Background

The efficacy of flibanserin in treating hypoactive sexual desire disorder (HSDD) is based upon statistically significant improvements in sexual desire, satisfying sexual events, and distress. However, clinically meaningful benefit has not been well characterized.

Aim

Evaluate clinically meaningful benefit of flibanserin.

Methods

Data were pooled from 3 pivotal trials evaluating flibanserin 100 mg qhs in premenopausal women (flibanserin, n = 1192; placebo, n = 1215). Flibanserin trial data in postmenopausal women (flibanserin, n = 450; placebo, n = 476) were analyzed separately. Clinically meaningful benefit was evaluated by the Patient Global Impression of Improvement (PGI-I). Responders were determined through anchor-based analyses that used the PGI-I for key efficacy endpoints: satisfying sexual events (SSE), desire domain of the Female Sexual Function Index (FSFI-d), and distress associated with decreased sexual desire (FSDS-R13). Odds ratios were calculated to assess effect size and Kaplan-Meier analyses were performed to estimate onset time for treatment benefit.

Outcomes

PGI-I, anchor-based analyses for key efficacy endpoints (SSE, FSFI-d, FSDS-R13), odds ratios, onset time for treatment benefit.

Results

Based on the PGI-I, more patients reported clinically meaningful benefit with flibanserin treatment versus placebo (49.8% vs 33.6%, premenopausal cohort; 40.5% vs 28.7%, postmenopausal cohort). In anchor-based analyses, responder rates were significantly higher for premenopausal women on flibanserin (46.1%–55.2%) than placebo (34.1%–44.2%) for all 3 key efficacy endpoints (P < .0001). Responder rates for postmenopausal women on flibanserin were higher compared to placebo for SSE (29.8% vs 22.9%;P = .015) and FSFI-d (38.9% vs 26.3%;P = .0001). Odds ratios for key endpoints indicated that premenopausal women were 2.0–2.4 times as likely to be responders with flibanserin treatment compared to placebo. Postmenopausal women were 1.6 times as likely to be responders with flibanserin for FSFI-d. Kaplan-Meier analyses indicated significant separation between flibanserin and placebo for the key endpoints in both premenopausal and postmenopausal cohorts (log-rank testsP < .01) with earlier median response times among patients receiving flibanserin.

Clinical Implications

Patient-reported benefit assessments such as the PGI-I capture the patient's perspective and may be a useful approach in assessing overall clinical meaningfulness for sexual dysfunction therapies.

Strengths and Limitations

Strengths include a well-powered study with large enrollment, use of validated instruments, and self-assessment of treatment benefit. Limitations include pooling of trial data in premenopausal women with slightly different study designs and use of an endpoint (SSE) indirectly related to HSDD.

Conclusion

Assessment of clinically meaningful benefit and additional responder analyses provide further support for flibanserin's efficacy beyond numerical improvements in endpoint measures.

Simon JA, Clayton AH, Kim NN, et al. Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin. Sex Med 2022;10:100476.

Key Words: hypoactive sexual desire disorder, flibanserin, clinically meaningful benefit, anchor-based analysis

Study Design and Participants

In this analysis, data were pooled from 3 similarly designed, 24-week, randomized, double-blind, placebo-controlled studies (VIOLET, DAISY, BEGONIA) of flibanserin in premenopausal women with HSDD.6,7,8 Data from a 24-week, double-blind, placebo-controlled study of flibanserin in naturally postmenopausal women with HSDD (SNOWDROP) were analyzed separately.¹⁰ Conduct of each of these studies was consistent with the principles of the Declaration of Helsinki (1996) and the International Conference on Harmonisation Good Clinical Practice Guidelines. All studies were approved by an institutional review board or independent ethics committee at each investigative site, and all participants provided written informed consent before the initiation of study procedures. Clinical trials were funded by Boehringer Ingelheim while post-hoc analyses were funded by Valeant Pharmaceuticals and Sprout Pharmaceuticals.

Study methodology and primary results for each study included in these analyses have been published elsewhere.6,7,8,9,10 Briefly, premenopausal or naturally postmenopausal women with a diagnosis of acquired, generalized HSDD, as determined by criteria in theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), for ≥24 weeks and in a stable, monogamous, heterosexual relationship for ≥1 year were randomly assigned to receive flibanserin (dose groups varied by study) or placebo for up to 24 weeks. Exclusion criteria included sexual dysfunctions other than acquired, generalized HSDD, dyspareunia (not caused by inadequate foreplay stimulation or alleviated by lubricants), arousal disorder, or orgasm disorder (only allowed if deemed to be lesser concern to the woman than HSDD); major depressive disorder within the previous 6 months; substance abuse in the past year; or any ongoing serious clinical disorder.

Measures of Efficacy

Key measures of efficacy were patient-reported outcomes and included changes from baseline to end of study at week 24 in the frequency of satisfying sexual events (SSEs), least square mean change from baseline for Female Sexual Function Index desire domain (FSFI-d) scores, and Female Sexual Distress Scale-Revised, Item 13 (FSDS-R13) scores. SSE frequency (a coprimary endpoint in the trials) were entered by patients in electronic diaries. The FSFI is a self-report measure consisting of 19 items across 6 domains (desire, arousal, lubrication, orgasm, satisfaction, pain).^28,29 The FSFI-d score is reported on an adjusted scale of 1.2 – 6.0 and was a coprimary endpoint in the most recent premenopausal study (BEGONIA) and the postmenopausal study (SNOWDROP), and a key secondary endpoint in the first two clinical trials (VIOLET and DAISY) in premenopausal women.6,7,8^,10 The FSDS-R (a key secondary endpoint in the flibanserin trials) is a 13-item self-report questionnaire that assesses sexually related personal distress, with higher scores indicating greater distress.³⁰ Item 13 of the FSDS-R asks how frequently the respondent is bothered by low sexual desire; the score ranges from 0 (never) to 4 (always).³⁰

The Patient Global Impression of Improvement (PGI-I) was included as a secondary endpoint in the flibanserin trials to capture women's self-report of clinically meaningful treatment benefit during the studies.³¹ The PGI-I consisted of a single question: “How is your condition [ie, decreased sexual desire and feeling bothered by it] today compared with when you started study medication?” Possible responses were: 1 = “very much improved”, 2 = “much improved”, 3 = “minimally improved”, 4 = “no change”, 5 = “minimally worse”, 6 = “much worse”, and 7 = “very much worse”. Patients reporting any kind of improvement (1, 2, or 3) were considered responders.

Data Analyses

The full dataset from the clinical trials was made available to the authors and data were analyzed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). For the studies of premenopausal women, individual patient data were pooled for flibanserin 100 mg qhs (the FDA-approved dose) or placebo. The flibanserin group included patients uptitrated from 50 mg qhs to 100 mg qhs at week 2, as well as those who received 100 mg qhs for the entire study (24 weeks). Patients randomly assigned to non-approved, subtherapeutic flibanserin doses (25 mg twice daily, 50 mg qhs) or doses associated with higher rates of adverse events due to morning dosing (50 mg twice daily) were excluded from this analysis. In the study of postmenopausal women, all patients were randomly assigned to receive placebo or flibanserin 100 mg qhs for the entire study (24 weeks) with no uptitration.

The treated set, primarily used for safety analyses, consisted of those patients who were randomized to a treatment group and received at least one dose of study medication. The full analysis set, used for efficacy analyses, consisted of those patients who were randomized to a treatment group, received at least one dose of trial medication, and had at least one on-treatment efficacy assessment. Sample sizes varied among measures of efficacy based on the number of patients with both baseline and post-dose assessments for a given endpoint. Missing data were handled by using the method of last observation carried forward (LOCF). In sensitivity analyses, alternative missing data imputation methods (ie, baseline observation carried forward and mixed model repeated measures) yielded differences between flibanserin and placebo treatment groups that were consistent with LOCF.

Based upon guidance from the US Food and Drug Administration (FDA), additional assessments of clinically meaningful benefit (beyond the PGI-I) were performed through anchor-based analyses³² in which PGI-I scores were used to determine threshold values for key measures of efficacy (Figure 1). Thus, assessments of efficacy outcomes were “anchored” to the global ratings of overall change reported in the PGI-I. These analyses were prespecified during the design of the flibanserin trials. Similar anchor-based analyses were performed post-hoc for the premenopausal cohort pooled from the 3 pivotal trials. For each efficacy endpoint (FSFI-d, SSE, FSDS-R13), the mean change-from-baseline to week 24 in patients with a PGI-I response of “minimally improved’ (score of 3) was used to calculate a threshold value. Threshold values in each trial are shown inTable 1. Women with efficacy measures at week 24 that met or exceeded these threshold values were considered to be responders. As shown inFigure 1, this analysis enabled the determination of the percentage of HSDD patients who were defined as responders for each endpoint. The percentage of responders for each of the three key endpoints among the pooled premenopausal women and the postmenopausal women were compared between treatment groups using the Cochran-Mantel-Haenszel test.

In post-hoc exploratory analyses, odds ratios³³ of being a responder were also calculated for each key efficacy endpoint to provide a quantitative estimate of the likelihood of flibanserin treatment resulting in clinically significant benefit. For each efficacy endpoint, odds ratios were calculated by dividing the odds of being a responder in the flibanserin group by the odds of being a responder in the placebo group. Associated 95% confidence intervals for each odds ratio were also calculated. In addition, Kaplan-Meier analyses with log-rank tests were used to evaluate the time to benefit for flibanserin 100 mg qhs compared with placebo.

Patient Demographics

The pooled premenopausal analysis cohort consisted of 2,407 patients; 1,192 were treated with flibanserin 100 mg qhs and 1,215 were treated with placebo (Figure 2). The postmenopausal analysis cohort consisted of 926 patients; 450 were treated with flibanserin 100 mg qhs and 476 were treated with placebo (Figure 2). Demographic characteristics and baseline scores were similar between the flibanserin and placebo groups except for duration of relationship, where postmenopausal women were in a relationship with the same partner for twice as long as premenopausal women (Table 2). Duration of HSDD was similar between cohorts and treatment groups, ranging from 4.5 – 5.1 years. Mean total FSFI scores at baseline ranged from 15.9 – 19.3 and mean FSFI-d scores ranged from 1.8 – 1.9. The average frequency of SSEs at baseline was 2.7 per month in premenopausal women and 2.0 per month in postmenopausal women, while the mean FSDS-R13 score was 3.3 for both premenopausal and postmenopausal women.

Responder Analyses

In premenopausal women, clinically meaningful benefit was reported by 49.8% of patients in the flibanserin group versus 33.6% of patients in the placebo group, based upon responses to the PGI-I (“minimally improved” or greater). The distribution of responses for each treatment group is shown inFigure 3A. Similarly, in postmenopausal women, clinically meaningful benefit was reported by 40.5% of patients in the flibanserin group versus 28.7% of patients in the placebo group (Figure 3B). In both premenopausal and postmenopausal cohorts, fewer patients in the flibanserin groups reported either “no change” or “worsening” compared to those in the placebo groups.

In anchor-based analyses of key efficacy endpoints, 46 – 55% of premenopausal women receiving flibanserin were responders, while 34 – 44% of those receiving placebo were responders (Figure 4A). In postmenopausal women, 30 – 54% in the flibanserin group were responders, while 23 – 48% in the placebo group were responders (Figure 4B). In both premenopausal and postmenopausal women, the percentage of responders for each efficacy endpoint (based on PGI-I anchor analysis) was greater after treatment with flibanserin compared to placebo. All comparisons between flibanserin and placebo in anchor-based analyses were statistically significant except FSDS-R Item 13 in postmenopausal women.

Another evaluation method of efficacy is the estimation of effect size through the calculation of odds ratios. Depending on the assessment endpoint, premenopausal women were 2.3 – 2.4 times more likely to be responders when treated with flibanserin compared to placebo (Table 3). These odds ratios were statistically significant, as noted by the lower confidence intervals that were all greater than 1.0. Postmenopausal women treated with flibanserin were 1.6 times more likely to be responders compared to placebo treatment when assessed by FSFI-d (sexual desire). Odds ratios for SSE or FSDS-R13 did not reach statistical significance in postmenopausal women.

When time to benefit was analyzed using Kaplan-Meier analyses, there was significant separation between flibanserin and placebo for each efficacy endpoint for both premenopausal and postmenopausal women, as indicated by the log rankP values (Figure 5). For premenopausal women, the median times to benefit for patients receiving flibanserin were consistently shorter than the median times for patients receiving placebo (Table 4). Similarly, postmenopausal women receiving flibanserin had shorter median times to benefit for SSE and FSFI-d when compared to those receiving placebo. While median times to benefit for FSDS-R13 were similar between treatment groups in postmenopausal women, the overall difference between the Kaplan-Meier curves was statistically significant, as noted by the log-rankP value (Figure 5).

Strengths and Limitations

The strengths of these analyses include a large dataset from multiple randomized, placebo-controlled studies (2,465 premenopausal women and 947 postmenopausal women). Further, two of the three endpoints that were examined are validated instruments (FSFI and FSDS). Lastly, the use of patient-reported benefit data in these analyses directly assesses clinical meaningfulness of flibanserin therapy and supports statistically significant improvements in clinical trial endpoints that have been reported previously.

Our study has several limitations. The studies of flibanserin in premenopausal women were similar in many respects but did differ in their inclusion criteria (less restrictive in the third study in premenopausal women⁸) and coprimary endpoints (changing from SSE plus sexual desire score measured using an electronic diary^6,7 to number of SSEs and the FSFI-d score⁸). Also, SSE, which was used as a primary endpoint based on FDA recommendations for studies of female sexual dysfunction,⁴² has come under criticism for its lack of relevance and validity in the assessment of HSDD.⁴³ In addition, anchor-based analyses using the PGI-I are not widely published for drug efficacy studies and represent only one of several ways in which treatment benefit may be defined. Lastly, the analysis of the data in postmenopausal women did not include a second 24 week, placebo-controlled trial (PLUMERIA)⁴⁴ because this trial was discontinued early by the sponsor (Boehringer Ingelheim) when less than half of the participants had completed week 16. Early discontinuation of this trial was not due to any safety concern and occurred after the sponsor ended the development program.

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