Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of Bremelanotide.

Background: Hypoactive sexual desire disorder (HSDD), the most prevalent female sexual dysfunction, is characterized as persistent diminished desire for sexual activity accompanied by distress. The efficacy and safety of bremelanotide, a melanocortin receptor agonist approved by the U.S. Food and Drug Administration for treatment of acquired generalized HSDD in premenopausal women, were established in the phase 3 RECONNECT studies, two identically designed double-blind randomized placebo-controlled studies with an optional 52-week open-label extension. This report investigates efficacy of bremelanotide versus placebo according to prespecified subgroups (age, weight, body mass index [BMI], and bioavailable testosterone) in the RECONNECT studies. Materials and Methods: Patients self-administered bremelanotide 1.75 mg or placebo subcutaneously using an autoinjector, as needed, before sexual activity for 24 weeks. Efficacy was assessed using change from baseline to end-of-study for Female Sexual Function Index desire domain and Female Sexual Distress Scale-Desire/Arousal/Orgasm Item 13 for bremelanotide versus placebo. Results: Among 1202 patients included in the integrated and subgroup analyses, bremelanotide achieved statistically significant improvements in measures of increased desire and decreased distress associated with low desire across all age, weight, and BMI subgroups, and all baseline bioavailable testosterone quartiles, with few exceptions. Bremelanotide was further associated with statistically significant increases in reported sexual desire (p < 0.05) in patients not taking hormonal contraceptives, and with a numerical advantage in those taking hormonal contraceptives. Patients treated with bremelanotide experienced decreased distress compared with those in the placebo group at levels of statistical significance (p < 0.05) regardless of hormonal contraceptive use. Statistically significant improvements were observed in the presence or absence of decreased arousal, and regardless of HSDD duration. Conclusions: Bremelanotide was associated with statistically significant improvements in sexual desire and reduced distress across several prespecified subgroups, with few exceptions.

Safety Profile of Bremelanotide Across the Clinical Development Program.

Background: Bremelanotide, a melanocortin receptor agonist, is Food and Drug Administration (FDA)-approved for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Methods: Review of bremelanotide's safety profile from the clinical development program (phases 1 through 3). Results: The clinical development program comprised 3500 subjects in 43 completed studies. In the phase 3 studies, subjects took bremelanotide for up to 18 months. The most common adverse events (AEs) were nausea (40.0% vs. 1.3%), flushing (20.3% vs. 1.3%), headache (11.3% vs. 1.9%), and injection site reactions (5.4 vs. 0.5), bremelanotide versus placebo groups, respectively, in the integrated double-blind portion of the phase 3 studies (N = 1247). Nausea was the most common reason for bremelanotide discontinuation. There were no deaths; a few subjects experienced serious AEs. Focal hyperpigmentation was rare when bremelanotide was dosed in accordance with label recommendations, but it occurred in more than one-third of subjects following up to 16 consecutive daily dosings. Small and transient but statistically significant blood pressure increases were observed during ambulatory blood pressure monitoring. Most drug-drug interactions were not clinically significant, except for interactions that lowered plasma concentrations of indomethacin and naltrexone. In the double-blind portion of the integrated phase 3 studies, 70% of the bremelanotide group proceeded to the open-label phase of the studies versus 87% of those on placebo. Conclusions: The AEs associated with bremelanotide are mostly mild to moderate. Although not deemed clinically important, bremelanotide should be used with caution in patients at risk of cardiovascular disease, and blood pressure should be well controlled during treatment. Clinical Trial Registration number: NCT02333071 [Study 301] and NCT02338960 [Study 302].

Psychometric validation of the Female Sexual Distress Scale-Desire/Arousal/Orgasm.

BACKGROUND: For the treatment of female sexual dysfunction, the most relevant outcome measures are patient-reported treatment effects and changes in symptoms, underscoring the need for reliable, validated patient-reported outcome (PRO) instruments. The aim of this study was to evaluate the psychometric characteristics (validity and reliability) of the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) PRO measure, which was adapted from the validated FSDS-Revised (FSDS-R) questionnaire and added 2 questions involving arousal and orgasm. METHODS: Psychometric analyses were based on the data from a multicenter phase 2b dose-finding study that compared the safety and efficacy of bremelanotide versus placebo and were conducted in the evaluable modified intent-to-treat population (N = 325) from that study. Psychometric evaluation of the new items in the FSDS-DAO included confirmatory factor analyses, tests of internal consistency and test-retest reliability, examinations of convergent and discriminant validity, and determination of responsiveness. The validity of the FSDS-DAO was evaluated based on previously developed instruments, including the Female Sexual Function Index (FSFI), General Assessment Questionnaire (GAQ), Women's Inventory of Treatment Satisfaction (WITS-9), and Female Sexual Encounter Profile-Revised (FSEP-R). RESULTS: Confirmatory factor analyses demonstrated that the FSDS-DAO items fit very well (Bentler's comparative fit index of 0.929). Cronbach's α for the FSDS-DAO total score was ≥ 0.91 at Visits 1, 2, 5, and 12, demonstrating adequate internal consistency reliability. Test-retest reliability was acceptable with an intra-class coefficient of 0.61 and a Spearman's correlation coefficient score of 0.62 between Visits 1 and 2 (4 weeks). Acceptable construct validity was demonstrated by significant correlations with related PRO scales in the expected directions and magnitude. For example, participants reporting the worst levels of sexual function on the FSFI also showed the worst FSDS-DAO scores at Visits 5 and 12. The FSDS-DAO total score was responsive to change. CONCLUSIONS: Evidence supports the validity and reliability of the FSDS-DAO for assessing sexually related distress in women with female sexual arousal disorder and/or hypoactive sexual desire disorder; the addition of the arousal and orgasm items did not impact the validity and reliability of the measure. Clinical Trial Registration ClinicalTrials.gov NCT01382719.

The Patient Experience of Premenopausal Women Treated with Bremelanotide for Hypoactive Sexual Desire Disorder: RECONNECT Exit Study Results.

Background: Hypoactive sexual desire disorder (HSDD) has a significant negative impact on women's overall health and relationships with their partners. Primary analyses from the RECONNECT clinical trials demonstrated statistically significant and clinically meaningful improvements in sexual desire and related distress with bremelanotide relative to placebo in premenopausal women with HSDD. Exit surveys and patient interviews were conducted to evaluate the impact of HSDD and bremelanotide treatment from the patient's perspective. Materials and Methods: Upon completion of the double-blind study but before participation in the open-label extension, up to 250 participants were recruited to complete the quantitative exit survey (17 questions). A subset of up to 90 patients was invited to participate in the telephone interview (17 questions). Patients who volunteered to participate remained blinded to study drug until the survey and interviews were completed. Results: Quantitative exit surveys were completed by 242 RECONNECT participants; 80 of these women also completed qualitative telephone exit interviews. Participants who received bremelanotide described increased feelings of sexual desire, physical arousal, and improvements in overall quality of their sexual activities in their partner relationship. In comparison, women taking placebo reported benefits that did not include the physiological responses described by women receiving bremelanotide, such as positive experiences of seeking HSDD treatment and improved communication with their partner. Conclusions: Exit surveys and patient interviews support the primary findings from RECONNECT and provide quantitative and qualitative assessments of the impact of HSDD on patients' quality of life and the patients' perspectives on the impact of bremelanotide. Clinical trial numbers NCT02333071, NCT02338960.

Reliability and validity of the elements of desire questionnaire in premenopausal women with hypoactive sexual desire disorder.

BACKGROUND: The Elements of Desire Questionnaire (EDQ) is a patient-reported outcome (PRO) measure developed to evaluate sexual desire and was included in two identically designed phase 3 clinical trials (RECONNECT) as an exploratory endpoint. The EDQ was developed based on a literature review, qualitative research with patients with hypoactive sexual desire disorder (HSDD), and input from clinical experts. This instrument is intended to be used to collect efficacy data in clinical trials evaluating potential treatments for HSDD. The objective of this study was to evaluate the measurement properties of both the monthly and daily recall versions of the EDQ during the RECONNECT trials. METHODS: Participants completed the EDQ daily version for 7 consecutive days prior to selected monthly clinic visits. The monthly recall version was completed at each monthly clinic visit. The analysis population consisted of all subjects with Female Sexual Function Index (FSFI) data at baseline and ≥ 1 follow-up visit. RESULTS: At baseline, 1144 and 676 subjects completed the monthly and daily recall EDQs, respectively. The EDQ scores had good internal consistency and test-retest reliability. Monthly and daily recall EDQ scores were correlated with FSFI-desire domain scores at baseline and month 3. Scores from the monthly and daily recall versions were also correlated. After 6 months, there was a significantly greater improvement for bremelanotide versus placebo in both the monthly and daily recall versions (both P < 0.0001). CONCLUSIONS: The results demonstrated that EDQ exhibited good reliability, validity, and sensitivity to change. Consistent with other validated PRO measures of sexual desire, the EDQ provides additional insights into sexual desire. TRIAL REGISTRATION: NCT02338960 and NCT02333071 (RECONNECT studies).

Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials.

OBJECTIVE: To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder. METHODS: Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo. Sample size was estimated based on simulations from key endpoints in patients with hypoactive sexual desire disorder from a prior trial. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13. RESULTS: Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Most participants were white (85.6%), from U.S. sites (96.6%), and had a mean age of 39 years. From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo. CONCLUSIONS: Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder.

OBJECTIVE: To evaluate the long-term safety and efficacy of bremelanotide as treatment for hypoactive sexual desire disorder in premenopausal women. METHODS: Women who completed the 24-week double-blind core phase of RECONNECT, composed of two parallel phase 3 trials (301 and 302) examining the safety and efficacy of bremelanotide compared with placebo in premenopausal women with hypoactive sexual desire disorder, could enroll in the 52-week open-label extension, provided they had not experienced serious adverse events during the core phase. Efficacy was assessed using the coprimary endpoints from the core phase, and all adverse events were collected during the open-label extension. All statistical analyses were descriptive. RESULTS: The study 301 open-label extension began on July 17, 2015, and concluded on July 13, 2017; the study 302 open-label extension began on October 5, 2015, and concluded on June 29, 2017. Of the 856 eligible patients who completed the core phase, 684 elected to participate in the open-label extension, and 272 completed it. The most common treatment-emergent adverse events considered related to study drug were nausea (40.4%), flushing (20.6%), and headache (12.0%), and the only severe treatment-emergent adverse event experienced by more than one participant in both studies was nausea during the open-label extension. The change in Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 from baseline to end of the open-label extension ranged from 1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during the core phase, and 0.70-0.77 and -0.9, respectively, for patients who received placebo during the core phase. CONCLUSION: During the 52-week open-label extension of RECONNECT, no new safety signals were observed, and premenopausal women treated with bremelanotide exhibited sustained improvements in hypoactive sexual desire disorder symptoms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide.

BACKGROUND: Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful. AIM: To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD). METHODS: The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD. OUTCOMES: MCIDs based on the ROC curves for changes in Female Sexual Function Index-desire domain, Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events. RESULTS: Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P ≤ .03). CLINICAL IMPLICATIONS: These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD. STRENGTHS & LIMITATIONS: MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial. CONCLUSION: Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD. Althof S, Derogatis LR, Greenberg S, et al. Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide. J Sex Med 2019;16:1226-1235.

Phase I Randomized Placebo-controlled, Double-blind Study of the Safety and Tolerability of Bremelanotide Coadministered With Ethanol in Healthy Male and Female Participants.

PURPOSE: This was a Phase I study to evaluate the safety, tolerability, and hemodynamic and pharmacokinetic effects of bremelanotide (BMT) coadministered with ethanol to healthy male and female participants. METHODS: This was a randomized, placebo-controlled, double-blind, 3-period, 3-way crossover study. Individuals meeting the inclusion/exclusion criteria received BMT or placebo with or without ethanol at the research facility for 7 consecutive days. Participants were randomized to receive 1 of 6 treatment paths; each participant received single intranasal doses of BMT (20 mg) or placebo on days 1, 4, and 7, with or without oral ethanol (0.6 g/kg) while in a fasted state. The intranasal 20-mg dose of BMT has an exposure equivalent to ~1 to 2 times the subcutaneous dose currently being evaluated in Phase III studies. Vital signs, self-rated sedation scores, nursing and medical observations, and spontaneous reporting by participants provided the basis for evaluation of adverse events. A physical examination and a resting 12-lead electrocardiogram were performed at baseline and on study day 7. Blood and urine samples were obtained for clinical safety profile laboratory tests. FINDINGS: A total of 24 participants were enrolled (12 men; 12 women) and completed the study. Single doses of 20 mg intranasal BMT, administered with or without 0.6 g/kg ethanol, were found to be safe and generally well tolerated with mean maximum ethanol concentrations exceeding 80 mg/dL in women. No clinically significant pharmacokinetic interactions were found between ethanol and BMT either overall or by sex. No significant drug-related hypotensive or orthostatic hypotensive effects were noted. Treatment with BMT did not result in an increased frequency of treatment-emergent adverse events, and no participants discontinued the study because of adverse events. Physical examination, electrocardiography, and laboratory tests disclosed no clinically significant changes. IMPLICATIONS: Female sexual dysfunction is a multifactorial condition with anatomic, physiologic, medical, psychological, and social components. BMT is a synthetic peptide analogue of the naturally occurring hormone α-melanocyte-stimulating hormone and a melanocortin receptor agonist that is being developed for the treatment of hypoactive sexual desire disorder. Its mechanism of action involves activation of endogenous melanocortin hormone pathways involved in the sexual desire and arousal response. The results of this Phase I study found that BMT and ethanol can be safely coadministered and are generally well tolerated with no reports of drug-related serious adverse events. Phase III trials of subcutaneous BMT for the treatment of hypoactive sexual desire disorder in premenopausal women are in progress. ClinicalTrials.gov identifiers NCT02338960 and NCT02333071.

Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide.

BACKGROUND: Melanocortin receptor agonists that bind to the melanocortin receptor 4 may cause increases in blood pressure (BP). Bremelanotide is an on-demand, subcutaneous melanocortin-receptor agonist that binds to the melanocortin receptor 4 and is being developed for the treatment of female sexual dysfunction. METHODS: We studied the effects of bremelanotide administration on ambulatory BP and heart rate (HR), in a randomized, double-blind, placebo-controlled, and parallel-arm trial of three doses of bremelanotide (0.75, 1.25, and 1.75 mg) in 397 premenopausal women with female sexual dysfunction with normotension or controlled hypertension. Pharmacokinetic exposure was assessed in conjunction with ambulatory BP measurements. RESULTS: Increases in ambulatory SBP relative to placebo of 2.4 and 3.0 mmHg (1.25 mg; P values: 0.029 and 0.076) and 3.1 and 3.2 mmHg (1.75 mg; P values: 0.006 and 0.027), respectively, occurred following two doses, separated by 24 h at the 0 to 4-h postdose interval; peak increases typically lasted less than 15 min. Similar increases in the DBP were observed. Increases in BP were accompanied by reductions in HR during the 0-4-h interval for the 1.75-mg dose (-4.6 to -4.7 bpm; P < 0.001). Twenty-six participants discontinued after randomization due to prespecified increases in BP but the proportions were similar among the four treatment groups. CONCLUSION: These data show that ambulatory monitoring was a useful methodology to detect small, transient increases in ambulatory BP accompanied by reductions in HR following bremelanotide. Results of this trial led to appropriate in-clinic BP monitoring during the larger clinical development trials of this agent for female sexual dysfunction.

Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial.

AIM: Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women. METHODS: Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm. RESULTS: Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), -11.1 versus -6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache. CONCLUSION: In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).

Characterization of orgasmic difficulties by women: focus group evaluation.

INTRODUCTION: Female orgasmic disorder (FOD) is the second most prevalent sexual disorder in women. According to the most recent revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV-TR), the term "marked distress" is central to the diagnosis of FOD. In practice, the term "distress" for use as a criterion for a clinical diagnosis is a medical construct and may not correlate with the language used by women with FOD to describe what they are experiencing. AIM: The objective of this study was to explore the terminology used by women to describe their feeling associated with difficulties in achieving orgasm. METHODS: Women experiencing difficulties in achieving orgasm were invited to participate in a focus group. The focus groups included a characterization, picture sort and language exploration exercise and completing the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) to determine the impact and emotional associations of decreased/lack of orgasms. MAIN OUTCOME MEASURES: Patient reported terminology for characterization of their FOD, and validity of question 15 of FSDS-DAO. RESULTS: Sixty-seven percent (44/66) of the women used the word "frustrated" when asked, "What one word would you use to describe your orgasm difficulties?" In the language exploration exercise, the most common term used to describe emotions associated with decreased orgasm was "frustration." Responses (0 = never to 4 = always) to question 15 (frustrated by problems with orgasm) of the FSDS-DAO, ranged from 1 to 4 (mean 3.0) indicating that women were very frustrated. CONCLUSIONS: The term "frustrated" was the most relevant and common emotion women feel when they have difficulties in achieving orgasm. Additionally, the women consistently supported the content validity of question 15 of the FSDS-DAO. Despite the use of the term "distress" in the DSM-IV-TR criteria for FOD, the term reflects the medical construct required to become a sexual dysfunction and does not appear to be an accurate representation of most women's feelings of orgasm difficulties.

Safety and tolerability of testosterone patch therapy for up to 4 years in surgically menopausal women receiving oral or transdermal oestrogen.

Two clinical trials previously demonstrated the safety of 300 µg/day transdermal testosterone patch (TTP) treatment for up to 6 months in 1094 surgically menopausal women with hypoactive sexual desire disorder (HSDD). Adverse events (AE), clinical laboratory tests, vital signs, physical examinations and mammograms were evaluated in open-label extensions of these two trials for up to 4 years and are presented in this article. Nine hundred and sixty-seven patients received at least one application of the TTP resulting in 1092 patient-years of exposure. There was no increase over time in the rate of new occurrences or severity of AEs, serious AEs, or withdrawals due to AEs. The most common AEs associated with treatment were application site reactions and unwanted hair growth; however, most were mild and rarely resulted in study withdrawal. No clinically meaningful changes in serum chemistry, haematology, lipid profile, carbohydrate metabolism, renal and liver function or coagulation parameters were noted with up to 4 years of therapy. Consistent with age-appropriate expected rates, three cases of invasive breast cancer were observed. No important changes in the safety or tolerability profile of TTP were revealed with long-term use for up to 4 years in otherwise healthy oophorectomised women with HSDD on concomitant oestrogen.

Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder.

CONTEXT: Hypoactive sexual desire disorder (HSDD) is one of the most common sexual problems reported by women, but few studies have been conducted to evaluate treatments for this condition. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of a testosterone patch in surgically menopausal women with HSDD. DESIGN: The design was a randomized, double-blind, parallel-group, placebo-controlled, 24-wk study (the Intimate SM 1 study). SETTING: The study was performed at private or institutional practices. PATIENTS: The subjects studied were women, aged 26-70 yr, with HSDD after bilateral salpingo-oophorectomy who were receiving concomitant estrogen therapy. Placebo (n = 279) or testosterone 300 microg/d (n = 283) was administered. There were 19 patients who withdrew due to adverse events in the placebo group and 24 in the 300 mug/d testosterone group. INTERVENTION: Testosterone (300 microg/d) or placebo patches were applied twice weekly. MAIN OUTCOME MEASURE(S): The primary end point was the change in the frequency of total satisfying sexual activity at 24 wk. Secondary end points included other sexual functioning end points and safety assessments. RESULTS: At 24 wk, there was an increase from baseline in the frequency of total satisfying sexual activity of 2.10 episodes/4 wk in the testosterone group, which was significantly greater than the change of 0.98 episodes/4 wk in the placebo group (P = 0.0003). The testosterone group also experienced statistically significant improvements in sexual desire and a decrease in distress. The overall safety profile was similar in both treatment groups. CONCLUSION: In the Intimate SM 1 study, the testosterone patch improved sexual function and decreased distress in surgically menopausal women with HSDD and was well tolerated in this trial.

Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.

BACKGROUND: Oophorectomy reduces serum testosterone levels. We studied the efficacy and safety of transdermal testosterone in treating hypoactive sexual desire disorder in surgically menopausal women. METHODS: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial was conducted in women (aged 24-70 years) who developed distressful low sexual desire after bilateral salpingo-oophorectomy and hysterectomy and who were receiving oral estrogen therapy. Women were randomized to receive placebo (n = 119) or testosterone patches in dosages of 150 microg/d (n = 107), 300 microg/d (n = 110), or 450 microg/d (n = 111) twice weekly for 24 weeks. Sexual desire and frequency of satisfying sexual activity were primary efficacy outcome measures. RESULTS: Of the 447 women randomized, 318 (71%) completed the trial. Compared with placebo, women receiving the 300-microg/d testosterone patch had significantly greater increases from baseline in sexual desire (67% vs 48%; P = .05) and in frequency of satisfying sexual activity (79% vs 43%; P = .049). The 150-microg/d group showed no evidence of a treatment effect. The 450-microg/d group also was not statistically different from the 300-microg/d or placebo groups. Marginally significant linear dose-response trends were observed for total satisfying sexual activity and sexual desire at 24 weeks (P = .06 and .06, respectively). Adverse events occurred with similar frequency in both groups; no serious safety concerns were observed. CONCLUSIONS: The 300-microg/d testosterone patch increased sexual desire and frequency of satisfying sexual activity and was well tolerated in women who developed hypoactive sexual desire disorder after surgical menopause.