SEPSIS: L. Plantarum Trial

NCT05180201 | Completed Phase 2 DMC

• 1 other identifier: 1000072200
• Study Type: interventional
• Target: 519
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Microbial Colonization; Tolerance; Safety Issues; Infant ALL

Keywords

Probiotic; Synbiotic; Young infants; Bangladesh

Outcome Measures

Primary Outcomes (6)

• Average absolute abundance of L. plantarum ATCC 202195 in stool, measured as cells/g faces or cells/ng DNA

  Absolute abundance (AA) of L. plantarum ATCC 202195 (LP202195) in stool samples refers to the log number of cells of LP202195 per mass of total extracted DNA and/or mass of stool as measured by qPCR. AA will be defined as the stool abundance of LP202195 from day 14 to 60 of age, based on up to 5 post-intervention period stool samples. However, additional analyses will involve variations on the outcome definition based on a) the age at which samples were collected and, b) timing of collection in relation to the intervention period.

  Up to 60 days of age

• Average relative abundance of L. plantarum ATCC 202195 in stool, measured as a ratio

  Relative abundance (RA) refers to the proportion of LP202195 relative to the total bacterial load, where total bacterial load is determined by the absolute quantification of 16S rRNA gene copies as measured by qPCR. RA will be defined as the stool abundance of LP202195 from day 14 to 60 of age, based on up to 5 post-intervention period stool samples. However, additional analyses will involve variations on the outcome definition based on a) the age at which samples were collected and, b) timing of collection in relation to the intervention period.

  Up to 60 days of age

• Other microbial efficacy outcomes: L. plantarum ATCC 202195 Colonization

  Colonization is a dichotomous variable (colonized or not) defined as a stool AA of L. plantarum ATCC 202195 that exceeds a specified threshold. Empirical distributions across all groups will be used to derive plausible thresholds of colonization based on qPCR.

  Up to 60 days of age

• Other microbial efficacy outcomes: Time to L. plantarum ATCC 202195 colonization

  Time to colonization is defined as the earliest age (in days) at which an infant's stool had an AA value that exceeded the threshold for colonization based on qPCR.

  Up to 60 days of age

• Other microbial efficacy outcomes: Stool inflammatory markers

  Stool inflammatory markers include stool concentrations of calprotectin (µg/g) and myeloperoxidase (ng/ml) derived from standard curves based on ELISAs.

  Up to 60 days of age

• Other microbial efficacy outcomes: Stool pH

  Stool pH will be expressed as a continuous outcome and categorized as low if stool pH \<4.5.

  Up to 60 days of age

Secondary Outcomes (43)

• Cumulative incidence of episodes of culture-confirmed lactobacillus spp. related severe infection (Primary clinical safety outcome)

  Up to 60 days of age

• Cumulative incidence of episodes of detectable L. plantarum ATCC 202195 bacteremia (ancillary safety measure, IF FEASIBLE)

  Up to 60 days of age

• Frequency of hemoglobin (g/L or g/dL) below reference limit

  Up to 60 days of age

• Frequency of white blood cell count (10^9 cells/L) above or below reference limit

  Up to 60 days of age

• Frequency of platelet count (10^9 cells/L) above or below reference limit

  Up to 60 days of age

Study Arms (5)

LP7+FOS

EXPERIMENTAL

Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) with 150mg fructooligosaccharide (FOS) and 100mg maltodextrin, for 7 days.

Dietary Supplement: Synbiotic

LP7

EXPERIMENTAL

Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) plus 250mg maltodextrin, for 7 days.

Dietary Supplement: Probiotic

LP1+FOS

EXPERIMENTAL

Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) with 150mg FOS and 100mg maltodextrin, for one day, followed by 6 days of placebo (250mg maltodextrin).

Dietary Supplement: Synbiotic; Other: Placebo

LP1

EXPERIMENTAL

Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) plus 250mg maltodextrin for one day, followed by 6 days of placebo (250 mg maltodextrin).

Dietary Supplement: Probiotic; Other: Placebo

Placebo

PLACEBO COMPARATOR

Once daily oral administration of placebo (250 mg maltodextrin), for 7 days.

Other: Placebo

Interventions

Synbiotic DIETARY_SUPPLEMENT

Lactiplantibacillus plantarum ATCC 202195 with fructooligosaccharide

LP1+FOS; LP7+FOS

Probiotic DIETARY_SUPPLEMENT

Lactiplantibacillus plantarum ATCC 202195

LP1; LP7

Placebo OTHER

Maltodextrin

LP1; LP1+FOS; Placebo

Eligibility Criteria

• Age: 0 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Infants up to and including four days of age\*
• Infant delivered at a study hospital
• Orally feeding currently\*\*
• Informed consent by parent or guardian
• Intends to maintain residence within the defined catchment areas (upon discharge from hospital) until 60 days of age.

You may not qualify if:

• Birthweight \< 1500 grams\*\*\*
• Death or major surgery considered to be highly probable within first week of life\*\*\*\*
• Major congenital anomaly of the gastrointestinal tract
• Maternal HIV infection and/or history of mother ever receiving anti-retroviral drug(s) for presumed HIV infection\*\*\*\*\*
• Current mechanical ventilation and/or cardiac support (e.g., inotropes) and/or administration/prescription of parenteral antibiotics\*
• Any prenatal or postpartum use of non-dietary probiotic supplement by mother during current pregnancy\*\*\*\*\*\*
• Any postnatal administration of non-dietary probiotic or prebiotic supplements to infant
• Current participation of the infant in another clinical trial
• Resides in the same household as another infant previously enrolled in the study, or any study within the research platform, who is currently \<60 days of age; however, twins may all be enrolled simultaneously in this trial.
• Multiple gestation for which the number of liveborn infants from the same pregnancy exceeds two (i.e., triplets or higher order multiples).
• '\*Day of birth is considered day 0 of life. Therefore, the infant could be enrolled on days 0, 1, 2, 3 or 4 of life.
• '\*\*These criteria are time-varying, so will be reassessed on a daily basis until no longer eligible for another reason (i.e., beyond day 4 of life) as long as the infant remains potentially eligible by other criteria. Orally feeding is defined as being able to take a probiotic or synbiotic supplement by mouth on a daily basis.
• '\*\*\*Current infant weight, as measured and documented by study personnel, will be used if birth weight is missing, illegibly recorded, or suspected of being an error (e.g., implausible value, discrepancy of greater than 15% between documented birth weight and measured screening weight).
• '\*\*\*\* Major surgery as an operative procedure to explore and/or repair an organ or tissue that is performed under general anaesthesia. Examples relevant to the neonatal period include: ligation of patent ductus arteriosus, repair of abdominal wall defects, repair bowel perforation due to of necrotizing enterocolitis, repair of tracheoesophageal fistula and/or esophageal atresia, and repair of myelomeningocele. Conversely, examples of common procedures in newborns not considered major surgery include circumcision, tongue tie release, removal of extra digit (polydactyly).
• '\*\*\*\*\*Although HIV in very young infants will be rare in this context, there is a low but non-zero theoretical risk that a baby born to an HIV positive mother could be significantly compromised, particularly in cases where in utero transmission occurred earlier in pregnancy. Both the HIV positive mother and infant are expected to represent a unique population in regards to their respective microbiomes, and excluding them should not affect generalizability of results to the population as a whole. The number of HIV positive infants is anticipated to be too low to conduct sub-group analyses and thus, it would not be possible to make meaningful inferences about this population, even if they were to be included in the study. Testing for HIV infection will not be performed as a study procedure; therefore, this criterion will be based on information available from the medical record.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• International Centre for Diarrhoeal Disease Research, Bangladesh: collaborator
• Child Health Research Foundation, Bangladesh: collaborator
• Boston University: collaborator
• University of California, San Diego: collaborator

Study Sites (2)

Maternal Child Health Training Institute

Dhaka, Bangladesh

Location

Mohammadpur Fertility Services Training Centre

Dhaka, Bangladesh

Location

Related Publications (1)

• Pell LG, Qamar H, Bassani DG, Heasley C, Funk C, Chen C-Y, Shawon J, O'Callaghan KM, Pullenayegum E, Hamer DH, Haque R, Kabir M, Ahmed T, O'Kelly C, Hossain MI, Khan AZ, Loutet MG, Islam MS, Morris SK, Shah PS, Sherman PM, Sultana S, Mahmud AA, Saha SK, Sarker SA, Roth DE. Neonatal administration of Lactiplantibacillus plantarum ATCC 202195 with or without fructooligosaccharide in Bangladesh: a placebo-controlled randomized trial. mSphere. 2025 Mar 25;10(3):e0103224. doi: 10.1128/msphere.01032-24. Epub 2025 Feb 24.

  PMID: 39992135 DERIVED

MeSH Terms

Conditions

Communicable Diseases

Interventions

Synbiotics; Probiotics

Condition Hierarchy (Ancestors)

Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Prebiotics; Dietary Supplements; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages

Study Officials

• Daniel Roth, MD, PhD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Allocation concealment and blinding of participants, study personnel, and investigators.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician

Model Details: Randomized, placebo-controlled, parallel-design multi-arm trial

Study Record Dates

• First Submitted: November 25, 2021
• First Posted: January 6, 2022
• Study Start: January 7, 2022
• Primary Completion: June 21, 2022
• Study Completion: November 10, 2022
• Last Updated: April 13, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: To be determined
• Access Criteria: To be determined.

Locations

BA (2)