Randomized Controlled Trials - The Basics

Dr. Sathish Kumar, MD,DCH Professor of Pediatrics CMC, Vellore Outline

• Randomised controlled trials/Randomisation

• Main strengths and weaknesses

• Types of RCTS

• Analysing their results

• How to conduct them?

• How to report RCT? Epidemiological study designs

Lancet 2002; 359: 57–61 Hierarchy of Epidemiologic Study Design Randomly assigned 12 sailors to 6 different candidate treatments for scurvy First RCT in medicine

• Sir A. Bradford Hill, an epidemiologist for England's Medical Research Council.

• Trial, published in the British Medical Journal in 1948, tested whether streptomycin is effective in treating tuberculosis. What is a randomized controlled trial? ”An epidemiological in which subjects in a population are randomly allocated into groups, usually called study and control groups to receive and not receive an experimental preventive or therapetuic procedure, maneuver, or intervention” - John M.Last

Randomisation is the only unique feature of RCTs Randomised control

Intervention Intervention Group Group Population of interest

Sample population Control Control Group Group

Randomisation

Assessment (T0) Assessment (T1) Why Randomise?

• Tends to produce comparable groups

• To get evenly balanced - measured and unmeasured, known and unknown prognostic factors and other characteristics of the participants at the time of randomisation x What elements of a trial can be randomized? • Most common unit is individual patient

• Sometimes groups are randomized=cluster • Examples: families, schools, towns, hospitals, communities

• Worry about contamination in cluster randomization

• Special statistical techniques needed to cope with the loss of independence of the individual units Example of a cluster randomized trial How is randomization achieved?

• Two steps involved: • Generation of allocation sequence • Implementation of allocation (concealment of allocation)

• While both are important, there is evidence that concealment of allocation is more critical Generation of allocation sequence – Fixed Randomization procedures • Simple randomization • Analogous to a repeated fair coin tossing

• Restricted randomization • • Done to ensure equal balance of arms throughout all portions of the study

• Stratified randomization • Individuals are identified based on important covariates (sex, age, etc.) and then randomization occurs within the strata Simple randomisation Block randomization A block randomization method can be used to periodically enforce a balance in the number of patients assigned to each treatment.

A block randomization can be implemented in three steps: Step 1: Choose the block size and the number of blocks needed to cover the number of patients in the study. Step 2: List all possible permutations of treatments in a block. Step 3: Generate a randomization code for the order in which to select each block.

Example: Step 1: Given a sample size of 24 and using a block size of 4, we need six blocks.

Step 2: There are six possible permutations that allow two As and two Bs in each box: AABB, ABAB, ABBA, BAAB, BABA and BBAA. Stratified randomisation

Stratified randomization takes the balance correction suggested by blocking one step further Concealment of allocation • Preventing foreknowledge of the next allocations

• if randomization is unconcealed-- they may systematically enroll sicker-- or less sick-- patients to either treatment or control groups.

• Defeat the purpose of randomization and the study will yield a biased result

• Don’t confuse with blinding of participants, personnel, etc

Example: RCT of open vs laparoscopic appendectomy Advantages of RCT

• Efficient for investigating causality because ‘cause’ precedes the ‘effect’

• Possible factors balanced- both known and unknown

• Randomisation facilitates simple statistical analysis

• Practical way to minimise several sources of bias (notably, selection bias) Disadvantages of RCT • Subjects are often a highly selected group and volunteers may differ from population of interest (i.e., generalizability may suffer).

• Not suitable for rare outcomes

• Not suitable for outcomes requiring long or extensive follow-up

• Adherence/withdrawal issues

• Limitations of external

• Complex, Expensive, time consuming, ethically questionable 3. Types of RCTs

• Based on the type of interventions being evaluated

• Based on how participants are exposed to interventions

• Based on the number of participants

• Based on whether goal is evaluation of superiority vs. equivalence

• Based on whether investigators and/or participants know which intervention is being studied RCTs Classified According to the Different Aspects of Interventions Evaluated

• Based on the outcome of interest

• Efficacy vs effectiveness trials

• Phase I, II, III, IV trials Efficacy vs. effectiveness trials • Efficacy—does the intervention work in the people who actually receive it? • These trials tend to be explanatory • confirm a physiological or clinical hypothesis

• Effectiveness—how does the intervention work in those offered it • Tend to be pragmatic • inform a clinical or policy decision by providing evidence for adoption of the intervention into real-world clinical practice. ‘Explanatory’ and ‘Pragmatic’ questions Explanatory Pragmatic • Does it work in the real world • Can it work in an ideal …..? setting …..? • Effectiveness • Efficacy • Choice between alternative • Hypothesis testing approaches to health care • Placebo controlled • Standard care • Double blind • Open Efficacy Trial Pragmatic Trial Clinical Trial phases

Safety & Efficacy Safety

Safety & dosing RCT Classification Based on hypothesis Testing superiority, equivalence/noninferiority

Δ: margin for equivalence/noninferiority. Example of equivalence trial Why do an equivalence trial?

• Existing effective treatment

• Placebo-controlled trial unethical • Life-threatening illness.

• New treatment not substantially better than existing treatment. • May have fewer side effects, greater convenience, lower cost, higher quality of life, or provide an alternative or second line therapy. Example of Non-inferiority trials RCTs Classification

• Based on how the participants are exposed to the intervention

• Parallel trials

• Crossover trials

• Trials with factorial design Simple, two-arm (parallel) RCT

Treatment Group/ Arm Control Group/ Arm

Exp. Drug • Most common clinical design.

• Complete randomized design in which each patient receives one and only one treatment in a randomized fashion. Simple, two-arm (parallel) RCT Cross over design...

RANDOMIZATION

Group A Group B

Drug A Drug B

WASH OUT PERIOD WASH OUT PERIOD

Drug B Drug A Example: Crossover trial Factorial designs 2× 2 Factorial design

+ Drug A Drug B Drug A+B Neither Drug

•Used when it is desired to study the influence of a number of factors on the treatments compared as well as their with different treatments. Example: factorial design RCTs Classification

• Based on the number of participants

• N-of-1 trials to mega-trials

• Fixed size

• Sequential trials N-of-1 trial

• Form of crossover trial • Each participant receives the experimental arm for a period of time and then the control/comparison arm during a different period of time • There can be many such periods of time in these studies • XCCCXXCCXX • The participant does not know which intervention is occurring during each period

Eligible patient Drug Placebo Placebo Drug Drug Placebo Example: N-of-1 trial Mega-trials (“Large simple trials”)

• These studies are meant to be HUGE but to collect only a limited amount of data (to make them affordable and practical)

• Are usually multi-center

• Can pick up small effects Example: Mega-trial Randomized Withdrawal Design

Exp. Intervention

WITHDRAWN FROM STUDY

• Here, individuals who respond (+)ly to an experimental intervention are randomized to continue receiving that intervention or to receive a placebo. • Return of symptoms in placebo group causes withdrawal of subject from that group. Lancet. 2008 Mar 22;371(9617):998-100

Open Label Lead in phase N=56 Double Blind withdrawal Open Label extension

Randomised, double-blind, placebo-controlled, withdrawal study

Tocilizumab 8 mg/kg Tocilizumab (n=25) Ped ACR30 -98% every 2 weeks Ped ACR50 -94% Ped ACR 70 -90% Placebo (n=23)

ACR 30 response Tocilizumab - 16/20 (80%) ACR 30 response Placebo - 4/23 (17%) CRP < 5 mg/L P= <0.0001 51/56 (98%) P=0.003

6 weeks 12 weeks 48 weeks RCTs Classification

• Based on level of blinding • Open trials

• Single blind trials

• Double blind trials

• Triple and quadruple-blind trials Blinding

• Relevant groups who may/may not have knowledge of treatment assignments • Participants • Investigators/clinicians administering intervention • Investigators assessing outcomes • Data analyst(s)

• Open trials • All participants and investigators know who is getting which intervention • E.g. medical vs. surgical treatments Single, double, triple, and beyond • Single-blind • The participants (usually) or the investigators assessing outcome (alternately) do not the assignments

• Double-blind • Two groups do not know— usually it is the participants and the outcome assessors/investigators

• Triple or quadruple blinding • Three or four of the relevant groups are not aware of the treatment assignment Allocation concealment Vs Blinding

Randomisation

Time

Concealment of allocation Blinding

Selection bias Performance bias Minimizing bias in RCT • Can occur at all phases: • Planning, selection of participants, administration of interventions, measurement of outcomes, analysis of data, interpretation and reporting of results, publication of reports

1) Allocation bias - Randomisation

2) Performance bias

3) Assessment bias

4) Attrition bias - loss-to-follow-up bias

4 5) Allocation concealment - Blinding 9 Other biases

During the course of a trial - inappropriate handling of withdrawals, drop outs, and protocol violations

Intention to treat analysis Per protocol analysis

Intention to treat analysis – all study participants are included in the analyses as part of the groups to which they were randomized regardless of whether they completed the study or not Bias due to not using intention-to-treat analysis Analysis of data

• RCT are set up to test hypotheses

• Null hypothesis (H0) -Intervention will have no impact on the outcome measure (ie, that the outcome of interest will be similar in both the test and control groups)

• Alternative hypothesis (H1) - Intervention will have a meaningful effect and that this effect will be statistically significant. Measuring Outcomes

• Outcomes at fixed points in time • Proportion with outcome at each follow up • Logistic or log • Odds ratio (OR) or prevalence rate ratio (PRR) intervention/control

• Events in person time • Rate of outcomes per 100 person years • , incidence rate ratio (IRR) intervention/control

• Time-to-event • Time from enrollment until outcome • Cox proportional hazard regression, hazards ratio (HR) • Kaplan-Meier survival analyses, log rank test

• Statistical significance refers to the likelihood that the results obtained in a study were not due to chance alone

- Probability(p) values * Probability that the observed difference between two treatment groups might have occurred by chance * < 0.05 – Statistically significant

- Confidence intervals * The 95% CI of the estimate will be the within which we are 95% certain that the true population treatment effect will lie Clinical significance

• Clinical significance - Difference in between groups that could be considered to be important in clinical decision making, regardless of whether the difference is statistically significant or not.

• Magnitude and statistical significance are numerical calculations, but judgments about the clinical significance or clinical importance of the measured effect are relative to the topic of interest. Statistical significance Vs Clinical significance

A minimum sample of 60 in each group had a 90% power of detecting a difference of 0.40° F change between the baseline and the last follow up Conducting a RCT

The protocol Measure baseline variables • Rationale Randomize • Aims and objectives, Research questions • Eliminates baseline confounding Blinding the intervention • Design of the study: selection of • As important as randomization patients, drugs and doses, assessment, • Eliminates biased measurement of outcome withdrawals, data analysis, data discharge Follow subjects • Ethics: patient consent, adverse events Adherence to protocol • Documentation Lost to follow up Select participants • Likely to benefit and not be harmed Measure outcome • Positive results/Negative results • Likely to adhere • Clinically important measures • Should be representative of the • Adverse events population • Specific primary & secondary outcomes • Adequate sample size is key features of RCT Stopping rules

• Trials should have predefined stopping rules to avoid: • Preventing undue risk to participants (e.g., treatment causes adverse effects)

• Depriving the control group of an effective intervention

• Continuing an ineffective intervention (“futility” or conditional power analysis) Trial Monitoring

• Trials must be approved by and monitored by Institutional Review Boards (IRBs) for ethics and safety

• Trials should have an independent monitoring system to periodically review data and ensure participant safety

• Data monitoring committee (DMC) or Data Safety and Monitoring Board (DSMB)

• The DMC or DSMB should have the authority to terminate or change the trial procedures

• Trials should report all adverse events You should be familiar with CONSORT CONSORT: checklist and flow diagram Summarize …

• Gold standard” of research designs • Individual patients are randomly allocated to receive the experimental treatment (intervention group) or the standard treatment (control group) • Randomisation guards against selection bias between the two treatment groups • Standard statistical analysis • Good • May lack generalisability due to highly selected participants • Can be costly to set up and conduct, ethical issues Thank you