Clinical Trials Designs

Professor Tarek Tawfik Amin

Epidemiology and Public Health, Faculty of Medicine, Cairo University

Geneva Foundation for Medical Education and Training

Asian Pacific Organization for Cancer Prevention

International Osteoporosis Foundation Wiley Innovative Panel

amin55@myway.com dramin55@gmail.com

Basic Research Competency Program for Research Coordinators August 2015, MEDC, Faculty Of Medicine, Cairo University, Cairo, Egypt.

Clinical trials designs

• It is generally accepted that an appropriate trial design includes a sufficiently large sample size and statistical power, and methods for minimizing bias to enable the results to be reliably interpreted. • The randomized, parallel-group

controlled clinical trial design is generally considered as the gold standard, but in some situations it is difficult to use this design.

• Selection bias: biased allocation of patients to treatment or placebo groups; • Performance bias: the unequal

provision of care apart from the treatment under evaluation; • Detection bias: biased

assessment of the outcome; • Attrition bias: biased occurrence

and handling of deviations from protocol and loss-to-follow-up.

Potential Problems with trails designs

• Good-quality central randomization can minimize selection bias.

• Double-blind follow-up and outcome evaluation can minimize the other biases, the trial outcome should be measured in a blinded manner, by someone who is not involved in the patient’s care.

• Specific methods for the management of missing data exist, e.g. replacement of missing measurements in designs with intra-individual assessments, and intention-to-treat analyses.

• A specific statistical analysis plan is necessary for all trial designs, and should be defined a priori, in the trial protocol.

These biases can be minimized using validated methodology

Intension to treat [ITT] analysis • According to Fisher et al. (1990), the ITT analysis

includes all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol.

• ITT analysis includes every subject who is randomized according to randomized treatment assignment. It ignores noncompliance, protocol deviations, withdrawal, and anything that happens after randomization.

• ITT analysis is usually described as “once randomized, always analyzed”. ITT analysis avoids over optimistic estimates of the efficacy of an intervention resulting from the removal of non-compliers by accepting that noncompliance and protocol deviations are likely to occur in actual clinical practice.

Clinical trials designs

Parallel Group Design: The Gold Standard Treatment group

Control group

Randomization

Randomization

Dose 3

Dose 2

Dose 1

Placebo

Most commonly used Possible in almost any situationRequires larger sample size Randomization to one of two or moretreatment groups, with a pre-specifiedrandomization ratio.

Advantages Disadvantages

1- Design simple to understand and to implement.2- Treatment groups can have different numbers of patients.3- Analysis and interpretation of results is simple

1- Larger sample size often required.2- Difficulties with recruitment possible, if placebo-controlled.3- Cannot estimate the contribution of inter- andintra-patient variability to the overall variability

Factorial design: based on parallel design

• With the 2 × 2 factorial design trial, participants are randomized to treatment A or corresponding placebo to test one hypothesis, and randomized again within each group to treatment B or corresponding placebo to test a second hypothesis [enabling two different hypotheses to be tested simultaneously].

• Requires no interaction between treatments A and B (loss of power).

• Enables measurement of an effect or an interaction which otherwise might not be apparent.

Factorial design Comparison: Treatment B vs. placebo

Treatment B(n=200)

Placebo B(n=200)

Treatment ATreatment B

(n=100)

Placebo A(n=200)

Treatment A(n=200)

Placebo APlacebo B(n=100)

Placebo ATreatment B

(n=100)

Treatment APlacebo B(n=100)

Com

paris

on: T

reat

men

t A v

s. pl

aceb

o

Advantages Disadvantages 1- Can answer two or more questions with one trial 2- Time-saving for the trial sponsor3- Requires fewer patients to obtain the answer to two or more question

1- Need to be sure that there is no interaction between treatments A and B

Cross-over design

Group A

Group B

Placebo

Active Treatment

Placebo

Active Treatment

Period I Period II

Wash out Time

Advantages Disadvantages 1- Smaller sample size than parallel groups.2- Results depending only on within patient variability.3- Often used in healthy volunteers (forphase I clinical trials

1- Stable chronic diseases (assumes patient’s state is comparable at the start of both periods of treatment).2- Endpoint must not be sensitive to learning processes. 3- Requires a wash-out period between treatment periods.4- Follow-up is at least twice as long compared with corresponding parallel group trials (attrition). 5- The analysis must confirm the absence of treatment - period interaction (the carry over)

Latin Square Design • Latin-square design differs from cross-over

design in terms of the number of studied treatments.

• Latin-square design is used when more than two treatments are compared in the same trial.

• For example when three treatments are considered in the trial, the corresponding Latin-square involves three treatment periods and two wash-out periods occurring between each treatment period for each of the three groups of patients

N-of-1 Design Period 1 Period 2 Period 3 Period 4 Period 5 Period 6

Treatment B B A A BA

Sequence I Sequence II Sequence I

- N of 1 trials or single-subject designs are defined as time series designs in which an intervention is evaluated in one single patient. - Typical single patient trial consists of experimental/control treatment periods repeated a number of times. - The order of treatment is randomly assigned within each treatment period pair. - Known as a structured within-patient randomized controlled multi-crossover trial design. - The primary objective of such a trial is to determine the treatment preference for the individual patient.

Advantages Disadvantages 1- Provides an estimate of individual effectiveness (personalized medicine)2- Patients are more likely to have better adherence to treatment, and understand their disease and treatment better

Same as cross-over design

N-of-1 design

The Delayed Start Design

Treatment group

Placebo group

Randomization

Indications and pre-requisites 1- Can be used to assess disease progression as well as disease relapses (or other short term outcomes). 2- The treatment periods are sufficiently long for a therapeutic effect to be obtained with minimal attrition and the same number in both groups3- Sufficient number of follow-up visits to measure the treatment effect to allow a precise estimation of the treatment effect slope.

Phase I Phase II

All receive treatment

Delayed start

The Delayed Start Design

Advantages Disadvantages 1- Allows more patients to receive active treatment2- Can distinguish effects on symptoms and effects on the disease evolution (progression and relapse)

1- At the start of the second phase, the patients are not comparable. 2- No real blinding for the second period (phase II) 3- Carry over effect possible.

Trials minimizing time on inactive treatment or placebo

• Randomized withdrawal, • Early escape, • Randomized placebo phase, • Stepped wedge designs

General description • Randomized withdrawal design:- All eligible patients with the disease

being studied receive open-label treatment for a specified period to identify a subgroup of patients who can successfully achieve a pre-defined level of response.

- The patients in this subgroup are then randomized to continue the tested treatment or to receive a placebo in a double-blind fashion.

- The randomized withdrawal design aims to evaluate the optimal duration of a treatment in patients who respond to the treatment.

• In the randomized early escape design:

- For patients who do not respond to therapy: time on ineffective treatment is minimized.

- Both these designs are combined in the three-stage randomized trial design.

• In randomized placebo phase and stepped wedge trials:

- the time spent on placebo is minimized, and all patients receive the active treatment at the end

Randomized placebo-phase Trial start

Trial end

Time

1- All patients receive the tested treatment inthe end–but have varying lengths of timeon placebo.2- Randomization of time from enrolment tostarting tested treatment3- Assumes that a response will occursometime after an effective treatment isgiven, so that patients who start thetreatment earlier should, on average,respond sooner

Placebo

Advantages Disadvantages 1- Can be used for disease-modifyingtherapies, in diseases with a rapid,unfavorable evolution. 2- All patientsreceive active treatment

1- Variable length of placebo period reducesstatistical power2- Low and intermediate potency therapies showlarge variability for response3- Limited ability to estimate size of treatmenteffect

Stepped Wedge Pa

rticip

ants

/clu

ster

s Time periods

- All patients receive tested treatment in the end. - Intervention allocated sequentially to participants (either as individuals or clusters of individuals)For a 5-step wedge design, all patients start with control then for the following five time periods individual or clusters randomized to treatment to finish in the last period with all patients receiving tested treatment.

Placebo

Treatment

Advantages Disadvantages

1- Useful when there is a prior belief that treatment will do more good than harm

1- There might be a risk of contamination between intervention participants, and a need for blind assessment of outcome

Randomized withdrawal

Screen

Lack of efficiency Withdrawal

Adverse event Withdrawal

Titrate to effect with

active treatment

Randomize

Active treatme

nt

Control

Assessment

- Used to assess treatment continuation in patients who are responding to the treatment.- Randomization of responders to continue treatment or switch to placebo- The treatment effect is overestimated since only responders are included (and compared to placebo)- All patients initially receive the tested treatment; responders are randomized to continue treatment or to receive placebo

Advantages Disadvantages

1- Reduces the time on placebo since only responders are randomized to placebo.2- For use in chronic diseases,. 3- Can assess if treatment needs to be continued or can be stopped

1- Not suitable for unpredictable diseases (e.g. spontaneous remission) or those with slow evolution2- Possible carry-over effect for adverse effect

- Patients withdrawn if they satisfy a priori failure criterion- Randomization to active treatment or placebo - Reduces the time on placebo or in treatment failure.- Difficult to define a binary failure/success outcome.- Analyze failure rate, so minimizes exposure to ineffective treatment- Only short-term efficacy evaluated.- Loss of power if significant number of patients ‘escape

Early Escape

Adaptive randomization (play the winner, drop the looser

designs)• The play-the-winner and the drop-the-loser designs

aim to favor the group with the best chance of success by increasing the probability of patients being randomized to that group.

• For adaptive randomization designs, the procedure is best described by using the urn model .

• The response of each patient after treatment plays an essential role in the determination of subsequent compositions of balls in the urn.

Design Study

Parallel group

• Phosphodiesterase-5 inhibition for pulmonary hypertension in heart failure • Vigabatrin in infantile spasms due to tuberous sclerosis (comparative parallel design)• Stiripentol in Dravet syndrome (placebo controlled parallel design)

Factorial • Aspirin and simvastatin for pulmonary arterial hypertension

Cross over - Amantadine in Huntington disease - Oral sildenafil therapy in severe pulmonary artery hypertension- Sirolimus therapy to halt the progression of ADPKD

Latin Square

- Plasma exchange for induction and cyclosporine A for maintaining remission in Wegener’s granulomatosis- Assessment of disease flare in patients with systematic lupus erythematosus

N-of-1 - Amitriptyline in fibromyalgia - Tramadol to treat chronic cough - L-arginine in ornithine transcarbamylase deficiency carrier

Design Study

Delayed start

Rasagiline in Parkinson’s Disease

Randomized placebo-phase

Low dose phenelzine in the chronic fatigue syndrome

Stepped wedge

- Long-term efficacy of HBV vaccine to prevent liver cancer and chronic liver disease - School-based anti-smoking campaign, (delivered by one team of facilitators who travel to each school)

Randomized withdrawal

- Withdrawal of hydroxychloroquine sulfate in systemic lupus erythematosus - Etanercept in children with polyarticular juvenile rheumatoid arthritis - Vigabatrin withdrawal randomized study in children with epilepsy - Antipsychotic withdrawal with Alzheimer’s Disease - Stiripentol withdrawal design in children with partial epilepsy

Early escape

Intravenously golimumab in patients with active rheumatoid arthritis [36]Pain control for post-operative pain

Post test 1- Randomization:a. Reduces selection bias b. Reduces performance biasc. Not required in cross-over design 2- Gold standard of clinical research trial:d. Cross-over e. Latin square f. Placebo withdrawal g. Parallel groups3- Parallel group design: h. Require large sample sizei. Applicable only in some situation j. Possibility of carry over effect

4- N-of-1 design: a. Suitable for testing ne drugs b. Used in personalized medicinec. Involves many patients5- Cross-over design: d. Suffer from selection bias e. Can measure inter-subject’s variabilityf. There no possibility of carry over 6-Factoial design: a- inappropriate to use in drug interactionb. Require stable chronic condition c. None of the above.

7- All except one of the following design is characterized by provision of treatment to all groups:

a. Delayed start b. Parallel group c. Factorial d. Cross-over design 8- In wedged stepped design: e. All participants starts with placebo f. All start with treatment g. Randomization is not required h. No contamination is possible9- In randomized withdrawal: i. All groups receive treatment and screened for the

response j. Only used in chronic stable diseasesk. There is no possibility of carry over effect

Case 1 • Assessing the efficacy of L-arginine vs

placebo in a patient with ornithine transcarbamylase deficiency (OTCD).

• Female carriers of this autosomal genetic disorder may be asymptomatic, or have symptoms ranging from protein aversion only, to profound neurological impairment and death due to secondary encephalopathy.

• Arginine supplementation is required, but it is not certain if mildly symptomatic females will benefit from this treatment.

Case 2 • The trial of intravenous immunoglobulin in

patients with poly-articular juvenile rheumatoid arthritis resistant to other treatments.

• The outcome was‘ clinically important improvement’ ,which is reversible, but relatively slow (>3 months). If the investigators had wanted to minimize time on placebo.

Case 3 • To assess a potentially disease-

modifying neuro-protective drug, rasagiline in patients with Parkinson’s disease.

• The primary endpoint was based on the Unified Parkinson’s Disease Rating Scale (UPDRS; a 176-point scale with higher numbers indicating more severe disease); this outcome is reversible and the response can be considered to be slow.

Case 4

• Risks and benefits of aspirin and beta carotene in the prevention of cardiovascular disease and cancer

Case 5Protective effect of tamoxifen in older

women with stage II breast cancerTamoxifen vs. placebo

Thank you