VENUS II: the second us-based phase 3 study of ulipristal acetate (UPA) for treatment of symptomatic uterine fibroids (UF)

and transvaginal ultrasound), and changes in bone mineral density (BMD) were assessed. RESULTS: In Cohort 1, 259 women were randomized and treated; 80% completed treatment. Cohort 1 responses for the primary endpoint were 92% elagolix alone, 85% elagolix+LDA, 79% elagolix+SDA, and 27% placebo (all p< .001 vs. placebo). Elagolix treatment alone was associated with hot flushes and a decrease in BMD; add-back therapy attenuated these hypoestrogenic effects in a dose-dependent manner. At month 6, the most common endometrial biopsy category from women in elagolix groups was normal quiescent/minimally stimulated endometrium. All groups had a decrease in endometrial thickness (mean change from baseline to month 6 in mm: elagolix alone ¼ -0.52, elagolix+LDA ¼ -1.33 [p%.05 vs. placebo], elagolix+SDA ¼ -0.56, placebo ¼ 2.1). Similar efficacy and safety results were observed in Cohort 2. CONCLUSIONS: Elagolix with or without add-back significantly reduced MBL in UF-associated HMB. Add-back therapy attenuated the hypoestrogenic effects of elagolix. There were no adverse endometrial findings. Supported by: AbbVie, Inc. O-63 Monday, October 30, 2017 11:30 AM ELAGOLIX IMPROVES QUALITY OF LIFE IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS: EVIDENCE FROM A PHASE 2B RANDOMIZED TRIAL. M. Diamond,a A. M. Soliman,b J. Gao,b C. Owens,b K. Chwalisz,c D. F. Archer.d aAugusta University, Augusta, GA; bAbbVie Inc., North Chicago, IL; cResearch and Development, AbbVie Inc., North Chicago, IL; dDepartment of Obstetrics & Gynecology, Eastern Virginia Medical School, Norfolk, VA. OBJECTIVE: To evaluate the impact of elagolix, an oral gonadotropinreleasing hormone antagonist, on the health-related quality of life (HRQL) in women with heavy menstrual bleeding (HMB) associated with uterine fibroids (UF). DESIGN: Phase 2b, randomized, double-blind, multicenter, placebocontrolled, parallel group trial with 6-month treatment duration in premenopausal women aged 18 to 51 years with HMB (defined as > 80 mL blood loss per menstrual cycle) associated with UF. MATERIALS AND METHODS: Trial consisted of two cohorts: elagolix 300 mg BID in cohort 1 and elagolix 600 mg QD in cohort 2. Each cohort had four arms: placebo, elagolix alone, and two elagolix plus add-back arms (low dose [LDA], estradiol [E2] 0.5 mg/norethindrone acetate 0.1 mg [NETA], and standard dose [SDA], 1.0 mg E2/0.5mg NETA). HRQL was assessed using the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire at baseline and months 1, 3 and 6 of treatment. Changes from baseline scores for symptom severity scale, HRQL subscales and HRQL total scale were assessed using analysis of covariance models that controlled for baseline scores. RESULTS: A total of 201 women in cohort 1 were included in the analysis (Table 1). Mean reductions from baseline to month 6 in the symptom severity scores and mean increases in HRQL total scores were greater in all elagolix treatment arms compared to placebo (p%0.001; lower symptom severity and higher HRQL scores indicate better HRQL). The increases in mean scores from baseline to 6 months were statistically significant in all elagolix arms compared to placebo in HRQL subscales of concern, activities, energy/ mood, control and self-consciousness (p%0.001); improvement in the sexual

function subscale was statistically significant for elagolix 300 mg BID only (p%0.01). Results were similar in cohort 2. CONCLUSIONS: Elagolix with and without hormonal add-back therapy improved symptom severity and HRQL among women with HMB associated with UF. Supported by: AbbVie Inc. funded the study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. O-64 Monday, October 30, 2017 11:45 AM VENUS II: THE SECOND US-BASED PHASE 3 STUDY OF ULIPRISTAL ACETATE (UPA) FOR TREATMENT OF SYMPTOMATIC UTERINE FIBROIDS (UF). J. Liu,a D. Soper,b A. S. Lukes,c P. Gee,d T. Kimble,e R. Kroll,f M. Mallick,g A. Chan,g V. Sniukiene,g L. P. Shulman.h aCase Western Reserve School of Medicine, Cleveland, OH; bMedical University of South Carolina, Charleston, SC; cCarolina Women’s Research & Wellness Center, Durham, NC; dWillowbend Health & Wellness, Frisco, TX; eEastern Virginia Medical School, Norfolk, VA; f Seattle Women’s, Seattle, WA; gAllergan plc, Jersey City, NJ; hNorthwestern University, Feinberg School of Medicine, Chicago, IL. OBJECTIVE: Determine efficacy and safety of UPA vs placebo (PBO) for treatment of symptomatic UF. DESIGN: VENUS II (NCT02147158) was a phase 3, randomized, doubleblind, placebo-controlled, partial-crossover study. MATERIALS AND METHODS: Premenopausal (FSH %20 mIU/mL) women 18-50 y were randomized to receive two 12 wk courses of once-daily UPA or PBO, separated by treatment-free period of 2 menses. Upon completion, patients were followed for 12 wk. Patients were randomized to 6 treatment arms at a 1:1:2:1:2:1 ratio, with Course 1/Course 2 dosing of PBO/UPA 5 mg (Arm 1), PBO/UPA 10 mg (Arm 2), UPA 5 mg/5 mg (Arm 3), UPA 5 mg/PBO (Arm 4), UPA 10 mg/10 mg (Arm 5), or UPA 10 mg/PBO (Arm 6). Eligibility criteria: cycles R22 and %35 days, heavy/prolonged bleeding for R4 of last 6 cycles, blood loss R80 mL by alkaline hematin method, R1 discrete UF of any size and location by transvaginal ultrasound, and %20 wk uterine size. Coprimary endpoints were amenorrhea rate and time to amenorrhea in course 1. Amenorrhea was defined as no bleeding (spotting permitted) for last R35 consecutive days on treatment. Adverse events (AEs) were also assessed. RESULTS: Course 1: 157, 162, and 113 patients were randomized to UPA 10 mg, UPA 5 mg, and PBO, respectively. Significantly more patients achieved amenorrhea with UPA (10 mg, 54.8%; 5 mg, 42.0%) vs PBO (0%; both p<0.0001). UPA demonstrated superiority over PBO in time to amenorrhea (both p<0.0001). Course 2: Significantly more patients achieved/maintained amenorrhea with UPA (10 mg [Arm 5], 57.3%; 5 mg [Arm 3], 40.5%) vs PBO (8.0% [Arms 4 and 6]; both p<0.0001). Common AEs (R5% in any UPA group) during course 1 and 1st off-treatment were hot flush (UPA total vs PBO, 9.5% vs 1.7%), headache (7.3% vs 5.2%), fatigue (4.4% vs 4.3%), and nausea (5.4% vs 4.3%), and for course 2 and 2nd offtreatment was headache (4.0% vs 2.7%). Fifteen patients discontinued UPA and 10 discontinued PBO due to an AE. No deaths were reported. One serious AE was judged to be treatment related (UPA 5 mg, uterine hemorrhage). CONCLUSIONS: Consistent with VENUS I and the European studies, both doses of UPA were superior to PBO in the proportion of women

Table 1. UFS-QOL mean scores at baseline and mean changes from baseline to Month 6 in Cohort 1

Placebo (N¼49)

UFS-QOL scale Symptom severity HRQL Total Concern Activities Energy/Mood Control Self-conscious Sexual function

62.8, -19.2 37.7, 16.0 28.2, 13.3 39.6, 15.3 41.7, 19.1 44.8, 18.0 29.4, 12.1 36.2, 18.1

Elagolix 300 BID (N¼49)

Elagolix 300 BID+LDA (N¼52)

Elagolix 300 BID+SDA (N¼51)

64.7, -49.8*** 39.3, 46.9*** 24.1, 61.6*** 40.5, 50.1*** 44.8, 41.7*** 46.5, 42.0*** 37.6, 41.9*** 39.0, 35.7**

61.8, -40.7*** 41.1, 42.4*** 27.1, 54.1*** 42.1, 45.5*** 42.9, 39.7*** 48.8, 36.6*** 39.6, 38.6*** 49.5, 29.9

63.5, -37.2*** 37.7, 38.6*** 27.2, 50.7*** 37, 42.6*** 41.6, 37.3*** 44.8, 32.7*** 34.0, 30.2*** 40.5, 25.7 (a)

Note: In each column, the first number is the mean score at baseline and the second number is the least squares mean change in score from baseline to Month 6. Estimates based on modified intent-to-treat analysis set. ***, **, * statistically significant at 0.001, 0.01, and 0.05 level, respectively. (a) N¼50

FERTILITY & STERILITYÒ

e27

achieving amenorrhea and time to amenorrhea. Both UPA 10 mg and 5 mg were generally well tolerated. Numerically greater responses in efficacy were observed with UPA 10 mg vs 5 mg, though the safety profiles were similar. Supported by: Allergan plc O-65 Monday, October 30, 2017 12:00 PM QUALITY OF LIFE WITH ULIPRISTAL ACETATE (UPA) TREATMENT OF SYMPTOMATIC UTERINE FIBROIDS (UF): VENUS II STUDY. R. Kroll,a J. H. Liu,b D. Soper,c A. S. Lukes,d P. Gee,e T. Kimble,f M. Mallick,g P. Gillard,h A. Harrington,h V. Sniukiene,g L. P. Shulman.i aSeattle Women’s, Seattle, WA; bCase Western Reserve School of Medicine, Cleveland, OH; cMedical University of South Carolina, Charleston, SC; dCarolina Women’s Research & Wellness Center, Durham, NC; eWillowbend Health & Wellness, Frisco, TX; fEastern Virginia Medical School, Norfolk, VA; gAllergan plc, Jersey City, NJ; hAllergan plc, Irvine, CA; iNorthwestern University, Feinberg School of Medicine, Chicago, IL. OBJECTIVE: Assess the impact on quality of life with UPA vs placebo (PBO) in women with symptomatic UF. DESIGN: VENUS II (NCT02147158) was a phase 3, randomized, doubleblind, placebo-controlled, partial-crossover study. MATERIALS AND METHODS: Premenopausal (FSH %20 mIU/mL) women 18-50 y were randomized to receive two 12-wk courses of once-daily UPA or PBO, separated by a treatment-free period of 2 menses. Upon completion, patients were followed for 12 wk. Patients were randomized to 6 treatment arms at a 1:1:2:1:2:1 ratio, with Course 1/Course 2 dosing of PBO/UPA 5 mg (Arm 1), PBO/UPA 10 mg (Arm 2), UPA 5 mg/5 mg (Arm 3), UPA 5 mg/PBO (Arm 4), UPA 10 mg/10 mg (Arm 5), or UPA 10 mg/PBO (Arm 6). Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire (UFS-QoL) change from baseline to end of treatment Course 1 and 2 was evaluated. UFS-QoL scores included the Health-Related Quality of Life (HRQoL) Total Score, Revised Activities subscale score, and remaining subscale scores (Concern, Control, Self-Consciousness, Sexual Function, Symptom Severity, Energy/Mood, and Original Activities). Higher scores indicate improvement, except Symptom Severity where lower scores indicate improvement. ANCOVA least square mean estimates and corresponding p-values for mean differences were used to compare UPA with PBO, controlling for pooled center and baseline value. RESULTS: Course 1: 157, 162, and 113 patients were randomized to UPA 10 mg, UPA 5 mg, and PBO, respectively. Mean change from baseline in HRQoL Total Score was significantly greater with UPA (10 mg, 51.0; 5 mg, 42.9) vs PBO (11.2; both p<0.0001). Improvements were also observed for Revised Activities subscale score (UPA 10 mg, 56.7; 5 mg, 48.3; PBO, 13.0; both p<0.0001) and remaining UFS-QoL subscales (p<0.0001 for UPA vs PBO). Course 2: Similar trends were observed, with significant improvements for UPA vs PBO in HRQoL Total Score (mean change from baseline: 10 mg [Arm 5], 49.8; 5 mg [Arm 3], 44.5; PBO [Arms 4 and 6], 18.4; both p<0.0001), Revised Activities subscale score (10 mg, 54.9; 5 mg, 50.7; PBO, 20.9; both p<0.0001), and remaining subscales (p<0.01 for UPA vs PBO). CONCLUSIONS: UPA 10 mg and 5 mg significantly improved quality of life and reduced limitations on social and physical activities for women with symptomatic UF versus placebo. Significant improvement in all UFS-QoL subscales demonstrates that UPA treatment improves a woman’s ability to lead a normal life. Supported by: Allergan plc O-66 Monday, October 30, 2017 12:15 PM ULIPRISTAL ACETATE (UPA) TREATMENT OF SYMPTOMATIC UTERINE FIBROIDS (UF): VENUS II SUBGROUP ANALYSES BY RACE AND BMI. D. Soper,a A. S. Lukes,b P. Gee,c T. Kimble,d R. Kroll,e M. Mallick,f A. Chan,f V. Sniukiene,f L. P. Shulman,g J. Liu.h aMedical University of South Carolina, Charleston, SC; bCarolina Women’s Research & Wellness Center, Durham, NC; cWillowbend Health & Wellness, Frisco, TX; dEastern Virginia Medical School, Norfolk, VA; eSeattle Women’s, Seattle, WA; fAllergan plc, Jersey City, NJ; gNorthwestern University, Feinberg School of Medicine, Chicago, IL; hCase Western Reserve School of Medicine, Cleveland, OH. OBJECTIVE: Evaluate the efficacy of UPA vs placebo (PBO) for symptomatic UF treatment by race and BMI.

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ASRM Abstracts

DESIGN: VENUS II (NCT02147158) was a phase 3, randomized, doubleblind, placebo-controlled, partial-crossover study. MATERIALS AND METHODS: Premenopausal (FSH %20 mIU/mL) women 18-50 y were randomized to receive two 12-wk courses of once-daily UPA or PBO, separated by a treatment-free period of 2 menses. Upon completion, patients were followed for 12 wk. Patients were randomized to 6 treatment arms at a 1:1:2:1:2:1 ratio, with Course 1/Course 2 dosing of PBO/UPA 5 mg (Arm 1), PBO/UPA 10 mg (Arm 2), UPA 5 mg/5 mg (Arm 3), UPA 5 mg/PBO (Arm 4), UPA 10 mg/10 mg (Arm 5), or UPA 10 mg/PBO (Arm 6). Assessments included amenorrhea rate (no bleeding [spotting permitted] for last R35 consecutive days on treatment) and least square mean change from baseline in the Uterine Fibroid Symptom and HealthRelated Quality of Life (UFS-QoL) questionnaire Revised Activities subscale (higher scores indicate improvement of physical and social activities). Subgroup analyses evaluated efficacy by race (black or non-black; self-identified) and BMI (<30 kg/m2 or R30 kg/m2). RESULTS: In Course 1, 157, 162, and 113 patients were randomized to UPA 10 mg, UPA 5 mg, and PBO, respectively. Overall, 66.9% of patients were black and 56.7% had BMI R30 kg/m2. In black and non-black patients, more patients achieved amenorrhea with UPA 10 mg (48.6% and 68.0%) and UPA 5 mg (34.8% and 59.6%) versus placebo (0% for both), respectively. Similar results were observed regardless of BMI, with higher amenorrhea rates following UPA 10 mg and 5 mg vs placebo (R30 kg/m2: 58.4% and 47.3% vs 0%; <30 kg/m2: 50.0% and 33.8% vs 0%), respectively. Higher amenorrhea rates with UPA (Arms 3 or 5) vs PBO (Arms 4 and 6) were also observed in Course 2, regardless of race or BMI. For the UFS-QoL Revised Activities subscale, mean change from baseline to end of treatment in Course 1 was greater with UPA 10 mg and 5 mg vs PBO in all subgroups evaluated (black: 53.1 and 47.7 vs 14.0; non-black: 63.1 and 50.4 vs 10.8; BMI R30 kg/m2: 53.7 and 51.1 vs 12.3; BMI <30 kg/m2: 60.0 and 43.9 vs 13.6), respectively. CONCLUSIONS: UPA 10 mg and 5 mg showed higher responses than PBO in the proportion of women achieving amenorrhea, regardless of race and BMI. Both doses of UPA also led to increased QoL, with improvements in physical and social activities compared with placebo in all subgroups evaluated. Numerically greater responses were observed with UPA 10 mg vs 5 mg. Supported by: Allergan plc ENVIRONMENT AND REPRODUCTION O-67 Monday, October 30, 2017 11:00 AM URINARY CONCENTRATIONS OF DEET METABOLITES AND SEMEN PARAMETERS AMONG MEN ATTENDING A FERTILITY CENTER. T. Segal,a L. Minguez-Alarcon,b Y. Chiu,c P. Williams,d F. Nassan,e R. Dadd,f M. Ospina,g A. Calafat,h R. Hauser.i aReproductive Endocrinology & Infertility, University Hospitals Cleveland Medical Center, Beachwood, OH; bHarvard T H Chan School of Public Health, Boston, MA; c Nutrition, Harvard School of Public Health, Boston, MA; dBiostatistics and Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA; eEnvironmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; fDepartment of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; gNational Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA; hCDC, Atlanta, GA; iHarvard Chan School of Public Health, Boston, MA. OBJECTIVE: The recent rise in public health concerns regarding mosquito-borne diseases such as Zika, have led to an increased use of N,N-diethyl-m-toluamide (DEET) insect repellents, especially among couples planning pregnancy. However, the reproductive health effects of DEET and its metabolites, 3-(diethylcarbamoyl) benzoic acid (DCBA) and N,N-diethyl-3-hydroxymethylbenzamide (DHMB) remain understudied. We explored whether urinary concentrations of DEET and its metabolites are associated with semen parameters among men attending a fertility center. DESIGN: Between 2007 and 2015, 90 men participating in a prospective cohort study at a fertility center provided 171 urine samples and 250 semen samples. MATERIALS AND METHODS: The urinary concentrations of DEET, DHMB and DCBA were quantified by isotope dilution tandem mass spectrometry and adjusted using specific gravity (SG). Linear mixed-effects models with random subject effects to account for repeated semen measurements within the same man were used to estimate the association between tertiles of SG-adjusted urinary DCBA concentrations and semen parameters,

Vol. 108, No. 3, Supplement, September 2017