Paediatrics, Underweight
Conditions
Keywords
Weight-for-age Z score, Underweight infants, Bifidobacterium longum, B. infantis, Bi-26 supplementation
Brief summary
The burden of disease experienced by underweight children is significant, particularly in low- and middle-income countries. Gut dysbiosis, an imbalance in microbial composition, is thought to play a role in nutrient malabsorption leading to underweight infants and failure to thrive. Bifidobacterium longum subspecies infantis (B. infantis) is a commensal bacterial strain important in the breakdown of human milk oligosaccharides (HMOs). A decrease in abundance or absence of B. infantis could lead to inadequate HMO processing, elevating intestinal pH and increasing the risk of pathogen overgrowth. Bi-26 is a B. infantis probiotic strain that is being evaluated in this study for its impact on weight gain and other health outcomes in underweight infants.
Interventions
DIETARY_SUPPLEMENTPlacebo
A once-daily oral dose of placebo maltodextrin will be provided to infants for 28 days
DIETARY_SUPPLEMENTB. infantis Bi-26
A once-daily oral dose of Bi-26 will be provided to infants for 28 days.
Sponsors
Gates Medical Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Days to 120 Days
Healthy volunteers
No
Inclusion criteria
* Participant must be between 30 days and 120 days of age (inclusive), at the time of enrollment (study Day 1) * Hospitalized for acute non-surgical illness * Completed acute stabilization phase of treatment, including fluid rehydration and antibiotic course, prior to enrollment (study Day 1) * WAZ at enrollment (study Day 1) is less than negative 2 (\<-2) * Any sex * Participant's parent(s)/legal guardian is capable of giving informed consent which includes agreement to comply with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol * Participant's parent(s)/legal guardian agrees to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and have no current plans to relocate from the study area for the duration of the study * Participant's parent(s)/legal guardian has easy access to reliable refrigeration (for storage of investigational product) * Participant receives some feedings from breastmilk and mother intends to continue breastfeeding.
Exclusion criteria
* Congenital condition (suspected or confirmed) that the investigator considers likely to interfere with feeding or with normal growth and development * Infant has not been discharged from hospital since birth or has not been at home for at least one week since birth * Infant hospitalized with septic shock during current hospitalization * Infant required mechanical ventilation during current hospitalization * Infant with acute kidney injury on hospital admission * Infant with severe jaundice and suspected kernicterus * Infant receiving treatment for suspected or confirmed tuberculosis, or suspected or confirmed human immunodeficiency virus (HIV) infection * Ongoing infant antibiotic (e.g. as prophylaxis in sickle cell disease) and/or probiotic usage * Ongoing maternal antibiotic and/or probiotic usage for breast-feeding infants * Inability of participant's parent(s)/legal guardian to comply with protocol requirements, as per investigator assessment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weight-for-age Z Score (WAZ) at Day 56 | Baseline (Day 1) to Day 56 | The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight. Least Squares Mean, 95% Confidence Interval, and p-value was derived from mixed model repeated measures with treatment and visit as factors and baseline WAZ, baseline age (days), and study intervention compliance as covariates. The treatment\*visit interaction terms were included and used to estimate the adjusted mean difference in Change from Baseline in WAZ between Bi-26 and Placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in WAZ Over Time Through Day 90 | Baseline (Day 1) to Day 90 | The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight. Least Squares Mean, 95% Confidence Interval, and p-value was derived from mixed model repeated measures with treatment and visit as factors and baseline WAZ, baseline age (days), and study intervention compliance as covariates. The treatment\*visit interaction terms were included and used to estimate the adjusted mean difference in Change from Baseline in WAZ between Bi-26 and Placebo. |
| Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Baseline (Day 1) to Day 56 | The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight. |
| Percentage of Participants Who Achieved a Score of WAZ > -2 at Day 56 | At Day 56 | The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight. |
| Change From Baseline in Weight to Day 56 | Baseline (Day 1) to Day 56 | Weight (grams) was summarized using descriptive statistics. Baseline (Day 1) was defined as the last available value prior to the participant receiving the first dose of the study intervention. Change from Baseline was defined as post-dose visit value minus Baseline value. |
| Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to Day 90 | An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE is considered treatment emergent if it started on or after the date of first dose of study intervention administration. Serious TEAE is any untoward medical occurrences at any dose of study medication that: results in death; is life threatening; requires inpatient hospitalization or causes prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect and is an important medical event. |
| Percentage of Participants With Presence of B. Infantis in Stool | At Days 1, 28, 56 and 90 | Stool samples were collected at defined time points to analyze the present of B.infantis. |
| Percentage of Participants Re-hospitalized | Baseline to Day 56 | Hospitalizations are due to acute non-surgical illness. Percentage of participants re-hospitalized at Day 56 has been presented |
Countries
Pakistan
Participant flow
Recruitment details
This was a Phase 3, randomized, double-blind study that evaluated the impact of Bi-26 (strain of Bifidobacterium longum, B. infantis) supplementation on weight gain in underweight infants.
Pre-assignment details
A total of 40 participants were enrolled from 1 country and were randomized 1:1 in experimental and placebo groups.
Participants by arm
| Arm | Count |
|---|---|
| Bi-26 Supplementation Participants received Bi-26 supplementation once-daily orally for 28 days. | 20 |
| Placebo Participants received placebo (maltodextrin) once-daily orally for 28 days. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Bi-26 Supplementation |
|---|---|---|---|
| Age, Continuous | 66.6 Days STANDARD_DEVIATION 23.6 | 62.1 Days STANDARD_DEVIATION 22.6 | 57.6 Days STANDARD_DEVIATION 21.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 40 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 1 / 20 |
| other Total, other adverse events | 7 / 20 | 14 / 20 |
| serious Total, serious adverse events | 1 / 20 | 5 / 20 |
Outcome results
Primary
Change From Baseline in Weight-for-age Z Score (WAZ) at Day 56
The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight. Least Squares Mean, 95% Confidence Interval, and p-value was derived from mixed model repeated measures with treatment and visit as factors and baseline WAZ, baseline age (days), and study intervention compliance as covariates. The treatment\*visit interaction terms were included and used to estimate the adjusted mean difference in Change from Baseline in WAZ between Bi-26 and Placebo.
Time frame: Baseline (Day 1) to Day 56
Population: Modified Intention to Treat Population comprised of all participants randomly assigned to study intervention, who received any dose, including a partial dose of the study intervention.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Bi-26 Supplementation | Change From Baseline in Weight-for-age Z Score (WAZ) at Day 56 | 0.78 Z-score |
| Placebo | Change From Baseline in Weight-for-age Z Score (WAZ) at Day 56 | 0.67 Z-score |
p-value: 0.686395% CI: [-0.44, 0.67]Mixed Models Analysis
Secondary
Change From Baseline in WAZ Over Time Through Day 90
The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight. Least Squares Mean, 95% Confidence Interval, and p-value was derived from mixed model repeated measures with treatment and visit as factors and baseline WAZ, baseline age (days), and study intervention compliance as covariates. The treatment\*visit interaction terms were included and used to estimate the adjusted mean difference in Change from Baseline in WAZ between Bi-26 and Placebo.
Time frame: Baseline (Day 1) to Day 90
Population: Modified Intention to Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Bi-26 Supplementation | Change From Baseline in WAZ Over Time Through Day 90 | 1.09 Z-score |
| Placebo | Change From Baseline in WAZ Over Time Through Day 90 | 1.00 Z-score |
p-value: 0.727595% CI: [-0.46, 0.66]Mixed Models Analysis
Secondary
Change From Baseline in Weight to Day 56
Weight (grams) was summarized using descriptive statistics. Baseline (Day 1) was defined as the last available value prior to the participant receiving the first dose of the study intervention. Change from Baseline was defined as post-dose visit value minus Baseline value.
Time frame: Baseline (Day 1) to Day 56
Population: Modified Intention to Treat Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Bi-26 Supplementation | Change From Baseline in Weight to Day 56 | 1491.47 Grams |
| Placebo | Change From Baseline in Weight to Day 56 | 1382.17 Grams |
p-value: 0.556795% CI: [-259.76, 478.36]Mixed Models Analysis
Secondary
Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE is considered treatment emergent if it started on or after the date of first dose of study intervention administration. Serious TEAE is any untoward medical occurrences at any dose of study medication that: results in death; is life threatening; requires inpatient hospitalization or causes prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect and is an important medical event.
Time frame: Up to Day 90
Population: Safety Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bi-26 Supplementation | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 8 Participants |
| Bi-26 Supplementation | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAE | 1 Participants |
| Placebo | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 16 Participants |
| Placebo | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAE | 5 Participants |
Secondary
Percentage of Participants Re-hospitalized
Hospitalizations are due to acute non-surgical illness. Percentage of participants re-hospitalized at Day 56 has been presented
Time frame: Baseline to Day 56
Population: Safety Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bi-26 Supplementation | Percentage of Participants Re-hospitalized | NA Percentage of participants |
| Placebo | Percentage of Participants Re-hospitalized | 20 Percentage of participants |
Secondary
Percentage of Participants Who Achieved a Score of WAZ > -2 at Day 56
The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight.
Time frame: At Day 56
Population: PP Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bi-26 Supplementation | Percentage of Participants Who Achieved a Score of WAZ > -2 at Day 56 | 19 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved a Score of WAZ > -2 at Day 56 | 14 Percentage of participants |
Secondary
Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56
The Weight-for-Age Z-score (WAZ) is an anthropometric measure used to classify a child's nutritional status. The WAZ measures the number of standard deviations of a child's actual weight from the median weight of children of the same age based on the World Health Organization (WHO) child growth standards (reference population). WAZ of 0 represents the median weight for age in the reference population. WAZ ≥-3 to \<-2 standard deviations below the WHO child growth standards median is considered moderately underweight and WAZ \<-3 is considered severely underweight.
Time frame: Baseline (Day 1) to Day 56
Population: Per-Protocol (PP) Population comprised of all participants randomly assigned to study intervention, who received the study intervention, have a Day 90 visit, and did not substantially deviate from the protocol procedures.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bi-26 Supplementation | Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Increase of >= 0.3 units | 87.5 Percentage of participants |
| Bi-26 Supplementation | Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Increase of >= 0.4 units | 87.5 Percentage of participants |
| Bi-26 Supplementation | Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Increase of >= 0.5 units | 68.8 Percentage of participants |
| Placebo | Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Increase of >= 0.3 units | 64.3 Percentage of participants |
| Placebo | Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Increase of >= 0.4 units | 64.3 Percentage of participants |
| Placebo | Percentage of Participants With a ≥ 0.3, ≥ 0.4, and ≥ 0.5 Change in WAZ From Baseline at Day 56 | Increase of >= 0.5 units | 64.3 Percentage of participants |
Secondary
Percentage of Participants With Presence of B. Infantis in Stool
Stool samples were collected at defined time points to analyze the present of B.infantis.
Time frame: At Days 1, 28, 56 and 90
Population: PP Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bi-26 Supplementation | Percentage of Participants With Presence of B. Infantis in Stool | Day 1 | 62.5 Percentage of participants |
| Bi-26 Supplementation | Percentage of Participants With Presence of B. Infantis in Stool | Day 28 | 100.0 Percentage of participants |
| Bi-26 Supplementation | Percentage of Participants With Presence of B. Infantis in Stool | Day 56 | 100.0 Percentage of participants |
| Bi-26 Supplementation | Percentage of Participants With Presence of B. Infantis in Stool | Day 90 | 93.8 Percentage of participants |
| Placebo | Percentage of Participants With Presence of B. Infantis in Stool | Day 90 | 57.1 Percentage of participants |
| Placebo | Percentage of Participants With Presence of B. Infantis in Stool | Day 1 | 50.0 Percentage of participants |
| Placebo | Percentage of Participants With Presence of B. Infantis in Stool | Day 56 | 57.1 Percentage of participants |
| Placebo | Percentage of Participants With Presence of B. Infantis in Stool | Day 28 | 57.1 Percentage of participants |