Continued Efficacy and Safety of Flibanserin in Premenopausal Women with Hypoactive Sexual Desire Disorder (HSDD): Results from a Randomized Withdrawal Trial

Abstract

Introduction Flibanserin is a 5-HT1A agonist/5-HT2A antagonist that has been shown to increase sexual desire and reduce distress in premenopausal women with Hypoactive Sexual Desire Disorder (HSDD). Aim To assess the efficacy and safety of flibanserin over 24 weeks of double-blind treatment vs. placebo in premenopausal women with HSDD who showed a predefined response after 24 weeks of open-label treatment with flibanserin. Methods Women (N = 738) were treated with open-label, flexible-dose flibanserin (50 mg or 100 mg/day) for 24 weeks. At week 24, women who showed a predefined response, measured using an eDiary, were randomized to 24 weeks of continued flibanserin therapy at optimized dosage (N = 163) or placebo (N = 170). The criteria for entering the double-blind phase were an increase from baseline to weeks 21–24 of ≥2 satisfying sexual events (SSE) and/or ≥4 “desire days.” A “desire day” was one in which a woman reported more than “no” desire. Main Outcome Measures Coprimary endpoints were change from randomization to study end in SSE and desire score. Secondary measures included change in Female Sexual Function Index (FSFI) total and desire domain scores and Female Sexual Distress Scale-Revised (FSDS-R) total and Item 13 scores. Results During the open-label period, mean SSE and desire score approximately doubled, and FSFI, FSDS-R total, and Item 13 scores improved. At the end of the double-blind period, flibanserin was superior to placebo in change from randomization in SSE, desire score, FSFI desire domain and total scores, and FSDS-R total and Item 13 scores (P < 0.05, for all). Flibanserin was well tolerated, and withdrawal reactions were not observed. Conclusion old> At the end of the 24-week randomized withdrawal phase of a 48-week trial in premenopausal women with HSDD, flibanserin was superior to placebo on measures of SSE, sexual desire, overall sexual function, and sexual distress. Flibanserin was well tolerated, and no withdrawal reactions were observed following discontinuation.

Statistical and Epistemological Issues in the Evaluation of Treatment Efficacy of Pharmaceutical, Psychological, and Combination Treatments for Women's Sexual Desire Difficulties

“…Gao et al (2015) restricted their sample to four published RCTs and reported a standardized mean difference in SSEs of .59. Jaspers et al (2016) replicated this effect using the same sample of published studies with an additional published study in which only women who showed improvement in an open-label phase were retained and randomized to treatment or placebo (Goldfischer et al, 2011 (2016) and Clayton and Pyke (2016) suggested that future research could focus on direct comparisons between pharmaceutical and psychological treatments, or combination treatments for low desire in women. At this critical juncture of the clinical science on treatment of women's sexual difficulties, we welcome the opportunity to directly compare pharmaceutical and psychological treatments for low sexual desire.…”

Flibanserin: First Global Approval

“…In ROSE [31], women who had responded to flibanserin during a 24-week open-label flexible-dose period continued to experience benefit with flibanserin at a stable optimized dosage in a subsequent 24-week double-blind, placebocontrolled period. At the end of this double-blind phase, flibanserin recipients had significantly (p \ 0.05) smaller reductions in monthly SSE number (mean change from randomization baseline of -1.4 vs. -2.3) and eDiary sexual desire score (mean change from randomization baseline of -4.9 vs. -8.2) than placebo recipients (coprimary endpoints).…”

“…Longer-term data for flibanserin in premenopausal women with HSDD are currently available from two studies, known as ROSE (NCT00277914) [31] and SUNFLOWER (NCT00441558) [32]. In ROSE [31], women who had responded to flibanserin during a 24-week open-label flexible-dose period continued to experience benefit with flibanserin at a stable optimized dosage in a subsequent 24-week double-blind, placebocontrolled period.…”

“…The drug was also associated with smaller (p \ 0.05) increases in sexual dysfunction-related distress (FSDS-R total score and item 13 score) and smaller (p \ 0.01) declines in sexual desire (FSFI desire domain score) and sexual function (FSFI total score) than placebo. Of the 738 women in the open-label period (flibanserin 50 mg once daily at bedtime for 4 weeks then, if needed, titrated to 100 mg once daily at bedtime or 50 mg twice daily over the next 12 weeks), 333 achieved a prespecified response and were subsequently randomized to receive double-blind therapy [31].…”

Flibanserin

“…How long will the positive results be maintained? When 738 positive responders at the end of the pivotal trials were randomized to placebo or flibanserin and continued foranadditional24 weeks,theflibanseringroupwassuperior on all measures (Goldfischer et al, 2011). In a separate open label 52-week study of 962 women, 42 % of the nonremitters remitted and 90 % of remitters maintained their improved status (Jayne, Simon, Taylor, Kimura, & Lesko, 2012).…”