Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials

Objectives: Two identical 12-week, randomized, double-blind, placebo-controlled, multi-arm, parallel-group Phase III studies (Study P012, NCT00560833; Study P013, NCT00535288) evaluated the efficacy and safety of esmirtazapine, an investigational medicine, for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women. Methods: Participants were randomized to placebo or esmirtazapine (2.25, 4.5, 9.0, or 18.0 mg). Co-primary efficacy endpoints (daily frequency and severity of moderate to severe VMS, both at weeks 4 and 12) were based on participative LogPad daily diaries. Adverse events (AEs) were recorded. Results: In Studies P012 and P013, 942 and 946 participants were randomized, respectively. Compared with placebo, esmirtazapine significantly reduced the mean daily frequency by 1.4–2.2 moderate to severe VMS at weeks 4 and 12 (both ≥4.5 mg) and mean daily severity by 0.06–0.08 symptoms at weeks 4 (≥4.5 mg) and 12 (9.0 mg P012; 18.0 mg P013 only). Esmirtazapine was generally well tolerated with a more favorable safety profile at lower doses. Somnolence and fatigue were the most frequently reported AEs. Conclusions: Esmirtazapine reduced the frequency and severity of moderate to severe VMS associated with menopause and was generally well tolerated in the study population.研究目的：两项完全一致的12周随机双盲安慰剂对照多臂平行组III期临床试验（研究P012，临床试验编号NCT00560833；研究P013，临床试验编号NCT00535288），评估试验药物艾司米塔齐平（esmirtazapine）治疗绝经后女性中度至重度血管舒缩症状（Vasomotor Symptoms, VMS）的有效性与安全性。 研究方法：受试者被随机分配至安慰剂组或艾司米塔齐平（2.25、4.5、9.0或18.0 mg）给药组。共同主要有效性终点为中度至重度血管舒缩症状的每日发作频率与严重程度，分别在第4周和第12周进行评估，数据来源于受试者自行填写的LogPad每日日记。同时记录不良事件（Adverse Events, AEs）。 研究结果：在P012和P013两项研究中，分别有942名和946名受试者完成随机入组。与安慰剂组相比，艾司米塔齐平（剂量≥4.5 mg）可在第4周和第12周时使中度至重度血管舒缩症状的日均发作频率显著降低1.4~2.2次；在第4周（剂量≥4.5 mg）及第12周（P012研究为9.0 mg剂量组，P013研究仅18.0 mg剂量组）可使日均症状严重程度显著降低0.06~0.08个评分单位。艾司米塔齐平总体耐受性良好，较低剂量下的安全性特征更优。嗜睡与疲劳是最常报告的不良事件。 研究结论：艾司米塔齐平可减轻绝经相关中度至重度血管舒缩症状的发作频率与严重程度，且在本研究人群中总体耐受性良好。