Moderate to Severe Vasomotor Symptoms in Postmenopausal, Women
Conditions
Brief summary
This study will assess the safety, tolerability, and efficacy of MK-6913 for the treatment of moderate-to-very-severe vasomotor symptoms (hot flashes or hot flushes) in postmenopausal women. The primary study hypothesis is that one or more doses of MK-6913 will result in a significantly greater reduction from baseline, compared to placebo, in the number of moderate to very severe hot flashes after 4 weeks of treatment.
Interventions
DRUGMK-6913
DRUG17-β estradiol
DRUGPlacebo to MK-6913
DRUGPlacebo to 17-β estradiol
DRUGMK-6913 25 mg
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
35 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Woman with at least 50 moderate to very severe hot flash episodes per week * Postmenopausal * Between 45 and 60 years of age if naturally menopausal, or between 35 and 60 if she underwent a bilateral oophorectomy * Not receiving hormone therapy * Has had both a normal mammogram and a normal Pap test in the past 6 months * Generally healthy
Exclusion criteria
* A history of cancer, except for certain skin cancers * Undiagnosed vaginal bleeding or any uterine endometrial disorder * Currently uses tobacco products, or has used them in the last 6 months * Has human immunodeficiency virus (HIV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Number of Weekly Moderate to Very Severe Hot Flashes (Excluding Outliers) at Week 4 | Baseline and Week 4 | Hot flashes were recorded in real time and hot flashes recorded retrospectively in the morning and evening reports in a diary day via the Hot Flash e-diary were summed to determine the total number of hot flashes over a diary day. The total number of weekly moderate or worse hot flashes were calculated as the sum of the total number of hot flashes that occur over a diary week (non-missing diary day), divided by the number of days of diary completion, and multiplied by 7 (standardized week). At least 4 non-missing diary days were required to define the total number of weekly moderate or worse hot flashes. Hot flash data was excluded for participants whose number of moderate to severe hot flashes per week were in the top 1% of number of hot flashes reported to exclude any outlier effect. |
| Number of Participants Who Experienced at Least One or More Adverse Events (AE) | Up to 6 weeks | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to 4 weeks | An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Weekly Hot Flash Severity Score (Combining Severe and Very Severe Score) at Week 4 | Baseline and Week 4 | Hot flash severity score is calculated by the sum of: the number of mild hot flashes, 2 times number of moderate hot flashes, 3 times the number of severe hot flashes, and 4 times the number of very severe hot flashes. This sum was standardized to a 7-day week if there were any missing days in the e-diary. The severity of each hot flash was recorded by the Hot Flash e-diary. |
| Change From Baseline in Follicle-stimulating Hormone (FSH) Level at Week 4 | Baseline and Week 4 | FSH was measured to assess estrogen receptor (ER) selectivity (a biomarker for ERα activity and a pharmacodynamic endpoint). |
Participant flow
Recruitment details
Thirty sites in the United States, Canada, France, Belgium, New Zealand, and Australia received IRB/ERC approval. Of the 354 participants screened for inclusion, 255 participants were excluded during screening (235 participants did not meet specific exclusion criteria). Ninety-nine participants were randomized for the study.
Pre-assignment details
The study was terminated at the end of Stage 1 so no participants entered Stage 2 and no participants received MK-6913 25 mg.
Participants by arm
| Arm | Count |
|---|---|
| MK-6913 75 mg MK-6913 75 mg and matching placebo for 17β-estradiol 1 mg once daily for 4 weeks | 34 |
| 17-β Estradiol 1 mg 17β-estradiol 1 mg and matching placebo for MK-6913 75 mg once daily for 4 weeks | 32 |
| Placebo Matching placebo for MK-6913 75 mg and matching placebo for 17β-estradiol 1 mg once daily for 4 weeks | 33 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | MK-6913 75 mg | 17-β Estradiol 1 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 52.1 Years STANDARD_DEVIATION 3.9 | 53.2 Years STANDARD_DEVIATION 3.9 | 52.2 Years STANDARD_DEVIATION 4.2 | 52.5 Years STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 34 Participants | 32 Participants | 33 Participants | 99 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 34 | 15 / 32 | 16 / 33 |
| serious Total, serious adverse events | 0 / 34 | 0 / 32 | 0 / 33 |
Outcome results
Primary
Number of Participants Who Discontinued Study Drug Due to an AE
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 4 weeks
Population: The APaT population is all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-6913 75 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
| 17-β Estradiol 1 mg | Number of Participants Who Discontinued Study Drug Due to an AE | 1 Participants |
| Placebo | Number of Participants Who Discontinued Study Drug Due to an AE | 0 Participants |
Primary
Number of Participants Who Experienced at Least One or More Adverse Events (AE)
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 6 weeks
Population: The All-Patients-as Treated (APaT) population is all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-6913 75 mg | Number of Participants Who Experienced at Least One or More Adverse Events (AE) | 17 Participants |
| 17-β Estradiol 1 mg | Number of Participants Who Experienced at Least One or More Adverse Events (AE) | 15 Participants |
| Placebo | Number of Participants Who Experienced at Least One or More Adverse Events (AE) | 16 Participants |
Primary
Percent Change From Baseline in the Number of Weekly Moderate to Very Severe Hot Flashes (Excluding Outliers) at Week 4
Hot flashes were recorded in real time and hot flashes recorded retrospectively in the morning and evening reports in a diary day via the Hot Flash e-diary were summed to determine the total number of hot flashes over a diary day. The total number of weekly moderate or worse hot flashes were calculated as the sum of the total number of hot flashes that occur over a diary week (non-missing diary day), divided by the number of days of diary completion, and multiplied by 7 (standardized week). At least 4 non-missing diary days were required to define the total number of weekly moderate or worse hot flashes. Hot flash data was excluded for participants whose number of moderate to severe hot flashes per week were in the top 1% of number of hot flashes reported to exclude any outlier effect.
Time frame: Baseline and Week 4
Population: The Full Analysis Set (FAS) population consists of all randomized participants who receive at least 1 dose of study treatment, have at least 1 post-randomization observation for the analysis endpoint, and have baseline data for those analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-6913 75 mg | Percent Change From Baseline in the Number of Weekly Moderate to Very Severe Hot Flashes (Excluding Outliers) at Week 4 | -40.69 Percent change |
| 17-β Estradiol 1 mg | Percent Change From Baseline in the Number of Weekly Moderate to Very Severe Hot Flashes (Excluding Outliers) at Week 4 | -51.86 Percent change |
| Placebo | Percent Change From Baseline in the Number of Weekly Moderate to Very Severe Hot Flashes (Excluding Outliers) at Week 4 | -34.41 Percent change |
p-value: 0.48895% CI: [-24.2, 11.64]Longitudinal Data Analysis (LDA)
p-value: 0.06995% CI: [-36.28, 1.38]Longitudinal Data Analysis
Secondary
Change From Baseline in Follicle-stimulating Hormone (FSH) Level at Week 4
FSH was measured to assess estrogen receptor (ER) selectivity (a biomarker for ERα activity and a pharmacodynamic endpoint).
Time frame: Baseline and Week 4
Population: The Per-Protocol (PP) population excludes participants due to important deviations from the protocol that may substantially affect the results of the primary and key secondary efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-6913 75 mg | Change From Baseline in Follicle-stimulating Hormone (FSH) Level at Week 4 | -2.02 mIU/mL |
| 17-β Estradiol 1 mg | Change From Baseline in Follicle-stimulating Hormone (FSH) Level at Week 4 | -17.48 mIU/mL |
| Placebo | Change From Baseline in Follicle-stimulating Hormone (FSH) Level at Week 4 | -2.96 mIU/mL |
p-value: 0.82790% CI: [-6.19, 8.07]ANCOVA
p-value: 0.00190% CI: [-21.73, -7.32]ANCOVA
Secondary
Percent Change From Baseline in the Weekly Hot Flash Severity Score (Combining Severe and Very Severe Score) at Week 4
Hot flash severity score is calculated by the sum of: the number of mild hot flashes, 2 times number of moderate hot flashes, 3 times the number of severe hot flashes, and 4 times the number of very severe hot flashes. This sum was standardized to a 7-day week if there were any missing days in the e-diary. The severity of each hot flash was recorded by the Hot Flash e-diary.
Time frame: Baseline and Week 4
Population: The Full Analysis Set (FAS) population consists of all randomized participants who receive at least 1 dose of study treatment, have at least 1 post-randomization observation for the analysis endpoint, and have baseline data for those analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-6913 75 mg | Percent Change From Baseline in the Weekly Hot Flash Severity Score (Combining Severe and Very Severe Score) at Week 4 | -39.92 Percent change |
| 17-β Estradiol 1 mg | Percent Change From Baseline in the Weekly Hot Flash Severity Score (Combining Severe and Very Severe Score) at Week 4 | -45.09 Percent change |
| Placebo | Percent Change From Baseline in the Weekly Hot Flash Severity Score (Combining Severe and Very Severe Score) at Week 4 | -33.87 Percent change |
p-value: 0.52995% CI: [-25.06, 12.96]Longitudinal Data Analysis (LDA)
p-value: 0.26495% CI: [-31.03, 8.59]Longitudinal Data Analysis