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

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 3

Conditions: Menopause; Vasomotor Symptoms

Treatments: Drug: esmirtazapine; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT00560833

MK-8265-012 (Other Identifier)

P06459

46101 (Other Identifier)

2004-000469-36 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 943 patients

Sex: Female

Ages: 40 to 65 years old

Volunteers: No Healthy Volunteers

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.
• In case the menopausal status of a subject was unclear because of a hysterectomy, the serum FSH level had to be >40 mIU/mL. If the date of the last menstruation was not clear because of perimenopausal hormone use, then the subject had to have a serum FSH level >40 mIU/mL after completion of a washout period (see exclusion criteria below); 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

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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943 participants in 5 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo

Esmirtazapine 2.25 mg

Experimental group

Description:

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

Treatment:

Drug: esmirtazapine

Esmirtazapine 4.5 mg

Experimental group

Description:

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

Treatment:

Drug: esmirtazapine

Esmirtazapine 9 mg

Experimental group

Description:

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

Treatment:

Drug: esmirtazapine

Esmirtazapine 18 mg

Experimental group

Description:

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

Treatment:

Drug: esmirtazapine