Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: OASIS 1 and 2 Randomized Clinical Trials

Abstract

Importance: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed.

Objective: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms.

Design, setting, and participants: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023).

Intervention: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks.

Main outcomes and measures: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12.

Results: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable.

Conclusions and relevance: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS.

Trial registration: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.

Figure 1.. Recruitment, Randomization, and Participant Flow in the OASIS 1 and OASIS 2 Trials

“Did not complete study” indicates did not complete all phases of the trial including the last visit (follow-up). ^aSix participants withdrew consent and 1 was not rescreened per protocol. ^bThree participants (0.8%) in OASIS 1 were randomized but did not receive treatment intervention and were, therefore, excluded from the safety analysis sets. One participant in the placebo group of each trial incorrectly received elinzanetant initially, and both were assigned to the elinzanetant groups for analyses based on the safety analysis set. ^cNo information provided by investigator. ^dWithdrew because of work.

Figure 2.. Change From Baseline in Average Daily Vasomotor Symptom (VMS) Frequency and Severity by Treatment Group and Study

Score range 0-3 (0 indicates no moderate or severe vasomotor symptoms [at baseline] and no mild, moderate, or severe vasomotor symptoms [post baseline]; 1, mild; 2, moderate; and 3, severe symptoms; higher scores indicate greater vasomotor symptom severity). Data shown are means (95% CIs). Zoomed-in presentation along the y-axis for illustration purposes. Only outliers within the displayed scale are visible. Connecting lines over time join arithmetic means by treatment group. A boxplot presentation of the full distribution is provided in eFigure 1 in Supplement 3 and the descriptive summary and data range are available in eTable 5 in Supplement 3. Placebo-elinzanetant, 120 mg, refers to the participants receiving placebo who were switched to receive elinzanetant after week 12. Efficacy analyses were performed on the full analysis set. The circles indicate outside values.

Figure 3.. Change From Baseline in PROMIS SD SF 8b Total T Score^a and MENQOL Total Score^b by Treatment Group and Study

A reduction in Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF 8b) total T score and Menopause-Specific Quality of Life (MENQOL) questionnaire total score corresponded to an improvement in symptoms. Efficacy analyses were performed on the full analysis set. Connecting lines over time join arithmetic means by treatment group. The circles indicate outside values. ^aFor PROMIS SD SF 8b, the score ranges from 28.9 to 76.5 (<55, normal; 55-60, mild; 60-70, moderate; and >70, severe sleep disturbance). Higher scores indicate greater severity of sleep disturbance. ^bFor MENQOL, the score ranges from 1 to 8; higher scores indicate greater bother; and 0.9-point within-patient change represent a clinically meaningful difference.