Postmenopausal SymptomsPhase 3NCT00535288

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

A Phase 3 study testing Esmirtazapine in people with Postmenopausal Symptoms and Menopause, run by Merck Sharp & Dohme LLC.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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 more about this study

Who is it for?: Ages 40 to 65 years, women only
Conditions the study is for: Postmenopausal Symptoms, Menopause, Vasomotor Symptoms
What is being tested?: Esmirtazapine
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 946 participants
Where: No sites listed yet
Study dates: 15 Sep 2004to 15 Jan 2006
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 40 to 65 years
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

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;

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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.

Who cannot join

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;

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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.

About this study

Official title: A Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Four Different Doses of Org 50081 in the Treatment of Moderate to Severe Vasomotor Symptoms Associated With the Menopause

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: Postmenopausal Symptoms, Menopause, Vasomotor Symptoms
Being tested: Esmirtazapine, Placebo

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

EsmirtazapineDrug
Also called Esmirtazapine maleate, SCH 900265, Org 50081
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.
PlaceboDrug
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.

Study groups in NCT00535288
Study group	Role	What they receive
Placebo	Placebo comparator	Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks. Receives: Drug: Placebo
Esmirtazapine 2.25 mg	Experimental	Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks. Receives: Drug: Esmirtazapine
Esmirtazapine 4.5 mg	Experimental	Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks. Receives: Drug: Esmirtazapine
Esmirtazapine 9 mg	Experimental	Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks. Receives: Drug: Esmirtazapine
Esmirtazapine 18 mg	Experimental	Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks. Receives: Drug: Esmirtazapine

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and Week 12

Secondary outcomes (10)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

15 Sep 200415 Jan 2006

First posted26 Sep 2007 (estimated)
Study start15 Sep 2004
Primary completion15 Jan 2006
Study completion15 Jan 2006

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Postmenopausal SymptomsStudies of the same condition, open and under way.
More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 946 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00535288
Sponsor's protocol ID: P06472
Other IDs: White Moonstone, 177001
Status last verified: Mar 2019
First submitted: 24 Sep 2007
Last updated: 2 Apr 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

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

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Migraine Menopause Study
Migraine, Menopausal
Active, not recruitingObservational study
The Impact of Osteosarcopenia on Falls, Kinesiophobia, and Quality of Life in Postmenopausal Women
Osteosarcopenia, Sarcopenia
Active, not recruitingPhase 1/2
Study Evaluating ABCL635 for Vasomotor Symptoms of Menopause
Vasomotor Symptoms Associated With Menopause, Healthy Volunteers
Recruiting
The Impact of Overnight Active Temperature Regulation on the Gut Microbiome, Inflammation, and Circadian Rhythm.
Poor Sleep Quality, Gut Microbiome

All Postmenopausal Symptoms trials

Study at a glance

From the registry record, last updated by the sponsor on 2 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Four Different Doses of Org 50081 in the Treatment of Moderate to Severe Vasomotor Symptoms Associated With the Menopause
ClinicalTrials.gov ID: NCT00535288
Acronym / sponsor ID: P06472
Conditions: Postmenopausal Symptoms, Menopause, Vasomotor Symptoms
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 946 participants (actual)
Lead sponsor: Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
Study start: 15 Sep 2004 (actual)
Primary completion: 15 Jan 2006 (actual)
Study completion: 15 Jan 2006 (actual)
First posted: 26 Sep 2007 (estimated)
Results: Posted 30 Jul 2014

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 5

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

Who may qualify

Ages: 40 to 65 years
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (9 listed)

Postmenopausal women, defined as:
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;

Key exclusion criteria (26 listed)

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;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
EsmirtazapineAlso: Esmirtazapine maleate, SCH 900265, Org 50081Four 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.	Drug	Esmirtazapine 18 mg, Esmirtazapine 2.25 mg, Esmirtazapine 4.5 mg, Esmirtazapine 9 mg
PlaceboEncapsulated 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.	Drug	Placebo

Primary outcome

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4
Time frame: Baseline and 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.
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4
Time frame: 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 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.
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12
Time frame: Baseline and 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.
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12
Time frame: 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 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.

10 secondary outcomes

Change 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
Change 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
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week
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
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
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
Time frame: Baseline and up to Week 12
Total Number of Responders by Week
Time frame: Up to 12 weeks
Total Number of Remitters by Week
Time frame: Up to 12 weeks
Change From Baseline in Women's Health Questionnaire (WHQ) Sleep Problems Symptoms Domain Score at Week 12
Time frame: Baseline and Week 12
Change From Baseline in WHQ Vasomotor Symptoms Domain Score at Week 12
Time frame: Baseline and Week 12

Results and safety

Results posted to the registry on 30 Jul 2014, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Placebo	314	260
Esmirtazapine 2.25 mg	162	130
Esmirtazapine 4.5 mg	160	127
Esmirtazapine 9 mg	151	122
Esmirtazapine 18 mg	158	116

Primary outcome: Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4

Time frame: Baseline and Week 4. Mean (Standard Deviation). Unit: Events per day

Measure	Placebo n = 283	Esmirtazapine 2.25 mg n = 146	Esmirtazapine 4.5 mg n = 144	Esmirtazapine 9 mg n = 134	Esmirtazapine 18 mg n = 138
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)

Placebo vs Esmirtazapine 2.25 mg: Difference between least squares means: -1.2 (95% CI -2.2 to -0.2), p <0.01, ANCOVA
Placebo vs Esmirtazapine 4.5 mg: Difference between least squares means: -1.7 (95% CI -2.7 to -0.7), p <0.01, ANCOVA
Placebo vs Esmirtazapine 9 mg: Difference between least squares means: -1.4 (95% CI -2.4 to -0.4), p <0.01, ANCOVA

Population analysed: The Intent-to-Treat (ITT) population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Primary outcome: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4

Time frame: Baseline and Week 4. Mean (Standard Deviation). Unit: Severity score

Measure	Placebo n = 283	Esmirtazapine 2.25 mg n = 146	Esmirtazapine 4.5 mg n = 144	Esmirtazapine 9 mg n = 134	Esmirtazapine 18 mg n = 138
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)

Placebo vs Esmirtazapine 2.25 mg: Difference between least squares means: -0.07 (95% CI -0.12 to -0.01), p <0.01, ANCOVA
Placebo vs Esmirtazapine 4.5 mg: Difference between least squares means: -0.06 (95% CI -0.11 to -0.01), p = 0.02, ANCOVA
Placebo vs Esmirtazapine 9 mg: Difference between least squares means: -0.07 (95% CI -0.13 to -0.02), p <0.01, ANCOVA

Population analysed: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Primary outcome: Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12

Time frame: Baseline and Week 12. Mean (Standard Deviation). Unit: Events per day

Measure	Placebo n = 283	Esmirtazapine 2.25 mg n = 146	Esmirtazapine 4.5 mg n = 144	Esmirtazapine 9 mg n = 134	Esmirtazapine 18 mg n = 138
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)

Placebo vs Esmirtazapine 2.25 mg: Difference between least squares means: -1.0 (95% CI -2.1 to 0.1), p = 0.08, ANCOVA
Placebo vs Esmirtazapine 4.5 mg: Difference between least squares means: -1.6 (95% CI -2.7 to -0.5), p <0.01, ANCOVA
Placebo vs Esmirtazapine 9 mg: Difference between least squares means: -1.5 (95% CI -2.7 to -0.4), p <0.01, ANCOVA

Population analysed: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Primary outcome: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12

Time frame: Baseline and Week 12. Mean (Standard Deviation). Unit: Severity score

Measure	Placebo n = 283	Esmirtazapine 2.25 mg n = 146	Esmirtazapine 4.5 mg n = 144	Esmirtazapine 9 mg n = 134	Esmirtazapine 18 mg n = 138
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)

Placebo vs Esmirtazapine 2.25 mg: Difference between least squares means: -0.06 (95% CI -0.12 to 0.00), p = 0.07, ANCOVA
Placebo vs Esmirtazapine 4.5 mg: Difference between least squares means: -0.05 (95% CI -0.11 to 0.02), p = 0.24, ANCOVA
Placebo vs Esmirtazapine 9 mg: Difference between least squares means: -0.04 (95% CI -0.11 to 0.02), p = 0.29, ANCOVA

Population analysed: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

10 secondary outcomes are reported in the full results.

Adverse events

Time frame: 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.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo	2 of 314 (0.6%)	91 of 314 (29%)	Not reported
Esmirtazapine 2.25 mg	1 of 162 (0.6%)	71 of 162 (43.8%)	Not reported
Esmertazapine 4.5 mg	1 of 160 (0.6%)	70 of 160 (43.8%)	Not reported
Esmirtazapine 9 mg	3 of 151 (2%)	58 of 151 (38.4%)	Not reported
Esmirtazapine 18 mg	1 of 158 (0.6%)	80 of 158 (50.6%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 2 Apr 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 30712391Birkhaeuser 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.
Individual participant dataSharing planned: Yes. http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Merck Sharp & Dohme LLC

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Esmirtazapine in people with Postmenopausal Symptoms and Menopause, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Jul 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4 (time frame: Baseline and Week 4). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00535288, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Apr 2019.

Trial summary

Key requirements

Who may be able to join

Who cannot join

About this study

What participants receive

What is being measured

Timeline

Resources

More details

Publications

Study at a glance

Clinical summary

Study design

Who may qualify

Key inclusion criteria (9 listed)

Key exclusion criteria (26 listed)

Interventions

Primary outcome

Results and safety

Participant flow

Primary outcome: Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4

Primary outcome: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4

Primary outcome: Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12

Primary outcome: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12

Adverse events

Research links

Related trials for Postmenopausal Symptoms

Referral and contact

Questions about this trial

Participant flow

Primary outcome: Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4

Primary outcome: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4

Primary outcome: Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12

Primary outcome: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12

Adverse events