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

NCT ID: NCT00560833

Last Updated: 2019-04-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 943 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-10-15
• Study Completion Date: 2006-01-15

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Esmirtazapine 2.25 mg

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

Group Type: EXPERIMENTAL

esmirtazapine

Intervention Type: DRUG

Esmirtazapine 4.5 mg

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

Group Type: EXPERIMENTAL

esmirtazapine

Intervention Type: DRUG

Esmirtazapine 9 mg

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

Group Type: EXPERIMENTAL

esmirtazapine

Intervention Type: DRUG

Esmirtazapine 18 mg

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

Group Type: EXPERIMENTAL

esmirtazapine

Intervention Type: DRUG

Interventions

esmirtazapine

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

Esmirtazapine maleate; SCH 900265; Org 50081

Eligibility Criteria

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.

Exclusion Criteria

• 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
• any clinically relevant (opinion of investigator) abnormal finding during physical, gynecological and breast examination at screening; abnormal, clinically significant results of mammography. Mammography had to have been performed within the last 9 months prior to screening, otherwise it had to be done before inclusion into the trial. For non-US sites, if local laws or guidelines did not allow or advise such frequent mammograms, the documented local laws or guidelines were to be followed; 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). A cervical smear had to have been performed within the last 9 months prior to screening, otherwise it had to be done before inclusion into the trial; hematological or biochemical values at screening outside the reference ranges considered clinically relevant in the opinion of the investigator
• 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

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

References

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.

Reference Type: RESULT

PMID: 30712391 (View on PubMed)

Study Documents

Document Type: CSR Synopsis

View Document

Other Identifiers

46101

Identifier Type: OTHER

Identifier Source: secondary_id

MK-8265-012

Identifier Type: OTHER

Identifier Source: secondary_id

2004-000469-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P06459

Identifier Type: -

Identifier Source: org_study_id