Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study.

OBJECTIVE: This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. METHODS: In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5-7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. RESULTS: The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: -2304.3 ml, minimum: -27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). CONCLUSIONS: Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75-30 mg/day.

Long-term safety and efficacy of nalmefene in Japanese patients with alcohol dependence.

AIM: The safety and efficacy of nalmefene in Japanese patients with high or very high World Health Organization drinking risk level of alcohol dependence were assessed in a multicenter, randomized, double-blind, placebo-controlled, phase 3 (lead-in) study. Here, the long-term safety and efficacy of nalmefene in an open-label extension of the lead-in study are presented. METHODS: Patients who completed the 24-week lead-in study were eligible for the extension study, where they were treated with nalmefene 20 mg as needed for 24 weeks. The long-term safety and efficacy of nalmefene 20 mg during the total 48-week period were evaluated. Treatment-emergent adverse events during the study period were recorded and change from baseline in the number of heavy drinking days and total alcohol consumption were calculated. RESULTS: Overall, long-term nalmefene 20 mg was well tolerated; the main treatment-emergent adverse events reported in ≥5% of patients included nasopharyngitis (37.2%), nausea (36.5%), somnolence (21.2%), dizziness (16.8%), malaise (14.6%), and vomiting (12.4%). The number of heavy drinking days and total alcohol consumption decreased from baseline to 48 weeks (mixed model for repeated measures, least squares mean ± standard error, -15.09 ± 0.77 days/month and -53.20 ± 2.29 g/day, respectively) during the study. CONCLUSION: This long-term evaluation in Japanese patients with high or very high drinking risk levels of alcohol dependence indicated that nalmefene was safe, well tolerated, and efficacious.

Nalmefene in alcohol-dependent patients with a high drinking risk: Randomized controlled trial.

AIMS: Reducing alcohol consumption is one treatment approach for alcohol-dependent patients. This study compared nalmefene 20 mg and 10 mg with placebo, combined with psychosocial support, in alcohol-dependent Japanese patients with a high or very high drinking risk level (DRL). METHODS: This was a multicenter, randomized, double-blind, phase 3 study conducted in alcohol-dependent patients with a high or very high DRL. Patients were randomized to 24 weeks of treatment with as-needed nalmefene 20 mg, 10 mg, or placebo with psychosocial support. The primary endpoint was change in heavy drinking days (HDD) from baseline to week 12. A key secondary endpoint was the change in total alcohol consumption (TAC) from baseline to week 12. RESULTS: At week 12, 234, 206, and 154 patients who received placebo, nalmefene 20 mg, and 10 mg were included in the primary endpoint analysis. Compared with placebo, nalmefene was associated with significant reductions in HDD at week 12 (difference in 20 mg group, -4.34 days/month; 95% confidence interval [CI]: -6.05 to -2.62; P < 0.0001; difference in 10 mg group, -4.18 days/month; 95%CI: -6.05 to -2.32; P < 0.0001), as well as a significant reduction in TAC at week 12 (P < 0.0001). The incidence of treatment-emergent adverse events was 87.9%, 84.8%, and 79.2% in the groups receiving nalmefene 20 mg, 10 mg, and placebo, respectively. These events were mostly of mild or moderate severity. CONCLUSIONS: Nalmefene 20 mg or 10 mg effectively reduced alcohol consumption and was well tolerated in alcohol-dependent patients with a high or very high DRL.