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

Evaluating the Renoprotective Effect of Paracetamol in Paediatric Severe Malaria: a Randomised Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Kidney Injury; Malaria,Falciparum; Severe Malaria; Paracetamol
• Intervention / Treatment: Drug: Paracetamol; Procedure: Mechanical antipyresis

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

• Study Type: Interventional
• Enrollment (Estimated): 460
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Katherine Plewes, Dr.; Phone Number: +1-604-603-4033; Email: katherine@tropmedres.ac
• Study Contact Backup: Name: Arjen Dondorp, Prof.; Phone Number: 6303 +662-203-6333; Email: arjen@tropmedres.ac

Study Locations

• Congo, The Democratic Republic of the
  • Congo
    • Kinshasa, Congo, Congo, The Democratic Republic of the
      • Recruiting
      • The Kinshasa Medical Oxford Research Unit (KIMORU)
      • Contact: Marie Onyamboko, Dr.; Phone Number: +243990024201; Email: akatshimarie@yahoo.fr
      • Contact: Caterina Fanello, Dr.; Phone Number: +447900278768; Email: caterina.fanello@ndm.ox.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 14 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Paracetamol 15 mg/kg/dose 6 hourly for 72 hours	Drug: Paracetamol; Paracetamol 15 mg/kg/dose IV 6 hourly for 72 hours; Other Names: Acetaminophen; Acetyl-Para-Aminophenol (APAP)
Sham Comparator: Arm 2; Mechanical antipyresis (i.e. loose clothing, tepid sponging, fanning and cooling blanket) if fever in the first 72 hours.	Procedure: Mechanical antipyresis; Mechanical antipyresis (i.e. loose clothing, tepid sponging, fanning and cooling blanket) if fever in the first 72 hours. If a temperature >38.5°C persists despite mechanical antipyresis, or if deemed necessary by the treating clinician, then paracetamol can be administered according to local practice (paracetamol IV 15 mg/kg as needed).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute kidney injury (AKI) or death among patients enrolled without AKI (Composite outcome)	Composite outcome of development of AKI (defined as creatinine ≥26.5 µmol/L or ≥1.5x baseline), or death at any timepoint	during first 7 days of enrolment
Acute kidney injury (AKI) progression or death among patients enrolled with AKI (Composite outcome)	Composite outcome of worsening of AKI (defined as creatinine ≥2x baseline, or ≥3x baseline, or initiation of RRT or eGFR <35 ml/min/ 1.73 m2) or death at any timepoint.	during first 7 days of enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with serious adverse events	Number of patients with serious adverse events (mortality and/or hepatotoxicity, as defined by Hy's Law).	AST/ALT/total bilirubin during the first 5 days from enrolment; mortality assessed Day 0 to 7.
Proportion of patients who develop Major Adverse Kidney Events (MAKE) composite	Major Adverse Kidney Events (MAKE) composite, defined as ≥ 1 efficacy renal endpoints: (i) death, (ii) need for renal replacement therapy, (iii)≥ 50% reduction in eGFR from baseline to 90 days.	90 days
Fever clearance time	Time taken for aural temperature: (i) to fall < 37.5°C (FCT-A), and (ii) to fall < 37.5°C and remain there for >24 h (FCT-B)	6-hourly temperature assessments during first 7 days from enrolment
Coma recovery	Time until Glasgow Coma Score (GCS) return to 15 (or Blantyre Coma Score (BCS) return to 5 in preverbal children)	6-hourly GCS/BCS assessments during first 7 days from enrolment
Longitudinal change in renal function	As measured by creatinine concentration (umol/L)	During the first 7 days from enrolment
Longitudinal change in markers of hemolysis	As measured by cell-free haemoglobin (ug/mL), haemopexin (ug/mL), haptoglobin (ug/mL), haem (uM), F2-isoprostane (pg/mL) and isofurans (pg/mL) concentrations	during the first 3 days from enrolment
Longitudinal change of endothelial activation	As measured by concentrations of angiopoietin-Tie2 pathway markers (i.e. Ang-1, Ang-2, sTie2, sTie1)	during the first 3 days from enrolment
Longitudinal change of immune activation	As measured by soluble triggering receptor expressed on myeloid cells concentration (sTREM-1; pg/mL)	during the first 3 days from enrolment
Longitudinal change of AKI biomarker	As measured by cystatin-C concentration (Cys-C; ug/mL)	during the first 3 days from enrolment
Parasite (parasites/ul) clearance	as measured by time until two consecutive negative smears (hours), and by rate using the parasite clearance estimator to determine slope half-life (hours) from 12-hourly parasite counts.	12-hourly parasitemia assessments during first 7 days from enrolment
Exploratory analysis with sex	Primary efficacy analyses will be analysed using a logistic regression model to obtain odds ratios, comparing the odds of a combined endpoint of kidney function deterioration or death between treatment groups. A multivariable model including an interaction term (sex and treatment) will be assessed in the primary analyses to explore potential differences between males and females.	During first 7 days from enrolment
Pharmacokinetic properties	Population pharmacokinetic model (relative bioavailability, mean transit absorption time (hours), apparent oral elimination clearance (L/hours), apparent volume of distribution (L)	during the first 24 hours from enrolment
Pharmacokinetic properties	Peak plasma concentration (Cmax; mg/L)	during the first 24 hours from enrolment
Pharmacokinetic properties	Time to peak plasma concentration (Tmax; hours)	during the first 24 hours from enrolment
Pharmacokinetic properties	Terminal elimination (t1/2; hours)	during the first 24 hours from enrolment
Pharmacokinetic properties	Area under the plasma drug concentration-time curve (AUC0-24; mg×h×L-1)	during the first 24 hours from enrolment
Pharmacodynamic relationships	Pharmacodynamic effects on creatinine concentration (mol/L)	during first 7 days from enrolment
Pharmacodynamic relationships	Pharmacodynamic effects on liver toxicity, as measured by AST and ALT (U/L)	during first 7 days from enrolment
Pharmacodynamic relationships	Pharmacodynamic effects on temperature (Celsius)	during first 7 days from enrolment
Pharmacodynamic relationships	Pharmacodynamic effects on parasitemia, as measured by parasites/ul and slope half-life	during first 7 days from enrolment
Pharmacodynamic relationships	Pharmacodynamic effects on GCS (or BCS in pre-verbal children)	during first 7 days from enrolment

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: Mahidol Oxford Tropical Medicine Research Unit; Kinshasa Medical Oxford Research Unit
• Investigators: Principal Investigator: Katherine Plewes, Dr., Mahidol Oxford Tropical Medicine Research Unit

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2021
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: January 29, 2020
• First Posted (Actual): January 31, 2020

Study Record Updates

• Last Update Posted (Estimated): June 13, 2023
• Last Update Submitted That Met QC Criteria: June 9, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Acute Kidney Injury; Paracetamol; Falciparum; Renoprotection; Severe Malaria
• Additional Relevant MeSH Terms: Infections; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Malaria; Acute Kidney Injury; Malaria, Falciparum; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: H19-03570

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy with other researchers to use in the future. Datasets will be de-identified to ensure patient privacy and confidentiality.
• IPD Sharing Time Frame: After completion of trial activities and reporting
• IPD Sharing Access Criteria: MORU Data Sharing Policy. (http://www.tropmedres.ac/data-sharing-policy)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No