Introduction to Randomized Clinical Trials

1
Introduction toRandomized Clinical Trials

• Deborah Grady
• Professor of Medicine
• University of California, San Francisco

2
Randomized Trials

• Rationale
• Basic designs
• Participants
• Intervention
• Blinding
• Outcomes
• Adherence
• Follow-up

3
Rationale

• Why do a randomized blinded trial
• minimize confounding
• minimize co-interventions
• minimize biased outcome ascertainment
• Why not do a randomized trial
• major ethical issues
• narrow research question
• expensive
• long time from idea to paper
• Generally reserved for mature questions

4
Basic Trial Design
Population
Intervention
Randomization
Sample
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Randomization

• Participants are assigned to treatment groups by
  chance with a known probability
• Random number table or computer
• Tamper-proof system
• ordered, sealed envelopes
• centralized system (phone, fax, web)

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Value of Randomization

• Balances baseline characteristics of the
  treatment groups
• eliminates confounding due to measured and
  unmeasured factors
• provides an unbiased comparison between groups
• Does NOT maintain balance after randomization

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Variations of Randomization

• Fixed Allocation - probability fixed
• Simple - flip a coin
• Blocked - randomize consecutive small batches
• Stratified - separate randomization in strata
• Clustered - randomize groups
• Adaptive - probability changes
• N in the groups (biased coin)
• baseline characteristics
• outcome (play the winner two-armed bandit)

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Cross-over Design
Population
Intervention
Randomization
Sample
Placebo
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Factorial Design
Int A and Int B
Population
Int A and Pbo B
Sample
Pbo A and Int B
Pbo A and Pbo B
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Vitamin D and Strength in the Elderly

• Muscle strength and renal function decline with
  aging
• Declining renal function results in low levels of
  1,25 D
• Vitamin D deficiency causes myopathy and
  treatment improves strength

RQ Does treatment with vitamin D improve
strength?
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Participants

• Inclusion criteria to maximize
• rate of outcomes (old, weak)
• likely benefit from intervention (renal dz,
  institutionalized, vitamin D deficiency)
• generalizability
• ease of recruitment

(none of the above)
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Exclusion Criteria

• Intervention unsafe
• Intervention unlikely to be effective
• Unlikely to adhere to the intervention
• Run in
• Unlikely to complete follow-up
• Practical problems

Practice Parsimony Preserve Generalizability
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Choice of Intervention

• Maximize
• effectiveness (highest tolerable dose)
• safety (lowest effective dose)
• generalizability
• trial design/conduct
• recruitment
• compliance
• blinding

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Vitamin D for Muscle Strength

• Consider
• Dose - in renal insufficiency 0.25 - 1.0 ug SQ
  1,25 D daily normalizes calcium
• Duration - few months usually restores strength
  in patients with rickets and myopathy
• Route - SQ vs. PO?
• Titration to normal 1, 25-D level or normal
  (safe) urine calcium?

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Choice of Control

• Inert placebo usually best
• Active therapy or standard of care
• Active Comparator Trial - new therapy more
  effective than standard
• Ho two treatments equally effective
• Ha one treatment more effective
• Equivalence Trial - new therapy equivalent
• Ho two treatments differ by at least X
• Ha two treatments differ by less than X

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Equivalence Trials

• Advantage
• answers clinical question
• may be more ethical
• Disadvantage
• may require larger sample size
• negative result may be due to low power
• cant tell if either better than placebo

Only reasonable if potential advantage of new
therapy
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Trial of New Depression Drug

• Approved SSRIs effective for depression, but
  often cause loss of libido
• New drug thought to be as effective as old with
  no effect on libido
• Untreated depression can result in suicide

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Trial of Smiletraline for Depression

• Placebo controlled trial
• expected improvement 25 over placebo
• Ho no difference
• Ha 20 difference with a .05, b .90
• sample size 100/group
• Compare smiletraline to sertraline
• expect no difference
• Ho difference no greater than /-10
• sample size 125/group

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Why Blind?

• Maintains balanced groups during follow-up
• Eliminates
• cointervention
• biased outcome ascertainment
• biased measurement of outcome

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Physicians Health Study

• 22,071 male physicians
• Aspirin 325 mg QOD or placebo
• Follow-up 5 years
• Outcomes - CVD events and death
• Many physicians had study drug tested for ASA

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Cointerventions

• Unintended effective interventions
• participants use other therapy or change behavior
• study staff, medical providers, family or friends
  treat participants differently
• Nondifferential - decreases power
• Differential - causes bias

22
Oral Contraceptive Pills to Prevent Pregnancy

• 18,000 women age 21-35 years
• Randomly assigned to OCPs or usual birth control
  method
• Followed Q6 months for 2 years
• Pregnancy risk decreased 75
• VTE risk increased 5-fold

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Biased Outcome Ascertainment

• If group assignment is known
• participants may report symptoms or outcomes
  differently
• physicians or investigators may elicit symptoms
  or outcomes differently

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Canadian Cooperative MS Trial

• 165 patients with multiple sclerosis
• plasma exchange cyclo pred
• sham plasma exchange placebo meds
• Outcome structured neurologic exam by blinded
  and unblinded neurologists
• More improvement with plasma exchange by
  unblinded, but not blinded assessment

Noseworthy, Neurology, 1994
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Biased Outcome Adjudication

• Study staff who decide if a change or outcome has
  occurred may
• classify similar events differently in treatment
  groups
• Problematic with soft outcomes
• investigator judgement
• participant reported symptoms, scales

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Why Not Blind?

• Impossible
• surgery
• exercise
• diet
• education
• Possible, but
• dangerous
• painful
• cumbersome

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Is It Really Blinded?

• Difficult even for drugs
• identical placebo difficult to prepare
• drug may smell, taste, feel different
• drug may cause side effects
• test results may unblind
• participants may test drug

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What if You Cant Blind?

• Be courageous
• Do the best you can
• minimize differential cointervention
• blind those measuring outcome
• use hard outcomes
• Measure degree of unblinding

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Be Courageous

• Laparoscopic lysis of adhesions for pelvic pain
• Internal mammary ligation for angina
• Orthoscopic debridement for OA
• Sham burr holes for fetal tissue implants for
  Parkinsons

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Do the Best You Can

• Exercise to prevent coronary events
• exercise - supervised exercise to 80 maximum
  capacity 30 min 3/wk
• control - supervised exercise to 40 maximum
  capacity 30 min 3/wk
• Psychotherapy for schizophrenia
• therapy - psychotherapy weekly
• control - advice about diet, exercise, and
  smoking weekly

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Use a Hard Outcome

• Death
• Measurements
• test results
• MVO2 vs.. self-reported exercise ability
• Doppler evaluation vs.. swollen leg for DVT
• scales and diaries vs. investigator judgment
• Geriatric Depression Scale vs. improved
• 7-day urinary diary vs. dry

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Adherence

• Intervention cannot work if it isnt used
• Adherence measures
• intervention
• pill count, diaries, biologic measure, measuring
  device in dispenser
• visits
• study measurements

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Womens Health Initiative

• RQ Does calcium plus vitamin D reduce risk of
  fractures in postmenopausal women?
• Design Randomized trial
• Subjects 36,282 PM women enrolled in WHI
• Intervention 1 gm calcium 400 IU vitamin D
• Outcome clinical fractures
• Adherence at end of trial 60 and about 60 of
  placebo group was taking calcium

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Follow-up

• RQ Does diet and exercise reduce risk of
  developing type 2 diabetes in persons with
  glucose intolerance?
• Design Randomized trial
• Subjects 2500 with glucose intolerance
• Intervention low fat weight loss diet and
  moderate intensity aerobic exercise
• Measurements Predictor treatment
• outcome development of frank diabetes

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Diet and Exercise to Prevent Diabetes in Persons
with Glucose Intolerance

• DM No DM
• D E
• No D E

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Maximizing Adherence and Follow-up

• Choose subjects likely to adhere
• exclude if likely nonadherent
• complete several visits before randomization
• ?complete a run-in
• Intervention easy and safe
• Visits easy and enjoyable
• frequent enough to be engaging
• evening visits, travel and parking reimbursement
• personal relationships with participants
• Measurements easy, safe and painless
• Never discontinue participants

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Outcomes in Clinical Trials

• Efficacy Outcomes
• Primary
• Secondary
• Surrogate
• Composite
• Adverse Effects
• rare
• common

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Raloxifene Use for the Heart

• Potential Outcomes
• Mortality
• CHD events (death, MI, ACS)
• Stroke
• Breast cancer
• Fracture
• LDL-cholesterol
• Quality of life

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How to Proceed?

• Measure all outcomes
• Pick one primary outcome
• estimate sample size
• FDA requirement
• Make all the rest secondary

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Adverse Events and Side Effects

• Anticipated
• use specific questions
• Unanticipated
• ask about general adverse experiences
• Rare
• sample size inadequate
• Common
• multiple differences between groups

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High Quality Randomized Trials

• Tamper-proof randomization
• Blinding of participants, study staff, lab staff,
  outcome ascertainment and adjudication
• Adherence to study intervention
• Complete follow-up
• Adequate power