# Presentation: 715050

## AGGRENOXTM AdvisoryCommittee Meeting

## Manfred Haehl, MD

- Senior Vice President, Medical & DrugRegulatory AffairsBoehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, Connecticut

## AGGRENOXTM Proposed Indication

- AGGRENOXTM Proposed Indication

**To reduce the combined risk of death ****and non-fatal stroke in patients who ****have had transient ischemia of the brain****or completed ischemic stroke**

## FDA Approved Aspirin Label (1998)

- FDA Approved Aspirin Label (1998)

- “To reduce the combined risk of death and non-fatal stroke in patients who have had ischemicstroke or transient ischemia of the brain due to fibrin platelet emboli.” (dose 50–325 mg/d)
**Based on relative risk reduction of 13–18%****(63 FR 56802)**

## Nonfatal Stroke in Nine Randomized, Placebo-Controlled Trials1 of Aspirinin TIA or Stroke Patients

**Eight Other Studies**	399/3406	372/2584	18	(5, 30)	0.010
**Combined**	569/5055	585/4233	20	(9, 29)	<0.001

- Nonfatal Stroke in Nine Randomized, Placebo-Controlled Trials1 of Aspirinin TIA or Stroke Patients

**	****	****	****Odds Reduction**
**	****Aspirin****	****Placebo****	****(95% CI)****	*****P*****-Value****2**

- 1AITIA (1977), AITIA (1978), AICLA (1983), DANISH (1983), SWEDISH (1987),SALT (1991), UK-TIA (1991), EAFT (1993).
- 2Cochran Mantel-Haenszel test, stratified by study.

## ESPS-1

**2500 patients, TID dosing**
- 75 mg dipyridamole instant/330 mg Aspirin
- Placebo

## ESPS-2

**6602 patients, BID dosing**
- AGGRENOXTM
- ASA
- ER-DP
- Placebo

## AGGRENOXTM

## 200 mg ER–Dipyridamole Granules

**+**
**25 mg Immediate Release ASA**

**ASA**

- Dipyridamole

- HP cellulose
- protective
- coating:
- water soluble
- polymers

- Tartaric acid:
- dipyridamole solubiliser

- Sustained release coating:
- water insoluble polymers

- Dipyridamole depot pellets

## AGGRENOXTM ESPS-2 Findings

- AGGRENOXTM ESPS-2 Findings

- Highly significant additive risk reduction for stroke
- Safety comparable to components
- Trend (N.S.) reduction in death consistent with previous ASA findings
- Robust and reliable findings

## Characteristics of a Single Adequate and Well-Controlled Study for Effectiveness Claim

- Large multicenter study
- Consistency across study subsets
- Multiple studies in a single study
- Multiple endpoints involving different events
- Statistically very persuasive finding

## FDA Regulations for Fixed-Combination Prescription Drugs (21 CFR § 300.50)

- FDA Regulations for Fixed-Combination Prescription Drugs (21 CFR § 300.50)

- Each component makes a contributionto the claimed effects
- The dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy

## Participants and Guests

- J. Donald Easton, MD (Professor and Chairmanof Neurology, Brown University – RI Hospital)
- David G. Sherman, MD (Professor and Chief of Neurology, The University of Texas Health Science Center)
- Charles Hennekens, MD (Visiting Professor of Epidemiology and Public Health, University of Miami, School of Medicine, Miami, FL and Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK)

## 
John Pathy, MD (Director and Emeritus Professor, Health Care Research Unit, University of  Wales, Cardiff)
Hans Christoph Diener, MD (Professor and Chairman Department of Neurology, University of Essen, Germany)

- John Pathy, MD (Director and Emeritus Professor, Health Care Research Unit, University of  Wales, Cardiff)
- Hans Christoph Diener, MD (Professor and Chairman Department of Neurology, University of Essen, Germany)

- Participants and Guests

## Agenda

**Introduction**	Manfred Haehl, MD
- 		Senior Vice President for Medical & Drug Regulatory Affairs
- 		Boehringer Ingelheim Pharmaceuticals
**Stroke Management**	Gregory W. Albers, MD
- 		Associate Professor of Neurology
- 		Director of the Stanford Stroke Center
**Development Rationale**	Thomas Müller, MD, PhD
- 		Head, Haemostasis Laboratory
- 		Blood Transfusion Center of the German Red Cross
- 		Oldenburg, Germany
**Clinical Findings**
- 	**Efficacy**	James Street, PhD
- 		Sr. Biostatistician
- 		Boehringer Ingelheim Pharmaceuticals
**	****Safety**	Kenneth J. Rakowski, MD
- 		Head, Drug Surveillance and Information
- 		Boehringer Ingelheim Pharmaceuticals
**Conclusions**	Manfred Haehl, MD

## Slide 16

## FDA Guidance – Single Trial*

- *Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drugand Biological Products.

**“****Reliance on a single study will generally****be limited to situations in which a trial has demonstrated a clinically meaningful effect****on mortality, irreversible morbidity, or prevention of a disease with potentially****serious outcome, such that confirmation****of the result in a second trial would be****ethically difficult or impossible.” **

## Clinical Trial of AGGRENOXTM

**ESPS-2 (1996)**
- 6602 patients
- 200 mg ER-DP/25 mg ASA bid (AGGRENOXTM formulation)
- 37% RRR vs Placebo (Stroke)
- Tolerability comparable to components

## AGGRENOXTM

**	****Capsule containing**
- 200 mg Extended Release Dipyridamole  (ER-DP) Granules
-  +
- 25 mg Immediate Release Aspirin (ASA) Tablet

## Aspirin

## FDA Approved Aspirin Label (1980)

- FDA Approved Aspirin Label (1980)

- “For reducing the risk of recurrent transient ischemic attacks (TIA) or stroke in men who have had transient ischemia of the brain due to fibrin platelet emboli.” (dose 1,300 mg/d)
- “...inadequate evidence of efficacy in women”
- “...no evidence of benefit in treatment of completed stroke”