Dose-Finding Safety and Efficacy Trial of Org 50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (177001/P06472/MK-8265-013)
Condition: Postmenopausal Symptoms; Menopause; Vasomotor Symptoms
Intervention: Esmirtazapine; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Mirtazapine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 946.0
Sex: Female
Minimum age: 40 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

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.

          -  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 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

               -  α-adrenergic agents

               -  β-blockers

               -  dopamine agonists/antagonists

               -  opiates, barbiturates

               -  raloxifene

               -  homeopathic menopausal preparations or other preparations intended to treat
                  climacteric or Central Nervous System (CNS) symptoms

               -  hepatic microsomal enzyme-inducing drugs or drugs known to affect or interfere
                  with the pharmacokinetics of mirtazapine;

          -  Any condition or disease that could affect or interfere with the pharmacokinetics of
             mirtazapine;

          -  Subjects sensitive to trial medication or its components;

          -  Use of any investigational drug and/or participation in another clinical trial within
             the last eight weeks prior to screening;

          -  History of alcohol and/or drug abuse within the last two years prior to screening.