Blinding, Intervention and Controls

1
Blinding, Intervention and Controls

• Deborah Grady, MD, MPH
• Professor of Medicine
• UCSF

2
The Importance of BLINDING

• Why blind?
• What is blinding?
• What to do when blinding is difficult or
  impossible

3
Why Randomize?

• Assures that groups are balanced
• Balances both measured and unmeasured variables
• Balances groups only at baseline

4
Why Blind?

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

5
Womens Health Study

• 39,876 female health care providers
• Aspirin 100 mg every other day or placebo
• Follow-up 10 years
• Outcomes - CVD events and death

6
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

7
Oral Contraceptive Pills to Prevent Pregnancy

• 18,021 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

8
Biased Outcome Ascertainment

• If group assignment is known
• participants may report symptoms or outcomes
  differently
• physicians or investigators may elicit symptoms
  or outcomes differently
• Problematic with soft outcomes
• chest pain
• disability
• satisfaction

9
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 neurologists

Noseworthy, Neurology, 1994
10
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

11
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

12
Why Not Blind?

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

13
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

14
What if You (Think You) Cant Blind?

• Be clever and/or courageous
• Do the best you can
• minimize differential cointervention
• blind those ascertaining and adjudicating
  outcomes
• use hard outcomes
• Measure degree of unblinding

15
Be Clever

• Garlic for cholesterol lowering
• odorless, tasteless garlic preparation
• identical placebo
• Dietary soy protein for hot flushes
• soy protein meal
• animal protein meal with same calories
• Paced respiration for hot flushes
• Resperate to slow respiratory rate
• Resperate that does not slow resp. rate

16
Be Courageous

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

17
Do the Best You Can

• Yoga to treat metabolic syndrome
• yoga - weekly class, home practice
• control - ?
• Psychotherapy for schizophrenia
• therapy - psychotherapy weekly
• control - ?
• Computer-based exercises for prevention of
  dementia
• training 10 per day using biofeedback
• control ?

18
Use a Hard Outcome

• Death
• Measurements
• lab values
• UA vs. dysuria and frequency
• MRI of knee vs. knee pain questionnaire
• 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

19
Measure Degree of Unblinding

• In trials that are partially blinded
• ask participants and study staff to guess
  treatment
• should be correct about 50 of the time
• If unblinding substantial - assess impact in
  discussion of paper

20
Choice of Intervention

• Type (drug, education, surgery)
• Intensity, dose, route
• Frequency
• Duration
• Titration

21
Principles

• Maximize benefit
• Minimize risk
• Generalizable to clinical practice
• Strengthen trial design/conduct
• recruitment
• compliance
• follow-up
• blinding

22
Vitamin D for Muscle Strength

• Presumed mechanism
• normalize 1,25--OHD
• Risks
• hypercalcuria, hypercalcemia
• Dose
• 0.25 - 1.0 mg SQ QD normalizes calcium
• Duration
• 6 months (long enough to restore strength)

23
Yoga for Control of Diabetes

• Presumed mechanism
• reduces sympathetic tone
• Risks
• muscle aches and injuries
• Dose
• teaching session 2/wk for 90 minutes
• Duration
• 12 weeks

24
Dose Titration

• 300 women with urge incontinence
• Randomized to Detrol 1 mg BID or placebo
• If inadequate effect titrate dose to TID, then to
  ii pills BID
• Outcomes - frequency of incontinence episodes and
  side effects

25
Several Doses of Drug

• MORE Trial
• 7704 women with osteoporosis
• 60 or 120mg raloxifene or placebo
• followed for 3 years for fracture
• identify best dose
• show dose-response effect
• larger sample size
• more complex analyses

26
Multiple Interventions

• Combination interventions
• MRFIT
• Ornish regimen
• Multidrug HIV therapy
• Advantages
• maximize benefit
• mimic clinical practice
• Disadvantages -?

27
Background Treatments

• Add intervention to standard care
• new CHF med or placebo in addition to
• diuretic, ACEI, bb, aldosterone blocker
• Advantages
• mimic clinical practice
• ethical
• Disadvantages -?

28
Choice of Control

• Inert placebo usually best choice
• Ho no difference between groups
• Ha there is a difference
• Active therapy for control
• equivalence (noninferiority) trial
• Ho not more than a stated difference between
  groups
• Ha more than a stated difference

29
Equivalence Trials

• Advantage
• better answer to clinical question
• 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 good standard of care and
  potential advantage of new therapy

30
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

31
Trial of Smiletraline for Depression

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

32
BLINDING

• As important as randomization to prevent
  potential bias due to
• co-intervention
• outcome ascertainment
• outcome measurement
• Difficult to accomplish
• If not possible, do your best
• minimize co-intervention
• blind those ascertaining and adjudicating outcome
• use hard outcomes

33
Choice of Intervention

• Maximize benefit vs. risk
• Generalizable to clinical practice
• Strengthen trial design
• Ethical

34
Choice of Control

• Placebo generally best
• Consider equivalence trial if clear standard of
  care