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SEPSIS: L. Plantarum Trial

T

The Hospital for Sick Children

Status and phase

Completed
Phase 2

Conditions

Infant ALL
Microbial Colonization
Safety Issues
Tolerance

Treatments

Dietary Supplement: Synbiotic
Dietary Supplement: Probiotic
Other: Placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT05180201
1000072200

Details and patient eligibility

About

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.

Full 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.

Enrollment

519 patients

Sex

All

Ages

Under 49 years old

Volunteers

Accepts Healthy Volunteers

Inclusion criteria

  • 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.

Exclusion criteria

  • 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.

'******Non-dietary probiotic supplement is a commercial (store-bought) probiotic product that is consumed in the form of a capsule, powder, liquid, etc., although it may be mixed into a food or drink at the time of consumption. In contrast, a dietary probiotic is an ingredient of a food or beverage that either occurs naturally or is added during home production or the commercial manufacturing process (e.g., yoghurt or fermented drinks).

Trial design

Primary purpose

Prevention

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

519 participants in 5 patient groups, including a placebo group

LP7+FOS
Experimental group
Description:
Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) with 150mg fructooligosaccharide (FOS) and 100mg maltodextrin, for 7 days.
Treatment:
Dietary Supplement: Synbiotic
LP7
Experimental group
Description:
Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) plus 250mg maltodextrin, for 7 days.
Treatment:
Dietary Supplement: Probiotic
LP1+FOS
Experimental group
Description:
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).
Treatment:
Other: Placebo
Dietary Supplement: Synbiotic
LP1
Experimental group
Description:
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).
Treatment:
Other: Placebo
Dietary Supplement: Probiotic
Placebo
Placebo Comparator group
Description:
Once daily oral administration of placebo (250 mg maltodextrin), for 7 days.
Treatment:
Other: Placebo

Trial contacts and locations

2

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Data sourced from clinicaltrials.gov

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