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A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder.

ABSTRACT: OBJECTIVE:Major depressive disorder is often chronic, with relapse and recurrence common. Levomilnacipran extended-release is a potent and selective serotonin and reuptake inhibitor approved in the United States for treatment of major depressive disorder in adults. The objective of this study (NCT01085812) was to evaluate the efficacy, safety, and tolerability of levomilnacipran extended-release in the prevention of relapse in patients with major depressive disorder. DESIGN:A 24-week Phase III randomized, double-blind, controlled trial comparing levomilnacipran extended-release 40-120mg/day with placebo for relapse prevention in patients with major depressive disorder who had responded to 12-week, open-label treatment with levomilnacipran extended-release. Statistical power was calculated on the assumption that 38 percent of placebo and 20 percent of levomilnacipran extended-release patients would relapse. SETTING:Thirty-six outpatient study centers throughout the United States and Canada. PARTICIPANTS:Of 348 patients who met randomization criteria and entered double-blind treatment, three discontinued prior to treatment, 112 were randomized to placebo, and 233 to levomilnacipran extended-release. MEASUREMENTS: PRIMARY OUTCOME:Time to relapse was analyzed using the Cox proportional hazard-regression model with treatment group and baseline Montgomery-Åsberg Depression Rating Scale score as explanatory variables. Safety was also evaluated. RESULTS:Time to relapse was longer for levomilnacipran extended-release versus placebo (hazard ratio [95% confidence interval] = 0.68 [0.40][1.17]), but the treatment difference was not statistically significant (P=0.165). A relatively low percentage of patients from either group relapsed (placebo=20.5%, levomilnacipran extended-release=13.9%). CONCLUSION:This study did not detect between-treatment group differences, potentially due to lower than expected relapse rates in the placebo group. Levomilnacipran extended-release was generally well tolerated.

SUBMITTER: Shiovitz T

PROVIDER: S-EPMC3960779 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder.

Shiovitz Thomas T Greenberg William M WM Chen Changzheng C Forero Giovanna G Gommoll Carl P CP

Innovations in clinical neuroscience 20140101 1-2

<h4>Objective</h4>Major depressive disorder is often chronic, with relapse and recurrence common. Levomilnacipran extended-release is a potent and selective serotonin and reuptake inhibitor approved in the United States for treatment of major depressive disorder in adults. The objective of this study (NCT01085812) was to evaluate the efficacy, safety, and tolerability of levomilnacipran extended-release in the prevention of relapse in patients with major depressive disorder.<h4>Design</h4>A 24-w ...[more]

PMID: 24653937

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Project description:ObjectiveLevomilnacipran ER is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). Efficacy and safety have been evaluated in five Phase II/III studies, four of which met the pre-specified primary efficacy outcome. Results of the negative trial (ClinicalTrials.gov NCT00969150) are reported here.MethodsA Phase III randomized, double-blind, placebo-controlled trial comparing flexible-dose levomilnacipran ER 40-120 mg/day with placebo was conducted in outpatients with MDD. Patients met the DSM-IV-TR criteria for MDD, had a current episode of depression of at least 4 weeks' duration, and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥30. The study comprised a 1-week, single-blind, placebo lead-in, 8-week double-blind treatment, and a 2-week down-taper. The primary and secondary efficacy measures were change from baseline to Week 8 in MADRS and Sheehan Disability Scale (SDS) total scores, respectively, analyzed using a mixed-effects model for repeated measures approach. Safety outcomes included adverse events (AEs), laboratory and vital sign measures, the Columbia-Suicide Severity Rating Scale, and the Arizona Sexual Experiences Scale (ASEX).ResultsThree hundred and fifty-five patients received the study drug and had ≥1 post-baseline MADRS total score assessment (ITT Population); 81.9% of placebo and 77.1% of levomilnacipran ER patients completed the study. For levomilnacipran ER vs placebo, MADRS (-15.7 vs -14.2) and SDS (-8.8 vs -8.2) total score improvements, and rates of MADRS response (38.5% vs 34.8%) and remission (25.3% vs 23.8%) were numerically greater but differences were not statistically significant. Levomilnacipran ER was generally well tolerated. More levomilnacipran ER patients vs placebo reported AEs; the most common AEs for levomilnacipran ER were nausea (17%) and headache (16%). Mean changes in most safety measures were small and similar between groups. There were no meaningful differences in total ASEX scores between groups.LimitationsShort duration of treatment, inclusion and exclusion criteria, and lack of an active comparator.ConclusionNumerical improvements for levomilnacipran ER vs placebo were detected in this study, but the differences were not statistically significant; levomilnacipran ER was generally well tolerated.

Project description:In this post hoc analysis, improvement in functional impairment in patients with major depressive disorder (MDD) treated with levomilnacipran extended release (ER) was evaluated by assessing shifts from more severe to less severe functional impairment categories on individual Sheehan Disability Scale (SDS) subscales.SDS data were pooled from 5 phase II/III studies conducted between December 2006 and March 2012 of levomilnacipran ER versus placebo in adult patients with MDD (DSM-IV-TR criteria). Proportions of patients shifting from moderate-extreme baseline impairment (score ? 4) to mild-no impairment (score ? 3) at end of treatment were assessed for each SDS subscale. Proportions of patients shifting from marked-extreme (score ? 7) baseline impairment to moderate-no (score ? 6) or mild-no impairment (score ? 3) at end of treatment, and shifts in which patients worsened from moderate-no to marked-extreme impairment, were also evaluated.A significantly higher proportion of patients treated with levomilnacipran ER than placebo-treated patients improved from more severe categories of functional impairment at baseline to less severe impairment categories across all SDS subscales: work/school, social life, and family life/home responsibilities (P < .01). Depending on the SDS subscale, 48%-55% of levomilnacipran ER-treated patients with moderate-extreme impairment at baseline improved to mild or no impairment, compared with no more than 40% of placebo patients on any subscale. Almost half (42%-47%) of levomilnacipran ER-treated patients versus only about one-third (29%-34%) of placebo patients improved from marked-extreme to mild or no impairment across functional domains.These results suggest that functional improvement was observed across the SDS functional domains. To our knowledge, this is the first such categorical analysis of functional improvement, as measured by the SDS, for an antidepressant.ClinicalTrials.gov identifiers: NCT00969709, NCT01377194, NCT00969150, and NCT01034462 and EudraCT identifier: 2006-002404-34.

Dataset Information

A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder.

Publications

A Randomized, Double-blind, Placebo-controlled Trial of the Efficacy and Safety of Levomilnacipran ER 40-120mg/day for Prevention of Relapse in Patients with Major Depressive Disorder.

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