A sustained-release formulation of the investigational drug levomilnacipran was found superior to placebo for improving depressive symptoms in adults with major depressive disorder.
The randomized, double-blind phase III trial included more than 700 patients. Treatment also was associated with significant and clinically meaningful improvements in functional health and well-being, the investigators reported.
Patients were randomized to receive daily treatment at dosages of 40 mg, 80 mg, or 120 mg of levomilnacipran SR, a selective serotonin and norepinephrine reuptake inhibitor (SNRI). Improvement in depressive symptoms was dose proportional and statistically significant, compared with placebo, reported Carl Gommoll of Forest Research Institute and his colleagues in a poster at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
On the Montgomery-Asberg Depression Rating Scale–Clinician Rated (MADRS-CR), the least-squares mean difference (LSMD) versus placebo for total score change from baseline was –3.23 for the 40-mg group, –3.99 for the 80-mg group, and –4.86 for the 120-mg group (181, 181, and 183 patients, respectively), the investigators said.
The 80-mg and 120-mg groups also experienced significantly greater improvement, compared with placebo, on the Sheehan Disability Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions–Severity and –Improvement assessments.
In a post hoc analysis, the superiority of levomilnacipran SR at the 80-mg and 120-mg doses was demonstrated across symptom domains, as evidenced by significantly greater decreases in most MADRS-CR single-item scores, the investigators reported.
In a separate analysis and poster presentation, Steven I. Blum, also of Forest Research Institute, and his colleagues reported that the patients treated with levomilnacipran SR experienced significantly greater improvement in Mental Component Summary scores on the SF-36v2 acute Health Survey, compared with those in the placebo group (LSMD of 4.4).
“A treatment advantage of three points in the mean treatment group difference is considered clinically relevant,” the investigators explained, also noting that the treatment group patients experienced significant improvements, compared with the placebo group, on the individual SF-36 dimensions of general health, vitality, social functioning, role emotional, and mental health (LSMDs of 2.3, 2.4, 3.1, 3.1, and 4.3, respectively).
These differences also exceeded minimally important difference thresholds for the domain and are considered clinically relevant, they said.
Improvements with treatment vs. placebo also were seen on the Physical Component Summary and other individual dimensions of the SF-36 (specifically, physical functions, role physical, and bodily pain), but these did not reach statistical significance.
These findings suggest that treatment with levomilnacipran SR is associated with clinically meaningful, statistically significant improvements in functional health and well being, the investigators said.
Together, the findings of these two analyses of phase III trial data contribute to a recent series of positive findings with respect to levomilnacipran SR, which the investigators describe as a “potent and selective SNRI with 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition and over 10-fold greater selectivity for norepinephrine reuptake inhibition, compared with duloxetine and venlafaxine.”
The sustained-release formulation was developed to allow once-daily dosing and was shown in a prior, flexible-dose (75-100 mg) randomized controlled trial to be superior to placebo on all efficacy measures.
Patients in the current double-blind, multicenter, parallel-group, fixed-dose study were adults aged 18-65 years who met the Diagnostic and Statistical Manual-IV-TR (text revision) criteria for major depressive disorder. All had a current major depressive episode of at least 8 weeks’ duration at study entry, as well as a score of 30 or more (mean of 36) on MADRS-CR.
Following a 1-week, single-blind placebo lead-in period, participants were randomized in a double-blind fashion to 8 weeks of active treatment or placebo. Those in the levomilnacipran SR treatment groups received an initial dose of 20 mg, titrated to the target dose over 7 days. The treatment phase was followed by a 2-week double-blind down-taper.
Treatment was generally well tolerated, although significantly more treatment-group patients (7.3%, 14.5%, and 6.7% for the 40-, 80-, and 120-mg groups) than placebo-group patients (1.7%) discontinued because of adverse events, the investigators noted.
The most common treatment-emergent adverse events were nausea, constipation, heart rate increase, and hyperhidrosis; most were mild or moderate in intensity.
The positive findings with respect to levomilnacipran SR reinforce its potential as an effective treatment option for adults with MDD, according to a statement from Forest Laboratories Inc., released earlier this year. The statement noted that the company anticipates filing a new drug application with the U.S. Food and Drug Administration in the third quarter of 2012.
This study was supported by Forest Laboratories and Pierre Fabre Medicament, the makers of levomilnacipran SR. Forest Research Institute, which employs both Dr. Blum and Dr. Gommoll, is the scientific division of Forest Laboratories.