Clinical Evaluation of Effectiveness and Safety of Combined Use of Dietary Supplements Amberen® and Smart B® in Women with Climacteric Syndrome in Perimenopause.

INTRODUCTION: Perimenopause is a time of transition in a woman's life that links her reproductive years to the cessation of ovulation, or menopause. For many women, this time is characterized by a variety of physiological and lifestyle changes, including increasing irregularity in menstrual bleeding, frequency and severity of vasomotor symptoms, etc. Therapies evaluated specifically for the perimenopausal women are very limited. This study aimed to evaluate the effectiveness and safety of Amberen® (a succinate-based non-hormonal supplement) combined with a Smart B® (vitamin B) complex in women with typical (without complications) mild to moderate climacteric syndrome during perimenopause. METHODS: Women up to 50 years of age, in perimenopause, with vasomotor and psychosomatic symptoms of the climacteric syndrome were enrolled for the study. The trial was randomized, double-blinded, placebo-controlled, comparative, and prospective. RESULTS: A total of 106 participants were enrolled in the trial and, per protocol, 105 completed the trial. We observed statistically significant improvements in most of the Greene Climacteric Scale symptoms, State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS), and Well-being, Activity, and Mood (WAM) scores. The intervention was well tolerated with few adverse effects reported to be mild and transient. CONCLUSION: The use of this dietary supplement is safe and eliminates or improves vasomotor and psychosomatic symptoms of climacteric symptoms in perimenopausal women: it improves sleep and cognitive abilities, lowers depression and anxiety, improves mood and well-being, and positively affects quality of life. GOV IDENTIFIER: NCT03897738.

Use of Sotrovimab in Pregnancy: Experiences from the COVID-19 International Drug Pregnancy Registry.

INTRODUCTION: Available data regarding the safety and efficacy of sotrovimab in pregnant patients remain limited due to their exclusion from clinical trials. METHODS: The COVID-19 International Drug Pregnancy Registry (COVID-PR) was established to gather comprehensive safety data from pregnant women who have received monoclonal antibody (mAb) or antiviral treatments for mild, moderate, or severe coronavirus disease 2019 (COVID-19) during pregnancy. Participants actively contributed self-reported data concerning their COVID-19 symptoms, in addition to sociodemographic and health-related characteristics. Obstetric, neonatal, and infant outcomes were also documented, with follow-up extending up to 12 months after childbirth. RESULTS: As of 30 November 2023, sotrovimab was administered to 39 participants enrolled in the COVID-PR. At the time of this report, 26 participants had given birth, with nine deliveries performed via cesarean section. The infants' birthweight ranged from 2381 g to 4762 g, with a mean of 3439.91 g. Twenty-five infants were born at ≥37 weeks. A total of 31 adverse events (AEs) were reported by 12 participants. The most frequently reported AE was gestational hypertension, observed in three participants. COVID-19 re-infection, fatigue, gestational diabetes, headache, and morning sickness were each reported by two participants. Of the reported AEs, eight (in five participants) were classified as serious, including four AEs (prolonged labor, pre-eclampsia, polyhydramnios, premature labor) that affected pregnancy. Seven of these eight serious AEs (SAEs) were found to be unrelated to sotrovimab, with one event (urinary retention) not assessable. A total of 44 AEs were reported in 19 delivered infants or in utero fetuses. The most common were COVID-19 (n = 6 events), ear infection (n = 5 events), neonatal dyspnea (n = 3 events), and respiratory syncytial virus infection (n = 3 events). Sixteen AEs (in 11 infants/fetuses) were classified as serious, including one report each of fetal cardiac disorder, congenital ankyloglossia, persistent right umbilical vein, and congenital hydronephrosis; the latter was considered a major congenital malformation. For all assessable SAEs, causality of sotrovimab treatment was ruled out based on lack of a temporal relationship alone or in combination with absence of a plausible mechanism. CONCLUSION: A sizable proportion of sotrovimab-treated participants in the COVID-PR had underlying medical conditions associated with an increased risk of severe COVID-19. None of the assessable SAEs were considered to be related to sotrovimab treatment.

No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis.

STUDY QUESTION: Is exposure to dydrogesterone a risk factor for congenital anomalies when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in assisted reproductive technology (ART)? SUMMARY ANSWER: Dydrogesterone, when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in ART, is not a relevant additional risk factor for congenital anomalies. WHAT IS KNOWN ALREADY: Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins. STUDY DESIGN SIZE DURATION: A systematic review was conducted according to a pre-specified protocol with searches on Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was limited to human studies, with no restrictions on language, geographical region, or date. The search algorithm used a PICO (Population, Intervention, Comparison, Outcome)-style approach combining both simple search terms and medical subject heading terms. As congenital anomalies are mostly reported as secondary outcomes, the search term 'safety' was added. PARTICIPANTS/MATERIALS SETTING METHODS: Interventional study and observational study (OS) designs were eligible for inclusion. Inclusion criteria were: women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the use of dydrogesterone in the first trimester compared with placebo, no treatment or other interventions; and reporting of congenital anomalies in newborns or infants ≤12 months old (primary outcome). Two authors (A.K., M.R.N.) independently extracted the following data: general study information, study population details, intervention and comparator(s), and frequencies of congenital anomalies (classification, time of determination, and type). Risk of bias focused on the reporting of congenital malformations and was assessed using the Cochrane Risk of Bias Tool Version 2 or the ROBINS-I tool. The GRADEproGDT platform was used to generate the GRADE summary of findings table. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 897 records retrieved during the literature search, 47 were assessed for eligibility. Nine studies were included in the final analysis: six randomized controlled trials (RCTs) and three OSs. Among the RCTs, three had a low risk and three a high risk of bias. Two of the OSs were considered to have a serious risk of bias and one with critical risk of bias and was excluded for the evidence syntheses. The eight remaining studies included a total of 5070 participants and 2680 live births from 16 countries. In the meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55; 1.55] with low certainty. When the two OSs were included, the overall RR was 1.11 [95% CI 0.73; 1.68] with low certainty. LIMITATIONS REASONS FOR CAUTION: The studies included in the analysis do not report congenital anomalies as the primary outcome; reporting of congenital anomalies was often not standardized. WIDER IMPLICATIONS OF THE FINDINGS: This systematic literature review and meta-analysis provide clear reassurance to both clinicians and patients that dydrogesterone is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors. The results of this work represent the highest current level of evidence for the question of congenital anomalies, which removes the existing uncertainty caused by poor quality and retracted studies. STUDY FUNDING/COMPETING INTERESTS: Editorial support was provided by Highfield Communication Consultancy, Oxford, UK, sponsored by Abbott Products Operations AG, Allschwil, Switzerland. A.K., J.A.G.-V., L.P.S., J.N.v.d.A., and J.F.S. received honoraria from Abbott for preparation and participation in an advisory board. J.A.G.-V. received grants and lecture fees from Merck, Organon, Ferring, Gedeon Richter, and Theramex. M.R.N. has no conflicts of interest. J.N.v.d.A. and J.A.G.-V. have no other conflicts of interest. A.K. received payment from Abbott for a talk at the IVF Worldwide congress on 22 September 2023. J.F.S. has received grants from the National Institutes of Health, royalties/licences from Elsevier and Prescient Medicine (SOLVD Health), consulting fees from Burroughs Wellcome Fund (BWF) and Bayer, honoraria from Magee Women's Research Institute, Wisconsin National Primate Research Centre, University of Kansas and Oakridge National Research Laboratory, Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support to attend meetings for the International Academy of Human Reproduction (IAHR). J.F.S. has patents related to diagnosis and treatment of PCOS and prediction of preterm birth. J.F.S. participates on advisory boards for SOLVD Health, Wisconsin National Primate Research Centre, and FHI360, was the past President board member of the Society for Reproductive Investigation, has a leadership role for the following organizations: Scientific Advisory Board, SOLVD Health, EAB Chair for contraceptive technology initiative, FHI360, EAB member, Wisconsin National Primate Research Centre, Advisory Board for MWRI Summit, Chair of BWF NextGen Pregnancy Research Panel, Medical Executive Committee at the Howard, and Georgeanna Jones Foundation, and is Vice President, IAHR. L.P.S. has received consulting fees from Shield Pharmaceuticals, Scynexis, Organon, Natera, Celula China, AiVF, Agile, Daiichi Sankyo, American Regent, and Medicem, honoraria from Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support from BD Diagnostics. L.P.S. participates on the data safety monitoring board for Astellas and is a Chair of DSMB for fezolinetant. Abbott played no role in the funding of the study or in study design, data collection, data analysis, data interpretation, or writing of the report. TRIAL REGISTRATION NUMBER: PROSPERO 2022 CRD42022356977.

OvaPrint-A Cell-free DNA Methylation Liquid Biopsy for the Risk Assessment of High-grade Serous Ovarian Cancer.

PURPOSE: High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathologic assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study, we developed a cell-free DNA (cfDNA) methylation liquid biopsy for the risk assessment of early-stage HGSOC. EXPERIMENTAL DESIGN: We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMR) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1,677 DMRs and constructed a classifier (OvaPrint) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade and borderline samples to assess the generalizability of OvaPrint. A total of 372 samples (tissue n = 59, plasma n = 313) were analyzed in this study. RESULTS: OvaPrint achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential. CONCLUSIONS: OvaPrint is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.

A critical appraisal of safety data on dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis.

No data support the suggestion that first-trimester dydrogesterone use increases the risk of fetal abnormalities; however, two low-quality retrospective studies (one retracted by the journal) have suggested such a link. A scoping review and meta-analysis were carried out to address this discrepancy. The literature was reviewed but it was not possible to identify any evidence of a plausible mechanism for potential causality between dydrogesterone and fetal abnormalities. To investigate whether any evidence existed, a preliminary meta-analysis was undertaken of clinical studies published since 2005 on first-trimester dydrogesterone use with assessment of fetal abnormalities. A fixed effects model was used to determine pooled odds ratios with 95% confidence intervals (95% CI). From 83 articles identified, six randomized controlled trials were included. Pooled risk ratios (RR) for maternal dydrogesterone use and fetal abnormalities gave a RR approaching 1 (RR 0.96; 95% CI 0.57, 1.62), confirming previous conclusions of no causal association between fetal abnormalities and first-trimester dydrogesterone use. Physicians, scientists and journal reviewers should exercise due diligence to prevent promulgation of retracted data. We are confident in using dydrogesterone, if indicated, in the treatment of threatened or recurrent miscarriage, and believe that its favourable safety profile should extend to its appropriate use in assisted reproductive technologies.

Iron Deficiency in Women's Health: New Insights into Diagnosis and Treatment.

Iron deficiency (ID), with or without anemia, is commonly found worldwide and affects the health and wellbeing of pregnant and nonpregnant women. Symptoms of ID- which include fatigue, pica (ice craving), restless legs syndrome, poor concentration and work function, increased susceptibility to infection, and cardiovascular stress- can cause significant morbidity and reduced quality of life. The etiologies of iron deficiency in women are usually specific to each community. In the developing world, iron deficiency is usually associated with poor iron intake and parasitic infections, whereas in higher income regions, iron deficiency is typically the result of heavy, abnormal uterine bleeding, and pregnancy. Iron-poor diets and poor iron absorption resulting from gut disorders can also play a role. Diagnosis of iron deficiency is usually straightforward and characterized by a low ferritin level; however, the diagnosis can be challenging in women with concomitant inflammatory disorders, in which case a low percent transferrin saturation, performed after an overnight fast, can inform on the need for iron. Therapy is frequently initiated with oral iron salts; however, use of these oral regimens is commonly associated with adverse events, mostly gastrointestinal in nature, that have been shown to adversely impact compliance, continuation, and the achievement of therapeutic goals. A further impediment to the effectiveness of oral iron is its poor absorption because of comorbidity (i.e., celiac disease, gastritis, etc.), surgery (bariatric), or physiologic inhibitory mechanisms. As such, intravenous (IV) iron regimens are increasingly being used to treat ID, as such regimens have been shown to avoid the gastrointestinal adverse events commonly associated with oral regimens. Indeed, IV iron has been shown to provide adequate iron replacement in women with functional iron deficiencies as well as those with ID resulting from inflammatory disorders- patients often resistant to oral iron therapy. More recent IV iron regimens have been shown to provide iron replacement in a safe and effective manner, being associated with more salutary adverse event profiles than earlier IV iron regimens. In fact, these iron regimens can provide a complete replacement dose in a single 15-60-min visit.

Disparities among infertility patients regarding genetic carrier screening, sex selection, and gene editing.

PURPOSE: The purpose of this study is to evaluate the perspectives of infertility patients regarding genetic carrier screening, embryo sex selection, embryo research, and gene editing. METHODS: An anonymous 32-question survey was distributed electronically to all patients who seen at a single academic fertility center for at least one visit between June 2018 and September 2019. Survey questions evaluated patient perspectives on genetic carrier screening, embryo sex selection, embryo research, and gene editing. RESULTS: There were 1460 survey responses (32.0% response rate). There were significant differences in the proportion of respondents receiving genetic carrier screening between racial groups, 73.1% of White, 45.5% of Black, 49.4% of Hispanic, and 62.8% of Asian respondents. The likelihood of having genetic carrier screening was also significantly influenced by respondent income, insurance status, and religion. Religion significantly influenced the acceptance of embryonic research and embryonic sex selection. While only 8.9% felt that genetically modifying embryos for physical traits should be allowed, 74.1% felt that genetic modification to correct disease should be allowed. CONCLUSION: Racial, religious, and socioeconomic factors significantly impacted respondents' likelihood to have genetic carrier screening and views on embryo sex selection, embryo research, and gene editing. These findings highlight the importance of tailoring genetic counseling to the individual, acknowledging individual and cultural differences in agreement with genetic testing and emerging genetic therapies.

Genetic ancestry analysis on >93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines.

PURPOSE: Carrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient's self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk. METHODS: For 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data. RESULTS: Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in at-risk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds-who did not self-report the associated ethnicity-had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve. CONCLUSION: Substantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.

Hot flashes are associated with altered brain function during a memory task.

OBJECTIVE: Vasomotor symptoms (VMS) are associated with decreased memory performance and alterations in brain function. We conducted a preliminary examination of VMS and patterns of brain activity during a verbal memory task to provide insights into the VMS-related brain mechanisms that can contribute to memory problems in midlife women. METHODS: Fourteen postmenopausal women (mean age 53.5, 64% African-American) with moderate-to-severe VMS (>35/wk) and not taking hormone therapy completed functional magnetic resonance imaging (fMRI) assessments during word encoding and recognition, 24-hour physiologic VMS monitoring, symptom questionnaires, and two verbal memory tests. RESULTS: In regression analyses, a higher number of physiologic VMS, but not reported VMS, was associated with worse verbal memory on immediate and delayed logical memory (r = 0.53 and r = 0.72, P < 0.05). On fMRI assessments, a higher number of physiologic VMS, but not subjective VMS, was associated with greater activation in the left orbitofrontal cortex, left medial and superior frontal gyrus, right superior frontal gyrus, and right parahippocampal gyrus during the encoding task (P < 0.005). During the recognition task, physiologic VMS were associated with greater activation in the left medial and superior frontal gyrus, left parahippocampal gyrus and hippocampus, right medial and superior frontal gyrus, right parahippocampal gyrus and hippocampus (P < 0.005), and with decreased activation in the ventral medial prefrontal cortex (P < 0.005). Those associations were independent of symptoms and hormone levels. CONCLUSIONS: Preliminary data suggest that VMS may contribute to memory performance through effects on the hippocampus and prefrontal cortex. Larger studies are warranted to determine the robustness of these initial observations. : Video Summary:http://links.lww.com/MENO/A508.

Video Summary:http://links.lww.com/MENO/A508.

Succinate-Based Dietary Supplement for Menopausal Symptoms: A Pooled Analysis of Two Identical Randomized, Double-Blind, Placebo-Controlled Clinical Trials.

BACKGROUND: To evaluate the efficacy of a succinate-based dietary supplement (SBDS; Amberen) in symptomatic menopausal women using a larger sample size derived by pooling data from two identical trials. METHODS: Raw data were pooled from two identical randomized, multicenter, double-blinded, placebo-controlled, 90-day clinical trials. Women aged 42-60 years with mild to moderate vasomotor and psychosomatic menopausal symptoms were included (114 in the treatment group and 113 in the placebo group). Symptoms were assessed by the Greene Climacteric Scale and State-Trait Anxiety Inventory. Changes in body mass index, body weight, waist and hip circumferences, and plasma levels of follicle stimulating hormone, luteinizing hormone, estradiol, leptin, and apolipoproteins A1 and B were also evaluated. RESULTS: SBDS use resulted in significant improvements in several endpoints including alleviation of 16 of 21 menopausal symptoms (p ≤ 0.05, Greene Scale) and a decrease in anxiety (p < 0.0001, State-Trait Anxiety Inventory) when compared to placebo. Significant reductions were observed in weight, body mass index, and waist and hip circumferences in the supplement cohort. Evaluation of physiological parameters showed a significant increase in serum estradiol levels compared to baseline (p < 0.0001) among users of the SBDS. Levels of follicle stimulating hormone and luteinizing hormone decreased slightly in both groups, without significant differences between the groups. Leptin levels decreased with statistical significance in the SBDS cohort compared to placebo (p=0.027). For those with initial leptin concentrations above the reference range, leptin decreased significantly in the SBDS group compared to the baseline (p < 0.0001) and to placebo (p=0.027). CONCLUSIONS: The pooled analysis reaffirms the outcomes from the individual trials. A nonhormonal, succinate-based dietary supplement is shown to relieve menopausal symptoms when compared to a placebo regimen in a randomized, double-blinded clinical trial.

Assessing the impact of delayed blastulation using time lapse morphokinetics and preimplantation genetic testing in an IVF patient population.

PURPOSE: There is clinical evidence that early cleavage timing parameters predictive of blastocyst development also correlate with embryo implantation potential. The aim of this study is to determine the developmental competency of embryos with delayed blastulation. METHODS: Retrospective study performed from 2015 to 2016 at the Division of Reproductive Endocrinology and Infertility at Northwestern University. RESULTS: A total of 2,292 embryos from 524 patients were included. Day 6 blastocysts had statistically significant longer times for every time point analyzed than day 5 blastocysts (p < 0.001). We found no statistically significant difference in euploidy rates between day 5 (44%) and day 6 (41%) embryos (p = 0.573). t7 and t8 time points were independent predictors of euploidy after controlling for day of biopsy (p < 0.015 and p < 0.014, respectively). Intrauterine pregnancy (IUP) and live birth (LB) were less likely to occur after transferring day 6 embryos (p = 0.0033 and p = 0.0359) without previous genetic testing. However, in embryos that undergo preimplantation genetic testing for aneuploidy (PGT-A), there were no significant differences in IUP or LB rates. CONCLUSION: Early time-lapse points can be used to predict embryo development. Day of blastulation may be an independent predictor IUP, with day 6 blastocysts having lower pregnancy and live birth rates. Our data suggests that day 5 and day 6 PGT-A tested embryos show similar rates of euploidy, suggesting that differences in PR seen in the non-PGT-A tested group may be caused by factors other than aneuploidy. Genetic testing technologies in combination with time-lapse microscopy may provide further information to improve IVF outcomes.

Clinical Performance Comparison of Two In-Vitro Diagnostic Multivariate Index Assays (IVDMIAs) for Presurgical Assessment for Ovarian Cancer Risk.

INTRODUCTION: Adnexal or pelvic mass is a finding that commonly raises suspicion for malignancy, especially for ovarian cancer. Proper identification prior to surgery would permit appropriate referral to a specialty center in cases likely to be ovarian cancer, as optimal outcomes in such cases are obtained when surgical staging and treatment are provided at the time of initial surgery. METHODS: We compared the screening capabilities of two in vitro diagnostic multivariate index assays (IVDMIAs), a new IVDMIA (second-generation multivariate index assay: MIA2G) and a currently used triage algorithm (Risk of Ovarian Malignancy Assay: ROMA). RESULTS: Among 245 subjects (24.7%) determined to have a malignancy, ROMA misclassified 51 malignancies (including 10 high-grade ovarian malignancies), whereas MIA2G misclassified 22 (including 5 high-grade ovarian malignancies). Early stage cancers were more frequently misclassified by ROMA (20 vs. 8 cases). The rate of "test-negative" malignancies was significantly higher for ROMA, while the rate of "test-positive" benign cases was significantly higher for MIA2G. CONCLUSION: Triage algorithms play an important role in improving clinical outcomes for women presenting with an adnexal mass regardless of the eventual diagnosis. In this study, MIA2G was shown to correctly predict more cases of ovarian cancer than the ROMA algorithm. FUNDING: Aspira Labs/Vermillion Inc.

Adjunctive Agents for Cervical Preparation in Second Trimester Surgical Abortion.

Late second trimester dilation and evacuation is a challenging subset of surgical abortion. Among the reasons for this is the degree of cervical dilation required to safely extricate fetal parts. Cervical dilation is traditionally achieved by placing multiple sets of osmotic dilators over two or more days prior to the evacuation procedure; however, there is interest in shortening cervical preparation time. The use of adjuvant mifepristone and misoprostol in conjunction with osmotic dilators has been studied for this purpose, and their use demonstrates that adequate cervical dilation can be achieved in less time than with dilators alone. We present a review of the current evidence surrounding adjunctive agents for cervical preparation, and contend that for women presenting for surgical abortion care above 19 weeks gestation, the use of adjunctive mifepristone and/or misoprostol should be strongly considered along with osmotic dilator insertion when cervical preparation in less than 24 h is needed.

Health-Related Quality of Life With Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To investigate effects of ulipristal acetate on health-related quality of life (QOL) and symptom severity in women with symptomatic uterine leiomyomas and abnormal uterine bleeding. METHODS: Women were randomized to ulipristal (5 mg, 10 mg) or placebo in two phase 3, multicenter, double-blind, placebo-controlled trials (VENUS I and II). Health-related QOL and symptom severity were assessed at baseline, and over one (VENUS I and II) and two (VENUS II) 12-week treatment courses using the Uterine Fibroid Symptom Health-Related Quality of Life questionnaire. In pooled VENUS I and II data, change from baseline to the end of the first course for each Uterine Fibroid Symptom Health-Related Quality of Life scale was analyzed, including a Revised Activities subscale that measured physical and social activities. The proportion of women achieving meaningful change in the Symptom Severity (20 or more points), Health-Related QOL Total (20 or more points), and Revised Activities (30 or more points) scales was calculated. In VENUS II data, change from baseline to the end of each course in each scale was analyzed for each treatment arm. RESULTS: In pooled analyses, the intent-to-treat population included 589 patients (placebo, n=169; ulipristal 5 mg, n=215; ulipristal 10 mg, n=205). Significantly greater improvements from baseline in all Uterine Fibroid Symptom Health-Related Quality of Life scales were observed with both ulipristal doses compared with placebo (P<.001). A meaningful change in Revised Activities was achieved by 51 patients receiving placebo (34.9%), compared with 144 (73.5%; OR 5.0 [97.5% CI 2.9-8.6]) and 141 (80.6%; OR 7.9 [97.5% CI 4.3-14.6]) patients receiving ulipristal 5 mg, and 10 mg, respectively. In VENUS II, at end of courses 1 and 2, both ulipristal doses demonstrated significant improvements from baseline compared with placebo for all Uterine Fibroid Symptom Health-Related Quality of Life scales (P<.01). Mean Revised Activities scores showed that beneficial ulipristal effects were maintained in course 2, and improvements occurred on switching to ulipristal; results for other scales were similar. CONCLUSION: Ulipristal was associated with significant improvements in health-related QOL and symptom severity compared with placebo for women with symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147197 and NCT02147158. FUNDING SOURCE: Allergan plc, Dublin, Ireland.

Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18-50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo. RESULTS: From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3-51.1]) and 86 of 157 (54.8% [97.5% CI 45.5-63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0-3.8]) patients treated with placebo achieved amenorrhea (P<.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P<.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P<.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively. CONCLUSION: Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147158.