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Clinical Trial Efficacy

Clinical Trial Efficacy

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Clinical Trial Efficacy

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  1. Clinical Trial Efficacy James Street, PhD Senior Biostatistician Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut

  2. ESPS-2The Second EuropeanStroke Prevention Study • Tested the safety and efficacy of ER-DP and ASA, alone and in combination, to prevent stroke and death in patients with prior TIA or ischemic stroke • Addressed four primary clinical questions • Does low-dose ASA prevent stroke or death? • Does ER-DP prevent stroke or death? • Are the effects of ER-DP and ASA additive when combined in AGGRENOX™? • Is AGGRENOX™ well tolerated?

  3. ESPS-2Study Design • Multicenter, randomized, double-blind,placebo-controlled • 2 x 2 factorial design • 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke) • Treatment and follow-up time: 2 years(visits at 1 and 3 months, then at 3-month intervals)

  4. ESPS-2Geographical Distributionof Participating Centers 3 13 countries 59 centers 6602 patients 4 2 2 15 8 9 4 2 2 1 3 4

  5. ESPS-2Study Design • Multicenter, randomized, double-blind,placebo-controlled • 2 x 2 factorial design • 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke) • Treatment and follow-up time: 2 years(visits at 1 and 3 months, then at 3-month intervals)

  6. ESPS-2Treatment Arms • N = 6602 Placebo (n = 1649) ASA25 mg bid (n = 1649) ER-DP200 mg bid (n = 1654) AGGRENOX™25 mg ASA/200 mg ER-DP bid (n = 1650)

  7. Qualifying Events TIAStroke AGGRENOX™ 24.4% 75.5% DP 23.5% 76.5% ASA 23.8% 76.2% Placebo 23.0% 77.0% Overall23.7% 76.3%

  8. Entry Criteria • Men and women >18 years of age • Ischemic stroke or TIA within threemonths prior to randomization • Neurological and general clinical conditionstabilized before entry • Exclusion criteria • No history of gastric bleeding or other bleeding disturbances • Active peptic ulcer • Known hypersensitivity to study medications • Any life-threatening condition

  9. Sample Size and Interim Analysis • Protocol-planned sample size = 5000 patients • One interim analysis planned in protocol • Consider early termination for efficacy • Re-estimate sample size • Blind to treatment • Steering and Ethics Committees agreed to increase sample size to 7000 patients

  10. Primary Efficacy Endpoints • MMAG*-confirmed endpoint stroke (fatal or non-fatal) • Death (any cause) • MMAG blind to treatment • *MMAG = Morbidity and Mortality Assessment Group.

  11. Secondary Efficacy Endpoints • Four secondary endpoints identified in protocol • Transient Ischemic Attacks • Myocardial Infarction • Other Vascular Events (PE, DVT, PAO, RVA) • Ischemic Events (stroke, MI, sudden death) • MMAG-reviewed secondary endpoints other than TIA

  12. Supportive Analysesof Primary Endpoints • Numerous robustness tests • Exploratory subgroup analyses, including: • Gender • Age • Type of qualifying event • History of TIA or stroke prior to qualifying event • History of MI • Hypertension • Atrial fibrillation • Geographic location...

  13. Analysis Plans • Primary analyses conducted per protocol • Two-year follow-up • Intent-to-treat • Gehan-Wilcoxon survival analysis • Factorial analysis • Secondary and robustness analysis plans confirmed at pre-NDA meeting

  14. Factorial Design • Can detect drug effects with fewer patients • Main effects of ER-DP and ASA • ER-DP groups vs No ER-DP groups • ASA groups vs No ASA groups • Interaction of ER-DP with ASA • Compare ER-DP effects with/without ASA • Design allows pairwise comparisonsof any two treatment arms

  15. ESPS-2Results • Primary endpoint: Stroke • Primary analysis • Robustness analyses • Secondary endpoints • TIA • OVE • Ischemic events • MI • Primary endpoint: Death • Composite endpoint: Non-Fatal Stroke or Death

  16. Treatment Cessation AGGRENOXTM ER-DP ASA Placebo Overall % % % % % • Total No. 1650 1654 1649 1649 6602of Patients • Completed 62.2 61.9 68.2 66.0 64.6Study • Treated until 57.3 55.8 62.0 59.4 58.6month-24Treated until 5.0 6.0 6.2 6.5 5.9death • Ceased 37.8 38.1 31.8 34.0 35.4Treatment

  17. Stroke 1 0.95 0.9 AggrenoxTM ER-DP ASA Placebo 0.85 0.8 0.75 Kaplan-Meier Estimateof Survival 6 12 18 24 Months of Follow-Up

  18. STROKEPrimary Factorial Analysis Relative Risk Gehan-WilcoxonFactorial Effect Reduction % P-Value ER-DP 18.9 .001 ASA 21.2 <.001 Interaction –.850

  19. STROKESupportive Pairwise Comparison Relative Risk Gehan-WilcoxonComparison Reduction % P-Value AGGRENOXTM vs ASA22.1 .008 AGGRENOXTM vs ER-DP24.4 .002 AGGRENOXTM vs Placebo36.8 <.001 ER-DP vs Placebo 16.5 .036 ASA vs Placebo 18.9 .009

  20. STROKERobustness Analyses Main Effects AggrenoxTMversus Analysis ER-DP ASA ER-DP ASA Placebo Primary .001 <.001 .002 .008 <.001 Cox-Adjusted .001 <.001 .003 .007 <.001 Logrank .001 <.001 .003 .010 <.001 Stratified by Center .001 <.001 .002 .006 <.001 Investigator-diagnosed .001 <.001 .003 .007 <.001 First 5002 .001 <.001 .002 .001 <.001 Worst-case .001 <.001 .003 .013 <.001

  21. CONCLUSIONStroke Endpoint • Low-dose (50 mg/d) ASA prevents stroke • ER-DP prevents stroke to a comparable degree • AGGRENOX™ exhibits additive benefits • Results highly statistically significant and robust

  22. SECONDARY ENDPOINTSSummary Odds Reduction % ER-DP vs ASA vs AGGRENOXTMEndpoint No ER-DP No ASA vs Placebo Stroke* 22% (.001) 24% (<.001) 41% (<.001) TIA 20% (.001) 25% (<.001) 40% (<.001) OVE 40% (.004) 34% (.012) 62% (<.001) Ischemic Event 20% (.001) 21% (<.001) 38% (<.001) MI 1% (.939) 21% (.100) 23% (.217) *Primary endpoint, included for reference.

  23. SECONDARY ENDPOINTSConclusion • TIA, OVE and Ischemic Events confirm the efficacy of ER-DP and ASA both individually and additively in the combination AGGRENOX™ • Acute MI showed a positive trend on AGGRENOX™ vs placebo, consistent with effect of ASA component

  24. Patient Survival AggrenoxTM ER-DP ASA Placebo 1.00 0.95 Kaplan-Meier Estimate of Survival 0.90 0.85 0.80 0.75 0 6 12 18 24 Months of Follow-Up

  25. DEATHPrimary Factorial Analysis Relative Risk Gehan-WilcoxonFactorial Effect Reduction % P-Value ER-DP 3.1 .725 ASA 6.5 .239 Interaction – .420

  26. DEATHSupportive Pairwise Comparison Pairwise Relative Risk Gehan-WilcoxonComparison Reduction % P-Value AGGRENOXTM vs ASA -2.0 .744 AGGRENOXTM vs ER-DP 1.6 .791 AGGRENOXTM vs Placebo 9.2 .285 ER-DP vs Placebo7.7 .421 ASA vs Placebo 11.0 .162

  27. CONCLUSIONDeath Endpoint • No statistically significant risk reduction found • ~10% risk reduction in death on AGGRENOX™,comparable to that on ASA alone • Risk reductions comparable to those seenin meta-analyses of placebo-controlled studiesof ASA in stroke and TIA patients

  28. Nonfatal Stroke or Death DP + ASA ASA DP Placebo 1 0.95 0.9 Kaplan-Meier Estimate of Survival 0.85 0.8 0.75 6 12 18 24 Months of Follow-Up

  29. NONFATAL STROKE OR DEATHPrimary Factorial Analysis Relative Risk Gehan-WilcoxonFactorial Effect Reduction % P-Value ER-DP 14.0 .003 ASA 12.2 .002 Interaction – .504

  30. NONFATAL STROKE OR DEATHSupportive Pairwise Comparison Pairwise Relative Risk Gehan-WilcoxonComparison Reduction % P-Value AGGRENOXTM vs ASA 12.1 .084 AGGRENOXTM vs ER-DP 10.3 .079 AGGRENOXTM vs Placebo 24.4 <.001 ER-DP vs Placebo15.7 .012 ASA vs Placebo 13.9 .009

  31. NONFATAL STROKE OR DEATHConclusion • Factorial analysis shows • Highly significant efficacy of both components • Additive efficacy in AGGRENOX™ • Pairwise comparisons show • 24.4% risk reduction on AGGRENOX™ vs placebo (P = .00002) • Favorable trends on AGGRENOX™ vs components

  32. Efficacy Conclusion • AGGRENOXTM is significantly more effective than aspirin alone and dipyridamole alone in reducing the risk of stroke in TIA and stroke patients • This conclusion is based on reliable, well-controlled, generalizable evidence • Large, multicenter trial • Factorial design demonstrating effectiveness of monotherapies and additive effectiveness of the combination • Statistically very persuasive findings • Consistency across subgroups • Significant benefit on distinct, prespecified endpoints