Pilot of a Prebiotic and Probiotic Trial in Young Infants With Severe Acute Malnutrition

NCT03666572 | Completed Phase 2 DMC

• 1 other identifier: PR-17112
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 1

Brief Summary

Malnutrition is an ever-present problem worldwide. It is estimated that over 18 million children under the age of 5 are affected by the most extreme form of undernutrition, severe acute malnutrition (SAM). In spite of having standardized management protocols, in many hospitals, inpatient mortality reaches up to 30%. Infectious morbidity is common among survivors. Diarrhea, severe intestinal inflammation, low concentrations of fecal short-chain fatty acids (SCFAs), and severe systemic inflammation are significantly associated with mortality in SAM. Investigators of this study have earlier shown that the gut microbiota in children with SAM is immature and is causally related to SAM. Human milk contains between 10 and 20 g/liter of oligosaccharides (human milk oligosaccharides-HMOs) which is the third most abundant solid component after lactose and lipids. HMOs are resistant to gastrointestinal digestion in host infants, and thus the greater part of HMOs reached the colon and may act as prebiotics to shape a healthy gut ecosystem by stimulating the growth of useful microorganisms by acting as receptor analogs to inhibit the binding of various pathogens and toxins to epithelial cells. Probiotics are live organisms beneficial for a healthy life. The human digestive tract possesses a diverse microbial community throughout its extent, which supports their hosts generally for healthy living. Bifidobacterium spp. is dominant microbiota in infants who are exclusively breastfed and these infants are less likely to suffer from diarrhea. According to recent studies among the most common probiotics genera Lactobacillus and Bifidobacterium, the latter is more abundant in the gut. To carry out their functional activities, Bifidobacteria must be able to survive the gastrointestinal tract transit and persist, at least transiently, in the host. The population of Bifidobacteria in the gut community drastically decreases after weaning. Certain Bifidobacteria possess the metabolic capabilities to break down the HMOs. Consequently, it is observed that HMOs support the growth of select Bifidobacteria in the gut of the infant. Research done at icddr,b and Washington University indicates that gut microbes are related to undernutrition and that children with SAM have gut dysbiosis that mediates some of the pathologies of their condition. The standard of care in these children should be reinforced by an intervention that corrects the gut dysbiosis, improves weight gain during nutritional rehabilitation, and reduces infectious morbidity. Investigators do not have any published data on the microbiome response to probiotic supplementation (with and without prebiotics) in malnourished infants or preserving the microbiome with probiotics in non-malnourished children. A short-term pilot study should be conducted to evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in malnourished populations to justify a larger study of clinical outcomes. Additionally, non-malnourished infants who are hospitalized for infectious conditions face challenges related to gut dysbiosis caused by antibiotic usage. Here the investigators will evaluate the ability of a probiotic intervention to rescue the microbiome of primarily breastfed non-malnourished infants. Intervention: Bifidobacterium longum subspecies infantis (EVC001) with and without prebiotic supplementation for 28 days. Objectives: To evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in infants under 6 months with severe acute malnutrition and to compare the microbiome response with healthy infants with a probiotic. Methods: Single-blind RCT, stratified randomization will be based on infant age at the time of transfer to the Nutritional Rehabilitation Unit (NRU). 3 treatment arms for infants with SAM

1. 1.Placebo (Lactose)
2. 2.Bifidobacterium infantis alone (Bif)
3. 3.Bifidobacterium infantis + prebiotic Lacto-N-neotetraose \[LNnT\] (Bif+prebiotic) Age at enrollment
4. 4.2-3.9 months of age
5. 5.4-5.9 months of age 1 open-label treatment arm for 18 non-malnourished primarily breastfed infants: Bifidobacterium infantis alone (Bif)
6. 6.Group 1 (SAM): Infants between 2 and \<6 months old with SAM as defined by weight-for-length Z score \< -3 either sex, caregiver willing to provide consent for enrolment of the infant, caregiver willing to stay in the NRU for about 15 days, residence within 15 km from icddr,b
7. 7.Group 2 (non-malnourished): Non-malnourished infants (WLZ ≥ -1) \<6 months old who are hospitalized for treatment with antibiotics for the infection, infants receiving at least 50% of nutritional intake from breast milk at the time of hospitalization, either sex, residence within 15 km from icddr,b

Conditions

Severe Acute Malnutrition

Keywords

Severe Acute Malnutrition; Young Infants under 6 months age; Microbiome; Prebiotics; Probiotics

Outcome Measures

Primary Outcomes (1)

• Number of colonization of Bifidobacterium infantis in the intestine of the study participants as measured by qPCR during and after 28 days of supplementation (with and without prebiotics)

  Number of colonization of Bifidobacterium infantis in the intestine of the study participants as measured by qPCR during and after 28 days of supplementation (with and without prebiotics)

  28 days

Secondary Outcomes (18)

• Baseline composition of gut microbiota of the study participants as estimated by metagenomic analysis

  28 days

• Bifidobacterium colonization (relative abundance) estimated by metagenomic analysis during/after supplementation of 28 days

  28 days

• Colonization of naturally occurring Bifidobacterium infantis strains identified by qPCR

  28 days

• Baseline stool pH

  At screening

• Change from baseline in stool pH during supplementation for 28 days

  28 days

Study Arms (4)

B. infantis alone (Bif) in SAM infants

ACTIVE COMPARATOR

B. infantis alone (Bif) in Severe Acute Malnourished infants

Other: Bifidobacterium infantis with prebiotic Lacto-N-neotetraose [LNnT]; Other: Placebo (Lactose)

B. infantis + prebiotic Lacto-N-neotetraose [LNnT]

ACTIVE COMPARATOR

B. infantis + prebiotic Lacto-N-neotetraose \[LNnT\] (Bif+prebiotic) in Severe Acute Malnourished infants

Other: Bifidobacterium infantis

Placebo (Lactose)

PLACEBO COMPARATOR

Placebo (Lactose) in Severe Acute Malnourished infants

Other: Bifidobacterium infantis; Other: Bifidobacterium infantis with prebiotic Lacto-N-neotetraose [LNnT]

B. infantis alone (Bif) in Not SAM Infants

ACTIVE COMPARATOR

B. infantis alone (Bif) in not Severe Acute Malnourished infants

Other: Bifidobacterium infantis; Other: Bifidobacterium infantis with prebiotic Lacto-N-neotetraose [LNnT]; Other: Placebo (Lactose)

Interventions

Bifidobacterium infantis OTHER

Bifidobacterium longum subsp. infantis (EVC001)

B. infantis + prebiotic Lacto-N-neotetraose [LNnT]; B. infantis alone (Bif) in Not SAM Infants; Placebo (Lactose)

Bifidobacterium infantis with prebiotic Lacto-N-neotetraose [LNnT] OTHER

Bifidobacterium infantis with prebiotic Lacto-N-neotetraose \[LNnT\]

B. infantis alone (Bif) in Not SAM Infants; B. infantis alone (Bif) in SAM infants; Placebo (Lactose)

Placebo (Lactose) OTHER

Placebo (Lactose)

B. infantis alone (Bif) in Not SAM Infants; B. infantis alone (Bif) in SAM infants

Eligibility Criteria

• Age: 2 Months - 6 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Group 1 (SAM):
• Infants between 2 and \<6 months old with SAM as defined by weight-for-length \< -3 Z and/ or bilateral pedal edema
• either sex
• caregiver willing to provide consent for enrolment of the infant
• caregiver willing to stay in the Nutritional Rehabilitation Unit for about 15 days
• residence within 15 km from icddr,b
• Group 2 (non-malnourished):
• Non-malnourished infants (WLZ ≥ -1) \<6 months old who are hospitalized for treatment with antibiotics for infection (infants who come with a history of antibiotic intake for 3 days or more will be eligible; the last dose of such an antibiotic will have to be taken within last 24hours, the antibiotic intake should be documented by the verification of a prescription, the bottle of antibiotic or asking the caregiver about the name of antibiotic or its price and how it is reconstituted)
• infant receiving at least 50% of nutritional intake from breast milk at the time of hospitalization
• either sex
• residence within 15 km from icddr,b

You may not qualify if:

• Septic shock or very severe pneumonia requiring assisted ventilation
• acute kidney injury on admission
• congenital defects interfering with feeding such as cleft palate
• chromosomal anomalies
• jaundice
• tuberculosis
• presence of bilateral pedal edema ongoing maternal antibiotic usage for breastfeeding infants
• Infants receiving ≥75% of nutrition from breast milk
• Infants receiving \<50% of nutrition from breast milk

Sponsors & Collaborators

• International Centre for Diarrhoeal Disease Research, Bangladesh: lead

Study Sites (1)

Dhaka Hospital, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)

Dhaka, Bangladesh

Location

Related Publications (24)

• Chassaing B, Srinivasan G, Delgado MA, Young AN, Gewirtz AT, Vijay-Kumar M. Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS One. 2012;7(9):e44328. doi: 10.1371/journal.pone.0044328. Epub 2012 Sep 5.

  PMID: 22957064 BACKGROUND

• Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature. 2014 May 15;509(7500):357-60. doi: 10.1038/nature13178. Epub 2014 Apr 16.

  PMID: 24739969 BACKGROUND

• Dulay AT, Buhimschi CS, Zhao G, Oliver EA, Mbele A, Jing S, Buhimschi IA. Soluble TLR2 is present in human amniotic fluid and modulates the intraamniotic inflammatory response to infection. J Immunol. 2009 Jun 1;182(11):7244-53. doi: 10.4049/jimmunol.0803517.

  PMID: 19454721 BACKGROUND

• Grenov B, Namusoke H, Lanyero B, Nabukeera-Barungi N, Ritz C, Molgaard C, Friis H, Michaelsen KF. Effect of Probiotics on Diarrhea in Children With Severe Acute Malnutrition: A Randomized Controlled Study in Uganda. J Pediatr Gastroenterol Nutr. 2017 Mar;64(3):396-403. doi: 10.1097/MPG.0000000000001515.

  PMID: 28079729 BACKGROUND

• Hock BD, Kato M, McKenzie JL, Hart DN. A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera. Int Immunol. 2001 Jul;13(7):959-67. doi: 10.1093/intimm/13.7.959.

  PMID: 11431426 BACKGROUND

• Hunt KM, Foster JA, Forney LJ, Schutte UM, Beck DL, Abdo Z, Fox LK, Williams JE, McGuire MK, McGuire MA. Characterization of the diversity and temporal stability of bacterial communities in human milk. PLoS One. 2011;6(6):e21313. doi: 10.1371/journal.pone.0021313. Epub 2011 Jun 17.

  PMID: 21695057 BACKGROUND

• Islam MM, Peerson JM, Ahmed T, Dewey KG, Brown KH. Effects of varied energy density of complementary foods on breast-milk intakes and total energy consumption by healthy, breastfed Bangladeshi children. Am J Clin Nutr. 2006 Apr;83(4):851-8. doi: 10.1093/ajcn/83.4.851.

  PMID: 16600938 BACKGROUND

• Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A, Sadler K, Bahwere P, Collins S. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet. 2009 Jul 11;374(9684):136-44. doi: 10.1016/S0140-6736(09)60884-9.

  PMID: 19595348 BACKGROUND

• Handelsman J, Rondon MR, Brady SF, Clardy J, Goodman RM. Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem Biol. 1998 Oct;5(10):R245-9. doi: 10.1016/s1074-5521(98)90108-9.

  PMID: 9818143 BACKGROUND

• Kuroishi T, Tanaka Y, Sakai A, Sugawara Y, Komine K, Sugawara S. Human parotid saliva contains soluble toll-like receptor (TLR) 2 and modulates TLR2-mediated interleukin-8 production by monocytic cells. Mol Immunol. 2007 Mar;44(8):1969-76. doi: 10.1016/j.molimm.2006.09.028. Epub 2006 Nov 1.

  PMID: 17081611 BACKGROUND

• Lepage P, Leclerc MC, Joossens M, Mondot S, Blottiere HM, Raes J, Ehrlich D, Dore J. A metagenomic insight into our gut's microbiome. Gut. 2013 Jan;62(1):146-58. doi: 10.1136/gutjnl-2011-301805. Epub 2012 Apr 23.

  PMID: 22525886 BACKGROUND

• LeBouder E, Rey-Nores JE, Rushmere NK, Grigorov M, Lawn SD, Affolter M, Griffin GE, Ferrara P, Schiffrin EJ, Morgan BP, Labeta MO. Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol. 2003 Dec 15;171(12):6680-9. doi: 10.4049/jimmunol.171.12.6680.

  PMID: 14662871 BACKGROUND

• Human Microbiome Project Consortium. A framework for human microbiome research. Nature. 2012 Jun 13;486(7402):215-21. doi: 10.1038/nature11209.

  PMID: 22699610 BACKGROUND

• Panigrahi P, Parida S, Nanda NC, Satpathy R, Pradhan L, Chandel DS, Baccaglini L, Mohapatra A, Mohapatra SS, Misra PR, Chaudhry R, Chen HH, Johnson JA, Morris JG, Paneth N, Gewolb IH. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017 Aug 24;548(7668):407-412. doi: 10.1038/nature23480. Epub 2017 Aug 16.

  PMID: 28813414 BACKGROUND

• Prata MM, Havt A, Bolick DT, Pinkerton R, Lima A, Guerrant RL. Comparisons between myeloperoxidase, lactoferrin, calprotectin and lipocalin-2, as fecal biomarkers of intestinal inflammation in malnourished children. J Transl Sci. 2016;2(2):134-139. doi: 10.15761/JTS.1000130. Epub 2016 Mar 25.

  PMID: 27746954 BACKGROUND

• Roudkenar MH, Kuwahara Y, Baba T, Roushandeh AM, Ebishima S, Abe S, Ohkubo Y, Fukumoto M. Oxidative stress induced lipocalin 2 gene expression: addressing its expression under the harmful conditions. J Radiat Res. 2007 Jan;48(1):39-44. doi: 10.1269/jrr.06057. Epub 2007 Jan 16.

  PMID: 17229997 BACKGROUND

• Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008 Oct;26(10):1135-45. doi: 10.1038/nbt1486.

  PMID: 18846087 BACKGROUND

• Sheridan PO, Bindels LB, Saulnier DM, Reid G, Nova E, Holmgren K, O'Toole PW, Bunn J, Delzenne N, Scott KP. Can prebiotics and probiotics improve therapeutic outcomes for undernourished individuals? Gut Microbes. 2014 Jan-Feb;5(1):74-82. doi: 10.4161/gmic.27252. Epub 2013 Dec 16.

  PMID: 24637591 BACKGROUND

• Smilowitz JT, Moya J, Breck MA, Cook C, Fineberg A, Angkustsiri K, Underwood MA. Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial. BMC Pediatr. 2017 May 30;17(1):133. doi: 10.1186/s12887-017-0886-9.

  PMID: 28558732 BACKGROUND

• Tringe SG, von Mering C, Kobayashi A, Salamov AA, Chen K, Chang HW, Podar M, Short JM, Mathur EJ, Detter JC, Bork P, Hugenholtz P, Rubin EM. Comparative metagenomics of microbial communities. Science. 2005 Apr 22;308(5721):554-7. doi: 10.1126/science.1107851.

  PMID: 15845853 BACKGROUND

• Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS. Application of metagenomics in the human gut microbiome. World J Gastroenterol. 2015 Jan 21;21(3):803-14. doi: 10.3748/wjg.v21.i3.803.

  PMID: 25624713 BACKGROUND

• Williams JE, Price WJ, Shafii B, Yahvah KM, Bode L, McGuire MA, McGuire MK. Relationships Among Microbial Communities, Maternal Cells, Oligosaccharides, and Macronutrients in Human Milk. J Hum Lact. 2017 Aug;33(3):540-551. doi: 10.1177/0890334417709433. Epub 2017 Jun 13.

  PMID: 28609134 BACKGROUND

• Woese CR, Fox GE. Phylogenetic structure of the prokaryotic domain: the primary kingdoms. Proc Natl Acad Sci U S A. 1977 Nov;74(11):5088-90. doi: 10.1073/pnas.74.11.5088.

  PMID: 270744 BACKGROUND

• Nuzhat S, Palit P, Mahfuz M, Islam MR, Hasan SMT, Islam MM, Sarker SA, Kyle DJ, Flannery RL, Vinjamuri A, Lebrilla CB, Ahmed T. Association of human milk oligosaccharides and nutritional status of young infants among Bangladeshi mother-infant dyads. Sci Rep. 2022 Jun 8;12(1):9456. doi: 10.1038/s41598-022-13296-w.

  PMID: 35676397 DERIVED

MeSH Terms

Conditions

Severe Acute Malnutrition

Interventions

lacto-N-neotetraose; Lactose

Condition Hierarchy (Ancestors)

Malnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Study Officials

• Tahmeed Ahmed, MBBS, PhD

  International Centre for Diarrhoeal Disease Research, Bangladesh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 3 treatment arms for infants with SAM * Placebo (Lactose) * B. infantis alone (Bif) * B. infantis + prebiotic Lacto-N-neotetraose \[LNnT\] (Bif+prebiotic) Age at enrollment * 2-3.9 months of age * 4-5.9 months of age 1. open-label treatment arm for 18 non-malnourished primarily breastfed infants - B. infantis alone (Bif)

Study Record Dates

• First Submitted: August 28, 2018
• First Posted: September 12, 2018
• Study Start: September 21, 2018
• Primary Completion: August 26, 2019
• Study Completion: March 18, 2020
• Last Updated: February 4, 2021

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

BA (1)