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. 2026 Feb 20.
doi: 10.1038/s41390-026-04826-7. Online ahead of print.

Live biotherapeutic product IBP-9414 (L. reuteri) in very low birth weight infants: the Connection Study

Josef Neu  1 , Teresa Del Moral  2 , Scott O Guthrie  3   4 , Mark L Hudak  5 , Flavia Indrio  6 , Jae H Kim  7 , Anders Kronström  8 , Camilia R Martin  9 , Neena Modi  10 , Jonas Rastad  8 , Thomas J Schnitzer  11 , Rachana Singh  12 , Staffan Strömberg  8 , Hania Szajewska  13 , Marcus Thuresson  8 , Michael Caplan  14   15
Affiliations

Live biotherapeutic product IBP-9414 (L. reuteri) in very low birth weight infants: the Connection Study

Josef Neu et al. Pediatr Res. .

Abstract

Background: Very low birth weight (VLBW) infants experience high rates of serious intestinal health outcomes, including death. The Connection Study evaluated the efficacy and safety of the live biotherapeutic product IBP-9414 (L. reuteri) versus placebo in necrotizing enterocolitis (NEC), sustained feeding tolerance (SFT), and all-cause mortality in this population.

Methods: In this prospective, double-blind phase 3 trial, 2158 VLBW infants were randomized 1:1 to IBP-9414 or placebo within 48 hours of birth, with daily dosing until 346/7 weeks postmenstrual age. Primary endpoints were NEC incidence and time to SFT. Secondary endpoints included all-cause mortality incidence.

Results: IBP-9414 treatment compared with placebo did not result in statistically significant reductions in the primary endpoints, NEC incidence (relative risk [RR]: 0.85, p > 0.05) or time to SFT (hazard ratio: 1.10, p > 0.05). However, there was a reduction in all-cause mortality with IBP-9414 treatment, with mortality incidences of 6.2% in the IBP-9414 group versus 8.5% in the placebo group (RR: 0.73, p = 0.036). Adverse event rates were similar between the groups. There was no evidence of IBP-9414 in any blood culture.

Conclusions: IBP-9414 treatment was safe and reduced mortality compared with placebo in vulnerable VLBW infants.

Impact: The Connection Study provides evidence that the live biotherapeutic product IBP-9414 (L. reuteri) treatment was safe and reduced both mortality and surgically-confirmed necrotizing enterocolitis (NEC) in vulnerable very low birth weight (VLBW) infants. The Connection Study findings support the use of IBP-9414 in VLBW infants and its potential to safely improve their intestinal mortality and morbidity.

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Conflict of interest statement

Competing interests: Josef Neu reports funding from Infant Bacterial Therapeutics for the Principal Investigator role provided to the University of Florida, Mead Johnson for speaker bureau, personal honorarium, Abbott Laboratories for expert witness testimony, personal payment, IPOKRaTES Foundation for speaker travel costs, personal payment, Nestle Nutrition Institute and Medela for Global Scientific Advisory Board, personal payment. Teresa Del Moral reports funding from Infant Bacterial Therapeutics for the Principal Investigator role, institutional payment, and Advisory Board, personal payment. Scott O. Guthrie reports funding from ONY BioTech and Infant Bacterial Therapeutics for consultancy, personal payment, National Association of Neonatal Nurses 2024 Conference, and Academy of Neonatal Nursing 2024 Conference honoraria for speaking at the conference. Mark L. Hudak reports funding from Aerogen for a clinical trial provided to the University of Florida (completed), Infant Bacterial Therapeutics for clinical trials provided to the University of Florida (completed), NIH for clinical studies provided to the University of Florida, UpToDate for annual stipend for review of two articles, Infant Bacterial Therapeutics and Aerogen for consultancy, personal payment, NIH DIVA study for Chair of the DSMB Chair, Northeast Florida Healthy Start Coalition Voluntary participation, unfunded. Flavia Indrio reports funding from Infant Bacterial Therapeutics for consultancy, personal payment, Danone Nestle Nutrition Institute, and BioGaia for speaker fees, personal payment. Jae H. Kim reports funding from Fresenius-Kabi for an industry-sponsored research study, payment to institution, UpToDate for authorship of articles, personal payment, Infant Bacterial Therapeutics and Medela for Advisory Board, personal payment, Carag for consultant work, personal payment, Mother’s Milk is Best for clinical advisory, personal payment, Medela for workshop speaker, personal payment, Medela for Attending Human Milk Institute Symposium, personal payment, FETO Trial at Cincinnati Children’s for participation on a Data Safety Monitoring Board or Advisory Board, unpaid, NEC Society and UC Health Milk Bank Scientific Advisory Council, unpaid, Astarte Medical, Nicolette, and Innara Health personally owned stock/stock options. Anders Kronström is an employee of Infant Bacterial Therapeutics. Camilia R. Martin reports funding from Mead Johnson Nutrition, institutional payment, Baxter International and Infant Bacterial Therapeutics for consultancy, personal payment, Baxter International for speaker fees, personal payment, Winston & Strawn on behalf of Abbott Nutrition for expert testimony, personal payment, Plakous Therapeutics, LactaLogics, Vitara Biomedical, and Evive Biotech for advisory board, personal payment, NEC Society for Scientific Advisory Council, unpaid, Mead Johnson Nutrition for product support for active grant to institution. Neena Modi reports funding from Infant Bacterial Therapeutics consultancy (Advisory Board), personal payment. Jonas Rastad is an employee of Infant Bacterial Therapeutics. Thomas J. Schnitzer reports funding from Regeneron, Pfizer, Eli Lilly, Amgen, Taiwan Liposome Company, Novartis, Techfields, Paradigm, KolonTissueGene, GSK, and Vertex for grants/contracts to Northwestern University, Pfizer, Lilly, IBSA, GSK, Tremeau, Moebius Medical, Paradigm, Techfields, AstraZeneca, and Infant Bacterial Therapeutics for consulting fees, personal payment, IQVIA, AstraZeneca, Alira Health, and Horizon Therapeutics for Data Safety Monitoring Board/Advisory Board, personal payments. Rachana Singh reports funding from Infant Bacterial Therapeutics as the study sponsor, institutional payment, consulting fees, personal payment, Mead Johnson, and Abbott for expert testimony, and personal payment. Staffan Strömberg is an employee of Infant Bacterial Therapeutics. Hania Szajewska reports funding from Ausnutria for Grant/Funding, institutional payment, Winclove for financial donation to and study product support for the Medical University of Warsaw, Nestle Nutrition Institute, Nestle Health Science, and Danone/Nutricia for consultancy, personal payment, Infant Bacterial Therapeutics for consultancy (Advisory Board), personal payment, Abbott, BioGaia, Biocodex, Danone/Nutricia, Nestlé, NNI, Mead Johnson, and Novalac for speaker fees, personal payment, Nutricia Research Foundation for Advisory Board, personal payment, board member of the International Scientific Association for Probiotics and Prebiotics (ISAPP), unpaid. Marcus Thuresson is employed by Statisticon for which Infant Bacterial Therapeutics is a client. Michael Caplan reports funding from Infant Bacterial Therapeutics for the Advisory Board, personal payment. Consent statement: The Investigator or his/her representative explained the nature of the study to the legally authorized representative(s) (LAR) (parent or guardian) of the prospective infant participant, and answered all questions regarding this study, prior to obtaining informed consent. The Investigator obtained informed consent from the LAR(s) of each patient enrolled in the study, in accordance with the current version of the Good Clinical Practice guidelines and the laws and regulations of the country in which the investigation was being conducted.

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