Evaluation of the Pharmacokinetics and Safety of BAY3427080 (NT-814) in Post-Menopausal Women With Vasomotor Symptoms

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, double-blind, randomized, placebo-controlled multiple ascending dose study in post-menopausal women with vasomotor symptoms. Single ascending doses of NT-814 will be investigated in 4 cohorts. Each cohort will comprise of 20 subjects. Subjects will be dosed for 14 days.

Official Title
-----------------
Evaluation of the Pharmacokinetics and Safety of NT-814 in Post-Menopausal Women With Vasomotor Symptoms

Conditions
-----------------
Post-menopausal Vasomotor Symptoms

Intervention / Treatment
-----------------
* Drug: BAY3427080
* Drug: Placebo (for BAY3427080)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Post-menopausal female subjects experiencing frequent moderate to severe hot flashes.Menopause will be defined as: 12 months of spontaneous amenorrhea; OR at least 6 weeks' post-surgical bilateral oophorectomy with or without hysterectomy. Exclusion Criteria: BMI > 35kg/m2. Any active comorbid disease, ECG or laboratory result deemed by the investigator to be clinically significant and which could impact safety during study conduct or that could interfere with the study evaluation, procedures or completion. Use of prohibited medications defined in the protocol. Inability or unwillingness to comply with study procedures or requirements.

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: BAY3427080 Placebo<br> | Drug: Placebo (for BAY3427080)<br> <br> |
| Experimental: 50mg BAY3427080<br> | Drug: BAY3427080<br> <br> * Other names: NT-814;|
| Experimental: 100mg BAY3427080<br> | Drug: BAY3427080<br> <br> * Other names: NT-814;|
| Experimental: 150mg BAY3427080<br> | Drug: BAY3427080<br> <br> * Other names: NT-814;|
| Experimental: 300mg BAY3427080<br> | Drug: BAY3427080<br> <br> * Other names: NT-814;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of BAY3427080 | Cmax is the maximum observed plasma concentration of BAY3427080 was presented. Blood samples were taken within 30 minutes prior to dose administration. | On Day 1, Day 7 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours) and on Day 14 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0, 48.0, 72.0 hours) | 
| Time to Reach Maximum Observed Drug Concentration in Plasma (Tmax) of BAY3427080 | Time of occurrence of Cmax.Time to reach maximum plasma concentration of BAY3427080 was presented. Blood samples for Tmax were taken within 30 minutes prior to dose administration. | On Day 1, Day 7 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours) and on Day 14 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0, 48.0, 72.0 hours) | 
| Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of BAY3427080 | AUC from time zero extrapolated to infinity of BAY3427080 was presented. AUC0-∞ was only estimated following the Day 1 dose. | Day 1 (pre-dose and post-dose (0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0 and 24.0 hours) | 
| Area Under the Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-τ) of BAY3427080 | Area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration of BAY3427080 was presented. Blood samples for (AUC0-τ) were taken within 30 minutes prior to dose administration. | On Day 1, Day 7 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours) and on Day 14 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0, 48.0, 72.0 hours) | 
| Terminal Elimination Half-life (t½) of BAY3427080 | Terminal elimination half-life of BAY3427080 was presented. Blood samples were taken within 30 minutes prior to dose administration. | On Day 1, Day 7 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours) and on Day 14 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0, 48.0, 72.0 hours) | 
| Apparent Clearance (CL/F) of BAY3427080 | Apparent clearance of BAY3427080 was presented. Blood samples were taken within 30 minutes prior to dose administration. | On Day 1, Day 7 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0 hours) and on Day 14 (Pre-dose; 0.5; 1.0; 1.5; 2.0; 2.5; 3.0; 4.0; 5.0; 6.0; 8.0; 12.0; 24.0, 48.0, 72.0 hours) | 
| Number of Participants With Clinically Significant Abnormalities Detected Upon Physical Examination. | A physician or appropriately qualified delegate conducted a full physical examination. Clinically significance was decided by investigator. The findings are presented as abnormal (clinically significant). | At day 14 | 
| Number of Participants With Clinically Significant Abnormalities on the 12-lead ECGs | Reported results are cardiovascular system-examination findings at day 14. Clinically significance was decided by investigator. The findings are presented as abnormal (clinically significant). | At day 14 | 
| Number of Participants With Arrhythmias as Assessed by Continuous Holter Monitoring. | Holter monitors were supplied by iCardiac Technologies. Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14 and remained in place until 24-hour assessments were completed. | Baseline (day -1) and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Diastolic Blood Pressure (Standing) | Diastolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in standing position. | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Diastolic Blood Pressure (Sitting) | Diastolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in sitting position. | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Systolic Blood Pressure (Standing) | Systolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in standing position. | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Systolic Blood Pressure (Sitting) | Systolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in sitting position. | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Pulse Rate | Pulse rate was measured just prior to dosing (approx. 30 mins). | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Respiratory Rate | Respiratory rate was measured just prior to dosing (approx. 30 mins). | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Oxygen Saturation | Oxygen Saturation was measured just prior to dosing (approx. 30 mins). | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Oral Body Temperature | Temperature was measured just prior to dosing (approx. 30 mins). | Baseline and day 14 | 
| Change From Baseline at Day 14 in Vital Signs: Weight | Weight was measured just prior to dosing (approx. 30 mins). | Baseline and day 14 | 
| Change From Baseline at Day 15 for Laboratory Hormones Results : Adrenocorticotropic Hormone (ADTH) and Estradiol. | Blood samples for the assessment of ACTH and Estradiol were collected upon participants admission to the unit. | Baseline and day 15 | 
| Change From Baseline at Day 15 for Laboratory Hormones Results: Follicle Stimulating Hormone | Blood samples for the assessment of Follicle Stimulating were collected upon participants admission to the unit. | Baseline and day 15 | 
| Change From Baseline at Day 15 for Laboratory Hormones Results : Triiodothyronine Uptake | Blood samples for the assessment of Triiodothyronine were collected upon participants admission to the unit. | Baseline and day 15 | 
| Change From Baseline at Day 15 for Laboratory Hormones Results: Thyrotropin | Blood samples for the assessment of Thyrotropin were collected upon participants admission to the unit. | Baseline and day 15 | 
| Change From Baseline at Day 15 for Laboratory Hormones Results : Cortisol, Testosterone, Thyroxine and Triiodothyronine | Blood samples for the assessment of Cortisol, Testosterone, Thyroxine and Triiodothyronine were collected upon participants admission to the unit. | Baseline and day 15 | 
| Change From Baseline at Day 14 for Clinical Laboratory Parameters LIPIDS : Cholesterol, Triglycerides, HDL Cholesterol and LDL Cholesterol. | Blood samples for the assessment of Cholesterol, Triglycerides,high-density lipoprotein (HDL)Cholesterol and low-density lipoprotein (LDL) Cholesterol were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Immature Granulocytes. | Blood samples for the assessment of Neutrophils/Leukocytes, Lymphocytes /Leukocytes, Monocytes/Leukocytes, Eosinophils/Leukocytes, Basophils/Leukocytes and Immature Granulocytes/ Leukocytes were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Clinical Laboratory Parameters HEMATOLOGY: Leukocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Immature Granulocytes and Platelets. | Blood samples for the assessment of Leukocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Immature Granulocytes and Platelets were collected upon participant's admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin Concentration | Blood samples for the assessment of Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HB)concentration were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes | Blood samples for the assessment of Erythrocytes were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume. | Blood samples for the assessment of Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes Mean Corpuscular Hemoglobin | Blood samples for the assessment of Erythrocytes Mean Corpuscular Hemoglobin were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes Distribution Width. | Blood samples for the assessment of Erythrocytes Distribution Width were collected upon participants admission to the unit. Erythrocytes distribution width (in percentage) = 1 SD of Erythrocyte volume/MCV x 100% | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Hematocrit. | Blood samples for the assessment of Hematocrit were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters CHEMISTRY: Protein and Albumin. | Blood samples for the assessment of Protein and Albumin were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters CHEMISTRY: Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Gamma Glutamyl Transferase and Creatine Kinase | Blood samples for the assessment of Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Gamma Glutamyl Transferase and Creatine Kinase were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Laboratory Parameters CHEMISTRY: Urate, Bilirubin and Creatinine. | Blood samples for the assessment of Urate, Bilirubin and Creatinine were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for Clinical Laboratory Parameters CHEMISTRY: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Phosphate, Glucose, Magnesium and Urea Nitrogen. | Blood samples for the assessment of Sodium, Potassium, Chloride, Bicarbonate, Calcium, Phosphate, Glucose, Magnesium and Urea Nitrogen were collected upon participant's admission to the unit. | Baseline and day 14 | 
| Laboratory Parameters CHEMISTRY: Glomerular Filtration Rate African at Baseline | Blood samples for the assessment of Glomerular Filtration Rate African were collected upon participants admission to the unit. | At Baseline | 
| Laboratory Parameters CHEMISTRY: Glomerular Filtration Rate Caucasian at Baseline | Blood samples for the assessment of Glomerular Filtration Rate Caucasian were collected upon participants admission to the unit. | At Baseline | 
| Change From Baseline at Day 14 for COAGULATION: Prothrombin International Normalized Ratio (INR) | Blood samples for the assessment of Prothrombin International Normalized Ratio were collected upon participants admission to the unit. | Baseline and day 14 | 
| Change From Baseline at Day 14 for COAGULATION: Prothrombin Time and Activated Partial Thromboplastin Time | Blood samples for the assessment of Prothrombin Time and Activated Partial Thromboplastin Time were collected upon participants admission to the unit. | Baseline and day 14 | 
| Heart Rate (HR) - Change From Baseline (Day -1) at Day 14 | Heart rate was measured as part of the 12-lead electrocardiogram. Resting ECG recordings were made.Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14. | Baseline (day -1) and day 14 | 
| Mean PR Interval - Change From Baseline (Day -1) at Day 14 | PR Interval was measured as part of the 12-lead electrocardiogram. Resting ECG recordings were made. Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14. | Baseline (day -1) and day 14 | 
| Mean QRS Duration - Change From Baseline (Day -1) at Day 14 | QRS Duration was measured as part of the 12-lead electrocardiogram. Resting ECG recordings were made. Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14. | Baseline (day -1) and day 14 | 
| Mean QT Interval - Change From Baseline (Day -1) at Day 14 | QT Interval was measured as part of the 12-lead electrocardiogram. Resting ECG recordings were made. Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14. | Baseline (day -1) and day 14 | 
| Mean QTcF Interval (Fridericia's Correction Formula, QTcF) - Change From Baseline (Day -1) at Day 14 | Fridericia-corrected QTcF interval was evaluated as part of the 12-lead electrocardiogram. Resting ECG recordings were made. Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14. | Baseline (day -1) and day 14 | 
| Mean QTcB Interval (Bazett's Correction Formula, QTcB) - Change From Baseline (Day -1) at Day 14 | Bazett-corrected QTcB interval was evaluated as part of the 12-lead electrocardiogram. Resting ECG recordings were made. Holter monitors were fitted to participants upon admission in clinic on Day -1 and Day 14. | Baseline (day -1) and day 14 | 
| Nature and Severity of Adverse Events (AEs) up to Day 21 | An AE was defined as any untoward medical occurrence in a subject or clinical trial subject administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product. Serious Adverse Event (SAE) is an adverse event that at any dose: Results in death, Is life-threatening (i.e. the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it was more severe), Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Is considered to be an important medical event. | On or after first drug administration up to end of study (Day 21). | 
| Withdrawals Due to AEs up to Day 21 | An AE was defined as any untoward medical occurrence in a subject or clinical trial subject administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product. Serious Adverse Event (SAE) is an adverse event that at any dose: Results in death, Is life-threatening (i.e. the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it was more severe), Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Is considered to be an important medical event. | On or after first drug administration up to end of study (Day 21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Frequency of Hot Flushes From Baseline (Day -1) at Days 7, 14 as Assessed by Skin Conductance | Sternal skin conductance monitors (the Bahr MonitorTM) and the associated algorithm software were supplied by Simplex Scientific LLC (Middleton, USA). Participants were instructed to push a button on the skin conductance monitor when they sensed a hot flush when fitted with the monitor and then provide details of the hot flush in the continuous hot flush diary. Sternal skin conductance monitors were fitted on Day -1 (24 hours±1 hour prior to the planned study drug administration on Day 1) and remained in place until after the Day 7 24-hour assessments were completed (on Day 8). Refitted around 30 minutes prior to study drug administration on Day 14 and remained in place until after the 24-hour assessments were completed on Day 15. | Baseline (day -1) and days 7, 14 | 
| Change From Baseline (Week -1) at Weeks 1, 2 in Frequency of Moderate to Severe Hot Flushes as Measured by Twice Daily Paper Diary Throughout Study | Hot flush frequency and hot flush severity were obtained using the Hot Flush paper Diary. Subjects documented the number of individual hot flushes experienced and rated the severity of each on a scale of 1 to 3 (mild = 1, moderate = 2, severe = 3). The diaries were completed based on recall twice daily, in the morning and evening. | Baseline (week -1) and Week 1 ,Week 2 | 
| Change From Baseline (Week -1) at Weeks 1, 2 in Average Daily Severity of Hot Flushes as Measured by Twice Daily Paper Diary | Participants documented the number of individual hot flushes experienced and rated the severity of each on a scale of 1 to 3 (mild = 1, moderate = 2, severe = 3). The diaries were completed based on recall twice daily, in the morning and evening. | Baseline (week -1) and weeks 1, Week 2 | 
| Change From Baseline (Week -1) at Weeks 1, 2 in Average Daily Hot Flushes Severity Score as Measured by Twice Daily Paper Diary. | The hot flushes severity score was a composite of the frequency and severity of hot flushes, and was calculated as follows: number of mild hot flushes recorded on Day Y + number of moderate hot flushes recorded on Day Y × 2 + number of severe hot flushes recorded on Day Y × 3. Higher scores mean more severe hot flushes. | Baseline (week -1) and week 1 , 2 | 
| Change in Frequency From Baseline (Day -1), at Days 7, 14 of Hot Flushes as Measured by Continuous Day Time Diary. | Subjects recorded each hot flush and its severity on a scale of 1 to 3 (mild = 1, moderate = 2, severe = 3) in the hot flush paper diary as they occurred during the day and night. | Baseline(day -1) and Day 7, 14 | 
| Change From Baseline (Week -1) at Weeks 1, 2 in Night-time Awakenings (NTA) Secondary to Hot Flushes as Measured by Paper Diary | The number of NTAs secondary to hot flushes was the sum of the number of moderate and severe night-time hot flushes recorded the following morning (twice-daily hot flush diary) or recorded contemporaneously on the continuous diary. | Baseline (week-1) and weeks 1 , 2 | 
| Change From Baseline (Day-1) to Day 1 and Day 7 in Luteinizing Hormone (AUC0-8) | Change in Luteinizing Hormone(LH) AUC from time zero to 8 hours. Pre-dose samples for LH were taken within 30 minutes prior to dose administration. | baseline (day-1) to day 1 and day 7, pre-dose and post-dose (0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0 and 24.0 hours) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Post-menopausal, Hot flashes