Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials
Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials
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DOI：
10.1016/s0140-6736(18)31551-4
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发表时间：
2018-09-22
期刊：
影响因子：
168.9
通讯作者：
Kanes, Stephen
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文献类型：
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作者：
Meltzer-Brody, Samantha;Colquhoun, Helen;Kanes, Stephen
背景：产后抑郁症与大量发病率相关，迫切需要改进药物治疗方案。我们评估了布雷沙诺酮注射液（以前的SAGE-547注射液），一种γ -氨基丁酸a型（GABA(a)）受体的阳性变构调节剂，用于治疗中度至重度产后抑郁症。方法：我们在美国30个临床研究中心和专业精神科进行了两项双盲、随机、安慰剂对照的3期试验。符合条件的女性年龄为18-45岁，产后筛查后6个月或更短，产后抑郁症和符合条件的17项汉密尔顿抑郁量表（HAM-D）评分（研究1 >= 26；研究2 20-25）。需要透析的肾功能衰竭、贫血、已知对异孕酮或黄体酮过敏、或有精神分裂症、双相情感障碍或分裂情感性障碍病史的妇女被排除在外。在研究1中，患者被随机分配（1:1:1）接受单次静脉注射布雷沙诺酮90 μ g/kg / h (BRX90)，布雷沙诺酮60 μ g/kg / h （BRX60）或匹配安慰剂60小时，或在研究2中（1:1）接受BRX90或匹配安慰剂60小时。患者、研究小组、现场工作人员和主要研究者对治疗分配不知情。主要疗效终点是在开始输注研究药物或安慰剂的所有患者中，进行有效的hamd基线评估，并至少进行一次基线后hamd评估，从基线到60小时17项hamd总分的变化。安全人群包括所有开始输注研究药物或安慰剂的随机患者。随访至第30天。试验已完成并在ClinicalTrials.gov注册，编号NCT02942004（研究1）和NCT02942017（研究2）。研究1的参与者于2016年8月1日至2017年10月19日，研究2的参与者于2016年7月25日至2017年10月11日。我们在两项研究中同时筛选了375名女性，其中138名在研究1中被随机分配接受BRX90 （n=45）、BRX60 （n=47）或安慰剂（n=46）， 108名在研究2中被随机分配接受BRX90 （n=54）或安慰剂（n=54）。在研究1中，60小时时，BRX60组HAM-D总分较基线的最小二乘（LS）平均下降为19.5分（SE 1.2）， BRX90组为17.7分（1.2），而安慰剂组为14.0分（1.1）（BRX60组差异为-5.5 [95% CI -8.8至-2.2],p=0.0013； BRX90组差异为-3.7 [95% CI -6.9至-0.5],p=0.0252）。在研究2中，60 h时，BRX90组HAM-D总分较基线的LS平均下降14.6分（SE 0.8），而安慰剂组为12.1分（SE 0.8）（差异为-2.5 [95% CI -4.5至-0.5],p=0.0160）。在研究1中，BRX60组的19例患者和BRX90组的22例患者出现了不良事件，而安慰剂组的22例患者出现了不良事件。在研究2中，BRX90组有25例患者出现不良事件，而安慰剂组有24例患者出现不良事件。brexanolone组最常见的治疗诱发不良事件是头痛(n = 7 BRX60组,n = 6 BRX90组和安慰剂组(n = 7研究1,n = 9 BRX90组和安慰剂组n = 6研究2)、头晕(n = 6 BRX60组,n = 6 BRX90组和安慰剂组(n = 1研究1,n = 5 BRX90组和安慰剂组(n = 4研究2),和嗜睡(n = 7 BRX60组和n = 2 BRX90组和安慰剂组(n = 3研究1,n = 4 BRX90组和安慰剂组(n = 2为研究2)。在研究1中，BRX60组中有1例患者在随访期间出现两次严重不良事件（自杀意念和故意过量企图）。在研究2中，BRX90组中有1例患者出现两种严重不良事件（意识状态改变和晕厥），被认为与治疗有关。与安慰剂相比，给予布雷沙诺酮注射液治疗产后抑郁症可在60 h时显著降低HAM-D总分，且在研究期间具有快速起效和持久的治疗反应。我们的研究结果表明，布雷沙诺酮注射液是一种治疗产后抑郁症的新型药物，有可能改善这种疾病的治疗选择。
Background Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of gamma-aminobutyric-acid type A (GABA(A)) receptors, for the treatment of moderate to severe post-partum depression.Methods We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post part-um or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (>= 26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 mu g/kg per h (BRX90), brexanolone 60 mu g/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2).Findings Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19.5 points (SE 1.2) in the BRX60 group and 17.7 points (1.2) in the BRX90 group compared with 14.0 points (1.1) in the placebo group (difference -5.5 [95% CI -8.8 to -2.2], p=0.0013 for the BRX60 group; -3.7 [95% CI -6.9 to -0.5], p=0.0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14.6 points (SE 0.8) in the BRX90 group compared with 12.1 points (SE 0.8) for the placebo group (difference -2.5 [95% CI -4.5 to -0.5], p=0.0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related.Interpretation Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for postpartum depression that has the potential to improve treatment options for women with this disorder.