Labelled Carbon Sucrose Breath Test (13C-SBT) as a Marker of Environmental Enteropathy (SBT4EE)

Validation and Field-applicability of a 13C-Sucrose Breath Test to Assess Carbohydrate Uptake and Utilization in Environmental Enteropathy Among Children in Resource Poor Settings: A Multi-site Prospective Study

Linear growth failure, a manifestation of chronic undernutrition in early childhood, is a recalcitrant problem in resource constrained settings. The underlying causes of growth failure are multifactorial, but persistent and recurrent infection and inflammation of the gastrointestinal tract and immune activation, a condition commonly referred to as environmental enteropathy, is an important contributor. A highly enriched 13C-Sucrose Breath Test, a measure of sucrase-isomaltase activity, will be evaluated as a non-invasive biomarker of environmental enteropathy, and more specifically of intestinal brush border enzyme activity in 6 resource poor countries (Bangladesh, India, Jamaica, Kenya, Peru and Zambia) in 100 volunteers aged 12-15 months (total n=600) and evaluated relative to the lactose rhamnose test and linear and ponderal growth over a 3-6 month period following biomarker assessment. Field usability will also be assessed.

Study Overview

• Status: Recruiting
• Conditions: Intestinal Permeability; Enteropathy; Malnutrition, Child; Glucose-Galactose Malabsorption; Linear Growth Failure

Detailed Description

Environmental enteropathy is associated with linear and ponderal growth shortfalls in young children in resource constrained settings. However, the physiological alterations of intestinal function that accompany both the demonstrable evidence of inflammation and architectural changes seen in biopsies from effected children have yet to be elucidated, and this knowledge gap limits the development of effective strategies to optimally manage the condition. Furthermore, a limited number of non-invasive assays exist with which to assess the presence of environmental enteropathy in low resource settings. This study aims 1) to determine if sucrose-isomaltase enzyme is altered in children with environmental enteropathy by using a 13C-Sucrose breath test 2) to determine if the test is able to be employed in resource limited settings.

• Study Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

• Study Contact: Name: Margaret N Kosek, MD; Phone Number: 434-243-9552; Email: mkosek@virginia.edu
• Study Contact Backup: Name: Victor Owino, PhD; Email: V.Owino@iaea.org

Study Locations

• Australia
  • Adelaide, Australia
    • Recruiting
    • Flinders University
    • Contact: Roger Yazbek, PhD; Email: roger.yazbek@flinders.edu.au
• Bangladesh
  • Dhaka, Bangladesh
    • Recruiting
    • Nutrition and Clincial Services Division, icddr, b
    • Contact: Sayeeda Huq, PhD; Email: sayeeda@icddrb.org
• India
  • Bengaluru, India
    • Recruiting
    • CBCI Society for Medical Education, St John's Research Institute
    • Contact: Nirupama Shivakumar, MBBS, DCH; Email: nirupama.s@sjri.res.in
• Jamaica
  • Kingston, Jamaica
    • Not yet recruiting
    • Tropical Metabolism Research Unit, University of West Indies
    • Contact: Sherine White, MSc; Email: sherine.whyte@uwimona.edu.jm
• Kenya
  • Kakamega, Kenya
    • Recruiting
    • Masinde Muliro University of Science and Technology
    • Contact: Silvenus Konyole, PhD; Email: konyole2000@yahoo.com
• Peru
  • Iquitos, Peru
    • Completed
    • Investigaciones Biomedicas, Asociacion Benefica PRISMA
• United Kingdom
  • East Kilbride, United Kingdom
    • Recruiting
    • Scottish Universities Environmental Research Centre
    • Contact: Douglas Morrison, PhD; Email: douglas.morrison@glasgow.ac.uk
• Zambia
  • Lusaka, Zambia
    • Not yet recruiting
    • Tropical Gastroenterology & Nutrition Ltd
    • Contact: Paul Kelly, MD; Email: m.p.kelly@qmul.ac.uk
  • Ndola, Zambia
    • Not yet recruiting
    • Tropical Diseases Research Centre
    • Contact: Justin Chileshe, MSc; Email: chilesej@tdrc.org.zm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 1 year (Child)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Because of exigent test requirements enrollment will be restricted to convenience samples from populations near centers of excellence in nutritional studies in Dhaka, Bangladesh (the International Centre for Diarrhoeal Disease Research); Bangalore, India (St. John's Research Institute, St. John's National Academy of Health Sciences); Kingston, Jamaica (The Tropical Metabolism Research Unit of the Caribbean Institute for Health Research, University of West Indies); Kakamega, Kenya (Masinde Muliro University of Science and Technology); Iquitos, Peru44 (Asociación Benefica PRISMA and the University of Virginia); and Ndola, Zambia (Tropical Disease Research Centre). These sites represent a range of epidemiologic contexts which will enhance the cross-context applicability of study results.

Description

Inclusion Criteria:

All children will be recruited and enrolled through convenience sampling, either at the community level (if the study site has previously censused the community) or through child clinic visits.

Exclusion Criteria:

1. Severe acute malnutrition
2. HIV positive
3. Weight for height Z >+2
4. Known medical illness contributing to growth failure

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of SBT to Lactulose rhamnose (LR) test-% dose 90 min	The 13C-SBT (cumulative percent of dose recovered at 90 minutes post administration) will be compared to LR ratio (the ratio of the percent recovery of administered lactulose and mannitol)	6 months after enrollment is completed
Comparison of SBT to Lactulose rhamnose (LR) test- time to 50% recovery	The 13C-SBT (time to 50% area under the curve of 13C tracer, expressed in minutes ) will be compared to LR ratio (the ratio of the percent recovery of administered lactulose and mannitol)	6 months after enrollment is completed
Correlation of SBT (% recovery at 90 minutes) to Lactulose rhamnose (LR) test-Lactulose recovery	The 13C-SBT (cumulative percent of dose recovered at 90 minutes post administration) will be compared to the percent lactulose recovery at 90 minutes post administration	6 months after enrollment is completed
Correlation of SBT (time to 50% recovery) to Lactulose rhamnose (LR) test-Lactulose recovery	The 13C-SBT (time to 50% area under the curve 13C tracer, expressed in minutes) will be compared to the percent lactulose recovery at 90 minutes post administration	6 months after enrollment is completed
Correlation of SBT (% dose recovered at 09 minutes) to Lactulose rhamnose (LR) test-Mannitol recovery	The 13C-SBT (cumulative percent of dose of 13C recovered at 90 minutes post administration) will be compared to percent mannitol recovery	6 months after enrollment is completed
Correlation of SBT (time to recovery of 50% of dose) to Lactulose rhamnose (LR) test-Mannitol recovery	The 13C-SBT (time to 50% area under the curve 13C tracer, expressed in minutes) will be compared to percent mannitol recovery	6 months after enrollment is completed
Characterize the relationship between SBT (% of dose recovered at 90 min) and baseline childhood anthropometrics (attained length)	We will compare results of the SBT test expressed as cumulative percent of dose recovered at 90 minutes post administration and LAZ (length for age Z-score as defined by 2006 World Health Organization norms, cross-sectional)	6 months after enrollment is completed
Characterize the relationship between SBT (time to recovery of 50% of dose) and baseline childhood anthropometrics (attained length)	We will compare results of the SBT test expressed as time to 50% area under the curve 13C tracer, expressed in minutes and LAZ (length for age Z-score as defined by 2006 World Health Organization norms, cross-sectional)	6 months after enrollment is completed
Characterize the relationship between SBT and childhood anthropometrics (attained weight)	We will compare results of the SBT test expressed as the cumulative percent of dose recovered at 90 minutes post administration and WAZ (weight for age Z-score as defined by 2006 World Health Organization norms, cross-sectional)	6 months after enrollment is completed
Characterize the relationship between SBT and childhood anthropometrics (attained weight for height)	We will compare results of the SBT test expressed as time to 50% area under the curve 13C tracer, expressed in minutes and WAZ (weight for age Z-score as defined by 2006 World Health Organization norms, cross-sectional)	6 months after enrollment is completed
Characterize the relationship between SBT (time to 50% recovery of 13C) and childhood linear growth, 3 months	We will compare values for the 13C-SBT expressed as time to 50% area under the curve 13C tracer, expressed in minutes and change in length for age Z score (WHO 2006 reference standards) over the subsequent 3 months	6 months after enrollment is completed
Characterize the relationship between SBT and childhood linear growth, 6 months	We will compare values for the 13C-SBT expressed as time to 50% area under the curve 13C tracer, expressed in minutes and change in length for age Z score (WHO 2006 reference standards) over the subsequent 6 months	6 months after enrollment is completed
Characterize the relationship between SBT (% dose recovered at 90 min)and childhood linear growth, 3 months	We will compare the 13C-SBT tests results (cumulative percent of dose recovered at 90 minutes post administration) and change in LAZ over the subsequent 3 months	6 months after enrollment is completed
Characterize the relationship between SBT and childhood linear growth	We will compare the 13C-SBT tests results (cumulative percent of dose recovered at 90 minutes post administration) and change in LAZ over the subsequent 6 months	6 months after enrollment is completed

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the relationship between the 13C-SBT (% recovery 90min) and fecal myeloperoxidase	Compare fecal myeloperoxidase concentration (ng/mL) with 13SBT (% of cumulative dose recovered at 90 minutes, expressed as %)	Six months from the enrollment of the last subject
Assess the relationship between SBT ( time to recovery of 50% of the 13C-tracer) and fecal myeloperoxidase	Compare fecal myeloperoxidase concentration (ng/mL) with 13SBT (time to recovery of 50% of the administered 13C tracer, measured in minutes)	Six months from the enrollment of the last subject
Assess the relationship between the 13C-SBT (% recovery 90 min) and serum fatty acid binding protein	Compare serum fatty acid binding protein concentration (ng/mL), with 13SBT as assessed by % of administered dose recovered at 90 minutes	Six months from the enrollment of the last subject
Assess the relationship between the 13C-SBT (time to 50% recovery) and serum fatty acid binding protein concentration	Compare serum fatty acid binding protein concentration (ng/mL) with 13SBT as measured by the time (in minutes) to the recovery of 50% of the administered dose of 13C.	Six months from the enrollment of the last subject
Assess the relationship between the 13C-SBT (time to 50% recovery) and kynurenine tryptophan ratio	Compare time to recovery of 50% of 13C probe of SBT with kynurenine tryptophan ratio (molar ratio of KT multiplied by 1000)	Six months from the enrollment of the last subject
Assess the relationship between the 13C-SBT (% recovery at 90 minutes) and kynurenine tryptophan ratio,	Compare 13C SBT as measured by % recovery of 13C probe at 90 minutes with kynurenine tryptophan ratio	Six months from the enrollment of the last subject
Assess the relationship between the 13C-SBT as assessed by percent of 13C tracer recovered in at 90 minutes and fecal alpha-antitrypsin concentration	Compare 13CSBT as measured by the percent of tracer recovered at 90 minutes with fecal anti-trypsin concentration (mg/g)	Six months from the enrollment of the last subject
Assess the relationship between the 13C-SBT as measured by the time to 50% recovery of 13C and fecal alpha-antitrypsin	Compare 13C SBT as measured by the time to 50% recovery of 13C with fecal anti-trypsin concentration (mg/g)	Six months from the enrollment of the last subject

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reproducibility of the 13C-SBT test , percent of dose recovered in first 90 minutes	We will assess the coefficient of variation and correlation coefficient between repeated cumulative percent of dose recovered at 90 minutes post administration on separate SBT tests administered one week apart done on the same child (Peru site only).	Six months from the enrollment of the last subject
Reproducibility of the 13C-SBT test, time to 50% area under the curve of 13C tracer, expressed in minutes	We will assess the coefficient of variation and correlation coefficient between repeated SBT tests 7 days apart as assessed by the time to 50% area under the curve of 13C tracer, expressed in minutes from the same child (Peru site only).	Six months from the enrollment of the last subject
Epidemiologic factors that influence 13C-SBT measure, percent of dose recovered at 90 minutes	Determine if significant associations exist between 13C-SBT measured as cumulative percent of dose recovered at 90 minutes post administration and the WAMI index.The WAMI index is a previously validated composite index of environmental variables to create a index that expresses the socioeconomic and physical environment in diverse geographical contexts (PMID 24656134)	Six months from the enrollment of the last subject
Epidemiologic factors that influence 13C-SBT measure, time to 50% AUC recovered	Determine if significant associations exist between 13C-SBT measured as the time to recovery of 50% of the administered tracer and the WAMI index. The WAMI index is a previously validated composite index of environmental variables to create a index that expresses the socioeconomic and physical environment in diverse geographical contexts ((PMID 24656134).	Six months from the enrollment of the last subject

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: University of Michigan; International Centre for Diarrhoeal Disease Research, Bangladesh; International Atomic Energy Agency; Gastroenterology Services, Ltd.; Flinders University; Tropical Diseases Research Centre, Zambia; The University of The West Indies; St. John's Research Institute; Scottish Universities Environmental Research Centre; Mmust Masinde Muliro University of Science and Technology; Asociacion Benefica Prisma
• Investigators: Study Chair: Victor Owino, PhD, International Atomic Energy Agency

Publications and helpful links

General Publications

• Lee GO, Schillinger R, Shivakumar N, Whyte S, Huq S, Ochieng Konyole S, Chileshe J, Paredes-Olortegui M, Owino V, Yazbeck R, Kosek MN, Kelly P, Morrison D. Optimisation, validation and field applicability of a 13C-sucrose breath test to assess intestinal function in environmental enteropathy among children in resource poor settings: study protocol for a prospective study in Bangladesh, India, Kenya, Jamaica, Peru and Zambia. BMJ Open. 2020 Nov 17;10(11):e035841. doi: 10.1136/bmjopen-2019-035841.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: July 20, 2019
• First Submitted That Met QC Criteria: September 26, 2019
• First Posted (Actual): September 30, 2019

Study Record Updates

• Last Update Posted (Actual): October 6, 2021
• Last Update Submitted That Met QC Criteria: October 5, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Gastrointestinal Diseases; Nutrition Disorders; Intestinal Diseases; Malnutrition; Failure to Thrive; Malabsorption Syndromes; Child Nutrition Disorders
• Other Study ID Numbers: CE0783.19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No