Peripheral & Central Nervous System Advisory Committee

Public Meeting

(April 28, 1999)

Statistical Review of Aggrenox (Dipyridamole/Aspirin) capsule

 

Mushfiqur Rashid, Ph.D.

Mathematical Statistician

Division of Biometrics II

CDER/FDA

 

 

 

 

 

 

 

1. Introduction

 

2. Study design and sample size

3. Efficacy results

4. Statistical Issues

5. Reviewer’s comments

 

 

 

 

 

Introduction

Drug: Aggrenox (extended release Dipyridamole 200 mg/Aspirin 25 mg b.i.d.) Capsule

Indication:

Prevention of :

  1. Secondary stroke (non-fatal and fatal)

(2) Death (any cause)

 

 

 

Primary endpoints:

  1. Stroke (fatal or non-fatal)
  2. Death (all causes including fatal stroke)

c) Stroke or Death (composite endpoint)

Only (a) and (b) specified in the protocol.

 

 

 

 

Study Design

A Randomized, Double Blind, Multi-center, Parallel Group Design with four treatment arms:

    1. DP/ASA (Aggrenox)
    2. DP alone
    3. ASA alone

(4) Placebo

 

 

 

 

 

 

Primary Comparisons of Interest for the Combination Drug:

(1) DP/ASA vs. DP alone

and

(2) DP/ASA vs. ASA alone

Both tests require statistical significance in favor of the combination drug.

 

 

 

 

Sample Size Estimation
  1. 5000 patients (1250 in each arm) originally planned in the protocol based on 33% risk reduction between Aggrenox and placebo.
  2. Following the interim analysis, the risk reduction was assumed to be 22%.

3. Based on the interim analysis(about 4000 patients) results, sample size increased to 7000 patients.

4. In general, increasing sample size affects the Type I error rate.

 

Efficacy Analyses
  1. Comparison of "Survival" Curves based on Gehan-Wilcoxon Test
  2. Descriptive Measures:

Risk reduction (RR)

Survival rate increase (SRI)

 

 

 

 

 

 

 

Efficacy Results

- Stroke

- Death

- Composite (Death or Stroke)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stroke

Table 1: Drug Comparisons

Comparison

p-value

(G-W)

K-M stroke free rate

RR%

SRI

%

DP/ASA

Vs DP

DP/ASA

Vs ASA

ASA Vs

Placebo

DP Vs

Placebo

.002

.008

.009

.036

89.9 vs.

86.7

89.9 vs.

87.1

87.1 vs.

84.1

86.7 vs.

84.1

 

24.7

 

23.1

18.3

 

16.3

3.7

 

3.2

 

3.6

 

3.1

Figure 1: K-M Curves: Stroke Free Rate for DP/ASA, DP and Placebo

 

 

 

 

 

 

 

 

Figure 2: K-M Curves: Stroke Free Rate for DP/ASA, ASA and Placebo

 

 

 

 

 

 

Deaths

Table 2: Drug comparisons for deaths

comparison

p-value

(G-W )

K-M survival

RR%

SRI%

DP/ASA

Vs. DP

DP/ASA

Vs. ASA

ASA Vs.

Placebo

DP Vs.

Placebo

.79

 

.74

 

.16

 

.42

88.7 vs. 88.5

88.7 vs. 88.9

88.9 vs. 87.6

88.5 vs. 87.6

1.3

 

-2.7

 

10.9

 

7.3

.2

 

-.2

 

1.5

 

1.0

 

 

Figure 3: Survival Curves: Death for DP+ASA, DP and Placebo

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 4: Survival Curves: Death for DP+ASA, ASA and Placebo

 

 

 

 

Stroke or Death:

Table 3: Drug Comparisons

Comparisons

p-value

(G-W)

K-M stroke/death free rate

RR%

SRI%

DP/ASA vs. DP

DP/ASA vs. ASA

DP vs. Placebo

ASA vs. Placebo

.079

 

.084

 

.012

 

.009

82.4 vs. 80.3

 

82.4 vs. 79.9

 

80.3 vs. 76.7

 

79.9 vs. 76.7

10.3

 

12.1

 

15.7

 

13.9

2.6

 

3.1 4.7

 

4.2

 

Table 4: Multiple Endpoint Adjustments: Hochberg - 3 endpoints

 

Stroke or Death

DP/ASA

Vs. DP

DP/ASA

Vs. ASA

 

 

P-value

(G-W)

Unadj.

Adj.

 

Unadj.

Adj.

.079 .157

.084 .167

 

 

 

 

 

Figure 5: Survival Curves of Stroke or Death for DP/ASA vs. DP

 

 

 

 

 

 

 

 

Figure 6: Survival Curves of Stroke or Death for DP/ASA vs. ASA

 

 

 

 

 

 

 

 

 

 

 

 

 

Internal Consistency:

Results for Stroke or Death by region

 

 

 

 

 

 

 

 

 

 

 

 

Table 5: Comparisons by Region (Stroke or Death)

Region

DP/ASA

Vs. DP

DP/ASA

Vs. ASA

DP

vs. PL

 

ASA vs.

PL

Scandinavia .51 .47 .32 .36 (n=1665)

N. Europe .88 .32 .02 .12

(n=2425)

S. Europe .02 .05 .51 .27

(n=1075)

U. K. .81 .43 .22 .03

and Ireland

(n=1437)

 

 

Summary of Issues:
  1. Primary end-points not well defined in advance:

Adjustment needed for multiple endpoints

2. Sample size is increased at the interim analysis:

Adjustments needed for the increase in sample size

  1. Internal consistency not supported in the study

Reviewer’s Comments:

From a statistical perspective:

1. The study has shown that the combination drug product is effective only in stroke (fatal and non-fatal). It is not clear that there is any benefit for fatal stroke.

2. Significance efficacy results are not demonstrated for either mortality or the composite endpoint.