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

NCT00535288 | Completed Phase 3 Results

• 3 other identifiers: P06472White Moonstone177001
• Study Type: interventional
• Target: 946
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Postmenopausal Symptoms; Menopause; Vasomotor Symptoms

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  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

  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

  Baseline and up to Week 12

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

  Baseline and up to Week 12

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

  Baseline and up to Week 12

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

  Baseline and up to Week 12

Study Arms (5)

Placebo

PLACEBO COMPARATOR

Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.

Drug: Placebo

Esmirtazapine 2.25 mg

EXPERIMENTAL

Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.

Drug: Esmirtazapine

Esmirtazapine 4.5 mg

EXPERIMENTAL

Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.

Drug: Esmirtazapine

Esmirtazapine 9 mg

EXPERIMENTAL

Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.

Drug: Esmirtazapine

Esmirtazapine 18 mg

EXPERIMENTAL

Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.

Drug: Esmirtazapine

Interventions

Esmirtazapine DRUG

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

Esmirtazapine 18 mg; Esmirtazapine 2.25 mg; Esmirtazapine 4.5 mg; Esmirtazapine 9 mg

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Postmenopausal women, defined as:
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• 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.

  PMID: 30712391 RESULT

MeSH Terms

Interventions

Mirtazapine

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2007
• First Posted: September 26, 2007
• Study Start: September 15, 2004
• Primary Completion: January 15, 2006
• Study Completion: January 15, 2006
• Last Updated: April 2, 2019
• Results First Posted: July 30, 2014

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will share