Severe Vasomotor Symptoms Research Articles

Fezolinetant (Veozah) for menopausal vasomotor symptoms.

Fezolinetant (Veozah – Astellas), a first-in-class neurokinin 3 (NK3) receptor antagonist, has been approved by the FDA for treatment of moderate to severe vasomotor symptoms (VMS) due to menopause.

Sexual function scores are associated with the severity of vasomotor symptoms, age and sense of coherence in postmenopausal women.

Sexual function scores are associated with the severity of vasomotor symptoms, age and sense of coherence in postmenopausal women.

Vasomotor symptoms associated with menopause prevalence and impact among women in Brazil, Canada, Mexico, and Nordic Europe: a cross-sectional survey

Objective: This study investigated the prevalence and impact of moderate to severe vasomotor symptoms, related treatment patterns, and experiences in women.

Evaluating response to interventions for vasomotor symptoms in patients with breast cancer: A patient-centered approach.

e24126 Background: Vasomotor symptoms (VMS), such as hot flashes, are a common reason for early discontinuation of endocrine therapy for patients (pts) with breast cancer (BC). The optimal intervention for VMS remains unknown. Using a novel symptom change analysis and regression trees, we examined whether clinically important change in VMS severity depends on baseline symptomatology. Methods: In this prospective study, pts with BC experiencing VMS chose either a lifestyle (LS), or non-LS (i.e. complementary and alternative therapies [CAM], prescription medications [PM], or endocrine therapy modification [ETM]) intervention. The primary outcome was change in symptom severity using the 10-point Hot Flush Rating Scale (HFRS). Patients declining interventions were included as controls. At the end of the 6-week intervention, participants rated the effectiveness of their chosen intervention on a five-point Likert scale. A logistic sigmoid function and Bayesian optimization were used to weight the change in VMS score based on baseline VMS severity. A regression tree was trained to predict which intervention resulted in the greatest improvement in VMS at 6 weeks. Results: 100 baseline and follow-up questionnaires from 85 pts were included in an intention to treat analysis. The median baseline HFRS was 5.0 (IQR 3.33 ,7.00). Selected interventions included LS (27%), CAM (25%), PM (11%) and ETM (8%), with 29% declining interventions. After removal of missing data, 59 individuals provided responses for both the HFRS score and the effectiveness score. Higher baseline HFRS scores had greater impact on symptom change scores. The largest difference in VMS improvement was noted between the non-LS (median symptom change –0.82, IQR –2.00, –0.01) and LS/control groups (median symptom change – 0.38, IQR –1.46, 0.00) (Table 1). Of non-LS interventions, CAM had the greatest improvement in VMS severity. Pre-menopausal individuals who pursued LS interventions had the least improvement in VMS severity. Conclusions: Interventions for VMS were most impactful among pts with greater baseline symptoms. While LS interventions were the most commonly selected intervention, the resulting improvement in symptoms at 6 weeks was negligible, and alternative strategies should be encouraged. Future studies integrating pt preferences and accounting for baseline symptom severity are needed. [Table: see text]

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 < 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 < 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 < 0.0005) in the ITT cohort (7.5 (SEM 0.1) to 3.4 (SEM 0.2) (p < 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 < 0.0005) in the ITT cohort (7.9 (SEM 0.4) to 17.3 (SEM 0.5) (p < 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 .

Antimüllerian Hormone as a Tool to Predict the Age at Menopause.

This study aimed to assess an eligible cut-off value of anti-Müllerian hormone (AMH) to detect ovarian senescence in a group of premenopausal Greek women to evaluate the possible link between AMH-values and the severity of climacteric symptoms during a follow-up of 24 months. This study included 180 women (group A, 96 women of late reproductive stage/early perimenopause; group B, 84 women in late perimenopause). We measured AMH blood levels and assessed climacteric symptoms using the Greene scale. Log-AMH is inversely associated with postmenopausal status. The AMH cut-off of 0.012 ng/mL predicts the postmenopausal status with a sensitivity of 24.2% and specificity of 30.5%. The postmenopausal stage associated with age (OR = 1.320, 95%CI: 1.084-1.320) and AMH (values ≥ vs. <0.012 ng/mL, OR = 0.225, 95%CI: 0.098-0.529, p-value < 0.001). Moreover, the severity of vasomotor symptoms (VMS) was only associated inversely with AMH (b-coefficient = -0.272, p-value = 0.027). In conclusion, AMH levels measured in the late premenopausal period are inversely associated with the time to ovarian senescence. In contrast, AMH levels measured in the perimenopausal period are inversely associated only with the severity of VMS. Therefore, a cut-off of 0.012 ng/mL predicts menopause with low sensitivity and specificity, making it challenging to use in a clinical setting.

Effect of Serelys Homme on the Incidence and Severity of Vasomotor Symptoms and Quality-of-Life Impairments in Patients Receiving Hormone Therapy and Radiation for Localized Prostate Cancer: Results of the ESCULAPE Phase 2 Prospective Study

Androgen deprivation therapy (ADT) may cause vasomotor symptoms (VMS) including hot flushes and sweats, which affect quality of life (QoL). Serelys Homme is a nonhormonal and a natural origin product that could affect VMS in men undergoing ADT. We evaluated effectiveness and tolerance of Serelys Homme administration on VMS and QoL of patients undergoing combined ADT and radiation therapy for prostate cancer. Between April 2017 and July 2019, 103 patients were screened, and 53 patients refused to participate in the study. Serelys Homme therapy consisted of a daily administration of 2 tablets for 6 months. Patients were evaluated with 4 questionnaires including the adapted Modified Rankin Scale (adapted-MRS), European Quality of Life 5 Dimensions 3 Level Version (EQ 5D3L), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and Hot Flash Related Daily Interference Scale (HFRDIS) at day 0, day 90 (D90), and day 180 (D180). Statistical evaluation was performed using the Wilcoxon rank sign test. A 2-sided P < .05 was considered statistically significant. Among the 50 patients, 4 withdrew after inclusion. All patients (n=46) received either postoperative or definitive radiation therapy combined with a short (n=15) or long course (n=31) of ADT. Serelys Homme administration significantly decreased the rate of patients who had ≥7 VMS and 3 to 6 VMS per day. The number of patients presenting with moderate or severe VMS was decreased at D90 (P=.005) and at D180 (P=.005). In addition, VMS duration was reduced at D90 (P=.002) and D180 (P < .001). Finally, at D90 and D180, 11.1% and 16.0% of patients, respectively, with initial severe or moderate VMS had a complete response without further symptoms. Among QoL parameters, fatigue decreased significantly. Effectiveness evaluated by doctors was rated as moderate or good to excellent VMS control in 20% and 60% of the patients, respectively. No side effects were recorded in the whole population. This study demonstrated effectiveness and excellent tolerance of Serelys Homme. We observed a significant reduction of the frequency, duration, and intensity of hot flushes and sweats induced by ADT. Serelys Homme increased QoL scores. These encouraging results open the prospect to further studies and Serelys Homme use in patients undergoing ADT for prostate cancer.

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.

Post-Menopausal Quality of Life Claims: Overlooking the Requirements of Normal Science and Fundamental Measurement in ICER'S Cost-Effectiveness Assessment of Fezolinetant for Moderate to Severe Vasomotor Symptoms.

One of the signal failures in health technology assessment is the absence of consideration given, not only to the standards of normal science, but to those of fundamental measurement. A recent evidence report by the Institute for Clinical and Economic Review (ICER) is emblematic of this failure. Based on a simple linear regression model that translates aggregate scores from the ordinal Menopause-specific Quality of Life Questionnaire (MENQOL) to the ordinal EuroQol EQ-5D-5L, ICER has applied these scores to an assumption driven model simulation to produce preferences, QALYs and incremental cost-per-QALY claims for fezolinetant for moderate to severe symptoms associated with menopause. Unfortunately, the attempt to crosswalk multidimensional or multiattribute ordinal scores is mathematically impossible. The 'created' EQ-5D-5L preferences are, as a result, of no interest. The overall result is that the ICER modelled claims for cost-effectiveness fail the required standards for normal science and fundamental measurement. fundamental are impossible. This is unfortunate, although it might be possible to assess certain domains of the MENQOL for their approximation to an interval score with the application of the Rasch Rating Scale Model, this will not support quality of life claims. A preferred approach would be to consider an alternative latent trait for quality of life in menopause, applying Rasch Measurement Theory (RMT), to develop a polytomous instrument that has the required measurement properties. The purpose of this commentary is to point out, as a number of previous commentaries have done, that this framework for creating assumption driven simulated modelled claims has no role in decisions for product assessment, access to formulary and pricing. This commentary expands upon these previous commentaries in placing RMT is the context of a needed paradigm shift to support the evolution of objective knowledge. This is critical if we are to understand, from the individual's perspective, not only an accurate assessment of the burden of menopause but to see this as part of an on-going research program that has to rely on fundamental measurement.

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.

Climacteric symptoms, age, and sense of coherence are associated with sexual function scores in women after menopause.

Postmenopausal sexual function presupposes the integration of hormonal, neural, and vascular interactions and is subject to optimal crosstalk among psychological, interpersonal, cultural, and environmental factors. Sense of coherence (SOC) reflects a person's ability to cope with stressors and may influence the occurrence of menopausal symptoms and sexual dysfunction. To investigate the association of severity of climacteric symptoms, cardiometabolic risk factors, and SOC with sexual function in postmenopausal women. Overall 281 sexually active postmenopausal women without significant psychopathology or cardiovascular disease attending the Menopause Unit of Aretaieion Hospital were evaluated by the Female Sexual Function Index (FSFI), Greene Climacteric Scale, Beck Depression Scale, and Sense of Coherence Scale. Hormonal and biochemical parameters and cardiometabolic risk factors were evaluated. FSFI scores <26.5 were considered pathologic. Total and subdomain scores of sexual response were determined. Pathologic FSFI scores were found in 79.7% of the sample. Linear models of multivariable regression analysis showed that FSFI scores were associated with (1) Beck scores (b = -0.200; 95% CI, -0.472 to -0.073, P = .001), vasomotor symptom severity (b = -0.324; 95% CI, -0.985 to 0.051; P < .001), and age and (2) SOC (b = 0.150, 95% CI, 0.036-0.331; P = .008), vasomotor symptom severity (b = -0.361; 95% CI, -0.743 to 0.245; P < .001), and age. Both models were adjusted for menopausal age, diabetes mellitus, hypertension, type of menopause, and menopausal hormone therapy intake. SOC was associated with Beck depression scores (β = -0.487, P < .001; Greene Climacteric Scale total scores, β= -0.199, P < .001). FSFI score <26.5 vs >26.5 was associated with SOC (odds ratio,0.982; 95% CI, 0.563 to 1.947; P = .006) and moderate to severe vasomotor symptom severity (odds ratio,2.476; 95% CI, 1.478 to 3.120; P = .009) independent of age, diabetes mellitus, hypertension, menopausal hormone therapy intake, type of menopause, or Beck depression classification. The results indicate the importance of psychometric assessment of postmenopausal women when presenting with scores of low sexual function. The severity of vasomotor symptoms should also be addressed in any case. This is the first study investigating the relationship between SOC and sexuality in menopause in a carefully selected homogenous population. Limitations included the cross-sectional design and the fact that sexual distress was not assessed. Pathologic FSFI scores were highly prevalent in this sample of postmenopausal women. FSFI is associated positively with age and severity of vasomotor symptoms and negatively with SOC.

Возможности медикаментозной коррекции климактерического синдрома у больных онкологическими заболеваниями органов репродуктивной системы

Aim: To assess the severity of menopausal symptoms and quality of life in patients with iatrogenic menopause depending on the therapy. Design: A randomised parallel group clinical study. Materials and methods. The study enrolled 60 patients of reproductive age with iatrogenic menopause following bilateral ovariectomy who had a history of reproductive tumours. The patients were randomised into 2 groups. Group 1 (n = 34) was treated with escitalopram as follows: 5 mg once daily — 7 days, 10 mg once daily — 2 weeks, then 10 mg daily (subgroup 1а) or 20 mg daily (subgroup 1b) — 12 weeks. A dose of 20 mg daily was used where the frequency and severity of menopausal symptoms did not fall below 50 % in 3 weeks with a dose of 10 mg daily. Group 2 patients (n = 26) were prescribed an herbal product called cimicifuga racemosa essence (BNO 1055) at a dose of 6.5 mg 1 tablet once daily for 15 weeks. The patients' condition was assessed using a daily hot flash questionnaire; Quality of Life Questionnaire SF-36; Greene Climacteric Scale; and Insomnia Severity Index. Results. The number of hot flushes reduced in all subgroups; however, the reduction was statistically significant only in subgroup 1a. Greene Climacteric Scale showed that following 15 weeks of therapy in subgroup 1a there was significant reduction in the intensity of menopausal symptoms, anxiety and depression, improved somatic signs, reduced severity of vasomotor symptoms, and improved libido vs. baseline. Subgroup 1b patients demonstrated statistically significant reduction in menopausal symptoms and anxiety. Group 2 had marked reduction in menopausal symptoms and depression. Intergroup comparison demonstrates that the most marked effect from the therapy on menopausal symptoms, anxiety, depression and severity of vasomotor symptoms was observed in subgroup 1а vs. subgroup 1b and group 2. Quality-of-life assessment showed significant improvement in the physical component in group 2 patients, while psychological improvements were better in subgroup 1а after 15 weeks of therapy. Subgroup 1a patients had significant reduction in Insomnia Severity Index, while subgroup 1b and group 2 patients did not demonstrate any significant reduction in this parameter. Conclusion. Patients, for whom hormonal menopause therapy is contraindicated, including patients with hormone-driven malignancies, require therapy to improve their quality of life, manage their menopausal syndrome, correct psychoemotional state and improve sleep. The study demonstrated efficacy both of non-hormonal antidepressant escitalopram (a selective serotonin reuptake inhibitor) and BNO 1055 essence (a medicinal product). In mild and moderate menopausal syndrome, it is recommended to use BNO essence, while severe cases should be treated with 10 mg escitalopram daily, and therapy efficacy should be assessed after 3 weeks of therapy. Key words: menopause, malignancies, menopausal syndrome, selective serotonin reuptake inhibitor, antidepressants, cimicifuga racemosa, BNO 1055.

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.

OR06-5 Fezolinetant for Treatment of Moderate-to-severe Vasomotor Symptoms Associated with Menopause: Results from a 52-week Study (Skylight 2)

Abstract Background SKYLIGHT 2 (NCT04003142) investigated safety and efficacy of fezolinetant (a neurokinin-3 receptor antagonist) on frequency and severity of moderate-to-severe vasomotor symptoms (VMS) and sleep disturbance. In this analysis, persistence of fezolinetant efficacy was investigated over 52 weeks. Methods This double-blind Phase 3 study randomized women aged ≥40–65 years with moderate-to-severe VMS associated with menopause (average of ≥7 hot flashes/day) to once-daily placebo or fezolinetant 30mg or 45mg for 12 weeks. Women completing 12 weeks entered an extension period, with those on placebo re-randomized to fezolinetant 30mg or 45mg (placebo/fezolinetant), and those originally on fezolinetant remaining on their dose for an additional 40-weeks. Fezolinetant efficacy was evaluated vs placebo for 12-weeks through change in VMS frequency, VMS severity, and Patient-reported Outcomes Measurement Information System Sleep Disturbance–Short Form 8b (PROMIS) Total Score. Persistence of efficacy for fezolinetant was evaluated descriptively (without statistical comparisons) over the extension period. Results The analysis comprised 484 women (fezolinetant 30mg n=166, fezolinetant 45mg n=167, placebo/fezolinetant 30mg n=76, placebo/fezolinetant 45mg n=75). Improvement in VMS frequency and severity observed through week 12 (statistically significant differences vs placebo) was maintained throughout the 52-week total study period for those receiving fezolinetant. Fezolinetant demonstrated further reductions in VMS frequency and severity from baseline to beyond week 12. For VMS frequency, there was a least squares (LS) mean (SE) baseline-to-week 12 reduction of –6.83 (0.39) VMS/day for fezolinetant 30mg and –7.50 (0.39) for 45mg, and a mean (SD) baseline-to-week 52 reduction of –8.03 (4.53) for fezolinetant 30mg and –8.48 (3.98) for 45mg. For VMS severity, LS mean (SE) baseline-to-week 12 reduction was –0.64 (0.06) for 30mg and –0.77 (0.06) for 45mg, and mean (SD) baseline-to-week 52 reduction was –0.83 (0.82) for fezolinetant 30mg, and –0.95 (0.78) for 45mg. Women re-randomized from placebo to fezolinetant experienced a reduction in frequency and severity of VMS consistent with that in women receiving fezolinetant throughout the study. Fezolinetant also reduced PROMIS-assessed sleep disturbance, with a LS mean (SE) baseline-to-week 12 reduction of –4.1 (0.5) for fezolinetant 30mg and –5.5 (0.5) for 45mg (statistically significant difference vs placebo for fezolinetant 45mg) and a mean (SD) baseline-to-week 52 reduction of – 6.3 (7.3) for fezolinetant 30mg and –5.7 (7.9) for 45mg. The safety profile observed for the 40-week extension period was consistent with that of the 12-week placebo-controlled period. Conclusion Fezolinetant 30mg and 45mg once daily were efficacious for treatment of moderate-to-severe VMS associated with menopause. Efficacy was persistent and reductions in VMS frequency were maintained during the extension period, at levels consistent with weeks 1 through 12. Fezolinetant 45mg improved sleep at week 12 and improvement was maintained through the active treatment extension period. No safety signals of concern were apparent for either fezolinetant dose. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Estimation of placebo effect in randomized placebo-controlled trials for moderate or severe vasomotor symptoms: a meta-analysis.

The Food and Drug Administration guidance recommended that for the indication of vasomotor symptoms (VMS), studies should enroll participants with minimum of seven to eight moderate to severe VMS per day at baseline, and coprimary endpoints should be the mean change in frequency/severity at weeks 4 and 12. This study aimed to estimate placebo effects in randomized controlled trials (RCTs) fulfilling this guidance. PubMed was searched using the following terms: "vasomotor symptom or hot flash or hot flashes or hot flash or hot flashes [title/abstract]," "menopause or climacteric," "RCT or randomized controlled or randomized controlled," "placebo [title/abstract]," and "frequency or severity." Inclusion criteria were as follows: (1) placebo controlled RCTs, (2) enrolling women with moderate or severe VMS with a minimal frequency more than seven to eight times per day or 50 times per week, and (3) efficacy measurements including mean change in VMS frequency from baseline at week 12. A random-effects model was used in the meta-analysis. Seventeen studies were included for the estimation of VMS frequency reduction and 13 studies for severity. Estimated change of VMS frequency in placebo arms was -5.44 times per day (95% CI, -5.81 to -5.07 times per day) at week 12. For VMS severity, the estimated change at week 12 was -0.36 (95% CI, -0.46 to -0.27). Substantial and consistent placebo effects were observed in RCTs for VMS treatment. These data suggest a reduction of 5.44 times per day in frequency and 0.36 in severity might be observed as a placebo effect.

Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial

Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms. We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18-70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138. Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 -39% [95% CI -46 to -31] vs placebo -26% [-33 to -18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events. Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy. QUE Oncology.

Physical Activity History And Severity Of Vasomotor Symptoms In Menopausal Females

Estrogen influences thermoregulation of the human body. Accompanied by the loss of estrogen, the onset of menopause can cause disruptive vasomotor symptoms (VMS). VMS present intense physical and psychological discomfort for woman including a sudden feeling of warmth spreading through the upper body, a flushed appearance, rapid heartbeat, perspiration, and anxiety. As much as 80% of menopausal females report hot flushes daily for up to 10 years of their life. Previous research explores treatment options to reduce VMS, but few studies look for activity levels and intensity to predict severity of VMS. PURPOSE: The purpose of this study was to investigate the associations between physical activity levels and the severity of hot flushes in menopausal and post-menopausal females. METHODS:101 females ages 41-79 (mean = 57 ± 8.09) were recruited on social media and local fitness studios to complete an online survey. Females were included in this project if they were in any phase of menopause transition or post-menopausal. The questionnaire required subjects to rate 12 different menopausal symptoms on a 5-category Likert Scale ranging from none to very severe. The participants were asked to recall their activity levels in minutes per week and to categorize their minutes in intensities. Subjects self-reported their exercise intensity as vigorous, moderate, or low physical activity. Subjects’ total activity minutes was categorized into quartiles in SPSS and subjects were grouped as low total activity, moderate total activity, high total activity, and very high total activity. Pearson Correlation coefficient was used to investigate relationships between volume of exercise, intensity of exercise, and severity of hot flushes. RESULTS: We found a statistically significant positive relationship between very high volume of moderate activity and severity of hot flushes. (r = 0.526, p = 0.007). CONCLUSION: These findings demonstrate that a very high volume of moderate exercise weekly may contribute to a greater severity of VMS for menopausal females. The practical implications of this study can influence exercise recommendations for menopausal females.

Complaints of reduced cognitive functioning during perimenopause: a cross-sectional analysis of the Japan Nurses’ Health Study

BackgroundMany women experience various symptoms during the period of menopausal transition, including complaints of reduced cognitive functioning. However, these complaints are not necessarily recognized as core menopausal symptoms. In this study, we sought to characterize subjective complaints of reduced cognitive functioning by analyzing cross-sectional data from the Japan Nurses’ Health Study (JNHS).MethodsThe JNHS 4-year follow-up questionnaire containing a 21-item climacteric symptom checklist, which included a question about “poor memory or forgetfulness”, was mailed between 2005 and 2011 to all JNHS participants, regardless of their age at the time of the survey. We estimated the prevalence of slight and severe complaints in 5-year age-groups. We used principal component analysis to explore the underlying factors among the 21 symptoms during the menopausal transition period in women aged 45–54 years at the time of the survey. We also examined risk factors for complaints using multivariable modified Poisson regression analysis.ResultsIn total, 12,507 women responded to the 4-year survey. The mean age at the time of the 4-year survey was 46.5 years (range 27–82). “Poor memory or forgetfulness” showed a peak prevalence of 81.7% (severe 27.9%; slight 53.8%) at 50–54 years, and gradually decreased after 55 years. Principal component analysis indicated that “poor memory or forgetfulness” belonged to somatic symptoms and was close to psychological symptoms in women aged 45–54 years. In women aged 45–54 years, the complaint was also significantly associated with hot flashes and sweats. Multivariable modified Poisson regression analysis showed that menopausal status (uncertain and postmenopausal), less sleep (sleep of < 5 h and sleep of 5– < 6 h), night-shift work, and severe vasomotor symptoms (VMS) were significantly associated with the prevalence of severe complaints of reduced cognitive functioning in women aged 45–54 years.ConclusionsWe found that prevalence of “poor memory or forgetfulness” was highest during the menopausal transition period and among perimenopausal women. This subjective complaint was associated with somatic, psychological complaints and VMS. It may be useful for women with cognitive problems in the transition period to consider management of comorbid menopausal symptoms.

Feasibility of a novel wrist-worn thermal device for management of vasomotor symptoms in patients with prostate cancer.

5067 Background: Vasomotor symptoms (VMS), or hot flashes, are a common side effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). VMS negatively impact sleep, fatigue, and quality of life (QOL) in PCa survivors. There are few nonpharmacological treatments for VMS. The Embr Wave is a wearable thermal device that applies cooling to thermoreceptors on the inside of the wrist and has been associated with patient reported decreases in hot flash interference in women. We performed a single-arm feasibility study evaluating the Embr Wave for management of VMS in PCa survivors. Methods: 57 PCa survivors reporting bothersome hot flashes were enrolled and instructed to use the device as needed for VMS during the 4-week study. The primary outcome was device usage recorded by the device (minutes and sessions). Additional outcomes included the change in patient reported Hot Flash Related Daily Interference Scale (HFRDIS, range 0-10) and Patient Reported Outcomes Measurement Information System Sleep Disturbance 4a (PROMIS SD, range 0-100) and Sleep Related Impairment 8a (PROMIS SRI, range 0-100). Study procedures were conducted remotely using a virtual clinical trial management platform. Results: The study was conducted from May to Dec 2021 in the US. 44 men completed the study; 39 had retrievable usage data. Median age was 66 (range 57-78) years and median 3 (1-23) years since PCa diagnosis. The most common hormonal treatments were leuprolide (n=22), abiraterone (n=13), and enzalutamide (n=6). Baseline scores indicated moderate hot flash interference and mild sleep disturbance (Table). Mean±SD (median) usage of the Embr device was 3.2±2.5 (2.3) hours and 7.6±3.6 (7.5) sessions per day. 26 (67%) participants reported using the device 7 days/nights each week. Improvements were observed in HFRDIS, PROMIS SD, and PROMIS SRI scores (Table). There were also improvements in subjective ratings of hot flash frequency, duration, interference with daily life/sleep, bothersomeness and control (all p&lt;0.01). The majority (69%) of participants reported that the device was effective at helping them manage hot flashes. No adverse events were reported. Conclusions: Results of this study support the feasibility of use of the thermal device for management of bothersome hot flashes in PCa survivors. Future randomized controlled studies are warranted to evaluate patient reported outcomes related to frequency and severity of VMS, sleep quality, fatigue, and overall QOL, in addition to defining the potential utility of the Embr thermal device in PCa survivors experiencing VMS. Clinical trial information: NCT04892914. [Table: see text]