Clinical trial NCT00560833: Dose-Finding Safety and Efficacy Trial of Org50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (46101/P06459/MK-8265-012)
Official title: A Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Four Different Doses of Org 50081 in the Treatment of Moderate to Severe Vasomotor Symptoms Associated With the Menopause
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Menopause
Vasomotor Symptoms
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2007-11-20
Enrollment: 943
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4
timeFrame: Baseline and Week 4
measure: Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12
timeFrame: Baseline and Week 12
measure: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4
timeFrame: Baseline and Week 4
measure: Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12
timeFrame: Baseline and Week 12
Other outcomes:
Locations:
Study officials:
References:
citation: 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.