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Introduction to Randomized Clinical Trials. Deborah Grady Professor of Medicine University of California, San Francisco. Randomized Trials. Rationale Basic designs Participants Intervention Blinding Outcomes Adherence Follow-up. Rationale. Why do a randomized blinded trial

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introduction to randomized clinical trials

Introduction toRandomized Clinical Trials

Deborah Grady

Professor of Medicine

University of California, San Francisco

randomized trials
Randomized Trials
  • Rationale
  • Basic designs
  • Participants
  • Intervention
  • Blinding
  • Outcomes
  • Adherence
  • Follow-up
  • 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
basic trial design



+ Blinding



Basic Trial Design





  • 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)
value of randomization
Value of Randomization
  • Balances baseline characteristics of the treatment groups
    • eliminates confounding due to measured andunmeasured factors
    • provides an unbiased comparison between groups
  • Does NOT maintain balance after randomization
variations of randomization
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)
cross over design







Cross-over Design






factorial design





Factorial Design

Int A and Int B


Int A and Pbo B


Pbo A and Int B

Pbo A and Pbo B

vitamin d and strength in the elderly
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?

  • 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)

exclusion criteria
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

choice of intervention
Choice of Intervention
  • Maximize
    • effectiveness (highest tolerable dose)
    • safety (lowest effective dose)
    • generalizability
    • trial design/conduct
      • recruitment
      • compliance
      • blinding
vitamin d for muscle strength
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?
choice of control
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
equivalence trials
Equivalence Trials
  • Advantage
    • answers clinical question
    • may be more ethical
  • Disadvantage
    • may require larger sample size
    • negative result may be due to low power
    • can’t tell if either better than placebo

Only reasonable if potential advantage of new therapy

trial of new depression drug
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
trial of smiletraline for depression
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
why blind
Why Blind?
  • Maintains balanced groups during follow-up
  • Eliminates
    • cointervention
    • biased outcome ascertainment
    • biased measurement of outcome
physicians health study
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
  • 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
oral contraceptive pills to prevent pregnancy
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
biased outcome ascertainment
Biased Outcome Ascertainment
  • If group assignment is known
    • participants may report symptoms or outcomes differently
    • physicians or investigators may elicit symptoms or outcomes differently
canadian cooperative ms trial
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

biased outcome adjudication
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
why not blind
Why Not Blind?
  • Impossible
    • surgery
    • exercise
    • diet
    • education
  • Possible, but
    • dangerous
    • painful
    • cumbersome
is it really blinded
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
what if you can t blind
What if You “Can’t” Blind?
  • Be courageous
  • Do the best you can
    • minimize differential cointervention
    • blind those measuring outcome
    • use “hard” outcomes
  • Measure degree of unblinding
be courageous
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 Parkinson’s
do the best you can
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
use a hard outcome
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”
  • Intervention cannot work if it isn’t used
  • Adherence measures
    • intervention
      • pill count, diaries, biologic measure, measuring device in dispenser
    • visits
    • study measurements
women s health initiative
Women’s 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

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

diet and exercise to prevent diabetes in persons with glucose intolerance










RR = .5; p = .001

Diet and Exercise to Prevent Diabetes in Persons with Glucose Intolerance


D & E

No D& E

maximizing adherence and follow up
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
outcomes in clinical trials
Outcomes in Clinical Trials
  • Efficacy Outcomes
    • Primary
    • Secondary
    • Surrogate
    • Composite
  • Adverse Effects
    • rare
    • common
raloxifene use for the heart
Raloxifene Use for the Heart
  • Potential Outcomes
    • Mortality
    • CHD events (death, MI, ACS)
    • Stroke
    • Breast cancer
    • Fracture
    • LDL-cholesterol
    • Quality of life
how to proceed
How to Proceed?
  • Measure all outcomes
  • Pick one primary outcome
    • estimate sample size
    • FDA requirement
  • Make all the rest secondary
adverse events and side effects
Adverse Events and Side Effects
  • Anticipated
    • use specific questions
  • Unanticipated
    • ask about general adverse experiences
  • Rare
    • sample size inadequate
  • Common
    • multiple differences between groups
high quality randomized trials
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