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. Yeo & 13 others Sue 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 journalArticleResearchpeer-review

    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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    Falciparum Malaria
    Acetaminophen
    Therapeutics
    Creatinine
    Hemoglobins
    Pharmacokinetics
    Kidney
    Safety
    Safety Management
    Bangladesh
    Hemolysis
    Acute Kidney Injury
    Malaria
    Fever
    Randomized Controlled Trials
    Clinical Trials
    Confidence Intervals
    Mortality

    Cite this

    Plewes, Katherine ; Kingston, Hugh W.F. ; Ghose, Aniruddha ; Wattanakul, Thanaporn ; Hassan, Md Mahtab Uddin ; Haider, Md Shafiul ; Dutta, Prodip K. ; Islam, Md Akhterul ; Alam, Shamsul ; Jahangir, Selim Md ; Zahed, A. S.M. ; Sattar, Md Abdus ; Chowdhury, M. A.Hassan ; Herdman, M. Trent ; Leopold, Stije J. ; Ishioka, Haruhiko ; Piera, Kim A. ; Charunwatthana, Prakaykaew ; Silamut, Kamolrat ; Yeo, Tsin W. ; Lee, Sue J. ; Mukaka, Mavuto ; Maude, Richard J. ; Turner, Gareth D.H. ; Faiz, Md Abul ; Tarning, Joel ; Oates, John A. ; Anstey, Nicholas M. ; White, Nicholas J. ; Day, Nicholas P.J. ; Hossain, Md Amir ; Roberts, L. Jackson ; Dondorp, Arjen M. / Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria : A Randomized, Controlled, Open-Label Trial. In: Clinical Infectious Diseases. 2018 ; Vol. 67, No. 7. pp. 991-999.
    @article{0e412cb305aa44cf8159899b6a1ec040,
    title = "Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial",
    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.",
    keywords = "acetaminophen, acute kidney injury, cell-free hemoglobin, falciparum malaria, oxidative stress",
    author = "Katherine Plewes and Kingston, {Hugh W.F.} and Aniruddha Ghose and Thanaporn Wattanakul and Hassan, {Md Mahtab Uddin} and Haider, {Md Shafiul} and Dutta, {Prodip K.} and Islam, {Md Akhterul} and Shamsul Alam and Jahangir, {Selim Md} and Zahed, {A. S.M.} and Sattar, {Md Abdus} and Chowdhury, {M. A.Hassan} and Herdman, {M. Trent} and Leopold, {Stije J.} and Haruhiko Ishioka and Piera, {Kim A.} and Prakaykaew Charunwatthana and Kamolrat Silamut and Yeo, {Tsin W.} and Lee, {Sue J.} and Mavuto Mukaka and Maude, {Richard J.} and Turner, {Gareth D.H.} and Faiz, {Md Abul} and Joel Tarning and Oates, {John A.} and Anstey, {Nicholas M.} and White, {Nicholas J.} and Day, {Nicholas P.J.} and Hossain, {Md Amir} and Roberts, {L. Jackson} and Dondorp, {Arjen M.}",
    year = "2018",
    month = "9",
    day = "14",
    doi = "10.1093/cid/ciy213",
    language = "English",
    volume = "67",
    pages = "991--999",
    journal = "Clinical Infectious Diseases",
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    Plewes, K, Kingston, HWF, Ghose, A, Wattanakul, T, Hassan, MMU, Haider, MS, Dutta, PK, Islam, MA, Alam, S, Jahangir, SM, Zahed, ASM, Sattar, MA, Chowdhury, MAH, Herdman, MT, Leopold, SJ, Ishioka, H, Piera, KA, Charunwatthana, P, Silamut, K, Yeo, TW, Lee, SJ, Mukaka, M, Maude, RJ, Turner, GDH, Faiz, MA, Tarning, J, Oates, JA, Anstey, NM, White, NJ, Day, NPJ, Hossain, MA, Roberts, LJ & Dondorp, AM 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, vol. 67, no. 7, pp. 991-999. https://doi.org/10.1093/cid/ciy213

    Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria : A Randomized, Controlled, Open-Label Trial. / Plewes, Katherine; Kingston, Hugh W.F.; Ghose, Aniruddha; Wattanakul, Thanaporn; Hassan, Md Mahtab Uddin; Haider, Md Shafiul; Dutta, Prodip K.; Islam, Md Akhterul; Alam, Shamsul; Jahangir, Selim Md; Zahed, A. S.M.; Sattar, Md Abdus; Chowdhury, M. A.Hassan; Herdman, M. Trent; Leopold, Stije J.; Ishioka, Haruhiko; Piera, Kim A.; Charunwatthana, Prakaykaew; Silamut, Kamolrat; Yeo, Tsin W.; Lee, Sue J.; Mukaka, Mavuto; Maude, Richard J.; Turner, Gareth D.H.; Faiz, Md Abul; Tarning, Joel; Oates, John A.; Anstey, Nicholas M.; White, Nicholas J.; Day, Nicholas P.J.; Hossain, Md Amir; Roberts, L. Jackson; Dondorp, Arjen M.

    In: Clinical Infectious Diseases, Vol. 67, No. 7, 14.09.2018, p. 991-999.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria

    T2 - A Randomized, Controlled, Open-Label Trial

    AU - Plewes, Katherine

    AU - Kingston, Hugh W.F.

    AU - Ghose, Aniruddha

    AU - Wattanakul, Thanaporn

    AU - Hassan, Md Mahtab Uddin

    AU - Haider, Md Shafiul

    AU - Dutta, Prodip K.

    AU - Islam, Md Akhterul

    AU - Alam, Shamsul

    AU - Jahangir, Selim Md

    AU - Zahed, A. S.M.

    AU - Sattar, Md Abdus

    AU - Chowdhury, M. A.Hassan

    AU - Herdman, M. Trent

    AU - Leopold, Stije J.

    AU - Ishioka, Haruhiko

    AU - Piera, Kim A.

    AU - Charunwatthana, Prakaykaew

    AU - Silamut, Kamolrat

    AU - Yeo, Tsin W.

    AU - Lee, Sue J.

    AU - Mukaka, Mavuto

    AU - Maude, Richard J.

    AU - Turner, Gareth D.H.

    AU - Faiz, Md Abul

    AU - Tarning, Joel

    AU - Oates, John A.

    AU - Anstey, Nicholas M.

    AU - White, Nicholas J.

    AU - Day, Nicholas P.J.

    AU - Hossain, Md Amir

    AU - Roberts, L. Jackson

    AU - Dondorp, Arjen M.

    PY - 2018/9/14

    Y1 - 2018/9/14

    N2 - 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.

    AB - 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.

    KW - acetaminophen

    KW - acute kidney injury

    KW - cell-free hemoglobin

    KW - falciparum malaria

    KW - oxidative stress

    UR - http://www.scopus.com/inward/record.url?scp=85045900185&partnerID=8YFLogxK

    U2 - 10.1093/cid/ciy213

    DO - 10.1093/cid/ciy213

    M3 - Article

    VL - 67

    SP - 991

    EP - 999

    JO - Clinical Infectious Diseases

    JF - Clinical Infectious Diseases

    SN - 1058-4838

    IS - 7

    ER -