Clinical trial NCT04251351: Effect of Paracetamol on Kidney Function in Severe Malaria
Official title: Evaluating the Renoprotective Effect of Paracetamol in Paediatric Severe Malaria: a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Severe Malaria
Malaria,Falciparum
Acute Kidney Injury
Paracetamol
Keywords: Severe Malaria
Falciparum
Paracetamol
Renoprotection
Acute Kidney Injury
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
name: Kinshasa Medical Oxford Research Unit
First posted: 2020-01-31
Enrollment: 460
Sex: ALL
Minimum age (years): 1
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prior to randomization, participants 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
Primary purpose: PREVENTION

Brief 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.

Detailed 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

Eligibility criteria: Inclusion Criteria:

1. Male or Female, patients aged 1 to ≤ 14 years
2. Severe P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. 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
3. Temperature \>38°C on admission or fever during the preceding 48 hours.
4. Less than 24 hours of antimalarial therapy
5. 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:

1. Contraindication or known allergy to paracetamol
2. Known chronic liver disease or tender hepatomegaly
3. Known chronic kidney disease, history of renal replacement therapy or renal biopsy
4. Participants who are already enrolled in another research trial involving an investigational product or have participated to the same study before

Primary outcomes:
measure: Acute kidney injury (AKI) or death among patients enrolled without AKI (Composite outcome)
timeFrame: during first 7 days of enrolment
measure: Acute kidney injury (AKI) progression or death among patients enrolled with AKI (Composite outcome)
timeFrame: during first 7 days of enrolment
Secondary outcomes:
measure: Number of patients with serious adverse events
timeFrame: AST/ALT/total bilirubin during the first 5 days from enrolment; mortality assessed Day 0 to 7.
measure: Proportion of patients who develop Major Adverse Kidney Events (MAKE) composite
timeFrame: 90 days
measure: Fever clearance time
timeFrame: 6-hourly temperature assessments during first 7 days from enrolment
measure: Coma recovery
timeFrame: 6-hourly GCS/BCS assessments during first 7 days from enrolment
measure: Longitudinal change in renal function
timeFrame: During the first 7 days from enrolment
measure: Longitudinal change in markers of hemolysis
timeFrame: during the first 3 days from enrolment
measure: Longitudinal change of endothelial activation
timeFrame: during the first 3 days from enrolment
measure: Longitudinal change of immune activation
timeFrame: during the first 3 days from enrolment
measure: Longitudinal change of AKI biomarker
timeFrame: during the first 3 days from enrolment
measure: Parasite (parasites/ul) clearance
timeFrame: 12-hourly parasitemia assessments during first 7 days from enrolment
measure: Exploratory analysis with sex
timeFrame: During first 7 days from enrolment
measure: Pharmacokinetic properties
timeFrame: during the first 24 hours from enrolment
measure: Pharmacokinetic properties
timeFrame: during the first 24 hours from enrolment
measure: Pharmacokinetic properties
timeFrame: during the first 24 hours from enrolment
measure: Pharmacokinetic properties
timeFrame: during the first 24 hours from enrolment
measure: Pharmacokinetic properties
timeFrame: during the first 24 hours from enrolment
measure: Pharmacodynamic relationships
timeFrame: during first 7 days from enrolment
measure: Pharmacodynamic relationships
timeFrame: during first 7 days from enrolment
measure: Pharmacodynamic relationships
timeFrame: during first 7 days from enrolment
measure: Pharmacodynamic relationships
timeFrame: during first 7 days from enrolment
measure: Pharmacodynamic relationships
timeFrame: during first 7 days from enrolment
Other outcomes:
Locations:
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: The Kinshasa Medical Oxford Research Unit (KIMORU)
state: Congo
Study officials:
affiliation: Mahidol Oxford Tropical Medicine Research Unit
name: Katherine Plewes, Dr.
role: PRINCIPAL_INVESTIGATOR
References: