Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial

Katherine Plewes, Hugh W.F. Kingston, Aniruddha Ghose, Thanaporn Wattanakul, Md Mahtab Uddin Hassan, Md Shafiul Haider, Prodip K. Dutta, Md Akhterul Islam, Shamsul Alam, Selim Md Jahangir, A. S.M. Zahed, Md Abdus Sattar, M. A.Hassan Chowdhury, M. Trent Herdman, Stije J. Leopold, Haruhiko Ishioka, Kim A. Piera, Prakaykaew Charunwatthana, Kamolrat Silamut, Tsin W. YeoSue J. Lee, Mavuto Mukaka, Richard J. Maude, Gareth D.H. Turner, Md Abul Faiz, Joel Tarning, John A. Oates, Nicholas M. Anstey, Nicholas J. White, Nicholas P.J. Day, Md Amir Hossain, L. Jackson Roberts, Arjen M. Dondorp

    Research output: Contribution to journalArticle

    Abstract

    Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria.

    Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin.

    Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P =.043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P =.010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P =.034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity.

    Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration NCT01641289.

    Original languageEnglish
    Pages (from-to)991-999
    Number of pages9
    JournalClinical Infectious Diseases
    Volume67
    Issue number7
    Early online date12 Mar 2018
    DOIs
    Publication statusPublished - 14 Sep 2018

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    Plewes, K., Kingston, H. W. F., Ghose, A., Wattanakul, T., Hassan, M. M. U., Haider, M. S., Dutta, P. K., Islam, M. A., Alam, S., Jahangir, S. M., Zahed, A. S. M., Sattar, M. A., Chowdhury, M. A. H., Herdman, M. T., Leopold, S. J., Ishioka, H., Piera, K. A., Charunwatthana, P., Silamut, K., ... Dondorp, A. M. (2018). Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial. Clinical Infectious Diseases, 67(7), 991-999. https://doi.org/10.1093/cid/ciy213