1 / 33

Clinical Trial Efficacy

Clinical Trial Efficacy. James Street, PhD. Senior Biostatistician Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut. ESPS-2 The Second European Stroke Prevention Study.

kristin
Download Presentation

Clinical Trial Efficacy

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related