Acute Kidney Injury Clinical Trial
— PROTECtSOfficial title:
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.
Status | Recruiting |
Enrollment | 460 |
Est. completion date | November 1, 2025 |
Est. primary completion date | June 1, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 1 Year to 14 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Congo, The Democratic Republic of the | The Kinshasa Medical Oxford Research Unit (KIMORU) | Kinshasa | Congo |
Lead Sponsor | Collaborator |
---|---|
University of British Columbia | Kinshasa Medical Oxford Research Unit, Mahidol Oxford Tropical Medicine Research Unit |
Congo, The Democratic Republic of the,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | 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. | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | Longitudinal change in renal function | As measured by creatinine concentration (umol/L) | During the first 7 days from enrolment | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | Longitudinal change of AKI biomarker | As measured by cystatin-C concentration (Cys-C; ug/mL) | during the first 3 days from enrolment | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | Pharmacokinetic properties | Peak plasma concentration (Cmax; mg/L) | during the first 24 hours from enrolment | |
Secondary | Pharmacokinetic properties | Time to peak plasma concentration (Tmax; hours) | during the first 24 hours from enrolment | |
Secondary | Pharmacokinetic properties | Terminal elimination (t1/2; hours) | during the first 24 hours from enrolment | |
Secondary | Pharmacokinetic properties | Area under the plasma drug concentration-time curve (AUC0-24; mg×h×L-1) | during the first 24 hours from enrolment | |
Secondary | Pharmacodynamic relationships | Pharmacodynamic effects on creatinine concentration (mol/L) | during first 7 days from enrolment | |
Secondary | Pharmacodynamic relationships | Pharmacodynamic effects on liver toxicity, as measured by AST and ALT (U/L) | during first 7 days from enrolment | |
Secondary | Pharmacodynamic relationships | Pharmacodynamic effects on temperature (Celsius) | during first 7 days from enrolment | |
Secondary | Pharmacodynamic relationships | Pharmacodynamic effects on parasitemia, as measured by parasites/ul and slope half-life | during first 7 days from enrolment | |
Secondary | Pharmacodynamic relationships | Pharmacodynamic effects on GCS (or BCS in pre-verbal children) | during first 7 days from enrolment |
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