Clinical trial NCT03588013: Study of Environmental Enteropathy and Malnutrition in Pakistan
Official title: Study of Environmental Enteropathy and Malnutrition in Pakistan
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Malnutrition, Child
Enteropathy
Vaccine Response Impaired
Stunting
Gastrointestinal Disease
Lead sponsor: Aga Khan University
Sponsor class: OTHER
Collaborators: name: University of Virginia
name: Children's Hospital Medical Center, Cincinnati
name: Bill and Melinda Gates Foundation
name: Washington University School of Medicine
name: Massachusetts General Hospital
First posted: 2018-07-17
Enrollment: 416
Sex: ALL
Minimum age (years): 0
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1. Moderately or severely malnourished (weight for height Z score (WHZ) \< -2) children
2. Well-nourished (WHZ \> 0) children
3. Control group of children in the US with celiac disease
4. Control group of children in the US with Crohn's disease
5. Control group of healthy age-matched children in the US
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Nutritional status in children assessed by measuring parameters of growth at 3-6 months of age
timeFrame: Approximately 3-6 months after entry into study
measure: Nutritional status in children assessed by measuring parameters of growth at 9 months of age
timeFrame: At approximately 9 months after entry into study
measure: Association of biomarkers with Environmental Enteropathy at 3-6 months of age
timeFrame: Approximately 3-6 months after entry into study
measure: Association of biomarkers with Environmental Enteropathy at 9 months of age
timeFrame: At approximately 9 months after entry into study
measure: Association of biomarkers with Environmental Enteropathy at the time of endoscopy and biopsy
timeFrame: At approximately 15 months after entry into study
measure: The use of UGI biopsy tissue for histopathological and multiomic workup for validation of biomarkers associated with EE
timeFrame: At approximately 15 months after entry into study
Secondary outcomes:
Other outcomes:
Locations:
city: Karachi
country: Pakistan
facility: Aga Khan University
state: Sindh
Study officials:
affiliation: Aga Khan University
name: Syed Asad Ali, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Virginia
name: Sean R Moore, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.