Abstract and Introduction
Abstract
Objective. The purpose of this study was to assess the 1-year maintenance of the efficacy of desvenlafaxine 100 mg/day (administered as desvenlafaxine succinate) established on week 12 in a 1-year, double-blind, randomized, placebo-controlled trial in postmenopausal women seeking treatment of bothersome vasomotor symptoms.
Methods. Primary efficacy endpoints were changes in hot flush (HF) frequency and severity on weeks 12, 26, and 52 in an efficacy substudy population (≥50 moderate and severe HFs per week at baseline). Secondary endpoints were Greene Climacteric Scale, Patient Global Impression Symptom Rating, and Patient Global Impression of Change scores (weeks 12, 26, and 52) for the main study efficacy population. Safety was assessed throughout the trial.
Results. The mean baseline HF frequency (efficacy substudy population, n = 365) was 12 moderate and severe HFs per day; the mean baseline severity score was 2.4. At 1 year, women treated with desvenlafaxine maintained the efficacy established on week 12. Desvenlafaxine reduced HF frequency by 7.47 moderate and severe HFs per day on week 12 (adjusted mean difference from placebo, −2.48; 95% CI, −3.47 to −1.50; P < 0.001) and by 7.70 moderate and severe HFs per day on month 12 (adjusted mean difference from placebo, −2.86; 95% CI, −4.14 to −1.57; P < 0.001). Desvenlafaxine reduced the mean severity score by 0.63 on week 12 (placebo, −0.30; P < 0.001) and by 0.75 on month 12 (placebo, −0.44; P = 0.003). Reductions in Greene Climacteric Scale total score (main study efficacy population, n = 1,950) were significantly greater for desvenlafaxine than for placebo on months 3, 6, and 12 (all P < 0.001). Treatment-emergent adverse event rates were 84% for desvenlafaxine and 79% for placebo (P = 0.006). Full safety results are reported separately.
Conclusions. The treatment efficacy of desvenlafaxine 100 mg/day achieved on week 12 in postmenopausal women with vasomotor symptoms is maintained for 1 year.
Introduction
Desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the US Food and Drug Administration for the treatment of major depressive disorder, is one of several nonhormonal agents with serotonergic and/or noradrenergic activity that has been assessed for efficacy in treating vasomotor symptoms (VMS) associated with menopause. Serotonin and norepinephrine pathways project to hypothalamic areas involved in temperature regulation, and in vivo studies in animal models have demonstrated that desvenlafaxine selectively increases hypothalamic levels of the two neurotransmitters.
Desvenlafaxine has been undergoing clinical development for the treatment of moderate to severe VMS associated with menopause. Administered at the lowest effective dose of 100 mg/day, desvenlafaxine significantly reduced the number of moderate and severe hot flushes (HFs) by approximately 60% to 65% per day at 12 weeks compared with approximately 50% for placebo in three prior published studies. Improvement in HF frequency was not significant for desvenlafaxine compared with placebo in a fourth trial. Reductions in the number of HFs with desvenlafaxine treatment were rapid in all studies, with median times to 50% reduction of 7 to 13 days compared with 24 to 28 days for placebo.
This article presents efficacy data from a year-long, multicenter, randomized, double-blind, placebo-controlled safety and efficacy trial of a large population of postmenopausal women with bothersome VMS. The safety data for this trial are published separately because a primary endpoint of the trial was to estimate the risk of ischemic cardiovascular (CV) events in postmenopausal women during longer-term treatment with desvenlafaxine 100 mg/day. The overall 12-month safety and efficacy study had a target enrollment of approximately 2,000 participants to allow for an estimation of the risk of ischemic CV events. Included in the study protocol was an efficacy substudy—which enrolled a subset of the participants who met the criterion of 50 or more moderate and severe HFs per week at baseline—designed to assess the clinical relevance of changes in the number and severity of HFs observed with desvenlafaxine treatment. Efficacy substudy participants provided HF data, in addition to completing assessments for the larger safety and efficacy trial. The 12-week efficacy results from the trial have been reported previously. These results showed that desvenlafaxine treatment in the modified-intent-to-treat (MITT) efficacy substudy population was associated with a rapid reduction in the number of HFs (median number of days to 50% reduction: desvenlafaxine, 13; placebo, 48). Both the number and the severity of HFs were significantly reduced with desvenlafaxine treatment compared with placebo as early as week 1. Desvenlafaxine reduced the number of moderate and severe HFs by 55% from baseline on week 4 and by 62% from baseline on week 12 compared with 31% and 38%, respectively, for placebo (both P < 0.001). Furthermore, the improvement associated with desvenlafaxine treatment was determined to be clinically meaningful to the study participants.
Efficacy data, including HF number and severity for efficacy substudy participants and self-administered questionnaires for main study participants (including the efficacy substudy participants), continued to be collected on months 6 and 12. The objective of this analysis was to assess the long-term maintenance of the efficacy of desvenlafaxine 100 mg/day on months 6 and 12 in both the efficacy substudy population and the main study population.