Here are the designs I would recommend for each case: Case 1: N-of-1 design. This design is well-suited for testing the efficacy of a treatment for an individual patient, as in this case assessing L-arginine for a carrier of OTCD. Case 2: Randomized withdrawal design. This minimizes time on placebo by giving all patients open-label treatment initially to identify responders, who are then randomized to continue treatment or placebo. This is appropriate given the reversible but relatively slow outcome. Case 3: Delayed start design. This can distinguish treatment effects on symptoms from effects on disease progression, which is important given the primary endpoint of changes on the UPDRS scale for Parkinson

1. 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.

2. Clinical trials designs

3. • 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.

4. • 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

5. • 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

6. 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.

7. Clinical trials designs

8. 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 situation
Requires larger sample size
Randomization to one of two or more
treatment groups, with a pre-specified
randomization 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- and
intra-patient variability to the
overall variability

9. 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.

10. Factorial design
Comparison: Treatment B vs. placebo
Treatment B
(n=200)
Placebo B
(n=200)
Treatment A
Treatment B
(n=100)
Placebo A
(n=200)
Treatment A
(n=200)
Placebo A
Placebo B
(n=100)
Placebo A
Treatment B
(n=100)
Treatment A
Placebo B
(n=100)
Comparison:TreatmentAvs.placebo
Advantages Disadvantages
1- Can answer two or more questions
with one trial
2- Time-saving for the trial sponsor
3- 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

11. 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 (for
phase 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)

12. 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

13. 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.

14. 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

15. 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 groups
3- 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

16. The Delayed Start Design
Advantages Disadvantages
1- Allows more patients to receive
active treatment
2- 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.

17. Trials minimizing time on inactive treatment
or placebo
• Randomized withdrawal,
• Early escape,
• Randomized placebo phase,
• Stepped wedge designs

18. 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.

19. • 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

20. Randomized placebo-phase
Trial start
Trial end
Time
1- All patients receive the tested treatment in
the end–but have varying lengths of time
on placebo.
2- Randomization of time from enrolment to
starting tested treatment
3- Assumes that a response will occur
sometime after an effective treatment is
given, so that patients who start the
treatment earlier should, on average,
respond sooner
Placebo
Advantages Disadvantages
1- Can be used for
disease-modifying
therapies, in diseases with
a rapid,
unfavorable evolution.
2- All patients
receive active treatment
1- Variable length of placebo period
reduces
statistical power
2- Low and intermediate potency
therapies show
large variability for response
3- Limited ability to estimate size of

21. Stepped Wedge
Participants/clusters 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

22. Randomized withdrawal
Screen
Lack of efficiency
Withdrawal
Adverse event
Withdrawal
Titrate to
effect with
active
treatment
Randomize
Active
treatment
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

23. 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 evolution
2- Possible carry-over effect
for adverse effect

24. - 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

25. 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.

26. 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

27. 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

28. Post test
1- Randomization:
a. Reduces selection bias
b. Reduces performance bias
c. Not required in cross-over design
2- Gold standard of clinical research trial:
a. Cross-over
b. Latin square
c. Placebo withdrawal
d. Parallel groups
3- Parallel group design:
a. Require large sample size
b. Applicable only in some situation
c. Possibility of carry over effect

29. 4- N-of-1 design:
a. Suitable for testing ne drugs
b. Used in personalized medicine
c. Involves many patients
5- Cross-over design:
a. Suffer from selection bias
b. Can measure inter-subject’s variability
c. There no possibility of carry over
6-Factoial design:
a- inappropriate to use in drug interaction
b. Require stable chronic condition
c. None of the above.

30. 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:
a. All participants starts with placebo
b. All start with treatment
c. Randomization is not required
d. No contamination is possible
9- In randomized withdrawal:
a. All groups receive treatment and screened for the response
b. Only used in chronic stable diseases
c. There is no possibility of carry over effect

31. 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.

32. 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.

33. 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.

34. Case 4
• Risks and benefits of aspirin and
beta carotene in the prevention
of cardiovascular disease and
cancer

35. Case 5
Protective effect of tamoxifen in older women
with stage II breast cancer
Tamoxifen vs. placebo

36. Thank you