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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 943
- 主要终点
- Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 40 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Placebo
Participants receive placebo, encapsulated tablets, orally (PO), once daily (QD) for up to 12 weeks
干预措施: Placebo (Drug)
Esmirtazapine 2.25 mg
Participants receive esmirtazapine 2.25 mg, encapsulated tablets, PO, QD for up to 12 weeks
干预措施: esmirtazapine (Drug)
Esmirtazapine 4.5 mg
Participants receive esmirtazapine 4.5 mg, encapsulated tablets, PO, QD for up to 12 weeks
干预措施: esmirtazapine (Drug)
Esmirtazapine 9 mg
Participants receive esmirtazapine 9 mg, encapsulated tablets, PO, QD for up to 12 weeks
干预措施: esmirtazapine (Drug)
Esmirtazapine 18 mg
Participants receive esmirtazapine 18 mg, encapsulated tablets, PO, QD for up to 12 weeks
干预措施: esmirtazapine (Drug)
结局指标
主要结局
Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 4
时间窗: Baseline and Week 4
Participants recorded the frequency of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Change From Baseline in Average Daily Frequency of Vasomotor Symptoms (Frequency Score A) at Week 12
时间窗: Baseline and Week 12
Participants recorded the frequency of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4
时间窗: Baseline and Week 4
Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12
时间窗: Baseline and Week 12
Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.
次要结局
- Change From Baseline in Vasomotor Symptoms Score Per Women's Health Questionnaire (WHQ) at Week 12(Baseline and Week 12)