Dose-Finding Safety and Efficacy Trial of Org 50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (177001/P06472/MK-8265-013)

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.

The most direct treatment of 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 were investigated in women with moderate to severe vasomotor symptoms associated with the menopause. The primary objective of this trial was to demonstrate superior efficacy in at least one of the four doses of esmirtazapine as compared to placebo on the four following co-primary endpoints: 1) the mean change from baseline in average daily frequency of moderate and severe vasomotor symptoms at Week 4; 2) the mean change from baseline in average daily frequency of moderate and severe vasomotor symptoms at Week 12; 3) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 4; 4) the mean change from baseline in average daily severity of moderate and severe vasomotor symptoms at Week 12. The number and severity of hot flushes was recorded by means of electronic diary by the subjects.

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.