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. Outcome Outcome + Blinding Control Placebo 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 andunmeasured 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. Washout Placebo Intervention Washout Outcome Outcome Cross-over Design Population Intervention Randomization Sample Placebo

9. Outcome Outcome Outcome Outcome 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 • can’t 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 “Can’t” 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 Parkinson’s

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 isn’t used • Adherence measures • intervention • pill count, diaries, biologic measure, measuring device in dispenser • visits • study measurements

37. 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

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. 65 560 625 500 625 125 1250 190 1060 RR = .5; p = .001 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