Dataset Information

A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.

ABSTRACT: OBJECTIVE:Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS. METHODS:Menopausal women aged >40-65 years with moderate/severe VMS (?50?episodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90?mg BID or 30, 60, 120?mg QD, or placebo for 12 weeks. Primary outcomes were reduction in moderate/severe VMS frequency and severity ([number of moderate VMS ×?2] + [number of severe VMS ×?3]/total daily moderate/severe VMS) at weeks 4 and 12. Response (?50% reduction in moderate/severe VMS frequency) was a key secondary outcome. RESULTS:Of 352 treated participants, 287 completed the study. Fezolinetant reduced moderate/severe VMS frequency by -1.9 to -3.5/day at week 4 and -1.8 to -2.6/day at week 12 (all P?

SUBMITTER: Fraser GL

PROVIDER: S-EPMC7147405 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.

Fraser Graeme L GL Lederman Samuel S Waldbaum Arthur A Kroll Robin R Santoro Nanette N Lee Misun M Skillern Laurence L Ramael Steven S

Menopause (New York, N.Y.) 20200401 4

<h4>Objective</h4>Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS.<h4>Methods</h4>Menopausal women aged >40-65 years with moderate/severe VMS (≥50 episodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90 mg ...[more]

PMID: 32102086

Similar Datasets

Project description:Abstract Vasomotor symptoms (VMS; eg, hot flashes, night sweats) are caused by a loss of thermoregulatory control. The thermoregulatory center in the brain is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. The activity of KNDy neurons is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen negative-feedback. Declining estrogen levels at menopause disturb this balance, leading to VMS. Fezolinetant is an antagonist at NK3R that acts to moderate KNDy neuron function for the treatment of VMS (1). The aim of the current trial was to evaluate fezolinetant dose levels and treatment regimen in VMS. In this phase 2b, double-blind trial (NCT03192176), menopausal women age >40−65 y with moderate/severe VMS (≥50/wk) were randomized to one of the following: fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo (PBO). Coprimary efficacy outcomes were frequency and severity of moderate/severe VMS at wk 4 and 12. Secondary efficacy outcomes included changes in moderate/severe VMS frequency and severity by study wk. Of 356 women randomized, 352 received ≥1 dose study drug (safety population; mean [SD] age: 54.6 [4.7] y; 73% white) and 287 (81%) completed the study: PBO: 37/44 (84%); fezolinetant: 250/312 (80%). The most common reasons for discontinuation were withdrawal of consent (6.7%) and AEs (5.9%). All fezolinetant dose groups demonstrated reductions in VMS frequency and severity at wk 4 and 12. Significant dose responses were observed in all coprimary efficacy endpoints. The differences from PBO in least squares (LS) mean changes from baseline in moderate/severe VMS frequency per day at wk 4 were −1.9, −3.0, −2.8, and −3.5 for 15, 30, 60, and 90 mg BID, respectively, and −2.3, −3.0, and −2.4 for 30, 60, and 120 mg QD, respectively, with a common SE of 0.8 (all P<.05). The differences from PBO in LS mean change from baseline in moderate/severe VMS frequency per day at wk 12 were −1.8, −2.1, −2.3, and −2.6 for 15, 30, 60, and 90 mg BID, respectively, and −2.1, −2.6, and −2.1 for 30, 60, and 120 mg QD, respectively, with a common SE of ~0.7 (all P<.05). Dose response was apparent in frequency and severity as early as at wk 1. The majority of TEAEs were mild or moderate in severity. There were no deaths or serious treatment-related TEAEs. This study demonstrates that fezolinetant is a safe and effective nonhormonal treatment for rapid reduction of moderate/severe menopausal VMS. 1Fraser GL, et al. Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes [abstract OR16-5]. Endocr Rev. 2017;38(3).

Project description:ObjectiveIn the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs).MethodsIn this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs).ResultsOf 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: -1.8; fezolinetant: range, -1.9 to -3.6) and 12 (placebo: -2.3; fezolinetant: range, -2.9 to -4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: -2.2; fezolinetant: range, -2.5 to -3.8) and 12 (placebo: -2.9; fezolinetant: range, -3.3 to -4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: -1.7; fezolinetant: range, -2.1 to -3.3; week 12, placebo: -2.1; fezolinetant: range, -2.7 to -3.6).ConclusionsOral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.

Dataset Information

A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.

Publications

A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets