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Introduction to Randomized Clinical Trials

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Introduction to Randomized Clinical Trials Deborah Grady Professor of Medicine University of California, San Francisco Randomized Trials Rationale Basic designs ... – PowerPoint PPT presentation

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Title: 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
5
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)

6
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

7
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)

8
Cross-over Design
Population
Intervention
Randomization
Sample
Placebo
9
Factorial Design
Int A and Int B
Population
Int A and Pbo B
Sample
Pbo A and Int B
Pbo A and Pbo B
10
Vitamin D and Strength in the Elderly
  • Muscle strength and renal function decline with
    aging
  • Vitamin D deficiency causes myopathy and rx with
    1,25-D improves strength
  • Declining renal function results in low levels of
    1,25 D

RQ Does treatment with vitamin D improve
strength?
11
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)
12
Exclusion Criteria
  • Intervention unsafe
  • Intervention unlikely to be effective
  • Unlikely to adhere to the intervention
  • Unlikely to complete follow-up
  • Practical problems

Practice Parsimony Preserve Generalizability
13
Choice of Intervention
  • Maximize
  • effectiveness (highest tolerable dose)
  • safety (lowest effective dose)
  • generalizability
  • trial design/conduct
  • recruitment
  • compliance
  • blinding

14
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?

15
Several Doses of DrugMORE Trial
60 mg raloxifene/day
7705 PM women with osteoporosis
120 mg raloxifene/day
placebo
  • identify best dose
  • show dose-response effect
  • larger sample size
  • more complex analyses

16
Multiple Interventions
  • Combination interventions
  • MRFIT
  • Ornish regimen
  • Multidrug HIV therapy
  • Advantages
  • maximize benefit
  • generalizable to clinical practice
  • Disadvantage - which is effective?

17
Choice of Control
  • Inert placebo usually best, but might not be
    possible
  • Active therapy for control
  • equivalence trial
  • Ho not more than a stated difference between
    groups
  • Ha one treatment better

18
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
19
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

20
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

21
Why Blind?
  • Maintains balanced groups during follow-up
  • Eliminates
  • cointervention
  • biased outcome ascertainment
  • biased measurement of outcome

22
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

23
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

24
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

25
Biased Outcome Ascertainment
  • If group assignment is known
  • participants may report symptoms or outcomes
    differently
  • physicians or investigators may elicit symptoms
    or outcomes differently

26
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
27
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

28
What is Blinding?
  • Single blind - participants are not aware of
    treatment group
  • Double blind - both participants and
    investigators unaware
  • Triple blind - various meanings
  • persons who perform tests
  • outcome adjudicators
  • safety monitoring group

29
Why Not Blind?
  • Impossible
  • surgery
  • exercise
  • diet
  • education
  • Possible, but
  • dangerous
  • painful
  • cumbersome

30
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

31
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

32
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

33
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

34
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

35
Measure Degree of Unblinding
  • In trials that are partially blinded
  • ask participants to guess treatment
  • ask study staff to guess treatment
  • If unblinding substantial - assess impact in
    discussion of paper

36
Adherence
  • Intervention cannot work if it isnt used
  • Adherence measures
  • intervention
  • pill count, diaries, biologic measure, measuring
    device in dispenser
  • visits
  • study measurements

37
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

38
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

39
Diet and Exercise to Prevent Diabetes in Persons
with Glucose Intolerance
  • DM No DM
  • D E
  • No D E

40
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
  • night visits, travel and parking reimbursement
  • personal relationships with participants
  • Measurements easy, safe and painless
  • Never discontinue participants

41
Outcomes in Clinical Trials
  • Efficacy Outcomes
  • Primary
  • Secondary
  • Surrogate
  • Composite
  • Adverse Effects
  • rare
  • common

42
Raloxifene Use for the Heart
  • Potential Outcomes
  • Mortality
  • CHD events (death, MI, ACS)
  • Stroke
  • Breast cancer
  • Fracture
  • LDL-cholesterol
  • Quality of life

43
How to Proceed?
  • Measure all outcomes
  • Pick one primary outcome
  • estimate sample size
  • FDA requirement
  • Make all the rest secondary

44
Adverse Events and Side Effects
  • Anticipated
  • use specific questions
  • Unanticipated
  • ask about general adverse experiences
  • Rare
  • sample size inadequate
  • Common
  • multiple differences between groups

45
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
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