Scientific Program - Friday, February 26, 2016

010

A Placebo-Controlled, Randomized, Double-Blind, Three Period, Three-Way Crossover Study on the Hemodynamic and Pharmacokinetic Interactions of Bremelanotide and Ethanol
Lucas, J¹; DeRogatis, LR²; Jordan, R¹
1: Palatin Technologies, USA; 2: Maryland Center for Sexual Health, USA

Objectives: Evaluate the safety and tolerability of bremelanotide when co-administered with ethanol, and the hemodynamic and pharmacokinetic (PK) interactions in healthy test subjects.

Materials and Methods: This was a placebo-controlled, randomized, double-blind, three period, three-way crossover study. Subjects meeting the inclusion/exclusion criteria were enrolled and treated at the research facility for 7 consecutive days. Randomly assigned to one of six Treatment Paths, the subjects received single doses of 20 mg bremelanotide or placebo, administered with or without 0.6 g/kg ethanol on Study Day 1, 4, and 7. Blood samples were collected for PK evaluation. The hemodynamic effect of co-administration of bremelanotide and ethanol was examined using orthostatic vital sign checks. Vital signs, self-rated sedation scores, nursing and medical observations, and spontaneous reporting by subjects provided the basis for evaluation of adverse events (AEs). A physical examination and a resting 12-lead ECG were performed at baseline and on Study Day 7. Blood and urine were obtained for clinical safety laboratory tests.

Results: A total of 24 subjects were enrolled (12 men; 12 women), of whom all completed the study. Single doses of 20 mg intranasal bremelanotide, with exposure equivalent to approximately 1 to 2 x the subcutaneous dose currently being evaluated in Phase 3, were administered with or without 0.6 g/kg ethanol, and were found to be safe and generally well tolerated. No significant drug-related hypotensive or orthostatic hypotensive effects were noted. Treatment with bremelanotide did not result in an increased frequency of treatment-emergent AEs and no subjects discontinued from the study due to AEs or serious AEs.

Conclusions: Female sexual dysfunction (FSD) is a multifactorial condition that has anatomical, physiological, medical, psychological, and social components. Bremelanotide is a synthetic peptide analog of the naturally occurring hormone alpha-melanocyte stimulating hormone (MSH) and a melanocortin agonist that is being developed for the treatment of hypoactive sexual desire disorder (HSDD). This novel mechanism of action involves activating endogenous melanocortin hormone pathways involved in the sexual desire and arousal response. This phase 1 study demonstrates that bremelanotide and ethanol can be safely co-administered and are generally well tolerated with no reports of drug-related serious AEs.

Disclosure:

Work supported by industry: yes, by Palatin Technologies (industry initiated, executed and funded study). The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

011

Efficacy of Multimodal Physiotherapy Treatment Compared to Overnight Topical Lidocaine in Women with Provoked Vestibulodynia: A Bi-center Randomized Controlled Trial
Morin, M¹; Dumoulin, C²; Bergeron, SB²; Mayrand, MH²; Khalifé, S³; Waddell, G¹; Dubois, MF¹; Dubois, O¹; Study Group, PVD⁴
1: University of Sherbrooke, Canada; 2: University of Montreal, Canada; 3: McGill University, Canada; 4: Canada

Objective: To evaluate the efficacy of multimodal physiotherapy in comparison to a frequent first-line treatment, topical overnight application of lidocaine, in women with provoked vestibulodynia (PVD).

Material and Methods: We conducted a bi-centric, parallel group randomized controlled trial involving 212 women diagnosed with PVD. Women were randomly assigned to receive either weekly sessions of multimodal physiotherapy or overnight application of topical lidocaine (5% ointment) for 10 weeks. Physiotherapy treatment included education, pelvic muscle exercises with biofeedback, manual therapy and insertion techniques. The primary outcome measure was pain intensity during intercourse as assessed with the numerical rating scale (NRS 0-10) at post-treatment. Secondary outcomes included the following validated questionnaires: Female Sexual Function Index, Female Sexual Distress Scale, treatment satisfaction (0-10) and Patient’s Global Impression of Change. Outcome assessors, investigators and the person in charge of data analysis were blinded to group assignation. Analysis was conducted by intention to treat, and treatment effects were calculated with repeated measure analysis of variance.

Results: Two hundred one participants (95%) completed the study. Both physiotherapy and lidocaine showed significant changes from baseline to post-treatment on all outcomes (all p<0.01). However, physiotherapy treatment was found more efficacious than lidocaine for reducing pain during intercourse. Mean (±SD) baseline and post-treatment pain intensity for the physiotherapy group were 7.3±1.5 and 2.9±2.1, versus 7.3±1.5 and 4.5±2.6 respectively for the lidocaine group (changes from baseline between the two groups 1.5 CI95% 0.9-2.1, p<0.001). Physiotherapy was also found more efficacious in reducing sexual distress as well as improving sexual function (p<0.001). Women in the physiotherapy treatment group also reported higher satisfaction with treatment (8.8/10 (SD1.4)) compared to lidocaine (5.5/10 (SD3.2); p<0.001)). Overall, 77% of women in the physiotherapy group reported being very much or much improved compared to 38% in the lidocaine group (p<0.001).

Conclusion: Findings of this study provide strong evidence that multimodal physiotherapy is effective for reducing pain and sexual distress as well as improving sexual function in women with PVD. Physiotherapy proved to be more effective than a frequent first-line treatment - overnight lidocaine topical application.

Disclosure:

Work supported by industry: no.

012

Potential Sexual Changes Resulting from LEEP
Rollston, R¹; Dell, A²; Komisaruk, BR³; Goldstein, SW⁴; Goldstein, I⁵
1: ETSU Quillen College of Medicine, USA; 2: UK; 3: Rutgers, USA; 4: San Diego Sexual Medicine, USA; 5: Alvarado Hospital, USA

Objectives: Komisaruk has provided evidence that the cervix is uniquely innervated by three separate neural pathways including the pelvic, hypogastric and vagus nerves. Cervical stimulation can induce orgasm. As described by some women, their cervical/myometrial orgasms are intense, sustained orgasm associated with deep myometrial contractions, that are exhausting and fulfilling and that are separate and distinct from more frequently described clitoral or anterior vaginal wall, peri-urethral stimulation orgasms. Women who have a hysterectomy lose their ability to have cervical/myometrial orgasm. Loop electrosurgical excision procedure (LEEP) was developed to treat women with biopsy-demonstrated abnormal cervical cells and to avoid hysterectomy. LEEP coagulates abnormal cervical tissue and surrounding blood vessels to prevent bleeding.

Materials and Methods: Motivated by a woman who was diagnosed with mild cevical dyskaryosis and underwent a LEEP and subsequently lost her orgasmic function, we performed a literature review using key words “orgasm”, “sexual function”, “LEEP procedure” etc.. It was hypothesized that LEEP may negatively impact sexual function in a subgroup of women by disrupting neural pathways that innervate the cervix.

Results: Our patient reported “feeling something wrong” post LEEP. Post-op, an intimate encounter with her partner resulted in decreased pleasure and inability to reach orgasm, although a mild contraction in the cervix was felt. Upon self-exploration the patient claimed her labia felt different, “unsensual,” and thereafter was unable to experience a strong climax or sexual fantasies, and only a warm feeling in her clitoris. Since the LEEP, she reports also having vaginal dryness and claims “mental numbness.” Inna reported on 89 premenopausal women with cervical dysplasia who had undergone LEEP at least 3 months previously, and were interviewed once on post-LEEP follow-up visits with a questionnaire on pre- and post-procedural sexual function. Inna found that the changes in the frequency of sexual intercourse, dysmenorrhea, and dyspareunia after LEEP were not statistically significant but the decreases in overall satisfaction, vaginal elasticity, and orgasmic satisfaction were statistically significant.

Conclusion: During LEEP, the triple cervix innervation is at risk for injury and may result in reduced sexual satisfaction and orgasm dysfunction.

Disclosure:

Work supported by industry: no. The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

013

Effect of Intravaginal Prasterone on Sexual Dysfunction in Postmenopausal Women with Vulvovaginal Atrophy
Labrie, F.¹; DeRogatis, L²; Archer, DF³; Martel, C¹
1: EndoCeutics Inc., Canada; 2: Maryland Center for Sexual Health, USA; 3: CONRAD Clinical Research Center, USA

Objective: Previous data have shown that intravaginal dehydroepiandrosterone (DHEA, prasterone) improved all the domains of sexual function, an effect most likely related to the local formation of androgens from DHEA. The objective was to confirm in a placebo-controlled, prospective, double-blind and randomized study the benefits of daily intravaginal DHEA for 12 weeks on sexual function using the Female Sexual Function Index (FSFI) questionnaire.

Material, Patients and Methods: Placebo was administered daily to 157 women while 325 women received 0.50% (6.5 mg) DHEA daily for 12 weeks. All women were postmenopausal meeting the criteria of vulvovaginal atrophy (VVA), namely moderate to severe dyspareunia as their most bothersome symptom of VVA in addition to having ≤5% of vaginal superficial cells and vaginal pH>5.0. The FSFI questionnaire was filled at baseline (screening and Day 1), 6 weeks and 12 weeks. Comparison between DHEA and placebo of the changes from baseline to 12 weeks was made using the ANCOVA test, with treatment group as the main factor and baseline value as the covariate. The six domains and total score of the FSFI questionnaire were evaluated.

Results: The FSFI domain desire increased over placebo by 0.24 unit (+49.0%, p=0.0105), arousal by 0.42 unit (+56.8%, p=0.0022), lubrication by 0.57 unit (+36.1%, p=0.0005), orgasm by 0.32 unit (+33.0%, p=0.047), satisfaction by 0.44 unit (+48.3%, p=0.0012) and pain at sexual activity by 0.62 unit (+39.2%, p=0.001). The total FSFI score, on the other hand, has shown a superiority of 2.59 units in the DHEA group compared to placebo or a 41.3% greater change than placebo (p=0.0006 over placebo).

Conclusion: The present data show that all the six domains of the FSFI are improved over placebo (by 33.0% to 56.8% and from p=0.047 to 0.0005), thus confirming the previously observed benefits of intravaginal DHEA on female sexual dysfunction by an action exerted exclusively at the level of the vagina, in the absence of biologically significant changes of serum steroid levels.

Disclosure:

Work supported by industry: yes, by EndoCeutics Inc. (industry initiated, executed and funded study). The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

014

A Phase 2 Program on Female Sexual Arousal Disorder and Hypoactive Sexual Desire Disorder: Patient Characteristics and Implications for Diagnosis and Treatment of Female Sexual Dysfunction
Althof, S¹; Kingsberg, S²; Symons, J³; Portman, D ³
1: Center for Marital and Sexual Health of South Florida; 2: University Hospitals Case Medical Center; 3: Sermonix Pharmaceuticals

Objectives: DSM-5 has combined the previously separate female sexual dysfunctions (FSD) of arousal and desire disorders into a single diagnosis, Female Sexual Interest/Arousal Disorder (FSAID). The implications of this change in terms of patient characteristics and on clinical investigations are unknown. A series of four randomized, double-blind, placebo-controlled trials were conducted to investigate the effect of lasofoxifene, an estrogen agonist/antagonist, on postmenopausal female sexual arousal disorder (FSAD) and hypoactive sexual desire disorder (HSDD) and may provide insight into the differences between these populations and the potential impact of the new DSM-5 diagnostic criteria on clinical trial design.

Materials and Methods: Postmenopausal women at least 44 years old were diagnosed based on these Sexual Function Questionnaire (SFQ) scores: For FSAD studies, a score of < 18 on the arousal subscale, and for HSDD studies, a score of <23 on the desire subscale. 681 women were enrolled in the FSAD studies, and 803 enrolled in the HSDD studies. All studies required a score of >15 on Female Sexual Distress Scale (FSDS), baseline number of satisfying sexual events (SSEs) and a structured interview conducted by a trained sexual medicine professional. Certain general health criteria also needed to be met from an inclusion or exclusion perspective.

Results: Women were 54-55 years of age on average. Regardless of their primary diagnosis, all women had desire and arousal scores that would indicate a dysfunction associated with those states. Likewise, the mean number of SSEs at baseline was no different in all of the groups in the studies, i.e., there was no distinguishable effect on the number of SSEs at baseline for either FSAD or HSDD groups. Finally, the level of distress associated with either FSAD or HSDD was not distinguishable between studies or groups at baseline.

Conclusion: There were significant areas of overlap in symptoms of arousal and desire in this phase 2 program. A structured interview was able to differentiate between FSAD and HSDD. The impact DSM-5 and a merger of arousal and desire disorders have on clinical trial enrolment and design is an important area for future research.

Disclosure:

Work supported by industry: yes, by Sermonix Pharmaceuticals (industry initiated, executed and funded study). The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

015

Evaluation of Clinical Meaningfulness in the Flibanserin HSDD Clinical Development Program
Simon, J¹; Brown, L²; Yuan, J²; Spigelman, S³
1: George Washington University and Women's Health and Research Consultants, USA; 2: Sprout Pharmaceuticals, Inc., USA; 3: Valeant Pharmaceuticals, Inc., USA

Objective: 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.

Methods: 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.

Results: The number of subjects who self-reported as responders based on a PGI-I score of 3 or better on SSE, FSFI-D and FSDS-R13, at Week 24 (FAS, LOCF) between flibanserin and placebo ranged from 9.7% (P< 0.01) to 14.6% (P=0.0004). The mean change from baseline at Week 24 in SSE for the responder group ranged from 4.3 to 5.8 SSE per month, compared to 1.9 to 2.5 SSE in the FAS, scores on the FSFI-D score ranged from 1.9 to 2.0 in responders compared to 0.9 to 1.0 in the FAS and on the FSDS-R13 responder scores ranged from -1.7 to -1.8 compared to -0.7 to -1.0 in the FAS.

Conclusion: In flibanserin’s pivotal trials, the PGI-I was used as an anchoring method to translate the magnitude of effect seen on validated and reliable PROs into a clinical meaningful change for the patient. A comparison of flibanserin’s FAS to the responder group showed that responders reported mean changes in key symptoms that, at times, was double the effect in the overall flibanserin treatment group, with an increase of more than 5 SSEs per month, an approximate two-point increase on the 4.8-point desire scale and an approximate 1.8-point improvement on the 5-point distress scale over baseline.

Disclosure:

Work supported by industry: yes, by Sprout Pharmaceuticals (industry initiated, executed and funded study). The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

016

Vulvoscopic Findings, Patient Reported Outcome (PRO) Measures, and Hormonal Blood Test Values in Menopausal Women with Female Sexual Dysfunction Pre- and Post-Hormonal Treatment: A Retrospective Single Center Study
da Silva, S¹; Espenschied, C²; Gagnon, C²; Minton, J³; Goldstein, I⁴
1: UCSD, USA; 2: San Diego Sexual Medicine, USA; 3: San Diego Sexual Medicine, USA; 4: Alvarado Hospital, USA

Objectives: Menopausal women frequently experience symptoms and signs associated with reduced sex steroid hormones. Estradiol deficiency related symptoms of GSM include dryness, burning, thinning, itching, urinary frequency and dyspareunia. Testosterone deficiency related symptoms include diminished sense of well-being, reduced muscle and bone mass, provoked vestibulodynia, and decreased sexual desire, arousability, and orgasmic pleasure. The hypothesisis is that with both high patient adherence and close health care provider monitoring, hormonal management will lead to subjective and objective improvements in signs and symptoms.

Materials and Methods: The aim of this study was to evaluate clinical benefit of hormonal replacement strategies for management of sexual dysfunction and GSM utilizing pre- and post-treatment: blood test monitoring; FSFI scores; and vulvoscopy findings. Charts from August 1, 2007 through December 1, 2015 were reviewed. Five bioidentical hormonal replacement efforts are designed to keep serum estradiol levels 35 - 50 pg/ml, serum progesterone levels at 1.0 ng/ml and calculated free testosterone levels at 0.8 ng/dl including daily topical vestibular and vaginal estradiol and testosterone applications. Subjects included were peri-menopausal or post-menopausal at their initial visit, naturally or surgically, and have both an initial and at least one follow-up vulvoscopy. Exclusions included cosmetic vulvar or vestibular surgery.

Results: 110 menopausal women (mean age 62 +/- 13 years) with sexual health complaints met study criteria. Mean follow-up was 2.6 +/- 1.3 years. Pre-treatment vulvoscopic findings of labia minora resorption, urethral meatus telescoping, clitoral atrophy, vestibular erythema tenderness and pallor, minimally robust peri-urethral tissue, minimal vaginal rugae, with thin, pale vaginal mucosa and abnormal vaginal pH were noted in 100%. Serum sex steroid values returned to ideal values in 81%. FSFI total scores increased more than 5 points in 72%. Post-treatment vulvoscopic changes revealed pink moist pain-free vestibular tissue in 63%.

Conclusion: Managing menopause with patient adherence and close monitoring, hormonal menopausal management has lead to subjective and objective improvement of female sexual function.

Disclosure:

Work supported by industry: no. The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

017

Meta-Analysis of Orgasmic and Overall Sexual Function Post Mid-Urethral Sling Surgery
Szell, N¹; Komisaruk, B²; Qu, H³; Shaw, M¹; Goldstein, S⁴; Goldstein, I⁴
1: St. John Providence Health System, USA; 2: Rutgers University, USA; 3: Oakland University, USA; 4: San Diego Sexual Medicine, USA

Objectives: More than 200,000 mid-urethral slings are placed yearly for stress urinary incontinence. About 14-20% of women experience worsening sexual function after sling placement and about 30% report worsening orgasm frequency/intensity, with statistically significant lowering of pre-op vs. post-op orgasm FSFI and PISQ scores. We postulate sling placement injures neural pathways regulating “female prostate” peri-urethral tissue lying adjacent to anterior vaginal wall. Meta-analysis for overall sexual function and orgasm was performed using FSFI and PISQ for transvaginal tape (TVT) and transobturator tape (TOT).

Materials and Methods: Effect sizes of pre-op and post-op questionnaire scores for overall sexual function and orgasm from the studies were calculated. Random-effects models were selected for Meta analyses. Statistical analysis involved determination of the ratio of total heterogeneity among various studies to total variability. The difference of overall sexual and orgasm functions were calculated by subtracting post-mid-urethral sling scores from pre-sling scores. Forest plots of effect sizes for overall sexual function were performed.

Results: Statistical analysis for the difference in orgasm showed the mean post-op score was significantly higher than mean pre-op score. For TVT alone, mean total sexual function and orgasm post-op scores were significantly higher than pre-op scores. For TOT alone, the mean total post-op score was significantly higher than pre-op, however the mean orgasm post-op score was not significantly higher than pre-op, mainly due to large variation in TOT data. Although the mean total and orgasm effect sizes were similar for TOT and TVT, the TOT effect sizes have much larger variations than TVT.

Conclusions: We believe the data support that a subgroup of women who derive primary orgasmic function from vaginally-elicited orgasms, through penetration or stimulation of the peri-urethral female prostate region, may lose this response following sling placement. The dissection for and placement of the mid-urethral sling clearly can compromise neural integrity of anterior vaginal wall, peri-urethral female prostate tissue.

Disclosure:

Work supported by industry: no.