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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04251351
Recruitment Status : Not yet recruiting
First Posted : January 31, 2020
Last Update Posted : March 24, 2020
Sponsor:
Collaborators:
Mahidol Oxford Tropical Medicine Research Unit
Kinshasa Medical Oxford Research Unit
Information provided by (Responsible Party):
Katherine Plewes, MD PhD, University of British Columbia

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.

Condition or disease Intervention/treatment Phase
Severe Malaria Malaria,Falciparum Acute Kidney Injury Paracetamol Drug: Paracetamol Procedure: Mechanical antipyresis Phase 3

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 March 2020 - June 2021. The total time to complete the study will be approximately 3 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 460 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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

Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Evaluating the Renoprotective Effect of Paracetamol in Paediatric Severe Malaria: a Randomised Controlled Trial
Estimated Study Start Date : June 1, 2020
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : January 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

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:
  • Acetyl-Para-Aminophenol (APAP)
  • Acetaminophen

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).





Primary Outcome Measures :
  1. Acute kidney injury (AKI) or death among patients enrolled without AKI (Composite outcome) [ Time Frame: during first 7 days of enrolment ]
    Composite outcome of development of AKI (defined as creatinine ≥26.5 µmol/L or ≥1.5x baseline), or death.

  2. Acute kidney injury (AKI) progression or death among patients enrolled with AKI (Composite outcome) [ Time Frame: during first 7 days of enrolment ]
    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.


Secondary Outcome Measures :
  1. Number of patients with serious adverse events [ Time Frame: during the first 5 days from enrolment ]
    Number of patients with serious adverse events (mortality and/or hepatotoxicity, as defined by Hy's Law).

  2. Proportion of patients who develop Major Adverse Kidney Events (MAKE) composite [ Time Frame: 90 days ]
    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.

  3. Fever clearance time [ Time Frame: 6-hourly temperature assessments during first 7 days from enrolment ]
    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)

  4. Coma recovery [ Time Frame: 6-hourly GCS/BCS assessments during first 7 days from enrolment ]
    Time until Glasgow Coma Score (GCS) return to 15 (or Blantyre Coma Score (BCS) return to 5 in preverbal children)

  5. Longitudinal change in renal function [ Time Frame: During the first 3 days from enrolment ]
    As measured by creatinine concentration (umol/L)

  6. Longitudinal change in markers of hemolysis [ Time Frame: during the first 3 days from enrolment ]
    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

  7. Longitudinal change of endothelial activation [ Time Frame: during the first 3 days from enrolment ]
    As measured by concentrations of angiopoietin-Tie2 pathway markers (i.e. Ang-1, Ang-2, sTie2, sTie1)

  8. Longitudinal change of immune activation [ Time Frame: during the first 3 days from enrolment ]
    As measured by soluble triggering receptor expressed on myeloid cells concentration (sTREM-1; pg/mL)

  9. Longitudinal change of AKI biomarker [ Time Frame: during the first 3 days from enrolment ]
    As measured by cystatin-C concentration (Cys-C; ug/mL)

  10. Parasite (parasites/ul) clearance [ Time Frame: 12-hourly parasitemia assessments during first 7 days from enrolment ]
    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.

  11. Exploratory analysis with sex [ Time Frame: During first 7 days from enrolment ]
    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.

  12. Pharmacokinetic properties [ Time Frame: during the first 24 hours from enrolment ]
    Population pharmacokinetic model (relative bioavailability, mean transit absorption time (hours), apparent oral elimination clearance (L/hours), apparent volume of distribution (L)

  13. Pharmacokinetic properties [ Time Frame: during the first 24 hours from enrolment ]
    Peak plasma concentration (Cmax; mg/L)

  14. Pharmacokinetic properties [ Time Frame: during the first 24 hours from enrolment ]
    Time to peak plasma concentration (Tmax; hours)

  15. Pharmacokinetic properties [ Time Frame: during the first 24 hours from enrolment ]
    Terminal elimination (t1/2; hours)

  16. Pharmacokinetic properties [ Time Frame: during the first 24 hours from enrolment ]
    Area under the plasma drug concentration-time curve (AUC0-24; mg×h×L-1)

  17. Pharmacodynamic relationships [ Time Frame: during first 7 days from enrolment ]
    Pharmacodynamic effects on creatinine concentration (mol/L)

  18. Pharmacodynamic relationships [ Time Frame: during first 7 days from enrolment ]
    Pharmacodynamic effects on liver toxicity, as measured by AST and ALT (U/L)

  19. Pharmacodynamic relationships [ Time Frame: during first 7 days from enrolment ]
    Pharmacodynamic effects on temperature (Celsius)

  20. Pharmacodynamic relationships [ Time Frame: during first 7 days from enrolment ]
    Pharmacodynamic effects on parasitemia, as measured by parasites/ul and slope half-life

  21. Pharmacodynamic relationships [ Time Frame: during first 7 days from enrolment ]
    Pharmacodynamic effects on GCS (or BCS in pre-verbal children)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 14 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04251351


Contacts
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Contact: Katherine Plewes, Dr. +1-604-603-4033 katherine@tropmedres.ac
Contact: Arjen Dondorp, Prof. +662-203-6333 ext 6303 arjen@tropmedres.ac

Locations
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Congo, The Democratic Republic of the
The Kinshasa Medical Oxford Research Unit (KIMORU)
Kinshasa, Congo, Congo, The Democratic Republic of the
Contact: Marie Onyamboko, Dr.    +243990024201    akatshimarie@yahoo.fr   
Contact: Caterina Fanello, Dr.    +447900278768    caterina.fanello@ndm.ox.ac.uk   
Sponsors and Collaborators
University of British Columbia
Mahidol Oxford Tropical Medicine Research Unit
Kinshasa Medical Oxford Research Unit
Investigators
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Principal Investigator: Katherine Plewes, Dr. Mahidol Oxford Tropical Medicine Research Unit
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Responsible Party: Katherine Plewes, MD PhD, Principal Investigator, University of British Columbia
ClinicalTrials.gov Identifier: NCT04251351    
Other Study ID Numbers: H19-03570
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: March 24, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Time Frame: After completion of trial activities and reporting
Access Criteria: MORU Data Sharing Policy. (http://www.tropmedres.ac/data-sharing-policy)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Katherine Plewes, MD PhD, University of British Columbia:
Severe Malaria
Falciparum
Paracetamol
Renoprotection
Acute Kidney Injury
Additional relevant MeSH terms:
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Malaria
Malaria, Falciparum
Acute Kidney Injury
Protozoan Infections
Parasitic Diseases
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics