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TICR Professional Conduct Statement Clarifications for this class

TICR Professional Conduct Statement Clarifications for this class. I will maintain the highest standards of academic honesty I will neither give nor receive aid in examinations or assignments unless such cooperation is expressly permitted by the instructor

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TICR Professional Conduct Statement Clarifications for this class

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  1. TICR Professional Conduct StatementClarifications for this class • I will maintain the highest standards of academic honesty • I will neither give nor receive aid in examinations or assignments unless such cooperation is expressly permitted by the instructor • I will conduct research in an unbiased manner, reports results truthfully, and credit ideas developed and work done by others • I will not use answer keys from prior years • I will write answers in my own words, and, when collaboration is permitted, acknowledge collaborators when answers are jointly formulated

  2. Randomized Trials: Design, Subjects, and Randomization Clay Johnston, MD, PhD Neurology and Epidemiology

  3. Randomized Trials: the Evidence in “Evidence-Based” • Today • Randomized trials: why bother? • Randomization • Adaptive designs • Selection of participants (Inclusion/exclusion) • Design options for trials • Factorial designs • Cross-over designs • Matched pairs • Cluster or group randomization

  4. Randomized Controlled Trial (RCT) An experiment in which subjects are randomly allocated into groups, usually called study and control groups, to receive or not to receive an experimental preventive or therapeutic procedure, maneuver, or intervention. The results are assessed by rigorous comparison of rates of disease, death, recovery, or other appropriate outcome in the study and control groups, respectively.

  5. Number of randomized trials published* * Based on Medline search restricted to “Randomized clinical trials”

  6. Disadvantages of RCTs • Expensive: typically in $ millions • Time Consuming: typically years • Can only answer a single question • May not apply to most patients in practice • May not be practical • Generally very difficult to get funded • Time consuming, organizationally complex Class dismissed.

  7. Alternatives to RCTs • Observational studies • Case-control studies • Cross-sectional studies • Cohort studies

  8. Reasons for doing RCTs • Only study design that can prove causation • Required by FDA (and others) for new drugs and some devices • Most influential to clinical practice

  9. Examples: When Have Trials Trumped Observational Studies • HRT and heart disease • Vitamin E and heart disease • Vitamin C and heart disease • Beta carotene and heart disease • Oats and colon cancer • “Epidemiology—Is It Time to Call It a Day?” • Editors of The International Journal of Epi

  10. Beta carotene and CV mortality

  11. “Epidemiology—Is It Time to Call It a Day? --Editors of The International Journal of Epi

  12. Major Observational Study Limitation • CHARM • Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity • Compared those taking vs. not taking either drug or placebo • 35% RRR in all-cause mortality • For drug and placebo. • Take home • Confounders are impossible to fully identify Lancet 2005, 366:2005

  13. CLINICAL TRIALS IN THE NEWS: • Lots of trials of things other than drugs • Surgical techniques • Weight loss

  14. Clinical Trials in the News:JAMA 1/5/05 Vs. Vs.

  15. RCT of 4 Popular Weight Loss Programs • Compare • Atkins (low carbohydrate) • Weight Watchers (low calorie/portion size) • Zone (high protein/low-glycemic load) • Ornish (very low fat) Vs. JAMA 1/5/05

  16. Diet study: Design N =160 Randomize to 1 of 4 diets Follow for 12 months Endpoints: • Weight loss • Heart disease risk factors (cholesterol, BP, triglycerides) JAMA 1/5/05

  17. Diet study: Results at 12 months Year Atkins Zone Weight Ornish watchers . Weight (kg) -3.9 -4.9 -4.6 -6.6 LDL (mg/dL) -13.5 -18.1 -14.2 -25.2 SBP (mm/Hg) 0.3 2.1 -4.1 0.9 JAMA 1/5/05

  18. Diet study: Summary • All diets lead to modest reductions in weight and cardiac risk factors • Poor compliance for all diets, especially Atkins and Ornish • Those who adhered well had better results JAMA 1/5/05

  19. Examples of major breakthroughs from RCTs • Protease inhibitors and AIDS • Aspirin and heart disease • Lipid lowering (statins) and heart disease

  20. NINDS Trials Table 2. Impact of Clinical Trials with Published Information on Societal Cost s and Benefits* References 10 Year Projections of Impact Quality - Adjusted Life Societal Quality Trial Title Cost of Life Years Utilization Treatment Costs Net Value 42 42 43, 44 Randomized Indomethacin Germinal 146,837 $ (92,8 57,340) $ 6,003,009,978 Matrix/Intraventricular Hemorrhage Prevention Trial 45 46, 47 Diazepam for Acute Repetitive Seizures NA $ (891,839,458) $ 890,276,155 48 48 - 50 51 Recombinan t Beta Interferon as Treatment for 4,038 $ 955,140,007 $ (800,131,189) Multiple Sclerosis 52 52 44, 53 - 55 Asymptomatic Carotid Artery Stenosis 92,820 $ 4,288,862,203 $ (590,564,802) Collaborative Study 56 56 57 - 60 Stroke Prevention In Atrial Fibrillation I 35,457 $ 145,402,116 $ 1,267,774,453 61 61 54, 55, 62 North American Symptomatic Carotid 49,304 $ 256,977,048 $ 1,666,447,880 Endarterectomy Trial 63 63 64, 65 Tissue Plasminogen Activator in Ischemic 134,066 $ (1,084,314,904) $ 6,469,781,905 Stroke 66 67 Extracranial/Intr acranial Arterial Anastomosis NA $ (325,476,690) $ 296,277,864 Study Total 462,522 $ 3,251,892,981 $ 15,202,872,245 *Negative numbers are in parentheses and represent soci etal cost savings. NA = not available. Net value includes cost of trial, treatment costs, and quality - adjusted life years valued at 2004 per capita gross domestic product ($40,310). Costs were inflated to 2004 dollars with the medical care portion of th e Consumer Price Index.

  21. RCTs aren’t Necessarily Expensive • Trial of consultation to improve K grants • N=50 • Trial of chocolate to reduce blood pressure (JAMA. 2007;298:49-60) • N=44 • Trial of zolpidem (Ambien) in coma (Ann Neurol 2007;62:5-7) • N=1

  22. So you want to do a randomized trial…

  23. Steps in a “Classical” Randomized, Controlled Trail (RCT) 1. Select participants 2. Measure baseline variables 3. Randomize (to 1 or more treatments) 4. Apply intervention 5/6. Follow-up--measure outcomes Most commonly: one treatment vs. control Can be used for various types of outcomes (binary, continuous)

  24. Randomization • Key element of RCT’s • Assures equal distribution of both... • Measured/known confounders • Unmeasured/unknown confounders • Important to do well • True random allocation • Tamper-proof (no peeking, altering order of participants, etc) • Simple randomization • Low tech • High tech

  25. Other types of randomization • Blocking*: equal after each n assignments • e.g., block size of 4, treatments a and b ababaabbabbabababbaabaab • Randomly choose blocks • Assures relatively equal number of patients in each treatment group • Disadvantages of blocking (in unblinded trials) • Can allow gaming. • Very commonly used *Formally: random, permuted blocks

  26. Randomized blocks to balance prognostic variables • Stratified permuted blocks • Blocks within strata of prognostic variable • e.g., Stroke prevention after TIA. Time from event a key predictor • Stratum <12 hour: aabb baba … >=12 hour: baab abab …. • Limited number of risk factors • Very commonly used in multicenter studies to balance within clinical center • Fancier techniques for assuring balance • Adaptive randomization

  27. Adaptive Randomization • Various designs that reduce the total number of subjects necessary when comparing multiple groups • Determine assignment on the fly based on prior data • Often used for dose finding • Simple designs based on a priori decision rules • Eg, go to next highest dose if no side effects in first 4 treated • Complex designs based on recalculation of odds • ASTIN trial of 15 doses of neutrophil inhibitory factor (Stroke, 2003)

  28. Implementation of randomization • Less challenging for blinded studies • Sealed envelopes in fixed order at clinical sites • List of drug numbers • a b a b b b a a • 1 2 3 4 5 6 7 8 • Clinic receives bottles labeled only by numbers--assign in order • IVRS: Interactive Voice Response System • Unblinded studies: important to keep next assignment secret • Problem with blocks within strata

  29. Randomization: Summary • Key element of clinical trials • Not really very complicated (usually)

  30. Who to Study: Principles for Inclusion/exclusion • Widest possible generalizability • Sufficiently high event rate (for power to be adequate) • Population in whom intervention likely to be effective and safe • Ease of recruitment • Likelihood of compliance with treatment and F/U

  31. Who to Study: Principles for Inclusion/exclusion Homogeneity --------------------Heterogeneity

  32. Explicit criteria for inclusion in a trial • Typically written as “inclusion/exclusion” criteria in protocol • Generally, the more explicit the better • Want centers or investigators to be consistent • Examples of exclusion criteria decisions 1. Women with headache vs. Women with debilitating headache (with explicit criteria) occurring >1/week. 2. Smokers vs Smokers of >=0.5 pack of cigarettes per day on average over the last 3 months.

  33. Valid reasons to exclude participants • Treatment would be unsafe • Adverse experience from active treatment • “Risk” of placebo • Active treatment cannot/unlikely to be effective • No risk of outcome • Disease type unlikely to respond • Competing/interfering treatment • Unlikely to adhere or follow-up • Practical problems

  34. Stricter Inclusion Criteria Slows Recruitment Recruitment Rate Inclusion Criteria Stricter 

  35. Enrollment rates in stroke trials

  36. Example of Inclusions/Exclusions in Protocol • Inclusion Criteria • Male or female > 40 years • TIA (> 10 minutes) or minor acute ischemic stroke (NIHSS < 2 at time of randomization) occurring less than 24 hours before randomization • Informed consent signed • Able to have MRI scan within 24 hours of symptoms onset • Exclusion Criteria • Related to absolute contraindications to the use of clopidogrel and/or ASA: • History of drug allergy to thienopyridine derivatives or ASA • Severe uncontrolled hypertension (SBP > 160 mm Hg or DBP > 110 mm Hg on two or more measures over the last 6 months) • History of clinically significant or persistent thrompocytopenia • History of clinically significant or persistent neutropenia • Women of child-bearing potential who are not following an effective method of contraception • Women who are breast-feeding

  37. Example of Inclusions/Exclusions in Protocol • Inclusion Criteria • Male or female > 40 years • TIA (> 10 minutes) or minor acute ischemic stroke (NIHSS < 2 at time of randomization) occurring less than 24 hours before randomization • Informed consent signed • Able to have MRI scan within 24 hours of symptoms onset • Exclusion Criteria • Related to absolute contraindications to the use of clopidogrel and/or ASA: • Related to concomitant or planned medication(s) / treatment(s): • Related to TIA/Stroke characteristics: • Related to the presence of other medical problems that would either interfere with participation in the trial or lead to inability to complete the trial:

  38. Exclusions/inclusions examples • Important impact on generalizability of both efficacy and safety • Example: Primary Stroke Prevention Trial • Chlorthalidone vs. placebo • Stroke rates dramatically increase with age • Stroke more common than MI after age 65 • Who should we include? • Age cut-off? • Atrial fibrillation?

  39. Inclusion, Exclusion: Conclusion • Many factors to balance in deciding who to include • Generally not a clear cut or single correct decision • Many academics have simplistic understanding of issues

  40. Alternative RCT designs: Large-simple vs. standard • Large simple: less information on more people • Balance loss of precision with sample size • Cost per patient with number of patients • Example: • Primary Prevention of Stroke Trial • COMMIT: 45,852 patients in China, adding clopidogrel to aspirin in acute MI • Standard: lots of info on few • Example: CASTIA trial

  41. Alternative RCT designs: Factorial design • Test of more than one treatment (vs. placebo) • Each drug alone and in combination • Allows multiple hypotheses in single trial • Efficient • Example: Physician’s Health Study • Test aspirin MI • beta carotene cancer

  42. Factorial design: Physician’s Heath Study Placebo Beta-carotene Aspirin vs. no aspirin (MI) Aspirin plus Beta-carotene Aspirin Beta carotene vs. no beta carotene (cancer)

  43. Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation of Noetic Trainings (MANTRA) II randomised study

  44. Factorial design: Primary Stroke Prevention Trial Placebo Chlorthal. Chlorthal. plus K Citr K Citr

  45. A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting • One third of patients have post-op N/V • 5200 patients randomized to test 6 individual medications • 2^6 = 64 combinations • Ondansetron • Dexamethosone • Droperidol • Propofol vs. other • Nitrogen vs. nitrous oxide • Remifentanil vs. fentanyl Apfel, C. C. et al. N Engl J Med 2004;350:2441-2451

  46. Factorial design issues • Do treatments interact? • Effect of chlorthalidone likely greater with potassium citrate on board • Must test for interaction of treatments • If present, power is lower: large sample required • May require more complicated stopping rules • May require more complicated analysis plan (eg, logistic regression)

  47. Factorial design conclusions • Factorial designs are seductive but complicated • Some attraction in combining a low-risk hypothesis with a high-risk hypothesis • Must weigh benefits in efficiency against compounded uncertainty and complexity

  48. Cross-over designs • Both active treatment and control are administered sequentially to all subjects • Subject serves as own control, random order • Compare treatment period vs. control period • Increases power by reducing person-to-person variability

  49. Cross-over designs • Diuretic vs. beta blocker for blood pressure • 1/2 get diuretic followed by beta blocker • 1/2 get beta blocker followed by diuretic • Migraine prophylaxis • Treatment x 3 months followed by placebo • Placebo x 3 months followed by treatment • Atrial Overdrive Pacing in sleep apnea • AOP x 1 month followed by control • Control x 1 month followed by AOP

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