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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Glucose-Galactose Malabsorption, Enteropathy, Malnutrition, Child, Intestinal Permeability, Linear Growth Failure

Participation Criteria
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Eligibility Criteria
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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: Severe acute malnutrition HIV positive Weight for height Z >+2 Known medical illness contributing to growth failure

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 15 Months

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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What is the study measuring?
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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 |