Randomized, double-blind, placebo-controlled study to assess the efficacy and safety of vortioxetine in Japanese patients with major depressive disorder.

AIM: The burden of major depressive disorder (MDD) in Japan is high. This study aimed to evaluate the efficacy and safety of the multimodal antidepressant vortioxetine in Japanese patients with MDD. METHODS: Japanese patients aged 20-75 years with recurrent MDD and a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 26 were randomized to vortioxetine 10 or 20 mg or placebo in a phase-3, double-blind, 8-week study. The primary end-point was change in MADRS total score from baseline. Secondary end-points included MADRS response and remission rates, change in Hamilton Rating Scale for Depression-17 item (HAM-D17) score, and other measures of depressive symptoms, including Clinical Global Impression of Severity (CGI-S), Clinical Global Impression of Improvement (CGI-I), and Sheehan Disability Scale (SDS). Cognitive function was assessed using Digit Symbol Substitution Test (DSST) score and Perceived Deficits Questionnaire-5 item (PDQ-5) score. RESULTS: Vortioxetine 10 mg (n = 165) and 20 mg (n = 163) reduced MADRS total score by 2.66 and 3.07 points versus placebo (n = 161) after 8 weeks (P < 0.01 for each dose), respectively. MADRS response and remission rates were also significantly greater with vortioxetine than with placebo (P < 0.05 for both doses). Vortioxetine 10 and 20 mg significantly improved HAM-D17 score, CGI-I score, and SDS total score after 8 weeks. PDQ-5 score was significantly improved in subjects administered vortioxetine, while DSST scores showed no significant difference. Vortioxetine was generally well tolerated. CONCLUSION: Vortioxetine at both the 10- and 20-mg/day doses demonstrated robust antidepressant efficacy in Japanese patients with MDD, and was well tolerated over the 8-week treatment period.

Randomized, double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20 mg/day vortioxetine in adults with major depressive disorder.

AIM: This study assessed the efficacy and safety of vortioxetine in adults with major depressive disorder. METHODS: In this double-blind, placebo-controlled study, 600 patients with major depressive disorder were randomly assigned (1:1:1:1) to receive vortioxetine 5, 10, or 20 mg, or placebo once daily for 8 weeks. The primary end-point was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8, evaluated by the last-observation-carried-forward method. Secondary end-points included response (≥ 50% decrease in the MADRS total score from baseline) and remission (MADRS total score ≤ 10), Clinical Global Impression Scale-Improvement, and change from baseline in Sheehan Disability Scale. Adverse events were summarized. RESULTS: Vortioxetine failed to show significant differences from placebo in the primary end-point. Nominally significant improvements over placebo were observed for vortioxetine doses of 10 and 20 mg when the primary end-point was evaluated using the mixed model for repeated measures as the secondary analysis, and 10 mg in secondary measures of response and patient functioning. Vortioxetine was well tolerated. Nausea, constipation, dry mouth, dizziness, and insomnia each occurred at a >twofold higher rate than placebo. Discontinuation symptom scores were comparable between all groups after 1 and 2 weeks following withdrawal of the study drug. CONCLUSION: While vortioxetine failed to meet significance versus placebo in the primary efficacy analysis, there was evidence of efficacy for the 10- and 20-mg doses in secondary analyses. Vortioxetine was safe and well tolerated. Additional studies appear warranted.

Randomized, 8-week, double-blind, placebo-controlled trial of vortioxetine in Japanese adults with major depressive disorder, followed by a 52-week open-label extension trial.

AIM: Safety and efficacy of vortioxetine (5-20 mg/day) in Japanese patients with major depressive disorder were evaluated in two phase 3 studies consisting of a short-term, 8-week, placebo-controlled, double-blind study followed by a long-term, 52-week, open-label extension study. METHODS: The primary end-point of the short-term study was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 8. The primary objective of the extension study was vortioxetine's long-term safety; efficacy end-points included change in MADRS total score, Clinical Global Impression Scale (CGI)-Severity (S) score from the long-term study baseline, and CGI-Improvement (CGI-I) score over 52 weeks. RESULTS: Of the 366 randomized patients, 338 completed the short-term study, and 119 patients continued into the extension study. Primary (analysis of covariance) and secondary (mixed model for repeated measurements) analyses in the short-term study showed numerically greater, but not statistically significant, decreases in change in MADRS total score from baseline between the vortioxetine and placebo groups at week 8. In the long-term study, 86.6% of patients reported at least one treatment-emergent adverse event, with the most common being nasopharyngitis (40.3%) and nausea (21%). MADRS total score and CGI-I and CGI-S scores improved with continued vortioxetine treatment from baseline of the open-label study to week 52. CONCLUSION: Vortioxetine failed to meet significance versus placebo in the primary efficacy analysis at week 8 in the short-term study. The extension trial indicated continued improvement of depressive symptoms from baseline of this study throughout the 52-week treatment period. Vortioxetine treatment was safe and well tolerated in both studies.

A randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-months depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer.

BACKGROUND: Luteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin. METHODS: We conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety. RESULTS: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2. CONCLUSIONS: Adjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.

Evaluation of the efficacy and tolerability of combination therapy with candesartan cilexetil and amlodipine besilate compared with candesartan cilexetil monotherapy and amlodipine besilate monotherapy in Japanese patients with mild-to-moderate essential hypertension: a multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Blood pressure is reported to be insufficiently controlled in >50% of patients with hypertension. Guidelines for the management of hypertension recommend using drugs with different mechanisms of action when >1 agent is needed to achieve the blood pressure target. The combination of an angiotensin II receptor blocker and a calcium channel blocker is recommended as the preferred antihypertensive medication combination, and candesartan cilexetil (CC) and amlodipine besilate (AML) are commonly used in Japan. OBJECTIVE: The objective of our study was to determine if the combination of CC 8 mg and AML 5 mg has a greater blood pressure-lowering effect than monotherapy with either component, and if the combination of CC 4 mg and AML 2.5 mg has a greater blood pressure-lowering effect than placebo. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in Japanese patients with mild-to-moderate essential hypertension. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive the combination of CC 4 or 8 mg with AML 2.5 or 5 mg, CC 8 mg monotherapy, AML 5 mg monotherapy, or placebo once daily in the fasting or fed state for 12 weeks. The primary end point was change from baseline in trough diastolic blood pressure, and the secondary end point was change from baseline in trough systolic blood pressure at the end of treatment. Tolerability was assessed based on adverse events, vital signs, and physical findings. RESULTS: Of 548 patients who received placebo during the run-in period, 444 were randomized to receive CC 8 mg/AML 5 mg (CC/AML 8/5 mg) (n = 101), 8/2.5 mg (n = 36), 4/5 mg (n = 36), 4/2.5 mg (n = 35), CC 8 mg (n = 100), AML 5 mg (n = 100), or placebo (n = 36). These 444 patients included 272 men and 172 women. The mean (SD) age was 56.9 (10.7) years and the mean baseline BP was 153.4/95.7 mm Hg. The antihypertensive effect in the CC/AML 8/5 mg group (-27.4/-16.3 mm Hg) was significantly higher than in the CC 8 mg group (-13.9/-7.8 mm Hg) or the AML 5 mg group (-19.9/-11.2 mm Hg) in terms of reduction in the seated trough diastolic blood pressure and systolic blood pressure (both P < 0.0001). The incidence and severity of adverse events in the CC/AML combination groups did not differ significantly from those in the monotherapy and placebo groups. CONCLUSIONS: In Japanese adult patients with mild-to-moderate essential hypertension, CC/AML 8/5 mg combination therapy was more effective in lowering blood pressure than CC 8 mg or AML 5 mg monotherapy. These combinations were also well tolerated. Japan Pharmaceutical Information Center registration number: Japic CTI-101054.