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Introduction to Randomized Clinical Trials

Introduction to Randomized Clinical Trials. Deborah Grady Professor of Medicine University of California, San Francisco. Randomized Trials. Rationale Basic designs Participants Intervention Blinding Outcomes Adherence Follow-up. Rationale. Why do a randomized blinded trial

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Introduction to Randomized Clinical Trials

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  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 • Declining renal function results in low levels of 1,25 D • Vitamin D deficiency causes myopathy and treatment improves strength 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 • Run in • 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. Choice of Control • Inert placebo usually best • Active therapy or “standard of care” • Active Comparator Trial - new therapy more effective than standard • Ho: two treatments equally effective • Ha: one treatment more effective • Equivalence Trial - new therapy equivalent • Ho: two treatments differ by at least X • Ha: two treatments differ by less than X

  16. 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

  17. 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

  18. 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

  19. Why Blind? • Maintains balanced groups during follow-up • Eliminates • cointervention • biased outcome ascertainment • biased measurement of outcome

  20. 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

  21. 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

  22. 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

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

  24. 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

  25. 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

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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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”

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

  33. 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

  34. 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

  35. 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

  36. 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 • evening visits, travel and parking reimbursement • personal relationships with participants • Measurements easy, safe and painless • Never discontinue participants

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

  38. Raloxifene Use for the Heart • Potential Outcomes • Mortality • CHD events (death, MI, ACS) • Stroke • Breast cancer • Fracture • LDL-cholesterol • Quality of life

  39. How to Proceed? • Measure all outcomes • Pick one primary outcome • estimate sample size • FDA requirement • Make all the rest secondary

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

  41. 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

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