Randomized Controlled Trials 1

SESSION 9: RANDOMIZED CONTROLLED TRIALS (RCTS)

Synonyms: Randomized Clinical Trials/Randomized Trials/Clinical trials

Lecture Objectives

1. To describe the important elements of RCTs.

2. To introduce design issues, including stratified randomization, crossovers, and factorial design.
3. To define the purpose of randomization and of blinding.
4. To illustrate the problems posed by noncompliance in RCTs.
5. To explain the ways of expressing results of RCTs.

Relevant Reading

David D. Celentano, Moyses Szklo. Gordis Epidemiology. 6th edition 2019 by Elsevier, Inc. Chapter 10. P197-
214.

RCT Design

The goal of healthcare in clinical practice and in public health, is to prevent or delay death or disability and to
improve the health of the patient or the population. The challenge is to select the best available preventive or
therapeutic measures to achieve this goal. To do so, we need to carry out a RCT which is considered the ideal
design or golden standard for evaluating both the efficacy and the side effects of new forms of intervention, as
shown in Figure 1.

Higher Lower
Meta-analysis

Systematic
reviews

RCTs
Evidence Quality Risk of Bias
Cohort studies

Case-control studies

Cross-sectional studies
Lower Higher
Case reports and case series

Figure 1: Hierarchy of evidence pyramid.

 Randomized Controlled Trials 2

The basic design of a RCT is shown in below Figure 2.

Improve

Randomly assigned
Intervention Group
"New treatment"
Do not improve

Defined study population

Control Group Improve

"Current treatment or
placebo"
Do not improve

Figure 2: Study design of randomized controlled trials.

Many RCTs are called parallel RCTs in which a participant receives the same treatment throughout the trial.
However, there is another type called crossover RCT in which a participant can switch treatments. In crossover
design subjects are randomized to new treatment or current treatment. After being observed for a certain period
of time on one therapy and after any changes are measured, the patients are switched to the other therapy. Both
groups are then again observed for a certain period of time, as shown in below Figure 3. Crossover design is
clearly not possible if the new therapy is surgical or if the new therapy cures the disease. In crossover RCTs, a
“washout” period describes the length of time that someone enrolled in a trial must not receive any treatment
before receiving the trial’s experimental therapy. A washout may be required before joining a trial or before
changing treatments within a trial. The “washout” period is designed to affirm that the effect of the period 1
intervention is worn off, so that the effect of period 2 intervention attributes to that intervention.

Figure 3: Crossover design of randomized controlled trials.

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Factorial design is a special form of RCT designs used to evaluate two or more interventions simultaneously. In
factorial design participants are randomized to one of 4 groups: one group receives both treatments A and B (AB),
one receives only treatment A (A0), one only treatment B (B0), and the remaining group receives neither treatment
A nor B (00). To preserve blinding, the latter three may be given the corresponding placebos. An example of a
factorial design is seen in below Figure 4. In this study more than 22,000 subjects were randomized using a 2 ×
2 factorial design that tested aspirin for prevention of cardiovascular diseases and beta carotene for prevention of
cancer. Each subject received one of four possible interventions: both aspirin and beta carotene (AB), neither
aspirin nor beta carotene (00), aspirin and beta carotene placebo (A0), or beta carotene and aspirin placebo (B0).

Study
population
22,071
Aspirin
Aspirin Placebo
+ -
Both Aspirin B-carotene
11,037 11,034
+ & B-carotene only
(AB) (B0)
Beta-
Neither
Beta carotene
Placebo Beta Placebo Aspirin only Aspirin nor
carotene carotene - (A0) B-carotene
5,520 5,520 5,514
5,517 (00)

Figure 4: Factorial designs using 2 by 2 table in the study of aspirin and beta-carotene.

RCT Uses

RCTs can be used for many purposes as it is ideal to assess and compare:

• New drugs and other treatments of disease,

• Tests of new health and medical care technology,
• New programs for screening and early detection of diseases,
• Different approaches to prevention,
• New ways of organizing and delivering health services.

Steps in Designing and Conducting an RCT

• Define study population: Identify, recruit, consent and maintain two comparable groups of participants.
• Random assignment: Allocate one group to be given the new treatment the other group to be given the
current treatment.
• Follow-up the two groups equally over a defined period of time.
• Assess the outcome using same criteria of outcome in both groups.
• Compare outcomes in the two groups to see how big is the difference in outcome and whether the
difference is attributable to the treatment.
 Randomized Controlled Trials 4

Random Assignment of Study Groups

Various methods can be sued for random assignment of study participants such as: toss (flip) a coin or use a table
of random numbers or use computer-generating programs. If we randomize properly, we achieve non-
predictability of the next assignment; so, we do not have to worry that any subjective biases of the investigators,
may be introduced into the process of selecting patients for one treatment group or the other.

Also, if the sample size is large enough, we hope that randomization will increase the likelihood that the groups
will be comparable to each other in regard to characteristics about which we may be concerned, such as sex, age,
race, and severity of disease - all factors that may affect prognosis. Randomization is not a guarantee of
comparability since chance may play a role in the process of random treatment assignment. However, if the
treatment groups that are being randomized are large enough, they will tend to be similar.

Figure 5: Nonrandomized versus randomized controlled studies.

Above Figure 5 presents a hypothetical example of the effect of lack of comparability on a comparison of
mortality rates of the groups being studied. Let us assume a study population of 2,000 subjects with myocardial
infarctions, of whom half receive an intervention and the other half do not. Let us further assume that of the 2,000
patients, 700 have an arrhythmia and 1,300 do not. Case-fatality in patients with the arrhythmia is 50%, and in
patients without the arrhythmia it is 10%.
 Randomized Controlled Trials 5

Let us look at the nonrandomized study on the left side of Figure 3. Because there is no randomization, the
intervention groups may not be comparable in the proportion of patients who have the arrhythmia. Perhaps 200
in the intervention group may have the arrhythmia (with a case-fatality of 50%) and 500 in the no-intervention
group may have the arrhythmia (with its 50% case-fatality). The resulting case-fatality will be 18% in the
intervention group and 30% in the no-intervention group.

We might conclude that the intervention is effective. However, let us now look at the randomized study on the
right side of Figure 3. As seen here, the groups are comparable, as is likely to occur when we randomize, so that
350 of the 1,000 patients in the intervention group and 350 of the 1,000 patients in the no intervention group have
the arrhythmia. When the case-fatality is calculated for this example, it is 24% in both groups. Thus, the difference
observed between intervention and no intervention when the groups were not comparable in terms of the
arrhythmia was entirely due to the noncomparability rather than to the effects of the intervention.

Stratified Randomization

Sometimes we may be concerned about comparability of the groups in terms of one or more characteristics that
may influence response to therapy in the groups being studied. Randomization does not ensure comparability. An
option that can be used is stratified randomization, an assignment method that can be helpful in increasing the
comparability of the study groups. let us say that we are concerned about age as a prognostic variable: prognosis
is worse in older patients. Therefore, we are concerned that the two treatment groups be comparable in age.
Although one of the benefits of randomization is that it may increase the comparability, it does not guarantee it.
It is still possible that after we randomize, we may, by chance, find that most of the older patients are in one group
and most of the younger patients are in the other.

Our results would then be impossible to interpret because the high-risk patients would be clustered in one group
and the low-risk patients in the other. Any difference in outcome between intervention groups may then be
attributable to this difference in age rather than to the effects of the intervention.

In stratified randomization, we first stratify study population by each variable that we consider important, and
then randomize participants to treatment groups within each stratum. Let us consider we are studying 1,000
patients and are concerned that sex and age are important determinants of prognosis. If we randomize, we do not
know what the composition of the groups may be in terms of sex and age; therefore, we decide to use stratified
randomization. We first stratify the 1,000 patients by sex into 600 males and 400 females. We then stratify the
males by age and the females by age. We now have four groups (strata): younger males, older males, younger
females, and older females. We now randomize within each group (stratum), and the result is a new treatment
group and a current treatment group for each of the four groups, as shown in below Figure 6.
 Randomized Controlled Trials 6

Figure 6: Hypothetical example of stratified randomization

Blinding (Masking)

Blinding is the act of concealing the true intervention from study participants and/or researchers to eliminate bias.
The nature of the intervention determines the level of blinding possible. The lower the level of blinding, the more
prone to bias and thus the less confidence in the generalizability of the results.

If the patient knows that s/he is receiving a new therapy, enthusiasm and certain psychological factors may operate
to elicit a positive response even if the therapy itself had no positive clinical effect. One way of making subjects
masked is by using a placebo, an inert substance that looks, tastes, and smells like the active agent. Sometimes
blinding is impossible, such as in comparisons of medical and surgical interventions.

There are two types of blinding in RCTs a single-blind RCTs and double-blind RCTs. Single-blind RCTs is when
the nature of intervention is concealed from either the study participants or the researcher. When concealing the
nature of intervention from both the participants and the researchers, we call it double-blind RCTs.

Noncompliance

Patients may agree to be randomized, but following randomization they may not comply with the assigned
treatment. Noncompliance may be overt or covert:

Overt non-compliance (dropouts): people may overtly articulate their refusal to comply or may stop participating
in the study.

Covert non-compliance: people stop taking the agent assigned without admitting this to the investigator.
Whenever possible, checks on potential noncompliance, for example, urine tests for the agent being tested.
 Randomized Controlled Trials 7

Drop-ins: when patients in the control group may be inadvertently take the agent assigned to the intervention
group. For example, in a trial of the effect of aspirin for prevention of myocardial infarction, patients were
randomized to aspirin or to no aspirin. However, a problem arose in that, because of the large number of
preparations that contain aspirin and many of the control patients might be taking aspirin without knowing it.

The effect of noncompliance on the study results will be to reduce any observed differences because the treatment
group will include some who did not receive the therapy, and the no-treatment group may include some who
received the treatment. Thus, even if there is a difference in the effects of the treatments, it will appear much
smaller.

Ways of Expressing the Results of RCTs

Below Table 1 shows an RCT that done to investigate the efficacy of prophylaxis with respiratory syncytial virus
(RSV) monoclonal antibody in reducing the incidence of hospitalizations due to RSV infections in high-risk
infants. In this RCT a total of 1,502 premature infants (≤ 35 weeks) were randomized to receive 5 intramuscular
shots of monoclonal antibody for the treatment group (1,002) and equivalent placebo shots given for the control
group (500). The children were followed for 150 days. See below Table 1.

Study groups Admitted Not admitted Total

Placebo group (no treatment) 53 447 500
Treatment with RSV monoclonal antibodies 48 954 1002
Total 101 1401 1502
Table 1: number of children admitted to hospital with RSV infection following placebo and RSV monoclonal
antibody treatment.

Ways of expressing results of above RCT, are shown below:

A. Absolute Risk Measures

1. Absolute Risk (AR)

• AR refers to the probability of an outcome occurring.
• AR in placebo group = 53/500 = 0.106 or 10.6% = probability of an infant being admitted with RSV
infection was 10.6% for those receiving placebo.
• AR in treatment group = 48/1002 = 0.048 or 4.8% = probability of an infant being admitted with RSV
infection was 4.8% for those receiving treatment.
 Randomized Controlled Trials 8

2. Absolute Risk Reduction (ARR); synonym Attributable Risk

• ARR is calculated as the arithmetic difference in the AR of an outcome in individuals who were exposed
to the intervention and the AR of the outcome in those unexposed to the intervention.
• ARR = risk rate in the placebo group – risk rate in the treatment group = 10.6% – 4.8% = 5.8% = receiving
intervention reduced an infant’s risk of being admitted with RSV infection by 5.8%.

3. Number of patients who would need to be treated (NNT)

• ARR is equivalent to the NNT.
• NNT is a more user-friendly way of reporting outcomes or describing the risk (easier to conceptualize).
• NNT is defined as the number of people who need to receive the intervention in order to achieve the
required outcome in one of them.
• NNT = 1/ARR = 1/0.058 = 17.2 (about 17 high-risk infants needed to receive intervention in order to
prevent one of them from being admitted to hospital with an RSV infection during the 150 days period).
• Another example to explain the NNT: if the mortality rate of a disease in the untreated group is 17% and
mortality rate in the treated group is 12%. NNT = 1/(0.17 - 0.12) = 1/0.05 = 20, we would need to treat 20
persons with that disease to prevent only one death.

B. Relative Risk Measures

1. Relative Risk (RR); synonyms: Risk Ratio or Incidence Rate Ratio (IRR)
• RR puts risk in comparative terms, and indicates the ratio of the risk of an outcome in the exposed
(intervention) group to the risk of the outcome in the unexposed (control) group.
• Risk of hospitalization in the intervention group was 0.048 (48.0%).
• Risk of hospitalization in the placebo group was 0.106 (10.6%).
• RR = 0.048/0.106 = 0.45 (45%) = probability of being admitted to hospital for those receiving treatment
was 0.45 times or about half of that of those receiving placebo.

2. Relative Risk Reduction (RRR)

• RRR measures how much the risk is reduced in the treatment group compared with the control group.
• RRR = 1 - RR
• RRR = 1 – 0.45 = 0.55 (55.0%) = the chance of a high-risk infant being admitted to hospital is reduced by
55% in the treatment group compared with the placebo group.