Dose-Finding Safety and Efficacy Trial of Org50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (46101/P06459/MK-8265-012)
Condition: Menopause; Vasomotor Symptoms
Intervention: esmirtazapine; Placebo
Intervention MeSH terms: Mirtazapine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 943.0
Sex: Female
Minimum age: 40 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

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.

          -  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