Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants
Elise Mank, Miguel Sáenz de Pipaón, Alexandre Lapillonne, Virgilio Carnielli, Thibault Senterre, Raanan Shamir, Letty van Toledo, Johannes B. van Goudoever, FIT-04 Study Group, Johannes B. van Goudoever, Elise Mank, Letty van Toledo, Elisabeth M. W. Kooi, Arend F. Bos, Richard A. van Lingen, Astrid Giezen, Miguel Sáenz de Pipáon, Marta Cabrera Lafuente, Esperanza Escribano, Manuel Sánchez Luna, María del Carmen Sánchez Gómez de Orgaz, Felix Castillo, Manuel Cidrás, Macarena Quesada, María L. Couce, Olalla López-Suárez, Máximo Vento, María Gormáz, Alexandre Lapillonne, Agnès Giuseppi, Virginie Rigourd, Jean‐Michel Hascoët, Emily Greze, Alain Beuchée, Nadia Mazille, Virgilio Carnielli, Chiara Biagetti, Maria Paola Bellagamba, Gianluca Lista, Paola Roggero, Orsola Amato, Paolo Tagliabue, Giovanni Vento, Simonetta Costa, Massimo Agosti, Laura Morlacchi, Thibault Senterre, Anne Vervoort, Pierre Maton, Christine Vandeputte, Katleen Plaskie, Luc M.G.I. Cornette, James D’haese, Filip Cools, Michel Sonnaert, Raanan Shamir, Ruben Bromiker, Gil Klinger, Shmuel Zangen, Mara Troitzky, Kyla Marks, Eilon Shany, Arieh Riskin, Ori Hochwald, Huda Jubran, Naim Shehadeh, Strauss Tzipora, L Leah, Dror Mandel, Alon Haham, Victoria Atanasova, Lyuben G. Veskov, Donka P. Uzunova, Zornica T. Malinova, Frank Jochum, Mario Rüdiger, Katrin L. Weber, Walter Mihatsch, Rahel Schuler, Andrea Nagy, Gergely Balázs, Judit T. Kiss, Anna Gajda, Hajnalka Szabó, Éva Szabó, Tamas Tenk, Sam Oddie, Rachel Wane, Elaine M. Boyle, Marie Hubbard, Stephen P. Wardle, Dushyant Batra, Tim Scorrer, Charlotte Groves, Jörn-Hendrik Weitkamp, Theresa J. Rogers, Ryan Moore, Devon Kuehn, K Ernst
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.