'Pre-Proof of Concept (Pre-POC)' Clinical Trials to Optimize Lead Microbiota-directed Complementary Food (MDCF) Prototypes for Their Ability to Repair Microbiota Immaturity and Establish Their Organoleptic Acceptability

Summary

Burden: According to Bangladesh Demographic Health Survey 2014, prevalence of stunting in under-five children is 36%. Severe acute malnutrition (SAM) is prevalent in about 3% of them. In absolute numbers, about 450,000 children suffer from SAM while several million children suffer from moderate acute malnutrition (MAM).

Knowledge gap: Investigators have already demonstrated that children with SAM have immature gut microbiota that is partially corrected with treatment. Through our earlier studies conducted in Bangladesh,investigators now also have idea about beneficial microbiota and food ingredients that support proliferation of these beneficial microbiota. Which composite food is better for children with SAM and MAM is not known.

Hypothesis (if any): The central hypothesis of our ongoing Breast Milk, Gut Microbiome and Immunity (BMMI) initiative proof of concept phase is that healthy growth in infancy and early childhood requires normal functional maturation of the gut microbiota. Related hypotheses are that (i) persistent defects in the development of this microbial 'organ' are causally related to stunting as well as the metabolic, immunologic and cognitive manifestations of undernutrition; and (ii) new approaches for durable repair of this microbiota immaturity including Microbiota-Directed Complementary Foods (MDCF) will provide a way to improve clinical outcomes.

Objectives:

1. Test 5 MDCF prototypes and nominate a lead MDCF formulation that has the greatest effect in promoting the representation of a broad range of age-discriminatory taxa and that has acceptable organoleptic properties. This nominated lead will be advanced to a fully powered clinical POC study in children with post-SAM MAM in 2018.
2. Determine whether once daily administration is as effective as twice daily administration of the lead MDCF in repairing microbiota immaturity.
3. Assess the durability of repair of immaturity by the lead MDCF by including a 4 week post-intervention phase in the final pre-POC study design.
4. Determine what effect enteropathogen burden (determined by PCR-based analysis of fecal samples) has on responses of age-discriminatory taxa to MDCFs, and reciprocally, the effect of MDCFs on enteropathogen burden.

Methods:

Investigators will conduct 3 Pre-POC studies in 12-18 month old children with MAM (Weight-for-Length Z-score, WLZ: between \<-2 to -3) and stunting (Length-for-Age Z-score, LAZ: between \<-2 to -3) over the course of approximately two years. The investigators will use a stratified randomization procedure based on age (i.e.2 levels: 12-15 months and \>15-18 months) to prevent imbalance between the treatment arms. This study will be undertaken at Mirpur area of Dhaka city. The investigators will design and produce 5 MDCF prototypes at the icddr,b Food Processing Laboratory in sufficient quantities for clinical studies (3 MDCF prototypes for study 1 and 2 MDCF prototypes for study 2). These formulations will be matched in energy density and micronutrient content of ready-to-use supplementary foods (RUSFs) used for MAM in Bangladesh and other countries, and will meet all other requirements for a complementary/supplementary food for 12-18 month old children with MAM and stunting.

Conditions

• Pre Proof of Concept Clinical Trial

Interventions

DIETARY_SUPPLEMENT

Microbiota Directed Complementary Food (MDCF)

For Study 1: Investigators will test 3 prototype MDCFs and the current RUSF standard of care for MAM to establish the effect size of each on MAZ repair in a 4 week twice daily intervention, with a 2 week post-intervention phase. Study 2: From study 1 Investigators will select most efficacious MDCF and compare with 2 additional MDCF prototypes to establish the effect size of each on MAZ repair in a 4 week twice daily intervention, with a 2 week post-intervention phase. Study 3: Investigators will select the lead MDCF from study 2 and examine the effects between the final MDCF versus current RUSF and also examine the impact dispensing of the lead MDCF once versus twice per day with a 4 week post-intervention period.

Sponsors & Collaborators

• Washington University School of Medicine

  collaborator OTHER

• International Centre for Diarrhoeal Disease Research, Bangladesh

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

12 Months

Max Age

18 Months

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2018-02-01

Primary Completion

2022-11-28

Completion

2022-11-28

Countries

• Bangladesh

Study Locations