The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

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1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 29/04/ Version 5 2. SYNOPSIS Title of Study: Investigator coordinator: Study centre(s): Efficacy and tolerance of cyproterone acetate versus medroxyprogesterone acetate versus venlafaxine LP in the treatment of hot flushes caused by leuprorelin mg in patients treated for a prostate adenocarcinoma. Multicentric, national, randomised, double blind study Professeur Jacques IRANI 106 urology centres Publication (reference): Not applicable Studied period: Date of first enrolment: 14 April 2004 Date of last completed: 06 December 2007 Phase of development: IIIb Objectives: Primary To compare the efficacy of three drugs (cyproterone acetate, medroxyprogesterone acetate, venlafaxine) in the treatment of hot flushes caused by leuprorelin LP mg in patients suffering from prostate cancer: frequency and severity of hot flushes. Secondary To evaluate in each treatment group: the tolerance profile of the study drugs, the impact of the treatment on the quality of life of patients and their satisfaction, the change in the frequency and severity of hot flushes after 4 and 8 weeks of treatment, the proportion of patients wishing to continue treatment after the end of the study. Methodology: Multicentric, national, randomised, double blind study Number of patients Planned: 540 patients were planned to be included and 351 to be randomised (117 patients per group Analysed: 919 patients were included and 311 were randomised (102 patients in Venlafaxine LP group, 101 patients in Cyproterone acetate group and 108 patients in Medroxyprogesterone acetate group) Diagnosis and main criteria for inclusion: Criteria checked at the inclusion visit V0: Inclusion criteria: a) Patient had a histologically proven prostatic adenocarcinoma, b) Patient has been on a GnRH agonist treatment for a duration of at least 1 year, c) Karnofsky index 70%, d) Patient who, after having been clearly informed, had given his written consent to participate in the study. Exclusion criteria a) Patient included in a therapeutic trial in the 3 months preceding the inclusion visit, b) Prescription of agonist planned in the context of neo-adjuvant hormonotherapy, c) Patient had symptomatic bone metastases, d) Patient already treated with hormonotherapy for his prostate cancer or had received an hormonal treatment other than a GnRH agonist for this cancer (apart from palliative care of flare-up with anti-androgens), Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 3/221

3 29/04/ Version 5 Diagnosis and main criteria for inclusion: (continued) e) Patient was unable to understand the information regarding the study provided to him, of giving his consent or who had refused to sign the informed consent sheet, f) Patient for whom risk follow up could not be guaranteed within the conditions stipulated in the protocol or was unable to complete the self-evaluation questionnaires, g) Diabetic, or patient with severe progressive disease: kidney, liver, cardiovascular (especially high uncontrolled BP), psychiatric, h) Thromboembolic history or concomitant thromboembolic disease, i) Patient had hepatocellular insufficiency or hepatic cytolysis (SGOT/SGPT > 3 times laboratory normal range) j) Patient had a contra-indication to one of the study drugs, k) Patient receiving corticotherapy or concomitant prescription for non-selective monoamine oxidase inhibitors (MAOI), serotonin re-uptake inhibitors, clonidine, gabapentine, veripride, tibolone or beta-alanine (prohibited drugs section listed in protocol page 39) l) Patient was undergoing medical treatment for a depressive phase or had been treated for this during the previous 2 years before inclusion, m) Patient with a history of congenital galactosemy, poor absorption of glucose or galactose syndrome or even a lactase deficiency n) Patient had had another cancer in the 5 previous years excluding basocellular epithelioma or in situ carcinoma. Criteria checked at the randomisation visit V1 Randomisation criterion: >14 hot flush instances in the week preceding randomisation and/or occurrence of hot flushes causing the patient to complain significantly and to spontaneously request treatment. Non-randomisation criteria: Patient reporting < 14 hot flush instances in the week preceding randomisation and a slight or moderate complaint, not necessitating treatment according to the investigator s opinion, Disease progression (biological and/or clinical) during the 6 months preceding randomisation, necessitating a change in the care of the prostate cancer, Patient was non compliant with the treatment procedures and/or treatments, Patient had prematurely stopped the study before randomisation, Refusal of the patient to follow the study, Contra-indication to one of the 3 study drugs Patient receiving corticotherapy or concomitant prescription for non-selective monoamine oxidase inhibitors (MAOI), serotonin re-uptake inhibitors, clonidine, gabapentine, veripride, tibolone or beta-alanine (see prohibited drugs section on page 39) Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 4/221

4 29/04/ Version 5 Study products Duration of treatment: Dose: 100 mg per day for 8 weeks and then placebo for 2 weeks Mode of administration: oral Batch number: CPM5834:33307A, CPM6221: 51436A, CPM6488: 54515A Dose: 75 mg per day for 8 weeks and then 37.5 mg per day for 2 weeks Mode of administration: oral Batch number: CPM5833:375099, CPM6220:375157, CPM6489: Dose: 20 mg per day for 8 weeks and then placebo for 2 weeks Mode of administration: oral Batch number: CPM5864: 4GVG12, CPM6222: 4GVG12, CPM6490: Clinofem 10mg: B865D 10 weeks of treatment for Venlafaxine 8 weeks of treatment for Cyproterone acetate and Medroxyprogesterone Criteria for evaluation: Efficacy: Primary criteria: Hot Flush (HF) score on week-4 after randomisation (variation in average score compared with evaluation at randomisation visit V1, expressed as a percentage) Secondary criteria: Frequency of HF on week 4 after randomisation (variation in average frequency compared with evaluation at randomisation visit V1, expressed as a percentage) % of patients with a decrease of more than 50% in HF score on week-4 after randomisation and those with a complete decrease compared with evaluation at randomisation visit V1, % of patients with a decrease in the level of complaint regarding HF at each visit compared with the evaluation at randomisation visit V1, HF score on week-8 of treatment (variation in average score compared with evaluation at randomisation visit V1 and expressed as a percentage), Change in the variation of the HF score between week-4 and week-8 of treatment, Change in the variation of the HF frequency between week-4 and week-8 of treatment, % of patients who wish to continue the treatment at the end of week-10, % of patients who wish to restart the treatment at the end of week-12, Impact of the treatment on the quality of life at each visit (EORTC quality of life questionnaire, QLQ-C30, version 3) Safety: Adverse events reported by patients and change in vital signs, excluding hot flushes Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 5/221

5 29/04/ Version 5 Statistical methods: Efficacy results: Quantitative variables were described (distribution) by their frequency, mean, standard deviation, standard deviation to the mean, median, first and third quartiles, extreme values (minimum and maximum) and missing data. Qualitative variables were described (allocation) by the frequency and percentage of each of the ways of answering, as well as the missing data that will be integrated into the calculation of the percentage. Tests were bilateral and considered as significant at the level of α=0.05. In case of significant difference between the 3 groups of treatment, all pairewise differences were tested with level of significance adjustement using the Bonferoni method (α =α/3). The primary criterion was the relative change in HF score after 4 weeks of treatment. The change was calculated as follows: [(HF score at month-7 HF score at month-6)/hf score at month-6] x 100. The HF scores at month-6 and month-7 and the calculated relative change were described. The relative change between the 3 groups of treatment was compared by a covariance analysis (parametric analysis or rank non parametric analysis depending on data distribution) with group of treatment and HF score at month-6 as covariates. In case a significant difference was characterised, all pairewise differences were tested (adjusted level of significance). Descriptive statistics were applied for all secondary criteria. Relative changes were compared between the groups with the same methodology as the primary criterion. Descriptive safety analysis was performed over 2 distinct study periods (month-0 to month-6 and month-6 to month-9), on the safety population. Primary objective The primary objective of the study was to compare the efficacy of three drugs (cyproterone acetate, medroxyprogesterone acetate, venlafaxine) in the treatment of hot flushes caused by leuprorelin LP mg in patients suffering from prostate cancer: frequency and severity of hot flushes. The median hot flushes score (HF score) was used. Between month-6 and month-7 (4 weeks of treatment), the relative change in HF score was significantly more important in the Cyproterone acetate (p<0.0001) and the Medroxyprogesterone acetate (p<0.0001) groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups (p=0.266). Similar results were obtained for the PP population. Secondary objectives The relative change in HF score between month-6 and month-8 was significantly more important in the Cyproterone acetate (p<0.0001) and the Medroxyprogesterone acetate (p<0.0001) groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups (p=1.000). The relative change in HF score at the last available score (after 4 or 8 weeks of treatment) was also significantly more important in the Cyproterone acetate (p<0.0001) and the Medroxyprogesterone acetate (p<0.0001) groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups (p=0.838). The relative change in HF score between month-6 and month-8 was significantly more important in the Cyproterone acetate (p<0.0001) and the Medroxyprogesterone acetate (p<0.0001) groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups (p=1.000). Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 6/221

6 29/04/ Version 5 Efficacy results: (continued) Secondary objectives (continued) Relative change in HF score between month-7 (after 4 weeks of treament) and month 8 (after 8 weeks of treatment, was significantly more important in the Cyproterone acetate (p=0.012) and the Medroxyprogesterone acetate (p=0.0001) groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups (p=0.668). The proportion of patients presenting with at least 50% improvement in HF score after 4 weeks of treatment was 46.9% in the Venlafaxine LP group, 86.6% in the Cyproterone acetate group and 86.5% in the Medroxyprogesterone acetate group (p<0.001). The relative change in the number of hot flushes per week was compared between the 3 groups of treatment and was significantly different (p<0.0001) for 3 periods during the study: between month-6 and month-7, between month-6 and month-8 and between month-7 and month-8 respectively. The decrease in the number of hot flushes per week was always significantly more important in the Cyproterone acetate and the Medroxyprogesterone acetate groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups. The proportion of patients presenting with complete regression of hot flushes after 4 weeks of treatment 8.3% in the Venlafaxine LP group, 38.1% of the Cyproterone acetate group and 24.0% the Medroxyprogesterone acetate group (p<0.001). The change in the level of complaints was classified as degradation, non change or improvement. The proportions of patients in each class were compared for 3 periods of time and significant differences were observed for change between month-6 and month-7 (p=0.011), change between month-6 and month-8 (p<0.001), and change between month-6 and month-9 (p=0.002). Overall, Medroxyprogesterone acetate and Cyproterone acetate led to a higher decrease in th elevel of complaints than Venlafaxine. The proportion of patients who wished to continue the study treatment after the 10 weeks of treatment planned in the protocol was 70.3% in the Venlafaxine LP group, 70.8% in the Cyproterone acetate group and 79.4% in the Medroxyprogesterone acetate group. No significant difference was observed between the 3 groups (p=0.282). After 12 weeks of treatment, the proportion of patients who wished to continue the study treatment was 52.8%) in the Venlafaxine LP group, 59.8% in the Cyproterone acetate group and 61.5% in the Medroxyprogesterone acetate group. No significant difference was observed between the 3 groups (p=0.458). Patients satisfaction was assessed by asking them at visits V2, V3 and V4 how they would rate the treatment efficacy. At visit V2, the proportion of patients who thought that the treatment was not very effective was 20.4% in the Venlafaxine LP group, 4.1% in the Cyproterone acetate group and 2.9% in the Medroxyprogesterone acetate group. At visit V3, they were 21.7% in the Venlafaxine LP group, 7.9% in the Cyproterone acetate group and 3.1% in the Medroxyprogesterone acetate group. At visit V4, they were 19.3% in the Venlafaxine LP group, 2.4% in the Cyproterone acetate group and 13.7% in the Medroxyprogesterone acetate group. A significant difference was characterised between the 3 groups of the study for all time points (p<0.001). The impact of the treatment on the quality of life of patients was assessed through the use of the QLQ-C30 questionnaire. Patients of the study were relatively in good health and the repartition of scores among the population made difficult to characterise score changes between the visits. Thus, caution should be taken for the interpretation QLQ-C30 analysis. Furthermore, for all significant differences characterised between the study groups, the median changes and the Q1 and Q3 values were equal to 0. As a conclusion, it seems difficult to conclude on the effect of the study treatments on the quality of life of the patients. Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 7/221

7 29/04/ Version 5 Safety results: The safety observed during this study showed that during the M0-M6 period (N=914), 367 patients (40.2%) presented with at least one adverse event (AE), 102 presented with at least 1 AE related to one of the study drug (Leuprorelin and/ or Flutamide) and 6 other cases leaded to discontinuation. 80 patients (8.8%) experienced serious adverse events (SAE). During the M6-M9 period, 41 patients (Venlafaxine LP group), 46 (Cyproterone acetate group) and 39 (Medroxyprogesterone acetate group) presented with at least one AE. In total, 16 patients (5.2%) experienced 19 SAEs. During the study, 10 patients experienced SAE related to the study product: 7 SAEs during M0-M6 and 3 SAEs during M6-M9. As regard to fatal cases, in total 12 patients died during the study: 4 patient died because of cardiac failure during the M0-M6 period and 8 patients during the M6- M9 period. Conclusion: Overall, 919 patients were included in the study. The patients average age was 72.7 years old (±7.3). Among these 919 patients, 222 patients were prematurely withdrawn from the study between V0 and V1. A total of 311 patients were randomised at M6 in one of the 3 groups of the study (102, 101 and 108 in Venlafaxine, Cyproterone acetate and Medroxyprogesterone groups respectively); After randomisation, 47 patients were prematurely withdrawn from the study. A total of 264 patients completed the study in accordance with the protocol. A total of 273 patients (31.0%) presented at least one protocol deviation and 67 patients (7.6%) showed at least one major protocol deviation. The analysis of the primary efficacy criterion on full analysis set (FAS) population was realised with 309 patients. The obtained results indicate that patients treated for 4 weeks with Cyproterone acetate or Medroxyprogesterone acetate reported significantly less hot flushes as assessed by the HF score than patients treated with Venlafaxine LP (p< in both cases). No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups (p=0.266). These results were confirmed after 8 and 12 weeks of treatment. Also, the proportion of patients presenting with at least 50% improvement in HF score after 4 weeks of treatment was 46.9% in the Venlafaxine LP group, 86.6% in the Cyproterone acetate group and 86.5% in the Medroxyprogesterone acetate group (p<0.001). The relative change in the number of hot flushes per week was compared between the 3 groups of treatment and was significantly different (p<0.0001) for 3 periods during the study: between month-6 and month-7, between month-6 and month-8 and between month-7 and month-8 respectively. The decrease in the number of hot flushes per week was always significantly more important in the Cyproterone acetate and the Medroxyprogesterone acetate groups compared to the Venlafaxine LP group. No significant difference was observed between the Cyproterone acetate and the Medroxyprogesterone acetate groups. The proportion of patients presenting with complete regression of hot flushes after 4 weeks of treatment 8.3% in the Venlafaxine LP group, 38.1% in the Cyproterone acetate group and 24.0% in the Medroxyprogesterone acetate group (p<0.001). The analysis of safety was realised with 914 patients for the M0-M6 period and with 309 patients for the M-M9 period. Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 8/221

8 29/04/ Version 5 Conclusion: (Continued) The safety profiles observed during this study showed that during the M0-M6 period (N=914), 367 patients presented with at least one adverse event (AE), 102 (11.2%) presented with at least 1 AE related to one of the study drug (Leuprorelin and/ or Flutamide) and 6 other cases leaded to discontinuation. 80 patients (8.8%) experienced serious adverse events (SAE). During the M6-M9 period, 41 patients (Venlafaxine LP group), 46 (Cyproterone acetate group) and 39 (Medroxyprogesterone acetate group) presented with at least one AE. In total, 16 patients (5.2%) experienced 19 SAEs. During the study, 10 patients experienced SAEs related to the study product: 7 SAEs during M0-M6 and 3 SAEs during M6-M9 (1 patient of each group). As regard to fatal cases, in total 12 patients died during the study: 4 patient during the M0-M6 period, 8 patients during the M6-M9 period. In conclusion, the results obtained show that Venlafaxine LP is a less potent treatment than Cyproterone acetate and the Medroxyprogesterone acetate for men with hot flushes caused by leuprorelin mg in patients treated for a prostate adenocarcinoma. Date of the report: 23/12/2009 Y:\FLE8105\REDACTION\ClinicalReport_FLEU100_V5_ doc 9/221