MSc Lecture 5 Complex RCTs

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MSc Lecture 5 - Complex RCTs

• John Norrie

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Overview

• Previous lecture simple RCT, and pragmatic vs.
  explanatory trials
• Why extend from simple 2-arm RCT?
• More complex RCTs
• A different model for randomisation and
  recruitment

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Simple 2-arm trial

• Patients are randomised to study or control group
• Study population
• Study Control
• (50) (50)
• Can have nm rather than 11 allocation
• E.g. 21 activecontrol

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Why extend simple 2-arm RCT?

• 1 Compare gt1 intervention
• May be the more ethical design
• Can be cheaper to do 1 trial investigating 2
  interventions than two separate trials
• 2 simple RCTs exclude those patients with
  strong preferences
• With a chance of getting 1 of 2 interventions
  more subjects may be willing to be randomised
• With data on those unwilling to be randomised the
  trial may be more generalisable
• 3 Contamination of treatment effects?
• So instead of randomising a patient, randomise a
  family, or a GP surgery, or a hospital cluster
  randomisation

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RCTs for more than one intervention

• Multi-arm trials
• Factorial designs
• Crossover designs

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Multi-arm trial

• Simplest extension to simple RCT
• Patients randomised to two or more study groups
  or control group
• Study population
• Intervention 1 Intervention 2 Control
• (33) (33) (33)

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Multi-arm trial (2)

• Advantages
• still simple to design
• allows head to head comparisons

• Disadvantages
• requires a larger overall sample size to achieve
  the same level of power
• Multiple comparisons
• rarely have power to detect significant
  differences between the interventions

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Factorial design (1)

• Compares more than one intervention
• Multiple layers of randomisation
• Notation
• 2x2 - indicates 2 trts each with 2 levels
• 2x2x2 - indicates 3 trts each with 2 levels
• Fractional factorial designs
• Many treatments, patients get a selection

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Factorial design (2) - 2x2 example

• Vitamin D and/or calcium supplementation to
  prevent re-fracture (RECORD)

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Factorial designs (3)

• Advantages
• reduced loss of power compared with multi-arm
  trial
• very efficient - two trials for the price of
  one
• allows possibility of exploring interaction
  effects

• Disadvantages
• requires no interaction between treatments for
  full power
• more difficult to operationalise

There are however studies with a factorial
design which specifically anticipate an
interaction
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Crossover trials

• Useful when studying patients with a chronic
  (long-term) disease
• Allows patients to receive both treatments
  sequentially
• patient acts as their own control

First period
A
B
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Crossover trial - example

• Renal dialysis - each patient receives dialysis 3
  times a week
• Two types of dialysis solution available -
  acetate and bicarbonate
• Thought that bicarb may reduce nausea and other
  symptoms
• Crossover trial
• each patient does a month on one solution
  followed by month on the other
• for each patient, the starting solution is
  assigned randomly

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Crossover trials

• Advantages
• requires fewer patients as each get both
  treatments
• background noise reduced as comparison is
  within-patient

• Disadvantages
• must be no carryover effect
• Washout periods
• gt 2 periods?
• Loss to follow up
• can only be used for short term outcomes e.g.
  symptom control
• requires chronic and stable illness - patients
  require same level of illness for both treatments

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Why extend simple RCT - reason 2

• Some RCTs compare very different treatments eg
  surgery vs. long term medication
• Patients with strong preferences not willing to
  be randomised
• Simple RCTs have to exclude those patients

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Patient preference trials

• If patients have a strong preference for a
  therapy they get that therapy
• If no strong preference, patients randomised
• Primary analysis still based on randomised groups
• Two studies a randomised study and an
  observational study

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Patient preference trial - example

• Two treatments for reflux disease
• medical management
• surgical management
• Four trial groups
• prefer surgery
• prefer medical
• randomised to surgery
• randomised to medical

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Patient preference trials

• Disadvantages
• harder to analyse and possibly to interpret
• may be unequal distribution across the four trial
  groups
• more complex informed consent

• Advantages
• recruitment maximised
• motivational factors maximised in the preference
  groups
• motivational factors equalised in the randomised
  groups
• results potentially more generalisable

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Why extend a simple RCT - reason 3

• There is a worry that there will be contamination
  of treatments across patients eg trial comparing
  two dietary interventions - what if 2 members of
  same family randomised to different diets?
• Potential solution - randomise intact groups
  (families) rather than individuals

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Cluster randomised trial

• Intact groups (known as clusters) rather than
  individuals randomised to each intervention
• Unit of randomisation should minimise risk of
  contamination eg family, practice, hospital ward

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A cluster RCT
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Cluster trials - issues

• Outcomes within a group of patients, or cluster,
  may be more similar than those across clusters -
  they are no longer independent
• A statistical measure of this similarity within
  clusters is the intra-cluster correlation
• Because patients not independent, study loses
  power
• The larger the intra-cluster correlation the
  larger the inflation required to the sample size
  to redress the loss of power

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Cluster trials

• Advantages
• minimises contamination between groups
• may be easier to organise practically

• Disadvantages
• requires larger trial
• patients within clusters not independent
• standard analysis techniques not appropriate
• analysis more complex

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Different model for randomisation (1)

• Standard procedure - get informed consent then
  randomise
• Potential problems
• patients may withdraw if they do not get the
  treatment they hoped for
• patients may comply poorly if they get the
  control treatment - thinking the experimental
  treatment is better anyway

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Different model for randomisation (2)

• Alternative approach - Zelens design
• randomise before obtaining consent
• only seek consent from those randomised to
  experimental treatment
• control patients not approached for consent
• Debate surrounds ethics of this approach - eg MRC
  do not accept this design as ethical

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Zelens design

• Advantages
• does not raise hopes of a new treatment which can
  then be denied by randomisation
• may avoid downward bias in those allocated to
  control

• Disadvantages
• ethics are debateable

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References

• Why are RCTs important BMJ 1998 316 201
• Pragmatic trials BMJ 1998 316285
• Crossover trials BMJ 1998 316 1719-1720
• Patient preference trials BMJ 1998 316 360
• Cluster trials BMJ 1998 316 1171-1172
• Zelens design BMJ 1998 316 606

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Exercise

• Four groups of six
• You are asked to design a trial to investigate
  the potential benefits of two interventions
  designed to reduce smoking in schoolchildren
• Prepare a 5 minute talk to describe a design
  which may be appropriate for this trial, with
  reasons why.
• The interventions are
• take-home information packs
• one-to-one sessions with school nurse

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Exercise (2)

• Your presentation should include
• Choice of design
• Randomise pupil or class or school?
• Two or multi-arm? Control? Factorial?
• Delivery of intervention
• How many times?
• Can we measure compliance did the students
  receive the advice?
• Choice of outcome
• What is the measure?
• How is it measured?
• Who measures it?
• Where is it measured?
• When is it measured?

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Exercise - Solutions

• Design?
• Individual or cluster randomisation?
• Problems with contamination?
• Type of study?
• Two arm info vs. nurse
• Need a control group?
• Crossover inappropriate?
• Factorial info vs. nurse vs. no advice vs. info
  nurse

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Exercise Solutions (II)

• Intervention
• How many times e.g. once or every week for 1
  month etc
• Should we measure attendance at the classes in
  which instruction is given, and attendance at
  school nurse 1-on-1s?

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Exercise Solutions (III)

• Outcome Reduction in smoking?
• Are there any smokers?
• What do the non-smokers tell us?
• What outcome?
• Smoking Yes/No
• Number of cigarettes
• Large number of zeroes?
• What about starting smoking?

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Exercise Solutions (IV)

• Outcome how measured?
• Self report?
• Invasive lab measure e.g. cotinine
• Outcome who measures?
• nurse or teacher or student?
• For cluster, proportion smoking?
• Outcome when measured?
• At baseline
• Within 1 week of intervention?
• Other issues
• Additional baseline information e.g. passive
  smoking?