CompletedNCT00535288Updated Apr 2, 2019Results posted

Dose-Finding Safety and Efficacy Trial of Org 50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (177001/P06472/MK-8265-013)

A Phase 3 interventional study of Esmirtazapine and Placebo in Postmenopausal Symptoms, Menopause and Vasomotor Symptoms, sponsored by Merck Sharp & Dohme LLC. Completed. Open to female participants aged 40 Years to 65 Years. Per ClinicalTrials.gov, last updated 2019-04-02.

Sponsored by Merck Sharp & Dohme LLC · Phase 3, Interventional, and Treatment

From the registry’s dates

Registered 3 years after the study started (first participant enrolled Sep 2004, registered Sep 2007).

Phase: Phase 3
Study type: Interventional
Enrollment: 946
Allocation: Randomized
Ages: 40 Years to 65 Years
Sex: Female

Study summary

To investigate efficacy and safety of 4 doses of esmirtazapine, compared to placebo, in the treatment of moderate to severe hot flushes (vasomotor symptoms) associated with the menopause. Co-primary efficacy endpoints are the frequency and severity of hot flushes after 4 and 12 weeks as compared to Baseline.

Read the detailed description

The most direct treatment of 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 were investigated in women with moderate to severe vasomotor symptoms associated with the menopause. The primary objective of this trial was to demonstrate superior efficacy in at least one of the four doses of esmirtazapine as compared to placebo on the four following co-primary endpoints: 1) the mean change from baseline in average daily frequency of moderate and severe vasomotor symptoms at Week 4; 2) the mean change from baseline in average daily frequency of moderate and severe vasomotor symptoms at Week 12; 3) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 4; 4) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 12. The number and severity of hot flushes was recorded by means of electronic diary by the subjects.

Conditions studied

Postmenopausal Symptoms
Menopause
Vasomotor Symptoms

In context

Lead sponsor

Merck Sharp & Dohme LLC is the lead sponsor of 2,114 studies on the registry; 133 are open to participants now.

Of its 489 completed or terminated interventional studies of FDA-regulated products, 362 (74%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 40 Years to 65 Years
Sexes eligible: Female
Accepts 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.
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.

Exclusion criteria

Exclusion Criteria:

History or presence of any malignancy, except non-melanoma skin cancers;
Any clinically unstable or uncontrolled renal, hepatic, endocrine, respiratory, hematological, neurological, cardiovascular or cerebrovascular disease that would put the subject at safety risk or mask measure of efficacy;
History of seizures or epilepsy;
History or presence of clinically significant depression or other psychiatric disorder which, in the opinion of the investigator, might compromise or confound the subject's participation in the trial;
Abnormal clinically relevant vaginal bleeding;
Any clinically relevant (opinion of investigator) abnormal finding during physical, gynecological and breast examination at screening;
Abnormal, clinically significant results of mammography;
Abnormal cervical smear test results (corresponding to Pap III and higher, including Low-Grade Squamous Intraepithelial Lesion (LSIL), High-Grade Squamous Intraepithelial Lesion (HSIL), Cervical Intraepithelial Neoplasia (CIN) 1 and higher);
Hematological or biochemical values at screening outside the reference ranges considered clinically relevant in the opinion of the investigator;
High Blood Pressure (BP);
Use of any drug product containing estrogens, progestins, androgens or tibolone prior to screening (and up to and including randomization) within a pre-specified period;
Any of the following treatments within the last 4 weeks prior to screening (and up to and including randomization):
- tricyclic antidepressants, Serotonin Noradrenergic Reuptake Inhibitors (SNRIs), SSRIs, Monoamine Oxidase (MAO)-inhibitors, mirtazapine
- antianxiety drugs, antipsychotics
- coumarin-derivatives
- α-adrenergic agents
- β-blockers
- dopamine agonists/antagonists
- opiates, barbiturates
- raloxifene
- homeopathic menopausal preparations or other preparations intended to treat climacteric or Central Nervous System (CNS) symptoms
- hepatic microsomal enzyme-inducing drugs or drugs known to affect or interfere with the pharmacokinetics of mirtazapine;
Any condition or disease that could affect or interfere with the pharmacokinetics of mirtazapine;
Subjects sensitive to trial medication or its components;
Use of any investigational drug and/or participation in another clinical trial within the last eight weeks prior to screening;
History of alcohol and/or drug abuse within the last two years prior to screening.

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 946 participants (actual)

Study arms

Placebo comparator
Placebo
Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.
Drug: Placebo
Experimental
Esmirtazapine 2.25 mg
Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.
Drug: Esmirtazapine
Experimental
Esmirtazapine 4.5 mg
Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.
Drug: Esmirtazapine
Experimental
Esmirtazapine 9 mg
Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.
Drug: Esmirtazapine
Experimental
Esmirtazapine 18 mg
Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.
Drug: Esmirtazapine

Interventions

DrugEsmirtazapine
Four different doses (2.25, 4.5, 9.0, and 18 mg) encapsulated esmirtazapine tablets in Swedish Orange hard gelatin DB-B capsules for blinding purposes. Encapsulated tablets were administered orally once daily in the evening prior to sleep for 12 weeks.
Also known as: Esmirtazapine maleate, SCH 900265, Org 50081
DrugPlacebo
Encapsulated placebo tablets in Swedish Orange hard gelatin DB-B capsules for blinding purposes. Encapsulated tablets were administered orally once daily in the evening prior to sleep for 12 weeks.

What researchers measure

Primary outcomes

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4
Participants recorded the frequency (number) 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
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 per week. 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 4
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12
Participants recorded the frequency (number) 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 12
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 per week. 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Week 12

Secondary outcomes

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12
Participants recorded the frequency (number) 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and Up to Week 12
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 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 per week. 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and up to Week 12
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week
Composite Score A was calculated as Severity Score A x Frequency Score A.
Time frame: Baseline and up to Week 12
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week
Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency Score B was based on the number of mild hot flushes + 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and up to Week 12
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week
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 B was calculated as the number of mild hot flushes + the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of all hot flushes per week. 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Time frame: Baseline and up to Week 12
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week
Composite Score B was calculated as Severity Score B x Frequency Score B.
Time frame: Baseline and up to Week 12
Total Number of Responders by Week
A participant was defined as a (hot flush) responder for a study week if a reduction of at least 50% for average daily frequency of moderate/severe vasomotor symptoms (hot flushes) (Frequency Score A) compared to Baseline was recorded. A study week was taken into account if at least 4 days were completely observed. The last observation was carried forward if there were less than 4 complete days observed. In cases where Week 1 did not have 4 days that were completely observed, the participant was considered a non-responder. An LOCF approach was used.
Time frame: Up to 12 weeks
Total Number of Remitters by Week
A participant was defined as a (hot flush) remitter for a study week if at most one moderate/severe vasomotor symptom per day on average was recorded. A study week was taken into account if at least 4 days were completely observed. The last observation was carried forward if there were less than 4 complete days observed. In cases where Week 1 did not have 4 days that were completely observed, the participant was considered a non-remitter.
Time frame: Up to 12 weeks
Change From Baseline in Women's Health Questionnaire (WHQ) Sleep Problems Symptoms Domain Score 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'. Sleep problems encompass Items 1, 11, and 29 of the 36 total items. The transformed sums of items 1, 11, and 29 were divided by 3 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better.
Time frame: Baseline and Week 12
Change From Baseline in WHQ Vasomotor Symptoms Domain Score 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

Results

Posted Jul 30, 2014

Participant flow

Participant flow — Overall Study
Milestone	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Started	314	162	160	151	158
Completed	260	130	127	122	116
Not completed	54	32	33	29	42
Withdrew: Adverse event	20	19	25	20	30
Withdrew: Lost to follow-up	0	3	0	0	0
Withdrew: Lack of efficacy	26	3	4	4	7
Withdrew: Unwilling to cooperate	6	6	3	3	4
Withdrew: Other	2	1	1	2	1

Outcome measures

PrimaryChange From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4

Participants recorded the frequency (number) 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
Reported as:: Mean · Events per day

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4
Events per day	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	12.1 ± 5.1	12.2 ± 5.1	12.6 ± 4.7	12.3 ± 4.4	11.5 ± 4.7
Week 4	-3.8 ± 4.5	-5.1 ± 4.1	-5.7 ± 4.8	-5.3 ± 3.8	-5.6 ± 4.4

Statistical analysis

Placebo vs Esmirtazapine 2.25 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -1.2 · 95% CI -2.2 to -0.2Factors for treatment group and (pooled) center and a covariate for the baseline frequency
Placebo vs Esmirtazapine 4.5 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -1.7 · 95% CI -2.7 to -0.7Factors for treatment group and (pooled) center and a covariate for the baseline frequency
Placebo vs Esmirtazapine 9 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate) · Difference between least squares means: -1.4 · 95% CI -2.4 to -0.4Factors for treatment group and (pooled) center and a covariate for the baseline frequency
Placebo vs Esmirtazapine 18 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate) · Difference between least squares means: -1.9 · 95% CI -2.9 to -0.9Factors for treatment group and (pooled) center and a covariate for the baseline frequency

PrimaryChange 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 per week. 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Time frame:: Baseline and Week 4
Reported as:: Mean · Severity score

Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4
Severity score	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	2.45 ± 0.30	2.45 ± 0.30	2.45 ± 0.32	2.46 ± 0.30	2.40 ± 0.27
Week 4	-0.07 ± 0.20	-0.14 ± 0.23	-0.13 ± 0.23	-0.15 ± 0.24	-0.15 ± 0.23

Statistical analysis

Placebo vs Esmirtazapine 2.25 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.07 · 95% CI -0.12 to -0.01Factors for treatment group and (pooled) center and a covariate for the baseline severity
Placebo vs Esmirtazapine 4.5 mg · ANCOVA · p = 0.02 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.06 · 95% CI -0.11 to -0.01Factors for treatment group and (pooled) center and a covariate for the baseline severity
Placebo vs Esmirtazapine 9 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.07 · 95% CI -0.13 to -0.02Factors for treatment group and (pooled) center and a covariate for the baseline severity
Placebo vs Esmirtazapine 18 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.08 · 95% CI -0.14 to -0.03Factors for treatment group and (pooled) center and a covariate for the baseline severity

PrimaryChange From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12

Participants recorded the frequency (number) 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Time frame:: Baseline and Week 12
Reported as:: Mean · Events per day

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12
Events per day	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	12.1 ± 5.1	12.2 ± 5.1	12.6 ± 4.7	12.3 ± 4.4	11.5 ± 4.7
Week 12	-4.2 ± 5.3	-5.2 ± 4.6	-6.0 ± 4.9	-5.8 ± 4.3	-6.0 ± 4.6

Statistical analysis

Placebo vs Esmirtazapine 2.25 mg · ANCOVA · p = 0.08 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -1.0 · 95% CI -2.1 to 0.1Factors for treatment group and (pooled) center and a covariate for the baseline frequency
Placebo vs Esmirtazapine 4.5 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -1.6 · 95% CI -2.7 to -0.5Factors for treatment group and (pooled) center and a covariate for the baseline frequency
Placebo vs Esmirtazapine 9 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -1.5 · 95% CI -2.7 to -0.4Factors for treatment group and (pooled) center and a covariate for the baseline frequency
Placebo vs Esmirtazapine 18 mg · ANCOVA · p = <0.01 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -2.0 · 95% CI -3.1 to -0.9Factors for treatment group and (pooled) center and a covariate for the baseline frequency

SecondaryChange From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12

Time frame:: Baseline and Up to Week 12
Reported as:: Mean · Events per day

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12
Events per day	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	12.10 ± 5.10	12.19 ± 5.07	12.56 ± 4.66	12.30 ± 4.39	11.52 ± 4.67
Week 1	-2.21 ± 3.37	-3.20 ± 3.35	-4.08 ± 3.79	-3.63 ± 2.89	-4.18 ± 3.83
Week 2	-3.25 ± 4.08	-4.72 ± 3.85	-5.19 ± 4.59	-4.88 ± 3.24	-5.39 ± 3.96
Week 3	-3.71 ± 4.39	-4.82 ± 4.08	-5.68 ± 4.74	-5.13 ± 3.68	-5.59 ± 4.05
Week 5	-3.90 ± 4.82	-5.29 ± 4.28	-5.83 ± 4.72	-5.50 ± 3.79	-5.54 ± 4.48
Week 6	-4.02 ± 4.90	-5.41 ± 4.43	-5.96 ± 4.79	-5.58 ± 3.89	-5.62 ± 4.71
Week 7	-4.11 ± 4.96	-5.33 ± 4.30	-6.10 ± 4.87	-5.69 ± 4.28	-5.93 ± 4.63
Week 8	-4.04 ± 5.05	-5.19 ± 4.49	-6.14 ± 4.72	-5.86 ± 4.52	-5.72 ± 4.36
Week 9	-4.11 ± 5.18	-5.15 ± 4.65	-6.23 ± 4.90	-5.96 ± 4.39	-5.95 ± 4.77
Week 10	-4.11 ± 5.42	-5.18 ± 4.54	-5.97 ± 4.79	-6.00 ± 4.36	-6.11 ± 4.66
Week 11	-4.20 ± 5.38	-5.30 ± 4.65	-6.03 ± 4.86	-5.86 ± 4.34	-5.91 ± 4.57

SecondaryChange From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12

Time frame:: Baseline and up to Week 12
Reported as:: Mean · Severity score

Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12
Severity score	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	2.447 ± 0.301	2.451 ± 0.297	2.449 ± 0.315	2.460 ± 0.296	2.400 ± 0.274
Week 1	-0.045 ± 0.124	-0.081 ± 0.153	-0.085 ± 0.151	-0.085 ± 0.159	-0.108 ± 0.150
Week 2	-0.063 ± 0.172	-0.117 ± 0.199	-0.111 ± 0.212	-0.140 ± 0.200	-0.136 ± 0.178
Week 3	-0.071 ± 0.195	-0.133 ± 0.214	-0.119 ± 0.214	-0.150 ± 0.200	-0.137 ± 0.240
Week 5	-0.080 ± 0.215	-0.141 ± 0.233	-0.123 ± 0.227	-0.154 ± 0.225	-0.151 ± 0.232
Week 6	-0.075 ± 0.215	-0.136 ± 0.246	-0.127 ± 0.234	-0.140 ± 0.236	-0.152 ± 0.245
Week 7	-0.088 ± 0.233	-0.144 ± 0.236	-0.131 ± 0.260	-0.140 ± 0.253	-0.144 ± 0.257
Week 8	-0.082 ± 0.239	-0.142 ± 0.242	-0.124 ± 0.270	-0.139 ± 0.254	-0.133 ± 0.247
Week 9	-0.083 ± 0.242	-0.142 ± 0.257	-0.137 ± 0.260	-0.130 ± 0.265	-0.144 ± 0.246
Week 10	-0.084 ± 0.255	-0.147 ± 0.261	-0.125 ± 0.263	-0.141 ± 0.258	-0.162 ± 0.252
Week 11	-0.078 ± 0.261	-0.159 ± 0.273	-0.130 ± 0.273	-0.124 ± 0.257	-0.156 ± 0.257

PrimaryChange From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12

Time frame:: Baseline and Week 12
Reported as:: Mean · Severity score

Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12
Severity score	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	2.45 ± 0.30	2.45 ± 0.30	2.45 ± 0.32	2.46 ± 0.30	2.40 ± 0.27
Week 12	-0.08 ± 0.26	-0.15 ± 0.27	-0.13 ± 0.27	-0.13 ± 0.26	-0.15 ± .026

Statistical analysis

Placebo vs Esmirtazapine 2.25 mg · ANCOVA · p = 0.07 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.06 · 95% CI -0.12 to 0.00Factors for treatment group and (pooled) center and a covariate for the baseline severity
Placebo vs Esmirtazapine 4.5 mg · ANCOVA · p = 0.24 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.05 · 95% CI -0.11 to 0.02Factors for treatment group and (pooled) center and a covariate for the baseline severity
Placebo vs Esmirtazapine 9 mg · ANCOVA · p = 0.29 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.04 · 95% CI -0.11 to 0.02Factors for treatment group and (pooled) center and a covariate for the baseline severity
Placebo vs Esmirtazapine 18 mg · ANCOVA · p = 0.02 (Confidence intervals and p-values were adjusted by (2-sided) Dunnett many-to-one comparison at 0.05 overall Type 1 error rate.) · Difference between least squares means: -0.07 · 95% CI -0.14 to -0.01Factors for treatment group and (pooled) center and a covariate for the baseline severity

SecondaryChange From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week

Composite Score A was calculated as Severity Score A x Frequency Score A.

Time frame:: Baseline and up to Week 12
Reported as:: Mean · Composite score

Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week
Composite score	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	30.19 ± 15.42	30.41 ± 14.56	31.03 ± 12.98	30.40 ± 11.81	27.87 ± 12.56
Week 1	-5.65 ± 8.99	-8.48 ± 9.10	-10.28 ± 9.19	-9.43 ± 7.84	-10.63 ± 9.63
Week 2	-8.28 ± 10.93	-12.32 ± 10.18	-12.98 ± 11.36	-12.70 ± 8.75	-13.54 ± 9.89
Week 3	-9.46 ± 11.92	-12.63 ± 11.09	-14.22 ± 11.88	-13.39 ± 9.82	-13.89 ± 10.28
Week 4	-9.79 ± 12.39	-13.18 ± 11.29	-14.42 ± 11.88	-13.70 ± 10.28	-13.72 ± 11.38
Week 5	-9.96 ± 13.19	-13.65 ± 11.77	-14.47 ± 11.65	-14.16 ± 10.09	-13.72 ± 11.33
Week 6	-10.22 ± 13.40	-13.89 ± 11.88	-14.84 ± 11.92	-14.24 ± 10.26	-13.95 ± 12.05
Week 7	-10.42 ± 13.49	-13.73 ± 11.66	-15.11 ± 12.32	-14.42 ± 11.23	-14.72 ± 11.87
Week 8	-10.20 ± 13.71	-13.31 ± 11.98	-15.19 ± 11.93	-14.73 ± 11.56	-14.08 ± 11.21
Week 9	-10.30 ± 14.06	-13.20 ± 12.54	-15.40 ± 12.18	-14.93 ± 11.20	-14.67 ± 12.30
Week 10	-10.26 ± 14.77	-13.30 ± 12.34	-14.76 ± 12.07	-15.03 ± 11.24	-15.08 ± 12.09
Week 11	-10.53 ± 14.73	-13.58 ± 12.61	-14.92 ± 12.41	-14.58 ± 11.28	14.57 ± 11.85
Week 12	-10.42 ± 14.56	-13.25 ± 12.52	-14.88 ± 12.49	-14.36 ± 11.17	-14.71 ± 12.17

SecondaryChange From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week

Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency Score B was based on the number of mild hot flushes + 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Time frame:: Baseline and up to Week 12
Reported as:: Mean · Events per day

Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week
Events per day	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	13.29 ± 5.35	13.48 ± 5.35	13.66 ± 4.96	13.41 ± 4.61	13.00 ± 6.09
Week 1	-2.22 ± 3.41	-3.24 ± 3.23	-3.81 ± 3.33	-3.57 ± 2.96	-4.16 ± 4.69
Week 2	-3.35 ± 4.17	-4.81 ± 4.03	-5.19 ± 4.46	-4.79 ± 3.28	-5.50 ± 4.75
Week 3	-3.83 ± 4.46	-5.05 ± 4.15	-5.66 ± 4.74	-5.08 ± 3.72	-5.79 ± 4.88
Week 4	-3.97 ± 4.63	-5.37 ± 4.14	-6.01 ± 4.80	-5.38 ± 3.98	-5.85 ± 5.30
Week 5	-4.06 ± 4.91	-5.61 ± 4.46	-6.13 ± 4.81	-5.57 ± 4.03	-5.90 ± 5.31
Week 6	-4.25 ± 4.86	-5.82 ± 4.51	-6.32 ± 4.89	-5.75 ± 4.11	-5.89 ± 5.24
Week 7	-4.27 ± 4.85	-5.69 ± 4.36	-6.47 ± 4.89	-5.90 ± 4.45	-6.15 ± 5.18
Week 8	-4.19 ± 4.94	-5.54 ± 4.50	-6.51 ± 4.72	-6.06 ± 4.55	-6.03 ± 4.73
Week 9	-4.30 ± 5.06	-5.47 ± 4.71	-6.59 ± 4.79	-6.08 ± 4.51	-6.26 ± 5.26
Week 10	-4.29 ± 5.39	-5.59 ± 4.73	-6.36 ± 4.81	-6.18 ± 4.46	-6.35 ± 5.05
Week 11	-4.43 ± 5.42	-5.68 ± 4.83	-6.45 ± 4.91	-6.08 ± 4.48	-6.28 ± 4.98
Week 12	-4.40 ± 5.44	-5.63 ± 4.71	-6.45 ± 4.96	-6.10 ± 4.48	-6.32 ± 4.99

SecondaryChange From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week

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 B was calculated as the number of mild hot flushes + the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of all hot flushes per week. 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 (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Time frame:: Baseline and up to Week 12
Reported as:: Mean · Severity score

Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week
Severity score	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	2.332 ± 0.369	2.331 ± 0.375	2.349 ± 0.373	2.350 ± 0.347	2.270 ± 0.332
Week 1	-0.080 ± 0.220	-0.132 ± 0.246	-0.167 ± 0.245	-0.140 ± 0.245	-0.192 ± 0.273
Week 2	-0.111 ± 0.291	-0.210 ± 0.342	-0.223 ± 0.341	-0.225 ± 0.341	-0.250 ± 0.312
Week 3	-0.121 ± 0.307	-0.217 ± 0.373	-0.246 ± 0.400	-0.240 ± 0.337	-0.272 ± 0.389
Week 4	-0.113 ± 0.312	-0.224 ± 0.409	-0.240 ± 0.388	-0.249 ± 0.387	-0.273 ± 0.411
Week 5	-0.124 ± 0.354	-0.234 ± 0.411	-0.228 ± 0.403	-0.254 ± 0.368	-0.266 ± 0.409
Week 6	-0.121 ± 0.360	-0.222 ± 0.429	-0.214 ± 0.386	-0.245 ± 0.396	-0.275 ± 0.436
Week 7	-0.142 ± 0.389	-0.234 ± 0.433	-0.232 ± 0.444	-0.242 ± 0.424	-0.287 ± 0.460
Week 8	-0.139 ± 0.408	-0.251 ± 0.440	-0.234 ± 0.467	-0.251 ± 0.447	-0.273 ± 0.463
Week 9	-0.136 ± 0.408	-0.245 ± 0.438	-0.256 ± 0.454	-0.256 ± 0.462	-0.292 ± 0.474
Week 10	-0.143 ± 0.431	-0.244 ± 0.452	-0.257 ± 0.465	-0.257 ± 0.467	-0.307 ± 0.460
Week 11	-0.149 ± 0.439	-0.260 ± 0.467	-0.245 ± 0.463	-0.224 ± 0.459	-0.308 ± 0.477
Week 12	-0.152 ± 0.457	-0.255 ± 0.471	-0.240 ± 0.465	-0.210 ± 0.450	-0.280 ± 0.472

SecondaryChange From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week

Composite Score B was calculated as Severity Score B x Frequency Score B.

Time frame:: Baseline and up to Week 12
Reported as:: Mean · Composite score

Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week
Composite score	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	31.39 ± 15.37	31.70 ± 14.47	32.13 ± 12.91	31.51 ± 11.80	29.35 ± 13.55
Week 1	-5.66 ± 8.94	-8.53 ± 8.85	-10.01 ± 8.60	-9.37 ± 7.74	-10.61 ± 10.31
Week 2	-8.38 ± 10.91	-12.40 ± 10.12	-12.98 ± 11.05	-12.60 ± 8.58	-13.64 ± 10.46
Week 3	-9.57 ± 11.88	-12.86 ± 10.89	-14.40 ± 11.69	-13.34 ± 9.69	-14.09 ± 10.80
Week 4	-9.93 ± 12.36	-13.48 ± 11.06	-14.69 ± 11.89	-13.75 ± 10.24	-14.01 ± 11.91
Week 5	-10.12 ± 13.13	-13.96 ± 11.65	014.78 ± 11.54	-14.22 ± 10.12	-14.08 ± 11.82
Week 6	-10.45 ± 13.24	-14.29 ± 11.65	-15.19 ± 11.83	-14.40 ± 10.30	-14.21 ± 12.22
Week 7	-10.58 ± 13.23	-14.09 ± 11.45	-15.48 ± 12.16	-14.63 ± 11.18	-14.93 ± 12.04
Week 8	-10.34 ± 13.43	-13.66 ± 11.73	-15.56 ± 11.76	-14.92 ± 11.38	-14.40 ± 11.18
Week 9	-10.49 ± 13.78	-13.53 ± 12.33	-15.77 ± 11.91	-15.05 ± 11.09	-14.98 ± 12.44
Week 10	-10.44 ± 14.56	-13.71 ± 12.27	-15.15 ± 11.92	-15.21 ± 11.11	-15.32 ± 12.09
Week 11	-10.76 ± 14.57	-13.96 ± 12.53	-15.34 ± 12.27	-14.79 ± 11.16	-14.95 ± 11.95
Week 12	-10.66 ± 14.44	-13.66 ± 12.32	-15.32 ± 12.38	-14.71 ± 11.11	-15.04 ± 12.17

SecondaryTotal Number of Responders by Week

A participant was defined as a (hot flush) responder for a study week if a reduction of at least 50% for average daily frequency of moderate/severe vasomotor symptoms (hot flushes) (Frequency Score A) compared to Baseline was recorded. A study week was taken into account if at least 4 days were completely observed. The last observation was carried forward if there were less than 4 complete days observed. In cases where Week 1 did not have 4 days that were completely observed, the participant was considered a non-responder. An LOCF approach was used.

Time frame:: Up to 12 weeks
Reported as:: Number · Participants

Total Number of Responders by Week
Participants	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Week 1	37	29	35	32	42
Week 2	56	49	60	48	65
Week 3	85	53	63	47	72
Week 4	76	58	70	52	71
Week 5	76	63	65	56	71
Week 6	84	67	70	55	69
Week 7	89	59	72	60	75
Week 8	93	65	73	66	72
Week 9	96	67	74	68	75
Week 10	97	65	73	67	77
Week 11	95	70	78	65	72
Week 12	99	70	75	65	77

SecondaryTotal Number of Remitters by Week

A participant was defined as a (hot flush) remitter for a study week if at most one moderate/severe vasomotor symptom per day on average was recorded. A study week was taken into account if at least 4 days were completely observed. The last observation was carried forward if there were less than 4 complete days observed. In cases where Week 1 did not have 4 days that were completely observed, the participant was considered a non-remitter.

Time frame:: Up to 12 weeks
Reported as:: Number · Participants

Total Number of Remitters by Week
Participants	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Week 1	3	2	7	2	2
Week 2	6	11	13	8	13
Week 3	8	15	16	7	17
Week 4	10	15	18	15	17
Week 5	13	18	16	12	17
Week 6	15	15	21	13	18
Week 7	19	19	22	16	21
Week 8	23	19	25	18	21
Week 9	24	19	25	19	26
Week 10	25	19	25	23	25
Week 11	25	22	23	21	28
Week 12	27	23	24	20	26

SecondaryChange From Baseline in Women's Health Questionnaire (WHQ) Sleep Problems Symptoms Domain Score 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'. Sleep problems encompass Items 1, 11, and 29 of the 36 total items. The transformed sums of items 1, 11, and 29 were divided by 3 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better.

Time frame:: Baseline and Week 12
Reported as:: Mean · Score on a scale

Change From Baseline in Women's Health Questionnaire (WHQ) Sleep Problems Symptoms Domain Score at Week 12
Score on a scale	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Baseline	0.714 ± 0.291	0.659 ± 0.321	0.684 ± 0.298	0.688 ± 0.270	0.693 ± 0.260
Week 12	-0.140 ± 0.325	-0.232 ± 0.338	-0.251 ± 0.336	-0.224 ± 0.381	-0.195 ± 0.328

SecondaryChange From Baseline in WHQ Vasomotor Symptoms Domain Score 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
Reported as:: Mean · Score on a scale

Change From Baseline in WHQ Vasomotor Symptoms Domain Score at Week 12
Score on a scale	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18mg
Baseline	0.983 ± 0.091	0.989 ± 0.0873	0.993 ± 0.061	0.984 ± 0.087	0.984 ± 0.087
Week 12	-0.085 ± 0.260	-0.196 ± 0.349	-0.224 ± 0.381	-0.117 ± 0.277	-0.164 ± 0.314

Adverse events

Collected over Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Placebo	—	2/314 (0.6%)	91/314 (29%)
Esmirtazapine 2.25 mg	—	1/162 (0.6%)	71/162 (43.8%)
Esmertazapine 4.5 mg	—	1/160 (0.6%)	70/160 (43.8%)
Esmirtazapine 9 mg	—	3/151 (2%)	58/151 (38.4%)
Esmirtazapine 18 mg	—	1/158 (0.6%)	80/158 (50.6%)

Most frequent serious events

Most frequent serious events
Event	Placebo	Esmirtazapine 2.25 mg	Esmertazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
Wolff-Parkinson-White SyndromeCardiac disorders	0/314	0/162	0/160	1/151	0/158
AstheniaGeneral disorders	0/314	0/162	0/160	1/151	0/158
Non-cardiac chest painGeneral disorders	0/314	0/162	0/160	1/151	0/158
Ovarian fibromaNeoplasms benign, malignant and unspecified (incl cysts and polyps)	0/314	0/162	0/160	1/151	0/158
Syncope vasovagalNervous system disorders	1/314	0/162	0/160	0/151	1/158
DiverticulitisInfections and infestations	0/314	0/162	1/160	0/151	0/158
Diverticular perforationGastrointestinal disorders	0/314	1/162	0/160	0/151	0/158
NightmarePsychiatric disorders	1/314	0/162	0/160	0/151	0/158
Suicidal ideationPsychiatric disorders	1/314	0/162	0/160	0/151	0/158

Most frequent other events

Showing 10 of 12

Most frequent other events
Event	Placebo	Esmirtazapine 2.25 mg	Esmertazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg
SomnolenceNervous system disorders	6/314	19/162	21/160	11/151	27/158
FatigueGeneral disorders	9/314	16/162	26/160	16/151	23/158
Weight increasedInvestigations	6/314	7/162	13/160	11/151	18/158
HeadacheNervous system disorders	33/314	14/162	9/160	5/151	13/158
Increased appetiteMetabolism and nutrition disorders	4/314	8/162	8/160	10/151	14/158
DizzinessNervous system disorders	12/314	8/162	4/160	5/151	13/158
Dry mouthGastrointestinal disorders	6/314	8/162	7/160	12/151	9/158
Abdominal distensionGastrointestinal disorders	5/314	2/162	3/160	4/151	10/158
Menopausal symptomsReproductive system and breast disorders	8/314	5/162	10/160	6/151	4/158
Oedema peripheralGeneral disorders	3/314	9/162	8/160	3/151	6/158

Baseline characteristics

Age, Continuous
Age, Continuous(Years)	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg	Total
Mean	53.5 ± 4.9	53.8 ± 5.0	53.7 ± 4.8	54.7 ± 4.6	53.5 ± 4.7	53.8 ± 4.8

Sex: Female, Male
Sex: Female, Male(Participants)	Placebo	Esmirtazapine 2.25 mg	Esmirtazapine 4.5 mg	Esmirtazapine 9 mg	Esmirtazapine 18 mg	Total
Female	314	162	160	151	158	945
Male	0	0	0	0	0	0

Study locations

No study locations are listed for this record.

References and documents

Publications

Birkhaeuser M, Bitzer J, Braat S, Ramos Y. Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials. Climacteric. 2019 Jun;22(3):312-322. doi: 10.1080/13697137.2018.1561664. Epub 2019 Feb 4. PubMed 30712391 ↗

Individual participant data

Plan to share: Yes — http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Apr 2, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT00535288
Lead sponsor: Merck Sharp & Dohme LLC
Responsible party: Sponsor
First posted: Sep 26, 2007
Start date: Sep 15, 2004
Primary completion: Jan 15, 2006
Completion: Jan 15, 2006
Results posted: Jul 30, 2014
Last update: Apr 2, 2019

Study contacts

Medical Director

study director · Merck Sharp & Dohme LLC

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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