shoe). 2.The left shoe stops after 7 minutes.
20 charging problem.
21 charging problem.
22 charging problem
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23 the right shoe stops working after 15 minutes of treatment
24 strange noises at left shoe when it works
Total N 27
3 Overall conclusions
Effectiveness Analysis:
The use of Medic Shoes has shown a significant improvement in the mean weekly
average daily pain intensity measured using the NPS. The primary endpoint.
Improvements were shown also in the maximal daily pain intensity measured using
NPS, DN4 questionnaire, sleep interference score and Short McGill Questionnaires (at
section A and C).
No changes were obtained in Blood pressure and HbA1c parameters.
Changes in rescue medication could not be assessed due to an uninformative records
in the patients’ diaries…
Improvements were obtained at week 4, the primary endpoints visit.
Results for Intention to treat (ITT) and Per protocol (PP) have shown the same trend.
Only 10 subjects achieved week 12 of FU, therefore, most of the results did not show
statistical significance changes. A further investigation for the long term period is
required to conclude.
Safety Analysis:
The device has been shown to be safe without significant side effects.
SAEs reported were not related to the device.
48
Confidential

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Medic Shoe Ltd.

CLINICAL STUDY REPORT

A Phase 3 study to assess the efficacy and safety

Date 20 September 2018

Name: Medic Shoe Ltd.

Address: 41 Gordon st.

Name: Professor Julio Wainstein

Center01: Wolfson Medical Center

Study CRO, Author and study

GCP Clinical Studies

Protocol No. MS1

Version 1: 20 September 2018

Study Phase Phase 3

Medic Shoes Ltd.

Medic Shoes Ltd.

GCP Clinical Studies Ltd.

GCP Clinical Studies Ltd.

1.1 Title of Clinical Investigation

1.2 The Purpose of the Clinical Investigation

1.2.1 Primary Endpoint

1.2.2 Secondary Performance Endpoint

1.2.3 Secondary Safety Endpoint

1.3 Description of the Population

1.3.1 Inclusion Criteria

Day 1 Inclusion Criteria

1.3.2 Exclusion criteria

1.3.3 Sample Size

1.4 Clinical Investigation Methods

1.4.1 Methods of study

This was a single-arm, open-label, study to be conducted at two centres in Israel.

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

 Average and maximum daily pain intensity as measured on an 11-point numerical

1.5 Investigational Study Device

1.6 Study Arms

This is a non-comparative single arm study.

1.7 Study Duration

1.8 Data Analysis and Statistical Methods

Safety Analysis Set

Primary Efficacy Analysis Set

Secondary Efficacy Analysis Set

1.8.1 Statistical Analysis

1.8.1.2 Primary Endpoint.

1.8.1.3 Secondary Endpoints

A p-value of less than 5% (0.05) was considered statistically significant.

2.3 The Disposal of Subjects and Investigational Device

Screen Failures Eligible subjects that

Subject ID Reason for Screen Failure

Inclusion #5: Average of 4 to 9 in the weekly average daily

01-023 SAE, not device related

02-004 Low Compliance during Run-in

02-011 Withdrew Consent. Did not arrive to Visit 2

Inclusion #4: Presence of ongoing pain due to DPN for at

Inclusion #4: Presence of ongoing pain due to DPN for at

Inclusion #5: Average of 4 to 9 in the weekly average daily

Inclusion #4: Presence of ongoing pain due to DPN for at

02-026 AE, not device related

02-028 Withdrew Consent. Did not arrive to Visit 2

2.4.1 Ethnicity Age and Gender

2.4.2 Concomitant Medication

The Table does not include data from screen failures:

Table 2: Concomitant Medication

2.4.3 Medical History

Musculoskeletal and connective Arthralgia 1