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

Pediatric Research (2026)Cite this article

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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Data availability

Deidentified individual participant data, in addition to study protocols, the statistical analysis plan, and the informed consent form, will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to info@ibtherapeutics.com.

References

  1. Horbar, J. D. et al. Trends in mortality and morbidities for infants born 24 to 28 weeks in the US: 1997-2021. Pediatrics 153, e2023064153 (2024).

    Article  PubMed  Google Scholar 

  2. Bell, E. F. et al. Mortality, in-hospital morbidity, care practices, and 2-year outcomes for extremely preterm infants in the US, 2013-2018. JAMA 327, 248–263 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Embleton, N. D., Zalewski, S. & Berrington, J. E. Probiotics for prevention of necrotizing enterocolitis and sepsis in preterm infants. Curr. Opin. Infect. Dis. 29, 256–261 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Sharif, S., Meader, N., Oddie, S. J., Rojas-Reyes, M. X. & McGuire, W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst. Rev. 10, CD005496 (2023).

    PubMed  PubMed Central  Google Scholar 

  5. Sun, J. et al. Effects of probiotics on necrotizing enterocolitis, sepsis, intraventricular hemorrhage, mortality, length of hospital stay, and weight gain in very preterm infants: a meta-analysis. Adv. Nutr. 8, 749–763 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wala, S. J. et al. Contemporary Use of Prophylactic Probiotics in NICUs in the United States: A Survey Update. J. Perinatol. 44, 739–744 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  7. FDA Raises Concerns About Probiotic Products Sold for Use in Hospitalized Preterm Infants, https://www.fda.gov/news-events/press-announcements/fda-raises-concerns-about-probiotic-products-sold-use-hospitalized-preterm-infants (2023).

  8. Use of Probiotics in Preterm Infants, https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/october-2023.html#a3_1a (2023).

  9. Cordaillat-Simmons, M., Rouanet, A. & Pot, B. Live biotherapeutic products: the importance of a defined regulatory framework. Exp. Mol. Med 52, 1397–1406 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. van den Akker, C. H. P. et al. Reevaluating the FDA’s warning against the use of probiotics in preterm neonates: a societal statement by ESPGHAN and EFCNI. J. Pediatr. Gastroenterol. Nutr. 78, 1403–1408 (2024).

    Article  PubMed  Google Scholar 

  11. IBP-9414 for the Prevention of Necrotizing Enterocolitis - the Connection Study, https://clinicaltrials.gov/study/NCT03978000 (2019).

  12. Neu, J. et al. Clinical characteristics of necrotizing enterocolitis diagnosed by independent adjudication of abdominal radiographs, laparotomy, or autopsy in preterm infants in the “Connection Trial”. Am. J. Perinatol. 42, 268–280 (2025).

    Article  PubMed  Google Scholar 

  13. Neu, J. et al. Progression of enteral feeding volumes in extremely low birth weight infants in the “Connection Trial. Am. J. Perinatol. 41, e2717–e2726 (2024).

    Article  PubMed  Google Scholar 

  14. Guthrie S. O. et al. Association of clinical events to the time to a strict definition of sustained feeding tolerance in premature infants in the ´Connection Trial’. Br. J. Gastroenterol. 4, 264–272 (2022).

  15. Neu J. et al. Clinical outcomes correlating to a one-day shift in sustained feeding tolerance in very low birth weight infants in the ‘Connection Trial’. Br. J. Gastroenterol. 4, 255–260 (2022).

  16. Altman D. G. Practical Statistics for Medical Research (Chapman and Hall/CRC, 1991).

  17. Humberg, A. et al. Preterm birth and sustained inflammation: consequences for the neonate. Semin Immunopathol. 42, 451–468 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Duess, J. W. et al. Necrotizing Enterocolitis, Gut Microbes, and Sepsis. Gut Microbes, (2023).

  19. Konnikova, Y. et al. Late enteral feedings are associated with intestinal inflammation and adverse neonatal outcomes. PLoS One 10, e0132924 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Martin, C. R. et al. Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr. Pathol. 32, 222–234 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Epstein, A. A. et al. Injury to the subventricular zone stem cell niche is associated with intestinal perforation in preterm infants and predicts future motor impairment. Cell Stem Cell 4, 467–483.e6 (2024).

    Article  Google Scholar 

  22. Wang, F. S. et al. Intestinal tract and parenteral multi-organ sequential pathological injury caused by necrotizing Enterocolitis. BMC Pediatrics 20, 418 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peng, Y. et al. Lactobacillus Reuteri in digestive system diseases: focus on clinical trials and mechanisms. Front Cell Infect. Microbiol 13, 1254198 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Birthweight and Gestation, https://www.cdc.gov/nchs/fastats/birthweight.htm#:~:text=Number%20of%20babies%20born%20low,Percent%20born%20preterm:%2010.41%25 (2023).

  25. Ang, J. L., Athalye-Jape, G., Rao, S., Bulsara, M. & Patole, S. Limosilactobacillus Reuteri DSM 17938 as a probiotic in preterm infants: an updated systematic review with meta-analysis and trial sequential analysis. J. Parenter. Enter. Nutr. 47, 963–981 (2023).

    Article  Google Scholar 

  26. Alshaikh, B. N. et al. Effectiveness and Risks of Probiotics in Preterm Infants. Lid - E2024069102 [Pii] Lid - https://doi.org/10.1542/Peds.2024-069102 [Doi].

  27. IBT is granted breakthrough therapy designation for its drug candidate, https://ibtherapeutics.com/press-releases/ibt-is-granted-breakthrough-therapy-designation-for-its-drug-candidate/ (2025).

  28. Patel, R. M., Ferguson, J., McElroy, S. J., Khashu, M. & Caplan, M. S. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr. Res. 88, 10–15 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Martin, C. R. Definitions of necrotizing enterocolitis: what are we defining and is machine learning the answer? Pediatr. Res 91, 488–489 (2022).

    Article  PubMed  Google Scholar 

  30. Dantes, G. et al. Clinical predictors of spontaneous intestinal perforation vs necrotizing enterocolitis in extremely and very low birth weight neonates. J. Pediatr. Surg. 59, 161608 (2024).

    Article  PubMed  Google Scholar 

  31. Rausch, L. A., Hanna, D. N., Patel, A. & Blakely, M. L. Review of necrotizing enterocolitis and spontaneous intestinal perforation clinical presentation, treatment, and outcomes. Clin. Perinatol. 49, 955–964 (2022).

    Article  PubMed  Google Scholar 

  32. Rehan, V. K. et al. Observer variability in interpretation of abdominal radiographs of infants with suspected necrotizing Enterocolitis. Clin. Pediatr. 38, 637–643 (1999).

    Article  CAS  Google Scholar 

  33. Amin, S. C., Pappas, C., Iyengar, H. & Maheshwari, A. Short Bowel Syndrome in the NICU. Clin. Perinat. 40, 53–68 (2013).

    Article  Google Scholar 

  34. Stey, A. et al. Outcomes and costs of surgical treatments of necrotizing Enterocolitis. Pediatrics 135, e1190–e1197 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Spreckels, J. E. et al. Lactobacillus Reuteri colonisation of extremely preterm infants in a randomised placebo-controlled trial. Microorganisms 9, 915 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 Vaccine. NEJM 383, 2603–3615 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Randomised Trial of Cholesterol Lowering in 4444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 https://pubmed.ncbi.nlm.nih.gov/7968073/ (1994).

  38. Patel, R. M. et al. Causes and timing of death in extremely premature infants from 2000 through 2011. NEJM 372, 331–340 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Neu J. et al. https://ibtherapeutics.com/wp-content/uploads/2016/03/Hot-topics-poster-1128.pdf (2016).

Download references

Acknowledgements

We thank the many participating infants whose caregivers gave consent for them to be treated with the investigational product in the trial setting, and we thank all Connection Study site investigators and research support staff at the participating centers and the Pediatrix network for their valuable contributions to the study. Publication management was provided by Sanjiv Sharma, MBA, and Sofie Naumburg, MS, of Infant Bacterial Therapeutics. Cara Bertozzi, PhD, provided medical writing support for this manuscript and was funded by Infant Bacterial Therapeutics.

Funding

This trial was supported by Infant Bacterial Therapeutics. The Sponsor provided financial support for data center operations, statistical analysis, and personnel costs. They had a direct role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. University of Florida College of Medicine, Gainesville, FL, USA

    Josef Neu

  2. University of Miami, Miami, FL, USA

    Teresa Del Moral

  3. Vanderbilt University School of Medicine, Nashville, TN, USA

    Scott O. Guthrie

  4. Jackson-Madison County General Hospital, Jackson, TN, USA

    Scott O. Guthrie

  5. University of Florida College of Medicine, Jacksonville, FL, USA

    Mark L. Hudak

  6. University of Salento, Lecce, Italy

    Flavia Indrio

  7. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Jae H. Kim

  8. Infant Bacterial Therapeutics AB, Stockholm, Sweden

    Anders Kronström, Jonas Rastad, Staffan Strömberg & Marcus Thuresson

  9. Weill Cornell Medicine, New York City, NY, USA

    Camilia R. Martin

  10. Imperial College London, London, UK

    Neena Modi

  11. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Thomas J. Schnitzer

  12. Tufts University School of Medicine, Boston, MA, USA

    Rachana Singh

  13. Medical University of Warsaw, Warsaw, Poland

    Hania Szajewska

  14. Endeavor Health NorthShore Hospitals, Evanston, IL, USA

    Michael Caplan

  15. University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    Michael Caplan

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  1. Josef Neu
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Contributions

J.N. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. He was involved in the study concept and design; acquisition, analysis, or interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. TD.M., M.L.H., F.I., J.H.K., C.R.M., N.M., R.S., H.S., and M.C. were involved in the acquisition, analysis, or interpretation of data; and critical revision of the manuscript for important intellectual content. S.O was involved in the study concept and design; acquisition, analysis, or interpretation of data; and critical revision of the manuscript for important intellectual content. A.K. and J.R., T.J, and S.S. were involved in the study concept and design; acquisition, analysis, or interpretation of data; and critical revision of the manuscript for important intellectual content. M.T. was involved in the study concept and design; acquisition, analysis, or interpretation of data; critical revision of the manuscript for important intellectual content; and statistical analysis. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Josef Neu.

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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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Neu, J., Del Moral, T., Guthrie, S.O. et al. Live biotherapeutic product IBP-9414 (L. reuteri) in very low birth weight infants: the Connection Study. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-04826-7

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