A Study of BAY3427080 (NT-814) in the Treatment of Moderate to Severe Post-menopausal Vasomotor Symptoms (SWITCH-1)

A Study of BAY3427080 (NT-814) in the Treatment of Moderate to Severe Post-menopausal Vasomotor Symptoms

A Double-Blind, Randomised, Placebo Controlled, Adaptive Design Study of the Efficacy, Safety and Pharmacokinetics of NT-814 in Female Subjects With Moderate to Severe Vasomotor Symptoms Associated With the Menopause

The purpose of this study is to determine the effectiveness of BAY3427080 (NT-814), taken once a day, in the treatment of troublesome post-menopausal symptoms.

This is a multi-centre, multi-country, double-blind, randomised, placebo-controlled Phase 2b study. The study will have a single-blind run-in period and will be adaptive with respect to the number of subjects recruited into each dose group. Four doses of BAY3427080 (40 mg once a day, 80 mg once a day, 120 mg once a day and 160 mg once a day) will be investigated and compared to placebo, in five parallel groups. Subjects will participate in the study for a total of approximately 19 weeks, comprising a screening period of 1 week, a 14 week treatment period, and then a final follow up visit 4 weeks after the end of the treatment period. There will be a total of 8 visits whilst participating in the study. Subjects will record their hot flashes in an electronic diary during the screening period to establish eligibility and throughout the study after randomisation.

Mean Change From Baseline in Mean Daily Frequency of Moderate and Severe Hot Flushes From Baseline to Week 4

Participants recorded daily in their electronic diary (eDiary) the frequency and severity of hot flushes during the treatment period. The baseline assessment for hot flushes was calculated using the last 7 days (not necessarily consecutive days) with an available data in the evening and/or the morning of the baseline diary completion period. A diary day was comprised of the evening entry of this day and the morning entry of the following day, in that order. Mean daily frequency = Sum of number of hot flushes filled in the diary during the last 7 diary days (with at least one available data in the evening and/or morning) divided by 7. Moderate: Sensation of heat with sweating, but able to continue activity. Severe: Sensation of heat with sweating, causing cessation (stopping) of activity.

Mean Change From Baseline in Mean Daily Frequency of Moderate and Severe Hot Flushes From Baseline to Week 12

Participants recorded daily in their electronic diary (eDiary) the frequency and severity of hot flushes during the treatment period. The baseline assessment for hot flushes was calculated using the last 7 days (not necessarily consecutive days) with an available data in the evening and/or the morning of the baseline diary completion period. A diary day was comprised of the evening entry of this day and the morning entry of the following day, in that order. Mean daily frequency = Sum of number of hot flushes filled in the diary during the last 7 diary days (with at least one available data in the evening and/or morning) divided by 7. Moderate: Sensation of heat with sweating, but able to continue activity. Severe: Sensation of heat with sweating, causing cessation (stopping) of activity.

Mean Change From Baseline in Mean Severity of Moderate and Severe Hot Flushes From Baseline to Week 4

Participants recorded daily in their eDiary the frequency and severity of hot flushes during the treatment period. Mean weekly severity = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). Severity is graded by the women from 1 to 3 (1 = mild; 2 = moderate; 3 = severe).

Mean Change From Baseline in Mean Severity of Moderate and Severe Hot Flushes From Baseline to Week 12

Participants recorded daily in their eDiary the frequency and severity of hot flushes during the treatment period. Mean weekly severity = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). Severity was graded by the women from 1 to 3 (1 = mild; 2 = moderate; 3 = severe).

Mean Change From Baseline in Frequency of Mean Daily Moderate and Severe Hot Flushes From Baseline to Weeks 1, 2, 8 and 16

Participants recorded daily in their electronic diary (eDiary) the frequency and severity of hot flushes during the treatment period. The baseline assessment for hot flushes was calculated using the last 7 days (not necessarily consecutive days) with an available data in the evening and/or the morning of the baseline diary completion period. A diary day was comprised of the evening entry of this day and the morning entry of the following day, in that order. Mean daily frequency = Sum of number of hot flushes filled in the diary during the last 7 diary days (with at least one available data in the evening and/or morning) divided by 7. Moderate: Sensation of heat with sweating, but able to continue activity. Severe: Sensation of heat with sweating, causing cessation (stopping) of activity.

Mean Change From Baseline in Mean Severity of Moderate and Severe Hot Flushes From Baseline to Weeks 1, 2, 8 and 16

Participants recorded daily in their diary the frequency and severity of hot flushes during the treatment period. Mean weekly severity = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). Severity is graded by the women from 1 to 3 (1 = mild; 2 = moderate; 3 = severe).

Mean Change From Baseline in Mean Daily Frequency of All Hot Flushes From Baseline to Weeks 1, 2, 4, 8, 12 and 16

Participants recorded daily in their electronic diary (eDiary) the frequency and severity of hot flushes during the treatment period. The baseline assessment for hot flushes was calculated using the last 7 days (not necessarily consecutive days) with an available data in the evening and/or the morning of the baseline diary completion period. A diary day was comprised of the evening entry of this day and the morning entry of the following day, in that order. Mean daily frequency = Sum of number of hot flushes filled in the diary during the last 7 diary days (with at least one available data in the evening and/or morning) divided by 7. Moderate: Sensation of heat with sweating, but able to continue activity. Severe: Sensation of heat with sweating, causing cessation (stopping) of activity.

Mean Change From Baseline in Mean Severity of All Hot Flushes From Baseline to Weeks 1, 2, 4, 8, 12 and 16

Participants recorded daily in their diary the frequency and severity of hot flushes during the treatment period. Mean weekly severity = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). Severity is graded by the women from 1 to 3 (1 = mild; 2 = moderate; 3 = severe).

Mean Change From Baseline in the Mean Daily Hot Flush Score (Frequency x Severity) at Weeks 1, 2, 4, 8, 12 and 16

Mean daily Hot Flushes score = Sum of (frequency x severity) filled in the diary during the last 7 days (with at least one available data in the evening and/or morning) divided by 7. Severity is graded by the women from 1 to 3 (1 = mild; 2 = moderate; 3 = severe).

Number of Participants With ≥50% and ≥80% Reduction From Baseline in Mean Daily Hot Flushes Frequency at Week 12

The percent change from baseline at a visit Week 12 was calculated. Percent change = (change from baseline in mean daily frequency of moderate and severe hot flushes from baseline to Week 12 / Mean daily frequency of moderate and severe hot flushes at baseline) * 100. A participant was considered as a responder with a reduction of ≥50% (or ≥80%) if the percent change was ≤-50 (or ≤-80).

Mean Change From Baseline in Number of All Night-time Awakenings (NTA) at Weeks 1, 2, 4, 8, 12 and 16

Participants were provided with an eDiary to document the number of night-time awakenings (NTA). Each evening, participants recorded the total number of hot flushes of each severity experienced that day since waking. Each morning upon waking, subjects recorded the number of times they woke up in the night and the total number of hot flushes of each severity experienced during the night.

Mean Change From Baseline in Mean Daily Number of NTAs Secondary to Hot Flushes at Weeks 1, 2, 4, 8, 12 and 16

Subjects were provided with an eDiary to document the number of night-time awakenings (NTA). Each evening, subjects recorded the total number of hot flashes of each severity experienced that day since waking. Each morning upon waking, subjects recorded the number of times they woke up in the night and the total number of hot flushes of each severity experienced during the night. Night-time awakenings secondary to hot flashes corresponded to severe hot flash recorded on the morning diary, and all NTAs corresponded to the data recorded in the "Total number of times you woke up last night?" field from the eDiary recorded in the morning. Number of NTAs secondary to hot flushes could not be higher than the number of all NTAs.

Change From Baseline in the Global and Individual Domain Scores of the Pittsburgh Sleep Quality Index (PSQI) at Weeks 4, 8, 12 and 16

The PSQI is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. The PSQI uses 19 individual items to generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction, each scored 0 (no difficulty) to 3 (severe difficulty). The sum of scores for these seven components yields one global score (range 0 to 21). Higher scores indicated worse sleep quality.

The ISI is a brief self-report questionnaire assessing the nature, severity, and impact of insomnia. The ISI comprises seven items assessing the perceived severity of difficulties initiating sleep, staying asleep, and early morning awakenings, satisfaction with current sleep pattern, interference with daily functioning, noticeability of impairment attributed to the sleep problem, and degree of distress or concern caused by the sleep problem. Participants rated each item on a scale of 0 to 4, yielding a total score ranging from 0 to 28. The total score was calculated by adding the scores for all seven items. Higher scores indicated severe insomnia.

Change From Baseline in the Hot Flush Related Daily Interference Scale (HFRDIS) Scores at Weeks 2, 4, 8, 12 and 16

The HFRDIS is a 10-item, self-report questionnaire assessing the impact of hot flushes on a woman's life during the past week. For each of the 10 items, participants rated how much hot flushes had interfered with that aspect of their life on a scale of 0 (not at all) to 10 (very much so). The total score was calculated by adding the scores for all 10 items. Higher scores indicated greater interference.

Change From Baseline in the Menopause-specific Quality-of-Life Questionnaire Intervention Version (MenQoL-I) Scores at Weeks 4, 8, 12 and 16

The MenQoL-I is a validated questionnaire used to measure condition-specific quality of life in menopausal women. It is composed of 32 items across four domains (physical, vasomotor, psychosocial and sexual). For each item, participants recorded whether they had experienced the problem in the past month, and if so, they rated how bothered they were by the problem on a scale of 0 (not at all bothered) to 6 (extremely bothered). The item scores were converted to a score ranging from 1 to 8. Domain scores are calculated by averaging the converted individual item scores (range 1-8) related to the respective domain. (Domains: Vasomotor - items 1 to 3, Psychosocial - items 4 to 10, Physical- items 11- to 26, Sexual - items 27 to 29). For a MENQOL total score the aggregated mean of the mean domain scores is calculated. Higher scores indicate greater bother.

The BDI-II is a 21-item questionnaire assessing the intensity of depressive symptoms over the past 2 weeks. It is composed of items relating to symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. Participants rated each item on a scale of 0 to 3 to give a total score ranging from 0 to 63, with a higher score suggesting more severe depressive symptoms.

Blood samples for analysis of plasma elinzanetant concentrations were collected at Weeks 2, 4, 8, and 12. A small number of participants had elinzanetant concentrations below the LOQ for the assay (1.5 ng/mL) at two or more visits (three participants in each of the 40 mg, 120 mg, and 160 mg groups, four in 80 mg group), indicating that these subjects were non compliant with treatment.

A Treatment-Emergent Adverse Events (TEAE) is defined as any adverse event (serious and non-serious) with the onset date on or after the date of first dosing with study treatment. Safety Analysis Set.

A Treatment-Emergent Adverse Events (TEAE) is defined as any adverse event (serious and non-serious) with the onset date on or after the date of first dosing with study treatment.

A concomitant medication is defined as any medication used on or after date and time of first randomised treatment. All concomitant medications taken during the study were recorded in the eCRF. Any medication that was not specifically prohibited was allowed. (1) Antidiarrheals, intestinal antiinflammatory/antiinfective agents.

Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature, weight, waist circumference, and height, were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

Vital signs, including systolic and diastolic blood pressure were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature, weight, waist circumference, and height, were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature, weight, waist circumference, and height, were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature, weight, waist circumference, and height, were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature, weight, waist circumference, and height, were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature, weight, waist circumference, and height, were measured at the time points and recorded in the eCRF. All vital signs were reviewed by the Investigator or delegated physician.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reported results are cardiovascular system-examination findings. Normal ECG was decided by investigator. The findings are presented as Normal ECG.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reported results are cardiovascular system-examination findings. Abnormal not clinically significant ECG findings were decided by investigator. The findings are presented as Abnormal not clinically significant ECG.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reported results are cardiovascular system-examination findings. Abnormal clinically significant ECG findings were decided by investigator. The findings are presented as Abnormal clinically significant ECG.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. The same model of ECG recorder was used throughout the study for any given subject wherever possible. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reports were then filed with the subject's medical record. In categories the number of subjects analyzed (N) for each week is mentioned for each reporting group respectively.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. The same model of ECG recorder was used throughout the study for any given subject wherever possible. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reports were then filed with the subject's medical record.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. The same model of ECG recorder was used throughout the study for any given subject wherever possible. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reports were then filed with the subject's medical record.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. The same model of ECG recorder was used throughout the study for any given subject wherever possible. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reports were then filed with the subject's medical record. QTc: QT corrected interval.

All ECGs were performed after the subject had rested for 5 minutes in a semi-recumbent position. The same model of ECG recorder was used throughout the study for any given subject wherever possible. All ECG reports were reviewed, signed and dated by the Investigator or delegated physician. Reports were then filed with the subject's medical record. QTcF: QT interval with Fridericia's correction.

Number of Subjects With Absolute QTcF Values by Category at Each Visit: ≤450, >450 to ≤480, >480 to ≤500, >500 Msec

Number of Subjects With Change From Baseline in ECG QTcF Values by Category at Weeks 2, 4, 8, 12 and 16: ≤0, >0 to ≤30, >30 to ≤60, >60 Msec

Change From Baseline in the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) at Weeks 4, 12 and 16

The Columbia Suicide Severity Rating Scale (C-SSRS) is a rating scale created to evaluate suicidality in adults and children over the age of 12. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The version used was the eC-SSRS, which is a subject-reported version of the scale. Shifts from baseline versus post-baseline to demonstrate changes in categories (cat) were reported using cat 1 (No Suicidal Ideation or Behaviour), cat 2 (Suicidal Ideation) and cat 3 (Suicidal Behaviour).

Change From Baseline at Weeks 2, 4, 12 and 16 for Clinical Laboratory Parameters Hematology: Erythrocytes

Blood samples for clinical hematology assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 12 and 16 for Clinical Laboratory Parameters Hematology: Hematocrit

Blood samples for clinical hematology assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Hematology: Hemoglobin

Blood samples for clinical hematology assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Hematology: Erythrocytes Mean Corpuscular Volume

Blood samples for clinical hematology assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Hematology: Leukocytes, Platelets, Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils

Blood samples for clinical hematology assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Hematology: Leukocytes, Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils

Blood samples for clinical hematology assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 8, 12 and 16 in Clinical Laboratory Parameters Biochemistry: Sodium, Potassium, Glucose, Urea Nitrogen, Calcium, Phosphate, Bicarbonate, Magnesium and Chloride

Blood samples for clinical chemistry assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 8, 12 and 16 in Clinical Laboratory Parameters Biochemistry: Creatinine and Bilirubin

Blood samples for clinical chemistry assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 8, 12 and 16 in Clinical Laboratory Parameters Biochemistry: Creatinine Kinase, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase and Gamma Glutamyl Transferase

Blood samples for clinical chemistry assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 8, 12 and 16 in Clinical Laboratory Parameters Biochemistry: Protein and Albumin

Blood samples for clinical chemistry assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 2, 4, 8, 12 and 16 in Clinical Laboratory Parameters Biochemistry: Hemoglobin A1C

Blood samples for clinical chemistry assessment were collected and sent to the central laboratory for analysis.

Change From Baseline at Weeks 12 and 16 in Clinical Laboratory Parameters Bone: Bone Specific Alkaline Phosphatase and Procollagen 1 N-Terminal Propeptide

Blood for assessment of bone turnover markers was collected and sent to the central laboratory for analysis.

Urine for urinalysis was collected and sent to the central laboratory for analysis. Urine pH was measured on a pH scale.

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Urinalysis: Specific Gravity

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Urinalysis: Glucose, Bilirubin, Ketones, Occult Blood, Protein, Urobilinogen and Nitrite

Urine for urinalysis was collected and sent to the central laboratory for analysis. Clinical relevance was judged by the investigator. Assessment was done using standard laboratory practice. For evaluation of the chemical properties of the urine sample test strips were used which have test pads of chemicals that change color when they come in contact with reagents. The degree of color change correlates with the amount of reagent present. Each color block represents a range of values. Range and direction of scores for reagents nitrite and urobilinogen: negative = normal; positive = abnormal. Range and direction of scores for all other reagents tested: negative = normal; trace, 1+, 2+, 3+ = abnormal, the higher the value, the higher the concentration of the reagent tested.

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Urinalysis: Erythrocytes and Leukocytes

Urine for urinalysis was collected and sent to the central laboratory for analysis. Results are reported according to the amount present in the microscope's field of view at high magnification (/HPF [high-power field]).

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Urinalysis: Hyaline Casts

Urine for urinalysis was collected and sent to the central laboratory for analysis. Results are reported according to the amount present in the microscope's field of view at low magnification (/LPF [low-power field]).

Change From Baseline at Weeks 2, 4, 12 and 16 in Clinical Laboratory Parameters Urinalysis: Bacteria, Yeast Cells, Granular Casts, RBC Casts, Waxy Casts, WBC Casts, Calcium Oxalate Crystals, Triple Phosphate Crystals and Uric Acid Crystals

Urine for urinalysis was collected and sent to the central laboratory for analysis. The evaluation of components in the urine samples such as bacteria, yeast, red blood cells (RBC), white blood cells (WBC), casts and crystals was performed by microscopy. Results are reported according to the amount present in the microscope's field of view at low magnification (/LPF [low-power field]) and high magnification (/HPF [high-power field]). Range and direction of scores microscopic identification of urine components: Bacteria: none seen, 1+, 2+, 3+,4+, TNTC (too numerous to count). Other urine components: none seen=normal; few, moderate, many, TNTC = abnormal. The higher the value, the higher the concentration of the component evaluated.

Key Inclusion Criteria: Postmenopausal Body mass index between 18 and 38 kg/m2, inclusive Subject experiences moderate or severe hot flashes Key Exclusion Criteria: Inability to comply with the use of prohibited and allowed medications as described in the protocol. Any prior or ongoing history of clinically relevant drug or alcohol abuse within 12 months of Screening. Any clinically significant prior or ongoing history of arrhythmias, either determined through clinical history or on ECG evaluation. Any clinically significant abnormal laboratory test result(s) measured at Screening. Any active ongoing condition that could have caused difficulty in interpreting vasomotor symptoms. Uncontrolled hypertension. A history or hyperthyroidism, hypothyroidism or abnormal thyroid function tests at Screening. Treated hypothyroidism with normal thyroid function test results at Screening is acceptable.

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