The Importance of BLINDING

1
The Importance of BLINDING

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

2
Why Randomize?

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

3
Why Blind?

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

4
Physicians Health Study

• 22,071 male physicians
• Aspirin 325 mg QOD or placebo
• Follow-up 5 years
• Outcomes - CVD events and death

5
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

6
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

7
Biased Outcome Ascertainment

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

8
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
9
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

10
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

11
Why Not Blind?

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

12
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

13
What if You Cant Blind?

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

14
Be Clever

• Garlic for cholesterol lowering
• odorless, tasteless garlic prep
• Dietary soy protein for flushes
• soy protein meal
• animal protein meal with same calories
• Lysis of adhesions for pelvic pain
• laparoscopy with lysis
• laparoscopy without lysis

15
Be Courageous

• Acupuncture for dysmenorrhea
• Internal mammary ligation for angina
• Orthoscopic debridement for pain due to
  osteoarthritis
• Type of surgery for stress UI
• Sham burr holes for fetal tissue implants for
  Parkinsons

16
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

17
Do the Best You Can

• Hormone therapy to prevent CHD
• separate gyn staff to manage bleeding and breast
  tenderness
• lipoproteins revealed only if dangerous
• Bisphosphonate to prevent fracture
• densitometer output masked
• change in BMD reported if dangerous

18
Use a Hard Outcome

• Death
• Measurements
• lab values
• HgA1C vs. diabetes severity scale
• UA vs. dysuria and frequency
• test results
• MVO2 vs. self-reported exercise ability
• doppler evaluation of DVT vs. swollen leg
• scales and diaries vs. investigator judgment
• Geriatric Depression Scale vs. improved
• 7-day urinary diary vs. dry

19
HERS Table 1Baseline Characteristics

• HRT Placebo
• Age (years) 67 67
• White () 88 90
• Current Smoker () 13 13
• Diabetes () 19 18
• Blood pressure (mmHg) 135 135
• LDL-C (mg/dL) 145 145
• BMI gt 27 (kg/m2) 57 55
• Prior estrogen use () 24 23

20
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

21
Choice of Intervention

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

22
Principles

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

23
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
• long enough to restore strength

24
HERS

• Hormone possibilities
• estrogen only (CEE, E2)
• estrogen progestin (cyclic, daily)
• oral, transdermal
• CEE 0.625 MPA 2.5 mg QD
• estrogen effective in cohort studies
• thought safe
• decreased bleeding, unblinding
• increased compliance

25
Dose Titration

• 300 women with urge UI
• randomized to detrol 1 mg BID or placebo
• if inadequate relief, pill first increased to
  TID, then dose doubled
• outcome - number of incontinent episodes/week

26
Dose Titration

• 100 men over 70 yo
• randomized to 0.5 mg 1,25D or placebo
• if 24H urine calcium gt 300mg, dose cut in half
• outcome - quadriceps muscle strength on
  dynamometer (kg)

27
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

28
Multiple Interventions

• Combination interventions
• HERS
• MRFIT
• Ornish regimen
• Multidrug HIV therapy
• Advantage - maximize benefit
• Disadvantage - which is effective?

29
Choice of Control

• Inert placebo usually best choice
• Active therapy for control
• equivalence trial
• Ho not more than a stated difference between
  groups
• Ha one treatment better

30
Equivalence Trials

• Advantage
• answers 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 potential advantage of new
  therapy

31
Trial of New Depression Drug

• Known effective treatment for depression, but
  significant side effects
• New drug thought to be as effective as old drugs,
  but without side effects
• Untreated depression can result in suicide

32
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
• expect no difference
• Ho difference no greater than /-10
• sample size 125/group

33
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 assessing outcome
• use hard outcomes

34
Choice of Intervention

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