Frequency Of Vasomotor Symptoms Research Articles

Validation and Application of Thresholds to Define Meaningful Change in Vasomotor Symptoms Frequency: Analysis of Pooled SKYLIGHT1 and 2 Data.

Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data. This analysis pooled data from two identical phase3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30mg, 45mg, or placebo (SKYLIGHT1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better." In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week4 and - 6.20 (5.18) at week12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week4 (odds ratio range 2.48-2.91; P < 0.001) and week12 (odds ratio range 1.908-2.68; P < 0.001). PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option. NCT04003155 and NCT04003142.

Treating moderate-to-severe menopausal vasomotor symptoms with fezolinetant: analysis of responders using pooled data from two phase 3 studies (SKYLIGHT 1 and 2).

The aims of the study were to further characterize the efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms (VMS) due to menopause using responder analysis and to investigate whether efficacy, not adjusted for placebo, resulted in clinically meaningful within-patient change. This prespecified analysis used pooled data from two phase 3, randomized, double-blind, placebo-controlled studies (SKYLIGHT 1 and 2). Responders were those experiencing ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. Responder analysis was performed for patient-reported outcome (PRO) measures to evaluate participants achieving a clinically meaningful within-patient change (not placebo adjusted) at week 4 and 12 versus baseline. Single responders were based on outcomes of VMS frequency, Patient-Reported Outcomes Measurement Information System Sleep Disturbance-Short Form 8b Total Score, Menopause-Specific Quality of Life (MENQoL) Total Score, and MENQoL VMS Domain Score. Double and triple responder analyses combined VMS frequency plus one or more of the PRO. Patient Global Impression of Change VMS was deemed a suitable anchor measure for meaningful within-patient change in VMS frequency. A greater proportion of fezolinetant-treated versus placebo-treated participants had ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. A greater proportion of responders were observed in the fezolinetant groups versus placebo at week 12 in all four single responder analyses. In the double and triple responder analyses, odds ratios were supportive of a beneficial effect for both doses of fezolinetant versus placebo. Fezolinetant was associated with significantly higher within-patient clinically meaningful improvement in important PRO, including VMS frequency, PROMIS SD SF 8b Total Score, MENQoL Total Score, and MENQoL VMS Domain Score.

Does everyday discrimination account for the increased risk of vasomotor symptoms in Black women?: the Study of Women's Health Across the Nation (SWAN).

Vasomotor symptoms (VMS), including hot flashes and night sweats, are hallmark symptoms of the menopause transition. Previous research has documented greater frequency, duration, and severity of VMS in Black women compared with women from other racial/ethnic groups, even after accounting for other factors. This analysis examined the association between discrimination and VMS and the extent to which discrimination accounts for the disproportionate burden of VMS in Black women. Using available discrimination and VMS data from the SWAN cohort study (n = 2,377, 48% White, 32% Black, 6% Japanese, 4% Chinese, and 9% Hispanic women) followed approximately yearly in midlife from premenopause (42-52 y) through postmenopause (~20 y), we assessed concurrent associations between discrimination and VMS frequency in the past 2 weeks using weighted generalized mixed models. We also assessed associations between chronic discrimination across first four visits and VMS trajectories from premenopause to postmenopause using weighted multinomial logistic regression. Models were adjusted for known risk factors for VMS. Higher levels of discrimination were associated with concurrent reporting of any (odds ratio [OR], 1.57 [1.31-1.89]) and frequent (≥6 d) VMS (OR, 1.55 [1.21-1.99]). After adjustment, associations remained significant for any (OR, 1.30 [1.09-1.54]) but not frequent VMS. For any VMS trajectories, chronic discrimination was associated with "continuously high" (OR, 1.69 [1.03-2.77]) and "high pre-FMP-decline post-FMP" (OR, 1.70 [1.01-2.88]) versus "FMP-onset low" trajectories. After adjusting for discrimination, odds of reporting any, frequent, and of being in the "continuously high" any VMS trajectory remained elevated for Black versus White women. Discrimination is associated with greater concurrent risk of any (but not frequent) VMS, and chronic discrimination is associated with a continuously high reporting of any VMS over time, independent of known risk factors. Adjusting for discrimination attenuates but does not eliminate the increased risk of VMS for Black women.

Efficacy and safety of fezolinetant for vasomotor symptoms in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials.

Vasomotor symptoms (VMS), such as hot flashes and night sweats, are highly prevalent and burdensome for women experiencing menopausal transition. Fezolinetant, a selective neurokinin 3 receptor (NK3R) antagonist, is a potential therapeutic option for mitigating VMS. Our aim is to assess the efficacy and evaluate the safety profile of fezolinetant compared with placebo in post-menopausal women suffering from VMS, by pooling all the relevant data and reflecting the most current evidence. An extensive literature search was performed in the PubMed, Medline and Cochrane Library databases from inception until June 2023 to identify relevant trials. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for continuous outcomes. Risk ratios (RRs) were calculated for dichotomous outcomes. All statistical analyses were performed using R Statistical Software. A total of six randomized controlled trials were added. For the frequency of daily VMS, the combined pooled result favored the fezolinetant group over placebo (MD -2.38, 95% CI -2.64 to -2.12; P < 0.001, I2 = 0%). For the severity of daily VMS, fezolinetant was again found to be superior to the placebo group (MD -0.40, 95% CI -0.51 to -0.29; P < 0.001, I2 = 70%). Fezolinetant (120 mg) consistently demonstrated a significant reduction in the severity of daily moderate/severe VMS compared with other doses at both 4 and 12 weeks. Patient-reported outcomes (PROs) of Greene Climacteric Scale (GCS), PROMIS the Sleep Disturbance Short Form 8b and Menopause-Specific Quality of Life (MENQoL) scores indicated significant improvement with fezolinetant. No significant difference in efficacy of fezolinetant at 4 and 12 weeks were observed in any outcome. As for safety, no significant differences in the treatment emergent adverse events at 12 weeks were found between fezolinetant and placebo. Our study significantly favors fezolinetant over placebo regarding the primary efficacy outcomes of daily moderate to severe VMS frequency and severity, including PROs, while both the groups are comparable in terms of treatment emergent adverse events. Further studies are needed to confirm these findings.

Multimodal, Technology-Assisted Intervention for the Management of Menopause after Cancer Improves Cancer-Related Quality of Life-Results from the Menopause after Cancer (Mac) Study.

Vasomotor symptoms (VMSs) associated with menopause represent a significant challenge for many patients after cancer treatment, particularly if conventional menopausal hormone therapy (MHT) is contraindicated. The Menopause after Cancer (MAC) Study (NCT04766229) was a single-arm phase II trial examining the impact of a composite intervention consisting of (1) the use of non-hormonal pharmacotherapy to manage VMS, (2) digital cognitive behavioral therapy for insomnia (dCBT-I) using Sleepio (Big Health), (3) self-management strategies for VMS delivered via the myPatientSpace mobile application and (4) nomination of an additional support person/partner on quality of life (QoL) in women with moderate-to-severe VMS after cancer. The primary outcome was a change in cancer-specific global QoL assessed by the EORTC QLC C-30 v3 at 6 months. Secondary outcomes included the frequency of VMS, the bother/interference of VMS and insomnia symptoms. In total, 204 women (82% previous breast cancer) with a median age of 49 years (range 28-66) were recruited. A total of 120 women completed the protocol. Global QoL scores increased from 62.2 (95%CI 58.6-65.4) to 70.4 (95%CI 67.1-73.8) at 6 months (p < 0.001) in the intention to treatment (ITT) cohort (n = 204) and from 62 (95%CI 58.6-65.4) to 70.4 (95%CI 67.1-73.8) at 6 months (p < 0.001) in the per-protocol (PP) cohort (n = 120). At least 50% reductions were noticed in the frequency of VMS as well as the degree of bother/interference of VMS at six months. The prevalence of insomnia reduced from 93.1% at the baseline to 45.2% at 6 months (p < 0.001). The Sleep Condition Indicator increased from 8.5 (SEM 0.4) to 17.3 (SEM 0.5) (p < 0.0005) in the ITT cohort and 7.9 (SEM 0.4) to 17.3 (SEM 0.5) (p < 0.001) in the PP cohort. A targeted composite intervention improves the quality of life for cancer patients with frequent and bothersome vasomotor symptoms with additional benefits on frequency, the bother/interference of VMS and insomnia symptoms.

Efficacy and Safety of Fezolinetant for the Treatment of Menopause-Associated Vasomotor Symptoms: A Meta-analysis.

To evaluate the efficacy and adverse events of fezolinetant for treating vasomotor symptoms (VMS) of menopause. PubMed/MEDLINE, ClinicalTrials.gov , EMBASE, Cochrane Database, Scopus, and WHO International Clinical Trials Registry Platform were searched through June 2023 for publications and randomized controlled trials on fezolinetant compared with placebo in menopausal women who experienced moderate-to-severe VMS. Our literature search identified 330 articles, of which five studies with six reports were included in our meta-analysis per our eligibility criteria. The risk of bias was evaluated using Cochrane's RoB 2 (Risk of Bias version 2) tool, quality of evidence was graded using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, and outcome measures data for effect size were pooled in random-effects model and rated. A total of 2,168 participants from five randomized clinical trials (six reports) were included. Fezolinetant significantly lowered VMS frequency, with pooled mean difference of 2.62 (95% CI, 1.84-3.41). The pooled mean difference for fezolinetant compared with placebo for the MENQOL (Menopause-Specific Quality of Life) measure was -0.60 (95% CI, -0.92 to -0.28), and the mean percentage improvement in VMS frequency was 22.51% (95% CI, 15.35-29.67). Fezolinetant was associated with improvement in sleep quality when compared with placebo. Fezolinetant is effective in lowering moderate-to-severe VMS frequency and sleep disturbances in postmenopausal women. PROSPERO, CRD42023427616.

Efficacy and safety of fezolinetant, a neurokinin-3 antagonist, in treating vasomotor symptoms in postmenopausal women: A systematic review and meta-analysis.

Menopause causes a variety of symptoms such as hot flashes and night sweats. While menopausal hormonal therapy has been used for managing postmenopausal vasomotor symptoms (VMS) for quite a while, it has a considerably poor safety profile. To review and analyze existing data to evaluate the efficacy of the neurokinin-3 antagonist, fezolinetant, in treating postmenopausal VMS and to assess its safety profile. A thorough literature search was performed on PubMed, Cochrane Library, and Google Scholar in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020, to find publications on the efficacy of fezolinetant for postmenopausal VMS. Changes in the frequency and severity scores of moderate/severe VMS and changes in the Hot Flash-Related Daily Interference Scale (HFRDIS), Greene Climacteric Scale (GCS), and Menopause-Specific Quality of Life (MENQoL) were the efficacy outcomes. Adverse events, drug-related treatment-emergent adverse effects (TEAEs), drug-related dropouts, hepatotoxicity, endometrial hyperplasia or tumor, and uterine bleeding were all safety outcomes. We used Review Manager 5.4 for pooling risk ratios (RRs) and mean differences (MDs) for dichotomous and continuous outcomes, respectively. A P value of < .05 was considered significant. There was a significant reduction in mean daily VMS frequency at weeks 4 and 12 (MD, -2.36; 95% confidence interval [CI], -2.85 to -1.87; P < .00001, for week 12) and also a significant decrease in VMS severity scores in the treatment group. Furthermore, improvements in MENQoL, HFRDIS, and GCS scores were observed. There was no significant difference in adverse events while drug-related TEAEs (RR, 1.21; 95% CI, 0.90-1.63; P = .21) showed a slight increase with fezolinetant. Drug-related dropouts were again similar across the 2 groups. Uterine bleeding had a lower incidence while endometrial events and hepatotoxicity showed a statistically insignificant, increasing trend in the fezolinetant group. Fezolinetant can be a treatment option for postmenopausal VMS but warns of a risk increase in endometrial hyperplasia or tumors. The heterogeneity in the data being analyzed, short follow-up period, and small sample size in most of the included randomized controlled trials were the greatest limitations, which must be considered in further research and safety profile exploration.

Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause.

The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown. We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women. Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models. The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo. The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS. These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.

Correlations among Core Outcomes in Menopause-recommended vasomotor symptom outcomes in MsFLASH trials.

This study aimed to advance understanding of vasomotor symptom (VMS) outcomes measurement using pooled data from three Menopause Strategies Finding Lasting Answers to Symptoms and Health (MsFLASH) trials. Participants self-reported VMS frequency, severity, and bother using daily diaries; completed standardized measures of VMS interference, insomnia severity, and sleep quality/disturbance; and completed four treatment satisfaction items. Analyses included descriptive statistics, Pearson correlations (baseline pooled sample, posttreatment pooled sample, posttreatment placebo only), t tests, and analysis of variance. Participants were mostly postmenopausal (82.9%) and a mean of 54.5 years old. VMS frequency was fairly correlated with severity, bother, and interference for pooled baseline and placebo posttreatment samples ( r values = 0.21-0.39, P values < 0.001) and moderately correlated with severity, bother, and interference for pooled posttreatment ( r values = 0.40-0.44, P values < 0.001). VMS severity, bother, and interference were moderately correlated ( r values = 0.37-0.48, P values < 0.001), with one exception. VMS severity and bother were strongly correlated ( r values = 0.90-0.92, P values < 0.001). VMS interference was moderately correlated with insomnia ( r values = 0.45-0.54, P values < 0.001) and fairly to moderately correlated with sleep quality/disturbance ( r values = 0.31-0.44, P values < 0.001). Other VMS outcomes were weakly to fairly correlated with insomnia ( r values = 0.07-0.33, P values < 0.001 to < 0.05) and sleep quality/disturbance ( r values = 0.06-0.26, P values < 0.001 to > 0.05). Greater improvement in VMS and sleep over time was associated with higher treatment satisfaction ( P values < 0.001). This pooled analysis advances understanding of VMS outcomes measurement and has implications for selecting measures and creating future research.

Assessment of women’s treatment preferences for vasomotor symptoms due to menopause

ABSTRACT Background Several therapies for vasomotor symptoms (VMS) due to menopause are available. Treatment preferences and willingness-to-pay for VMS treatment among US women with VMS were evaluated. Methods An online survey of women with perimenopausal or postmenopausal VMS was conducted (3/15/21–4/23/21). A discrete choice experiment quantified the impact of 7 treatment attributes on VMS treatment choice: VMS frequency/severity reduction, sleep improvement, risk of breast cancer/cardiovascular events in 6 years, risk of short-term side effects, and out-of-pocket costs. Preference weights (PWs) with 95% confidence intervals (CIs) were estimated and reported. Results Among 467 women, 86.5% and 87.8% reported moderate to very severe VMS and sleep problems during the preceding month, respectively. Sleep improvement (PW: 0.843; 95% CI: 0.721, 0.965) and reduction in VMS frequency (PW: 0.658; 95% CI: 0.520, 0.796) and severity (PW: 0.628; 95% CI: 0.500, 0.756) most influenced treatment preference; risk of cardiovascular events (PW: 0.150; 95% CI: 0.069, 0.232) or breast cancer (PW: 0.401; 95% CI: 0.306, 0.496) in 6 years had lesser effect. Willingness-to-pay was an additional $35–$46/month for substantially improved sleep, 80% VMS frequency reduction, and reduction from severe to mild VMS. Conclusions Sleep improvement and reductions in VMS frequency/severity were the most important treatment attributes.

Fezolinetant: First Approval.

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signalling in the central nervous system is a non-hormonal strategy to modulate the activity of neurones that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause. This article summarizes the milestones in the development of fezolinetant leading to this first approval in this indication.

Association between vasomotor symptom frequency and weight gain in the Study of Women's Health Across the Nation.

The menopause transition is associated with weight gain in women. We examined whether changes in vasomotor symptom (VMS) frequency precede weight changes. This longitudinal retrospective analysis included data from the multisite, multiethnic Study of Women's Health Across the Nation. Women in premenopause or perimenopause aged 42 to 52 years at baseline self-reported VMS frequency (hot flashes/night sweats) and sleep problems at up to 10 annual visits. Menopause status, weight, body mass index, and waist circumference were compared across visits. The primary objective was to measure the association between VMS frequency and weight gain using a lagged approach with first-difference regression models. Secondary objectives were to statistically quantify mediation by sleep problems and moderation by menopause status and explore the association between cumulative, 10-year VMS exposure and long-term weight gain. The primary analysis sample included 2,361 participants (12,030 visits; 1995-2008). Increased VMS frequency across visits was associated with subsequently increased weight (0.24 kg), body mass index (0.08 kg/m 2 ), and waist circumference (0.20 cm). Cumulative exposure to a high frequency of VMS (≥6 d/2 wk) over 10 consecutive annual visits was associated with increases in weight measures, including a 3.0-cm increase in waist circumference. Contemporaneous sleep problems mediated no more than 27% of waist circumference increases. Menopause status was not a consistent moderator. This study demonstrates that increases in VMS, onset of a high frequency of VMS, and persistent VMS symptoms over time may precede weight gain in women.

Managing perimenopausal CNS symptoms

Complaints of cognitive difficulties are more common, and performance on objective cognitive tests declines, in the perimenopause compared to the premenopause. In longitudinal studies, the cognitive ability affected most reliably during the transition is verbal learning and memory, with some studies also showing effects on processing speed. These stage-related changes in cognition are not fully accounted for by age, mood or menopause symptoms, suggesting that changes in ovarian hormones likely play an important role. Studies of surgical menopause support that hypothesis. In addition, vasomotor symptoms (VMS), sleep disturbance and mood difficulties contribute to these changes. Increased frequency of VMS during the day and particularly at night, have been linked to changes in memory, as well as brain function, connectivity and structure. Initial evidence suggests that treating VMS may improve cognition, and large clinical trials are underway to determine if VMS may play a causal role in such changes. Importantly, the link between VMS and brain health is observed only when VMS are measured objectively using ambulatory skin conductance monitors. If these associations are found to be causal in future studies, then the treatment of VMS may be indicated to maintain cognitive performance. Nighttime VMS are associated with awakenings, and disturbed sleep is a key determinant of cognitive performance. Behavioral interventions for sleep disturbance, including sleep hygiene and insomnia cognitive behavioral therapy (iCBT) are evidence based to improve sleep. Depression and anxiety symptoms increase in the perimenopause and are associated with cognitive difficulties. Treating mood and anxiety with CBT and lifestyle interventions (i.e., exercise, yoga is therefore also important to optimizing cognition. Head-to-head clinical trial data suggests that conjugated equine estrogen but not oral estradiol improves mood in euthymic midlife women. Most women with a history of major depression depressive disorder (MDD) will experience a recurrence of MDD during the perimenopause. Although treating MDD is likely to improve cognition, research indicates that those with MDD continue to experience cognitive problems even when not experiencing a major depressive episode. There are no large randomized trials of hormone therapy on cognition in the perimenopause, though treating VMS with hormone therapy theoretically may confer benefits, particularly if those VMS are disrupting sleep.

The menopause after cancer study: A multimodal technology assisted intervention for the management of menopausal symptoms after cancer.

12024 Background: Vasomotor symptoms (VMS) of menopause represent a significant challenge for many patients after cancer treatment, particularly if menopausal hormone therapy (MHT) is contraindicated. Methods: The Menopause after Cancer (MAC) Study ( NCT04766229) was a single arm phase II trial examining the impact of a composite intervention on quality of life (QoL) in women with moderate to severe VMS after cancer. The intervention consisted of: (1) use of non-hormonal pharmacotherapy to manage VMS (citalopram for predominantly daytime VMS and/or gabapentin for predominantly nocturnal VMS) (2) digital cognitive behavioural therapy for insomnia using Sleepio (BigHealth), (3) self-management strategies for VMS delivered via a mobile application called myPatientSpace and (4) nomination of an additional support person/partner. The primary outcome was cancer specific QoL assessed by the EORTC QLQ C30 version 3 at 6 months. Secondary outcomes included frequency of VMS, bother/interference of VMS (hot flush rating scale [HFRS]) and prevalence of insomnia (sleep condition indicator [SCI] ≥16) at 6 months. Results: 205 women (82% history of breast cancer) with a median age of 49 years (range 28-66) were recruited. Date of diagnosis ranged from January 2004 until January 2022, with 65% of participants diagnosed from 2019 onwards. Participants had a median of 10 hot flashes in a day (SD 9.2) and 4 night sweats each night (SD 4.9). 17.1% were prescribed citalopram, 62.8% gabapentin alone and 20.1% were prescribed both medications. 120 women completed the protocol. In the intention to treat (ITT) cohort (n = 205) mean QoL scores increased from 62.2 (SEM 1.4) at baseline to 70.4 (SEM 1.7) at 6 months (p &lt; 0.001). In the per protocol (PP) cohort, (n = 120) mean QoL scores increased from 62 (SEM 1.7) to 70.4 (SEM 1.7) at 6 months (p &lt; 0.001). Clinically meaningful improvements were seen across multiple domains of the EORTC QLQ C30 including cognitive function, emotional function and social functioning. Frequency of VMS decreased by 50% at 6 months in the ITT and PP cohorts. Mean HFRS scores decreased from 7.6 (SEM 0.1) to 3.4 (SEM 0.2) at 6 months (p &lt; 0.0005) in the ITT cohort (7.5 (SEM 0.1) to 3.4 (SEM 0.2) (p &lt; 0.001) in the PP cohort) demonstrating reduction in bother/interference of VMS. The prevalence of insomnia reduced from 92% at baseline to 38.7% at 6 months (p = 0.006) in the ITT cohort (95.2% to 38.7% in the PP cohort (p = 0.006)). Mean SCI scores increased from 8.5 (SEM 0.4) at baseline to 17.3 (SEM 0.5) at 6 months (p &lt; 0.0005) in the ITT cohort (7.9 (SEM 0.4) to 17.3 (SEM 0.5) (p &lt; 0.001) in the PP cohort). Significant reductions in wakefulness after sleep onset and sleep onset latency were major contributors to this improvement in insomnia symptoms. Conclusions: The MAC study demonstrates that improvements in QoL can be achieved using this multimodal intervention to target VMS and insomnia after cancer. Clinical trial information: NCT04766229 .

Advancing menopause care in Australia: barriers and opportunities.

Advancing menopause care in Australia: barriers and opportunities.

Fezolinetant Treatment of Moderate-to-Severe Vasomotor Symptoms Associated With Menopause: Effect of Intrinsic and Extrinsic Factors in Two Phase 3 Studies [ID: 1356963

INTRODUCTION: Fezolinetant was well tolerated and effective in reducing the frequency and severity of menopause-associated, moderate-to-severe vasomotor symptoms (VMSs) in SKYLIGHT 1 and 2. This analysis investigated the relationship between intrinsic (individual-related) and extrinsic (outside-influence) factors and fezolinetant efficacy. METHODS: In these phase 3, double-blind, placebo-controlled, IRB-approved studies (NCT04003155 and NCT04003142), women aged 40 through 65 years with moderate-to-severe VMSs (seven or more hot flushes/day) were randomized to once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. For this pooled analysis, the influence of intrinsic and extrinsic factors on change from baseline to week 12 in the frequency of moderate-to-severe VMSs was assessed by subgroups using a mixed model for repeated measurement. RESULTS: One thousand twenty-two women took one or more dose (placebo, n=342; fezolinetant 30 mg, n=339; fezolinetant 45 mg, n=341). Consistent improvements in VMS frequency over placebo were observed across subgroups with fezolinetant 45 mg. For intrinsic factors, least-square mean differences (95% CI) between fezolinetant 45 mg and placebo were as follows: age less than 55 years, −2.78 (−3.74, −1.82); 55 years or older, −2.24 (−3.23, −1.24); White race, −2.17 (−2.93, −1.41); Black race, −3.67 (−5.32, −2.01); and body mass index of 30 kg/m2 or higher, −2.87 (−4.11, −1.63). Extrinsic factors showed the following differences: current smoker, −3.48 (−5.19, −1.77); former/never smoker, −2.32 (−3.08, −1.57); European resident, −1.50 (−2.73, −0.26); and North American resident, −2.95 (−3.78, −2.13). Similar efficacy trends were observed with fezolinetant 30 mg. CONCLUSION: Fezolinetant was efficacious in treating moderate-to-severe VMSs associated with menopause across the intrinsic and extrinsic factors investigated, demonstrating its potential utility in a broad population.

Efficacy and safety of ultra-low-dose estradiol and norethisterone in postmenopausal Brazilian women

Objective This study aimed to evaluate the efficacy and safety of oral ultra-low-dose continuous combination of 17β-estradiol (17β-E2) and norethisterone acetate (NETA) in postmenopausal Brazilian women. Methods Postmenopausal women (age 45–60 years) with amenorrhea >12 months and intact uterus, with moderate to severe vasomotor symptoms, were included. The vasomotor symptoms and endometrial bleeding were evaluated by a daily diary for 24 weeks, and the women were assessed at baseline and endpoint. Results A total of 118 women were included. The group treated with 0.5 mg 17β-E2/0.1 mg NETA (n = 58) showed a percentage reduction of 77.1% in the frequency of vasomotor symptoms versus 49.9% in the placebo group (n = 60) (p = 0.0001). The severity score showed a reduction in the treatment group when compared to the placebo (p < 0.0001). The adverse events were comparable between the groups; however, in the 0.5 mg 17β-E2/0.1 mg NETA group there were more complaints of vaginal bleeding; despite that, in most cycles in both treatment groups, more than 80% of women experienced amenorrhea. Conclusions The combination of 0.5 mg 17β-E2/0.1 mg NETA in a continuous combination regimen was shown to be effective in reducing the frequency and severity of vasomotor symptoms in Brazilian postmenopausal women.

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study

Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40-65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed. Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean -1·87 [SE 0·42; p<0·001], -2·07 [SE 0·42; p<0·001]) and week 12 (-2·39 [SE 0·44; p<0·001], -2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (-0·15 [0·06; p=0·012], -0·19 [0·06; p=0·002]) and week 12 (-0·24 [0·08; p=0·002], -0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation. Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. Astellas Pharma.

A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.

A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.5, 5, 10, or 15 mg or placebo once daily for 12 weeks. Outcomes were the vaginal maturation index and maturation value, genitourinary syndrome of menopause score, and the Menopause Rating Scale to assess health-related quality of life. We focused on E4 15 mg, the dose studied in ongoing phase 3 trials, and tested its effect versus placebo at 12 weeks using analysis of covariance. Least square (LS) mean percentages of parabasal and intermediate cells decreased, whereas superficial cells increased across E4 doses; for E4 15 mg, the respective changes were -10.81% (P = 0.0017), -20.96% (P = 0.0037), and +34.17% (P < 0.0001). E4 15 mg decreased LS mean intensity score for vaginal dryness and dyspareunia (-0.40, P = 0.03, and -0.47, P = 0.0006, respectively); symptom reporting decreased by 41% and 50%, respectively, and shifted to milder intensity categories. The overall Menopause Rating Scale score decreased with E4 15 mg (LS mean, -3.1; P = 0.069) and across doses was associated with a decreasing frequency and severity of VMS (r = 0.34 and r = 0.31, P < 0.001). E4 demonstrated estrogenic effects in the vagina and decreased signs of atrophy. E4 15 mg is a promising treatment option also for important menopausal symptoms other than VMS.

Fezolinetant: A Potential Treatment for Moderate to Severe Vasomotor Symptoms of Menopause.

The most common symptom of menopause is vasomotor symptoms (VMS), which occur in more than 80% of postmenopausal women. Furthermore, VMS are the manifestation of menopause for which women most commonly seek treatment, namely, to address their impacted quality of life, including sleep, and work-and non-work-related productivity. VMS vary in frequency, intensity and duration. Hormone therapy (HT) has been our most effective treatment for VMS and has been approved for this indication by the United States Food and Drug Administration (FDA). Despite being a safe and effective treatment option, many patients and providers are hesitant to consider HT. Moreover, HT is contraindicated for some women. While many over-the-counter and non-HT options are available, we lack data on the efficacy and safety of most of these. This has left a void for women. Fezolinetant was recently approved by the FDA for the treatment of moderate-to-severe VMS. So far, clinical trials have shown positive results in terms of safety and efficacy. Fezolinetant is a non-hormonal, neurokinin 3 receptor antagonist that works in the hypothalamus at the thermoregulatory centre. Blocking the non-hormonal neurokinin 3 receptor antagonist modulates hot flashes and night sweats. As early as 4 weeks from initiating fezolinetant, women experienced a statistically significant reduction of both severity and frequency of VMS per day, resulting in an improved quality of life.