Key Points
Question
Is elinzanetant effective and safe for treating moderate to severe vasomotor symptoms (VMS) in postmenopausal women?
Findings
In this randomized, placebo-controlled clinical trial of 628 postmenopausal women, elinzanetant significantly reduced the frequency of daily moderate to severe VMS at 12 weeks compared to placebo, and although no statistical hypotheses were defined for secondary or exploratory end points, descriptive analyses showed numerical advantages for elinzanetant vs placebo for improving VMS frequency and severity over 50 weeks and sleep disturbances and menopause-related quality of life over 52 weeks. Elinzanetant was not associated with hepatotoxic effects, endometrial hyperplasia, or meaningful changes in bone density or bone turnover markers, and treatment-related adverse events were more common with elinzanetant than placebo.
Meaning
The trial results suggest that elinzanetant shows promise in treating moderate to severe VMS.
Abstract
Importance
There is an unmet need for long-term, safe, effective, and hormone-free treatments for menopausal symptoms, including vasomotor symptoms (VMS) and sleep disturbances.
Objective
To evaluate the 52-week efficacy and safety of elinzanetant, a dual neurokinin-targeted therapy, for treating moderate to severe VMS associated with menopause.
Design, Setting, and Participants
OASIS-3 was a double-blind, placebo-controlled, randomized phase 3 clinical trial that was conducted at 83 sites in North America and Europe from August 27, 2021, to February 12, 2024, and included postmenopausal women aged 40 to 65 years who were seeking treatment for moderate to severe VMS (no requirement for a minimum number of VMS events per week). The data were analyzed on March 11, 2024.
Intervention
Once-daily oral elinzanetant, 120 mg, or matching placebo for 52 weeks.
Main Outcomes and Measures
The primary outcome was mean change from baseline to week 12 in the frequency of daily moderate to severe VMS, which was analyzed using a mixed model with repeated measures. Secondary end points included changes over 52 weeks in measures evaluating sleep disturbance and the effect on menopause-related quality of life. Exploratory end points included mean changes over 50 weeks in frequency and severity of daily moderate to severe VMS. Exploratory and secondary end points were analyzed using descriptive statistics. Safety was also assessed.
Results
Overall, 313 women (mean [SD] age, 54.6 [4.7] years; 51 [16.3%] were Black or African American, and 240 [76.7%] were White individuals; 34 [10.9%] were Hispanic or Latina) were randomized to receive elinzanetant and 315 (mean [SD] age, 54.9 [5.0] years; 44 [14.0%] Black or African American, 34 [10.8%] Hispanic or Latina, and 253 [80.3%] White individuals) to receive placebo. At week 12, the mean change from baseline in daily moderate to severe VMS frequency was −5.4 (95% CI, −6.3 to −4.5) for elinzanetant and −3.5 (95% CI, −4.1 to −2.9) for placebo; the least-squares mean difference for elinzanetant vs placebo was −1.6 (95% CI, −2.0 to −1.1; P < .001). Although no statistical hypotheses were defined, nor was the study powered to detect between-group differences for the secondary and exploratory end points, descriptive analyses showed numerical advantages for elinzanetant vs placebo for improving VMS frequency and severity over 50 weeks and sleep disturbances and menopause-related quality of life over 52 weeks. Regarding safety, elinzanetant was not associated with hepatotoxic effects, endometrial hyperplasia, or meaningful changes in bone density or bone turnover markers. Treatment-related adverse events were more common with elinzanetant than placebo (30.4% vs 14.6%); the most frequent were somnolence, fatigue, and headache.
Conclusions and Relevance
The OASIS-3 randomized clinical trial expanded on findings from the 26-week OASIS-1 and OASIS-2 trials, exploring the use of elinzanetant over a longer duration and in a broader population. Elinzanetant shows promise as a treatment for moderate to severe VMS.
Trial Registration
ClinicalTrials.gov Identifier: NCT05030584
This randomized clinical trial examines 52-week efficacy and safety of elinzanetant in treating moderate to severe vasomotor symptoms that are associated with menopause.
Introduction
Vasomotor symptoms (VMS; also known as hot flashes that can be experienced during the day or night and may cause sweating) and sleep disturbances are disruptive menopause-associated symptoms that are reported by up to 80% and 60% of menopausal women, respectively.1,2 These symptoms can have a substantial negative effect on health and quality of life.1,2,3,4,5,6 Hormone therapy (HT) is an effective option for menopausal symptoms but is not suitable for all women due to contraindications or personal preferences.7,8 Antidepressants are frequently used (often off-label) to treat VMS in many countries.7 However, these therapies have modest benefits compared with placebo, and some women experience tolerability issues, leading to reported discontinuation rates of up to 50% during the first 3 months.9,10 As VMS can last a mean of 7 to 10 years,11 there is an unmet need for alternative effective treatments that can be used safely for extended periods.
Hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons express several receptor/ligand pairs, including neurokinin (NK)–1 and NK-3 receptors and their respective ligands, substance P (SP) and neurokinin B (NKB).12,13,14,15 During and after the menopausal transition, declining estrogen levels lead to hypertrophy and hyperactivity of KNDy neurons, which is accompanied by an overexpression of neurotransmitters, including NKB and SP.12,13,14,15 This hyperactivation has been shown to be concurrent with thermoregulatory disruption that results in VMS.12,13,14,15 SP and NK-1 receptors may also have a role in peripheral vasodilatation and primary insomnia.16,17 Recently, the NK-3 receptor antagonist fezolinetant has been approved in several countries for treating moderate to severe VMS due to menopause.18,19,20
Elinzanetant is an antagonist of NK-1 and NK-3 receptors. The recent pivotal phase 3 trials OASIS-1 and OASIS-2 evaluated the efficacy and safety of elinzanetant over 26 weeks (comprising a 12-week placebo-controlled period and a 14-week elinzanetant treatment period) in postmenopausal women experiencing 50 or more moderate to severe VMS events over 7 days during screening.21,22 In both trials, compared with placebo, elinzanetant had statistically significantly greater mean reductions in moderate to severe VMS frequency and severity from baseline to weeks 4 and 12. Significant reductions from baseline in daily VMS frequency were observed as early as week 1 among participants taking elinzanetant, indicating a rapid onset of effect.21 Elinzanetant also resulted in statistically significant improvements in sleep disturbances and menopause-related quality of life vs placebo at week 12. Improvements in all these end points were numerically sustained over the 26-week study period.21
This 52-week OASIS-3 study was to our knowledge the first phase 3 clinical trial to evaluate elinzanetant for treating VMS beyond 6 months of use in postmenopausal women, with no eligibility requirement for a minimum number of moderate to severe VMS events per week. OASIS-3 expanded on the efficacy and safety profiles established in OASIS-1 and OASIS-2. As women may experience disruptive menopausal symptoms for multiple years, this study aimed to fulfill the need for longer-term evaluation of hormone-free alternative treatments for VMS.
Methods
Study Design
OASIS-3 was conducted from August 27, 2021 to February 12, 2024. OASIS-3 was a double-blind, placebo-controlled, randomized phase 3 trial that evaluated the efficacy and safety of elinzanetant in postmenopausal women with VMS over 52 weeks (Supplement 1 and Supplement 2; NCT05030584). This study was performed at 83 sites across North America and Europe. A list of investigators, sites, and locations can be found in the eAppendix in Supplement 3. Further study design information can be found in the eMethods in Supplement 3. This study followed the ICH guidelines.
This study included naturally or surgically postmenopausal women aged 40 to 65 years who were seeking treatment for moderate to severe VMS.23 Surgical menopause was defined as bilateral oophorectomy with or without hysterectomy at least 6 weeks before signing of informed consent. There was no requirement for a minimum number of VMS events per week. Exclusion criteria included abnormal liver parameters; disordered proliferative endometrium; endometrial polyp, hyperplasia, or malignant neoplasm; and current or history of cancer within the last 5 years (except basal and squamous cell skin tumors). Full inclusion and exclusion criteria can be found in eTable 1 in Supplement 3.
Following a prescreening and washout period for prohibited concomitant medications (see eTable 2 in Supplement 3), if applicable, participants underwent a screening period to determine eligibility for study participation. Eligible participants were randomized 1:1 to receive elinzanetant, 120 mg, or matching placebo orally once daily for the full study duration of 52 weeks. This randomization was performed centrally using an interactive voice/web response system (IxRS; Almac).
Investigators, participants, and the sponsor were masked throughout the study (see the eMethods in Supplement 3 for further details). Visits were scheduled every 4 weeks until week 12 and then approximately every 6 weeks until week 42, with an end-of-treatment visit at week 52 and follow-up 4 weeks later. Participants used handheld electronic devices to record all patient-reported outcomes. The full schedule of assessments is provided in eTable 3 in Supplement 3.
Outcomes
The primary end point was the mean change in moderate to severe VMS frequency from baseline to week 12, which was recorded using an electronic hot flash daily diary (HFDD). The last points at which the HFDD was collected were weeks 49 and 50 (eTable 3 in Supplement 3). The study was powered to detect statistical significance for the primary end point only. The secondary end points were mean changes from baseline in the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality Of Life (MENQOL) questionnaire total score over 52 weeks. Exploratory end points included mean changes in frequency and severity of moderate to severe VMS from baseline over 50 weeks (both also collected using the HFDD). Further information on outcomes can be found in the eMethods in Supplement 3.
For safety assessment, participants spontaneously reported adverse events (AEs) experienced during the study. The investigators or other qualified designees were responsible for detecting, documenting, and recording AEs. AE seriousness, intensity, and relatedness to the study intervention were assessed by the local site investigators. A treatment-emergent AE (TEAE) was defined as any AE occurring or worsening on or after the date of the first dose and up to 14 days after the last dose of study drug. An independent data safety monitoring board presided over the general safety of the participants in this trial. An independent, masked external liver safety monitoring board (LSMB) assessed cases that met the predefined criteria for close liver observation (CLO) to identify potential drug-induced liver injury (DILI). The criteria for CLO were aspartate transaminase (AST) or alanine transaminase (ALT) levels at more than 3 times the upper limit of normal (ULN) or alkaline phosphatase (ALP) levels at more than 2 times the ULN (as confirmed by retest). Fulfillment of liver injury criteria was evaluated by the LSMB according to the International Consensus Definition of DILI,24 and causality to study medication was evaluated using the causality assessment scoring of the Drug-Induced Liver Injury Network.25
Endometrial safety was evaluated through transvaginal ultrasonography and endometrial biopsy specimens, which were conducted at baseline and the end of treatment. Biopsy samples were evaluated independently by 3 masked external pathologists. Mammograms were performed at baseline and the end of treatment if this point aligned with the frequency of mammograms as recommended per local medical guidelines.
Bone mineral density (BMD; femoral neck, hip, and lumbar spine) was assessed using dual-energy radiography absorptiometry (DXA); the percentage change in BMD was calculated from baseline to week 24 and the end of treatment for all participants at sites where DXA was available (n = 43). Other factors evaluated at baseline and the end of treatment included changes in serum levels of bone turnover biomarkers (such as bone-specific ALP, procollagen type 1 N-terminal propeptide, 25-hydroxyvitamin D, and osteocalcin), hormone levels (including estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone), and body weight and composition.
Statistical Analysis
The primary end point was analyzed using a mixed model with repeated measures. Secondary and exploratory end points were assessed using descriptive statistics. The mixed model with repeated measures model, which assessed the change from baseline at week 12, included baseline, treatment, week, and region as fixed covariate effects, in addition to the interaction terms baseline by week and treatment by week. For further information on statistical analysis, please refer to the eMethods in Supplement 3.
The full analysis set (intention to treat) for efficacy assessment included all randomized participants, and the safety analysis set included all participants who received at least 1 dose of elinzanetant or placebo. The analysis set for BMD included all randomized participants in sites assigned to perform DXA scans who underwent a baseline and at least 1 postbaseline DXA scan and had not initiated HT or any other drugs affecting BMD during the study (other than vitamin D and calcium). Analyses were conducted using SAS, version 9.4 (SAS Institute), and statistical significance was set at a 1-sided .025 level.
Results
In total, 1524 women were screened, of whom 628 (41.2%) were randomized to elinzanetant (313 [49.8%]) and placebo (315 [50.2%]) (Figure 1). The mean (SD) age of participants was 54.7 (4.8) years. Baseline demographic characteristics were generally well balanced between the elinzanetant and placebo arms (Table 1). Protocol deviations were similar between the treatment arms (eTable 4 in Supplement 3). The number of participants who reported taking prohibited medication was also similar between treatment arms (eFigure 1 in Supplement 3).
Figure 1. Trial Profile.
Participant screening, randomization, and participant flow. AE indicates adverse event; BMD, bone mineral density VMS, vasomotor symptoms.
aOne participant provided 2 reasons for exclusion from the study (screen failure and participant decision).
bDid not include participants who discontinued the study drug but remained in the study and completed the posttreatment phase/follow-up.
cOne participant assigned to the placebo arm received elinzanetant at the week 8 visit by mistake; therefore, they were assigned to the elinzanetant, 120 mg, arm in the safety analysis set.
Table 1. Baseline Demographic Characteristics.
| Characteristic | No. (%) | |
|---|---|---|
| Elinzanetant, 120 mg (n = 313) | Placebo (n = 315) | |
| Self-reported race | ||
| Black or African American | 51 (16.3) | 44 (14.0) |
| White | 240 (76.7) | 253 (80.3) |
| Othera | 3 (1.0) | 3 (1.0) |
| Not reported | 19 (6.1) | 15 (4.8) |
| Hispanic or Latina | 34 (10.9) | 34 (10.8) |
| Age, mean (SD), y | 54.6 (4.7) | 54.9 (5.0) |
| BMI, mean (SD) | 27.6 (4.6) | 27.6 (4.8) |
| Smoking history | ||
| Never | 177 (56.5) | 189 (60.0) |
| Former | 72 (23.0) | 73 (23.2) |
| Current | 64 (20.4) | 53 (16.8) |
| Duration of amenorrhea, mean (SD), yb | 6.7 (6.0) | 7.2 (6.7) |
| Hysterectomyc | 88 (28.1) | 93 (29.5) |
| Oophorectomyd | 36 (11.5) | 46 (14.6) |
| Daily moderate to severe vasomotor symptom frequency, mean (SD) | 6.7 (7.2) | 6.8 (6.2) |
| PROMIS SD-SF-8b total T score assessing severity of sleep disturbances, mean (SD) | 57.4 (6.7) | 58.0 (7.6) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); PROMIS SD-SF-8b, Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b.
Included participants who self-reported their race as Asian, multiracial, or Native Hawaiian or other Pacific Islander.
For all participants (surgical and natural menopause included). Surgical menopause was defined as bilateral oophorectomy with or without hysterectomy at least 6 weeks before signing of informed consent.
Included all participants who had medical history of hysterectomy, hysterosalpingectomy, hysterosalpingo-oophorectomy, or radical hysterectomy.
Included all participants who had a medical history of oophorectomy, bilateral oophorectomy, hysterosalpingo-oophorectomy, salpingo-oophorectomy, bilateral salpingo-oophorectomy, or unilateral salpingo-oophorectomy.
At baseline, women experienced a mean of 6.7 (95% CI, 5.9-7.5) and 6.8 (95% CI, 6.1-7.5) moderate to severe VMS events per day in the elinzanetant and placebo arms, respectively. The mean change from baseline to week 12 was −5.4 (95% CI, −6.3 to −4.5) for the elinzanetant arm and −3.5 (95% CI, −4.1 to −2.9) for the placebo arm. The least-squares (LS) mean difference in the change from baseline for elinzanetant compared with placebo at week 12 was −1.6 (95% CI, −2.0 to −1.1; P < .001).
Based on descriptive analyses, the mean percentage changes from baseline to week 12 were −73.8% (95% CI, −78.6% to −69.1%) for elinzanetant and −47.0% (95% CI, −56.5% to −37.4%) for placebo. By week 50, women experienced a mean of 1.4 (95% CI, 1.1-1.7) and 3.5 (95% CI, 2.8-4.2) moderate to severe VMS events per day in the respective arms (Figure 2; eTable 5 in Supplement 3). Mean changes from baseline to week 12 in daily moderate to severe VMS severity were −1.2 (95% CI, −1.3 to −1.1) and −0.8 (95% CI, −0.9 to −0.7) in the elinzanetant and placebo arms, respectively (Figure 2; eTable 6 in Supplement 3). Baseline mean Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form SF 8b total T-scores were 57.4 (95% CI, 56.6-58.2) for elinzanetant and 58.0 (95% CI, 57.1-58.9) for placebo; mean changes from baseline to week 52 were −9.4 (95% CI, −10.7 to −8.0) and −5.7 (95% CI, −7.0 to −4.5), respectively (Figure 2; eTable 7 in Supplement 3). Mean baseline MENQOL total scores were 4.1 (95% CI, 4.0-4.3) for elinzanetant and 4.4 (95% CI, 4.2-4.6) for placebo; mean changes from baseline to week 52 were −1.3 (95% CI, −1.5 to −1.1) and −1.1 (95% CI, −1.3 to −0.9), respectively (Figure 2; eTable 8 in Supplement 3).
Figure 2. Mean Changes From Baseline in the Full Analysis Set.
Mean daily moderate to severe vasomotor symptom (VMS) frequency (A) and severity (B), Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD-SF-8b) total T score (C), and Menopause-Specific Quality Of Life Questionnaire (MENQOL) total score (D) over 50 or 52 weeks. Weeks 49 and 50 were the last points at which the hot flash daily diary was collected. All other patient-reported outcomes were collected until end of follow-up. Mean daily VMS severity during baseline was calculated as: [(2 × number of moderate VMS) + (3 × number of severe VMS)] / (total number of moderate and/or severe VMS on that day). Mean daily VMS severity during treatment was calculated as: [(1 × number of mild VMS) + (2 × number of moderate VMS) + (3 × number of severe VMS)] / (total number of mild, moderate, and/or severe VMS on that day).
Over the 52-week study duration, 70.0% and 61.1% of women in the elinzanetant and placebo arms, respectively, experienced at least 1 TEAE (Table 2). Treatment-related TEAEs were recorded in 95 (30.4%) and 46 (14.6%) women in the respective arms. Overall, 89.5% of the TEAEs in the elinzanetant arm and 89.6% in the placebo arm were mild or moderate in intensity. In both arms, the most frequently reported TEAEs were headache, COVID-19, fatigue, somnolence, and nasopharyngitis (Table 3). Incidences of TEAEs per 100 person-years can be found in eTable 9 in Supplement 3. The most frequently reported TEAEs considered to be treatment related were somnolence, fatigue, and headache (Table 3); 1 case of headache in each arm was assessed as severe, and all other cases of treatment-related somnolence, fatigue, or headache were mild or moderate. Discontinuation due to TEAEs was relatively low, at 12.5% in the elinzanetant arm and 4.1% in the placebo arm (Table 2). More participants in the elinzanetant arm permanently discontinued treatment (eFigure 2 in Supplement 3). Of the TEAEs leading to discontinuation in the elinzanetant arm, fatigue (5 [1.6%]) and headache (4 [1.3%]) were most frequently reported. Serious TEAEs occurred in 4.2% and 1.9% of women in the elinzanetant and placebo arms, respectively (eTable 10 in Supplement 3); none of the serious TEAEs were considered treatment related.
Table 2. Summary of TEAEs.
| TEAE | No. (%) | % (95% CI) | ||
|---|---|---|---|---|
| Elinzanetant, 120 mg (n = 313) | Placebo (n = 314) | Risk difference | Risk ratio | |
| Any TEAE | 219 (70.0) | 192 (61.1) | 8.8 (1.4 to 16.2) | 1.1 (1.0 to 1.3) |
| Any study drug–related TEAE | 95 (30.4) | 46 (14.6) | 15.7 (9.3 to 22.1) | 2.1 (1.5 to 2.8) |
| Any TEAE leading to discontinuation of study drug | 39 (12.5) | 13 (4.1) | 8.3 (4.1 to 12.6) | 3.0 (1.6 to 5.5) |
| Any serious TEAE | 13 (4.2) | 6 (1.9) | 2.2 (−0.4 to 4.9) | 2.2 (0.8 to 5.7) |
| Any study drug–related serious TEAE | 0 | 0 | NA | NA |
Abbreviations: NA, not applicable; TEAE, treatment-emergent adverse event.
Table 3. TEAEs by Preferred Term and TEAEs by Preferred Term as Assessed by the Investigator as Study Drug Related.
| TEAE | No. (%) | % (95% CI) | ||
|---|---|---|---|---|
| Elinzanetant, 120 mg (n = 313) | Placebo (n = 314) | Risk difference | Risk ratio | |
| By preferred term (≥2% in any treatment arm) | ||||
| Headache | 30 (9.6) | 22 (7.0) | 2.6 (−1.7 to 6.9) | 1.4 (0.8 to 2.3) |
| COVID-19 | 22 (7.0) | 32 (10.2) | −3.2 (−7.6 to 1.2) | 0.7 (0.4 to 1.2) |
| Fatigue | 21 (6.7) | 9 (2.9) | 3.8 (0.5 to 7.2) | 2.3 (1.1 to 5.0) |
| Somnolence | 16 (5.1) | 4 (1.3) | 3.8 (1.1 to 6.6) | 4.0 (1.4 to 11.9) |
| Nasopharyngitis | 15 (4.8) | 21 (6.7) | −1.9 (−5.5 to 1.7) | 0.7 (0.4 to 1.4) |
| Arthralgia | 12 (3.8) | 11 (3.5) | 0.3 (−2.6 to 3.3) | 1.1 (0.5 to 2.4) |
| Influenza | 12 (3.8) | 10 (3.2) | 0.7 (−2.2 to 3.5) | 1.2 (0.5 to 2.8) |
| Dizziness | 12 (3.8) | 5 (1.6) | 2.2 (−0.3 to 4.8) | 2.4 (0.9 to 6.8) |
| Diarrhea | 12 (3.8) | 3 (1.0) | 2.9 (0.5 to 5.3) | 4.0 (1.1 to 14.1) |
| Hypertension | 11 (3.5) | 9 (2.9) | 0.7 (−2.1 to 3.4) | 1.2 (0.5 to 2.9) |
| Dyspepsia | 10 (3.2) | 10 (3.2) | 0.0 (−2.7 to 2.8) | 1.0 (0.4 to 2.4) |
| Rash | 10 (3.2) | 4 (1.3) | 1.9 (−0.4 to 4.2) | 2.5 (0.8 to 7.9) |
| Urinary tract infection | 9 (2.9) | 14 (4.5) | −1.6 (−4.5 to 1.4) | 0.6 (0.3 to 1.5) |
| Nausea | 9 (2.9) | 11 (3.5) | −0.6 (−3.4 to 2.1) | 0.8 (0.3 to 2.0) |
| Back pain | 9 (2.9) | 10 (3.2) | −0.3 (−3.0 to 2.4) | 0.9 (0.4 to 2.2) |
| Hot flash | 9 (2.9) | 3 (1.0) | 1.9 (−0.2 to 4.1) | 3.0 (0.8 to 11.0) |
| Muscle spasms | 9 (2.9) | 2 (0.6) | 2.2 (0.2 to 4.3) | 4.5 (1.0 to 20.7) |
| Alopecia | 8 (2.6) | 4 (1.3) | 1.3 (−0.9 to 3.4) | 2.0 (0.6 to 6.6) |
| Upper respiratory tract infection | 7 (2.2) | 14 (4.5) | −2.2 (−5.0 to 0.6) | 0.5 (0.2 to 1.2) |
| Insomnia | 7 (2.2) | 6 (1.9) | 0.3 (−1.9 to 2.6) | 1.2 (0.4 to 3.4) |
| Abdominal pain upper | 7 (2.2) | 4 (1.3) | 1.0 (−1.1 to 3.0) | 1.8 (0.5 to 5.9) |
| Constipation | 7 (2.2) | 7 (2.2) | 0.0 (−2.3 to 2.3) | 1.0 (0.4 to 2.8) |
| Postmenopausal hemorrhage | 5 (1.6) | 7 (2.2) | −0.6 (−2.8 to 1.5) | 0.7 (0.2 to 2.2) |
| By preferred term as assessed by the investigator as study drug related (≥2% in any treatment arm) | ||||
| Somnolence | 15 (4.8) | 3 (1.0) | 3.8 (1.2 to 6.4) | 5.0 (1.5 to 17.2) |
| Fatigue | 13 (4.2) | 5 (1.6) | 2.6 (−0.1 to 5.2) | 2.6 (0.9 to 7.2) |
| Headache | 10 (3.2) | 5 (1.6) | 1.6 (−0.8 to 4.0) | 2.0 (0.7 to 5.8) |
| Dyspepsia | 8 (2.6) | 4 (1.3) | 1.3 (−0.9 to 3.4) | 2.0 (0.6 to 6.6) |
| Dizziness | 7 (2.2) | 3 (1.0) | 1.3 (−0.7 to 3.2) | 2.3 (0.6 to 9.0) |
Abbreviation: TEAE, treatment-emergent adverse event.
An endometrial biopsy was performed for all 446 participants with an intact uterus at baseline (although 3 participants [1 in the elinzanetant arm and 2 in the placebo arm] did not have an evaluable biopsy sample). Evaluable endometrial tissue samples were obtained for 116 of 140 participants (82.9%) in the elinzanetant arm and 106 of 132 participants (80.3%) in the placebo arm at the end of treatment. There were no cases of endometrial hyperplasia or malignant endometrial neoplasms. The mean (SD) changes in endometrial thickness from baseline to week 52 were 0.2 (1.9) and 0.0 (2.2) mm for elinzanetant and placebo, respectively (both clinically nonmeaningful).
Mammograms were obtained for 309 of 313 participants (98.7%) taking elinzanetant and 308 of 314 (98.1%) receiving placebo at baseline; no participants had clinically significant abnormal results. At the end of treatment, mammograms were obtained for 99 of 243 participants (40.7%) taking elinzanetant and 107 of 242 participants (44.2%) receiving placebo, which aligned with local recommendations for mammogram frequency. Clinically significant abnormal results were reported for 2 participants in the elinzanetant arm. One of them reported a serious AE of invasive ductal breast carcinoma; this was considered not treatment related by the investigator. For the other participant, a follow-up mammogram performed 4 weeks later showed normal results.
There were no clinically relevant changes in serum concentrations of estradiol, progesterone, luteinizing hormones, or follicle-stimulating hormones over the 52-week study period. Similarly, there were no clinically relevant changes in levels of bone turnover biomarkers. The mean (SD) percentage changes in BMD from baseline to week 52 for femoral neck, hip, and lumbar spine were clinically nonmeaningful at −0% (4.7%), −0.7% (4.2%), and −0.6% (3.3%) for elinzanetant (n = 173) and −1.2% (4.1%), −1.4% (3.0%), and −1.2% (3.1%) for placebo (n = 170), respectively. Body weight remained largely stable over the 52-week period; the mean (SD) changes from baseline in body weight were −0.6 (3.8) and −0.1 (4.3) kg in the elinzanetant and placebo arms, respectively. Body composition also remained stable, with small numerical mean (SD) changes from baseline in fat mass of −0.4 (3.0) and −0.5 (3.6) kg in the respective arms.
Liver enzyme level elevations were observed for a few women (eTable 11 in Supplement 3). Ten cases fulfilled the predefined CLO criteria: 6 in the elinzanetant arm and 4 in the placebo arm (eTable 12 in Supplement 3). The elevations of transaminase levels in women taking elinzanetant were all nonserious and assessed by the investigator as mild, except for 1 event, which was assessed as moderate. These elevations were mostly asymptomatic and resolved in 5 of the 6 cases; the final case had an unknown outcome. Of these 5 resolved cases, 3 resolved during ongoing treatment and 2 had onset of CLO after end of treatment (1 and 37 days after). In most cases, an alternative etiology was identified, and causality was assessed as unlikely to be treatment related, including the only case of elinzanetant treatment discontinuation. The only case with no alternative etiology and a probable causality due to the study drug was reported in the placebo arm. Cumulative incidence rates for ALT levels at 3 or more times the ULN and ALP levels at 3 or more time the ULN can be found in eTables 13 and 14 and eFigure 3 in Supplement 3. There were no Hy law cases (ie, no cases of ALT or AST levels ≥3 times the ULN, total bilirubin levels of ≥2 times the ULN, and ALP levels of <2 time the ULN; eFigure 4A in Supplement 3), no indication of cholestatic injury (ie, no cases of total bilirubin levels ≥2 times the ULN and ALP levels of ≥2 time the ULN; eFigure 4B in Supplement 3), and no cases associated with acute liver failure. According to the LSMB causality assessment, there was no hepatotoxic effect signal in this study.
Discussion
To our knowledge, OASIS-3 was the first trial to evaluate the 52-week efficacy and safety of elinzanetant for treating VMS in postmenopausal women compared with placebo, as well as the first trial with no eligibility requirement for a minimum number of moderate to severe VMS events per week. In this study, elinzanetant demonstrated a favorable efficacy and safety profile in treating moderate to severe VMS symptoms associated with menopause; elinzanetant treatment was also associated with numerical advantages in improving the secondary end points of sleep disturbances and menopause-related quality of life. Outcomes from this 52-week study were consistent with those observed in the 26-week OASIS-1 and OASIS-2 trials,21 contributing to the robustness of the findings and indicating the sustained benefit and safety of elinzanetant in a broad population with VMS over a prolonged duration of use.
Elinzanetant treatment resulted in statistically significant reductions in daily moderate to severe VMS frequency at week 12 vs placebo. A numerical reduction of 73.8% in daily moderate to severe VMS frequency was observed from baseline to week 12 in the elinzanetant arm, in contrast to 47.0% in the placebo arm. This placebo response was comparable with that reported in other VMS trials. For example, a Cochrane review reported a placebo response of 50.8% for studies investigating the efficacy of HT in reducing the frequency of VMS in menopausal women.26 Although no statistical hypothesis was defined for the secondary end points and the study was not powered to demonstrate a statistically significant difference between elinzanetant and placebo for those end points, descriptive analyses showed numerical advantages in the improvement of sleep disturbances and menopause-related quality of life over 52 weeks with elinzanetant. These findings were consistent with those from OASIS-1 and OASIS-2.
These OASIS-3 observations were made despite this study having no baseline requirements for a minimum number of moderate to severe VMS events per week. Phase 3 trials on VMS treatments generally recruit participants with a high frequency of moderate to severe VMS; for example, OASIS-1 and OASIS-2 required participants to have 50 or more moderate to severe VMS over 7 days during screening for inclusion,21 as requested by regulatory guidance. As such, the observed mean baseline moderate to severe VMS frequency in OASIS-3 was lower than that in OASIS-1 and OASIS-2 (6.7-6.8 per day vs 13.4-16.2 per day, respectively).21 Because menopausal women typically experience a mean of 4 to 5 VMS events per day,11 data from OASIS-3 may reflect a clinical population with VMS, and the favorable efficacy profile demonstrated by elinzanetant suggests its benefits in this population across a broad spectrum of disruptive menopausal symptoms.
OASIS-3 was placebo controlled for its entire duration, collecting data over 52 weeks to enable rigorous assessment of the safety and efficacy of elinzanetant. Consistent with results from the 26-week OASIS-1 and OASIS-2 trials (placebo controlled for the first 12 weeks),21 elinzanetant had a favorable safety profile in the longer-term OASIS-3 trial. Treatment-related TEAEs were more common with elinzanetant than placebo; the most frequently reported were somnolence, fatigue, and headache. However, most events were mild or moderate in intensity. Serious TEAEs occurred for a few participants, and none were considered treatment related by the investigator. There was no incidence of endometrial hyperplasia or malignant endometrial neoplasms, no clinically relevant change in endometrial thickness, and no indication of treatment-related safety concerns from mammograms. End-of-treatment mammograms were not performed for more than 50% of the study population, as the end-of-treatment point was not compatible with local recommendations for mammogram frequency. In both arms, the mean percentage changes in BMD were within the expected age-related loss per year of 1% to 2%.27 Body weight and composition also remained relatively stable over 52 weeks. Furthermore, liver enzyme elevations were closely monitored in all OASIS trials due to past observations of such elevations with NK-3–only receptor antagonists (eg, pavinetant and fezolinetant).28,29,30,31 Using the International Consensus Definition of DILI,24 the external independent LSMB concluded that there was no hepatotoxic effect signal in OASIS-3 for elinzanetant, which was consistent with findings from OASIS-1 and OASIS-2.21 These 52-week safety data for elinzanetant are important, as disruptive menopausal symptoms can be long-lasting and may require sustained treatment.11
Limitations
The limitations of this study included its limited generalizability to populations that differ in ethnicity, age, and health, as well as those taking medications that excluded participation in the trial. There was a proportional representation of Black or African American women and Hispanic or Latina women but limited representation of Asian and Native Hawaiian or Pacific Islander women. Another limitation was that this study was not powered to detect statistical significance for its secondary end points of sleep disturbances and menopause-related quality of life. OASIS-3 also did not include any inclusion criteria regarding sleep disturbances; the efficacy and safety of elinzanetant in participants meeting eligibility criteria for sleep disturbances associated with menopause are being explored in the phase 2 NIRVANA trial (NCT06112756). Additionally, OASIS-3 excluded women with recent history of cancer; the phase 3 OASIS-4 trial (NCT05587296) assesses the efficacy and safety of elinzanetant for treating VMS that is associated with endocrine therapy in women with or at high risk of breast cancer.
Conclusions
In this randomized clinical trial, elinzanetant demonstrated a favorable efficacy and safety profile over 52 weeks in a broad study population without baseline requirements for a minimum number of VMS events per week. This longer-term trial built on the findings from OASIS-1 and OASIS-2, suggesting that elinzanetant has the potential to be a well-tolerated treatment option for menopausal women with moderate to severe VMS.
Trial protocol
Statistical analysis plan
eMethods.
eFigure 1. Kaplan-Meier plot of the time from randomization to first intake of prohibited concomitant medication potentially having an impact on efficacy up of elinzanetant to Week 12
eFigure 2. Kaplan-Meier plot of the time from randomization to permanent discontinuation of randomized treatment up to Week 12
eFigure 3. Cumulative incidence plot of (A) time to ALT ≥3 x ULN by treatment group and (B) time to ALP ≥3 x ULN by treatment group
eFigure 4. (A) Hepatocellular drug-induced liver injury screening plot by elinzanetant 120 mg (weeks 1–52) and placebo (weeks 1–52); (B) Cholestatic drug-induced liver injury screening plot by elinzanetant 120 mg (weeks 1–52) and placebo (weeks 1–52)
eTable 1. Full inclusion/exclusion criteria
eTable 2. Prohibited concomitant medications
eTable 3. Schedule of assessments
eTable 4. Number of participants with protocol deviations
eTable 5. Moderate-to-severe daily vasomotor symptom frequency over time
eTable 6. Moderate-to-severe daily vasomotor symptom severity over time
eTable 7. PROMIS SD SF 8b total T-score over time
eTable 8. MENQOL total score over time
eTable 9. Exposure-adjusted incidence rate of treatment-emergent adverse events per 100 person-years (cut-off incidence rate ≥2.5% per 100 person-years in any treatment arm)
eTable 10. Serious treatment-emergent adverse events
eTable 11. Number of subjects by cumulative hepatic safety laboratory parameters
eTable 12. Causality assessment of close liver observation cases by the Liver Safety Monitoring Board
eTable 13. Cumulative incidence rate for ALT ≥3x ULN by treatment group
eTable 14. Cumulative incidence rate for ALP ≥3x ULN by treatment group
eAppendix. List of OASIS-3 study investigators, study sites, and site location per country
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
Statistical analysis plan
eMethods.
eFigure 1. Kaplan-Meier plot of the time from randomization to first intake of prohibited concomitant medication potentially having an impact on efficacy up of elinzanetant to Week 12
eFigure 2. Kaplan-Meier plot of the time from randomization to permanent discontinuation of randomized treatment up to Week 12
eFigure 3. Cumulative incidence plot of (A) time to ALT ≥3 x ULN by treatment group and (B) time to ALP ≥3 x ULN by treatment group
eFigure 4. (A) Hepatocellular drug-induced liver injury screening plot by elinzanetant 120 mg (weeks 1–52) and placebo (weeks 1–52); (B) Cholestatic drug-induced liver injury screening plot by elinzanetant 120 mg (weeks 1–52) and placebo (weeks 1–52)
eTable 1. Full inclusion/exclusion criteria
eTable 2. Prohibited concomitant medications
eTable 3. Schedule of assessments
eTable 4. Number of participants with protocol deviations
eTable 5. Moderate-to-severe daily vasomotor symptom frequency over time
eTable 6. Moderate-to-severe daily vasomotor symptom severity over time
eTable 7. PROMIS SD SF 8b total T-score over time
eTable 8. MENQOL total score over time
eTable 9. Exposure-adjusted incidence rate of treatment-emergent adverse events per 100 person-years (cut-off incidence rate ≥2.5% per 100 person-years in any treatment arm)
eTable 10. Serious treatment-emergent adverse events
eTable 11. Number of subjects by cumulative hepatic safety laboratory parameters
eTable 12. Causality assessment of close liver observation cases by the Liver Safety Monitoring Board
eTable 13. Cumulative incidence rate for ALT ≥3x ULN by treatment group
eTable 14. Cumulative incidence rate for ALP ≥3x ULN by treatment group
eAppendix. List of OASIS-3 study investigators, study sites, and site location per country
Data sharing statement