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Case Studies in Prevention Trial Design

Case Studies in Prevention Trial Design. Deborah Donnell, PhD SCHARP Vaccine and Infectious Disease Institute Fred Hutchinson Cancer Research Center. Case Studies. HPTN035 – Microbicide 4 arm HPTN039 – HSV-2 Acyclovir HPTN052 – Discordant couples HAART HPTN058 – IDU treatment Suboxone

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Case Studies in Prevention Trial Design

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  1. Case Studies in Prevention Trial Design Deborah Donnell, PhD SCHARP Vaccine and Infectious Disease Institute Fred Hutchinson Cancer Research Center

  2. Case Studies • HPTN035 – Microbicide 4 arm • HPTN039 – HSV-2 Acyclovir • HPTN052 – Discordant couples HAART • HPTN058 – IDU treatment Suboxone Tom Fleming – University of Washington Jim Hughes – University of Washington Barbra Richardson – University of Washington Ben Mâsse – FHCRC Ying Chen - FHCRC

  3. “How can we be so different and feel so much alike?” mused Flitter “And how can we feel so different and be so much alike?” wondered Pip.

  4. Selection criteria • Randomized Clinical Trials • HIV seroconversion endpoint • Approved and in the field • Biomedical interventions • Long-term adherence for on-going risk

  5. HPTN035: Microbicide Trial • Population: Women at sexual risk for HIV • 4 arms: gel arms blinded Active Inactive Arm 1: Pro 2000 Arm 3: Placebo Gel vs. Arm 2: BufferGel Arm 4: Condom Only • Intended Mechanism: • Microbicide = “Kill the microbe” • Protect/enhance natural defenses • Hypothesis: • Active vs. Placebo Gel reduces HIV infection by 33% • Active Gel vs. condom only reduces HIV infection by 33%

  6. HPTN039 : Acyclovir to prevent HIV acquisition • Population: HSV-2+, HIV uninfected • Women (in Southern Africa) • MSM (in Americas) • Two arms, double blinded • Arm1: Acyclovir twice daily • Arm 2: Placebo twice daily • Intended mechanism: • HSV-2 a suspected cofactor in HIV acquisition • Daily Acyclovir reduces herpes activation reduced lesions and/or lymphocyte activation reducing risk of HIV acquisition • Hypothesis: • Daily Acyclovir will reduce HIV acquisition by 50%

  7. HPTN052: Delayed vs. Immediate HAART in Discordant Couples • Population: • Discordant couples (index HIV infected; partner HIV uninfected) with CD4 350-550 in index • Two arm; unblinded • Arm 1: Immediate HAART for index • Arm 2: HAART initiated when clinically indicated for index • Mechanism: Immediate therapy Potential benefits • Partner: Lower risk of early transmission • Index : More sustained virologic response Lower risk of irreversible CD4 drop • Hypothesis: • Index on immediate vs. delayed strategy reduces HIV transmission to partner by 37%. Potential risks Partner : Transmission of resistant virus Index : Longer course of ART may reduce treatment options Poorer adherence/high resistance

  8. HPTN058: Suboxone treatment in opiate injectors • Targeted population: • Active opiate injectors (China and Thailand) • Two arm, unblinded • Arm 1: One year of Suboxone substitution therapy + one year counseling support • Arm 2: Suboxone detoxification + one year counseling support • Intended Mechanism: Biomedical + Behavioral • Biomedical support for cessation of injection drug use • Counseling support for long term behavior change • Hypothesis: • One year of Suboxone treatment and counseling will reduce death and HIV infection rate at 2 years by 42%

  9. Comparisons • Proof of Concept vs. Efficacy trial • Effect size • Adherence requirements • Durability of effect

  10. HPTN035 – Microbicide Phase II/IIb ? ? HPTN039 – Acyclovir Phase III 90% 2.5% HPTN052 – HAART strategy Phase III 90 % 2.5% HPTN058 – Suboxone for IDU Phase III 90% 2.5% Proof of Concept vs Effectiveness (aka Phase IIb vs Phase III) Power Size

  11. What is a Phase IIb design, anyway, and when would you use it?

  12. Goal of a clinical trial • Obtain a reliable answer to a clinically relevant question • Clinically relevant improvement in clinically relevant endpoint Definitive (Phase III) vs. Proof of concept (Phase IIb)

  13. Phase III 0% 33%

  14. Phase III 256 endpoints 10% 2.5% 0% 22% 33%

  15. Why consider a Phase IIb ? • No reliable information about efficacy • risk of taking too long, • using too many resources on something that may not work, or something in early development: …take a two step approach to establish proof of concept • Phase IIb questions: • Does this look like it might work? • Does this not work at all ? • Does this work better than we hoped?

  16. Phase III 256 endpoints 0% 22% 33% Phase IIb 96 endpoints 0% 15% 33% Fleming TR, Richardson BA, JID 2004.

  17. Phase III 256 endpoints 10% 2.5% 0% 22% 33% Phase IIb 96 endpoints 12% 20% 0% 15% 33% 52%

  18. Phase III 256 endpoints 10% 2.5% 0% 22% 33% Phase IIb 96 endpoints 10% 2.5% 0% 15% 33% 52%

  19. Phase III 256 endpoints 0% 22% 33% Phase IIb 96 endpoints 0% 15% 33% 52%

  20. Factors in play for Phase IIb vs. Phase III: Risk and Resources • Maturity/Definitiveness of the intervention and its intended mechanism • Microbicide vs. Acyclovir; Suboxone; HAART • State of results in the field • Success in other settings: perinatal vs. microbicides • Effectiveness on intended mediators; surrogates • Concurrent trials • Resources • Participants, staff and money to conduct a high quality trial

  21. Comparisons • Proof of Concept vs. Efficacy trial • Effect size • Adherence requirements • Durability of effect

  22. HPTN035 – Microbicide 33% vs. 0% Phase II/IIb HPTN039 – Acyclovir 49% vs. 0% Phase III HPTN052 – HAART strategy 37% vs. 0% Phase III HPTN058 – Suboxone for IDU 42% vs. 0% Phase III Targeted Effectiveness in HIV Prevention Targeted Effectiveness Number of people Number of Events 3100 96 [256] 3300 93 1750 cpls ~188 1500 ~132

  23. HPTN035 – Microbicide 33% vs. 0% Phase II/IIb HPTN039 – Acyclovir 49% vs. 0% Phase III HPTN052 – HAART strategy 37% vs. 0% Phase III HPTN058 – Suboxone for IDU 42% vs. 0% Phase III Targeted Effectiveness in HIV PreventionWhat is plausible ? Targeted Effectiveness No evidence of efficacy Time off drug in pregnancy Condom use and adherence Highly effective in treating HSV2 Time off drug in pregnancy Proven to reduce viral load Concept proven in perinatal trials Crossover to HAART Effective in treating opiate dependence HIV: 50% reduction Death: 25% effective reduction

  24. HPTN035 – Microbicide 33% Phase II/IIb HPTN039 – Acyclovir 49% Phase III HPTN052 – HAART strategy 37% Phase III HPTN058 – Suboxone for IDU 42% Phase III Low cost, low tech, low risk Woman controlled Low cost Lifetime prophylaxis High cost/infrastructure needs Significant side effects High cost/infrastructure needs Targeted Effectiveness in HIV PreventionIs it relevant for implementation? Targeted Effectiveness

  25. Comparisons • Proof of Concept vs. Efficacy trial • Effect size • Adherence requirements • Durability of effect

  26. HPTN035 – Microbicide Phase II/IIb HPTN039 – Acyclovir Phase III HPTN052 – HAART strategy Phase III HPTN058 – Suboxone for IDU Phase III Burden of Adherence Adherence Duration With each sex act12 – 30 mo Twice daily pill 12 – 18 mo Daily HAART regimen 5 – 7 yrs Three times/week (DOT) 1 yr

  27. HPTN035 – Microbicide Phase II/IIb HPTN039 – Acyclovir Phase III HPTN052 – HAART strategy Phase III HPTN058 – Suboxone for IDU Phase III Best Achievable Adherence for Effectiveness Targeted Adherence Self reported Adherence With each sex act83-85% adherence 87-92% retention Twice daily pill 90-95% adherence 91-96% retention Daily HAART regimen NA Three times/week (DOT) NA

  28. Effectiveness vs. Efficacy(a.k.a. “Intent to Treat”(ITT) vs. “Per Protocol” (PP)) • Biological efficacy (Theoretical: Does the intended mechanism, when delivered, work?) vs. • Effectiveness (Does the intervention, with best achievable adherence, as delivered in clinical trial, work?) vs. • Implemented (Real world: Does the intervention, when made available to people, work)

  29. Illustration: Microbicides • Biological Efficacy: • Unprotected vaginal sex with HIV infected man • Biological Efficacy (“Per protocol”) • Woman supplied with gel, with monthly counseling support for use of condoms and gel, who uses gel consistently. • Effectiveness (ITT) • Woman offered an ongoing supply of gel, with monthly counseling support for use of condoms and gel.

  30. Randomized trials are the gold standard for objective evidence Effectiveness is the most relevant prevention measure Randomization and Effectiveness Treatment R Placebo Balanced in Risk factors: measured and unmeasured

  31. Post-Randomization Selection Bias Treatment Adherent Placebo Treatment Risk factors: measured and unmeasured R Treatment Placebo Non-Adherent Placebo

  32. Examples of ITT vs. Per Protocol analysis • MIRA (July 2007) • Intent to treat: RR = 1.05 (CI: 0.84, 1.32) • Per-protocol (last sex act): RR = 0.90 (CI: 0.68, 1.17) • Per-protocol (consistent use): RR = 0.83 (CI: 0.61,1.14) • Acyclovir trial in Mwanza (Aug 2007) • Intent to treat RR = 1.02 • P-P (Pregnancy censored) RR = 1.08 (CI: 0.64-1.83) • P-P (90% adherent) RR = 0.58 (CI: 0.25-1.38) • STEP trial (Nov 2007) • ITT: Vaccine vs. Placebo 24 vs. 21 • Per-protocol: 19 vs. 11

  33. Comparisons • Proof of Concept vs. Efficacy trial • Effect size • Adherence requirements • Durability of effect

  34. HPTN035 – Microbicide Phase II/IIb HPTN039 – Acyclovir Phase III HPTN052 – HAART strategy Phase III HPTN058 – Suboxone for IDU Phase III Targeted Duration for Effectiveness Targeted Adherence Duration With each sex act12-30 mo Twice daily pill 12-18 mo Daily HAART regimen 5-7yrs Three times/week (DOT) 1yr

  35. HPTN035 Microbicide HPTN039 Acyclovir HPTN052 HAART strategy HPTN058 Suboxone IDU Years

  36. Duration of effect • Survival design maxim of “fixed number of events” • 88 events: mean 3.3 years with 300 people • 88 events: mean 1 year with 1000 people • Equivalent assuming proportional hazards • Inherent in design • Longevity of effect • Estimate effect is “average” reduction in infection (weighted by time on study) • Real world vs. Clinical trial setting • Intended use • Associated safety data • Adherence over time • Retention

  37. Non-proportional Hazard Designs • HPTN052 – HAART strategy • Immediate strategy likely to have early advantage; • Delayed strategy may defray this with better viral control from conserved treatment options; • Delayed strategy may be “almost as good” as immediate for preventing transmission over 5-7 years Trial designed with long follow-up, i.e. estimate decreased HR over 5-7 years, to deliberately average out the early effect • HPTN058 – IDU Suboxone • Likely early advantage while on suboxone (up to 1 year); potentially defrayed when suboxone removed Trial assesses difference in cumulative survival at 2 years • Interim monitoring requires special attention

  38. Conclusion • Trial design requires good collaboration • Determining design parameters: effectiveness, duration, endpoint analysis • Resources are finite but we need definitive answers • Givens: • Clinically relevant questions • Definitive answers • Role of adherence in achieving success requires ITT • Variables • Design depend on the prevention modality • Strategies for advancing the science differ because of the science • Each prevention modality has its own idiom

  39. “I wish you could see in the dark, too.” “We wish you could land on your feet,” Flitter replied. “How can we be so different and feel so much alike?” mused Flitter “And how can we feel so different and be so much alike?” wondered Pip.

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