SEPSIS: L. Plantarum Trial
Condition: Microbial Colonization; Tolerance; Safety Issues; Infant ALL
MeSH terms: Communicable Diseases; Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      Sepsis is a life-threatening clinical syndrome and a leading cause of neonatal deaths
      worldwide. The burden of neonatal sepsis and severe infection (SI) is particularly high in
      areas of South Asia and other resource-limited settings. The goal of the Synbiotics for the
      Early Prevention of Severe Infections in Infants (SEPSIS) phase II L. plantarum trial is to
      generate knowledge on the safety, tolerability and effects on the microbiome of
      Lactiplantibacillus plantarum, with or without fructooligosaccharide, in infants (birth to 60
      days of age) in Dhaka, Bangladesh. All data generated will support the design and
      implementation of a phase III trial to test the efficacy of the probiotic/synbiotic or other
      interventions for the prevention of SI, promotion of optimal growth and development, and
      effects on other health outcomes in early infancy.
    

Detailed description: 
      As a leading cause of neonatal morbidity and mortality, sepsis poses a common and serious
      threat for neonates. In 2017, sepsis, meningitis, and pneumonia accounted for an estimated
      540,000 newborn deaths worldwide, or approximately one-fifth of the world's annual neonatal
      deaths. Previous studies have suggested that South Asia has a relatively high incidence of
      possible serious bacterial infection (pSBI) in young infants, particularly in areas where
      neonatal and under-five mortality rates are highest.

      Recent randomized controlled trials (RCTs), including the Panigrahi et al. community-based
      trial in India, have demonstrated beneficial effects of probiotics and/or prebiotics,
      compared to placebo, for preventing infections in preterm and/or LBW infants. This is
      particularly important in low- and middle-income countries in Africa and South Asia, where
      low-cost preventative interventions to reduce the burden of SI (e.g., probiotics or
      synbiotics) could have an important impact on the burden of morbidity and mortality in young
      infants. However, there are limited data regarding the safety, tolerability and efficacy of
      L. plantarum ATCC 202195 in the general population of infants (rather than selected groups of
      preterm or hospitalized newborns) in South Asia.

      This phase II trial will generate new evidence about the safety, tolerability and
      colonization effects of L. plantarum ATCC 2020195 in young infants (birth to 60 days of age)
      in Dhaka, Bangladesh. The aims of this study are to:

        1. Estimate the effect of neonatal oral administration of Lactiplantibacillus plantarum (L.
           plantarum) ATCC 202195 (10^9 CFU/day) with or without fructooligosaccharide (FOS),
           versus placebo, on the absolute and relative stool abundance of L. plantarum ATCC 202195
           from 14 to 60 days of age. Primary analyses will examine the effect of a 7-day regimen
           of L. plantarum ATCC 202195 with FOS (LP7+FOS), and secondary analyses will examine a
           7-day regimen of L. plantarum ATCC 202195 without FOS (LP7), a 1-day regimen of L.
           plantarum ATCC 202195 with FOS (LP1+FOS), or a 1-day regimen of L. plantarum ATCC 202195
           without FOS (LP1).

        2. Determine if the absolute and relative stool abundance of L. plantarum ATCC 202195 from
           14 to 60 days of age in Bangladeshi infants following LP1+FOS is not lower than the
           abundance achieved with LP7+FOS. Secondary analyses will assess the non-inferiority of
           the 1- and 7-day LP regimens without FOS (LP1 or LP7, respectively) compared to LP7+FOS.

        3. Describe and compare the incidence and patterns of sustained and transient L. plantarum
           ATCC 202195 colonization (based on absolute and relative stool abundance) up to 6 months
           of age following administration of LP7+FOS, LP7, LP1+FOS or LP1, versus placebo, in
           Bangladeshi infants.

        4. Assess the safety of LP7+FOS, LP7, LP1+FOS or LP1, versus placebo, during the first 60
           days of age based on a) incidence of severe infection (SI) episodes associated with
           Lactobacillus spp.; b) incidence of detectable L. plantarum ATCC 202195 DNA in blood; c)
           adverse alterations in one or more biochemical or hematological parameters; and d)
           clinical serious adverse events.

        5. Estimate the effects of LP7+FOS, LP7, LP1+FOS or LP1, versus placebo, on stool pH and
           concentrations of stool inflammatory markers during the first 60 days of life.

        6. Assess the tolerability of LP7+FOS, LP7, LP1+FOS or LP1, versus placebo, following
           ingestion of the investigational product and during the period of administration (up to
           21 days of age), based on frequencies and/or durations of crying time, fussiness,
           abdominal distention, vomiting and diarrhea.

        7. Evaluate the effect of LP7+FOS, LP7, LP1+FOS or LP1, versus placebo, on stool iron
           content and antioxidant capacity (14 days of age) and iron status in infants (60 days of
           age).

        8. Estimate effects of LP7+FOS, LP7, LP1+FOS and LP1, versus placebo, on infant linear
           growth, ponderal growth and head circumference up to 6 months of age.

        9. Explore the effects of LP7+FOS, LP7, LP1+FOS or LP1, versus placebo, on the microbial
           community structure and diversity and metabolome of the infant's microbiota during the
           first 60 days of life and at 3 and 6 months of life.

       10. Compare the absolute and relative stool abundance of L. plantarum ATCC 202195 in mothers
           and siblings of infants administered LP7+FOS, LP7, LP1+FOS, LP1, versus placebo, up to
           60 days of age in the infant.

       11. Assess the possible modes of cross-contamination by L. plantarum ATCC 202195 in two
           public hospitals, field offices, laboratories and in households within the trial
           catchment area in Dhaka, Bangladesh.

      Study personnel will conduct active and passive clinical surveillance and routine specimen
      collection (e.g. stool, nasal, blood etc.). Additional specimen collection may also be
      triggered in the event of physician-confirmed clinical severe infection, or if infants meet
      the case definition of LRTI (fast breathing with at least one of the following: cough, nasal
      congestion, or runny nose) or are hospitalized with diarrhea and/or vomiting.
    

Intervention name(s): Synbiotic; Probiotic; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement; Other
Intervention description(s): Lactiplantibacillus plantarum ATCC 202195 with fructooligosaccharide; Lactiplantibacillus plantarum ATCC 202195; Maltodextrin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, placebo-controlled, parallel-design multi-arm trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Probiotic; Synbiotic; Young infants; Bangladesh