A phase I/II randomised controlled clinical trial to assess the feasibility, safety and preliminary effectiveness of paracetamol in resolving acute kidney injury in children with severe malaria.

Background: Acute kidney injury (AKI) is prevalent among children with severe malaria, contributing to considerable morbidity and mortality. Oxidative stress has been implicated in the pathophysiology of malaria-induced AKI, and paracetamol, with its antioxidant properties, has been proposed as a solution. Therefore, we conducted the first study in children to to assess the feasibility, safety and preliminary effectiveness of paracetamol in ameliorating AKI in severe malaria. Methods: We conducted a phase I/II open label parallel randomised controlled trial of 40 hospitalised children aged >6month to <12 years with malaria-induced AKI in eastern Uganda. Participants were randomized by a sealed envelope 1:1 to receive either oral paracetamol 20mg/kg 6-hourly for 48 hours or tepid sponging every 30 minutes until fever subsided. Only the assessors of the primary outcome were masked to the intervention. The primary outcome was renal recovery at 48 hours assessed using restricted mean survival time (RMST) in intention to treat population of children according to their randomisation groups. Results: Between 19 September 2021 and 25 August 2023, 250 children with haemoglobinuric severe malaria were screened and the 40 enrolled were randomly assigned paracetamol (n=20) or tepid sponging (n=20). The mean age was 6.54 (2.61) years. The mean time to renal recovery in the paracetamol group was 0.491 hours (95% CI: -9.265 to 10.248; p=0.921) longer than the no paracetamol group within 48 hours, but this difference was not statistically significant even after adjusting for age and weight: 1.04 hours (95% CI: -8.61, 10.70; p=0.832). The safety assessment indicated no significant differences in adverse events and hepatoxicity in either group. Conclusions: Although Paracetamol was safe, it did not significantly improve renal recovery in children with malaria-induced AKI. Further larger studies are needed to explore this role of paracetamol. The trial registration: ISRCTN84974248.