Menopause, Vasomotor Symptoms
Conditions
Brief summary
The most direct treatment of vasomotor symptions (hot flushes) may be by means of 5-HT2A receptor antagonist. Mirtazapine is a potent blocker of 5-HT2A receptors and was found to be effective in reducing the number and intensity of hot flushes in preliminary trials. Also several Selective Serotonin Reuptake Inhibitors (SSRIs) and other similar compounds have been investigated to manage hot flushes, confirming the role of the serotonergic system. In the present trial, the efficacy and safety of four different doses of esmirtazapine compared to placebo was investigated in women with moderate to severe vasomotor symptoms associated with the menopause. The primary study hypothesis was that esmirtazapine would show superior efficacy to placebo.
Interventions
DRUGesmirtazapine
DRUGPlacebo
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* postmenopausal women, defined as: * 12 months of spontaneous amenorrhea; * OR 6 months of spontaneous amenorrhea with serum Follicle Stimulating Hormone (FSH) levels \>40 mIU/mL; * OR 6 weeks post surgical bilateral oophorectomy with or without hysterectomy. * In case the menopausal status of a subject was unclear because of a hysterectomy, the serum FSH level had to be \>40 mIU/mL. If the date of the last menstruation was not clear because of perimenopausal hormone use, then the subject had to have a serum FSH level \>40 mIU/mL after completion of a washout period (see
Exclusion criteria
below); be \>= 40 and \<= 65 years of age; * have a body mass index (BMI) \>= 18 and \<= 32 kg/m\^2; * minimum of 7 moderate to severe hot flushes per day or 50 per week, as quantified from daily diary recordings during at least 7 days preceding randomization to trial medication; * able to handle the electronic diary device after training and having at least 80% compliance on complete daily diary entries during the period prior to randomization; * give voluntary written Informed Consent (IC) after the scope and nature of the investigation had been explained, before screening evaluations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4 | Baseline and Week 4 | Participants recorded the frequency of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward. |
| Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12 | Baseline and Week 12 | Participants recorded the frequency of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward. |
| Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 | Baseline and Week 4 | Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward. |
| Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 | Baseline and Week 12 | Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Baseline and Week 12 | The WHQ is a 36-item, user-friendly, and rapid way of assessing nine domains of physical and emotional health for mid-aged women. Participants self-administered the WHQ questionnaire; scoring is based on a 4-point scale as follows: 'Yes definitely=1', 'Yes sometimes=2', 'No not much=3' and 'No not at all=4'. Each score is transformed to a value '1' for scores '1' and '2' and to a value '0' for scores '3' and '4'. Vasomotor symptoms encompass Items 19 and 27 of the 36 total items. The transformed sums of items 19+27 are divided by 2 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better. |
Participant flow
Pre-assignment details
942 participants were randomly assigned to treatment in this study, however, one screened participant was given placebo treatment without a randomization assignment. This participant is included in the study placebo population.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants receive placebo, encapsulated tablets, orally (PO), once daily (QD) for up to 12 weeks | 317 |
| Esmirtazapine 2.25 mg Participants receive esmirtazapine 2.25 mg, encapsulated tablets, PO, QD for up to 12 weeks | 154 |
| Esmirtazapine 4.5 mg Participants receive esmirtazapine 4.5 mg, encapsulated tablets, PO, QD for up to 12 weeks | 160 |
| Esmirtazapine 9 mg Participants receive esmirtazapine 9 mg, encapsulated tablets, PO, QD for up to 12 weeks | 155 |
| Esmertazapine 18 mg Participants receive esmertazapine 18 mg, encapsulated tablet, PO, QD for up to 12 weeks | 155 |
| Total | 941 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 16 | 10 | 25 | 23 | 35 |
| Overall Study | Lack of Efficacy | 22 | 9 | 6 | 4 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Never received drug | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Other | 1 | 1 | 3 | 0 | 0 |
| Overall Study | Participant uncooperative | 5 | 5 | 4 | 4 | 2 |
Baseline characteristics
| Characteristic | Placebo | Esmirtazapine 2.25 mg | Esmirtazapine 4.5 mg | Esmirtazapine 9 mg | Esmertazapine 18 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 54.0 Years STANDARD_DEVIATION 4.4 | 53.4 Years STANDARD_DEVIATION 4.4 | 54.1 Years STANDARD_DEVIATION 4.2 | 54.9 Years STANDARD_DEVIATION 4.8 | 54.1 Years STANDARD_DEVIATION 4.5 | 54.1 Years STANDARD_DEVIATION 4.4 |
| Sex: Female, Male Female | 317 Participants | 154 Participants | 160 Participants | 155 Participants | 155 Participants | 941 Participants |
| Sex: Female, Male Male | 0 Participants | 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 | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 128 / 317 | 93 / 154 | 99 / 160 | 102 / 155 | 123 / 155 |
| serious Total, serious adverse events | 2 / 317 | 1 / 154 | 3 / 160 | 2 / 155 | 0 / 155 |
Outcome results
Primary
Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12
Participants recorded the frequency of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 12
Population: The ITT population, defined as all randomized particpants having at least one recorded pre-baseline value of the number of moderate and severe hot flushes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12 | -4.9 number of events | Standard Deviation 4.8 |
| Esmirtazapine 2.25 mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12 | -6.2 number of events | Standard Deviation 5.1 |
| Esmirtazapine 4.5 mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12 | -6.7 number of events | Standard Deviation 3.9 |
| Esmirtazapine 9 mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12 | -6.9 number of events | Standard Deviation 4.4 |
| Esmirtazapine 18mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12 | -6.5 number of events | Standard Deviation 4.4 |
p-value: 0.0695% CI: [-2, 0]ANCOVA
p-value: <0.0195% CI: [-3, -0.9]ANCOVA
p-value: <0.0195% CI: [-2.9, -0.9]ANCOVA
p-value: <0.0195% CI: [-2.6, -0.5]ANCOVA
Primary
Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4
Participants recorded the frequency of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 4
Population: The intent-to-treat (ITT) population, defined as all randomized particpants having at least one recorded pre-baseline value of the number of moderate and severe hot flushes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4 | -3.9 Number of events | Standard Deviation 4.2 |
| Esmirtazapine 2.25 mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4 | -5.6 Number of events | Standard Deviation 3.8 |
| Esmirtazapine 4.5 mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4 | -6.0 Number of events | Standard Deviation 3.6 |
| Esmirtazapine 9 mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4 | -6.0 Number of events | Standard Deviation 4 |
| Esmirtazapine 18mg | Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4 | -6.0 Number of events | Standard Deviation 4.4 |
p-value: <0.0195% CI: [-2.3, -0.4]ANCOVA
p-value: <0.0195% CI: [-3.1, -1.2]ANCOVA
p-value: <0.0195% CI: [-2.9, -1]ANCOVA
p-value: <0.0195% CI: [-2.9, -1]ANCOVA
Primary
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12
Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 12
Population: The ITT population, defined as all randomized particpants having at least one recorded pre-baseline value of the number of moderate and severe hot flushes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 | -0.12 score on a scale | Standard Deviation 0.28 |
| Esmirtazapine 2.25 mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 | -0.10 score on a scale | Standard Deviation 0.27 |
| Esmirtazapine 4.5 mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 | -0.15 score on a scale | Standard Deviation 0.29 |
| Esmirtazapine 9 mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 | -0.18 score on a scale | Standard Deviation 0.26 |
| Esmirtazapine 18mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 | -0.17 score on a scale | Standard Deviation 0.26 |
p-value: 195% CI: [-0.06, 0.07]ANCOVA
p-value: 0.7295% CI: [-0.09, 0.04]ANCOVA
p-value: 0.1395% CI: [-0.12, 0.01]ANCOVA
p-value: 0.1595% CI: [-0.12, 0.01]ANCOVA
Primary
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4
Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 4
Population: The ITT population, defined as all randomized particpants having at least one recorded pre-baseline value of the number of moderate and severe hot flushes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 | -0.09 score on a scale | Standard Deviation 0.23 |
| Esmirtazapine 2.25 mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 | -0.11 score on a scale | Standard Deviation 0.22 |
| Esmirtazapine 4.5 mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 | -0.15 score on a scale | Standard Deviation 0.25 |
| Esmirtazapine 9 mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 | -0.16 score on a scale | Standard Deviation 0.24 |
| Esmirtazapine 18mg | Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 | -0.15 score on a scale | Standard Deviation 0.24 |
p-value: 0.6295% CI: [-0.09, 0.03]ANCOVA
p-value: 0.0295% CI: [-0.12, -0.01]ANCOVA
p-value: 0.0195% CI: [-0.13, -0.01]ANCOVA
p-value: 0.0295% CI: [-0.12, -0.01]ANCOVA
Secondary
Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12
The WHQ is a 36-item, user-friendly, and rapid way of assessing nine domains of physical and emotional health for mid-aged women. Participants self-administered the WHQ questionnaire; scoring is based on a 4-point scale as follows: 'Yes definitely=1', 'Yes sometimes=2', 'No not much=3' and 'No not at all=4'. Each score is transformed to a value '1' for scores '1' and '2' and to a value '0' for scores '3' and '4'. Vasomotor symptoms encompass Items 19 and 27 of the 36 total items. The transformed sums of items 19+27 are divided by 2 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better.
Time frame: Baseline and Week 12
Population: All participants receiving study drug with diary compliance adequate for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Baseline | 0.984 Score on a scale | Standard Deviation 0.088 |
| Placebo | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Change from baseline | -0.151 Score on a scale | Standard Deviation 0.329 |
| Esmirtazapine 2.25 mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Baseline | 0.993 Score on a scale | Standard Deviation 0.06 |
| Esmirtazapine 2.25 mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Change from baseline | -0.235 Score on a scale | Standard Deviation 0.355 |
| Esmirtazapine 4.5 mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Baseline | 0.985 Score on a scale | Standard Deviation 0.085 |
| Esmirtazapine 4.5 mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Change from baseline | -0.256 Score on a scale | Standard Deviation 0.355 |
| Esmirtazapine 9 mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Change from baseline | -0.256 Score on a scale | Standard Deviation 0.372 |
| Esmirtazapine 9 mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Baseline | 0.981 Score on a scale | Standard Deviation 0.114 |
| Esmirtazapine 18mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Baseline | 0.985 Score on a scale | Standard Deviation 0.085 |
| Esmirtazapine 18mg | Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12 | Change from baseline | -0.246 Score on a scale | Standard Deviation 0.385 |