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

Phase 1

Completed

• Conditions: Post-menopausal Vasomotor Symptoms
• Interventions: Drug: Placebo (for BAY3427080); Drug: BAY3427080

• Registration Number: NCT02865538
• Lead Sponsor: Bayer

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-08-01
• Study First Submitted: 2016-08-03
• Study First Submitted QC: 2016-08-09
• Study First Posted: 2016-08-12
• Primary Completion: 2017-03-28
• Study Completion: 2017-03-28
• Disposition First Submitted: 2018-10-10
• Disposition First Submitted QC: 2018-10-10
• Disposition First Posted: 2018-10-11
• Results First Submitted: 2020-12-18
• Status Verified: 2021-01
• Results First Submitted QC: 2021-01-28
• Last Update Submitted: 2021-01-28
• Results First Posted: 2021-02-16
• Last Update Posted: 2021-02-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 76

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
BAY3427080 Placebo	Placebo (for BAY3427080)	-
50mg BAY3427080	BAY3427080	-
100mg BAY3427080	BAY3427080	-
150mg BAY3427080	BAY3427080	-
300mg BAY3427080	BAY3427080	-

Primary Outcome Measures

Name	Time	Method
Time to Reach Maximum Observed Drug Concentration in Plasma (Tmax) of BAY3427080	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 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.
Area Under the Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-τ) of BAY3427080	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 (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.
Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of BAY3427080	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)	AUC from time zero extrapolated to infinity of BAY3427080 was presented. AUC0-∞ was only estimated following the Day 1 dose.
Maximum Observed Plasma Concentration (Cmax) of BAY3427080	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)	Cmax is the maximum observed plasma concentration of BAY3427080 was presented. Blood samples were taken within 30 minutes prior to dose administration.
Number of Participants With Clinically Significant Abnormalities on the 12-lead ECGs	At day 14	Reported results are cardiovascular system-examination findings at day 14. Clinically significance was decided by investigator. The findings are presented as abnormal (clinically significant).
Terminal Elimination Half-life (t½) of BAY3427080	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 of BAY3427080 was presented. Blood samples were taken within 30 minutes prior to dose administration.
Apparent Clearance (CL/F) of BAY3427080	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 of BAY3427080 was presented. Blood samples were taken within 30 minutes prior to dose administration.
Number of Participants With Clinically Significant Abnormalities Detected Upon Physical Examination.	At day 14	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).
Number of Participants With Arrhythmias as Assessed by Continuous Holter Monitoring.	Baseline (day -1) and day 14	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.
Change From Baseline at Day 14 in Vital Signs: Diastolic Blood Pressure (Standing)	Baseline and day 14	Diastolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in standing position.
Change From Baseline at Day 14 in Vital Signs: Diastolic Blood Pressure (Sitting)	Baseline and day 14	Diastolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in sitting position.
Change From Baseline at Day 14 in Vital Signs: Systolic Blood Pressure (Standing)	Baseline and day 14	Systolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in standing position.
Change From Baseline at Day 14 in Vital Signs: Systolic Blood Pressure (Sitting)	Baseline and day 14	Systolic Blood Pressure was measured just prior to dosing (approx. 30 mins) in sitting position.
Change From Baseline at Day 14 in Vital Signs: Pulse Rate	Baseline and day 14	Pulse rate was measured just prior to dosing (approx. 30 mins).
Change From Baseline at Day 14 in Vital Signs: Respiratory Rate	Baseline and day 14	Respiratory rate was measured just prior to dosing (approx. 30 mins).
Change From Baseline at Day 14 in Vital Signs: Oxygen Saturation	Baseline and day 14	Oxygen Saturation was measured just prior to dosing (approx. 30 mins).
Change From Baseline at Day 14 in Vital Signs: Oral Body Temperature	Baseline and day 14	Temperature was measured just prior to dosing (approx. 30 mins).
Change From Baseline at Day 14 in Vital Signs: Weight	Baseline and day 14	Weight was measured just prior to dosing (approx. 30 mins).
Change From Baseline at Day 15 for Laboratory Hormones Results : Adrenocorticotropic Hormone (ADTH) and Estradiol.	Baseline and day 15	Blood samples for the assessment of ACTH and Estradiol were collected upon participants admission to the unit.
Change From Baseline at Day 15 for Laboratory Hormones Results: Follicle Stimulating Hormone	Baseline and day 15	Blood samples for the assessment of Follicle Stimulating were collected upon participants admission to the unit.
Change From Baseline at Day 15 for Laboratory Hormones Results : Triiodothyronine Uptake	Baseline and day 15	Blood samples for the assessment of Triiodothyronine were collected upon participants admission to the unit.
Change From Baseline at Day 15 for Laboratory Hormones Results: Thyrotropin	Baseline and day 15	Blood samples for the assessment of Thyrotropin were collected upon participants admission to the unit.
Change From Baseline at Day 15 for Laboratory Hormones Results : Cortisol, Testosterone, Thyroxine and Triiodothyronine	Baseline and day 15	Blood samples for the assessment of Cortisol, Testosterone, Thyroxine and Triiodothyronine were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Clinical Laboratory Parameters LIPIDS : Cholesterol, Triglycerides, HDL Cholesterol and LDL Cholesterol.	Baseline and day 14	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.
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Immature Granulocytes.	Baseline and day 14	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.
Change From Baseline at Day 14 for Clinical Laboratory Parameters HEMATOLOGY: Leukocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Immature Granulocytes and Platelets.	Baseline and day 14	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.
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin Concentration	Baseline and day 14	Blood samples for the assessment of Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HB)concentration were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes	Baseline and day 14	Blood samples for the assessment of Erythrocytes were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume.	Baseline and day 14	Blood samples for the assessment of Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes Mean Corpuscular Hemoglobin	Baseline and day 14	Blood samples for the assessment of Erythrocytes Mean Corpuscular Hemoglobin were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Erythrocytes Distribution Width.	Baseline and day 14	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%
Change From Baseline at Day 14 for Laboratory Parameters HEMATOLOGY: Hematocrit.	Baseline and day 14	Blood samples for the assessment of Hematocrit were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Laboratory Parameters CHEMISTRY: Protein and Albumin.	Baseline and day 14	Blood samples for the assessment of Protein and Albumin were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Laboratory Parameters CHEMISTRY: Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Gamma Glutamyl Transferase and Creatine Kinase	Baseline and day 14	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.
Change From Baseline at Day 14 for Laboratory Parameters CHEMISTRY: Urate, Bilirubin and Creatinine.	Baseline and day 14	Blood samples for the assessment of Urate, Bilirubin and Creatinine were collected upon participants admission to the unit.
Change From Baseline at Day 14 for Clinical Laboratory Parameters CHEMISTRY: Sodium, Potassium, Chloride, Bicarbonate, Calcium, Phosphate, Glucose, Magnesium and Urea Nitrogen.	Baseline and day 14	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.
Laboratory Parameters CHEMISTRY: Glomerular Filtration Rate African at Baseline	At Baseline	Blood samples for the assessment of Glomerular Filtration Rate African were collected upon participants admission to the unit.
Laboratory Parameters CHEMISTRY: Glomerular Filtration Rate Caucasian at Baseline	At Baseline	Blood samples for the assessment of Glomerular Filtration Rate Caucasian were collected upon participants admission to the unit.
Change From Baseline at Day 14 for COAGULATION: Prothrombin International Normalized Ratio (INR)	Baseline and day 14	Blood samples for the assessment of Prothrombin International Normalized Ratio were collected upon participants admission to the unit.
Change From Baseline at Day 14 for COAGULATION: Prothrombin Time and Activated Partial Thromboplastin Time	Baseline and day 14	Blood samples for the assessment of Prothrombin Time and Activated Partial Thromboplastin Time were collected upon participants admission to the unit.
Heart Rate (HR) - Change From Baseline (Day -1) at Day 14	Baseline (day -1) and 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.
Mean PR Interval - Change From Baseline (Day -1) at Day 14	Baseline (day -1) and 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.
Mean QRS Duration - Change From Baseline (Day -1) at Day 14	Baseline (day -1) and 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.
Mean QT Interval - Change From Baseline (Day -1) at Day 14	Baseline (day -1) and 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.
Mean QTcF Interval (Fridericia's Correction Formula, QTcF) - Change From Baseline (Day -1) at Day 14	Baseline (day -1) and 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.
Mean QTcB Interval (Bazett's Correction Formula, QTcB) - Change From Baseline (Day -1) at Day 14	Baseline (day -1) and 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.
Nature and Severity of Adverse Events (AEs) up to Day 21	On or after first drug administration up to end of study (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.
Withdrawals Due to AEs up to Day 21	On or after first drug administration up to end of study (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.

Secondary Outcome Measures

Name	Time	Method
Change in Frequency of Hot Flushes From Baseline (Day -1) at Days 7, 14 as Assessed by Skin Conductance	Baseline (day -1) and days 7, 14	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.
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	Baseline (week -1) and Week 1 ,Week 2	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.
Change From Baseline (Week -1) at Weeks 1, 2 in Average Daily Severity of Hot Flushes as Measured by Twice Daily Paper Diary	Baseline (week -1) and weeks 1, Week 2	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.
Change From Baseline (Week -1) at Weeks 1, 2 in Average Daily Hot Flushes Severity Score as Measured by Twice Daily Paper Diary.	Baseline (week -1) and week 1 , 2	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.
Change in Frequency From Baseline (Day -1), at Days 7, 14 of Hot Flushes as Measured by Continuous Day Time Diary.	Baseline(day -1) and Day 7, 14	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.
Change From Baseline (Week -1) at Weeks 1, 2 in Night-time Awakenings (NTA) Secondary to Hot Flushes as Measured by Paper Diary	Baseline (week-1) and weeks 1 , 2	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.
Change From Baseline (Day-1) to Day 1 and Day 7 in Luteinizing Hormone (AUC0-8)	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)	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.

Trial Locations

Locations (3)

QPS/MRA (Miami Clinical Research); 🇺🇸 Miami, Florida, United States

Avail Clinical Research; 🇺🇸 DeLand, Florida, United States

ICON Clinical Research Unit; 🇺🇸 San Antonio, Texas, United States