Mesalamine in Environmental Enteropathy

Study Overview
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Brief Summary
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Undernutrition is one of the most important health issues in Kenya. Children who are chronically undernourished do not reach their full potential and are at increased risk of infectious disease. Stunting occurs in a third of Kenyan children and has severe and long-term consequences in terms of health, development, and poverty. Several studies have shown that stunting is frequently associated with subclinical inflammation of the bowel, a condition referred to as Environmental Enteropathy (EE), previously known as 'tropical sprue' or 'tropical enteropathy'. EE is clinically similar to childhood inflammatory bowel diseases (IBD), including Crohn's disease. The treatment of IBD routinely involves provision of gut immunomodulatory agents, but this approach has never been tried in EE. This proposal outlines a pilot double-blind randomised placebo-controlled trial of mesalamine (also called mesalazine - the safest immunomodulator used in IBD with least systemic activity) in treatment of severely malnourished children with EE.

Official Title
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Randomised Placebo-controlled Trial of a Gut Immunomodulatory Agent (Mesalamine) to Tackle Environmental Enteropathy in Acutely Malnourished Children: A Pilot Study.

Conditions
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Malnutrition

Intervention / Treatment
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* Drug: Mesalamine
* Drug: Placebo granules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 1 to 5 years old. Provision of informed consent by parent or guardian. Stunting (height for age z score <-2) Severe malnutrition (one or more of mid-upper arm circumference <11.5cm, weight for height z score <-3, or nutritional oedema). Eligible for outpatient management of malnutrition (i.e. no evidence of acute infection, and passes 'appetite test' according to national guidelines). Evidence of chronic inflammation (elevated erythrocyte sedimentation rate, ESR >20mm/hr). Exclusion Criteria: Known HIV disease or tuberculosis. Known previous renal disease or asthma. Known allergy or hypersensitivity to mesalamine, other salicylate drugs, or any of the product ingredients. Biochemical evidence of acute renal or hepatic impairment on screening blood tests. Thrombocytopenia Recent (previous two weeks) bloody diarrhoea. Concurrent medication known to interact with the study drug (non-steroidal anti-inflammatory drugs, ranitidine, proton-pump inhibitors) Acute infection requiring treatment, e.g. lower respiratory tract infection or febrile illness. Other reason at the discretion of the attending clinician (independent of the trial team).

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesalamine<br>Mesalamine. Mesalamine granules. 30 mg/kg/day oral for 7 days followed by 50 mg/kg/day oral for 21 days if tolerated. | Drug: Mesalamine<br>* Mesalamine granules<br>* Other names: Mesalazine, Pentasa (trade name);|
| Placebo Comparator: Placebo granules<br>Placebo granules | Drug: Placebo granules<br>* Provided by Ferring Pharma<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events/serious adverse events | This trial represents the first time a member of a class of drugs are to be used in a particular vulnerable group patient group. It's primary purpose is to conduct an early evaluation of safety and acceptability in this and the study is not powered to address any specific outcomes. It represents a modified Phase IIa design | Day 0 to day 28 and day 0 to day 56 | 
| Compliance with treatment | This trial represents the first time a member of a class of drugs are to be used in a particular vulnerable group patient group. It's primary purpose is to conduct an early evaluation of safety and acceptability in this and the study is not powered to address any specific outcomes. It represents a modified Phase IIa design | Day 0 to day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in height | mm/day | Day 0 to 28 and day 0 to day 56 | 
| Changes in levels of anti-Endotoxin Core IgG (EndoCAb) |  | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in fecal calprotectin levels |  | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in plasma soluble-CD14 |  | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in plasma beta-2 microglobulin |  | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in plasma neopterin |  | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in weight | g/kg/day | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in mid-upper arm circumference | mm/day | Day 0 - Day 28 and Day 0 - Day 56 | 
| Changes in C-Reactive Protein |  | Day 0 - Day 28, and Day 0 - Day56 |