Introduction to Randomized Clinical Trials

1. Introduction toRandomized Clinical Trials Stephen Bent Associate Professor of Medicine University of California, San Francisco

2. Randomized Trials • Rationale • Basic designs • Participants • Intervention • Blinding • Outcomes • Adherence • Follow-up

3. Take Home Messages • 1. RCT’s really only do one thing • But, it’s a very important thing. • 2. RCT’s are the BEST study design for evaluating efficacy. • RCT’s compare mean responses • Not always what we’d like to know • RCT’s take a long time and cost $

4. Take Home Messages • What is bias? • What is confounding?

5. 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

6. Outcome Outcome + Blinding Control Placebo Basic Trial Design Population Intervention Randomization Sample

7. 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)

8. 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

9. 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

10. Washout Placebo Intervention Washout Outcome Outcome Cross-over Design Population Intervention Randomization Sample Placebo

11. 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

12. Participants • Inclusion criteria to maximize: • rate of outcomes (old, weak) • likely benefit from intervention • generalizability • ease of recruitment

13. 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

14. Choice of Intervention • Maximize • effectiveness (highest tolerable dose) • safety (lowest effective dose) • generalizability • trial design/conduct • recruitment • compliance • blinding

15. Choice of Control • Inert placebo usually best • Active therapy or “standard of care”

16. 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

17. Biased Outcome Ascertainment • If group assignment is known • participants may report symptoms or outcomes differently • physicians or investigators may elicit symptoms or outcomes differently

18. 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

19. 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

20. Why Not Blind? • Impossible • surgery • exercise • diet • education • Possible, but • dangerous • painful • cumbersome

21. 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

22. What if You “Can’t” Blind? Do the best you can • minimize differential cointervention • blind those measuring outcome • use “hard” outcomes Measure degree of unblinding

23. 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

24. 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

25. 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”

26. Adherence • Intervention cannot work if it isn’t used • Adherence measures • intervention • pill count, diaries, biologic measure, measuring device in dispenser • visits • study measurements

27. 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

28. Outcomes in Clinical Trials • Efficacy Outcomes • Primary • Secondary • Surrogate • Composite • Adverse Effects • rare • common

29. Adverse Events and Side Effects • Anticipated • use specific questions • Unanticipated • ask about general adverse experiences • Rare • sample size inadequate • Common • multiple differences between groups

30. A Randomized Controlled Trial of a Chinese Herbal Remedy to Increase Energy, Memory, Sexual Function, and Quality of Life in Elderly Adults in Beijing, China Stephen Bent, MD Osher Center for Integrative Medicine University of California, San Francisco

32. Longevity Treasure • Proprietary extract • 10 Chinese herbs • Believed to increase “Yang” • Marketed to improve • Energy, Memory, Sexual Function, Qi • Widespread use in China • US sales of over $1 million

33. Research Question • Does the daily use of Longevity Treasure lead to changes in energy, memory, sexual function, qi, or quality of life?

34. Methods • Design: Randomized Controlled Trial • Participants • Chinese residents of Beijing, age > 60 • Self-reported decreased energy, memory, or sexual interest • Recruitment – “word of mouth”

35. Exclusion Criteria • High Yang • Serious medical illness • Currently taking Longevity Treasure

36. Intervention • Random assignment to • Longevity Treasure, 4 capsules three times a day (30 days) • Identical placebo, 4 capsules, three times a day (30 days)

37. Outcomes • Assessed at baseline and 30 days • Primary • Change in quality of life, SF-12 questionnaire • Change in quality of life, Qi scale

38. Secondary Outcome Measures • Energy – questionnaire • Energy – physical tests • 6 minute walk • Step test • Grip strength • Chair stands • Foot tap • Memory – word and picture recall • Sexual function – 3-item questionnaire

43. Study Flow

44. Baseline Characteristics

45. Results: Primary Outcomes • SF-12, Mental Component (Baseline = 53) • Herbs: + 4.4 • Placebo: +2.5 • Difference: +1.9 points (95% CI, 0.1 to 3.6) • SF-12, Physical Component (Baseline = 50) • Herbs: +1.6 • Placebo: +1.7 • Difference: -0.1 (95% CI, -1.7 to 1.5)

46. Primary Outcome: Qi scale

47. Secondary Outcome Measures

48. Adverse Events

49. Summary • Longevity Treasure may improve mental health • 2 point increase on SF-12 mental health score • Similar improvement on SF-36 subscale • The benefit, if any, is small • Longevity Treasure does not improve • Memory • Sexual Function • Energy or Qi

50. Conclusions • Longevity Treasure cannot be strongly recommended without further supportive evidence • RCTs of Chinese herbs are feasible • More work is needed to explore Chinese concepts of quality of life and qi