CLINICAL TRIALS

Digant Gupta, MBBS, MPH

July 2019
 AGENDA

 Introduction
 Study question
 Study population
 Clinical trial designs
 Blinding
 Data collection and quality control
 Adverse effects
 Data analysis
 Reporting
Introduction

3
 INTRODUCTION TO CLINICAL TRIALS

A properly planned and executed clinical trial is a

powerful experimental technique for assessing the
effectiveness of an intervention..
 INTRODUCTION (CONT’D)..

Definition:

Clinical trial:

 Is a prospective study

 Compares effect and value of interventions

 Against a control in human beings

 INTRODUCTION (CONT’D)..

NEED FOR CLINICAL TRIALS?

 Determine whether the intervention has the postulated

effect
 To evaluate the benefit of an intervention and the
unwanted effects to recommend its use
 INTRODUCTION (CONT’D)..

PHASES OF CLINICAL TRIALS:

There are four phases:

 Phase I
 Phase II
 Phase III
 Phase IV
 INTRODUCTION (CONT’D)..

PHASE I CLINICAL TRIALS:

 “First In Man Studies”

 20 to 100 healthy volunteers

Objectives:

 Determine the pharmacokinetics and pharmacological

action of the Investigational product (IP)
 Assess adverse effects associated with different doses
 Get an indication about the efficacy
 Determine the Maximum tolerated dose (MTD)
 INTRODUCTION (CONT’D)..
PHASE II CLINICAL TRIALS:

 Performed after completion of Phase I studies when

sufficient safety data are obtained
 100 to 200 patients having the target disease but no other
confounding illness

Objectives:

 Efficacy demonstrated by the IP for the proposed indication

within the safe dose range as established in Phase I
 Short term adverse effects and risks are also assessed
 INTRODUCTION (CONT’D)..

PHASE III CLINICAL TRIALS:

 Done in large patient population (usually thousands)

 They are the type of patients that the IP is intended to treat
after it is marketed

Objective:

 Compare the new treatment with current standard

 INTRODUCTION (CONT’D)..

PHASE IV CLINICAL TRIALS:

 Also called “Post Marketing Surveillance studies”

 Done after the approval by FDA

Objectives:

 Condition of approval by FDA

 Long term safety studies required by FDA
Study question

12
 QUESTION UNDER STUDY

Each clinical trial must have a primary question. The

primary question as well as any secondary or subsidiary
questions, should be carefully selected, clearly defined and
stated in advance..
 QUESTION UNDER STUDY (CONT’D)..

Primary question?

Primary question is one which..

 Is capable of being adequately answered

 Determines the sample size of the study

Secondary question?

 The data collected for the purpose of answering the

primary question may also elucidate the secondary
questions
 QUESTION UNDER STUDY (CONT’D)..

Adverse effects

 Important questions about adverse effects should be

answered by the trial

 Nature and severity of adverse effects may be

unpredictable and cannot be specified before the study
 QUESTION UNDER STUDY (CONT’D)..

Natural history

 It is possible to study the natural history of a disease in

patients receiving either a placebo or no systematic
treatment by studying the baseline factors and their relation
to the specific outcomes

 Not the study hypotheses. Questions need not be specified

in advance
Study population

17
 STUDY POPULATION

The study population should be defined in advance, stating

unambiguous inclusion (eligibility) criteria. The impact that
these criteria will have on the study design, ability to
generalize and participant recruitment must be
considered..
 STUDY POPULATION (CONT’D)..

Definition:

Study population is:

 Subset of the population

 With the condition of interest

 Defined by eligibility criteria

 STUDY POPULATION (CONT’D)..

Population at large
Population
without Definition
condition of
condition
Population with condition

With
Entry
condition
criteria
but
ineligible
Study population

Eligible enrollment
but not
enrolled
Study sample
 STUDY POPULATION (CONT’D)..

Let us take an example:

In a study of survivors of Myocardial infarction we may

want to exclude people with severe hypertension. We will
have to specify the following criteria:

 Diastolic blood pressure over a specified limit (above 105 mm of Hg)

 How blood pressure will be determined?
 When is it to be determined?
 Which instrument is to be used?
 Who should measure it?
 Under what circumstances it is to be determined?
Clinical trial designs

22
 CLINICAL TRIAL DESIGNS

Sound scientific clinical investigation almost always

demands that a control group be used against which
the new intervention can be compared. Randomization
is the preferred way of assigning participants to control
and interventions group..
 CLINICAL TRIAL DESIGNS

They are of following types:

 Randomized control studies

 Non randomized concurrent studies
 Historical controls/Databases
 Parallel designs
 Cross over designs
 Factorial designs
 Studies of equivalency
 CLINICAL TRIAL DESIGNS

Randomized clinical trial is a prospective

study comparing the effectiveness of an
intervention against a control

Intervention Control
Drug(s) Placebo
Surgery No intervention
Device Best standard therapy
Behavior Modification
 CLINICAL TRIAL DESIGNS

Control group:
The group of subjects in a controlled study that receives no
treatment, a standard treatment, or a placebo.

Why control?
To allow discrimination of patient outcomes caused by
experimental intervention from those caused by other
factors
• Natural progression of disease
• Observer/patient expectations
• Other treatment
 CLINICAL TRIAL DESIGNS

Randomization:

 The process of assigning trial subjects to treatment or

control groups using an element of chance to determine
the assignments. Each patient has the same chance of
receiving any of the treatments under study

Why randomize?

 To reduce bias
 To produce more comparable groups

Disadvantage:
 Patient receiving placebo could be deprived of the new
therapy which may have been beneficial
 CLINICAL TRIAL DESIGNS
HOW IS RANDOMIZATION DONE?
 CLINICAL TRIAL DESIGNS
Randomization..

Produces comparable study

groups with respect to known
and unknown risk factors..

Removes investigator
bias..

Guarantees statistical
tests will have valid
significance levels..
 CLINICAL TRIAL DESIGNS
RANDOMIZATION
Treatments: Patients
A – drug A
1,2,3,4,5,6,7,8,9,10,11,12,
B – drug B
C – drug C
13,14,15,16,17,18,19,20,21
D – placebo P 22,23,24,25,26,27,28,29,30

Randomization decides which patient will receive

which treatment. Allocation of treatments to participants
is carried out using a chance mechanism
so that neither the patient nor the physician
know in advance which therapy will be assigned
 CLINICAL TRIAL DESIGNS

RANDOMIZATION

 Simple randomization
 Blocked randomization
 Stratified randomization
 CLINICAL TRIAL DESIGNS

Simple randomization:

 Simplest randomization is the toss of a coin

 A random digital table is also used

 A random number producing algorithms on computers may

also be used
 CLINICAL TRIAL DESIGNS
Blocked randomization:

 Participants are randomly assigned to with equal probability to groups

A or B then for each block of even size one half of the participants are
assigned to A and the other half to B

For e.g.
The two groups A and B could have the following 6 combinations:
 AABB, ABAB, BAAB, BABA, BBAA and ABBA

 One of these arrangements is selected at random and the four

participants are assigned accordingly

 This process can be repeated as many times as needed

 CLINICAL TRIAL DESIGNS
BLOCKED RANDOMIZATION:
Advantages:

Block 1 Block 2 Block 3

AABB ABBA BABA

1. Helps to keep Same no. of patients in different

groups in Multicentre trials
 CLINICAL TRIAL DESIGNS
Disadvantages

Block 1 Block 3
ABBA BABA

The last treatment may reveal itself due to

a particular drug effect…e.g.,a drug which
colures urine, or causes loose stools etc

Overcome this by making

the Investigator blind to block length
 CLINICAL TRIAL DESIGNS

Stratified Randomization

If Sex and Age are known to affect the outcome,

Stratification Blocks
Sex Age Block 1 Block 2 Block 3
F 40-60 ABAB BBAA AABB
F > 60 BAAB ABBA BBAA
M 40-60 BAAB ABBA BBAA
M > 60 AABB BAAB BABA
 CLINICAL TRIAL DESIGNS
Advantages
1. Minimizes bias with known factors
2. Increases the power to detect differences

Disadvantages

1. Delays randomization reaching different

centers
2. ‘Misclassification’ of patients to strata may be
revealed at the completion of the study!!
 CLINICAL TRIAL DESIGNS

Non – randomized concurrent control studies:

 No randomization
 Patients are allocated to either the intervention group or
the control group but this is not a random treatment
For e.g.
Comparison of survival results of patients treated at two
institutions one using the surgical procedure and the other
using more traditional medical care

Disadvantage:
 Study groups not comparable
 CLINICAL TRIAL DESIGNS

Historical controls/Databases:

 Non – randomized
 Non – concurrent
 New intervention is used in a series of participants and the
results that are obtained are compared to the outcome in a
previous series of comparable participants
 CLINICAL TRIAL DESIGNS

Historical controls/Databases:

Advantages:
 All new participants receive the new treatment and nobody
is deprived of the new treatment
 Greater patient participation, faster recruitment

Disadvantages:
 Inaccurate data
 Missing data
 Potential bias in treatment assignment
 CLINICAL TRIAL DESIGNS

Parallel study:
A parallel designed clinical trial compares the results of a treatment on
two separate groups of patients
 CLINICAL TRIAL DESIGNS

Parallel study:

Advantages:
• Simple, General Use
• Valid Comparison
• Universally accepted
• Straight-forward interpretation of results as they provide assurance
that any difference between treatments is in fact due to treatment
effects (or random chance), rather than some systematic
differences between the groups of subjects.

Disadvantages:
• Requires greater sample size
 CLINICAL TRIAL DESIGNS

Cross over design:

 A crossover study compares the results of a two treatment

on the same group of patients
 Special case of randomized control trial
 Each participant serves as his own control
 Crossover designs are generally not used in vaccine trials
because the immune system is permanently affected (or at
least affected for a long time). Thus, carry over effects are
always present
 CLINICAL TRIAL DESIGNS
Cross over design:
 CLINICAL TRIAL DESIGNS
Cross over design:
Population Intervention Washout Placebo

Sample Randomization

Placebo Washout Intervention

Outcome Outcome
 CLINICAL TRIAL DESIGNS
Cross over design:
Advantages:
 The influence of confounding covariates is reduced because each crossover
patient serves as his or her own control (i.e. there is no imbalance on any of the
covariates)
 Smaller sample size

Disadvantages:
 These studies are often done to improve the symptoms of patients with chronic
conditions; for curative treatments or rapidly changing conditions, cross-over
trials may not be feasible or ethical.
 Carry-over Effect: The carry-over effect between treatments confounds the
estimates of the treatment effects. In practice, "carry-over" effects can be avoided
with a sufficiently long "wash-out" period between treatments. However, the
planning for sufficiently long wash-out periods does require expert knowledge of
the dynamics of the treatment, which often is unknown.
 CLINICAL TRIAL DESIGNS

Factorial design:

 Evaluate two interventions compared with control in a single experiment.

 The simplest factorial design has two factors, each with two levels. This is
called a 2 x 2 factorial design. A simple factorial design would have one group
testing therapy A, another testing therapy B, a third group testing A and B
combined, and a control group testing neither A nor B.

 The first Physicians' Health Study investigated the use of aspirin and beta-
carotene in the prevention of cardiovascular disease and cancer. The study
used a 2 x 2 factorial design, with the treatments being aspirin versus matching
placebo and beta-carotene versus matching placebo. A total of 22,071
participants were randomized to the four combinations of treatments: aspirin +
beta-carotene, aspirin + beta-carotene placebo, aspirin placebo + beta-
carotene and aspirin placebo + beta-carotene placebo.
 CLINICAL TRIAL DESIGNS

Factorial design:
 CLINICAL TRIAL DESIGNS

Factorial design:

Int A and Int B Outcome

Population
Int A and Pbo B Outcome

Sample
Pbo A and Int B Outcome

Pbo A and Pbo B Outcome

 CLINICAL TRIAL DESIGNS

Factorial design:

Advantages:
• A greater precision can be obtained in estimating the overall main
factor effects
• Interaction between different factors can be explored
• An efficient way to test medicines in combination

Disadvantages:
• Less attractive
• More expensive
• Difficult to interpret
 CLINICAL TRIAL DESIGNS

Studies of equivalency:
 Also called trials with positive control
 To test if the new intervention is as good as the established
one
 The standard treatment that is used as a control has to be
really effective
 When using similar treatments we could compare:
 ease of administration
 nature of adverse effects
 change in quality of life
 cost
Blinding

52
 BLINDING

WHY?

TO REDUCE BIAS

BIAS:

 The difference between the true value and that actually

obtained due to all causes other than sampling variability
 BLINDING

Design technique to avoid bias:

Randomization

Blinding
 BLINDING

Types of blinding:

 Unblinded trials/Open trials

 Single blind trials
 Double blind trials
 Triple blind trials
 BLINDING

Unblinded trials/Open trials

 Both the investigator and the participant know the treatment given

Advantages:
 Easy to design and simple to carry out
 Less expensive
 For e.g. studies on surgical procedures, lifestyle changes etc

Disadvantages:
 Possibility of bias
 High dropout rates in patients who are not satisfied with treatment
 BLINDING

Single blinded trials

 Only the investigator knows the treatment being given

Advantages:
 Easy to design and simple to carry out
 Less expensive
 Knowing the treatment the investigators can use their best judgment
while caring for the patient

Disadvantages:
 Possibility of bias. Since the researcher knows, it is possible for the
researcher to treat the patient differently or to subconsciously hint to
the patient important treatment-related details, thus influencing the
outcome of the study
 BLINDING

Double blinded trials:

 Neither the investigator nor the patient knows the treatment
assigned
 Most common study design

Advantages:
 Risk of bias is reduced
 BLINDING

Problems encountered in double blinding:

Matching of drugs:
 The treatment drug and the placebo have to be exactly identical in
size, shape, color, texture, odor, taste. The containers also have to be
the same

Solution:
 Enclosing the medications in capsules
 Double dummy
 A technique for retaining the blind when administering supplies in a clinical
trial, when the two treatments cannot be made identical. Supplies are
prepared for Treatment A (active and indistinguishable placebo) and for
Treatment B (active and indistinguishable placebo).
 Subjects then take two sets of treatment; either A (active) and B (placebo),
or A (placebo) and B (active).
 BLINDING

Triple blinding:
 The investigator, subject and the data monitoring committee are all
unaware of the treatment assigned

Advantages:
 The data monitoring committee can evaluate the response variables
more objectively. It provides an additional layer of security to prevent
undue influence of study results by anyone directly involved with the
study

Disadvantages:
 Data monitoring committee has the ethical responsibility of to ensure
participant safety. So this design could be counter productive
 BLINDING
Reasons for subject blinding
If the treatment is known to the subject:
• Those on ‘no treatment’ or standard treatment may be discouraged and
drop out of the study
• Those on the new drug may exhibit a placebo effect (i.e., the new drug
may appear better when it actually is not)

Reasons for treatment team blinding

Treatment can be biased by knowledge of the treatment, especially if the
treatment team has preconceived ideas about either treatment through:
• Dose modifications
• Intensity of patient examinations
• Need for additional treatments
 BLINDING
Reasons for evaluator blinding
• If the endpoint is subjective, evaluator bias will lead to recording
more favourable responses on the preferred treatment
• Even supposedly ‘hard’ endpoints (e.g. blood pressure, MI) often
require clinical judgement

Reasons for monitoring committee blinding

• Treatments can be objectively evaluated
• Recommendations to stop the trial for ‘ethical’ reasons will not be
based on personal biases

→ Although blinded trials require extra effort, sometimes they

are the only way to get an objective answer to a clinical
question.
Data collection and quality
control

63
DATA COLLECTION AND QUALITY
CONTROL

Document ! Document ! Document !

If it is not documented… consider it not done!

Documentation is very important

 DATA COLLECTION AND QUALITY
CONTROL
Problems in data collection:

Missing data:
 Participants do not provide complete information
 Inadequate physical examination
 Carelessness in completing study forms/data entry

Incorrect data:
 Mislabeling of specimen
 Badly calibrated equipment
 DATA COLLECTION AND QUALITY
CONTROL
Measures to minimize poor quality data:

 Design of protocol and Manual

 Development of forms
 Training
 Pre-testing
 Data entry
 DATA COLLECTION AND QUALITY
CONTROL
Design of protocol and Manual

 Clear definition of entry and diagnostic criteria and

methodology
 A manual of procedures to be prepared for every clinical
trial
 DATA COLLECTION AND QUALITY
CONTROL
Development of forms
 Should provide all necessary information
 Should be clear
 Few write-in answers
 No essay questions

Training
 To promote standardization of procedures
 To help minimize errors
 Trained personnel should be tested and certified as
competent
 Periodic re-training and re-certification
 DATA COLLECTION AND QUALITY
CONTROL
Pre-testing
 Pre-testing of forms and procedures in a simulated
interview and examination to make sure procedures are
properly performed, forms are filled properly, examination
performed correctly and desired information obtained.
 Investigator grows familiar and comfortable with the
setting.
 Inadequacies in the structure and logic of the process can
be uncovered
 DATA COLLECTION AND QUALITY
CONTROL
Data Entry
 Recording on forms and then transferring it to a
microcomputer
 Data entry programs identify missing extreme or
inconsistent values and prohibit further data entry until
correction is made
 Training of staff is required
Adverse effects

71
 ADVERSE EFFECTS

Definition:

 Any clinical event, sign or symptom that goes in an

unwanted direction
 ADVERSE EFFECTS

Expected and unexpected adverse effects:

Expected adverse effect:

 Based on previous knowledge about the intervention or
similar drug known they are likely to occur

Unexpected adverse effects:

 Completely unanticipated problems that occur
 ADVERSE EFFECTS

The Adverse Event may be:

 A new illness
 Worsening of a sign or symptom of the condition under
treatment or of concomitant illness
 An effect of study medication, including
comparator/placebo or concomitant medication
 A combination of two or more of these factors
 ADVERSE EFFECTS

Definitions:

Adverse effects need to be well defined so that:

 Investigators record them in consistent manner
 The person reviewing is able to better assess the effects

They could be a constellation of signs, symptoms and laboratory

findings and should be well defined
 ADVERSE EFFECTS

Ascertainment:
Two methods:
 Participant volunteers complaint
 Elicit complaint by means of an checklist

Frequency of events:
 Number of participants who suffer the effect
 More number of participants with the occurrence of the
effects more reliable is the estimate of the frequency
 ADVERSE EFFECTS

Length of follow up:

 Longer the trial more the opportunity to discover the
adverse effects
 Duration follow up is also important as some drugs may not
cause certain adverse effects unless the subject has been
taking it for a minimum period

Individual susceptibility:
 Different people react differently to the interventions
 Age, gender, stage of the disease and many other
conditions affect the incidence and severity of the effects
 ADVERSE EFFECTS

Reporting adverse effects:

Four ways:

 Participant had or did not have an adverse effect

 Investigator provides an estimate of severity
 Frequency
 Showing time patterns
Data analysis

79
 Baseline Assessment
Baseline data: collected before the start of the treatment (before or
after randomization)
• Used to describe the population studied (i.e., ‘Table 1’)
• Used to stratify, or at least check for balance over prognostic
factors, demographic and socioeconomic characteristics, and
medical history data

Checking for treatment balance:

• Compare the baseline data for the subjects randomized to each
treatment arm
• Differences can be tested, but one should not conclude ‘no
imbalance’ if p-values are not significant (i.e., >0.5)
• Unless sample sizes are very large, rejecting H0 implies an
imbalance problem that should be addressed in the analysis
 Sample size estimation

• Early exploratory clinical trials: usually no sample size

justification is required
• Phase III confirmatory trials: determination of sample
size should be justifiable
– Main hypothesis of the trial (superiority/non-
inferiority/equivalence)
– Measure of outcome (continuous, categorical, time to event)
– Test statistic ( t-test ,χ2 test, or log-rank test)
– H0 and Ha , an important treatment difference () and SD (σ)
– Type I error rate : probability of concluding an ineffective drug is
effective
– Type II error rate : probability of concluding an effective drug is
ineffective
– Drop-out rate (withdraws and protocol violations)
 Analysis population (ITT or PP)
– Intent To Treat or ITT or full analysis (analyzed as randomized)
• all randomized subjects (with baseline measurement and at
least 1 post-treatment measurement)
– Preservation of the initial randomization in analysis is important
in preventing bias and in providing a secure foundation for
statistical tests
– It implies a conservative effect on the outcome of the trial, since
the non-compliers included in ITT analysis will generally diminish
the estimated treatment effect
– It may be reasonable to eliminate from the set of all randomized
subjects any subject who took no trial medication. The
intention-to-treat principle would be preserved despite the
exclusion of these patients provided, for example, that the
decision of whether or not to begin treatment could not be
influenced by knowledge of the assigned treatment
 Analysis population (ITT or PP)

– Per Protocol or PP or valid cases or efficacy sample

– defines a subset of the subjects in the full analysis set who are more
compliant with the protocol and is characterized by criteria such as
the following:
– the completion of a certain pre-specified minimal exposure to the
treatment regimen;
– the availability of measurements of the primary variable(s);
– the absence of any major protocol violations
– The use of the PP set may maximize the opportunity for a new
treatment to show additional efficacy in the analysis, and most
closely reflects the scientific model underlying the protocol
– However, the corresponding test of the hypothesis and estimate of
the treatment effect may not be conservative; the bias, which may
be severe, arises from the fact that adherence to the study protocol
may be related to treatment and outcome
 Analysis population (ITT or PP)

– In confirmatory trials it is usually appropriate to plan to

conduct both an analysis of the full analysis set and a per
protocol analysis, so that any differences between them can
be the subject of explicit discussion and interpretation

– When ITT and PP analysis lead to essentially the same

conclusions, confidence in the trial results is increased,
bearing in mind, however, that the need to exclude a
substantial proportion of subjects from the PP analysis throws
some doubt on the overall validity of the trial
 Handling of missing data

• There will almost always be some missing data

• Excluding some patients with missing data is not
compatible with the ITT principle
• Methods for the imputation of missing values (no
universally accepted method)
– Non-responder imputation (NRI) for binary data (more
conservative)
– Last observation carrying forward (LOCF)
– Other mathematical imputations
• Sensitivity analyses are essential – sensitivity of the results
of analysis to the method of handling missing values, especially if
the number of missing values is substantial
 Statistical methods

• Check the assumptions of the statistical method being

used to make comparisons
• Any transformations on the data likely to be required
before analysis
– mathematical transformations (logarithms, square root,
etc) for normalization of the outcome variables
• Choose an appropriate statistical method
• If the assumptions of proposed statistical method do not
hold, then alternative statistical approaches (eg, non-
parametric) should be described and pre-specified
Flow chart
Exposure
variable Normal Non-normal

1 group One-sample t test Sign test / Signed rank test

2 groups Two-sample t test Mann-Whitney U test

Continuous Paired Paired t test Wilcoxon signed rank test

>2 groups One-way ANOVA test Kruskal Wallis test

Continuous Pearson Corr / Linear Reg Spearman Corr / Linear Reg

1 group Chi-square test / Exact test

2 groups Chi-square test / Fisher’s exact test / Logistic regression

Outcome
Categorical Paired McNemar’s test / Kappa statistic
variable
>2 groups Chi-square test / Fisher’s exact test / Logistic regression

Continuous Logistic regression

2 groups KM plot with Log-rank test

Survival >2 groups KM plot with Log-rank test

87
Continuous Cox regression
Reporting

88
 CONSORT Statement
Product of CONSORT – Consolidated Standards of Reporting
Trials
o http://www.consort-statement.org
An evidence-based, minimum set of recommendations for
reporting randomized clinical trials
o Offers a standard way for authors to prepare reports of trial findings,
facilitating their complete and transparent reporting, and aiding their
critical appraisal and interpretation
Comprised of a 25-item checklist and a flow diagram
o Checklist: focuses on reporting how the trial was designed,
(conducted), analysed, and interpreted
 Enables readers to assess the validity of the results
o Flow diagram: displays the progress of all participants through the
trial
Newest version – CONSORT 2010 Statement published on
March, 2010
 The Checklist (1/4)

Title
• Identification as a randomized trial in the title
Abstract
• Structured summary of trial design, methods, results, and conclusions
Introduction
• Scientific background and explanation of rationale
• Specific objectives or hypotheses
Methods
• Description of trial design (such as parallel, factorial) including allocation
ratio
• Eligibility criteria for participants
• Settings and locations where the data were collected (i.e., study settings)
• The interventions for each group with sufficient details to allow replication,
including how and when they were actually administered
• Completely defined pre-specified primary and secondary outcome
measures, including how and when they were assessed
 The Checklist (2/4)

Methods (contd.)
• Any changes to trial outcomes after the trial commenced, with reasons
• How sample size was determined
• When applicable, explanation of any interim analyses and stopping
guidelines
• Randomization
 Method used to generate the random allocation sequence
 Type of randomization; details of any restriction (such as blocking and
block size)
 Mechanism used to implement the random allocation sequence (such as
sequentially numbered containers), describing any steps taken to conceal
the sequence until interventions were assigned
 Who generated the allocation sequence, who enrolled participants, and
who assigned participants to interventions
• If done, who was blinded after assignment to interventions (for example,
participants, care providers, those assessing outcomes) and how
• If relevant, description of the similarity of interventions
 The Checklist (3/4)
Methods (contd.)
• Statistical methods used to compare groups for primary and secondary outcomes.
• Methods for additional analyses, such as subgroup analyses and adjusted analyses

Results
• Participant flow diagram - for each group, the numbers of participants who were
randomly assigned, received intended treatment, and were analysed for the primary
outcome (see accompanying handout)
• For each group, losses and exclusions after randomization, together with reasons
• Dates defining the periods of recruitment and follow-up
• Why the trial ended or was stopped (i.e., reason(s) for stopped trial)
• A table showing baseline demographic and clinical characteristics for each group
• For each group, number of participants (denominator) included in each analysis
(i.e., numbers analyzed) and whether the analysis was an ‘intention-to-treat
analysis’
• For each primary and secondary outcome, results for each group, and the
estimated effect size and its precision (such as 95% confidence interval)
 The Checklist (4/4)

Results (contd.)
• Results of any other analyses performed, including subgroup analyses and
adjusted analyses, distinguishing pre-specified from exploratory
• All important harms or unintended effects in each group (i.e., harms/adverse
events)
Discussion
• Trial limitations, addressing sources of potential bias, imprecision, and, if
relevant, multiplicity of analyses
• Generalizability (external validity, applicability) of the trial findings
• Interpretation consistent with results, balancing benefits and harms, and
considering other relevant evidence
Other information
• Registration number and name of trial registry (clinicaltrials.gov)
• Where the full trial protocol can be accessed, if available
• Sources of funding and other support (such as supply of drugs), role of
funders
Thank you!

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