Neonatal administration of Lactiplantibacillus plantarum ATCC 202195 with or without fructooligosaccharide in Bangladesh: a placebo-controlled randomized trial

Abstract

Lactiplantibacillus plantarum ATCC 202195 (LP202195) plus fructooligosaccharide (FOS) for 7 days was previously shown to colonize the infant intestine up to 6 months of age and reduced sepsis rates among young infants in rural India. In a phase 2 randomized controlled trial in Dhaka, Bangladesh (N = 519), neonatal administration of LP202195 for 1 or 7 days, with or without FOS, increased LP202195 stool abundance from 14 to 60 days of age, versus placebo. Abundance progressively declined in the post-administration period and did not persist beyond 2 months of age. FOS did not affect LP202195 abundance or its duration of persistence. All regimens were well-tolerated and safe. The absence of LP202195 colonization was inconsistent with results from a prior trial. Additional large-scale trials of LP202195 ± FOS are needed to establish its efficacy in infants who do not become LP202195-colonized.

Importance: Among infants born in Dhaka, Bangladesh, a 7-day regimen of Lactiplantibacillus plantarum ATCC 202195 (LP202195) plus fructooligosaccharide (FOS) did not colonize the infant gastrointestinal (GI) tract. The absence of colonization is inconsistent with a prior study of the same synbiotic regimen in India, in which LP202195 was shown to persist in the infant GI tract for up to 6 months. Sustained LP202195 colonization was thought to be required for the probiotic to impart its beneficial impact on newborn sepsis. Therefore, additional trials are warranted to confirm the previously observed effects of LP202195 on infant clinical outcomes in the absence of LP202195 colonization. Moreover, since regimens of LP202195 that did not include FOS were indistinguishable from the synbiotic in terms of colonization, safety, and tolerability, future trials should assess the role of FOS for clinical efficacy; removing FOS would reduce costs, an important consideration for scale-up.

Clinical trials: This study has been registered at ClinicalTrials.gov as NCT05180201.

Keywords: colonization; developing countries; lactobacilli; neonate; probiotic; randomized controlled trial; safety; severe infection; synbiotic; tolerability.

Fig 1

Trial CONSORT flow diagram. ^aExclusions due to the administration or prescription of parenteral antibiotics or due to neonates not orally feeding were based on criteria documented at the last available screening visit, irrespective of the infant’s age when they were last screened. ^bAll infants who received zero doses of investigational product also had zero post-intervention stool samples collected between days 14 and 60, inclusive, and thus were not included in the safety and tolerability analyses or in the primary outcome analysis.

Fig 2

L. plantarum ATCC 202195 (LP202195), when administered to neonates in Dhaka, Bangladesh, for 1 or 7 days, with or without FOS, does not result in LP202195 colonization. (A) Longitudinal trajectories of LP202195 AA (cells/µg DNA) modeled as a function of days since first IP dose, up to 180 days since first dose, and (B) zooming in on the trajectories within the first 28 days since first IP dose. (C) Differences in AA of LP202195 (log₁₀ cells/µg DNA) across intervention groups, relative to the placebo group, are shown at discrete time points between 8 and 60 days since first IP dose. The vertical dashed blue line at 32 days since first dose indicates the time point at which the AA in the LP1 group was no longer significantly different from the AA in the placebo group. The vertical dashed red line at 60 days since first dose indicates the time point at which the AAs LP1 + FOS, LP7, and LP7 + FOS groups were no longer significantly different from the AA in the placebo group. (D) Predicted probabilities of high versus low AA of LP202195, by days since first dose. In each panel, the placebo group is shown with a black solid line, the LP1 group with the light blue solid line, the LP1 + FOS group with a dashed light blue line, the LP7 group with a solid red line, and the LP7 + FOS group with a dashed red line.