Abstract Introduction Female sexual arousal disorder (FSAD) is a persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement that causes marked distress or interpersonal difficulty. The biologic mechanisms leading to FSAD are similar to male erectile dysfunction. Objective To test the preliminary efficacy of topical Sildenafil Cream, 3.6% among women with FSAD in a randomized, placebo-controlled, double-blind, exploratory Phase 2b study. To describe, using validated 28-day recall instruments, changes in sexual function with treatment, and to validate exploratory sexual function questionnaires in a placebo-controlled trial. Methods Healthy pre-menopausal women, aged 18-years or older and their sexual partners, if applicable, were screened and provided written informed consent. An individual clinical interview with each volunteer was conducted in order to establish that FSAD was present and was the primary sexual dysfunction concern. Women at risk of pregnancy used effective contraception during the study. Women or their partners were excluded if they had un-controlled hypertension, a history of serious cardiac events (e.g. myocardial infarction, stroke), orthostatic hypotension or other serious medical co-morbidities. The co-primary efficacy endpoints were measured by the arousal sensation domain of the sexual function questionnaire (SFQ28) and question 14 of the female sexual distress scale (FSDS). After a one-month, no drug, run-in period, and a one-month, single-blind placebo, run-in period, 200 eligible women were randomized to receive Sildenafil Cream, 3.6% (n=101) versus placebo cream (n=99). Participants applied 2 grams of the investigational product to the clitoris, vestibule, labia minora and anterior distal vagina 10 – 20 minutes prior to each partnered or un-partnered sexual experience. During the 12-week, double-blind treatment period, participants were seen monthly and completed validated, 28-day recall questionnaires. Efficacy was also measured by a 12-question Arousal Diary (AD), completed within 24 hours of each sexual experience. Results Volunteers (n=833) underwent informed consent in this ethics board (Advarra Pro 00049161) and U.S. Food and Drug Administration approved study (IND 119922), registered at ClinicalTrials.gov (#NCT04948151). There were 1131 Sildenafil and 951 placebo exposed sexual experiences recorded in the AD during the double-blind treatment period. Sildenafil Cream, 3.6% treated women had a higher proportion of satisfactory sexual events than placebo users. At 12-weeks of use, there was improvement in the co-primary endpoint of arousal sensation consistent with how women reported meaningful improvement in an exit interview at the end of the study, although this did not achieve statistical significance. Sildenafil Cream, 3.6% treated women showed improvements in pre-specified exploratory endpoints that evaluated various aspects of the sexual experience including desire (p=0.02), arousal lubrication (p = 0.059) and orgasm (p=0.066) after 8 weeks of product use. Conclusions Data from this exploratory, placebo-controlled study of topical Sildenafil Cream, 3.6% for the treatment of FSAD in healthy premenopausal women support further clinical development of this first potential treatment for FSAD. Disclosure Yes, this is sponsored by industry/sponsor: Dare Bioscience and Strategic Sciences and Technologies (SST), LLC. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dare Bioscience and SST LLC.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction associated with personal distress in women, and is characterized by an absence or deficiency of sexual desire accompanied by distress. HSDD affects approximately 10% of women, with a similar prevalence regardless of age. Bremelanotide, a melanocortin receptor agonist and an analog of the endogenous neuropeptide α-melanocortin stimulating hormone, has been approved for the treatment of acquired, generalized HSDD in premenopausal women. The RECONNECT studies, which comprised two double-blind, randomized, placebo-controlled studies, demonstrated that subcutaneous self-administration of bremelanotide significantly improved sexual desire and decreased personal distress in premenopausal women with HSDD. To investigate the efficacy of bremelanotide across hormonal contraceptive subgroups in the RECONNECT studies. Patients self-administered bremelanotide 1.75 mg or placebo subcutaneously for 24 weeks, using an autoinjector pen as needed prior to sexual activity. Patients were evaluated (“yes” and “no” subgroups) based on concurrent use of hormonal contraceptives (including oral contraceptives and other estrogen-containing products). Efficacy was assessed using RECONNECT co-primary endpoints: change from baseline to end-of-study (EOS) for Female Sexual Function Index–desire domain (FSFI-D) and Female Sexual Distress Scale–Desire/Arousal/Orgasm (FSDS-DAO) Item 13 scores.

Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction in women, and is marked by persistently diminished or absent desire for sexual activity accompanied by personal distress. In the United States, HSDD affects approximately 10% of women aged 18 to 44 years. Bremelanotide, a melanocortin receptor agonist and an analog of the endogenous neuropeptide α-melanocortin stimulating hormone, is approved for the treatment of acquired, generalized HSDD in premenopausal women. The RECONNECT studies (Studies 301 and 302), two identically designed, double-blind, randomized, placebo-controlled trials, demonstrated that subcutaneous self-administration of bremelanotide, as needed, significantly improved sexual desire and decreased personal distress in premenopausal women with HSDD. Effect size is important to consider, as it indicates the magnitude of change as a result of the intervention under review.

In three pivotal, North American, randomized, placebo-controlled trials assessing the efficacy of flibanserin in premenopausal women with HSDD, 43–51% of patients responded to treatment with significantly increased sexual desire and 50–60% of patients responded with significantly decreased distress associated with sexual dysfunction. The prescribing information for flibanserin states that it may take up to 8 weeks for efficacy to emerge. However, earliest onset of response regarding overall sexual function has not been fully characterized.

Bremelanotide, a melanocortin-4-receptor agonist and an analog of the endogenous neuropeptide α-melanocyte stimulating hormone, is an investigational new drug that is currently being studied in premenopausal women diagnosed with hypoactive sexual desire disorder (HSDD). Clinical studies indicate that bremelanotide has greater efficacy in improving sexual desire and decreasing personal distress than placebo in premenopausal women with HSDD. The aim of this analysis was to determine whether bremelanotide demonstrated a treatment benefit in women with HSDD regardless of baseline FSFI total scores. The population (N=1202) in this analysis consisted of premenopausal women from two phase 3 studies (RECONNECT) who were divided into subgroups according to female sexual function index (FSFI) total score (sum of multiple domains) at screening. For inclusion in the studies, participants needed either FSFI total score ≤26 (if diagnosed with HSDD with/without symptoms of decreased arousal) or FSFI desire domain (FSFI-D) score of ≤5 (if diagnosed with HSDD without decreased arousal) regardless of total FSFI score. The FSFI-D and female sexual distress scale – desire arousal orgasm (FSDS-DAO) Item 13 were patient-reported outcomes (PROs) that served as co-primary endpoints of RECONNECT.

Journal Article 020 Bioidentical Combined Estradiol and Progesterone Capsules Improved Vaginal Dryness in Women with Vasomotor Symptoms Get access J. Simon, J. Simon George Washington University School of Medicine IntimMedicine Specialists Search for other works by this author on: Oxford Academic Google Scholar S. Parish, S. Parish Weill Cornell Medical College Search for other works by this author on: Oxford Academic Google Scholar B. Bernick, B. Bernick TherapeuticsMD Search for other works by this author on: Oxford Academic Google Scholar S. Graham, S. Graham TherapeuticsMD Search for other works by this author on: Oxford Academic Google Scholar S. Mirkin S. Mirkin TherapeuticMD Search for other works by this author on: Oxford Academic Google Scholar The Journal of Sexual Medicine, Volume 16, Issue Supplement_3, June 2019, Pages S9–S10, https://doi.org/10.1016/j.jsxm.2019.03.477 Published: 01 June 2019

Combined hormonal contraceptives (CHCs) may impact sexual function, in part due to interaction of the progestin component with the androgen receptor (AR). Previous reports on the effect of hormonal contraceptives on libido have been mixed, some showing decreases and others showing increases in libido. Annovera™, a 1-year contraceptive vaginal system (CVS) releasing 150 mcg segesterone acetate (SA) and 13 mcg ethinyl estradiol (EE) per day, was recently approved by the US Food and Drug Administration (August 2018). To review evidence from preclinical studies investigating the androgenicity of the SA component of the CVS, and data on its effects on sexual function or activity in women. We reviewed articles on studies that measured markers of androgenicity of SA and those that examined sexual function/activity in those using SA/EE CVS. Some aspects of sexual function and activity were assessed via a questionnaire completed by participants in an international phase 3, open-label, multi-center, 13-cycle trial evaluating the efficacy and safety of the SA/EE CVS.1,2 Participants completed the questionnaire at cycle 3 of CVS use and/or at study end; cycle 3 was used if end of study was not completed.

Female Sexual Dysfunction and the Genitourinary Syndrome of Menopause are highly prevalent after menopause leading to significant physical and emotional pain. Evidence suggests that both of these conditions are under-recognized and inadequately treated. Little is known about current levels of multidisciplinary healthcare professional (HCP) knowledge and applied clinical competence and confidence when managing these conditions. Since certain formats of CME education can improve the application of evidence-based medicine an online curriculum was designed to better understand current knowledge levels and to increase HCP knowledge and clinical competencies across diagnosis and treatment of GSM and FSD. To address widespread knowledge and treatment gaps in the management of GSM, VVA, FSD and dyspareunia a two-part online CME curriculum entitled Menopause and Sexual Health: An Update on Dyspareunia and Female Sexual Dysfunction was developed based on a needs assessment survey that included literature reviews and practitioner interviews. Data from a two-part curriculum was analyzed to evaluate learning across condition-specific learning objectives and general learning domains (knowledge, clinical competence, clinical confidence) using matched pre-and post-test questions and the RealIndex™ a measure of applied knowledge change across multiple curriculum activities.

Flibanserin is approved for the treatment of HSDD in premenopausal women. In a previous alcohol-interaction study where alcohol was co-administered with flibanserin, an increased incidence of hypotension and syncope was observed. This study was designed to evaluate the impact of the timing of alcohol consumption on the safety and tolerability of flibanserin in healthy premenopausal women. This was a single-center, randomized, placebo-controlled, double-blind, 4-treatment crossover study (N=64). Subjects (mean age: 32.5 ± 8.7) were randomized to either flibanserin 100mg or placebo in each of 2 Treatment Periods. On days 1-3 of each Treatment Period, subjects received daily doses of study drug to achieve a steady state. Following a standardized breakfast on days 4-10, subjects consumed either 0.4g/kg of alcohol administered with orange juice or orange juice alone 2, 4, or 6 hours prior to taking study drug at 1pm. Vital signs were subsequently monitored up to 10 hours. The primary endpoint was the proportion of subjects experiencing syncope or orthostatic hypotension-associated adverse events requiring medical intervention. Secondary endpoints included the proportion of subjects with hypotension (systolic bp < 90mmHg and/or diastolic bp < 60mmHg), symptoms of dizziness, lightheadedness, or faintness that resulted in no standing blood pressure, and the rates of syncope, orthostatic hypotension, dizziness, and somnolence.

Hypoactive sexual desire disorder (HSDD) is the most prevalent form of female sexual dysfunction in the United States, and is characterized by a decrease or lack of sexual desire accompanied by distress. Bremelanotide, a melanocortin-4-receptor (MC4R) agonist and an analog of the endogenous neuropeptide α-melanocyte stimulating hormone, is an investigational drug that is currently being evaluated in premenopausal women with HSDD. The RECONNECT studies, which comprised two replicate, phase 3 clinical trials, demonstrated that subcutaneous self-administration of bremelanotide significantly improved sexual desire and decreased personal distress in premenopausal women with HSDD. To assess the efficacy of bremelanotide across baseline free testosterone level quartile subgroups. The RECONNECT studies comprised two replicate studies with a 24-week, randomized, double-blind, placebo-controlled core study phase and an optional 52-week open-label safety extension phase. Participants self-administered bremelanotide 1.75 mg or placebo subcutaneously using an autoinjector, on demand, prior to sexual activity. A total of 1202 subjects were included in the integrated and subgroup analyses. Subjects were divided into subgroups according to free (bioavailable) testosterone level at screening. Free testosterone levels were calculated using baseline total testosterone, sex hormone-binding globulin (SHBG), and albumin levels. For the subgroup analysis, subjects with total testosterone levels >96 ng/dL or SHBG levels >170 nmol/L at screening were excluded, as those were above the normal physiological range. Efficacy was assessed using the co-primary endpoints of change from baseline to the end-of-study (EOS) for the Female Sexual Function Index-Desire domain (FSFI-D) and the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) Item 13 scores.

Prior to the approval of flibanserin, concerns were raised about an increased risk of severe hypotension and syncope when co-administered with alcohol. To further examine the severity of this pharmacodynamic interaction in a population of premenopausal women, three post-marketing alcohol interaction studies have been conducted. The findings from the third study are discussed here and provide additional insight into the significance of this interaction in a simulated real-world setting. This study was designed to evaluate the effect of the timing of ethanol consumption during an evening meal on the safety and tolerability of steady state flibanserin taken at bedtime as indicated. This was a single center, randomized, placebo-controlled, double-blind, 4-treatment crossover study in premenopausal subjects (N=24). Subjects (mean age: 34.5 ± 9.9) were randomized to flibanserin 100 mg or placebo, using a 1:1 ratio, in the first of two Treatment Periods and to the alternative therapy in the second Treatment Period. A washout period of at least 5 days separated treatment periods. On days 1-3 of each Treatment Period, subjects received bedtime doses of study drug at home in order to achieve steady state. On days 4 and 6, subjects consumed up to 2 units of wine (one unit consisted of 5 fluid ounces of 12% alcohol wine) or a matching non-alcoholic beverage with supper (served from 18:30-20:00). Vital signs were taken prior to supper and study drug administration, as well as upon awakening the next morning. Overnight, subjects were closely supervised, and blood pressure readings were obtained if a subject experienced any clinical symptoms of low blood pressure upon awakening during the night. The primary endpoint was the proportion of subjects experiencing syncope or orthostatic hypotension-associated adverse events requiring medical intervention. Secondary endpoints included the proportion of subjects with hypotension (systolic pressure < 90mmHg and/or diastolic < 60mmHg); symptoms of dizziness, lightheadedness, or faintness that resulted in no standing blood pressure; and the rates of adverse events of special interest (AESI): syncope, orthostatic hypotension, dizziness, and somnolence.

Introduction: Flibanserin is approved in the United States and Canada for the treatment of hypoactive sexual desire disorder in premenopausal women. Aim: The purpose of this trial was to evaluate the safety of concomitant administration of flibanserin with alcohol. Methods: In this single-center, randomized, double-blind, single-dose, crossover study, participants were randomly assigned to 1 of 12 sequences to receive each of 7 treatments: flibanserin 100 mg or placebo with ethanol 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg, or flibanserin 100 mg only. Treatments were administered using a worst-case approach that included morning dosing and consumption of alcohol within 10 minutes. Main Outcome Measure: The primary end point was the proportion of participants who experienced dizziness, syncope, or hypotension. Safety end points included orthostatic vital signs. Results: The study included 96 premenopausal women (mean age 31 +/- 8 years). The incidence of dizziness for ethanol + flibanserin was 39.8% for ethanol 0.6 g/kg, 34.1% for 0.4 g/kg, and 27.4% for 0.2 g/kg compared with 31.1% for flibanserin without ethanol. Based on the available vital signs data, there was no effect of ethanol concentration on orthostatic blood pressure, vertigo, or hypotension; no instances of syncope were observed. The overall incidence of adverse events (AEs) was similar when flibanserin was administered alone (96.7%) or with ethanol (90.5-97.6%). Clinical Implications: Consumption of the tested amounts of alcohol (0.2-0.6 g/kg) does not have an additive effect on the AE profile of flibanserin 100 mg in healthy premenopausal women. Strengths & Limitations: Strengths include the study population (premenopausal women, as indicated for flibanserin) and range of ethanol doses. Limitations include the morning dosing of study medication, which is inconsistent with the bedtime dosing recommended for flibanserin, and the method of handling missing vital sign measurements. Conclusion: Co-administration of flibanserin 100 mg with varying doses of ethanol resulted in few AEs of special interest, with no notable alcohol dose response. However, a significantly greater percentage of participants administered flibanserin with 0.6 g/kg and 0.4 g/kg of alcohol were characterized as "Participants in Whom Standing Blood Pressure Was Not Obtained" compared with participants administered flibanserin alone. Copyright (C) 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Women engage in sexual relations despite the absence of personal sexual interest. Such sexual activity has been termed: duty sex, obligatory sex, mercy sex, etc. Medical treatments (testosterone [Intrinsa®; Libigel®], flibanserin [Addyi®], bremelanotide [RekyndaTM], lasofoxifene [Fablyn®)]) for hypoactive sexual desire disorder (HSDD; DSM-IV-TR) have investigated thousands of women. Women enrolled in HSDD trials continue to have sexual relations with their partners despite their absence of desire. We have previously reported that the “normal” frequency of sexual activity (without interest), aka “mercy sex” in these trials (a worldwide convenience sample) is 2.57 times/28 days. (n=4483). Here we examine the differences in “mercy sex” frequency among 13 European countries (AUS=Austria, BEL=Belgium, CZE=Czech Republic, DEU=Germany, ESP=Spain, FIN=Finland, FRA=France, GBR=Great Britain, HUN=Hungary, ITA=Italy, NLD=Netherlands, NOR=Norway, SWE=Sweden) to assess the impact, if any, of geographical and cultural diversity. We analyzed baseline sexual activity data from the Orchid Trial (511.77; NCT00491829), a 24 week, randomized, double-blind, placebo controlled, trial of flibanserin in premenopausal European women with HSDD conducted between June 2007 and March 2009 at 86 clinical trial sites in 13 European countries. All subjects used contraception. The baseline frequency of sexual activity without interest, aka “mercy sex” in these trial participants was compared by country with the norms established above.

Addyi (flibanserin 100mg), is an orally administered, centrally-acting treatment for hypoactive sexual desire disorder in premenopausal women. Alcohol use is contraindicated due to Phase I study data suggesting increased risk of hypotension and syncope. Because the design of that alcohol challenge study [i.e., morning dosing of Addyi with high doses of ethanol (0.4–0.8 g/kg) consumed within 10 min] is inconsistent with prescribed dosing (q.h.s) and quantity of alcohol consumed in the general population, we assessed the effects of low-moderate alcohol use in premenopausal women taking Addyi as prescribed. Premenopausal women providing informed consent (n=24; mean age=38±6 y; mean BMI=24±3 kg/m2) consumed 1-2 glasses (125-250ml) of sulfite-free wine (12.5% ethanol) with a standardized 3-course dinner in a clinical research unit. Addyi was administered with 240 ml of water 5 min before bedtime (2.5 h after dinner). Subjects were awakened 8 h after dosing. Vital signs were assessed before and after dinner, and upon waking the next morning. Primary endpoints were the incidence and severity of adverse events (AEs) and changes in vital signs. Secondary endpoints were self-reported feeling of well-being and self-reported quality of sleep.

Bremelanotide (BMT) is a melanocortin receptor 4 agonist that is being investigated as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women. Clinical studies indicate that BMT has greater efficacy than placebo for treatment of HSDD. The objective of this integrated analysis was to investigate BMT efficacy vs placebo for subjects according to pre-specified patient reported outcome (PRO) definitions of HSDD at baseline. The total integrated population (N=1341) consisted of premenopausal women from two phase 3 studies (RECONNECT) and one phase 2 study who were divided into subgroups according to FSFI total score (sum of multiple domains) at screening. The FSFI desire domain (FSFI-D) and FSDS-DAO distress resulting from low desire (Item 13) were PROs that served as co-primary endpoints of the phase 3 studies. For subjects belonging to the lowest quartile (Q1) of baseline FSFI total scores (<16.5), the mean (SD) changes in FSFI-D from baseline for the BMT- and placebo-treated groups were 0.64 (1.13) and 0.31 (0.96), respectively. For baseline FSFI total score quartiles 2 (Q2: 16.5-20.49), 3 (Q3: 20.5-25.49), and 4 (Q4: ≥25.5), mean changes in FSFI-D for BMT vs placebo were 0.64 (0.96) vs 0.19 (0.96), 0.54 (1.11) vs 0.12 (0.99), and 0.57 (0.77) vs 0.46 (1.02), respectively. In the total integrated population, the respective mean (SD) changes in FSFI-D from baseline for the BMT and placebo arms were 0.62 (1.07) and 0.24 (0.97). For analysis of FSDS-DAO Item 13, quartiles 1-3 demonstrated mean changes (SD) from baseline for BMT vs placebo of -0.8 (1.19) vs -0.4 (1.10), -0.7 (1.17) vs -0.4 (1.06), and -0.7 (1.11) vs -0.4 (1.09), respectively. There was no difference in mean change [SD] between the BMT (-0.6 [1.14]) and placebo (-0.6 [1.06]) groups among subjects in Q4. In the total integrated population, the respective mean (SD) changes in FSDS-DAO Item 13 for the BMT and placebo arms were -0.7 (1.17) and -0.4 (1.08). For both endpoints, the estimated differences between treatment groups were confirmed as statistically significant (p<0.01) for Q1, Q2, and Q3, but not Q4. No clinically significant differences in SSE mean change from baseline were observed in any quartile of FSFI total score at screening.

To evaluate the efficacy of BMT as a treatment for HSDD in premenopausal women. The RECONNECT study comprises two Phase 3, multicenter trials (301, 302) consisting of a 4-week screening period; a Core Phase (4-week at-home placebo period with a 24-week randomized, double-blind treatment period). Participants self-administered BMT (1.75 mg) or placebo subcutaneously using an auto-injector, as-desired, prior to sexual activity. The co-primary-endpoints were change in the Female Sexual Function Index Desire Domain (FSFI-D) and Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) Item 13 scores. The responder analysis was based on self-assessed benefit (ie, score ≥5 on a 7-point Likert scale in response to the question “To what degree do you think you benefited from taking the study drug?”), and estimates of minimal clinically important differences (MCID) for each co-primary endpoint. 1202 women comprise the efficacy population, 856 of whom completed the double-blind phase. Participants were mean age 39 years; mean BMI 28.7 kg/m2; and about 84% were white. The most frequent diagnosis was HSDD with decreased arousal, and the mean time since diagnosis was ≥45 months. Both studies met the pre-specified co-primary efficacy endpoints. The most common reasons for not completing the double-blind phase were AEs (∼10% in both studies) and withdrawal of consent (∼9% in Study 301; 12% in Study 302). Women using BMT had significantly increased scores on the FSFI-D (Study 301: mean change 0.69 vs 0.24; P<0.0001; Study 302: 0.80 vs 0.16; P<0.0001). Scores for FSDS-DAO Item 13 showed a significant reduction in distress related to low desire for women using BMT (Study 301: Mean change -0.91 vs -0.34; P<0.0001; Study 302: -0.86 vs -0.38; P=0.0007). Responder Analyses: 59% of participants in Study 301 and 58% in Study 302 had a self-assessed benefit score ≥5. The computed MCIDs were a median value of 0.6 for baseline to endpoint changes in FSFI-D subscale scores and a median 1.0-point improvement on FSDS-DAO Item 13. Significant proportions of women met the MCID thresholds for both co-primary endpoints in both studies: FSFI-D: Study 301; P=0.0002; Study 302; P<0.0001; FSDS-DAO Item 13 (Study 301; P<0.0001; Study 302; P=0.0419).

To evaluate the Patient Global Impression of Improvement (PGI-I) to measure the clinical relevance of the magnitude of effect seen in the key efficacy endpoints in the Phase 3 pivotal flibanserin trials. Patient reported outcomes (PROs) were used to capture the key efficacy endpoints in flibanserin’s pivotal trials. Sexually Satisfying Events (SSEs) were captured using an electronic diary, sexual desire was measured using two methods, the desire domain of the Female Sexual Function Index (FSFI-D) and an electronic eDiary Desire and sexual distress was measured using the Female Sexual Distress Scale Revised (FSDS-R), item 13. The PGI-I was used as a clinical anchor to define responders for each of these endpoints. A responder was defined as a patient with a change from baseline in the endpoint value that was greater than the response threshold defined by the difference between “minimally improved” (score of 3) and “no change” (score of 4) on the PGI-I. Similar methodology was used to define responders for FSFI-D and FSDS-R13.