Effect of Paracetamol on Kidney Function in Severe Malaria (PROTECtS)

  • STATUS
    Recruiting
  • End date
    Nov 1, 2024
  • participants needed
    460
  • sponsor
    University of British Columbia
Updated on 5 March 2022

Summary

A randomised open labeled, parallel-group, controlled trial to assess the efficacy of paracetamol to reduce kidney dysfunction caused by cell-free haemoglobin-mediated oxidative damage in paediatric patients with falciparum malaria complicated by intravascular haemolysis.

Description

Kidney dysfunction is an independent predictor of mortality in both adults and children with severe malaria. In the largest studies of paediatric severe malaria, approximately 25% of children had kidney dysfunction and these patients accounted for roughly 50% of total deaths.

Although the multifactorial mechanism of severe malaria-associated AKI has primarily been studied in adults, evidence suggests that similar mechanisms of renal injury are involved in paediatric severe malaria. Cell-free haemoglobin (CFH) -mediated oxidative damage has recently been recognized as an important pathway in a range of common conditions, including rhabdomyolysis, primary pulmonary graft dysfunction, and haemolytic disorders, such as post-cardiac surgery, and malaria. During malaria infection, there is haemolysis of parasitized and uninfected red blood cells (RBCs). CFH-mediated lipid peroxidation generates F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs), which are considered robust in vivo measures of oxidative stress. F2-IsoPs are potent renal vasoconstrictors that act via thromboxane A2 receptors. Both F2-IsoPs and IsoFs have been associated with AKI in patients with rhabdomyolysis, sepsis, adults with severe malaria and haemolysis post-cardiopulmonary bypass (CPB). Further, elevated haemin and CFH concentrations were associated with mortality. In a cohort of children with severe malaria, elevated haem-to-haemopexin ratio was associated with stage 3 AKI, and 6-month mortality. These studies demonstrate that intravascular haemolysis occurs with increasing severity in paediatric malaria. Haem redox cycling between ferric (Fe3+) and ferryl (Fe4+) states generates globin radicals, inducing lipid peroxidation. These data suggested that haemolysis induces oxidative damage, and CFH-mediated oxidative damage contributes to AKI complicating paediatric malaria.

A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol acts as a potent inhibitor of haemoprotein-catalyzed lipid peroxidation, by reducing ferryl haem to its less toxic ferric state and quenching globin radicals. We hypothesize that this novel inhibitory mechanism of paracetamol may provide renal protection in children with severe malaria by reducing the haemoprotein-induced lipid peroxidation. As there is currently no consensus that exists concerning adequate medical treatment for severe malaria complicated by intravascular haemolysis and AKI, the potential application of this safe and extensively used drug would be of great benefit.

The study will be a randomised, open-labelled, controlled trial. Randomisation will be stratified into two groups : (i) Patients with no acute kidney injury (AKI) at enrolment, and (ii) Patients with AKI at enrolment. Both groups will be randomised into two arms: Arm 1: Paracetamol 15 mg/kg/dose 6 hourly for 72 hours Arm 2: Mechanical antipyresis if fever in the first 72 hours. All patients will receive intravenous artesunate followed by artemether-lumefantrine as soon as they are able to take oral medication or according to medical judgment.

The study will be conducted at the Kinshasa Medical Oxford Research Unit (KIMORU, Democratic Republic of the Congo, DRC). The recruitment phase of the study is expected to last 18 months, from September 2021 - February 2022. The total time to complete the study will be approximately 3 years.

Funder: Canadian Institutes of Health Research

CIHR grant reference number : PJT-162116

UBC grant number: 20R01487

Details
Condition Severe Malaria, Malaria,Falciparum, Acute Kidney Injury, Paracetamol
Treatment Paracetamol, Mechanical antipyresis
Clinical Study IdentifierNCT04251351
SponsorUniversity of British Columbia
Last Modified on5 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Male or Female, patients aged 1 to ≤ 14 years
Severe P. falciparum malaria, confirmed by positive blood smear with asexual forms of
falciparum or positive PfHRP2 rapid diagnostic test (RDT)
Pre-specified modified criteria for severe falciparum malaria
Upon hospital admission, asexual parasitaemia plus at least ONE of the
following
Glasgow coma score < 11/15 or Blantyre coma score <3/5 in pre-verbal children
Generalized convulsions (≥2 in 24 hours)
Jaundice (visible jaundice)
Severe anaemia (HCT <15%/Hb<5 g/dL: aged <12) Severe anaemia (HCT <20%/Hb<7 g/dL: aged ≥12)
Hyperparasitaemia (>10%)
Hypoglycaemia (glucose < 2.2 mmol/L; <40 mg/dL)
Kidney dysfunction (blood urea > 20 mmol/L)
Acidosis (venous bicarbonate <15 mmol/L or base excess less than -3.3mEq/L)
Venous lactate > 5 mmol/L
Shock (systolic blood pressure < 70 mmHg (<12 years) <80 mmHg (≥12 years) with cool extremities or capillary refill >3 seconds)
Respiratory distress (costal indrawing, use of accessory muscles, nasal flaring, deep breathing or severe tachypnea (respiratory rate>ULN for age)
Spontaneous bleeding
Prostration (inability to set upright, or drink) Abbreviations: HCT, haematocrit; Hb, haemoglobin; cannot be only severity criteria
Temperature >38°C on admission or fever during the preceding 48 hours
Less than 24 hours of antimalarial therapy
Attending caregiver of participant willing and able to give informed consent for participation in the study

Exclusion Criteria

The participant may not enter the trial if ANY of the following apply
Contraindication or known allergy to paracetamol
Known chronic liver disease or tender hepatomegaly
Known chronic kidney disease, history of renal replacement therapy or renal biopsy
Participants who are already enrolled in another research trial involving an investigational product or have participated to the same study before
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