Microbial ColonizationPhase 2NCT05180201
SEPSIS: L. Plantarum Trial
A Phase 2 study testing Synbiotic and Probiotic in people with Microbial Colonization and Tolerance, run by The Hospital for Sick Children at 2 sites in Bangladesh.
Trial 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. Read more about this study
- Who is it for?
- Ages 0 to 49 yearsHealthy volunteers can take part
- Conditions the study is for
- Microbial Colonization, Tolerance, Safety Issues
- What is being tested?
- Synbiotic and Probiotic
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 519 participants
- Where
- 2 sitesBangladesh
- Study dates
- 7 Jan 2022to 10 Nov 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 49 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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**
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- 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 locations and contacts
2 sites in 1 country.
Bangladesh2 sites
Maternal Child Health Training Institute
Dhaka
Mohammadpur Fertility Services Training Centre
Dhaka
About this study
Official title: 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
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.
Read the 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:
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- Conditions
- Microbial Colonization, Tolerance, Safety Issues, Infant ALL
- Being tested
- Synbiotic, Probiotic, Placebo
- Keywords
- Probiotic, Synbiotic, Young infants, Bangladesh
- Medical subject headings
- Communicable Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SynbioticDietary supplement
Lactiplantibacillus plantarum ATCC 202195 with fructooligosaccharide
ProbioticDietary supplement
Lactiplantibacillus plantarum ATCC 202195
PlaceboOther
Maltodextrin
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Dietary Supplement: Synbiotic |
| LP7 | Experimental | Once daily oral administration of L. plantarum ATCC 202195 (10^9 CFU/day) plus 250mg maltodextrin, for 7 days. Receives: 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). Receives: 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). Receives: Dietary Supplement: Probiotic; Other: Placebo |
| Placebo | Placebo comparator | Once daily oral administration of placebo (250 mg maltodextrin), for 7 days. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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)
An episode of severe infection (SI) for which the presumptive cause is Lactobacilli, implying isolation of lactobacillus spp. in blood (bacteremia), CSF (meningitis) or urine (urinary tract infection) based on conventional microbiological culture.
Measured: Up to 60 days of age
Cumulative incidence of episodes of detectable L. plantarum ATCC 202195 bacteremia (ancillary safety measure, IF FEASIBLE)
Presence of detectable L. plantarum ATCC 202915 in blood using ddPCR.
Measured: Up to 60 days of age
Frequency of hemoglobin (g/L or g/dL) below reference limit
Hemoglobin will be measured in routinely collected samples, and the proportion of values above the reference limit will be compared across intervention groups.
Measured: Up to 60 days of age
Frequency of white blood cell count (10^9 cells/L) above or below reference limit
White blood cell count will be measured in routinely collected samples, and the proportion of values above the reference limit will be compared across intervention groups.
Measured: Up to 60 days of age
Frequency of platelet count (10^9 cells/L) above or below reference limit
Platelet count will be measured in routinely collected samples, and the proportion of values above the reference limit will be compared across intervention groups.
Measured: Up to 60 days of age
Average hemoglobin (g/L or g/dL)
Hemoglobin will be measured in routinely collected samples, and the averages will be compared across intervention groups.
Measured: Up to 60 days of age
Average white blood cell count (10^9 cells/L)
White blood cell count will be measured in routinely collected samples, and the averages will be compared across intervention groups.
Measured: Up to 60 days of age
Average platelet count (10^9 cells/L)
Platelet cell count will be measured in routinely collected samples, and the averages will be compared across intervention groups.
Measured: Up to 60 days of age
Frequency of serum C-reactive protein (mg/L) above reference limit
C-reactive protein will be measured in routinely collected samples, and the proportion of values above the reference limit will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum C-reactive protein (mg/L)
C-reactive protein will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Frequency of serum procalcitonin (ug/L) above reference limit
Procalcitonin will be measured in routinely collected samples, and the proportion of values above the reference limit will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum procalcitonin (ug/L)
Procalcitonin will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum creatinine (μmol/L)
Creatinine will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum Alanine Aminotransferase (ALT) (U/L)
ALT will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum total bilirubin (μmol/L)
Bilirubin will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum conjugated bilirubin (μmol/L)
Bilirubin will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of serum albumin (g/L)
Albumin will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Average concentration of glucose (mmol/L)
Glucose will be measured in routinely collected samples, and group-average concentrations will be compared across intervention groups.
Measured: Up to 60 days of age
Safety outcomes: Serious adverse events
Serious adverse events (SAE) will be compared between groups for infants during the first 60 days of life.
Measured: 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
Indicator of immediate post-ingestion tolerability of the investigational product
Measured: Up to 21 days of age
Frequency of maternal report of vomiting, abdominal distension, and/or diarrhea (during the period of IP administration).
Indicator of post-ingestion tolerability of the investigational product
Measured: Up to 21 days of age
Frequency of IP not administered completely on a given day after one or two attempts due to intolerance.
Indicator of incomplete or failed dose administration due to intolerance
Measured: Up to 21 days of age
Frequency of maternal report of colic-type symptoms (fuss/crying)
Indicator of post-ingestion tolerability of the investigational product
Measured: Up to 21 days of age
Anthropometric outcomes: Length for age z-scores (LAZ)
Z-scores generated based on raw lengths and INTERGROWTH-21st or World Health Organization growth standards.
Measured: Up to 6 months of age
Anthropometric outcomes: Weight for age z-scores (WAZ)
Z-scores generated based on raw weights and INTERGROWTH-21st or World Health Organization growth standards.
Measured: Up to 6 months of age
Anthropometric outcomes: Weight-for-length z-scores (WLZ)
Z-scores generated based on raw lengths and weights and INTERGROWTH-21st or World Health Organization growth standards.
Measured: Up to 6 months of age
Anthropometric outcomes: Head circumference for age z-scores (HCAZ)
Z-scores generated based on raw head circumferences and INTERGROWTH-21st or World Health Organization growth standards.
Measured: Up to 6 months of age
Incidence of severe infection
"Severe infection" (clinical outcome) defined as: at least one sign of clinical severe infection (CSI) (i.e., poor feeding, lethargy, convulsions, severe chest in-drawing, fever, or hypothermia) documented by a physician and/or physician diagnosis of sepsis or another serious bacterial infection (SBI); and at least one of the following two criteria: 1) physician decision to admit to hospital, administration of at least one dose of a parenteral antibiotic on the day when CSI/sepsis/SBI is first ascertained, and treatment with parenteral antibiotics for at least 5 days or 2) blood and/or cerebrospinal fluid culture positive for a pathogenic bacterial or fungal organism
Measured: Up to 60 days of age
Other clinical outcomes: Non-injury death
Death due to any cause except death that was directly caused by physical trauma (medically certified cause of death and/or verbal autopsy) based on mother/caregiver report
Measured: Up to 6 months of age
Other clinical outcomes: Acute diarrhea
Maternal/caregiver report of ≥3 loose stools in 24 hours for <14 days, using the modified Amsterdam scale
Measured: Up to 6 months of age
Other clinical outcomes: Persistent diarrhea
Maternal/caregiver report of frequency and consistency of stool (≥3 loose stools in 24 hours for ≥14 days) using the modified Amsterdam scale
Measured: Up to 6 months of age
Other clinical outcomes: Vomiting
Any vomiting as reported by mother/caregiver
Measured: Up to 6 months of age
Other clinical outcomes: Persistent vomiting
Vomiting ≥3 times in a 24 hour period as reported by mother/caregiver.
Measured: Up to 6 months of age
Other clinical outcomes: Hospitalization
Any inpatient admission for acute illness; excludes admission for elective surgical procedures
Measured: Up to 6 months of age
Other clinical outcomes: Cry/fuss
Cry/fuss pattern questionnaire (up to 3-months of age) based on mother/caregiver report
Measured: Up to 6 months of age
Iron status and antioxidant capacity-related biomarkers: Stool
Total iron in stool samples at day 14 of life (µg of iron/g dry weight of feces) as measured by atomic absorption spectrometry
Measured: Up to 3 months of age
Iron status-related biomarkers: Blood
Serum ferritin (µg/L). Other measures if feasible: soluble transferrin receptor (mg/L) and hepcidin (ng/ml) at day 60 of age (approx.)
Measured: 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.
Indicator of environmental contamination by investigational product
Measured: Up to 60 days of life (of enrolled infant)
Average number of intended doses received, irrespective of timing of dose
Indicator of adherence to investigational product
Measured: Up to 21 days of age
Average proportion of doses received by day 10 of life
Indicator of adherence to investigational product
Measured: Up to 10 days of age
Average proportion of doses received on scheduled day
Indicator of adherence to investigational product
Measured: Up to 21 days of age
Average range (in days) between first and last dose
Indicator of adherence to investigational product
Measured: Up to 21 days of age
Frequency of participant loss to follow-up
Indicator of success of participant follow-up. Loss to follow-up defined as: 1) study personnel conclusively determine that a participant cannot be further contacted for the purposes of data collection for the remaining duration of scheduled follow-up visits OR 2) three months have passed since the scheduled but missed 6-month postnatal visit.
Measured: Up to 9 months of age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2022
- Study start7 Jan 2022
- Primary completion21 Jun 2022
- Study completion10 Nov 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Microbial ColonizationStudies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, placebo-controlled, parallel-design multi-arm trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 519 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Collaborators
- International Centre for Diarrhoeal Disease Research, Bangladesh, Child Health Research Foundation, Bangladesh, Boston University, University of California, San Diego
- Responsible party
- Principal investigator, Daniel Roth, The Hospital for Sick Children
- Investigators
- Daniel Roth, MD, PhD, Principal investigator, The Hospital for Sick Children
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05180201
- Sponsor's protocol ID
- 1000072200
- Status last verified
- Apr 2023
- First submitted
- 25 Nov 2021
- Last updated
- 13 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: A detailed data sharing plan will be developed.
Publications
Khan AZ, Roy AK, Qamar H, Pell LG, O'Callaghan KM, Sarker SA, Mahmud AA, Haque R, Akter S, Sultana S, Roth DE, Raqib R. Fecal iron quantification in a randomized controlled trial of Lactiplantibacillus plantarum ATCC 202195 in newborns in Dhaka, Bangladesh. Nutrition. 2026 Sep;149:113221. doi: 10.1016/j.nut.2026.113221. Epub 2026 Mar 27.
PubMed 42066676Pell 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.
PubMed 39992135
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05180201
- Acronym / sponsor ID
- 1000072200
- Conditions
- Microbial Colonization, Tolerance, Safety Issues, Infant ALL
- Keywords
- Probiotic, Synbiotic, Young infants, Bangladesh
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 519 participants (actual)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Collaborators
- International Centre for Diarrhoeal Disease Research, Bangladesh, Child Health Research Foundation, Bangladesh, Boston University, University of California, San Diego
- Study start
- 7 Jan 2022 (actual)
- Primary completion
- 21 Jun 2022 (actual)
- Study completion
- 10 Nov 2022 (actual)
- First posted
- 6 Jan 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
- Model description
- Randomized, placebo-controlled, parallel-design multi-arm trial
| Arm | Type | Receives |
|---|---|---|
| LP7+FOS | Experimental | Dietary Supplement: SynbioticOnce daily oral administration of L. plantarum ATCC 202195 (10^9 CFU/day) with 150mg fructooligosaccharide (FOS) and 100mg maltodextrin, for 7 days. |
| LP7 | Experimental | Dietary Supplement: ProbioticOnce daily oral administration of L. plantarum ATCC 202195 (10^9 CFU/day) plus 250mg maltodextrin, for 7 days. |
| LP1+FOS | Experimental | Dietary Supplement: Synbiotic, Other: PlaceboOnce 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). |
| LP1 | Experimental | Dietary Supplement: Probiotic, Other: PlaceboOnce 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). |
| Placebo | Placebo comparator | Other: PlaceboOnce daily oral administration of placebo (250 mg maltodextrin), for 7 days. |
Who may qualify
- Ages
- 0 to 49 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (16 listed)
- 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*
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SynbioticLactiplantibacillus plantarum ATCC 202195 with fructooligosaccharide | Dietary supplement | LP1+FOS, LP7+FOS |
| ProbioticLactiplantibacillus plantarum ATCC 202195 | Dietary supplement | LP1, LP7 |
| PlaceboMaltodextrin | Other | LP1, LP1+FOS, Placebo |
Primary outcome
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: 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.
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.
43 secondary outcomes
Cumulative incidence of episodes of culture-confirmed lactobacillus spp. related severe infection (Primary clinical safety outcome)
Time frame: Up to 60 days of age
Cumulative incidence of episodes of detectable L. plantarum ATCC 202195 bacteremia (ancillary safety measure, IF FEASIBLE)
Time frame: Up to 60 days of age
Frequency of hemoglobin (g/L or g/dL) below reference limit
Time frame: Up to 60 days of age
Frequency of white blood cell count (10^9 cells/L) above or below reference limit
Time frame: Up to 60 days of age
Frequency of platelet count (10^9 cells/L) above or below reference limit
Time frame: Up to 60 days of age
Average hemoglobin (g/L or g/dL)
Time frame: Up to 60 days of age
Average white blood cell count (10^9 cells/L)
Time frame: Up to 60 days of age
Average platelet count (10^9 cells/L)
Time frame: Up to 60 days of age
Frequency of serum C-reactive protein (mg/L) above reference limit
Time frame: Up to 60 days of age
Average concentration of serum C-reactive protein (mg/L)
Time frame: Up to 60 days of age
Frequency of serum procalcitonin (ug/L) above reference limit
Time frame: Up to 60 days of age
Average concentration of serum procalcitonin (ug/L)
Time frame: Up to 60 days of age
Average concentration of serum creatinine (μmol/L)
Time frame: Up to 60 days of age
Average concentration of serum Alanine Aminotransferase (ALT) (U/L)
Time frame: Up to 60 days of age
Average concentration of serum total bilirubin (μmol/L)
Time frame: Up to 60 days of age
Average concentration of serum conjugated bilirubin (μmol/L)
Time frame: Up to 60 days of age
Average concentration of serum albumin (g/L)
Time frame: Up to 60 days of age
Average concentration of glucose (mmol/L)
Time frame: Up to 60 days of age
Safety outcomes: Serious adverse events
Time frame: 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
Time frame: Up to 21 days of age
Frequency of maternal report of vomiting, abdominal distension, and/or diarrhea (during the period of IP administration).
Time frame: Up to 21 days of age
Frequency of IP not administered completely on a given day after one or two attempts due to intolerance.
Time frame: Up to 21 days of age
Frequency of maternal report of colic-type symptoms (fuss/crying)
Time frame: Up to 21 days of age
Anthropometric outcomes: Length for age z-scores (LAZ)
Time frame: Up to 6 months of age
Anthropometric outcomes: Weight for age z-scores (WAZ)
Time frame: Up to 6 months of age
Anthropometric outcomes: Weight-for-length z-scores (WLZ)
Time frame: Up to 6 months of age
Anthropometric outcomes: Head circumference for age z-scores (HCAZ)
Time frame: Up to 6 months of age
Incidence of severe infection
Time frame: Up to 60 days of age
Other clinical outcomes: Non-injury death
Time frame: Up to 6 months of age
Other clinical outcomes: Acute diarrhea
Time frame: Up to 6 months of age
Other clinical outcomes: Persistent diarrhea
Time frame: Up to 6 months of age
Other clinical outcomes: Vomiting
Time frame: Up to 6 months of age
Other clinical outcomes: Persistent vomiting
Time frame: Up to 6 months of age
Other clinical outcomes: Hospitalization
Time frame: Up to 6 months of age
Other clinical outcomes: Cry/fuss
Time frame: Up to 6 months of age
Iron status and antioxidant capacity-related biomarkers: Stool
Time frame: Up to 3 months of age
Iron status-related biomarkers: Blood
Time frame: 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.
Time frame: Up to 60 days of life (of enrolled infant)
Average number of intended doses received, irrespective of timing of dose
Time frame: Up to 21 days of age
Average proportion of doses received by day 10 of life
Time frame: Up to 10 days of age
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2023.
- Derived from this study: PubMed 42066676Khan AZ, Roy AK, Qamar H, Pell LG, O'Callaghan KM, Sarker SA, Mahmud AA, Haque R, Akter S, Sultana S, Roth DE, Raqib R. Fecal iron quantification in a randomized controlled trial of Lactiplantibacillus plantarum ATCC 202195 in newborns in Dhaka, Bangladesh. Nutrition. 2026 Sep;149:113221. doi: 10.1016/j.nut.2026.113221. Epub 2026 Mar 27.
- Derived from this study: PubMed 39992135Pell 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.
- Individual participant dataSharing planned: Yes. A detailed data sharing plan will be developed.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Daniel Roth, MD, PhD principal investigator
The Hospital for Sick Children
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Synbiotic and Probiotic in people with Microbial Colonization and Tolerance, run by The Hospital for Sick Children at 2 sites in Bangladesh.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Bangladesh. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05180201, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2023.