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Randomized (Clinical) Trial

Anwar Santoso
Dept. Cardiology – Vascular Medicine
Faculty of Medicine – Universitas Indonesia
National Cardiovascular Centre – Harapan Kita Hospital
Definition of RCTs
• Trials are cohort studies in which allocation to the
determinant is initiated by the investigators
• The allocation is made at random by some algorithm

• The determinant is allocated with the purpose of learning

about its effect on the outcome  experimental study

• RCTs have an important role in determining the efficacy

and safety of treatments

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
Early published RCT
RCT can be distinguished
• Phase-I trial is conducted after satisfactory findings have
been reported in animal experiments.
• The primary aims to determine the pharmacologic and metabolic
effects of the drugs in humans and to detect the most common side
effects.
• Study subjects usually are healthy volunteers
• It is called dose-escalating study
• Number of participants is no more than 100

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
 RCT can be distinguished (cont’d)

• Phase-II trial is studied firstly in the intended patients

• Emphasis is again on safety and on intermediate outcomes

• Drug studies often test several doses  find the optimal

dose for a large-scale study

• Number of participants is no more than 500

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
RCT can be distinguished (cont’d)
• Phase-III trial, the treatment is brought to a “real-life” with
outcomes that are considered to be clinically relevant
• This study is large (often 1000 or more patients) and costly.
• Registration must occur before the 1st patient enrolled
•  www.clinicaltrials.gov
• Responsibility of investigators to present the study design and give
an account of the results

• Phase-IV trial (post-marketing = surveillance trial) may

concentrate on the study of rare side effects after being marketed.
• It can be conducted to access new beneficial effects of registered
treatment

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
 RCT first step

• Define key elements of study (PICO)

• Population
• Intervention
• Comparator
• Outcome
• State primary hypothesis
• Expected results for primary outcome in population
• Eg. In patients with COVID-19, remdesivir is clinically benefit in
reducing in-hospital mortality compared to usual standard
treatment.
Structure of RCT
• Systematic differences between baseline
characteristics of the groups

• Want comparable groups at the start ?

1. Random sequence generation

2. Concealed allocation
Randomized
• Eliminate bias in selection/allocation
• Balances all confounders: known or unknown

Controlled
• Intervention compared to a control
• Control: active or placebo
• Both groups are identical except for intervention/exposure
• Investigator has control over the process

Trial
• Experimental intervention
• Effects unknown to investigator
Randomization
• Process by which, allocation of subjects to
treatment groups is left to chance (or randomness)

The major purpose of random assignment

• Ensure that the study groups are comparable on baseline
characteristics. It tends to balance the prognostic factors
• Reduce selection bias in allocation to groups
• Facilitate double blinding
• Facilitate measurement of outcome variables
How randomization is done?
Simple randomization

• This method is equivalent to tossing a coin for each

subject that enters a trial, such as
• Heads = active; Tails = placebo

• However, imbalanced randomization can happen in

smaller trials, reducing statistical power
• Eg. In trial of 10 participants, instead of 5 – 5 split 7 – 3 or
8-2 split can occur
Block randomization
• Block randomization is balanced within each block
• The basic idea of block randomization
• divide potential patient into m blocks of size 2n
• randomize each block such that n patients are allocated to A
and to B
• Then, choose the block randomly

• Example, two treatments of A and B and block size of 2 x

2=4
• Possible treatment allocations within each block are: (1) AABB,
(2) BBAA, (3) ABAB, (4) BABA, (5) ABBA, (6) BAAB
Stratified randomization
• An RCT may not be considered valid if it is well balanced
across prognostic factors
• Age group: < 40; 41 – 60; > 60 years
• Sex: male, female.
• Total number of strata 3 x 2 = 6
• Stratification can balance subjects on baseline covariates,
tend to produce comparable groups with regard to certain
characteritics
• Eg. gender, race, sex, disease severity  produce valid statistical test
• The block size should be relative small to maintain balance in
small strata
Flowchart for selecting a method of randomization

Zabor EC, et al Chest 2020; 158(1S): S79 – S87

 Some types of RCT
• Parallel group trial  the patient is the unit of randomization
and no intention to switch the allocated treatment within a
patient.

• Factorial design  there are several treatment modalities with

the patients being randomized twice
• It has the advantage of efficiency  favorable to recruit rare
diseases
• Pre-requisite is that there is no pharmacologic interaction
between the two regimens.

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
 Parallel Study Design

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015; Diabetologia 2011; 44: 1118 - 20
Joseph P, et al. Am Heart J 2018; 206: 72 – 79.
 Flow chart the design of ADVANCE study
(Factorial Design)

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015; Diabetologia 2011; 44: 1118 - 20
 Some types of RCT (cont’d)
• Crossover design  the primary comparison of treatment effects
is within a single patient
• A major advantage  it removes between-patient variability and offers a
more efficient approach to measure a treatment effect
• An draw back are period effect and carry-over effect may ensue

• Non-inferiority trial  the aim is not to determine whether a

specific treatment is superior to an alternative treatment.
Rather to show that a treatment is not worse than the
comparator.
• Typically, a new treatment is compared to currently available
“standard” treatment
• Non-inferiority margin is the threshold at which one still concludes that
the new treatment is not worse that the active treatment

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
 Crossover Study Design

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015; Diabetologia 2011; 44: 1118 - 20
Sarvasti Dy, Santoso A, et al. Vasc Health and Risk Man 2020; 16: 1 – 14.
Comparison of important aspects between
Superiority and Non-inferiority trials

Leung JT, et al. Heart 2020; 106: 99 – 104. doi: 10.1136/heartjnl-2019-315772

 Some types of RCT (cont’d)
• Cluster randomized trial  group of subjects are randomized as
opposed to individual subjects
• The advantage of this study are administrative convenience, ease of
application, ethical consideration.
• The design is more common in health service and policy research as
opposed to studies of drug intervention
• In this study, it is important to consider the impact of both the number
of clusters and the cluster size on the power of the study

Grobbee DE & Hoes AW. Randomized Trial in: Clinical Epidemiology. 2nd Ed. Burlington, MA. 2015
Roshandel G, et al. Lancet 2019; 394: 672 - 83
Blinding?
 Blinding
• Not known if subject getting new therapy or control
• Subjects
• Healthcare providers making management decisions
• Investigators collecting/analyzing data
• Prevents bias in management decisions and in
assessment of outcomes by subject or investigator
• Knowledge receiving placebo or active drug may
influence
• Administration of another therapy that my impact outcome
• Assessment of symptoms, signs (endpoints)
 Blinding
• Identical appearing therapies
• Real vs. sham surgery/procedure
• Surgical team uninvolved in further care/assessment
• Double-dummy
• Subjects receive identical active and control therapy together

• Side effect of a therapy may unblind subjects

• Assess whether unblinded
Allocation concealment impact results
Treatment Effect Overestimated Without
Randomization and Blinding
 Outcomes

• What do you want to achieve with the new intervention?

• Primary outcome
• Additional outcome
• Surrogate versus primary outcome
• Surrogate outcome: hs-CRP or adiponectin levels
 Clinically meaningful outcome preferred
• What study outcome would alter medical practice?
• Lab test (TNF-𝛼 or mortality?)

• Studies of surrogate outcome may indicate areas for further

research, but generally don’t alter patient management

• Some surrogate outcome are accepted as “true” indicators of

clinical outcome
• Eg. Blood pressure and cholesterol levels
Objective versus subjective outcomes
Assess the risk of bias and decide
if the results are trustworthy
Courtesy: Hardian, FK Undip_2021
Courtesy: Hardian, FK Undip_2021
Courtesy: Hardian, FK Undip_2021
Hipotesis mayor
• Hipotesis secara umum
• Dapat dipecah menjadi beberapa hipotesis
minor

Hipotesis minor
• Hipotesis secara spesifik  bivariat
• Hipotesis kerja