Probiotic Supplementation in Breastfed Newborn Infants

A Parallel-group, Randomized, Placebo-controlled Ascending Dose Phase I Study Protocol for Dietary Supplementation With Bifidobacterium Longum Subsp. Infantis (B. Infantis) in Healthy Breastfed Infants

The purpose of this study is to investigate the dose of a probiotic supplement (Bifidobacterium longum subsp. infantis) required to achieve predominant gut colonization in healthy newborn, breastfed infants. The study will also examine whether supplementation with this probiotic can reduce the chance of developing eczema and food allergies in enrolled infants.

Study Overview

• Status: Withdrawn
• Conditions: Atopic Dermatitis; Food Allergies
• Intervention / Treatment: Drug: Placebo; Drug: B. infantis

Detailed Description

The proposed phase I clinical trial is a parallel-group, placebo-controlled, randomized, double-blind ascending dose study of dietary supplementation with Bifidobacterium longum subsp. infantis (B. infantis) in healthy breastfed infants to evaluate its safety as well as determine the pharmacologically effective dose (ED) of B. infantis producing at least 50% gut colonization at six weeks of age. Infants will be enrolled sequentially in groups of five (three randomized to receive B. infantis and two to receive placebo). For each group, infants will be dosed with B. infantis or placebo on day 7 and day 14 of life. A calculated Maximally Recommended Starting Dose (MRSD) will be used to initiate the dose escalation and is defined below. Every two weeks, an additional group of five infants (randomized 3:2 to B. infantis and placebo) will be enrolled to receive progressively higher doses of B. infantis. Calculation of the appropriate dose escalation will be performed using a modified Fibonacci series as described below in an effort to identify the ED of B. infantis.

After the ED of B. infantis has been identified (defined as the dose capable of producing 50% gut colonization by six weeks of age) two additional sequential dose escalations will be performed. The purpose of the final two dose escalations is to determine if successively higher doses of B. infantis result in increased gut colonization or barrier protection; or, alternatively, if a Maximum Effective Dose (MaxED) for B. infantis exists above which there is no further increase in gut colonization or barrier protection. Following the final dose escalation, Hanley's Rule of Three will be applied in order to determine if lower-frequency adverse events are caused by B. infantis. Hanley's Rule of Three states that in order to identify any adverse events occurring at a frequency of 1:10 or greater with a 95% confidence interval, at least 30 subjects must be enrolled.

Study visits will be scheduled for weeks 1, 2, 6, 24, 36, 52 and 78. Parents will complete surveys at each study visit to monitor the infants for potential adverse events associated with probiotic administration including feeding intolerance, fevers, or bowel irregularities including constipation and diarrhea.

Stool samples will be collected twice weekly for the first six weeks of life then once weekly at weeks 24, 36, 52 and 78. Stool samples will be analyzed to determine the relative abundance of B. infantis over time, and the overall diversity of the gut microbiota with and without B. infantis supplementation. Stool will also be analyzed for milk oligosaccharides to verify consumption of breast milk and to correlate proportion of human milk oligosaccharides and free sugar monomers seen in the infant stool at various levels of B. infantis colonization.

At each study visit, infants will receive a full skin examination to evaluate for signs of atopic dermatitis (AD). The Infant Dermatitis Quality of Life Index (IDQOLI) will be administered to parents at each study visit to screen for possible signs of AD such as infant irritability, skin rashes and hypersensitivity. If AD is present, the Scoring Atopic Dermatitis (SCORAD) grading system will be used to assess severity. Urine samples will be collected at each study visit to measure levels of fatty acid binding proteins (FABPs) and glutathione-S-transferase (alpha-GST), which are non-invasive markers of gastrointestinal permeability that may indicate the presence of food allergies. Blood will be collected via finger or heel stick at weeks 6 and 52 for immune phenotyping (including measuring inflammatory cytokines and food-specific IgEs). In addition, levels of serum fatty acid binding proteins (FABPs) and glutathione-S-transferase (alpha-GST) will be measured as markers of gastrointestinal permeability and potential food allergy. Parents will also complete surveys at each study visit to monitor the infants for potential adverse events associated with probiotic administration including feeding intolerance, fevers, or bowel irregularities including constipation and diarrhea.

Entry into the study requires the intent to breastfeed exclusively for a minimum of six months. If mothers decide to discontinue breastfeeding during the study, the investigators will note that in the infant's chart and obtain an additional series of weekly stool samples for six weeks after discontinuation of breastfeeding. The purpose of this additional stool sample collection is to determine if discontinuation of breastfeeding has an impact on the level of existing B. infantis colonization in the infant gut.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95816
      • University of California, Davis Department of Dermatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 week (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy newborn infants between 1 and 7 days old with intent to be exclusively breastfed for a minimum of six (6) months

Exclusion Criteria:

• Infants given dietary supplementation, including other probiotics.
• Infants born prior to 34 weeks gestation.
• Infants below 10th percentile for body weight.
• Postnatal use of antibiotics (oral, intramuscular or intravenous) by either the mother or the infant. Of note, prenatal maternal Group B streptococcus prophylaxis is not a criterion for study exclusion.
• Family history of immunodeficiency syndrome(s).
• Infants with signs of a clinically apparent underlying immunodeficiency.
• Intent to use non-breast milk infant formula for feeding during the first six months.
• History of GI tract abnormality or infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: B.infantis; Infants in the experimental arm will have two doses of the probiotic Bifidobacterium longum subsp. infantis (B. infantis) on Day 7 and Day 14 of life.	Drug: B. infantis; Infants in the intervention group will receive two doses of B. infantis on Day 7 and Day 14 of life, while infants in the placebo group will be dosed with placebo on Day 7 and Day 14; Other Names: Probiotic
Placebo Comparator: Placebo; Infants in the experimental arm will have two doses of placebo (powdered maltodextrin) on Day 7 and Day 14 of life.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacologically effective dose (ED) of B. infantis	The primary endpoint of the study is identification of a pharmacologically effective dose of B. infantis required to produce predominant (>50%) gut colonization at six weeks of age	Two years
Safety of Probiotic Supplementation, as assessed by frequency of adverse events	An additional primary endpoint is to determine the safety of B. infantis supplementation in immunocompetent, full-term infants. Any adverse events including fever 102°F or higher, abdominal pain or colic, blood or pus in the stool, diarrhea or vomiting will be documented and dosing adjusted accordingly	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Milk Oligosaccharide Consumption	All stool samples will also be analyzed for the presence of oligosaccharides unique to breast milk and for the presence of free saccharide monomers, which are products of their incomplete digestion. B. infantis abundance will be correlated to these values.	2 years
Stool Microbiota Composition	In addition to determining the percent composition of B. infantis in infant stool samples, numerous other measures such as microbiota diversity and rate of B. infantis decline following cessation of breast feeding will also be determined.	2 years

Collaborators and Investigators

• Sponsor: Emanual Maverakis, MD

Publications and helpful links

General Publications

• Awasthi S, Wilken R, Patel F, German JB, Mills DA, Lebrilla CB, Kim K, Freeman SL, Smilowitz JT, Armstrong AW, Maverakis E. Dietary supplementation with Bifidobacterium longum subsp. infantis (B. infantis) in healthy breastfed infants: study protocol for a randomised controlled trial. Trials. 2016 Jul 22;17(1):340. doi: 10.1186/s13063-016-1467-1.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: November 7, 2014
• First Posted (Estimate): November 10, 2014

Study Record Updates

• Last Update Posted (Actual): November 15, 2019
• Last Update Submitted That Met QC Criteria: November 13, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Dermatitis; Food Hypersensitivity
• Other Study ID Numbers: 651698

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No