Safety, Tolerability and Effects on the Microbiome of Neonatal Administration of Lactiplantibacillus Plantarum ATCC 202195 With or Without Fructooligosaccharide for One or Seven Days: a Phase II Randomized Placebo-controlled Trial in Dhaka, Bangladesh
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Microbial Colonization
- Sponsor
- The Hospital for Sick Children
- Enrollment
- 519
- Locations
- 2
- Primary Endpoint
- Average absolute abundance of L. plantarum ATCC 202195 in stool, measured as cells/g faces or cells/ng DNA
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
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.
Investigators
Daniel Roth
Staff Physician
The Hospital for Sick Children
Eligibility Criteria
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).
Outcomes
Primary Outcomes
Average absolute abundance of L. plantarum ATCC 202195 in stool, measured as cells/g faces or cells/ng DNA
Time Frame: Up to 60 days of age
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.
Average relative abundance of L. plantarum ATCC 202195 in stool, measured as a ratio
Time Frame: Up to 60 days of age
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.
Other microbial efficacy outcomes: Time to L. plantarum ATCC 202195 colonization
Time Frame: Up to 60 days of age
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.
Other microbial efficacy outcomes: Stool inflammatory markers
Time Frame: Up to 60 days of age
Stool inflammatory markers include stool concentrations of calprotectin (µg/g) and myeloperoxidase (ng/ml) derived from standard curves based on ELISAs.
Other microbial efficacy outcomes: Stool pH
Time Frame: Up to 60 days of age
Stool pH will be expressed as a continuous outcome and categorized as low if stool pH \<4.5.
Other microbial efficacy outcomes: L. plantarum ATCC 202195 Colonization
Time Frame: Up to 60 days of age
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.
Secondary Outcomes
- 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)
- Average hemoglobin (g/L or g/dL)(Up to 60 days of age)
- Average white blood cell count (10^9 cells/L)(Up to 60 days of age)
- Average platelet count (10^9 cells/L)(Up to 60 days of age)
- Frequency of serum C-reactive protein (mg/L) above reference limit(Up to 60 days of age)
- Average concentration of serum C-reactive protein (mg/L)(Up to 60 days of age)
- Frequency of serum procalcitonin (ug/L) above reference limit(Up to 60 days of age)
- Average concentration of serum procalcitonin (ug/L)(Up to 60 days of age)
- Average concentration of serum creatinine (μmol/L)(Up to 60 days of age)
- Average concentration of serum Alanine Aminotransferase (ALT) (U/L)(Up to 60 days of age)
- Average concentration of serum total bilirubin (μmol/L)(Up to 60 days of age)
- Average concentration of serum conjugated bilirubin (μmol/L)(Up to 60 days of age)
- Average concentration of serum albumin (g/L)(Up to 60 days of age)
- Average concentration of glucose (mmol/L)(Up to 60 days of age)
- Safety outcomes: Serious adverse events(Up to 60 days of age)
- Frequency of dripping/drooling or spitting out the dose within the first minute of IP administration; or, vomiting within 30 minutes of IP administration(Up to 21 days of age)
- Frequency of maternal report of vomiting, abdominal distension, and/or diarrhea (during the period of IP administration).(Up to 21 days of age)
- Frequency of IP not administered completely on a given day after one or two attempts due to intolerance.(Up to 21 days of age)
- Frequency of maternal report of colic-type symptoms (fuss/crying)(Up to 21 days of age)
- Anthropometric outcomes: Length for age z-scores (LAZ)(Up to 6 months of age)
- Anthropometric outcomes: Weight for age z-scores (WAZ)(Up to 6 months of age)
- Anthropometric outcomes: Weight-for-length z-scores (WLZ)(Up to 6 months of age)
- Anthropometric outcomes: Head circumference for age z-scores (HCAZ)(Up to 6 months of age)
- Incidence of severe infection(Up to 60 days of age)
- Other clinical outcomes: Non-injury death(Up to 6 months of age)
- Other clinical outcomes: Acute diarrhea(Up to 6 months of age)
- Other clinical outcomes: Persistent diarrhea(Up to 6 months of age)
- Other clinical outcomes: Vomiting(Up to 6 months of age)
- Other clinical outcomes: Persistent vomiting(Up to 6 months of age)
- Other clinical outcomes: Hospitalization(Up to 6 months of age)
- Other clinical outcomes: Cry/fuss(Up to 6 months of age)
- Iron status and antioxidant capacity-related biomarkers: Stool(Up to 3 months of age)
- Iron status-related biomarkers: Blood(Up to 3 months of age)
- Average absolute and relative stool abundance (as defined above) of L. plantarum ATCC 202195 detected in non-supplemented siblings and mothers of infants who received the IP.(Up to 60 days of life (of enrolled infant))
- Average number of intended doses received, irrespective of timing of dose(Up to 21 days of age)
- Average proportion of doses received by day 10 of life(Up to 10 days of age)
- Average proportion of doses received on scheduled day(Up to 21 days of age)
- Average range (in days) between first and last dose(Up to 21 days of age)
- Frequency of participant loss to follow-up(Up to 9 months of age)