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Browsing Protocols by Author "Bandsma, Robert"

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    Pancreatic enzymes and bile acids: A non-antibiotic approach to treat intestinal dysbiosis in acutely ill severely malnourished children
    (Kamuzu University of Health Sciences, 20-09-08) Bandsma, Robert
    Background (Problem to be studied) 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 faecal microbiome (‘dysbiosis’). Apart from the large intestine, this dysbiosis is also present in the small 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 reduced and altered, respectively, 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. We recently reported that treating children with severe malnutrition with pancreatic enzymes led to a reduction in mortality in a pilot trial 08-Sep-2020 CONFIDENTIAL PB-SAM Version 1.2 Dated 1 September-2020 Page 6 of 440 which was not powered for mortality. Importantly, enzymes and bile acids produced by the pancreas and liver affect bacteria that reside in the intestinal lumen. We hypothesize that providing these enzymes exogenously to severely malnourished children will improve their clinical outcome by reducing dysbiosis, intestinal inflammation and sepsis. Objective The objective of this study is to determine whether treating ill severely malnourished children with pancreatic enzymes or bile acids improves mortality. Methodology We will conduct a double blind, randomized clinical trial in a 2x2 factorial design in hospitalized severely malnourished children. We will treat participants with paediatric formulations of pancreatic enzymes, bile acids, both or placebo(standard antibiotic therapy for SAM inpatient treatment) for 21 days. Participants will be followed up daily during their hospital stay and on day 21 and 60 after enrolment. We will conduct this trial in three stages to allow for careful interim evaluations to assess safety and study progress. In the first and second stage, we will conduct interim analyses to 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. Expected findings We expect mortality, deterioration, and readmission to be lower amongst children admitted to hospital and treated for complicated SAM by administration of pancreatic enzymes or bile acids compared to placebo. Dissemination 08-Sep-2020 CONFIDENTIAL PB-SAM Version 1.2 Dated 1 September-2020 Page 7 of 440 The findings of the study will be published in peer reviewed journal and will also be shared College of Medicine Ethics and Research Committee (COMREC), hospitals and the study community in all participating countries.