Blinding, Intervention and Controls

1. Blinding, Intervention and Controls Deborah Grady, MD, MPH Professor of Epidemiology and 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. Physicians’ Health Study • 22,071 male physicians • Aspirin 325 mg qod or placebo • Follow-up 5 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 • 18,000 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

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 • Correct guess about treatment group by patients did not affect outcome 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) Can’t 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 • Dietary soy protein for flushes • soy protein meal • animal protein meal with same calories • Laparoscopic treatment of pelvic pain • laparoscopy with lysis of adhesions • laparoscopy without lysis of adhesions

16. 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

17. Do the Best You Can • Exercise to prevent coronary events • exercise - supervised exercise to 80% maximum capacity 30 min 3/wk • control - ? • Psychotherapy for schizophrenia • therapy - psychotherapy weekly • control - ? • Paced respiration for hot flashes • training 10’ per day using biofeedback • control ?

18. 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

19. 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 vs. swollen leg for DVT • scales and diaries vs. investigator judgment • Geriatric Depression Scale vs. “improved” • 7-day urinary diary vs. “dry”

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 • 6 months (long enough to restore strength)

24. 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

25. Dose Titration • 300 women with urge incontinence • randomized to Detrol 1 mg BID • if inadequate effect titrate dose to TID, then to ii pills BID • outcomes - frequency of incontinent episodes and side effects • issues - blinding, analyses, interpretation

26. 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

27. Multiple Interventions • Combination interventions • HERS • MRFIT • Ornish regimen • Multidrug HIV therapy • Advantages • maximize benefit • mimic clinical practice • Disadvantage - which is effective?

28. Background Treatments • Test effect of adding to current standard of care • add to diuretic, ACEI, bb, aldosterone blocker • MRFIT • Ornish regimen • Multidrug HIV therapy • Advantages • maximize benefit • mimic clinical practice • Disadvantage - which is effective?

29. Choice of Control • Inert placebo usually best choice • Ho: no difference between groups in outcome • 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

30. Equivalence Trials • Advantage • better answer to clinical question • 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

31. 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

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 • Ho: difference no greater than +/-10% • Ha: difference 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 ascertaining and adjudicating outcome • use hard outcomes

34. Choice of Intervention • Maximize benefit vs. risk • Generalizable to clinical practice • Strengthen trial design • Ethical

35. Choice of Control • Placebo generally best • Consider equivalence trial if clear standard of care