br Statistical Analysis br Efficacy analyses were performed
Efficacy analyses were performed using the ITT population. Safety analyses were performed on all enrolled patients. Pharmacokinetic analysis was performed on a subset of 30 patients.
Efficacy was evaluated according to the current FDA-recommended method of KaplaneMeier
analysis and the current FDA standards for gonadotropin-releasing hormone analogue approval, which indicate that the lower bound of the 95% CI for the point estimate of the percentage of patients who achieve and maintained castrate testosterone levels during the treatment Lovastatin should not be >90%.
The percentage of patients with testosterone suppression ( 50 ng/dL) from days 28e168 was calculated by the KaplaneMeier method for right-censored observations.22 Patients in whom testosterone suppression failed were considered failures on the first day of a testosterone measurement >50 ng/dL. Patients who prematurely discontinued without T concentration > 50 ng/dL and those who were successfully suppressed through day 168 were censored at their last measured testosterone value. On FDA request, a more restricted analysis was performed treating missing testosterone values as failures.
Summary statistics were presented as sample size, mean (SD), SD, and median for continuous variables and group frequencies and percentages for categories of categorical variables. In general, percentages were calculated using the total nonmissing responses by time point. Pharmacokinetic and pharmacodynamic parameters were measured or calculated for Cmax and Tmax, considering 2 intervals: days 0e84 after first administration and days 84e168 after second administration. The statistical analysis was performed using SAS software, version 9.2 for Windows (SAS
Institute, Cary, North Carolina). The pharmacokinetic analysis was performed using WinNonlin software, version 6.1 (Certara USA Inc, Princeton, New Jersey) and SAS software, version 9.2. AEs and local adverse reactions were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 14.1.
All 163 study patients enrolled received at least 1 dose of the study medication and thus constituted the safety population. One patient was not included in the ITT population (n ¼ 162) because of consent withdrawal within a few days after the first study drug administration; thus, no efficacy assessment was available. The number of patients who completed the study was 151. Twelve patients
terminated the study prematurely for reasons not related to treatment (Figure 1).
Baseline enrollee demographic characteristics as well as prostate cancer stage of the ITT population are presented in Table I. All patients included in the ITT had testosterone levels >150 ng/dL at screening.
The trial assessed 2 intramuscular leuprolide acetate 22.5-mg depot injections separated by a 3-month interval. Castrate levels of testosterone ( 50 ng/dL) were achieved and maintained from days 28e168 in 96.8% (95% CI, 92.5%e98.7%). Five patients had a testosterone level above castration. One patient did not achieve castration at day 28; nevertheless, once castration was achieved, it was maintained. The other 4 patients did not maintain castration. Three of them presented an isolated testosterone escape (i.e. T levels > 50 ng/dL).
A more restricted analysis was performed that included not only patients with noncastrate testosterone levels but also patients with missing testosterone values between days 28 and 168 as failures. Four patients had a missing testosterone value, 1 of them at day 28, resulting overall in achievement and maintenance of castration of 94.3% (95% CI, 89.4%e97.0%).
After the first administration on day 0, leuprolide concentrations increased rapidly (Figure 3) from nondetectable to 46.1 and 33.6 ng/mL at 1 and 4 h, respectively. The peak was followed by a decrease during several days, maintaining sustained drug levels until the following dose on day 84. The profile of leuprolide concentrations after the second administration on day 84 was similar to that following the first dose on day 0. Hence, the leuprolide peak was followed by a decrease in