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Repros Therapeutics Inc.
Repros Therapeutics Inc.
01/28/2013 | Press release
ZA-301 Slide Presentation (PDF)
distributed by noodls on 01/29/2013 12:12
ZA-301
Site 9 Evaluation
Blinded Assessment
Repros Disclaimer
Any statements made by the Company that are not historical facts contained in this release are forward-looking statements that involve risks and uncertainties, including the ability to raise additional needed capital on a timely basis in order for it to continue to fund development of its Androxal® and Proellex® programs, have success in the clinical development of its technologies, the reliability of interim results to predict final study outcomes, and such other risks which are identified in the Company's most recent Annual Report on Form 10-K and in any subsequent quarterly reports on Form 10-Q. These documents are available on request from Repros Therapeutics or at www.sec.gov . Repros disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
ZA-301 Phase 3 Protocol Under an SPA
• Phase 3 pivotal studies being conducted under SPA
- 2 identical trials (BMI > 25, Age ≤ 60)
• 152 subjects in each trial (114 on Androxal, 38 on placebo)
- Men with morning T<300 ng/dL assessed twice on two separate days
• Up-titration from 12.5 to 25
• 3 month duration
- Co-Primary endpoints
• 75% of men achieve T in normal range (300-1040 ng/dL)
• Non inferior to placebo regarding change in sperm counts
Excerpt: FDA SPA Minutes
1) Proportion of subjects with average serum concentration (Cavg) for T in the normal range (i.e. serum T of 300 ng/dL - 1040 ng/dL).
2) Proportion of subjects with a 50% or greater decrease in sperm concentration from baseline to endpoint.
To demonstrate efficacy with regards to the first endpoint, at least 75% of subjects in the
Androxal group should achieve a Cavg for T in the normal range with the lower bound of the
95% confidence interval not below 67%. At least 100 Androxal subjects would be required to
demonstrate a point estimate of 75% or better.
For the second endpoint, Androxal should be non-inferior to placebo with respect to the difference in responder rates We have found a 20% non-inferiority margin to be acceptable in prior similar trials.
Values for serum T and sperm concentration at baseline and endpoint should be based on at least
two assessments. Semen sampling at each time point (baseline and endpoint) should be separated by at least 48 hours.
Cmax is an important safety issue. The percentage of patients with Cmax above the following three pre-determined limits (listed below) should be a secondary endpoint:
• Cmax>1500 ng/dL
• Cmax>1800 ng/dL and <2499 ng/dL
• Cmax>2500 ng/dL
Outcome Sensitivity
If the response rate is greater than 75%, then the required sample size to have the lower limit exceed 67% decreases considerably.
Here's a table with the minimum number of subjects that would be required to have the lower limit exceed 67% for each responder rate. The last column is what the lower limit of the 95% CI will be with N=113.
Responder Rate N Lower Limit of 95% CI
Lower Limit of 95% CI
with N=113
75% 113 67.02% 67.02%
80% 37 67.11% 72.62%
85% 16 67.50% 78.42%
90% 7 67.78% 84.47%
95% 3 70.34% 90.98%
Consulting Statistician
Comments
Assuming that 1% of the placebo group and 10% of the Androxal group experience a
50% or greater decrease in sperm concentraIon, and a 1:1 randomizaIon raIo, 53
subjects per group (106 subjects total) would be required to show that Androxal is
non-‐inferior to placebo in causing an abnormal sperm count at the 0.05 significance
level and assuming a non-‐inferiority limit of 20%. If you use a 2:1 randomizaIon raIo,
84 subjects in the Androxal group and 42 subjects in the placebo group (126 subjects
total) would be required. If you went with 150 subjects total and a 1:2 randomizaIon
raIo (100 Androxal + 50 placebo), that would give you 87% power.
• ProporIon of subjects with a 50% or greater decrease in sperm concentraIon from
baseline to endpoint.
Using a 3:1 or 4:1 randomizaIon raIo doesn't reduce the required placebo group
sample size significantly but it does inflate how many subjects in the Androxal arm
would be required (3:1 requires 114 Andoxal/38 placebo/152 total and 4:1 requires
144 Androxal/36 placebo/180 total).
ZA-301
|
• |
Mean Age - Site 9 (n=40): |
45.9 |
|
- Other 16 sites: |
46.6 |
|
|
• |
Mean BMI - Site 9: |
29.6 |
|
- Other 16 Sites: |
31.9 |
ZA-301
|
• |
Baseline Sperm |
Concentration |
|
- Site 9: |
17.6 x 106 sperm/mL |
|
|
- Other 16 Sites: |
80.7 x 106 sperm/ml |
|
|
• |
Baseline T - Site 9: |
167 ng/dL |
|
- Other 16 Sites: |
202 ng/dL |
ZA-301
500
450
400
350
300
250
200
150
100
50
0
Total T During Study
Baseline Week 6 Week 9
Site 9
Other 16 Sites
Drop outs before Week 6
Site 9: 3 out of 40
Others: 2 out of 111
ZA-301 Testosterone Endpoint
100
90
80
70
60
50
40
30
20
10
0
% of Subjects in Range Includes 25% of Subjects on Placebo Includes Penalty for Early Drop Outs
29 out of 40
76 out of 111
% in Range
Site 9
Other 16 Sites
Blinded Mean Sperm Counts
Subjects Completing Study
90
80
70
60 Number of Subjects <50% Site 9: 0 out of 21
50 *Other 16 Sites: 5 out of 30
40 3 measurements in doubt
30
20
10
0
Baseline End of Study
Site 9
Other 16 Sites
