NCT04542473

Pancreatic Enzymes and Bile Acids in Acutely Ill Severely Malnourished Children

Pancreatic Enzymes and Bile Acids: A Non-Antibiotic Approach to Treat Intestinal Dysbiosis in Acutely Ill Severely Malnourished Children

• Status: Unknown
• Phase: Phase 2 / Phase 3
• Study type: Interventional
• Enrollment: 400 (actual)
• Sponsor: University of Oxford · Academic / Other
• Sex: All
• Age: 2 Months – 59 Months
• Healthy volunteers: Not accepted

Summary

Children with severe malnutrition who are sick and admitted to hospitals have high mortality, usually because of infection. Malnourished children have more potentially harmful bacteria in their upper intestines than well-nourished children and this may contribute to inflammation in the gut and whole body. These bacteria may cross from the intestines to the bloodstream causing life-threatening infections. A related abnormality among malnourished children is reduction in the digestive enzymes made by the pancreas and the liver. Apart from helping with digestion of food, these enzymes are important in helping the body control bacteria in the upper intestines. It is therefore possible that treatment with digestive enzymes could help reduce the burden of harmful bacteria and thus lower inflammation and the risk of serious infection. One study conducted in Malawi has shown that children with severe malnutrition who were supplemented with pancreatic enzymes had a lower risk of dying. However, this was a small study and although promising, requires validation. No studies of supplementation with bile acids have been done among severely malnourished children. However, bile acids are commonly used to manage patients with liver function abnormalities, something that malnourished children suffer from as well. The investigators want to find out if supplementing these pancreatic enzymes and bile acids among ill children with severe acute malnutrition is safe and reduces the risk of death, deterioration or readmission to hospital.

Detailed description

Severely malnourished children who present with an acute illness have a high risk of mortality. Severe malnutrition is associated with intestinal inflammation and changes in the fecal microbiome ('dysbiosis'). Apart from in the large intestine, dysbiosis is also present in the small (upper) intestine, where increased bacterial density and altered microbial composition can contribute to intestinal inflammation and intestinal dysfunction which may ultimately contribute to the development of sepsis and death. The bacterial density and composition in the small intestine can be altered using antibiotics. However, apart from side effects, antibiotic use contributes to the development of antibiotic resistance, which is very common in hospitalized malnourished patients and can pose a threat to both individual and public health. In addition to intestinal dysbiosis and intestinal inflammation, children with severe malnutrition suffer from impaired exocrine pancreatic and hepatobiliary function, which are important for nutrient digestion and absorption to aid their recovery. One previous pilot trial showed that treating children with severe malnutrition with pancreatic enzymes led to a reduction in mortality. The investigators hypothesize that supplementing these enzymes exogenously to severely malnourished children will improve their clinical outcome by reducing dysbiosis, intestinal inflammation and sepsis. The objective of this study is to determine whether treating ill severely malnourished children with pancreatic enzymes or bile acids is safe and improves mortality. The investigators will conduct a double blind, randomized clinical trial in a 2x2 factorial design in hospitalized severely malnourished children. Participants will be treated with pediatric formulations of pancreatic enzymes, bile acids, both or placebo for 21 days. Participants will be followed up daily during their hospital stay and on day 21 and 60 after enrollment. This trial will be conducted in three stages to allow for careful interim evaluations to assess safety and study progress. After the first and second stage, interim analyses assess safety and likelihood of benefit before enrolling the full sample size to assess mortality as the primary outcome. Secondary outcomes include adverse events, length of hospital stay and growth. Exploratory outcomes will examine intestinal and systemic inflammation and metabolic changes to examine mechanisms affected by the interventions, and costs. Two sub-studies will be conducted. In Kenya and Bangladesh, daily blood gases, lactate and biochemistry for the first 5 days to assess early clinical progress. In Malawi and Uganda, hydrogen breath testing will be used to evaluate impact on upper small intestinal bacterial overgrowth. Overall, this trial will determine whether a non-antibiotic, bactericidal intervention given in additional to standard of care management reduces mortality in acutely ill severely malnourished children.

Conditions

• SEPSIS
• MALNUTRITION, CHILD

Interventions

Type	Name	Description
DRUG	Pancreatic Enzyme	CREON micro 5000
DRUG	Ursodeoxycholic acid	Ursodiol C24H40O4 suspension
OTHER	Pancreatic Enzyme placebo	Microcrystalline Cellulose,Macrogel 4000, Iron Oxide Yellow, Iron Oxide Red, Activated Charcoal.
OTHER	Ursodeoxycholic acid placebo	Sodium Citrate Dihydrate, Aspartame, Carboxymethylcellulose Sodium, Citric Acid Monohydrate, Dispersible Cellulose, Glycerol, Polysorbate-80, Saccharin Sodium,Sodium Benzoate, Sodium Methylparaben, Sodium Propylparaben

Timeline

• Start date: 2021-07-01
• Primary completion: 2023-10-31
• Completion: 2024-06-30
• First posted: 2020-09-09
• Last updated: 2023-02-24

Locations

4 sites across 4 countries: Bangladesh, Kenya, Malawi, Uganda