Undernutrition Clinical Trial
Official title:
Development of Shelf-Stable, Locally-Sourced, Microbiota-Directed Complementary Foods for Children With Undernutrition
Background: Children with acute malnutrition have immature gut microbial communities compared to age-matched children with healthy growth that can not be repaired by existing therapeutic foods (Subramanian et al., Nature. 2014). Hence, investigators' recent work in Bangladesh has focused on developing Microbiota-Directed Complementary Foods (MDCF) containing locally-available food ingredients, that repair the gut microbiota of children with acute malnutrition to a configuration that resembles that of healthy children living in the same urban community (Raman et al., Science 2019; Gherig et al., Science 2019). The investigators recently completed a randomized, controlled proof-of-concept (POC) study of current lead microbiota-directed complementary food, MDCF-2 compared to a standard ready-to-use supplementary food (RUSF), in Bangladeshi children with moderate acute malnutrition (MAM)(Chen et al., N Engl J Med 2021). Children who received MDCF-2 for 3 months exhibited significantly greater repair of their gut microbial communities and faster rates of ponderal growth compared to those treated with RUSF (a formulation that was not designed based on knowledge of its effects on the gut microbiota). The superior effect of MDCF-2 on gut microbiota repair and weight gain was even more notable as the RUSF was significantly more energy dense than MDCF-2. In the aforementioned POC study, MDCF-2 was prepared fresh daily in icddr,b field kitchens prior to distribution and supervised administration to study participants. The lack of a shelf-stable, bio-equivalent formulation of MDCF-2 limits the ability to perform larger studies in Bangladesh as well as in other geographic settings. This pre-POC study in Bangladeshi children with MAM will assess the bioequivalence of MDCF prototypes that the investigators have developed with the potential for improved storage stability compared to current MDCF-2, using the degree of microbiota repair after 4-weeks of treatment as the primary outcome. Objective: To develop a scalable, shelf-stable formulation that is bioequivalent to MDCF-2 with respect to microbiota repair in 8-12 month-old Bangladeshi children with MAM after 4-weeks of treatment. Methods: A 5-arm, randomized single-blind pre-POC study will be conducted in 8-12-month-old Bangladeshi children with MAM to compare the efficacy of alternative MDCF formulations in repairing their gut microbiomes compared to the repair produced by the current kitchen prepared MDCF-2 formulation. Arm 1 - Reference control: kitchen-prepared MDCF-2 Arm 2 - Ready-to-use supplementary food Arm 3 - Individually packaged, pre-measured sachets of MDCF-2 ingredients, combined and reconstituted in the home setting prior to consumption. Arm 4 - MDCF-2 shelf-stable foil pouch formulation with green banana powder. Arm 5 - MDCF shelf-stable foil pouch formulation with sweet potato instead of green banana.
Status | Recruiting |
Enrollment | 130 |
Est. completion date | February 28, 2025 |
Est. primary completion date | August 31, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 8 Months to 12 Months |
Eligibility | Inclusion Criteria: - Parent(s) willing to sign consent form - Child aged 8-12 months - WLZ score <-2 to -3 without bilateral pedal edema at the time of randomization - Parent(s) willing to bring the child to the feeding centre according to the pre-defined schedule Exclusion Criteria: Meeting any of the following criteria will exclude a subject from study participation - 1. Medical conditions: Malnourished children with complications requiring acute phase treatment in a hospital, children with tuberculosis (diagnosis based on WHO 2014 guidelines which have been incorporated in the national TB control guidelines of Bangladesh). The guidelines depend upon the following five diagnostic principles (three out of five should be positive): - Specific symptoms of TB - Specific signs of TB - Chest X-ray - Mantoux test - History of contact 2. Any congenital/acquired disorder affecting growth, i.e., known case of trisomy-21 or cerebral palsy; children on an exclusion diet for the treatment of persistent diarrhea; having known history of soy, peanut or milk protein allergy 3. Severe anemia (< 8 mg/dl) 4. Antibiotic use (within last 15 days before the onset of intervention) 5. Ongoing maternal antibiotic usage for breastfeeding infants 6. Receiving concurrent treatment for another condition |
Country | Name | City | State |
---|---|---|---|
Bangladesh | Mirpur | Dhaka |
Lead Sponsor | Collaborator |
---|---|
International Centre for Diarrhoeal Disease Research, Bangladesh | Washington University School of Medicine |
Bangladesh,
Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016 Jul;13(7):581-3. doi: 10.1038/nmeth.3869. Epub 2016 May 23. — View Citation
Chen RY, Mostafa I, Hibberd MC, Das S, Mahfuz M, Naila NN, Islam MM, Huq S, Alam MA, Zaman MU, Raman AS, Webber D, Zhou C, Sundaresan V, Ahsan K, Meier MF, Barratt MJ, Ahmed T, Gordon JI. A Microbiota-Directed Food Intervention for Undernourished Children — View Citation
Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Kung VL, Cheng J, Chen RY, Subramanian S, Cowardin CA, Meier MF, O'Donnell D, Talcott M, Spears LD, Semenkovich CF, Henrissat B, Giannone RJ, Hettich RL, Ilkayeva O, Muehlbauer M, Newgard CB, Sawyer C, Head RD — View Citation
Raman AS, Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Subramanian S, Kang G, Bessong PO, Lima AAM, Kosek MN, Petri WA Jr, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Huq S, Mostafa I, Islam M, Mahfuz M, Haque R, Ahmed T, Barratt MJ, Gordon JI. A sp — View Citation
Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, Barratt MJ, VanArendonk LG, Zhang Q, Province MA, Petri WA Jr, Ahmed T, Gordon JI. Persistent gut microbiota immaturity in malnourished Bangladesh — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Changes in the abundances of 7000 circulating plasma proteins | To expand our understanding of the biological pathways underlying growth impairment in children with MAM and its repair by MDCF-2, plasma proteins will be analyzed using SomaScan- based measurements. | Baseline to end of Week 4 | |
Other | Changes in the concentrations of fecal protein biomarkers of gut inflammation | To expand our understanding of the biological pathways underlying growth impairment in children with MAM and its repair by MDCF-2, fecal proteins will be analyzed using ELISA based measurements. | Baseline to end of Week 4 | |
Primary | Equivalence in the response to MDCF-2 and a test MDCF formulation, based on the change in representation of gut bacterial taxa after 4-weeks of treatment with MDCF-2, compared to the change after treatment with the test MDCF for 4-weeks. | V4-16S rDNA amplicons and shotgun sequencing datasets will be generated from fecal samples collected from each child in each group prior to, during, and after treatment to determine the abundances of MDCF-2 responsive bacterial taxa.
Equivalence will be defined as the absence of a statistically significant difference after 4-weeks of treatment in the representation of fecal bacterial taxa associated with the response to MDCF-2 in participants receiving a test MDCF, compared to the representation of these bacterial taxa in participants after receiving the reference MDCF-2 formulation for 4-weeks. |
Baseline to 4-weeks of treatment. |
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