8 - Studi Therapeutik - Rev

Therapy Study
Sitti Wahyuni
Evidence Based Medicine
Same slides modified from P.Trihono’s

CEEBM Unit, Cipto Mangunkusumo Hospital Faculty of Medicine
Universitas Indonesia
Clinical trial
• Is the specific form of EXPERIMENTAL STUDY (INTERVENTIONAL
STUDY)
• To determine cause – effect relationship
• The investigator assigns who should receive which treatment, and
analyzes the outcome of the intervention
• A cohort- prospective- interventional- experiment- controlled study
29/11/2022 Sitti Wahyuni/ EBM 2

Level of evidence in Therapeutic Study

Structure of a Simple Trial
Comparing Two Treatments
Population of patients
with condition

Classification of clinical trial
1. Type of intervention
• Majority form: Concern with the evaluation of drug therapy (drug trials)
• Other forms: Surgical procedures, radiotherapy for cancer, medical advice
(diet, psychological approach, health education, etc)
2. Objective of the study
• Pragmatic trial
• Explanatory trial

Pragmatic trial
• Attempt: To determine
Y
the cause-effect c a
relationship
• Assuming the
results will be
applied in actual Exp N
clinical practice
R b
• Preferably: binomial
outcome (Yes/ No)
Ctrl Y
• Analysis: Intention to
treat analysis where all
randomized subjects are
accounted for the final N
calculation according to
their original allocation
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a, b, & c are accounted
Sitti Wahyuni/ EBM
as failure of Exp arm 7
Explanatory trial
• Attempt to explain the cause-effect relationship
• Usually in laboratory investigations (pharmacology,
pharmacodynamics, etc)
• Analysis is on treatment analysis:
• only subjects who completed the trial are accounted in the
analysis
• Only minimal dropout is allowed, or replacement for dropouts

Key elements of RCT
Control
Randomization
Blinding
• Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

• Randomized Controlled Clinical Trial
1. Control
• The essence of any research is a comparison
• Compare the experience of a group of patients on new tx with a
control group of similar patients receiving standard tx
• Results of clinical trial based on different effects between control and
experiment groups

2. Randomization
• Random allocation/ assignment
• The process of assigning trial subjects to treatment or control group
using an element of chance to determine the assignments in order
to reduce bias
• Random allocation:
• Aimed to create comparable groups
• Balances the groups for prognostic factors
• If it not distributed evenly, it may exaggerate, cancel or counteract the effects
of treatment

Randomization
SINE QUA NON --- TRUE EXPERIMENTAL

To exclude CONFOUNDING BIAS
Usually = start of trial
Confounder
• Variable that explains (partially or wholly) the association between
independent and dependent variables, or masks the existing
association
• Might be unevenly distributed between experimental and control
groups
Example
Maternal Low birth weight
nutritional status infant
Low
social status
Another example of confounding
Drinking Drinking
Coffee Coffee
Smoking
Cigarettes
Pancreatic
Cancer
Pancreatic
Cancer
The relationship between coffee drinking and pancreatic cancer is confounded by

cigarette smoking.
3. Blinding= Masking
• A procedure in which one or more parties to the trial are kept unaware of the
treatment assignment
• Aim
• To reduce or eliminate bias, esp. measurement bias
• To avoid patients’ reporting symptoms or clinician’s interpretation being
affected by hunches about whether the treatment is effective
• Highly recommended whenever applicable
• May single or double blind (the patient, the treatment team, the evaluator, data
analysts)
• Double blind prevent patient and clinician from adding additional treatment to
just one of the groups
Is it really effective?
INTERVENTION Outcome
Drug A 70% cure rate
STUDY
PARTICIPANTS R
CONTROL Outcome
Drug B 50% cure rate

Influential factors for treatment outcome
If a patient treat with drug E and get the OutCome, the outcome (OC)
may be influenced by one or more of the following:
⚫ TE→ The treatment effect of d r u g
⚫ NC→ The natural course of the disease (including risk profile of the patients)
⚫ EF→ The extraneous factors given besides d r u g E
• Attention of the physician,etc
• Psychology of patient OC = TE + NC + EF + IE
• Adjustment lifestyle
• Co-medication
⚫ IE→ The measurement / information about the outcome

Are they really different?
NC1 + EF1 + IE1 + TE1 = TO1
NC2 + EF2 + IE2 + TE2 = TO2
NC = Natural Course: age, stage of disease, etc

EF = Extraneous Factors: concurrent drugs, more attention
IE = Information Error = measurement of outcome
TE = Treatment Effect
TO = Treatment Outcome

Are they really different?
NC1 + EF1 + IE1 + TE1 = TO1
NC2 + EF2 + IE2 + TE2 = TO2
NC= Natural Course: age, stage of disease, etc

EF= Extraneous Factors: concurrent drugs,
Blinding more attention
IE= Information Error = measurement of outcome
TE= Treatment Effect
Masking/blinding
TO= Treatment Outcome
Randomization
Randomized double blind controlled trial
Randomize Blind Placebo

Natural course +
Bias(NB)
Experimental + +(patient) +
Bias(EB)
Information +(investigator) +
Bias (IB)

Critical appraisal of clinical trial
- valid ➢ methods
- important ➢ results
- applicable ➢ discussion

GATE (GraphicApproachTo Epidemiology):
identifying where errors occur in Epidemiology studies
RAMBOMAN
Recruitment
Allocation
Maintenance
Blind
Objective
Measurements
ANalyses

R-A-M-B-OM-AN
• R→ was recruited participants relevant to the study objectives?→ who are the
findings applicable to?
• A→ was allocation to EG & CG successful?→ RCT: Allocated by randomization
• M→ how well were participants maintained in the groups they were allocated to
(i.e. to EG & CG) throughout the study? completeness of follow-up, compliance,
contamination co- interventions
• B→ Were outcomesmeasured blind to whether participant ( both ?)
• OM→ Were Outcomes Measured objectively?
• AN→ Were the ANalysis done appropriately?→ Intention to treat?

A. Validity
Primary guides
1. Was the assignment of patients t treatment randomized?→ Was the
randomization list concealed?
2. Was the follow up sufficiently long and complete?
3. Were all patients analyzed in the groups to which they were randomized?
Secondary guides: Some less important points

1. Were patients, health workers, and study personnel “blind” to
treatment?
2. Were the groups treated equally apart from the experimental therapy?
3. Were the groups similar at the start of the trial?

B. Importance
1. To measure the magnitude of the treatment effect

• P- value
• Relative Risk Reduction (RRR)
• Relative Risk Increase (RRI)
• Absolute Risk Reduction (ARR)
• Absolute Risk Increase (ARI)
• Number Needed to Treat (NNT)
• Number needed to harm (NNH)
2. To measure the precise is the treatment effect

• Construct Confidence Interval (CI)

Exercise
• Klissen TP, Feldman ME, Watters LK, Sutcliff T, Rowe PC. Nebulised budesonide for
children with mild to moderate croup. N Eng J Med 1994;331(5): 285-9.
• A randomized double-blind control trial on 3 mo – 5 yr old children with mild to
moderate croup (laryngotracheobronchitis)
• The experimental group: 2mg (4 ml) nebulized budesonide
• The control group: 4 ml nebulized normal saline.
• The event being prevented: hospital admission due to upper-airway obstruction
• Study protocol 54 children
• 27 (1 hospitalized, 26 non-hospitalized)→ received Budesonide
• 27 (7 hospitalized, 20 non-hospitalized)→ received NACL

The study protocol
1 HOSPITALIZED
27
NON
26 HOSPITALIZED
N=54 R
7 HOSPITALIZED
27
NON
20 HOSPITALIZED
Budesonide HOSPITALIZED
Normal saline NON HOSPITALIZED
Exercise
Upper airway obstruction
No Yes
Budesonide→ E 26 1 27
NaCl →C 20 7 27
X2 = ; df = 1; p = 0.04
CER = 7/27 = 0.26
EER = 1/27=0.04
RRR = (CER-EER)/CER = (0.26-0.04)/0.26 = 85%
• Is the percent reduction in risk in treated group compared to the control group
• Is a measure of how much the treatment studied has reduced the frequency of an adverse event
Exercise→ RRR
Control Experimental Relative risk
Event Rate (CER) Event Rate (EER) Reduction (RRR)
CER-EER) / CER
In the actual trial 26% 4% 85%
In the hypothetical 0.026% 0.004% 85%

trivial case

• Is the percent reduction in risk in treated group compared to the control group
• Is a measure of how much the treatment studied has reduced the frequency of an adverse event
• is the difference in risk between the control
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group and the treatment group
Sitti Wahyuni/ EBM 29
Exercise→ NNT
Upper airway
obstruction • CER = 7/27 = 0.26;
No Yes • EER = 1/27=0.04
• ARR = [CER-EER] = 0.26-0.04 = 0.22
• NNT = 1/ARR = 1/0.22 = 5
NaCl →C 20 7 27

• NNT= number needed to treat
• is the difference in risk between the control
• number of patients should be treated to group and the treatment group
avoid 1 bad outcome
• NNT = 1 / ARR

Interpretation
Number Needed to Treat (NNT)
• The Number Needed to Treat (NNT) is the number of children with light-mild
laryngopharyngeal- bronchitis you need to treat with Budesonide to prevent one
additional bad outcome (upper respiratory obstruction)
• If Budesonide has an NNT of 5, it means you have to treat 5 children with
Budesonide to prevent one additional child to be hospitalized due to upper
respiratory obstruction.

Exercise
IF= adverse effect
Mild Fever
No Yes
NaCl →C 21 6 27
CER = 6/27 = 0.2 • NNH= number needed to harm
EER = 19/27=0.7 • The number of patients needed
to harm (exposed) to increase
ARI = [CER-EER] = 0.2-0.7 = 0.5 one bad outcome
RRI = [CER-EER]/CER= 0.5/0.2=2.5 • NNH = 1 / ARI
NNH = 1/ARI = 1/0.5 = 2 • ARI: Absolut Risk Increase
Interpretation
Number Needed to Harm (NNH)
• The Number Needed to Harm (NNH) is the number of children with light-mild
laryngopharyngeal- bronchitis exposed to Budesonide to increase the risk of
having one additional mild fever
• If Budesonide has an NNH of 2, it means if you treat 2 children with Budesonide
you will have one additional child with mild fever

Summary of risks and benefits of therapy
Outcome CER EER RRR ARR NNT
Upper-airway 26% 4% 85% 22% 5
obstruction
• NNT: We would need to treat 5 children with group to prevent one additional
child from being hospitalized due to upper-airway obstruction
Outcome CER EER RRI ARI NNH

Mild fever 20% 70% 250% 50% 2
70%
• NNH: We would only treat 2 children with group 250% 50% 2
to harm one more child
NNT and NNH provide us a measure of the effort to expend

to prevent or cause 1 more bad outcome an effort : yield ratio
Control Event Experimental Absolute Risk Teduction NNH
Rate Event Rate
CER EER ARR (CER-EER) 1/AAR
In the trial 26% 4% 22% 2
In the 0.00026 0.00004 0.00022 5000

hypothetical
trivial case
CER = 6/27 = 0.26

EER = 1/27=0.04
ARR = (CER-EER) = 0.26-0.04 = 0.22
NNT = 1/ARR = 1/0.22 = 5

Confidence interval (CI)
NNT
is to precise the treatment effect CER = 6/27 = 0.26
EER = 1/27=0.04
CI for NNT (1/ARR) ARR = (CER-EER) = 0.26-0.04 = 0.22
NNT = 1/ARR = 1/0.22 = 5
• Calculate CI for ARR (diff
between proportion) 95%CI ARR
• Calculate 1/(upper CL of ARR) = ARR + 1.96 V(p1q1/n1 + p2q2/n2)
and 1/(lower CL of ARR) = 0.22 + 1.96 V(0.26x0.74)/27+(0.04x0.96/27)
= 0.22 + 1.96 x 0.092
= 0.22 + 0.18 = 0.04 ; 0.40
95%CI NNT
= 1/0,40 ; 1/0.04
= 3 ; 25
Applicability
Can you apply this valid, importantevidence about a treatment in caring for your
patient?
• Do these results apply to your patient?
• Is your patient so different from those in the trial that its results can not
help you?
• Is the treatment feasible in your setting
• Are your patient’s values and satisfied by the regimen? And its preferences
consequences?
• Do your patient and you have a clear assessment of their values and
preferences?
• Are they met by this regimen and its consequences?

8 - Studi Therapeutik - Rev

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Therapy Study

Same slides modified from P.Trihono’s

29/11/2022 Sitti Wahyuni/ EBM 2

29/11/2022 Sitti Wahyuni/ EBM 4

29/11/2022 Sitti Wahyuni/ EBM 5

29/11/2022 Sitti Wahyuni/ EBM 6

29/11/2022 Sitti Wahyuni/ EBM 8

• Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

29/11/2022 Sitti Wahyuni/ EBM 10

29/11/2022 Sitti Wahyuni/ EBM 11

SINE QUA NON --- TRUE EXPERIMENTAL

The relationship between coffee drinking and pancreatic cancer is confounded by

29/11/2022 Sitti Wahyuni/ EBM 16

29/11/2022 Sitti Wahyuni/ EBM 17

NC1 + EF1 + IE1 + TE1 = TO1

NC2 + EF2 + IE2 + TE2 = TO2

NC = Natural Course: age, stage of disease, etc

29/11/2022 Sitti Wahyuni/ EBM 18

NC1 + EF1 + IE1 + TE1 = TO1

NC2 + EF2 + IE2 + TE2 = TO2

NC= Natural Course: age, stage of disease, etc

Randomize Blind Placebo

29/11/2022 Sitti Wahyuni/ EBM 20

29/11/2022 Sitti Wahyuni/ EBM 21

29/11/2022 Sitti Wahyuni/ EBM 22

29/11/2022 Sitti Wahyuni/ EBM 23

Secondary guides: Some less important points

29/11/2022 Sitti Wahyuni/ EBM 24

1. To measure the magnitude of the treatment effect

2. To measure the precise is the treatment effect

29/11/2022 Sitti Wahyuni/ EBM 25

29/11/2022 Sitti Wahyuni/ EBM 26

In the actual trial 26% 4% 85%

In the hypothetical 0.026% 0.004% 85%

• Relative Risk Reduction (RRR)

• Absolute Risk Reduction (ARR)

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Outcome CER EER RRI ARI NNH

NNT and NNH provide us a measure of the effort to expend

In the 0.00026 0.00004 0.00022 5000

CER = 6/27 = 0.26

29/11/2022 Sitti Wahyuni/ EBM 35

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