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.

LanguageEnglish
Pages991-999
Number of pages9
JournalClinical Infectious Diseases
Volume67
Issue number7
Early online date12 Mar 2018
DOIs
StatePublished - 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, K., Kingston, H. W. F., Ghose, A., Wattanakul, T., Hassan, M. M. U., Haider, M. S., ... 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. DOI: 10.1093/cid/ciy213
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
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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.",
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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.}",
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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. DOI: 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 - Clinical Infectious Diseases

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

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U2 - 10.1093/cid/ciy213

DO - 10.1093/cid/ciy213

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SP - 991

EP - 999

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

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ER -