Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas.

OBJECTIVE: In the LIBERTY 1 and LIBERTY 2 placebo-controlled trials, once-daily relugolix combination therapy reduced menstrual blood loss volume and pain in women with heavy menstrual bleeding associated with uterine leiomyomas and was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. Here we report the long-term efficacy and safety of relugolix combination therapy treatment for up to 52 weeks. METHODS: Women with uterine leiomyoma-associated heavy menstrual bleeding who completed any treatment arm in either the LIBERTY 1 or LIBERTY 2 trial were eligible to enroll in a 28-week long-term extension study. All participants received once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) in the extension study. The primary efficacy endpoint was the proportion of women who achieved or maintained a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction in menstrual blood loss volume from LIBERTY study baseline to the last 35 days of treatment (defined as responders ). Analyses were conducted for all three randomized treatment groups from pivotal studies. RESULTS: Overall, 477 women enrolled, 476 were treated, and 363 (76.1%) completed 52 weeks. Among patients treated with relugolix combination therapy through 52 weeks (n=163), sustained improvement in heavy menstrual bleeding was observed in 87.7% (responders). The least squares mean menstrual blood loss volume reduction was 89.9%, with 70.6% of patients achieving amenorrhea. At week 52, 59.0% of patients with anemia at baseline had improvements in hemoglobin concentration of greater than 2 g/dL. Distress due to uterine leiomyoma-associated symptoms measured by the BPD (Bleeding and Pelvic Discomfort) scale score was reduced by 51.3 points. Sustained reductions in uterine and uterine leiomyoma volume were observed. Bone mineral density was preserved through week 52. CONCLUSION: Improvements in heavy menstrual bleeding and anemia and reduction of uterine leiomyoma-associated symptom burden were sustained through up to 52 weeks of treatment with relugolix combination therapy in women with uterine leiomyomas. No new safety concerns were identified, and BMD was maintained. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03049735; NCT03103087; NCT03412890. FUNDING SOURCE: Myovant Sciences GmbH.

Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: Phase 3 clinical trial results.

OBJECTIVE: To assess the contraceptive efficacy, safety, and tolerability of a contraceptive transdermal delivery system, (TDS; TWIRLAⓇ) containing levonorgestrel (LNG) and ethinyl estradiol (EE). STUDY DESIGN: This single-arm, open-label, multicenter, 1-year (13 cycle), phase 3 study enrolled sexually active women ≥18 years old at risk for pregnancy irrespective of body mass index (BMI). Women used patches in 28-day cycles (3 consecutive administrations of 7-day patches followed by 7 days off-treatment/patch-free week). We assessed contraceptive efficacy by the Pearl Index (PI) in women 18 to 35 years, excluding cycles without intercourse or when other contraceptive methods were used. RESULTS: The study enrolled 2032 demographically diverse women in the US, of which 35.3% had a BMI ≥30 kg/m2. In the primary efficacy analysis, the PI (95% confidence interval) was 5.8 (4.5-7.2) pregnancies per 100 woman-years. PIs trended higher as BMI increased; the PI was 4.3 (2.9-5.8) in women with BMI <30 kg/m2 and 8.6 (5.8-11.5) in women with BMI ≥30 kg/m2. Hormone-related treatment-emergent adverse events included nausea (4.1%) and headache (3.6%); 11% of women discontinued due to adverse events. Four women (all with BMIs ≥30 kg/m2) reported thromboembolic events considered related to treatment. CONCLUSIONS: The low-dose LNG/EE TDS was effective in preventing pregnancy in a population of women representative of US demographics. Efficacy was reduced in women with BMI ≥30 kg/m2. The TDS safety and tolerability profile was consistent with other similar dose combined hormonal contraceptives. Results of this phase 3 study supported the US Food and Drug Administration approval of TWIRLAⓇ for prevention of pregnancy in women with BMI <30 kg/m2. IMPLICATIONS: TDS (120 µg/day levonorgestrel and 30 µg/day ethinyl estradiol) is an effective, low-dose transdermal contraceptive patch with favorable tolerability profile approved for prevention of pregnancy in women with BMI <30 kg/m2. TDS has reduced effectiveness in women with BMI ≥30 kg/m2.

Physicians' views and practices concerning menopausal hormone therapy.

OBJECTIVE: To examine physicians' views and practices concerning estrogen+progestogen therapy (EPT). DESIGN: Questionnaires were mailed to a random sample of physicians in the United States (US) in 2003. A total of 1614 (53.8%) surveys were returned (633 obstetricians and gynecologists (Ob/Gyns), 571 family practitioners, and 410 internists). RESULTS: Only a minority of the physicians (16%) would offer EPT to menopausal women in the absence of menopausal symptoms (26% Ob/Gyn, 11% family practitioners, 6% internists, p<0.0001). However, many physicians (62%) believed that EPT could be offered "short term" to menopausal women with menopausal symptoms assuming no contraindications (82% Ob/Gyn, 54% family practitioners, 42% internists; p<0.0001). Irrespective of specialty, the strongest contraindications to EPT use reported by these physicians were personal history of breast cancer (93%), thrombosis (92%), cerebrovascular disease (84%), ischemic heart disease (74%), uterine cancer (73%), as well as women's subjective "concern" about breast cancer (57%). Procedures reported as always required by physicians for continuing women on EPT were breast examination (97%), mammogram (96%), blood pressure measurement (94%), and pelvic examination (91%). CONCLUSIONS: Internists and family practitioners address more contraindications to EPT use than Ob-Gyns. Although many physicians appear to be accepting of short-term use of EPT for menopausal indications in the absence of contraindications, the majority would not prescribe it for prophylactic purposes.

Disparities in contraceptive knowledge, attitude and use between Hispanic and non-Hispanic whites.

BACKGROUND: Higher rates of unwanted pregnancies and lower rates of contraceptive use have been reported among Hispanic women than among non-Hispanic whites. Despite these differences, it is unclear how these groups differ with respect to various psychosocial factors that are associated with contraceptive decision making, including contraceptive knowledge, attitudes, self-efficacy and social support. METHODS: A total of 443 sexually active, nonpregnant, low-income women (137 non-Hispanic whites, 74 US-born Hispanics and 231 non-US-born Hispanics) were surveyed at two publicly funded clinics. RESULTS: The greatest number of barriers to the effective use of contraception was seen among non-US-born Hispanic women. Fewer differences emerged between US-born Hispanics and whites, although differences continued to exist between the two groups in certain key areas. As compared to non-Hispanic whites, US-born Hispanic women had lower levels of social support for and self-efficacy in contraceptive use, desired larger families, had more religious objections to using birth control and were more those likely to believe that birth control use is the responsibility of women. As compared to whites, both US and non-US-born Hispanic women had significantly lower rates of ever-use of contraceptives that are highly effective in preventing pregnancy or in preventing disease transmission, and higher rates of unintended pregnancies. All associations were independent of known confounders. CONCLUSION: Despite improvements in contraceptive knowledge and attitude, birth control and disease-preventive practices did not improve significantly among Hispanics who were born in the United States. Hispanic women are at higher risk for unintended pregnancy than are non-Hispanic whites, irrespective of their US nativity.

Consistency of condom use among low-income hormonal contraceptive users.

CONTEXT: Hormonal contraceptive users may be at increased risk for HIV and other STDs. An understanding of their decisions and abilities to use condoms is needed to focus intervention programs aimed at improving their protective behaviors. METHODS: Between 1999 and 2001, 426 new users of depot medroxyprogesterone acetate (DMPA) and oral contraceptives were recruited from public clinics providing family planning services to low-income women and surveyed when they began their method and again three months later. Bivariate analyses examined the consistency of condom use across subgroups, and multivariate analyses assessed associations between consistent use and various characteristics. RESULTS: Among women who had used condoms consistently before starting on DMPA or the pill, 54% discontinued consistent use after taking these contraceptives. Overall, 20% of women consistently used condoms with their hormonal method, and such use did not vary significantly by contraceptive type. Seventy-five percent of women in non-monogamous relationships were inconsistent users, though nearly a third had been consistent users prior to beginning a hormonal method. Factors associated with an elevated likelihood of consistent use were the male partner's positive opinion of condoms (odds ratio, 3.3) and the woman's strong belief that condom use is important for vaginal intercourse (3.5) and even if the couple is using another form of birth control (4.1). CONCLUSIONS: Many women at highest risk for disease have a decreased likelihood of using condoms, and disease prevention programs should be customized to target these women. Educational efforts focusing on women's attitudes and negotiation skills may be the best means of increasing dual method use.

Cycle control, tolerability, and satisfaction among women switching from 30-35 microg ethinyl estradiol-containing oral contraceptives to the triphasic norgestimate/25 microg ethinyl estradiol-containing oral contraceptive Ortho Tri-Cyclen LO.

OBJECTIVE: To determine cycle control, tolerability, and satisfaction among women (aged 18-45) switching from oral contraceptives (OCs) containing 30-35 microg ethinyl estradiol (EE) to Ortho Tri-Cyclen LO (norgestimate 180/215/250 microg/EE 25 microg) and Loestrin Fe 1/20 (norethindrone acetate 1 mg/EE 20 microg). DESIGN: A subset of patients from a study comparing Ortho Tri-Cyclen LO (N = 864) with Loestrin Fe 1/20 (N = 565) was analyzed. The subset was defined as those who had taken a 30-35 microg EE-containing OC within 60 days of study start. The total number of cycles of exposure for the subset was 6,054 for Ortho Tri-Cyclen LO and 3,814 for Loestrin Fe 1/20. Additional analyses evaluated switchovers from Ortho Tri-Cyclen to Ortho Tri-Cyclen LO (N = 111). MAIN OUTCOME MEASURES: Cycle control was assessed by daily diary cards reporting the frequency, severity, and duration of bleeding/spotting. Discontinuation rates due to adverse events (AEs) were considered to reflect tolerability. Satisfaction was evaluated by questionnaire. RESULTS: The proportion of cycles in which subjects experienced breakthrough bleeding and/or spotting was significantly lower with Ortho Tri-Cyclen LO than Loestrin Fe 1/20. Discontinuations due to AEs and serious AEs were comparable for Ortho Tri-Cyclen LO (3.4% and 0.6%, respectively) and Loestrin Fe 1/20 (3.2% and 0.7%, respectively). More women on Ortho Tri-Cyclen LO versus Loestrin Fe 1/20 were very or somewhat satisfied at Cycle 6 (86% vs. 81.1%; P < 0.05) and last visit (81.6% vs. 78.1%; P < 0.05). At Cycle 6, 89.3% of Ortho Tri-Cyclen to Ortho Tri-Cyclen LO switchovers were very or somewhat satisfied, and 72.6% desired to continue taking Ortho Tri-Cyclen LO after study conclusion. Conclusions-Switchovers from OCs containing 30-35 microg EE to Ortho Tri-Cyclen LO had excellent cycle control and tolerability, and were satisfied.

Paternal influences on the timing of prenatal care among Hispanics.

OBJECTIVES: The purpose of this study was to examine the independent role of paternal influences on the onset of prenatal care among Hispanic women. METHODS: A total of 300 pregnant Hispanic women seeking prenatal care on or before their 35th week of gestation were surveyed about their and their partner's pregnancy intention. Women in this study were recruited from clinics providing services to low income and medically indigent women. RESULTS: Father's pregnancy intention had a protective effect on the timely onset of prenatal care. Pregnancies that were unintended by the mother but were intended by the father had a lower likelihood of delayed care, as compared to those unintended by both (Odds Ratio [OR] = .54, 95% confidence interval [CI] = .28, .99). This trend was stronger among married than non-married couples. CONCLUSION: Comprehensive efforts are needed to involve male partners in family planning as well as in programs aimed at expanding adequate pre- and postnatal behaviors within Hispanics.