Back to results

Study of Environmental Enteropathy and Malnutrition in Pakistan (SEEM)

Primary Purpose

Malnutrition, Child, Enteropathy, Vaccine Response Impaired

Status

Completed

Phase

Not Applicable

Locations

Pakistan

Study Type

Interventional

Intervention

Nutritional education

Ready to Use Therapeutic Food

Upper gastrointestinal endoscopy with biopsy

About this trial

This is an interventional prevention trial for Malnutrition, Child

Eligibility Criteria

0 Days - 10 Years (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Children aged 0-6 months from Matiari, Pakistan with weight for height Z score (WHZ) < -2 at the time of enrollment
Children aged 0 to 6 months from Matiari, Pakistan who would be growing normally, with WHZ > 0, to serve as controls
Healthy control children under the age of 3 years, who will undergo endoscopy at CCHMC
Children under the age of 6 years with newly diagnosed celiac disease per endoscopy at CCHMC
Children under the age of 10 years with newly diagnosed Crohn's disease per endoscopy at CCHMC

Exclusion Criteria:

For healthy control children < 3 years old undergoing endoscopy at CCHMC, biopsies and diagnoses should not supportive of eosinophilic esophagitis
For healthy control children < 3 years old undergoing endoscopy at CCHMC, biopsies and diagnoses should not supportive of celiac disease
For healthy control children < 3 years old undergoing endoscopy at CCHMC, biopsies and diagnoses should not supportive of inflammatory bowel disease
For healthy control children < 3 years old undergoing endoscopy at CCHMC, children should not have been treated with antibiotics ≤ 4 weeks prior to endoscopy

Sites / Locations

Aga Khan University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

No Intervention

Arm Label

Moderate/severe malnourishment

Well nourished children

US children with celiac disease

US children with Crohn's disease

Healthy age-matched US children

Arm Description

Pakistani children from age 0 to 6 months with weight for height Z score (WHZ) < -2 at the time of enrollment. Parents/caregivers of all participants will undergo a series of rehabilitative interventions to improve the child's nutrition and growth. Those participants who remain WHZ < -2 despite interventions are eligible for medical evaluation for more advanced workup of malnutrition, including UGI endoscopy and biopsy.

Pakistani children from age 0 to 6 months who would be growing normally, with WHZ > 0, to serve as controls. Parents/caregivers of all participants will undergo a series of rehabilitative interventions to improve the child's nutrition and growth.

Comparative group for the Pakistani WHZ <-2 children who undergo UGI endoscopy and biopsy. Environmental Enteropathy and celiac disease have some shared features therefore we plan to enroll children under the age of 6 years with newly diagnosed celiac disease per endoscopy at CCHMC to assess the extent to which gene signatures and associated biologic pathways for children with celiac disease or environmental enteropathy overlap or differ.

Comparative group for the Pakistani WHZ <-2 children who undergo UGI endoscopy and biopsy. As some differentially expressed ileal gene signatures for Crohn's disease bear remarkable similarities to individual gene expression patterns previously reported for EE, children under the age of 10 years with newly diagnosed Crohn's disease per endoscopy at CCHMC will be enrolled to study these similarities and any differences

Comparative group for the Pakistani WHZ <-2 children who undergo UGI endoscopy and biopsy. Number of upper gastrointestinal endoscopies performed in children less than 2 years old are limited in Pakistan, therefore US age-matched controls will be used; healthy children < 3 years old will be enrolled, who will undergo endoscopy at CCHMC as part of a diagnostic workup for digestive symptoms, but whose biopsies and diagnoses are not supportive of eosinophilic esophagitis, celiac disease, or inflammatory bowel disease, and who were not treated with antibiotics ≤ 4 weeks prior to endoscopy.

Outcomes

Primary Outcome Measures

Nutritional status in children assessed by measuring parameters of growth at 3-6 months of age

Our birth cohort will be assessed for nutritional status by measuring parameters of growth, length, weight and height. These measurements will be calculated as Z scores according to WHO tables and children will be divided into the appropriate categories: Stunting as Length for Age Z-score < -2 SD (standard deviation), underweight as Weight-for-Age Z-score < -2 SD and wasting as Weight-for-Length Z-score < -2 SD, or normal-for-age.

Nutritional status in children assessed by measuring parameters of growth at 9 months of age

Association of biomarkers with Environmental Enteropathy at 3-6 months of age

Serum, stool, and urine biomarkers of EE will be collected and tested in malnourished and well-nourished children

Association of biomarkers with Environmental Enteropathy at 9 months of age

Serum, stool, and urine biomarkers of EE will be collected and tested in malnourished and well-nourished children

Association of biomarkers with Environmental Enteropathy at the time of endoscopy and biopsy

Serum, stool, and urine biomarkers of EE will be collected and tested in those children who are eligible to undergo upper GI endoscopy and biopsy

The use of UGI biopsy tissue for histopathological and multiomic workup for validation of biomarkers associated with EE

Biopsy specimens from UGI endoscopy obtained from eligible children will be used for detailed histopathologic and multiomic work up to study the pathophysiology of EE, validate current biomarkers, and generate novel biomarker candidates

Secondary Outcome Measures

Full Information

NCT ID

NCT03588013

First Posted

June 19, 2018

Last Updated

September 6, 2021

Sponsor

Aga Khan University

Collaborators

University of Virginia, Children's Hospital Medical Center, Cincinnati, Bill and Melinda Gates Foundation, Washington University School of Medicine, Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03588013

Brief Title

Study of Environmental Enteropathy and Malnutrition in Pakistan

Acronym

SEEM

Official Title

Study of Environmental Enteropathy and Malnutrition in Pakistan

Study Type

Interventional

2. Study Status

Record Verification Date

September 2021

Overall Recruitment Status

Completed

Study Start Date

March 1, 2016 (Actual)

Primary Completion Date

July 31, 2019 (Actual)

Study Completion Date

July 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Aga Khan University

Collaborators

University of Virginia, Children's Hospital Medical Center, Cincinnati, Bill and Melinda Gates Foundation, Washington University School of Medicine, Massachusetts General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

Environmental Enteropathy (EE) is an acquired sub-clinical inflammatory gut condition in which alterations in intestinal structure, function, and local and systemic immune activation lead to impaired vaccine responses, decreased cognitive potential and undernutrition in low-middle income countries. Approximately half of all global deaths in children aged less than five years are attributable to undernutrition making the study of EE an area of critical priority. However, given the operational limitations and ethical considerations for safely obtaining intestinal biopsies from young children in low resource settings, there have been few detailed investigations of human intestinal tissue in this vulnerable patient group for whom reversal of EE would provide the greatest benefit. EE biomarkers have been studied in different settings but these have not been correlated with the gold standard histopathology confirmation. The Study of Environment Enteropathy and Malnutrition in Pakistan (SEEM Pakistan) is designed to better understand the pathophysiology, predictors, biomarkers, and potential management strategies of EE to inform strategies to eradicate this debilitating pathology.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malnutrition, Child, Enteropathy, Vaccine Response Impaired, Stunting, Gastrointestinal Disease

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Moderately or severely malnourished (weight for height Z score (WHZ) < -2) children Well-nourished (WHZ > 0) children Control group of children in the US with celiac disease Control group of children in the US with Crohn's disease Control group of healthy age-matched children in the US

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

416 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Moderate/severe malnourishment

Arm Type

Experimental

Arm Description

Arm Title

Well nourished children

Arm Type

Active Comparator

Arm Description

Arm Title

US children with celiac disease

Arm Type

No Intervention

Arm Description

Arm Title

US children with Crohn's disease

Arm Type

No Intervention

Arm Description

Arm Title

Healthy age-matched US children

Arm Type

No Intervention

Arm Description

Intervention Type

Other

Intervention Name(s)

Nutritional education

Other Intervention Name(s)

Education

Intervention Description

4 week home delivered educational program that will focus on breast feeding and complimentary feeding. If child remains WHZ < -2 at by 9 months of age families will be shown 10 minute educational video detailing best practices for complimentary feeding.

Intervention Type

Dietary Supplement

Intervention Name(s)

Ready to Use Therapeutic Food

Other Intervention Name(s)

RUTF

Intervention Description

If child remains WHZ < -2 despite nutritional education then will be managed according to Pakistan's Community Management of Acute Malnutrition protocol. This will include provision of ready to use therapeutic food (RUTF) to the child at home with close follow up. Utilization of the RUTF will be monitored closely by bi-weekly home visits.

Intervention Type

Procedure

Intervention Name(s)

Upper gastrointestinal endoscopy with biopsy

Other Intervention Name(s)

UGI endoscopy, Biopsy, Esophagoduodenoscopy

Intervention Description

If child remains at WHZ < -2 despite educational and dietary interventions, then will undergo medical evaluation for assessment of need for more advanced workup of malnutrition, including UGI endoscopy at AKUH. Results of the advanced work up, including the UGI endoscopy, will guide future management of these children.

Primary Outcome Measure Information:

Title

Nutritional status in children assessed by measuring parameters of growth at 3-6 months of age

Description

Time Frame

Approximately 3-6 months after entry into study

Title

Nutritional status in children assessed by measuring parameters of growth at 9 months of age

Description

Time Frame

At approximately 9 months after entry into study

Title

Association of biomarkers with Environmental Enteropathy at 3-6 months of age

Description

Serum, stool, and urine biomarkers of EE will be collected and tested in malnourished and well-nourished children

Time Frame

Approximately 3-6 months after entry into study

Title

Association of biomarkers with Environmental Enteropathy at 9 months of age

Description

Serum, stool, and urine biomarkers of EE will be collected and tested in malnourished and well-nourished children

Time Frame

At approximately 9 months after entry into study

Title

Association of biomarkers with Environmental Enteropathy at the time of endoscopy and biopsy

Description

Serum, stool, and urine biomarkers of EE will be collected and tested in those children who are eligible to undergo upper GI endoscopy and biopsy

Time Frame

At approximately 15 months after entry into study

Title

The use of UGI biopsy tissue for histopathological and multiomic workup for validation of biomarkers associated with EE

Description

Time Frame

At approximately 15 months after entry into study

10. Eligibility

Sex

All

Minimum Age & Unit of Time

0 Days

Maximum Age & Unit of Time

10 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Children aged 0-6 months from Matiari, Pakistan with weight for height Z score (WHZ) < -2 at the time of enrollment Children aged 0 to 6 months from Matiari, Pakistan who would be growing normally, with WHZ > 0, to serve as controls Healthy control children under the age of 3 years, who will undergo endoscopy at CCHMC Children under the age of 6 years with newly diagnosed celiac disease per endoscopy at CCHMC Children under the age of 10 years with newly diagnosed Crohn's disease per endoscopy at CCHMC Exclusion Criteria: For healthy control children < 3 years old undergoing endoscopy at CCHMC, biopsies and diagnoses should not supportive of eosinophilic esophagitis For healthy control children < 3 years old undergoing endoscopy at CCHMC, biopsies and diagnoses should not supportive of celiac disease For healthy control children < 3 years old undergoing endoscopy at CCHMC, biopsies and diagnoses should not supportive of inflammatory bowel disease For healthy control children < 3 years old undergoing endoscopy at CCHMC, children should not have been treated with antibiotics ≤ 4 weeks prior to endoscopy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Syed Asad Ali, MD, MPH

Organizational Affiliation

Aga Khan University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Sean R Moore, MD

Organizational Affiliation

University of Virginia

Official's Role

Principal Investigator

Facility Information:

Facility Name

Aga Khan University

City

Karachi

State/Province

Sindh

ZIP/Postal Code

74800

Country

Pakistan

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

35534310

Citation

Ahmed S, Iqbal J, Sadiq K, Umrani F, Rizvi A, Kabir F, Jamil Z, Syed S, Ehsan L, Zulqarnain F, Sajid M, Hotwani A, Rahman N, Ma JZ, McNeal M, Ann Costa Clemens S, Talat Iqbal N, Moore SR, Ali A. Association of Anti-Rotavirus IgA Seroconversion with Growth, Environmental Enteric Dysfunction and Enteropathogens in Rural Pakistani Infants. Vaccine. 2022 May 31;40(25):3444-3451. doi: 10.1016/j.vaccine.2022.04.032. Epub 2022 May 6.

Results Reference

derived

PubMed Identifier

34718665

Citation

Zhao X, Setchell KDR, Huang R, Mallawaarachchi I, Ehsan L, Dobrzykowski Iii E, Zhao J, Syed S, Ma JZ, Iqbal NT, Iqbal J, Sadiq K, Ahmed S, Haberman Y, Denson LA, Ali SA, Moore SR. Bile Acid Profiling Reveals Distinct Signatures in Undernourished Children with Environmental Enteric Dysfunction. J Nutr. 2021 Dec 3;151(12):3689-3700. doi: 10.1093/jn/nxab321.

Results Reference

derived

PubMed Identifier

33524399

Citation

Haberman Y, Iqbal NT, Ghandikota S, Mallawaarachchi I, Tzipi Braun, Dexheimer PJ, Rahman N, Hadar R, Sadiq K, Ahmad Z, Idress R, Iqbal J, Ahmed S, Hotwani A, Umrani F, Ehsan L, Medlock G, Syed S, Moskaluk C, Ma JZ, Jegga AG, Moore SR, Ali SA, Denson LA. Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction. Gastroenterology. 2021 May;160(6):2055-2071.e0. doi: 10.1053/j.gastro.2021.01.221. Epub 2021 Jan 29.

Results Reference

derived

PubMed Identifier

31331393

Citation

Iqbal NT, Syed S, Sadiq K, Khan MN, Iqbal J, Ma JZ, Umrani F, Ahmed S, Maier EA, Denson LA, Haberman Y, McNeal MM, Setchell KDR, Zhao X, Qureshi S, Shen L, Moskaluk CA, Liu TC, Yilmaz O, Brown DE, Barratt MJ, Kung VL, Gordon JI, Moore SR, Ali SA. Study of Environmental Enteropathy and Malnutrition (SEEM) in Pakistan: protocols for biopsy based biomarker discovery and validation. BMC Pediatr. 2019 Jul 22;19(1):247. doi: 10.1186/s12887-019-1564-x.

Results Reference

derived

Learn more about this trial

Study of Environmental Enteropathy and Malnutrition in Pakistan

We'll reach out to this number within 24 hrs