Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study

Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study

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J Psychiatry Neurosci 2014; 39(1): 40-9

David Bakish, MD; Anjana Bose, PhD; Carl Gommoll, MS; Changzheng Chen, PhD; Rene Nunez, MD; William M. Greenberg, MD; Michael Liebowitz, MD; Arif Khan, MD

Bakish — Ottawa Psychopharmacology Clinic, Ottawa, Ont., Canada; Bose — Forest Research Institute, at time of study, Jersey City, NJ, USA; Gommoll, Chen, Nunez, Greenberg — Forest Research Institute, Jersey City, NJ, USA; Liebowitz — Columbia University and The Medical Research Network, New York, NY, USA; Khan — Northwest Clinical Research Center, Bellevue, Wash., USA; and the Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, NC, USA

Abstract

Background: Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults. Methods: This 10- week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo- controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18–75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery–Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeatedmeasures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings.

Methods: This 10- week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo- controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18–75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery–Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings.

Results: The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/ day group. Study completion rates were similar among the groups (76%–83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (–3.3 [–5.5 to –1.1], p = 0.003) and 80 mg/day (–3.1, [–5.3 to –1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (–1.8, 95% [–3.6 to 0], p = 0.046) and 80 mg/day (–2.7 [–4.5 to –0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction.

Limitations: Limitations to our study included short treatment duration and lack of an active control arm.

Conclusion: Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population.

Clinical trial registration: NCT01377194.


Submitted Mar. 6, 2013; Revised Apr. 22, June 27, 2013; Accepted July 2, 2013.

Competing interests: D. Bakish is a recipient of grants as a principal investigator from Forest Laboratories and serves on the speaker’s bureau for Pfizer. M.L. Liebowitz has received grants from Pfizer, an investigator research contract from Forest Laboratories, and has stock options in Pherin Pharmaceuticals. A. Khan is the founder and Medical Director of Columbia Northwest Pharmaceuticals LLC and owns intellectual property rights for potential therapies for central nervous system disorders and other medical conditions. C.P. Gommoll, C. Chen, R. Nunez, and W.M. Greenberg are employees of Forest Research Institute, a subsidiary of Forest Laboratories. A. Bose was an employee of Forest Research Institute at the time of study and is currently employed by Otsuka Pharmaceutical Development & Commercialization.

Contributors: A. Bose, C. Gommoll, R. Nunez and W.M. Greenberg designed the study. D. Bakish acquired the data, which all authors analyzed. A. Bose and W.M. Greenberg wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.130040

Correspondence to: D. Bakish, Ottawa Psychopharmacology Clinic, 1929 Russell Rd., Suite 328, Ottawa ON K16 4G3; dbakish@opctrials.com