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Trials
Published in: Trials 1/2018

Open Access 01-12-2018 | Study protocol

The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial

Authors: Daniel J. Cooper, Katherine Plewes, Matthew J. Grigg, Giri S. Rajahram, Kim A. Piera, Timothy William, Mark D. Chatfield, Tsin Wen Yeo, Arjen M. Dondorp, Nicholas M. Anstey, Bridget E. Barber

Published in: Trials | Issue 1/2018

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Abstract

Background

Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage.

Methods

PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2-isoprostanes and isofurans) and markers of endothelial activation/Weibel–Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity.

Discussion

Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases.

Trial registration

Clinicaltrials.gov, NCT03056391. Registered on 12 October 2016.
Appendix
Available only for authorised users
Footnotes
1
P. knowlesi now accounts for over 90% of all reported malaria cases in Malaysia [4, 6, 37, 38]; however, microscopy is unreliable for distinguishing P. knowlesi from P. falciparum and P. vivax [39]. For blood films reported as P. falciparum, a Pf-HRP2-based rapid diagnostic test (First Response™; Premier Medical Corp. Ltd., India) is performed, and patients with a positive result are excluded. Patients with nominal P. vivax on microscopy are enrolled. Final species confirmation by PCR is performed on all patients; any patient with malaria due to a Plasmodium species other than P. knowlesi (including mixed P. knowlesi infections) will be excluded from all analyses.
 
2
Pregnant women are excluded due to uncertainty regarding potential adverse effects of untreated fever in pregnancy.
 
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Metadata
Title
The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial
Authors
Daniel J. Cooper
Katherine Plewes
Matthew J. Grigg
Giri S. Rajahram
Kim A. Piera
Timothy William
Mark D. Chatfield
Tsin Wen Yeo
Arjen M. Dondorp
Nicholas M. Anstey
Bridget E. Barber
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Trials / Issue 1/2018
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-018-2600-0

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