Dose-Finding Safety and Efficacy Trial of Org50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (46101/P06459/MK-8265-012)

NCT00560833 | Completed Phase 3 Results

• 4 other identifiers: P0645946101MK-8265-0122004-000469-36
• Study Type: interventional
• Target: 943
• Locations: 0 countries
• Sites: N/A

Brief Summary

The most direct treatment of vasomotor symptions (hot flushes) may be by means of 5-HT2A receptor antagonist. Mirtazapine is a potent blocker of 5-HT2A receptors and was found to be effective in reducing the number and intensity of hot flushes in preliminary trials. Also several Selective Serotonin Reuptake Inhibitors (SSRIs) and other similar compounds have been investigated to manage hot flushes, confirming the role of the serotonergic system. In the present trial, the efficacy and safety of four different doses of esmirtazapine compared to placebo was investigated in women with moderate to severe vasomotor symptoms associated with the menopause. The primary study hypothesis was that esmirtazapine would show superior efficacy to placebo.

Conditions

Menopause; Vasomotor Symptoms

Outcome Measures

Primary Outcomes (4)

• Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4

  Participants recorded the frequency of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

  Baseline and Week 4

• Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12

  Participants recorded the frequency of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

  Baseline and Week 12

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

  Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

  Baseline and Week 4

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

  Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

  Baseline and Week 12

Secondary Outcomes (1)

• Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12

  Baseline and Week 12

Study Arms (5)

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Esmirtazapine 2.25 mg

EXPERIMENTAL

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

Drug: esmirtazapine

Esmirtazapine 4.5 mg

EXPERIMENTAL

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

Drug: esmirtazapine

Esmirtazapine 9 mg

EXPERIMENTAL

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

Drug: esmirtazapine

Esmirtazapine 18 mg

EXPERIMENTAL

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

Drug: esmirtazapine

Interventions

esmirtazapine DRUG

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

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.

You may not qualify if:

• 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.
• 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 participant's participation in the trial; abnormal clinically relevant vaginal bleeding
• high blood pressure (BP) (sitting systolic BP \>170 mmHg and/or diastolic BP \>100 mmHg)
• use of any drug product containing estrogens, progestins, androgens, or tibolone prior to screening (and up to and including randomization) within specified time frames

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

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: November 16, 2007
• First Posted: November 20, 2007
• Study Start: October 15, 2004
• Primary Completion: January 15, 2006
• Study Completion: January 15, 2006
• Last Updated: April 2, 2019
• Results First Posted: June 30, 2014

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will share