# Presentation: 882977

## Clinical Trial Efficacy

- Senior Biostatistician
- Boehringer Ingelheim Pharmaceuticals, Inc.
- Ridgefield, Connecticut

**James Street, PhD**

## ESPS-2The Second EuropeanStroke 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 AGGRENOXTM?
- Is AGGRENOXTM well tolerated?

## ESPS-2Study 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)

## ESPS-2Geographical Distributionof Participating Centers

**1**

**2**

**4**

**15**

**8**

**4**

**9**

**2**

**2**

**2**

**4**

**3**

**3**

-     **13 countries**
**    ****59 centers**
**6602 patients**

**ESPS-2**Geographical Distributionof Participating Centers

## ESPS-2Study 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)

## ESPS-2Treatment Arms

**N = 6602**

**Placebo**
**(n = 1649)**

**ASA****25 mg bid**
**(n = 1649)**

**ER-DP****200 mg bid**
**(n = 1654)**

**AGGRENOXTM****25 mg ASA/****200 mg ER-DP ****bid**
**(n = 1650)**

## Qualifying Events

**AGGRENOXTM**	24.4%	75.5%
**DP** 		23.5%	76.5%
**ASA**	23.8%	76.2%
**Placebo**	23.0%	77.0%
**	****Overall**	**23.7%****	****76.3%**

## 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

## 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

## Primary Efficacy Endpoints

- MMAG*-confirmed endpoint stroke (fatal or non-fatal)
- Death (any cause)
**MMAG blind to treatment**

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

## 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

## Supportive Analysesof 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...

## 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

## 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

## Primary endpoint: Stroke
Primary analysis
Robustness analyses
Secondary endpoints
TIA
OVE
Ischemic events
MI
Primary endpoint: Death
Composite endpoint: Non-Fatal Stroke or Death

- Primary analysis
- Robustness analyses
- Secondary endpoints
- TIA
- OVE
- Ischemic events
- MI
- Primary endpoint: Death
- Composite endpoint: Non-Fatal Stroke or Death

**ESPS-2**Results

## Treatment Cessation

**Total No.****	**1650	1654	1649	1649	6602**of Patients**
**Completed****	**62.2	61.9	68.2	66.0	64.6**Study**
- 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	35.4**Treatment**

**	****AGGRENOX****TM****	****ER-DP****	****ASA****	****Placebo****	****Overall**
**	****%****	****%****	****%****	****%****	****%**

## Stroke

- 6

- 12

- 18

- 24

**Kaplan-Meier Estimate****of Survival**

**Months of Follow-Up**

## STROKEPrimary Factorial Analysis

**	****Relative Risk****	****Gehan-Wilcoxon****Factorial Effect****	****Reduction %****	*****P*****-Value**

**ER-DP****	**18.9	.001
**ASA****	**21.2	<.001
**Interaction****	**–**	**.850

## STROKESupportive Pairwise Comparison

**	****	****Relative Risk****	****Gehan-Wilcoxon****Comparison****	****Reduction %****	*****P*****-Value**

**AGGRENOX****TM ****vs ASA**** ****	**22.1	.008
**AGGRENOX****TM ****vs ER-DP**** ****	**24.4	.002
**AGGRENOX****TM ****vs Placebo****	**** **36.8	<.001
**ER-DP vs Placebo****	**16.5	.036
**ASA vs Placebo****	**18.9	.009

## STROKERobustness Analyses

**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

**	****Main Effects****	****Aggrenox****TM**** *****versus***

## CONCLUSIONStroke Endpoint

- Low-dose (50 mg/d) ASA prevents stroke
- ER-DP prevents stroke to a comparable degree
- AGGRENOXTM exhibits additive benefits
- Results highly statistically significant and robust

## SECONDARY ENDPOINTSSummary

**	****ER-DP vs****	****ASA vs****	****AGGRENOX****TM****Endpoint****	****No ER-DP****	****No ASA****	****vs Placebo**

**Odds Reduction %**

**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.

## SECONDARY ENDPOINTSConclusion

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

## Patient Survival

**Months of Follow-Up**

- 0.80

- 0.85

- 0.90

- 1.00

- 6

- 12

- 18

- 24

**Kaplan-Meier Estimate of Survival**

- 0

- 0.75

- 0.95

## DEATHPrimary Factorial Analysis

**ASA****	**6.5	.239
**Interaction****	**–	.420

**DEATH**Primary Factorial Analysis

**	****Relative Risk****	****Gehan-Wilcoxon****Factorial Effect ****	****Reduction %****	*****P*****-Value**

## DEATHSupportive Pairwise Comparison

**Pairwise ****	****Relative Risk****	****Gehan-Wilcoxon****Comparison ****	****Reduction %****	*****P*****-Value**

**AGGRENOX****TM ****vs ASA**** **	-2.0	.744
**AGGRENOX****TM ****vs ER-DP**** **	 1.6	.791
**AGGRENOX****TM ****vs Placebo**** **	9.2	.285
**ER-DP vs Placebo****	**7.7	.421
**ASA vs Placebo**	11.0	.162

## No statistically significant risk reduction found
~10% risk reduction in death on AGGRENOXTM,comparable to that on ASA alone
Risk reductions comparable to those seenin meta-analyses of placebo-controlled studiesof ASA in stroke and TIA patients

- ~10% risk reduction in death on AGGRENOXTM,comparable to that on ASA alone
- Risk reductions comparable to those seenin meta-analyses of placebo-controlled studiesof ASA in stroke and TIA patients

**CONCLUSION**Death Endpoint

## Nonfatal Stroke or Death

**Months of Follow-Up**

- 0.75

- 0.8

- 0.85

- 0.9

- 0.95

- 1

- 6

- 12

- 18

- 24

**Kaplan-Meier Estimate of Survival**

## NONFATAL STROKE OR DEATHPrimary Factorial Analysis

**ER-DP****	**14.0	.003
**ASA****	**12.2	.002
**Interaction****	**–	.504

**	****Relative Risk****	****Gehan-Wilcoxon****Factorial Effect ****	****Reduction %****	*****P*****-Value**

## NONFATAL STROKE OR DEATHSupportive Pairwise Comparison

**Pairwise ****	****Relative Risk****	****Gehan-Wilcoxon****Comparison ****	****Reduction %****	*****P*****-Value**

**AGGRENOX****TM ****vs ASA**** **	12.1	.084
**AGGRENOX****TM ****vs ER-DP**** **	 10.3	.079
**AGGRENOX****TM ****vs Placebo**** **	24.4	<.001
**ER-DP vs Placebo****	**15.7	.012
**ASA vs Placebo**	13.9	.009

## Factorial analysis shows
Highly significant efficacy of both components
Additive efficacy in AGGRENOXTM
Pairwise comparisons show
24.4% risk reduction on AGGRENOXTM vs placebo (P = .00002)
Favorable trends on AGGRENOXTM vs components

- Highly significant efficacy of both components
- Additive efficacy in AGGRENOXTM
- Pairwise comparisons show
- 24.4% risk reduction on AGGRENOXTM vs placebo (*P* = .00002)
- Favorable trends on AGGRENOXTM vs components

**NONFATAL STROKE OR DEATH** Conclusion

## 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

## Slide 33

## Efficacy Conclusion

- AGGRENOX   is significantly more effective than aspirin alone in reducing the risk of stroke in TIA and stroke patients
- This conclusion is based on reliable,well-controlled, generalizable, robust and highly significant evidence

## Summary Patient Disposition

**Intent-to-Treat****	**1649	(100.0)	1650	(100.0)	1654	(100.0)	1649	(100.0)	6602	(100.0)**Population**
**Completed****	**1088	(66.0)	1027	(62.2)	1023	(61.9)	1125	(68.2)	4263	(64.6**)****Study****	**Treated until	980	(59.4)	945	(57.3)	923	(55.8)	1023	(62.0)	3871	(58.6)	month-24	Treated until	108	(6.5)	82	(5.0)	100	(6.0)	102	(6.2)	392	(5.9)	death
**Ceased****	**561	(34.0)	623	(37.8)	631	(38.1)	524	(31.8)	2339	(35.4)**Treatment**

**	**** ****Placebo ****	****AGGRENOX****TM****	****ER-DP****	****ASA****	****Overall**
**	****n (%)****	****n (%)****	****n (%)****	****n (%)****	****n (%)**

**Total No.****	**1649	1650	1654	1649	6602**of Patients****Randomized**

**Treatment Group**

## Aggrenox®Safety

- Director, General Medicine
- Boehringer Ingelheim Pharmaceuticals, Inc.
- Ridgefield, Connecticut

**Alan Ranhosky, MD**

## ESPS-2The Second European Stroke Prevention Study

**ESPS-2**The Second European Stroke Prevention Study

- Tested efficacy of ASA/ER-DP for secondary stroke prevention
- Addressed clinical questions
- Does low-dose ASA prevent stroke?
- Does ER-DP prevent stroke?
- Is ASA/ER-DP superior to ASA alone?To ER-DP alone?
- Is ASA/ER-DP well tolerated?

## Multicenter, randomized, double-blind,placebo-controlled trial
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)

- 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)

**ESPS-2**Study Design

## ESPS-2Geographical Distributionof Participating Centers

**1**

**2**

**4**

**15**

**8**

**4**

**9**

**2**

**2**

**2**

**4**

**3**

**3**

-     **13 countries**
**    ****59 centers**
**6602 patients**

**ESPS-2**Geographical Distributionof Participating Centers

## ESPS-2Treatment Arms

**N = 6602**

**Placebo**
**(n = 1649)**

**ASA****25 mg BID**
**(n = 1649)**

**ER-DP****200 mg BID**
**(n = 1654)**

**ASA/ER-DP****25 mg ASA/****200 mg ER-DP ****BID**
**(n = 1650)**

## ESPS-22 x 2 Factorial Design

**ASA/ER-DP**

**ER-DP**

**Placebo**

**ASA**

**ESPS-2**2 x 2 Factorial Design

**Allows statistical detection of drug effects****with fewer patients**
- Comparing ASA vs no ASA, ER-DP vs no ER-DP
**Allows direct comparison between any two treatment arms**

## ESPS-2Primary Efficacy Endpoints

- MMAG-confirmed first stroke (fatal or non-fatal)
- Death (any cause)

## ESPS-2Protocol-Defined Secondary Efficacy Endpoints

- Transient ischemic attacks
- Other vascular events
- Myocardial infarction
- Ischemic events (stroke, MI, or sudden death)

## ESPS-2Other Secondary Efficacy Endpoints

- Fatal stroke
- Non-fatal stroke
- Non-fatal stroke or death
- Vascular death

## Use of Placebo Comparison

- Placebo comparison included because of conflicting data from previous stroke trials
- Placebo comparison needed to assesspotential benefits of low-dose ASA
- At the beginning of the trial (1988/89), all 60 independent ethical review committees (one at each study site) agreed that the use of placebo was appropriate

## GCP Compliance

- Use of several oversight committees
- Informed consent from every patient
- Ethics Committee approvals both locallyand centrally
- On-site monitoring
- Careful QA of case report forms

## Patient Survival

**Months of Follow-Up**

- 0.85

- 0.90

- 0.95

- 1.00

- 6

- 12

- 18

- 24

**Kaplan-Meier Estimate of Survival**

- 0

**Fatal**

**Non-Fatal**

## Fatal and Non-fatal Stroke Estimates of Survival 

**Months of Follow-Up**

**Kaplan-Meier Estimate of Survival**