Recombinant Bile Salt-Stimulated Lipase in Preterm Infant Feeding: A Randomized Phase 3 Study

Abstract

Introduction: Feeding strategies are critical for healthy growth in preterm infants. Bile salt-stimulated lipase (BSSL), present in human milk, is important for fat digestion and absorption but is inactivated during pasteurization and absent in formula. This study evaluated if recombinant human BSSL (rhBSSL) improves growth in preterm infants when added to formula or pasteurized breast milk.

Patients and methods: LAIF (Lipase Added to Infant Feeding) was a randomized, double-blind, placebo-controlled phase 3 study in infants born before 32 weeks of gestation. The primary efficacy variable was growth velocity (g/kg/day) during 4 weeks intervention. Follow-up visits were at 3 and 12 months. The study was performed at 54 centers in 10 European countries.

Results: In total 415 patients were randomized (rhBSSL n = 207, placebo n = 208), 410 patients were analyzed (rhBSSL n = 206, placebo n = 204) and 365 patients were followed until 12 months. Overall, there was no significantly improved growth velocity during rhBSSL treatment compared to placebo (16.77 vs. 16.56 g/kg/day, estimated difference 0.21 g/kg/day, 95% CI [-0.40; 0.83]), nor were secondary endpoints met. However, in a predefined subgroup, small for gestational age infants, there was a significant effect on growth in favor of rhBSSL during treatment. The incidence of adverse events was higher in the rhBSSL group during treatment.

Conclusions: Although this study did not meet its primary endpoint, except in a subgroup of infants small for gestational age, and there was an imbalance in short-term safety, these data provide insights in nutrition, growth and development in preterm infants.

Trial registration: ClinicalTrials.gov NCT01413581.

Conflict of interest statement

Competing Interests: MV, IP and KT are employed by Sobi and holders of company shares. OH had an annual honorarium from Sobi. CC, JMH, VC and AL have acted as consultants to Sobi. The other authors have indicated that they have no competing interest relevant to this manuscript to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT flow diagram of randomized patients.

AE; adverse event.

Fig 2. Clinical study design and number of patients.

A) The LAIF study design. The asterisk indicates a visit specific for ADA positive infants at 3 months. B) Number of randomized patients.

Fig 3. Treatment with rhBSSL does not improve growth in preterm infants.

A) Growth velocity during intervention (rhBSSL; N = 206, placebo; N = 204). CI; confidence interval, LS mean; least square mean. B) Body weight at baseline, 4 weeks, 3 months, and 12 months adjusted age. Box plot illustrating median and Q1/Q3. Whiskers extend to lowest/highest value within 1.5 interquartile range from Q1/Q3 and outliers are indicated. C) Body length and head circumference; change from baseline at 4 weeks. D) Growth restriction during intervention.

Fig 4. Treatment with rhBSSL improves growth in SGA infants during the 4 week treatment period.

A) Growth velocity during intervention for SGA/AGA-infants. Asterisk indicates significance for SGA infants; LS mean difference (rhBSSL-placebo) of 1.95 (95% CI; 0.38, 3.52) and no significance for AGA infants; LS mean difference of -0.10 (95% CI; (-0.76, 0.57). B) Infants with a growth