Pancreatic enzymes and/or bile acids for acutely ill severely malnourished children: a double blind randomized placebo-controlled trial

BackgroundTranslocation of bacteria across the intestinal barrier has been postulated to contribute to mortality among severely malnourished children. Pancreatic enzymes (PE) and bile acids (BA) have anti-bacterial properties in the small intestine, but severe malnutrition is associated with impaired exocrine pancreatic and hepatobiliary functions. We evaluated whether ancillary treatment with PE and BA improves survival in hospitalized, acutely ill, severely malnourished children. Methods and findingsWe conducted a multicenter, adaptive, 2x2 factorial, randomized, double-blinded controlled trial of PE and BA (ursodeoxycholic acid) administered for 21 days in hospitalized children with severe malnutrition. The primary outcome was mortality within 60 days of enrollment. Secondary outcomes included the incidence of Serious Adverse Events (SAEs); grade 3 or 4 toxicity events before day 21; number of days with diarrhoea; use of second- or third-line antibiotics during the admission; duration of initial hospitalization; and changes in anthropometry from enrolment to follow-up at 21 and 60 days after start of the intervention. We enrolled 429 children (median age 10.4 months (interquartile range (IQR) 4.8 18.0)). Participants were randomized to PE (n=213, 50%) or PE-placebo (n=216, 50%) and to BA (n=212, 49%) or BA-placebo (n=217, 51%). Mortality by day 60 did not differ between children assigned to PE compared to PE-placebo (36 children (17%) vs 35 (16%)), irrespective of being assigned BA or BA-placebo (Hazard ratio (HR) 1.02 (95% CI 0.64 1.62), P=0.94). Also, 39 children (18%) assigned to BA died compared to 32 (15%) with BA-placebo, irrespective of PE/PE-placebo (HR 1.27 (95%CI 0.79 2.02), P=0.32). The trial was stopped early based on futility. There were no significant differences in secondary outcomes, other than children assigned to BA spent fewer days on second-line antibiotics than those receiving BA-placebo. ConclusionsPancreatic enzymes and/or ursodeoxycholic acid do not reduce mortality, serious adverse events, or improve other clinical outcomes in hospitalized, acutely ill, severely malnourished children. FundingThe Bill and Melinda Gates Foundation. Pancreatic enzymes were provided at subsidized cost by Abbott Laboratories, Illinois, Untied States and ursodeoxycholic acid was provided in kind by Opsonin Pharma Ltd., Dhaka, Bangladesh.