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The Bangladesh Environmental Enteric Dysfunction Study (BEED)

This study is currently recruiting participants.
See Contacts and Locations
Verified August 2016 by International Centre for Diarrhoeal Disease Research, Bangladesh
Sponsor:
Collaborators:
Bill and Melinda Gates Foundation
University of Virginia
University of Washington
Dhaka Medical College
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Information provided by (Responsible Party):
International Centre for Diarrhoeal Disease Research, Bangladesh
ClinicalTrials.gov Identifier:
NCT02812615
First received: May 31, 2016
Last updated: August 15, 2017
Last verified: August 2016
  Purpose
This is a community-based intervention study which will be undertaken at Mirpur, Dhaka, Bangladesh. Participants will be recruited from two age groups: a child cohort (age 12 to 18 months) and an adult cohort (age 18 to 45 years). The child cohort will consist of stunted children (length for age Z score, LAZ < -2), children who are at risk of stunting (length for age Z score <-1 to -2) and child controls. The adult cohort will consist of malnourished adult cases (Body Mass Index <18.5) and adult controls. After screening the participants for any organic diseases and application of inclusion/exclusion criteria, they will receive nutrition interventions. Participants eligible for study will be tested for potential bio markers of environmental enteropathy (stool, urine and serum) once before and once after the nutritional intervention. Participants who will fail to respond to nutritional therapy (measured by anthropometric assessment) will become candidates for upper gastrointestinal endoscopy with biopsy. The study will include duodenal biopsies from a control group of children from University of Virginia Hospital in Charlottesville, Virginia who will undergo upper GI endoscopy as part of their clinical care as per the standard clinical protocol followed at the hospital. Adult controls (BMI > 18.5) for endoscopy will be collected from international centre for diarrhoeal disease research,Bangladesh staff clinic, Dhaka Medical College and Hospital (DMCH), Dhaka and Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka.

Condition Intervention
Malnutrition Infection Dietary Supplement: Egg Dietary Supplement: Milk Drug: Albendazole/Pyrantel Pamoate Behavioral: Nutritional counselling Dietary Supplement: Micronutrient sprinkles

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Stunting and Bangladesh Environmental Enteric Dysfunction Study

Resource links provided by NLM:


Further study details as provided by International Centre for Diarrhoeal Disease Research, Bangladesh:

Primary Outcome Measures:
  • Change in Length for Age Z score [ Time Frame: baseline and 3 months ]
    For stunted child participants, length and age data will be collected before and after the intervention period (3 months) and changes in length for age Z score will be measured.For at risk of stunting child participants, length and age data will be collected before and after the intervention period (2 months) and changes in length for age Z score will be measured.

  • Change in Body Mass Index [ Time Frame: baseline and 2 months ]
    For malnourished adult participants, height and and weight data will be collected before and after the intervention period (2 months) and changes in Body Mass Index will be measured.


Secondary Outcome Measures:
  • Change in stool Regeneration gene 1 Beta (Reg 1B) biomarker level [ Time Frame: baseline and 3 months ]
    Reg1 is known to promote intestinal epithelial cell proliferation, regeneration and repair, and is up-regulated in a variety of enteric infections and inflammatory conditions. A commercial ELISA assay will be run on fecal samples to measure Reg 1 levels.

  • Change in stool neopterin level [ Time Frame: baseline and 3 months ]
    Neopterin is a product of the breakdown of cyclic guanosine monophosphate (cGMP) when released from phagocytic cells, and an increase in neopterin can be found with the activation of cellular immune response. So, increased neopterin in stools will be used as a marker for an inflammatory immune response in the intestinal epithelium.

  • Change in stool myeloperoxidase level [ Time Frame: baseline and 3 months ]
    Derived from azurophil granules, which are a specific marker of polymorphonuclear leukocytes (PMN) activity, myeloperoxidase (MPO) catalyzes the oxidation of substances through hydrogen peroxide (H2O2). The MPO H2O2-system has a toxic effect on many micro-organisms such as bacteria, fungi, viruses and mycoplasma. MPO determination in the stool reflects the inflammatory activity of Crohn's disease or ulcerative colitis. During inflammation in the intestinal mucosa, neutrophils migrate towards the gut mucosa and release myeloperoxidase from granulocytes which can be detected in stools and used as a marker of intestinal inflammation. A commercial ELISA kit will be used to measure myeloperoxidase in stool specimens.

  • Change in stool Alpha-1-antitrypsin level [ Time Frame: baseline and 3 months ]
    Alpha-1-antitrypsin is an acute phase protein predominantly made in the liver, but also in intestinal macrophages, monocytes, and epithelial cells and released during inflammation. The presence of alpha-1-antitrypsin in the stool is a marker of intestinal inflammation, intestinal permeability and protein loss. A commercial ELISA kit will be utilized to measure alpha-1-antitrypsin in stool specimens.

  • Change in stool Calprotectin level [ Time Frame: baseline and 3 months ]
    Calprotectin is released by activated neutrophils, and it accounts for more than 40% of the cytosolic proteins of neutrophils. Elevated concentrations of calprotectin can be measured in plasma, cerebrospinal fluid, synovial fluid, urine, and feces when inflammation is present or in malignant conditions. The high fecal calprotectin concentrations can be explained by increased turnover of leukocytes in the gut wall and increased migration of neutrophils into the gut lumen . The fecal calprotectin results are expressed in mg of calprotectin per kilogram of wet feces within a normal reference range of <50 mg/kg.

  • Change in stool TaqMan Array Card (TAC) result [ Time Frame: baseline and 3 months ]
    The TaqMan Array Card (TAC) system is a real-time polymerase chain reaction format that is used to detect multiple infection targets. An enteric TaqMan Array Card can detect 27 enteropathogens, including viruses and helminths Fecal samples will be spiked with extrinsic controls, and total nucleic acid will be extracted. TAC allows fast, accurate, and quantitative detection of a broad spectrum of enteropathogens.

  • Change in gut microbiota maturity status [ Time Frame: baseline and 3 months ]
    The human gut microbiota undergoes a defined postnatal developmental program of assembly over the first 2-3 years of life that is perturbed in children with undernutrition and is not durably repaired by existing therapeutic foods. While these studies have identified a link between microbiota maturity and anthropometric measures of healthy growth in early childhood, the relationship between histopathologically defined Environmental Enteric Dysfunction and the configuration/maturation of the microbiota in the small and large intestines has not been studied.

  • Change in lactulose and rhamnose permeability test [ Time Frame: baseline and 3 months ]
    The lactulose and rhamnose permeability test will be used to measure intestinal permeability. The synthetic disaccharide, lactulose, is minimally absorbed via the paracellular route and then excreted unchanged in the urine, while the monosaccharide sugar rhamnose, being smaller is usually completely absorbed in the small intestine and excreted unchanged in the urine. An elevated lactulose: rhamnose ratio indicates increased permeability.

  • Change in blood C-reactive protein level [ Time Frame: baseline and 3 months ]
    C-reactive protein (CRP) is an acute phase protein and can be detected during infection. It is a measurement of enteric permeability across the gut membrane. A commercial ELISA kit will be used to measure the levels of CRP in plasma samples.

  • Change in blood Alpha-1-acid glycoprotein level [ Time Frame: baseline and 3 months ]
    Alpha-1-acid glycoprotein is an acute phase protein. Increased levels are found in the serum during systemic tissue injury, inflammation and infection. A commercial ELISA kit will be utilized to measure the levels of alpha-1-acid glycoprotein in plasma specimens.

  • Change in blood sCD14 level [ Time Frame: baseline and 3 months ]
    sCD14 is a protein receptor for lipopolysaccharide (LPS). Similar to the principle behind the anti-LPS antibody assay, once the LPS or endotoxin containing particles enters the bloodstream from the intestinal mucosa, they are bound to sCD14. An increase in sCD14 indicates an increase in endotoxin or LPS entering the bloodstream from the intestinal mucosa .

  • Change in blood kynurenine Tryptophan ratio [ Time Frame: baseline and 3 months ]
    Tryptophan is an essential amino acid that is central to cellular respiration and neurotransmission, and is a key immune mediator. During inflammation, tryptophan is metabolized by indoleamine 2,3-dioxygenase (IDO) to the toxic metabolite kynurenine. IDO activity is measured by the ratio of kynurenine to tryptophan. IDO activity correlates with disease severity in patients with chronic inflammatory diseases .

  • Change in blood Glucagon-like peptide-2 level [ Time Frame: baseline and 3 months ]
    Glucagon-like peptide-2 (GLP-2) is a newly discovered gastrointestinal peptide with 33% sequence homology to glucagon. GLP-2 has attracted interest because of its potent endocrine/paracrine actions. The peptide results from expression of the glucagon gene in the intestinal mucosa, from where it is released mainly in response to luminal contact with unabsorbed nutrients. In addition to mucosal growth, GLP-2 enhances activities of several intestinal brush-border enzymes, and it delays gastric transit, thereby increasing the intestinal capacity for nutrient absorption. Thus, it appears that GLP-2 serves to ensure an optimal intestinal capacity.

  • Change in blood ferritin level [ Time Frame: baseline and 3 months ]
    Serum ferritin is widely recognized as an acute phase reactant and marker of acute and chronic inflammation, and is nonspecifically elevated in a wide range of inflammatory conditions.

  • Change in blood zinc level [ Time Frame: baseline and 3 months ]
    Scientists have explored the overlapping nature of zinc deficiency and environmental enteropathy, and presented evidence for their interaction. Environmental Enteropathy (EE) leads to impaired zinc homeostasis, predominantly due to reduced absorptive capacity arising from disturbed intestinal architecture, and zinc deficiency exacerbates several of the proposed pathways that underlie EE, including intestinal permeability, enteric infection, and chronic inflammation.

  • Change in blood pepsinogen I & II level [ Time Frame: baseline and 3 months ]
    Gastric acid has an important pathophysiological role in human beings. Appropriate levels of gastric acid are needed to adequately absorb many nutrients including minerals and vitamins. It is also a crucial part of the immune system. The hypochlorhydria induced by H. pylori infection may also result in alterations in the gut microbiota and contribute to small intestinal permeability changes and malabsorption,In this study, we also want to investigate serum pepsinogen I & II to see their association with Environmental Enteric Dysfunction.

  • Change in blood Low density lipoprotein related receptor 1 (LRP1) level [ Time Frame: baseline and 3 months ]
    LRP1 is an endocytic receptor involved in trafficking at least 100 different molecules, including lipids and proteins/peptides involved in immune system function (e.g. antigen presentation) as well as viral proteins and toxins. The epigenetic data strongly suggest that LRP1 expression is reduced in stunted children compared to controls.

  • Change in blood metabolomic profile [ Time Frame: baseline and 3 months ]
    Gut inflammation is reflected in an altered serum metabolite profile; characterization of the metabolome can identify pathways and metabolite bio-markers that may be useful as a diagnostic for inflammation

  • Change in small intestinal bacterial overgrowth (SIBO) status [ Time Frame: baseline and 3 months ]
    Small intestine bacterial overgrowth (SIBO) is measured noninvasively by a hydrogen breath test, where oral glucose is administered and an increase of hydrogen in the breath SIBO of at least 12 parts per million is detected. Traditionally, SIBO has been considered a secondary condition that develops in the setting of altered intestinal anatomy, slowed intestinal motility, or aberrant gastrointestinal function.


Estimated Enrollment: 1575
Actual Study Start Date: March 7, 2016
Estimated Study Completion Date: October 31, 2019
Estimated Primary Completion Date: October 31, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Malnourished participants
After screening the participants for any organic diseases and application of inclusion/exclusion criteria, stunted children, children who are at risk of stunting and malnourished adult cases will receive one egg, 150 ml of milk 6 days a week for 3, 2 and 2 months respectively. Along with that participants will also get Anti-helminthic treatment (Albendazole/Pyrantel Pamoate) and nutritional counselling. Children will get one sachet of multiple micro-nutrient sprinkles per day to be administered at home with the mid-day meal for two months.
Dietary Supplement: Egg
After enrollment, participants will receive one large egg 6 days a week for 3, 2 and 2 months for stunted children, children at risk of stunting, and malnourished adults, respectively.
Dietary Supplement: Milk
After enrollment, participants will receive 150ml of milk 6 days a week for 3, 2 and 2 months for stunted children, children at risk of stunting, and malnourished adults, respectively.
Drug: Albendazole/Pyrantel Pamoate
As per the national guidelines, treatment will be provided based with 200 mg of Albendazole or 10mg/kg Pyrantel Pamoate single dose if the participants have not been treated for helminths in the preceding three months.
Behavioral: Nutritional counselling
Parents/caregivers will be given nutritional counselling
Dietary Supplement: Micronutrient sprinkles
For the child cohort, one sachet of multiple micro-nutrient sprinkles per day to be administered with the mid-day meal for two months

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Months to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Inclusion criteria for stunted children: All of the following criteria must be met for a subject to be eligible to participate in the study-

  • Parent(s) willing to sign consent form
  • Child age 12-18 months
  • LAZ < -2
  • Parent(s) willing to bring child to the study site every day for 3 months for nutritional therapy
  • Parents willing to have child undergo laboratory investigations and upper GI endoscopy and biopsy if the child fails to respond to nutritional therapy

Inclusion criteria for children who are at risk of stunting: All of the following criteria must be met for a subject to be eligible to participate in the study -

  • Parent(s) willing to sign consent form
  • Child age 12-18 months
  • LAZ between <-1 to -2
  • Parent(s) willing to bring child to the study site every day for 2 months for nutritional therapy
  • Parents willing to have child undergo endoscopy and biopsy if the child fails to respond to nutritional therapy

Inclusion criteria for malnourished adults: All of the following criteria must be met for a subject to be eligible to participate in the study -

  • Willing to sign consent form
  • Age 18-45 years
  • BMI < 18.5
  • Willing to visit the study site every day for 2 months for nutritional therapy
  • Willing to undergo endoscopy and biopsy if he/she fails to respond to nutritional therapy

Selection criteria for adult controls:

An equal number of age and sex matched adult controls will be enrolled form the subjects with functional dyspepsia (FD) with apparently normal health (normal BMI) and absence of organic diseases. FD subjects will be identified from the Gastroenterology outpatient department of Dhaka Medical College Hospital and international centre for diarrhoeal disease research, Bangladesh staff clinic who will undergo upper GI endoscopy for evaluation of dyspepsia and have normal endoscopic findings. Dyspepsia will be defined by pre-defined criteria (Rome III criteria) by a structured questionnaire which has been translated and validated in Bengali.

Exclusion Criteria:

Exclusion criteria for stunted children: Meeting any of the following criteria will exclude a subject from study participation -

  • Severe acute malnutrition (SAM), severe anemia (<8 g/dl), tuberculosis, other chronic diseases or any congenital disorder or deformity
  • Diarrhoea: Ongoing episode of diarrhoea, history of persistent diarrhoea in the past month or history of acute diarrhoea in the past 7 days
  • Known allergy to eggs or milk or milk intolerance

Exclusion criteria for children who are at risk of stunting: Meeting any of the following criteria will exclude a subject from study participation -

  • Severe acute malnutrition (SAM), severe anemia (<8 g/dl), tuberculosis, other chronic diseases or any congenital disorder or deformity
  • Diarrhoea: Ongoing episode of diarrhoea, history of persistent diarrhoea in the past month or history of acute diarrhoea in the past 7 days
  • Known allergy to eggs or milk or milk intolerance

Exclusion criteria for malnourished adults: Meeting any of the following criterions will exclude a subject from study participation-

  • Severe anemia (<8 g/dl), tuberculosis and other chronic diseases including diabetes mellitus or any congenital disorder or deformity
  • Pregnant women, lactating women, drug abusers, known psychiatric disorders
  • High clinical suspicion of cancer or other chronic or acute diseases that may cause malnutrition. Adult participants who fulfilled the inclusion criteria and not excluded through history and clinical examination based exclusion criteria will undergo screening tests for confirmation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02812615

Contacts
Contact: Tahmeed Ahmed, PhD tahmeed@icddrb.org
Contact: Mustafa Mahfuz, MPH mustafa@icddrb.org

Locations
Bangladesh
Mirpur Recruiting
Dhaka, Bangladesh, 1216
Contact: Tahmeed Ahmed, Ph.D    +88029827001-10 ext 2300    tahmeed@icddrb.org   
Contact: Mustafa Mustafa, MPH    9840523-32 ext 2304    mustafa@icddrb.org   
Principal Investigator: Mustafa Mustafa, MPH         
Sponsors and Collaborators
International Centre for Diarrhoeal Disease Research, Bangladesh
Bill and Melinda Gates Foundation
University of Virginia
University of Washington
Dhaka Medical College
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
  More Information

Responsible Party: International Centre for Diarrhoeal Disease Research, Bangladesh
ClinicalTrials.gov Identifier: NCT02812615     History of Changes
Other Study ID Numbers: 16007
Study First Received: May 31, 2016
Last Updated: August 15, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by International Centre for Diarrhoeal Disease Research, Bangladesh:
Environmental Enteric Dysfunction

Additional relevant MeSH terms:
Malnutrition
Nutrition Disorders
Micronutrients
Trace Elements
Albendazole
Pyrantel
Pyrantel Pamoate
Growth Substances
Physiological Effects of Drugs
Anthelmintics
Antiparasitic Agents
Anti-Infective Agents
Anticestodal Agents
Antiplatyhelmintic Agents
Antiprotozoal Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antinematodal Agents
Neuromuscular Depolarizing Agents
Neuromuscular Blocking Agents
Neuromuscular Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on August 18, 2017