Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial
Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial
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DOI：
10.1093/humrep/dey393
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发表时间：
2019-03-01
影响因子：
6.1
通讯作者：
Coomarasamy, A.
中科院分区：
文献类型：
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作者：
Eapen, A.;Joing, M.;Coomarasamy, A.
研究问题：在有不明原因反复流产史的妇女中，在妊娠早期给予重组人粒细胞集落刺激因子（rhG-CSF）是否能改善妊娠结局？概要答案在妊娠早期给予rhG-CSF并不能改善有不明原因反复妊娠丢失史的妇女的结局。已知的是什么在68名不明原因原发性反复流产妇女中进行的唯一一项关于粒细胞集落刺激因子治疗反复流产的随机对照研究发现，流产率显著降低，活产率显著提高。在文献中确定了另外四项观察性研究，其中G-CSF用于复发性流产人群，其中两项证实了临床妊娠率和活产率的统计学显著增加。安慰剂对照临床试验，涉及150名妇女的历史原因不明的复发性流产进行了21个网站，已确定的复发2014年6月23日至2016年6月5日期间在英国的流产诊所。参与者/材料，设置，方法一百五十名妇女的历史原因不明的反复妊娠丢失：76人被随机分配到rhG-CSF和74安慰剂。从妊娠3 - 5周开始，每日皮下注射重组人粒细胞集落刺激因子130 g或外观相同的安慰剂，最长持续9周。该试验使用了中心随机化和分配隐藏。主要结局是妊娠20周时的临床妊娠，如超声扫描所示。次要结局包括流产、活产、不良事件、死产、新生儿出生体重、研究药物暴露后临床实验室变量的变化、重大先天性异常、早产和抗药抗体形成的发生率。分析是由意向treat.Main结果和机会的作用共筛选了340名参与者的资格，其中150名妇女进行了随机。76名女性（中位年龄，32[IQR，29-34]岁;平均BMI，26.3[SD，4.2]）和74名女性（中位年龄，31[IQR，26-33]岁;平均BMI，25.8[SD，4.2]）随机接受安慰剂。所有女性均随访至主要结局，并超过活产。20周时的临床妊娠率以及活产率，rhG-CSF组为59.2%（45/76），安慰剂组为64.9%（48/74），相对风险为0.9（95%CI：0.7-1.2; P = 0.48）。没有证据表明两组之间的任何次要结局存在显著差异。rhG-CSF组52例（68.4%）受试者和安慰剂组43例（58.1%）受试者发生不良事件（AE）。1/46例观察到新生儿先天性畸形（2.1%）的婴儿在rhG-CSF组与1/49（2.0%），安慰剂组（RR为0.9; 95% CI：0.1-13.4; P = 0.93）。局限性，预防原因本试验在诊断为不明原因反复妊娠丢失的女性中进行，因此没有筛查试验更广泛的影响的发现据我们所知，这是第一个多中心的研究和最大的随机临床试验，以调查的有效性和安全性的粒细胞人集落刺激因子在妇女复发性流产。与唯一可用的单中心随机对照试验不同，我们的试验显示在妊娠的前三个月使用rhG-CSF没有显著增加临床妊娠或活产。研究资金/竞争兴趣本研究由诺拉治疗公司赞助和支持，530 Lytton Avenue，2nd Floor，Palo Alto，CA 94301，USA达里尔·卡特是诺拉治疗公司的联合创始人兼研究副总裁。并持有公司股份他拥有使用重组人粒细胞集落刺激因子减少不明原因的复发性流产的专利。Mark Joing、Paul Kwon和Jeff Tong曾经是或现在是诺拉治疗公司的员工。未报告与本文相关的其他潜在利益冲突。试验注册编号EUDRACT编号：2014-000084-40; ClinicalTrials.gov标识符：NCT 02156063试验注册日期2014年3月31日首例患者入组日期2014年6月23日
STUDY QUESTION Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss?SUMMARY ANSWER rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss.WHAT IS KNOWN ALREADY The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates.STUDY DESIGN, SIZE, DURATION A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK.PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 g or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat.MAIN RESULTS AND THE ROLE OF CHANCE A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93).LIMITATIONS, REASONS FOR CAUTION This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s.WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy.STUDY FUNDING/COMPETING INTEREST(S) This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported.TRIAL REGISTRATION NUMBER EUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063TRIAL REGISTRATION DATE 31 Mar 2014DATE OF FIRST PATIENT'S ENROLMENT 23 Jun 2014