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

Primary Purpose

Severe Malaria, Malaria,Falciparum, Acute Kidney Injury

Status
Recruiting
Phase
Phase 3
Locations
Congo, The Democratic Republic of the
Study Type
Interventional
Intervention
Paracetamol
Mechanical antipyresis
Sponsored by
University of British Columbia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Severe Malaria focused on measuring Severe Malaria, Falciparum, Paracetamol, Renoprotection, Acute Kidney Injury

Eligibility Criteria

1 Year - 14 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • The Kinshasa Medical Oxford Research Unit (KIMORU)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Arm 1

Arm 2

Arm Description

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

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

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

Number of patients with serious adverse events
Number of patients with serious adverse events (mortality and/or hepatotoxicity, as defined by Hy's Law).
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.
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)
Coma recovery
Time until Glasgow Coma Score (GCS) return to 15 (or Blantyre Coma Score (BCS) return to 5 in preverbal children)
Longitudinal change in renal function
As measured by creatinine concentration (umol/L)
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
Longitudinal change of endothelial activation
As measured by concentrations of angiopoietin-Tie2 pathway markers (i.e. Ang-1, Ang-2, sTie2, sTie1)
Longitudinal change of immune activation
As measured by soluble triggering receptor expressed on myeloid cells concentration (sTREM-1; pg/mL)
Longitudinal change of AKI biomarker
As measured by cystatin-C concentration (Cys-C; ug/mL)
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.
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.
Pharmacokinetic properties
Population pharmacokinetic model (relative bioavailability, mean transit absorption time (hours), apparent oral elimination clearance (L/hours), apparent volume of distribution (L)
Pharmacokinetic properties
Peak plasma concentration (Cmax; mg/L)
Pharmacokinetic properties
Time to peak plasma concentration (Tmax; hours)
Pharmacokinetic properties
Terminal elimination (t1/2; hours)
Pharmacokinetic properties
Area under the plasma drug concentration-time curve (AUC0-24; mg×h×L-1)
Pharmacodynamic relationships
Pharmacodynamic effects on creatinine concentration (mol/L)
Pharmacodynamic relationships
Pharmacodynamic effects on liver toxicity, as measured by AST and ALT (U/L)
Pharmacodynamic relationships
Pharmacodynamic effects on temperature (Celsius)
Pharmacodynamic relationships
Pharmacodynamic effects on parasitemia, as measured by parasites/ul and slope half-life
Pharmacodynamic relationships
Pharmacodynamic effects on GCS (or BCS in pre-verbal children)

Full Information

First Posted
December 17, 2019
Last Updated
June 9, 2023
Sponsor
University of British Columbia
Collaborators
Mahidol Oxford Tropical Medicine Research Unit, Kinshasa Medical Oxford Research Unit
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1. Study Identification

Unique Protocol Identification Number
NCT04251351
Brief Title
Effect of Paracetamol on Kidney Function in Severe Malaria
Acronym
PROTECtS
Official Title
Evaluating the Renoprotective Effect of Paracetamol in Paediatric Severe Malaria: a Randomised Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 13, 2021 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
November 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of British Columbia
Collaborators
Mahidol Oxford Tropical Medicine Research Unit, Kinshasa Medical Oxford Research Unit

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Malaria, Malaria,Falciparum, Acute Kidney Injury, Paracetamol
Keywords
Severe Malaria, Falciparum, Paracetamol, Renoprotection, Acute Kidney Injury

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
Masking
None (Open Label)
Allocation
Randomized
Enrollment
460 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1
Arm Type
Experimental
Arm Description
Paracetamol 15 mg/kg/dose 6 hourly for 72 hours
Arm Title
Arm 2
Arm Type
Sham Comparator
Arm Description
Mechanical antipyresis (i.e. loose clothing, tepid sponging, fanning and cooling blanket) if fever in the first 72 hours.
Intervention Type
Drug
Intervention Name(s)
Paracetamol
Other Intervention Name(s)
Acetyl-Para-Aminophenol (APAP), Acetaminophen
Intervention Description
Paracetamol 15 mg/kg/dose IV 6 hourly for 72 hours
Intervention Type
Procedure
Intervention Name(s)
Mechanical antipyresis
Intervention Description
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).
Primary Outcome Measure Information:
Title
Acute kidney injury (AKI) or death among patients enrolled without AKI (Composite outcome)
Description
Composite outcome of development of AKI (defined as creatinine ≥26.5 µmol/L or ≥1.5x baseline), or death at any timepoint
Time Frame
during first 7 days of enrolment
Title
Acute kidney injury (AKI) progression or death among patients enrolled with AKI (Composite outcome)
Description
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.
Time Frame
during first 7 days of enrolment
Secondary Outcome Measure Information:
Title
Number of patients with serious adverse events
Description
Number of patients with serious adverse events (mortality and/or hepatotoxicity, as defined by Hy's Law).
Time Frame
AST/ALT/total bilirubin during the first 5 days from enrolment; mortality assessed Day 0 to 7.
Title
Proportion of patients who develop Major Adverse Kidney Events (MAKE) composite
Description
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.
Time Frame
90 days
Title
Fever clearance time
Description
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)
Time Frame
6-hourly temperature assessments during first 7 days from enrolment
Title
Coma recovery
Description
Time until Glasgow Coma Score (GCS) return to 15 (or Blantyre Coma Score (BCS) return to 5 in preverbal children)
Time Frame
6-hourly GCS/BCS assessments during first 7 days from enrolment
Title
Longitudinal change in renal function
Description
As measured by creatinine concentration (umol/L)
Time Frame
During the first 7 days from enrolment
Title
Longitudinal change in markers of hemolysis
Description
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
Time Frame
during the first 3 days from enrolment
Title
Longitudinal change of endothelial activation
Description
As measured by concentrations of angiopoietin-Tie2 pathway markers (i.e. Ang-1, Ang-2, sTie2, sTie1)
Time Frame
during the first 3 days from enrolment
Title
Longitudinal change of immune activation
Description
As measured by soluble triggering receptor expressed on myeloid cells concentration (sTREM-1; pg/mL)
Time Frame
during the first 3 days from enrolment
Title
Longitudinal change of AKI biomarker
Description
As measured by cystatin-C concentration (Cys-C; ug/mL)
Time Frame
during the first 3 days from enrolment
Title
Parasite (parasites/ul) clearance
Description
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.
Time Frame
12-hourly parasitemia assessments during first 7 days from enrolment
Title
Exploratory analysis with sex
Description
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.
Time Frame
During first 7 days from enrolment
Title
Pharmacokinetic properties
Description
Population pharmacokinetic model (relative bioavailability, mean transit absorption time (hours), apparent oral elimination clearance (L/hours), apparent volume of distribution (L)
Time Frame
during the first 24 hours from enrolment
Title
Pharmacokinetic properties
Description
Peak plasma concentration (Cmax; mg/L)
Time Frame
during the first 24 hours from enrolment
Title
Pharmacokinetic properties
Description
Time to peak plasma concentration (Tmax; hours)
Time Frame
during the first 24 hours from enrolment
Title
Pharmacokinetic properties
Description
Terminal elimination (t1/2; hours)
Time Frame
during the first 24 hours from enrolment
Title
Pharmacokinetic properties
Description
Area under the plasma drug concentration-time curve (AUC0-24; mg×h×L-1)
Time Frame
during the first 24 hours from enrolment
Title
Pharmacodynamic relationships
Description
Pharmacodynamic effects on creatinine concentration (mol/L)
Time Frame
during first 7 days from enrolment
Title
Pharmacodynamic relationships
Description
Pharmacodynamic effects on liver toxicity, as measured by AST and ALT (U/L)
Time Frame
during first 7 days from enrolment
Title
Pharmacodynamic relationships
Description
Pharmacodynamic effects on temperature (Celsius)
Time Frame
during first 7 days from enrolment
Title
Pharmacodynamic relationships
Description
Pharmacodynamic effects on parasitemia, as measured by parasites/ul and slope half-life
Time Frame
during first 7 days from enrolment
Title
Pharmacodynamic relationships
Description
Pharmacodynamic effects on GCS (or BCS in pre-verbal children)
Time Frame
during first 7 days from enrolment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or Female, patients aged 1 to ≤ 14 years 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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Katherine Plewes, Dr.
Phone
+1-604-603-4033
Email
katherine@tropmedres.ac
First Name & Middle Initial & Last Name or Official Title & Degree
Arjen Dondorp, Prof.
Phone
+662-203-6333
Ext
6303
Email
arjen@tropmedres.ac
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Katherine Plewes, Dr.
Organizational Affiliation
Mahidol Oxford Tropical Medicine Research Unit
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Kinshasa Medical Oxford Research Unit (KIMORU)
City
Kinshasa
State/Province
Congo
Country
Congo, The Democratic Republic of the
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marie Onyamboko, Dr.
Phone
+243990024201
Email
akatshimarie@yahoo.fr
First Name & Middle Initial & Last Name & Degree
Caterina Fanello, Dr.
Phone
+447900278768
Email
caterina.fanello@ndm.ox.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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)

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Effect of Paracetamol on Kidney Function in Severe Malaria

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