Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants: A Randomized Clinical Trial

Abstract

Importance: 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.

Objective: 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.

Interventions: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT02510560.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Mank, Sáenz de Pipaón, Lapillonne, Senterre, van Toledo, and van Goudoever reported receiving grants from Nutrinia Ltd during the conduct of the study. Dr Sáenz de Pipaón reported receiving lecture fees and travel reimbursements from Nutrinia Ltd during the conduct of the study. Dr Senterre reported being employed with Baxter Healthcare Corporation after the study completion. Dr Shamir reported owning stock options from and serving as a medical consultant for Nutrinia Ltd during the conduct of the study. Dr van Goudoever reported being founder and director of the Dutch National Human Milk Bank; being a member of the National Health Council; and serving as chair of the Committee on Nutrition and Pregnancy. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram

Abbreviation: rh, recombinant human.

Figure 2.. Kaplan-Meier Curve of the Primary Outcome (Intention to Treat)

The primary outcome was the time to achieve full enteral feeding (FEF), which was defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days.