Department of Pediatrics-Neonatology, Amsterdam UMC, University of Amsterdam, Vrije Universiteit Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.
Department of Pediatrics-Neonatology, La Paz University Hospital, Autonoma University of Madrid, Madrid, Spain.
JAMA Pediatr. 2022 May 1;176(5):452-460. doi: 10.1001/jamapediatrics.2022.0020.
Feeding intolerance is a common condition among preterm infants owing to immaturity of the gastrointestinal tract. Enteral insulin appears to promote intestinal maturation. The insulin concentration in human milk declines rapidly post partum and insulin is absent in formula; therefore, recombinant human (rh) insulin for enteral administration as a supplement to human milk and formula may reduce feeding intolerance in preterm infants.
To assess the efficacy and safety of 2 different dosages of rh insulin as a supplement to both human milk and preterm formula.
DESIGN, SETTING, AND PARTICIPANTS: The FIT-04 multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the US. Preterm infants with a gestational age (GA) of 26 to 32 weeks and a birth weight of 500 g or more were enrolled between October 9, 2016, and April 25, 2018. Data were analyzed in January 2020.
Preterm infants were randomly assigned to receive low-dose rh insulin (400-μIU/mL milk), high-dose rh insulin (2000-μIU/mL milk), or placebo for 28 days.
The primary outcome was time to achieve full enteral feeding (FEF) defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days.
The final intention-to-treat analysis included 303 preterm infants (low-dose group: median [IQR] GA, 29.1 [28.1-30.4] weeks; 65 boys [59%]; median [IQR] birth weight, 1200 [976-1425] g; high-dose group: median [IQR] GA, 29.0 [27.7-30.5] weeks; 52 boys [55%]; median [IQR] birth weight, 1250 [1020-1445] g; placebo group: median [IQR] GA, 28.8 [27.6-30.4] weeks; 54 boys [55%]; median [IQR] birth weight, 1208 [1021-1430] g). The data safety monitoring board advised to discontinue the study early based on interim futility analysis (including the first 225 randomized infants), as the conditional power did not reach the prespecified threshold of 35% for both rh-insulin dosages. The study continued while the data safety monitoring board analyzed and discussed the data. In the final intention-to-treat analysis, the median (IQR) time to achieve FEF was significantly reduced in 94 infants receiving low-dose rh insulin (10.0 [7.0-21.8] days; P = .03) and in 82 infants receiving high-dose rh insulin (10.0 [6.0-15.0] days; P = .001) compared with 85 infants receiving placebo (14.0 [8.0-28.0] days). Compared with placebo, the difference in median (95% CI) time to FEF was 4.0 (1.0-8.0) days for the low-dose group and 4.0 (1.0-7.0) days for the high-dose group. Weight gain rates did not differ significantly between groups. Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 7 of 108 infants (6%) in the low-dose group, 4 of 88 infants (5%) in the high-dose group, and 10 of 97 infants (10%) in the placebo group. None of the infants developed serum insulin antibodies.
Results of this randomized clinical trial revealed that enteral administration of 2 different rh-insulin dosages was safe and compared with placebo, significantly reduced time to FEF in preterm infants with a GA of 26 to 32 weeks. These findings support the use of rh insulin as a supplement to human milk and preterm formula.
ClinicalTrials.gov Identifier: NCT02510560.
由于胃肠道不成熟，喂养不耐受是早产儿常见的一种情况。肠内胰岛素似乎可以促进肠道成熟。人乳中的胰岛素浓度在产后迅速下降，配方奶中不含胰岛素；因此，重组人（rh）胰岛素作为人乳和配方奶的补充剂，可能会减少早产儿的喂养不耐受。
评估 2 种不同剂量 rh 胰岛素作为人乳和早产儿配方奶补充剂的疗效和安全性。
设计、地点和参与者：这项 FIT-04 多中心、双盲、安慰剂对照随机临床试验在欧洲、以色列和美国的 46 个新生儿重症监护病房进行。纳入胎龄（GA）为 26 至 32 周、出生体重为 500 克或以上的早产儿。数据于 2020 年 1 月进行分析。
早产儿被随机分配接受低剂量 rh 胰岛素（400 μIU/mL 奶）、高剂量 rh 胰岛素（2000 μIU/mL 奶）或安慰剂治疗 28 天。
主要结局是达到完全经口喂养（FEF）的时间，定义为连续 3 天每天经口摄入 150 mL/kg 或更多。
最终的意向治疗分析包括 303 名早产儿（低剂量组：中位数[IQR]GA，29.1[28.1-30.4]周；65 名男孩[59%]；中位数[IQR]出生体重，1200[976-1425]g；高剂量组：中位数[IQR]GA，29.0[27.7-30.5]周；52 名男孩[55%]；中位数[IQR]出生体重，1250[1020-1445]g；安慰剂组：中位数[IQR]GA，28.8[27.6-30.4]周；54 名男孩[55%]；中位数[IQR]出生体重，1208[1021-1430]g）。数据安全监测委员会根据中期无效性分析（包括前 225 名随机婴儿）建议提前停止研究，因为这两种 rh 胰岛素剂量的条件效力未达到预设的 35%阈值。研究继续进行，同时数据安全监测委员会分析和讨论数据。在最终的意向治疗分析中，接受低剂量 rh 胰岛素治疗的 94 名婴儿（10.0[7.0-21.8]天；P =.03）和接受高剂量 rh 胰岛素治疗的 82 名婴儿（10.0[6.0-15.0]天；P =.001）达到 FEF 的时间明显缩短，而接受安慰剂治疗的 85 名婴儿（14.0[8.0-28.0]天）。与安慰剂相比，低剂量组和高剂量组达到 FEF 的中位（95%CI）时间差异分别为 4.0（1.0-8.0）天和 4.0（1.0-7.0）天。两组间的体重增加率无显著差异。低剂量组有 7 名（6%）婴儿发生坏死性小肠结肠炎（Bell 分期 2 或 3 期），高剂量组有 4 名（5%）婴儿，安慰剂组有 10 名（10%）婴儿。没有婴儿产生血清胰岛素抗体。
这项随机临床试验的结果表明，肠内给予 2 种不同剂量的 rh 胰岛素是安全的，与安慰剂相比，可显著缩短 26 至 32 周胎龄早产儿达到 FEF 的时间。这些发现支持 rh 胰岛素作为人乳和早产儿配方奶的补充剂。
ClinicalTrials.gov 标识符：NCT02510560。
