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

Clinical Trial EfficacyClinical Trial Efficacy

Senior BiostatisticianSenior BiostatisticianBoehringer Ingelheim Pharmaceuticals, Inc.Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, ConnecticutRidgefield, Connecticut

James Street, PhDJames Street, PhD

ESPS-2ESPS-2

The Second EuropeanThe Second EuropeanStroke Prevention StudyStroke Prevention Study Tested the safety and efficacy of ER-DP and ASA, Tested the safety and efficacy of ER-DP and ASA,

alone and in combination, to prevent stroke and alone and in combination, to prevent stroke and death in patients with prior TIA or ischemic strokedeath in patients with prior TIA or ischemic stroke

Addressed four primary clinical questionsAddressed four primary clinical questions– Does low-dose ASA prevent stroke or death?Does low-dose ASA prevent stroke or death?– Does ER-DP prevent stroke or death?Does ER-DP prevent stroke or death?– Are the effects of ER-DP and ASA additive when Are the effects of ER-DP and ASA additive when

combined in AGGRENOX™?combined in AGGRENOX™?– Is AGGRENOX™ well tolerated?Is AGGRENOX™ well tolerated?

ESPS-2ESPS-2

Study DesignStudy Design

Multicenter, randomized, double-blind,Multicenter, randomized, double-blind,placebo-controlledplacebo-controlled

2 x 2 factorial design2 x 2 factorial design

6602 patients from 59 centers, centrally randomized 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke)within 3 months of qualifying event (TIA or stroke)

Treatment and follow-up time: 2 yearsTreatment and follow-up time: 2 years(visits at 1 and 3 months, then at 3-month intervals)(visits at 1 and 3 months, then at 3-month intervals)

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3 13 countries13 countries 59 centers59 centers6602 patients6602 patients

ESPS-2ESPS-2

Geographical DistributionGeographical Distributionof Participating Centersof Participating Centers

ESPS-2ESPS-2

Study DesignStudy Design

Multicenter, randomized, double-blind,Multicenter, randomized, double-blind,placebo-controlledplacebo-controlled

2 x 2 factorial design2 x 2 factorial design

6602 patients from 59 centers, centrally randomized 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke)within 3 months of qualifying event (TIA or stroke)

Treatment and follow-up time: 2 yearsTreatment and follow-up time: 2 years(visits at 1 and 3 months, then at 3-month intervals)(visits at 1 and 3 months, then at 3-month intervals)

ESPS-2ESPS-2

Treatment ArmsTreatment Arms

N = 6602N = 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)

TIATIA StrokeStroke

AGGRENOX™AGGRENOX™ 24.4% 75.5%

DPDP 23.5% 76.5%

ASAASA 23.8% 76.2%

PlaceboPlacebo 23.0% 77.0%

OverallOverall 23.7%23.7% 76.3%76.3%

Qualifying EventsQualifying Events

Entry CriteriaEntry Criteria Men and women >18 years of age Men and women >18 years of age Ischemic stroke or TIA within threeIschemic stroke or TIA within three

months prior to randomizationmonths prior to randomization Neurological and general clinical conditionNeurological and general clinical condition

stabilized before entrystabilized before entry Exclusion criteriaExclusion criteria

– No history of gastric bleeding or other No history of gastric bleeding or other bleeding disturbancesbleeding disturbances

– Active peptic ulcerActive peptic ulcer– Known hypersensitivity to study medicationsKnown hypersensitivity to study medications– Any life-threatening conditionAny life-threatening condition

Sample Size and Interim AnalysisSample Size and Interim Analysis

Protocol-planned sample size = 5000 patientsProtocol-planned sample size = 5000 patients

One interim analysis planned in protocol One interim analysis planned in protocol – Consider early termination for efficacyConsider early termination for efficacy– Re-estimate sample sizeRe-estimate sample size– Blind to treatmentBlind to treatment

Steering and Ethics Committees agreed to Steering and Ethics Committees agreed to increase sample size to 7000 patients increase sample size to 7000 patients

Primary Efficacy EndpointsPrimary Efficacy Endpoints

MMAG*-confirmed endpoint stroke MMAG*-confirmed endpoint stroke (fatal or non-fatal)(fatal or non-fatal)

Death (any cause)Death (any cause)

MMAG blind to treatmentMMAG blind to treatment

**MMAG = Morbidity and Mortality Assessment Group.MMAG = Morbidity and Mortality Assessment Group.

Secondary Efficacy EndpointsSecondary Efficacy Endpoints

Four secondary endpoints identified in protocolFour secondary endpoints identified in protocol– Transient Ischemic AttacksTransient Ischemic Attacks– Myocardial InfarctionMyocardial Infarction– Other Vascular Events (PE, DVT, PAO, RVA) Other Vascular Events (PE, DVT, PAO, RVA) – Ischemic Events (stroke, MI, sudden death) Ischemic Events (stroke, MI, sudden death)

MMAG-reviewed secondary endpoints other than TIAMMAG-reviewed secondary endpoints other than TIA

Supportive AnalysesSupportive Analysesof Primary Endpointsof Primary Endpoints Numerous robustness testsNumerous robustness tests

Exploratory subgroup analyses, including:Exploratory subgroup analyses, including:– GenderGender– AgeAge– Type of qualifying eventType of qualifying event– History of TIA or stroke prior to qualifying eventHistory of TIA or stroke prior to qualifying event– History of MIHistory of MI– HypertensionHypertension– Atrial fibrillationAtrial fibrillation– Geographic location...Geographic location...

Analysis PlansAnalysis Plans

Primary analyses conducted per protocolPrimary analyses conducted per protocol– Two-year follow-upTwo-year follow-up– Intent-to-treatIntent-to-treat– Gehan-Wilcoxon survival analysisGehan-Wilcoxon survival analysis– Factorial analysisFactorial analysis

Secondary and robustness analysis plans Secondary and robustness analysis plans confirmed at pre-NDA meetingconfirmed at pre-NDA meeting

Factorial DesignFactorial Design

Can detect drug effects with fewer patientsCan detect drug effects with fewer patients

Main effectsMain effects of ER-DP and ASA of ER-DP and ASA– ER-DP groups vs No ER-DP groupsER-DP groups vs No ER-DP groups– ASA groups vs No ASA groupsASA groups vs No ASA groups

InteractionInteraction of ER-DP with ASA of ER-DP with ASA– Compare ER-DP effects with/without ASACompare ER-DP effects with/without ASA

Design allows Design allows pairwisepairwise comparisons comparisonsof any two treatment arms of any two treatment arms

Primary endpoint: StrokePrimary endpoint: Stroke– Primary analysisPrimary analysis– Robustness analysesRobustness analyses

Secondary endpointsSecondary endpoints– TIATIA– OVEOVE– Ischemic eventsIschemic events– MIMI

Primary endpoint: DeathPrimary endpoint: Death Composite endpoint: Non-Fatal Stroke or DeathComposite endpoint: Non-Fatal Stroke or Death

ESPS-2ESPS-2

ResultsResults

Treatment CessationTreatment Cessation

Total No.Total No. 16501650 16541654 16491649 16491649 66026602of Patientsof Patients

CompletedCompleted 62.262.2 61.961.9 68.268.2 66.066.0 64.664.6StudyStudy

Treated untilTreated until 57.357.3 55.855.8 62.062.0 59.459.4 58.658.6month-24month-24Treated untilTreated until 5.05.0 6.0 6.0 6.26.2 6.5 6.5 5.95.9deathdeath

CeasedCeased 37.837.8 38.138.1 31.831.8 34.034.0 35.435.4TreatmentTreatment

AGGRENOXAGGRENOXTMTM ER-DPER-DP ASAASA PlaceboPlacebo OverallOverall%% %% %% %% %%

StrokeStroke

0.750.75

0.80.8

0.850.85

0.90.9

0.950.95

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Months of Follow-UpMonths of Follow-Up

AggrenoxAggrenoxTMTM

ER-DPER-DPASAASAPlaceboPlacebo

STROKESTROKE

Primary Factorial AnalysisPrimary Factorial Analysis

Relative RiskRelative Risk Gehan-WilcoxonGehan-WilcoxonFactorial EffectFactorial Effect Reduction %Reduction % PP-Value-Value

ER-DPER-DP 18.918.9 .001.001

ASAASA 21.221.2 <.001<.001

InteractionInteraction –– .850.850

STROKESTROKE

Supportive Pairwise ComparisonSupportive Pairwise Comparison

Relative RiskRelative Risk Gehan-WilcoxonGehan-WilcoxonComparisonComparison Reduction %Reduction % PP-Value-Value

AGGRENOXAGGRENOXTM TM vs ASAvs ASA 22.122.1 .008.008

AGGRENOXAGGRENOXTM TM vs ER-DPvs ER-DP 24.424.4 .002.002

AGGRENOXAGGRENOXTM TM vs Placebovs Placebo 36.836.8 <.001<.001

ER-DP vs PlaceboER-DP vs Placebo 16.516.5 .036.036

ASA vs PlaceboASA vs Placebo 18.918.9 .009.009

STROKESTROKE

Robustness AnalysesRobustness Analyses

AnalysisAnalysis ER-DPER-DP ASAASA ER-DPER-DP ASAASA PlaceboPlacebo

PrimaryPrimary .001.001 <.001<.001 .002.002 .008.008 <.001<.001

Cox-AdjustedCox-Adjusted .001.001 <.001<.001 .003.003 .007.007 <.001<.001

LogrankLogrank .001.001 <.001<.001 .003.003 .010.010 <.001<.001

Stratified by CenterStratified by Center .001.001 <.001<.001 .002.002 .006.006 <.001<.001

Investigator-diagnosedInvestigator-diagnosed .001.001 <.001<.001 .003.003 .007.007 <.001<.001

First 5002First 5002 .001.001 <.001<.001 .002.002 .001.001 <.001<.001

Worst-caseWorst-case .001.001 <.001<.001 .003.003 .013.013 <.001<.001

Main EffectsMain Effects AggrenoxAggrenoxTMTM versusversus

CONCLUSIONCONCLUSION

Stroke EndpointStroke Endpoint

Low-dose (50 mg/d) ASA prevents stroke Low-dose (50 mg/d) ASA prevents stroke

ER-DP prevents stroke to a comparable degreeER-DP prevents stroke to a comparable degree

AGGRENOX™ exhibits additive benefitsAGGRENOX™ exhibits additive benefits

Results highly statistically significant and robustResults highly statistically significant and robust

SECONDARY ENDPOINTSSECONDARY ENDPOINTS

SummarySummary

ER-DP vsER-DP vs ASA vsASA vs AGGRENOXAGGRENOXTMTM

EndpointEndpoint No ER-DPNo ER-DP No ASANo ASA vs Placebovs Placebo

Odds Reduction %Odds Reduction %

Stroke*Stroke* 22%22% (.001)(.001) 24%24% (<.001)(<.001) 41%41% (<.001)(<.001)

TIATIA 20%20% (.001)(.001) 25%25% (<.001)(<.001) 40%40% (<.001)(<.001)

OVEOVE 40%40% (.004)(.004) 34%34% (.012) (.012) 62%62% (<.001)(<.001)

Ischemic EventIschemic Event 20%20% (.001)(.001) 21%21% (<.001)(<.001) 38%38% (<.001)(<.001)

MIMI 1%1% (.939)(.939) 21%21% (.100) (.100) 23%23% (.217) (.217)

*Primary endpoint, included for reference.*Primary endpoint, included for reference.

SECONDARY ENDPOINTSSECONDARY ENDPOINTS

ConclusionConclusion

TIA, OVE and Ischemic Events confirm the efficacy TIA, OVE and Ischemic Events confirm the efficacy of ER-DP and ASA both individually and additively in of ER-DP and ASA both individually and additively in the combination AGGRENOX™the combination AGGRENOX™

Acute MI showed a positive trend on AGGRENOX™ Acute MI showed a positive trend on AGGRENOX™ vs placebo, consistent with effect of ASA componentvs placebo, consistent with effect of ASA component


0.800.80

0.850.85

0.900.90

1.001.00

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Patient SurvivalPatient Survival

0.750.75

0.950.95

AggrenoxAggrenoxTMTM

ER-DPER-DPASAASAPlaceboPlacebo

ER-DPER-DP 3.13.1 .725.725

ASAASA 6.56.5 .239.239


DEATHDEATH


Relative RiskRelative Risk Gehan-WilcoxonGehan-WilcoxonFactorial Effect Factorial Effect Reduction %Reduction % PP-Value-Value

DEATHDEATH


Pairwise Pairwise Relative RiskRelative Risk Gehan-WilcoxonGehan-WilcoxonComparison Comparison Reduction %Reduction % PP-Value-Value

AGGRENOXAGGRENOXTM TM vs ASAvs ASA -2.0-2.0 .744.744

AGGRENOXAGGRENOXTM TM vs ER-DPvs ER-DP 1.6 1.6 .791.791

AGGRENOXAGGRENOXTM TM vs Placebovs Placebo 9.29.2 .285.285



No statistically significant risk reduction foundNo statistically significant risk reduction found

~10% risk reduction in death on AGGRENOX™,~10% risk reduction in death on AGGRENOX™,comparable to that on ASA alonecomparable to that on ASA alone

Risk reductions comparable to those seenRisk reductions comparable to those seenin meta-analyses of placebo-controlled studiesin meta-analyses of placebo-controlled studiesof ASA in stroke and TIA patientsof ASA in stroke and TIA patients

CONCLUSIONCONCLUSION

Death EndpointDeath Endpoint

Nonfatal Stroke or DeathNonfatal Stroke or Death


0.750.75

0.80.8

0.850.85

0.90.9

0.950.95

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DP + ASADP + ASAASAASADPDPPlaceboPlacebo

NONFATAL STROKE OR DEATHNONFATAL STROKE OR DEATH


ER-DPER-DP 14.014.0 .003.003

ASAASA 12.212.2 .002.002


Relative RiskRelative Risk Gehan-WilcoxonGehan-WilcoxonFactorial Effect Factorial Effect Reduction %Reduction % PP-Value-Value

NONFATAL STROKE OR DEATHNONFATAL STROKE OR DEATH


Pairwise Pairwise Relative RiskRelative Risk Gehan-WilcoxonGehan-WilcoxonComparison Comparison Reduction %Reduction % PP-Value-Value

AGGRENOXAGGRENOXTM TM vs ASAvs ASA 12.112.1 .084.084

AGGRENOXAGGRENOXTM TM vs ER-DPvs ER-DP 10.3 10.3 .079.079

AGGRENOXAGGRENOXTM TM vs Placebovs Placebo 24.424.4 <.001<.001



Factorial analysis showsFactorial analysis shows

– Highly significant efficacy of both componentsHighly significant efficacy of both components

– Additive efficacy in AGGRENOX™Additive efficacy in AGGRENOX™

Pairwise comparisons showPairwise comparisons show

– 24.4% risk reduction on AGGRENOX™ vs placebo 24.4% risk reduction on AGGRENOX™ vs placebo ((PP = .00002) = .00002)

– Favorable trends on AGGRENOX™ vs componentsFavorable trends on AGGRENOX™ vs components

NONFATAL STROKE OR DEATHNONFATAL STROKE OR DEATH ConclusionConclusion

Efficacy ConclusionEfficacy Conclusion AGGRENOXAGGRENOXTMTM is significantly more effective than is significantly more effective than

aspirin alone and dipyridamole alone in reducing aspirin alone and dipyridamole alone in reducing the risk of stroke in TIA and stroke patientsthe risk of stroke in TIA and stroke patients

This conclusion is based on reliable, well-controlled, This conclusion is based on reliable, well-controlled, generalizable evidencegeneralizable evidence– Large, multicenter trialLarge, multicenter trial– Factorial design demonstrating effectiveness of Factorial design demonstrating effectiveness of

monotherapies and additive effectiveness of monotherapies and additive effectiveness of the combinationthe combination

– Statistically very persuasive findingsStatistically very persuasive findings– Consistency across subgroupsConsistency across subgroups– Significant benefit on distinct, prespecified endpointsSignificant benefit on distinct, prespecified endpoints

Documents

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