布雷沙诺酮注射液治疗产后抑郁症:两项多中心、双盲、随机、安慰剂对照、3期临床试验。

PubMed ID
发表日期 2018年09月

原始出处 柳叶刀(英国伦敦)
Lancet (London, England)
作者 Meltzer-Brody  Samantha  Colquhoun  Helen  Riesenberg  Robert  Epperson  C Neill  Deligiannidis  Kristina M  Rubinow  David R  Li  Haihong  Sankoh  Abdul J  Clemson  Christine  Schacterle  Amy  Jonas  Jeffrey  Kanes  Stephen 

文献标题 布雷沙诺酮注射液治疗产后抑郁症:两项多中心、双盲、随机、安慰剂对照、3期临床试验。
Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.

文献摘要 BACKGROUND

产后抑郁症是与大量的发病率,改善药物治疗选择是迫切需要的。我们评估了brexanolone注射液(原SAGE-547注射液)对中重度产后抑郁症的治疗作用,brexanolone注射液是γ-氨基丁酸a型(GABAA)受体的阳性变构调节剂。

METHODS

我们在美国的30个临床研究中心和专业精神病院进行了两项双盲、随机、安慰剂对照的3期临床试验。符合条件的妇女年龄为18-45岁,产后6个月或以下,产后抑郁症和符合条件的17项汉密尔顿抑郁量表(HAM-D)得分(研究1≥26;研究2≥20-25)。排除需要透析的肾衰竭、贫血、已知对别孕孕酮或孕酮过敏、精神分裂症、双相情感障碍或分裂情感障碍病史的妇女。在研究1中,患者被随机分配(1:1:1)接受单次静脉注射布列沙诺酮90μg/kg/h(BRX90)、布列沙诺酮60μg/kg/h(BRX60)或匹配安慰剂60小时,或在研究2中接受(1:1)布列沙诺酮90或匹配安慰剂60小时。患者、研究团队、现场工作人员和主要研究人员都被蒙在鼓里,不知道如何分配治疗。主要疗效终点是60小时时17项HAM-D总分与基线的变化,在所有开始输注研究药物或安慰剂的患者中进行评估,具有有效的HAM-D基线评估,并且至少有一项基线后HAM-D评估。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。审判已经完成,并已登记在案临床试验.gov,编号NCT02942004(研究1)和NCT02942017(研究2)。

FINDINGS

参与者于2016年8月1日至2017年10月19日期间参加研究1,于2016年7月25日至2017年10月11日期间参加研究2。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中随机分配接受BRX90(n=54)或安慰剂(n=54)。在研究1中,与安慰剂组的14.0分(1.1)相比,在60小时时,BRX60组的HAM-D总分的最小二乘(LS)平均值比基线降低19.5分(SE 1.2),BRX90组为17.7分(1.2)(差异-5.5[95%CI-8.8至-2.2],BRX60组p=0.0013;-3.7[95%CI-6.9至-0.5],BRX90组p=0·0252)。在研究2中,在60小时时,BRX90组HAM-D总分的LS平均值较基线降低14.6分(SE 0.8),安慰剂组为12.1分(SE 0.8)(差异-2.5[95%CI-4.5 to-0.5],p=0.0160)。在研究1中,BRX60组有19名患者和BRX90组有22名患者出现不良事件,而安慰剂组有22名患者出现不良事件。在研究2中,BRX90组有25名患者出现不良事件,而安慰剂组有24名患者出现不良事件。布雷沙诺酮组最常见的治疗引起的不良事件是头痛(研究1中n=7 BRX60组和n=6 BRX90组vs n=7安慰剂组;研究2中n=9 BRX90组vs n=6安慰剂组)、头晕(研究1中n=6 BRX60组和n=6 BRX90组vs n=1安慰剂组;研究2中n=5 BRX90组vs n=4安慰剂组),以及嗜睡(研究1的n=7 BRX60组和n=2 BRX90组与n=3安慰剂组;研究2的n=4 BRX90组与n=2安慰剂组)。在研究1中,BRX60组的一名患者发生了两起严重的不良事件(自杀意念和在随访期间故意服用过量药物)。在研究2中,BRX90组的一名患者有两个严重的不良事件(意识状态改变和晕厥),这被认为与治疗有关。

INTERPRETATION

与安慰剂组相比,给予布雷沙诺酮注射液治疗产后抑郁症可显著降低60小时的HAM-D总分,且在研究期间起效迅速,治疗反应持久。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妇女的治疗选择。

FUNDING

Sage Therapeutics公司。


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 γ-aminobutyric-acid type A (GABAA) 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 partum 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 μg/kg per h (BRX90), brexanolone 60 μg/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 post-partum depression that has the potential to improve treatment options for women with this disorder.

FUNDING

Sage Therapeutics, Inc.


获取全文 10.1016/S0140-6736(18)31551-4