Menopause Hot Flashes
Conditions
Brief summary
The purpose of this study is to assess the efficacy and safety of MT-8554 for treatment of vasomotor symptoms (VMS) associated with menopause.
Detailed description
This is a Phase II randomized, double-blind, placebo-controlled study for dose selection in postmenopausal women with moderate to severe VMS, defined as follows: * Moderate: sensation of heat with sweating, able to continue activity * Severe: sensation of heat with sweating, causing cessation of activity This study is comprised of a screening period, a run-in period and a 12-week double-blind treatment period.
Interventions
DRUGMT-8554 1mg
MT-8554 1mg QD, oral, 12 weeks
DRUGMT-8554 5mg
MT-8554 5mg QD, oral, 12 weeks
DRUGMT-8554 10mg
MT-8554 10mg QD, oral, 12 weeks
DRUGPlacebo
Placebo QD, oral, 12 weeks
Sponsors
Tanabe Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Additional screening criteria check may apply for qualification: * Provide written informed consent to participate in this study * Spontaneous amenorrhea for ≥12 months; or spontaneous amenorrhea for at least 6 months and with follicle stimulating hormone (FSH) levels \>40 mIU/mL; or documented bilateral salpingo oophorectomy ≥6 weeks, with or without hysterectomy * 7 or more moderate to severe VMS per day, or 50 or more moderate to severe VMS per week * Have a consistent bedtime on at least 5 nights per week * Mean VMS frequency during the Placebo Run in period does not drop by more than 50% from the mean level reported for 2 weeks during the Screening period * VMS diary compliance \>50% * In the Investigator's opinion, subject is able to understand the nature of the study and any risk involved in participation, and is willing to cooperate and comply with the protocol restrictions and requirements
Exclusion criteria
Additional screening criteria check may apply for qualification: * History of any cancer within 5 years except for basal cell carcinoma * History of undiagnosed abnormal vaginal bleeding * History of Hepatitis B, Hepatitis C or HIV * History of psychiatric illness, excessive alcohol intake or use of recreational drugs who are unsuitable for study enrollment and compliance * Presence or history of severe adverse reaction or allergy to any drug * Peripheral vascular disease or disorders with associated vasculopathies * Clinically significant conditions which could interfere with the objectives of the study or the safety of the subject, as judged by the Investigator * Endometrial thickness of \>=5 mm as measured by transvaginal ultrasound * Abnormal result from baseline endometrial biopsy (i.e., endometrial hyperplasia or endometrial cancer) * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin ≥2.0 × upper limit of normal (ULN) above the reference range * Subjects of childbearing potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Baseline, Weeks 4 and 12 | The average daily frequency of moderate to severe VMS at a time point (Baseline, Weeks 4 and 12) was the average of the frequency of moderate to severe VMS of available diary days in a 7-day window. Changes in the average daily frequency of moderate to severe VMS at Week 4 and Week 12 compared to baseline were evaluated. |
| Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Baseline, Weeks 4 and 12 | The daily severity score of VMS was defined as (2xFmo + 3xFse)/(Fmo + Fse) for baseline, and (1xFmi + 2xFmo + 3xFse)/(Fmi + Fmo + Fse) for Weeks 4 and 12, where Fmi, Fmo, and Fse were the daily frequencies of mild, moderate, and severe VMS, respectively. The average daily severity score of mild to severe VMS at a time point (Baseline, Week 4 and Week 12) was the average of the daily severity of available diary days in the corresponding 7-day window. The severity score of VMS ranged from 0 (lowest severity) to 3 (highest severity). Change in the average daily severity score of mild to severe VMS at Week 4 and Week 12 compared to baseline were evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders at Weeks 4 and 12 | Week 4 and Week 12 | Subjects with cutoff number or greater reduction in the average daily frequency of moderate and severe VMS compared to baseline. The cutoff number was calculated using anchor-based method. The cutoff number was defined as numerical value to maximize the sensitivity and the specificity, using Patient Global Impression of Change (PGIC) as the anchor. |
| Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Baseline, Weeks 4 and 12 | The Insomnia Severity Index was a self-rated, 7-item validated sleep scale that measured clinical insomnia severity. The total score ranged from 0-28 where higher values indicated increased severity of insomnia. |
Countries
United States
Contacts
STUDY_DIRECTORHead of Medical Science
Tanabe Pharma America, Inc.
Participant flow
Pre-assignment details
One subject with dual status of the run-in-failure and randomized in error in MT-8554 5 mg group was excluded from the Randomized Population.
Participants by arm
| Arm | Count |
|---|---|
| MT-8554 1mg MT-8554 1mg QD, oral, 12 weeks | 95 |
| MT-8554 5mg MT-8554 5mg QD, oral, 12 weeks | 90 |
| MT-8554 10mg MT-8554 10mg QD, oral, 12 weeks | 93 |
| Placebo Placebo QD, oral, 12 weeks | 90 |
| Total | 368 |
Baseline characteristics
| Characteristic | Placebo | Total | MT-8554 1mg | MT-8554 5mg | MT-8554 10mg |
|---|---|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 6.25 | 55.2 years STANDARD_DEVIATION 6.43 | 54.5 years STANDARD_DEVIATION 6.27 | 54.6 years STANDARD_DEVIATION 6.62 | 56.0 years STANDARD_DEVIATION 6.55 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 92 Participants | 20 Participants | 25 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 62 Participants | 274 Participants | 74 Participants | 64 Participants | 74 Participants |
| Sex: Female, Male Female | 90 Participants | 368 Participants | 95 Participants | 90 Participants | 93 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 95 | 0 / 90 | 0 / 93 | 0 / 90 |
| other Total, other adverse events | 37 / 95 | 41 / 90 | 46 / 93 | 37 / 90 |
| serious Total, serious adverse events | 0 / 95 | 1 / 90 | 0 / 93 | 0 / 90 |
Outcome results
Primary
Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12
The average daily frequency of moderate to severe VMS at a time point (Baseline, Weeks 4 and 12) was the average of the frequency of moderate to severe VMS of available diary days in a 7-day window. Changes in the average daily frequency of moderate to severe VMS at Week 4 and Week 12 compared to baseline were evaluated.
Time frame: Baseline, Weeks 4 and 12
Population: Intent-to-treat (ITT) population=All randomized subjects who have at least 1 post-baseline efficacy assessment
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MT-8554 1mg | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 4 | -1.92 VMS per day | Standard Error 0.609 |
| MT-8554 1mg | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 12 | -2.91 VMS per day | Standard Error 0.69 |
| MT-8554 5mg | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 12 | -3.11 VMS per day | Standard Error 0.78 |
| MT-8554 5mg | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 4 | -2.75 VMS per day | Standard Error 0.705 |
| MT-8554 10mg | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 4 | -2.75 VMS per day | Standard Error 0.734 |
| MT-8554 10mg | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 12 | -3.38 VMS per day | Standard Error 0.821 |
| Placebo | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 4 | -1.39 VMS per day | Standard Error 0.705 |
| Placebo | Change From Baseline in the Average Daily Frequency of Moderate to Severe VMS at Weeks 4 and 12 | Week 12 | -2.78 VMS per day | Standard Error 0.779 |
Primary
Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12
The daily severity score of VMS was defined as (2xFmo + 3xFse)/(Fmo + Fse) for baseline, and (1xFmi + 2xFmo + 3xFse)/(Fmi + Fmo + Fse) for Weeks 4 and 12, where Fmi, Fmo, and Fse were the daily frequencies of mild, moderate, and severe VMS, respectively. The average daily severity score of mild to severe VMS at a time point (Baseline, Week 4 and Week 12) was the average of the daily severity of available diary days in the corresponding 7-day window. The severity score of VMS ranged from 0 (lowest severity) to 3 (highest severity). Change in the average daily severity score of mild to severe VMS at Week 4 and Week 12 compared to baseline were evaluated.
Time frame: Baseline, Weeks 4 and 12
Population: Intent-to-treat (ITT) population=All randomized subjects who have at least 1 post-baseline efficacy assessment
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MT-8554 1mg | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 4 | -0.302 VMS severity score per day | Standard Error 0.0609 |
| MT-8554 1mg | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 12 | -0.374 VMS severity score per day | Standard Error 0.0725 |
| MT-8554 5mg | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 12 | -0.481 VMS severity score per day | Standard Error 0.0822 |
| MT-8554 5mg | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 4 | -0.407 VMS severity score per day | Standard Error 0.0714 |
| MT-8554 10mg | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 4 | -0.305 VMS severity score per day | Standard Error 0.074 |
| MT-8554 10mg | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 12 | -0.433 VMS severity score per day | Standard Error 0.0864 |
| Placebo | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 4 | -0.316 VMS severity score per day | Standard Error 0.0712 |
| Placebo | Change From Baseline in the Average Daily Severity Score of Mild to Severe VMS at Weeks 4 and 12 | Week 12 | -0.388 VMS severity score per day | Standard Error 0.0819 |
Secondary
Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12
The Insomnia Severity Index was a self-rated, 7-item validated sleep scale that measured clinical insomnia severity. The total score ranged from 0-28 where higher values indicated increased severity of insomnia.
Time frame: Baseline, Weeks 4 and 12
Population: Intent-to-treat (ITT) population=All randomized subjects who have at least 1 post-baseline efficacy assessment
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MT-8554 1mg | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 4 | -1.8 units on a scale | Standard Error 0.49 |
| MT-8554 1mg | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 12 | -3.2 units on a scale | Standard Error 0.53 |
| MT-8554 5mg | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 12 | -2.7 units on a scale | Standard Error 0.55 |
| MT-8554 5mg | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 4 | -3.1 units on a scale | Standard Error 0.51 |
| MT-8554 10mg | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 4 | -3.6 units on a scale | Standard Error 0.55 |
| MT-8554 10mg | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 12 | -2.4 units on a scale | Standard Error 0.54 |
| Placebo | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 4 | -1.8 units on a scale | Standard Error 0.5 |
| Placebo | Change From Baseline in the Insomnia Severity Index at Week 4 and Week 12 | Week 12 | -3.0 units on a scale | Standard Error 0.55 |
Secondary
Percentage of Responders at Weeks 4 and 12
Subjects with cutoff number or greater reduction in the average daily frequency of moderate and severe VMS compared to baseline. The cutoff number was calculated using anchor-based method. The cutoff number was defined as numerical value to maximize the sensitivity and the specificity, using Patient Global Impression of Change (PGIC) as the anchor.
Time frame: Week 4 and Week 12
Population: Intent-to-treat (ITT) population=All randomized subjects who have at least 1 post-baseline efficacy assessment. The subjects without VMS frequency data at Week 4 were excluded from the analysis at Week 4. The subjects without VMS frequency data at Week 12 were excluded from the analysis at Week 12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MT-8554 1mg | Percentage of Responders at Weeks 4 and 12 | Week 4 | 31.8 percentage of subjects |
| MT-8554 1mg | Percentage of Responders at Weeks 4 and 12 | Week 12 | 44.4 percentage of subjects |
| MT-8554 5mg | Percentage of Responders at Weeks 4 and 12 | Week 12 | 60.5 percentage of subjects |
| MT-8554 5mg | Percentage of Responders at Weeks 4 and 12 | Week 4 | 52.4 percentage of subjects |
| MT-8554 10mg | Percentage of Responders at Weeks 4 and 12 | Week 4 | 36.1 percentage of subjects |
| MT-8554 10mg | Percentage of Responders at Weeks 4 and 12 | Week 12 | 54.1 percentage of subjects |
| Placebo | Percentage of Responders at Weeks 4 and 12 | Week 4 | 36.0 percentage of subjects |
| Placebo | Percentage of Responders at Weeks 4 and 12 | Week 12 | 54.1 percentage of subjects |