The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial

Abstract

Background: Acetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria but has not been evaluated in other infections with prominent hemolysis, including Plasmodium knowlesi malaria.

Methods: PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis.

Results: During 2016-2018, 396 patients (aged 12-96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively).

Conclusions: Acetaminophen did not improve creatinine among the entire cohort but may improve renal function in patients with severe knowlesi malaria and in those with AKI and hemolysis.

Clinical trials registration: NCT03056391.

Keywords: Plasmodium knowlesi; acetaminophen; acute kidney injury (AKI); malaria; randomized controlled trial (RCT).

Conflict of interest statement

Potential conflicts of interest. A. M. D. reports consulting fees paid to MORU by the Novartis Malaria Advisory Council; travel support provided by Gordon Malaria Conference organizers; is a member of the World Health Organization (WHO) Guidelines Development Group for antimalarial treatment, Scientific Advisory Board of the World-Wide Antimalarial Resistance Network, and Scientific Advisory Board of International Severe Acute Respiratory and Emerging Infection Consortium; and is the chair of the Artemisinin-resistance Initiative of the Global Fund Regional Steering Committee. G. S. R. reports grants from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (award 1R01AI160457-01) and the Malaysian Ministry of Health (award NMRR-19-4109-52172) and reports a leadership or fiduciary role on the Infectious Disease Society of Kota Kinabalu. J. T. reports consulting fees paid to Mahidol Oxford Research Unit (MORU) by the Novartis Malaria Advisory Council, is a member of the WHO working group on weight-band dosing harmonization to support the WHO-initiated Global Accelerator for Paediatric Formulations, is chair of the Coronavirus Disease 2019 Clinical Research Coalition, Clinical Pharmacology Working Group, is a member of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Infectious Diseases steering committee, and is a scientific advisor on the Drugs for Neglected Diseases initiative (DNDi) Programme: 21st Century Treatments for Sustainable Elimination of Leishmaniasis. T. W. Y. reports an international travel grant provided by the Pharmacometrics Japan Conference 2020. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Participant flow diagram. Abbreviations: HRP2, histidine-rich protein 2; PCR, polymerase chain reaction. aThirteen patients did not have either a 0-hour or 72-hour creatinine result and were excluded from the primary analysis (n = 6 in the acetaminophen arm and n = 7 in the control arm). There were 365 patients remaining in the final primary modified intention-to-treat analysis, including 181 patients in the acetaminophen arm and 184 in the control arm.

Figure 2.

Mixed effects model predicted values of mean percentage change in creatinine from baseline over time from 0 to 672 hours (28 days) in entire cohort (A); maximum cell-free hemoglobin (CFHb) ≥77 600 ng/mL (B); maximum CFHb <77 600 ng/mL (C); severe malaria (D); severe malaria and maximum CFHb ≥77 600 ng/mL (E); severe malaria and maximum CFHb <77 600 ng/mL (F); acute kidney injury (G); acute kidney injury and maximum CFHb ≥77 600 ng/mL (H); and acute kidney injury and maximum CFHb <77 600 ng/mL (I). P values below x-axes represent fixed effect interaction term of treatment (acetaminophen) × time. Abbreviation: APAP, acetaminophen.