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TREATMENT AND PREVENTION: CLINICAL AND PREVENTIVE TRIALS

TREATMENT AND PREVENTION: CLINICAL AND PREVENTIVE TRIALS. JEFFREY L. PROBSTFIELD, MD, FACP, FACC, FAHA, FESC, FSCT DIRECTOR, CLINICAL TRIALS SERVICE UNIT PROFESSOR OF MEDICINE (CARDIOLOGY) UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE AD. PPROFESSOR OF EPIDEMIOLOGY

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TREATMENT AND PREVENTION: CLINICAL AND PREVENTIVE TRIALS

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  1. TREATMENT AND PREVENTION: CLINICAL AND PREVENTIVE TRIALS JEFFREY L. PROBSTFIELD, MD, FACP, FACC, FAHA, FESC, FSCT DIRECTOR, CLINICAL TRIALS SERVICE UNIT PROFESSOR OF MEDICINE (CARDIOLOGY) UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE AD. PPROFESSOR OF EPIDEMIOLOGY UNIVERSITY OF WASHINIGTON SCHOOL OF PUBLIC HEALTH AND COMMUNITY MEDICINE

  2. SHORT COURSE: CLINICAL TRIALS OVERVIEW • OVERIEW OF TRIALS METHODOLOGY • BASIC ISSUES: CLINICAL TRIALS DESIGN • RECRUITMENT AND ADHERENCE • SUBGROUP ANALYSES • EQUIVALENCE AND NON-INFERIORITY TRIALS, AND SURROGATE OUTCOMES

  3. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: DEFINITION A properly planned and executed clinical trial is a powerful experimental technique for assessing the effectiveness of an intervention. “Ask a good question, get a clear answer!” not “Ask a good question, get a positive/negative answer!”

  4. Study Question In high risk people with IFG, IGT or early diabetes, does omega 3 PUFA supplementation reduce the risk of: Primary • Cardiovascular death? Secondary • MI, stroke or CV death? • Mortality? • Presumed arrhythmic death or cardiac arrest?

  5. Death HR 0.98; 95% CI, 0.89-1.07

  6. Fatalarrhythmia HR 1.10; 95% CI, 0.93-1.30

  7. CLINICAL TRIALS OVERVIEW INTRODUCTION Fredrickson - “The Indispensable Ordeal” Phases - I-IV Why Needed Problems in Timing Ethics Protocol References: Friedman, Furberg & DeMets - Fundamentals of Clinical Trials Peto, R et al - Br. J Cancer, 1976; 34:585-612 and 1977; 35:1-39

  8. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: WHAT IS THE QUESTION? Each clinical trial must have a primary question. The primary question, as well as any secondary or subsidiary questions, should be carefully selected, clearly defined and stated in advance.

  9. CLINICAL TRIALS OVERVIEW WHAT IS THE QUESTION? Primary Question Intervention Secondary Question(s) Response Variable Adverse Effects Surrogate Outcomes Ancillary Questions, Substudies Natural History Large, Simple Clinical Trials

  10. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: STUDY POPULATION The study population should be defined in advance, starting unambiguous inclusion (eligibility) criteria. The impact that these criteria will have on the study design, ability to generalize and participant recruitment must be considered.

  11. CLINICAL TRIALS OVERVIEW STUDY POPULATION Definition of Study Population: The study population is the subset of the Population with the condition or characteristics of interest defined by the eligibility criteria: Generalizability Recruitment

  12. KEY INCLUSION/EXCLUSION CRITERIA (HOPE) Inclusion Criteria Patients (age 55) at high risk for cardiovascular events because of: • any evidence of vascular disease (CHD, stroke, PVD) • diabetes + one other coronary risk factor Exclusion Criteria Heart failure or low EF On ACE-I or Vitamin E

  13. KEY HOPE BASELINE CHARACTERISTICS/DRUGS

  14. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: BASIC STUDY DESIGN Sound scientific clinical investigation almost always demands that a control group be used against which the new intervention can be compared. Randomization is the preferred way of assigning participants to control and intervention groups.

  15. CLINICAL TRIALS OVERVIEW • BASIC STUDY DESIGN • Randomized control studies • Nonrandomized concurrent control studies • Historical controls/databases • Cross-over designs • Withdrawal designs • Factorial designs • Hybrid designs • Studies of equivalency • Large simple clinical trials

  16. CROSSOVER DESIGNS • Each person serves as own control. • Two period crossover. • 1/2 receive A first and 1/2 B. • Order of interventions excluded. • Multiple Period crossover. • Order and sequence effects eliminated by design. • Insertion of “Washout Period”.

  17. FACTORIAL DESIGN • Motive: to ask two or more questions in same trial in an efficient manner. • Types: • 2x2 • 2x2x2 etc. • Incomplete/Partial

  18. DREAM: 2 x 2 factorial design-main effects analysis N = 5269 with IFG and/or IGT Rosiglitazone Placebo Ramipril Ramipril + Rosiglitazone Ramipril + Placebo Placebo Rosiglitazone + Placebo Placebo + Placebo DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  19. FACTORIAL DESIGN Indications • Interaction - small chance • Interaction - important • Interaction - must estimate Contraindications • Design too complex - adherence • Power of simple comparison greater • Interaction - large change

  20. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: THE RANDOMIZATION PROCESS Randomization tends to produce study groups comparable with respect to known and unknown risk factors, removes investigator bias in the allocation of participants, and guarantees that statistical tests will have a valid significance levels.

  21. CLINICAL TRIALS OVERVIEW • THE RANDOMIZATION PROCESS • “Your most powerful ally - preserve at all costs” • Fixed Allocations • Simple • Blocked • Stratified • Adaptive Randomization • Baseline Adaptive • Response Adaptive

  22. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: BLINDNESS A clinical trial, ideally, should have a double-blind design to avoid potential problems of bias during data collection and assessment . In studies where such a design is impossible, a single- blind approach and other measures to reduce potential bias are favored.

  23. CLINICAL TRIALS OVERVIEW • BLINDNESS • Types of Trials • Unblinded • Single-blind • Double-blind • Triple-blind • Special Problems • Matching of drugs • Coding of drugs • Unblinding of trials • Assessment of the blind

  24. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: SAMPLE SIZE Clinical trials should have sufficient statistical power to detect differences between groups considered to be of clinical interest. Therefore calculation of sample size with provision for adequate levels of significance and power is an essential part of planning

  25. CLINICAL TRIALS OVERVIEW SAMPLE SIZE Power Level of Significance Adherence Event Rate Effect Size Variability Dichotomous Response Variables Continuous Response Variables Repeated Measures “Time to Failure” Equivalency of Interventions Cluster Randomization Multiple Response Variables

  26. CLINICAL TRIAL RESULTS: TYPE 1 AND 2 ERRORS TYPE 1 ERROR-FALSE POSITIVE- ‘YOU THINK IT IS THERE, BUT IT ISN’T.” TYPE 2 ERROR-FALSE NEGATIVE- “YOU THINK IT ISN’T THERE, BUT IT IS.”

  27. HOPE Effects of ACE Inhibition (Ramipril 10 mg/day), CVD Morbidity and Mortality in 9297 High-risk CVD Participants Primary Outcome: MI/Stroke/CV Death QUIET Effects of ACE Inhibition (Quinapril 20 mg/day) in 1750 Participants with CAD Primary Outcome: (MI/CV Death/VT/VF ACE INHIBITORS, NOT THE SAME? HOPE vs. QUIET Lees R, et al. Am J Cardiol. 1996;78:1011-1016.The HOPE Study Investigators. N Engl J Med. 2000;342:145-153. QUIET = Quinapril Ischemic Events Trial

  28. Primary Outcome - Ramipril vs Placebo RR=078(0.70-0.86) P=0.000002

  29. Dagenais GR, et al. Lancet. 2006;368:581-88.

  30. Dagenais GR, et al. Lancet. 2006;368:581-88.

  31. Dagenais GR, et al. Lancet. 2006;368:581-88.

  32. Dagenais GR, et al. Lancet. 2006;368:581-88.

  33. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: BASELINE ASSESSMENT Relevant baseline data should be measured in all study participants before the start of intervention.

  34. CLINICAL TRIALS OVERVIEW • BASELINE ASSESSMENT • Use of Baseline • Comparability at baseline • Stratification and subgrouping • Evaluation of change • Natural history analysis • What Is True Baseline Measurement? • Balance and Imbalance • FAR TOO MUCH DATA IS COLLECTED

  35. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: Recruitment of Study Participants Successful recruitment depends on developing a careful plan with multiple strategies maintaining flexibility, establishing interim goals, and preparing to devote the necessary effort.

  36. CLINICAL TRIALS OVERVIEW RECRUITMENT OF STUDY PARTICIPANTS PLAN, PLAN, PLAN, PLAN Strategies and Sources Conduct Monitoring Problems Solutions Reasons for Participation http://depts.washington.edu/cardweb/fellowship/educational-resources.shtml

  37. RECRUITMENT:13 NHLBI STUDIES

  38. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: DATA COLLECTION AND QUALITY CONTROL During all phases of a study, sufficient effort should be spent to ensure that all key data critical to the interpretation of the trial are high quality.

  39. CLINICAL TRIALS OVERVIEW • DATA COLLECTION AND QUALITY CONTROL • Problems • DO WE CHECK ALL DATA---IF NOT, WHICH? • Variability • Minimize Poor Quality • Protocol/Manual Training Reduce Variability • Forms Pretesting Data Entry • Quality Control Monitoring-Source Documentation • Audits

  40. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: ASSESSING AND REPORTING ADVERSE EFFECTS Adequate attention needs to be given to the assessment, analysis and reporting of adverse effects to permit valid assessment of potential risk of interventions.

  41. CLINICAL TRIALS OVERVIEW • ASSESSING AND REPORTING ADVERSE EFFECTS • Determinants of Adverse Effects • Definition • Ascertainment • Frequency • Length of Follow-up • Individual Susceptibility • Analysis of Non-adherent Participants • Reporting - FDA Format

  42. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE Assessment of the effects of interventions of participants’ HRQL may be an important component of clinical trials, especially those that involve interventions directed at primary or secondary prevention of chronic disease.

  43. CLINICAL TRIALS OVERVIEW • ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE • Definitions • Primary HRQL Dimensions • Physical Functioning • Psychological Functioning • Social Functioning • Overall Life Satisfaction/Well Being • Perceptions of Health Stages • Additional Dimensions • Neuropsychological Functioning • Personal Productivity • Intimacy and Sexual Functions • Sleep Disturbance • Pain • Symptoms

  44. CLINICAL TRIALS OVERVIEW FUNDAMENTAL POINT: PARTICIPANT ADHERENCE Many potential adherence problems can be prevented or minimized before participant enrollment. Once a participant is enrolled, taking measures to enhance and monitor participant adherence is essential.

  45. CLINICAL TRIALS OVERVIEW PARTICIPANT ADHERENCE “Prevention is the key issue” Considerations before participant enrollment Maintaining good participant adherence Special Interventions Adherence monitoring Special populations

  46. EQUIPOSE AND THE ETHICS OF CLINICAL RESEARCH Benjamin Freedman, PhD EQUIPOSE “ - a state of genuine uncertainty on the part of the (all) clinical investigator(s) regarding the comparative therapeutic merits of each arm in a trial.” NEJM 1987; 317:141-145

  47. SAMPLE SIZE ADJUSTMENT FOR REDUCED ADHERENCE Key Point - Adherence correction term-sample size formula, a squared function. 2N = 2(z + z)2  (1 - 2)2(1-p)2 p = Reduction in Adherence k = Increase in Sample Size pk .01 1.02 .05 1.11 .10 1.23 .20 1.56 .30 2.04 .50 4.00

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