A Phase 2 interventional study of Synbiotic and Probiotic in Microbial Colonization, Tolerance and Safety Issues, sponsored by The Hospital for Sick Children. Completed at 2 sites in Bangladesh. Open to participants aged 0 Years to 49 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-04-13.
Sponsored by The Hospital for Sick Children · Phase 2, Interventional, and Prevention
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.
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:
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.
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Exclusion Criteria:
'*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).
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
Once daily oral administration of L. plantarum ATCC 202195 (10\^9 CFU/day) plus 250mg maltodextrin, for 7 days.
Dietary Supplement: Probiotic
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
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
Once daily oral administration of placebo (250 mg maltodextrin), for 7 days.
Other: Placebo
Lactiplantibacillus plantarum ATCC 202195 with fructooligosaccharide
Lactiplantibacillus plantarum ATCC 202195
Maltodextrin
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 60 days of age
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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
Indicator of immediate post-ingestion tolerability of the investigational product
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).
Indicator of post-ingestion tolerability of the investigational product
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.
Indicator of incomplete or failed dose administration due to intolerance
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to 6 months of age
Other clinical outcomes: Vomiting
Any vomiting as reported by mother/caregiver
Time frame: Up to 6 months of age
Other clinical outcomes: Persistent vomiting
Vomiting ≥3 times in a 24 hour period as reported by mother/caregiver.
Time frame: Up to 6 months of age
Other clinical outcomes: Hospitalization
Any inpatient admission for acute illness; excludes admission for elective surgical procedures
Time frame: 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
Time frame: 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
Time frame: 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.)
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.
Indicator of environmental contamination by investigational product
Time frame: 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
Time frame: Up to 21 days of age
Average proportion of doses received by day 10 of life
Indicator of adherence to investigational product
Time frame: Up to 10 days of age
Average proportion of doses received on scheduled day
Indicator of adherence to investigational product
Time frame: Up to 21 days of age
Average range (in days) between first and last dose
Indicator of adherence to investigational product
Time frame: 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.
Time frame: Up to 9 months of age
Plan to share: Yes — A detailed data sharing plan will be developed.
Supporting information: Study protocol, Sap, Icf, Csr, Analytic code
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