Mesalamine in Environmental Enteropathy

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

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.

Study Overview

• Status: Completed
• Conditions: Malnutrition
• Intervention / Treatment: Drug: Mesalamine; Drug: Placebo granules

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Kenya
  • Mathare
    • Nairobi, Mathare, Kenya
      • Baraka Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mesalamine; 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; Mesalamine granules; Other Names: Mesalazine, Pentasa (trade name)
PLACEBO_COMPARATOR: Placebo granules	Drug: Placebo granules; Provided by Ferring Pharma

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Kelsey Jones
• Collaborators: Imperial College London
• Investigators: Principal Investigator: Kelsey DJ Jones, MBBS BA MRCPCH, KEMRI-Wellcome Trust Research Programme and Imperial College London

Publications and helpful links

General Publications

• Jones KD, Hunten-Kirsch B, Laving AM, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M, Owino M, Fegan G, Murch SH, Sullivan PB, Warner JO, Berkley JA. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med. 2014 Aug 14;12:133. doi: 10.1186/s12916-014-0133-2.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (ACTUAL): May 1, 2014
• Study Completion (ACTUAL): May 1, 2014

Study Registration Dates

• First Submitted: April 15, 2013
• First Submitted That Met QC Criteria: April 23, 2013
• First Posted (ESTIMATE): April 26, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): July 11, 2014
• Last Update Submitted That Met QC Criteria: July 10, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Malnutrition; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Mesalamine
• Other Study ID Numbers: KEMRI_CT_2013/0016; SSC 2223 (OTHER: KEMRI Scientific Steering Committee)