Effect of Paracetamol on Kidney Function in Severe Malaria

NCT ID: NCT04251351

Last Updated: 2023-06-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 460 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-13
• Study Completion Date: 2025-11-01

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

Conditions

Severe Malaria; Malaria,Falciparum; Acute Kidney Injury; Paracetamol

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Arm 1

Paracetamol 15 mg/kg/dose 6 hourly for 72 hours

Group Type: EXPERIMENTAL

Paracetamol

Intervention Type: DRUG

Paracetamol 15 mg/kg/dose IV 6 hourly for 72 hours

Arm 2

Mechanical antipyresis (i.e. loose clothing, tepid sponging, fanning and cooling blanket) if fever in the first 72 hours.

Group Type: SHAM_COMPARATOR

Mechanical antipyresis

Intervention Type: PROCEDURE

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).

Interventions

Paracetamol

Paracetamol 15 mg/kg/dose IV 6 hourly for 72 hours

Intervention Type: DRUG

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).

Intervention Type: PROCEDURE

Other Intervention Names

Acetyl-Para-Aminophenol (APAP); Acetaminophen

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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mahidol Oxford Tropical Medicine Research Unit

OTHER

Sponsor Role: collaborator

Kinshasa Medical Oxford Research Unit

UNKNOWN

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Katherine Plewes, MD PhD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Katherine Plewes, Dr.

Role: PRINCIPAL_INVESTIGATOR

Mahidol Oxford Tropical Medicine Research Unit

Locations

The Kinshasa Medical Oxford Research Unit (KIMORU)

Kinshasa, Congo, Democratic Republic of the Congo

Site Status: RECRUITING

Countries

Democratic Republic of the Congo

Central Contacts

Katherine Plewes, Dr.

Role: CONTACT

katherine@tropmedres.ac

+1-604-603-4033

Arjen Dondorp, Prof.

Role: CONTACT

arjen@tropmedres.ac

+662-203-6333 ext. 6303

Facility Contacts

Marie Onyamboko, Dr.

Role: primary

akatshimarie@yahoo.fr

+243990024201

Caterina Fanello, Dr.

Role: backup

caterina.fanello@ndm.ox.ac.uk

+447900278768

Other Identifiers

H19-03570

Identifier Type: -

Identifier Source: org_study_id