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Paracetamol Effect on Oxidative Stress and Renal Function in Severe Malaria

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT01641289
First received: May 23, 2012
Last updated: March 16, 2016
Last verified: March 2016
  Purpose

Blackwater fever, characterized by intravascular haemolysis and hemoglobinuria, is an important cause of renal impairment and mortality in severe malaria caused by Plasmodium falciparum. The largest malaria clinical trials report blackwater incidences of 5-7% in Asian adults and 4% in African children with severe malaria treated with artesunate or quinine. The prevalence of blackwater fever in Chittagong, Bangladesh is 15% with associated rates of renal failure and mortality of 42.9% and 14.2% respectively.

The fundamental characteristic of blackwater fever is the presence of intravascular hemolysis of both infected and uninfected erythrocytes and release of free haemoglobin. The cytotoxic free haemoglobin present can cause severe oxidative damage as a result of haem redox cycling yielding ferric and ferryl heme, which generate radical species that induce lipid peroxidation and subsequent production of F2-isoprostanes (F2-IsoPs). Evidence suggests that F2-IsoPs generated by the hemoprotein-catalyzed oxidation of lipids are responsible for the oxidative damage and vasoconstriction associated with renal injury in haemolytic disorders and rhabdomyolysis.

A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol is a potent inhibitor of hemoprotein-catalyzed lipid peroxidation by reducing ferryl heme to its less toxic ferric state and quenching globin radicals. In a recent proof of concept trial, paracetamol at therapeutic levels was shown to significantly decrease oxidant kidney injury, improve renal function and reduce renal damage by inhibiting the hemoprotein-catalyzed lipid peroxidation in a rat model of rhabdomyolysis-induced renal injury. Since adults with severe malaria demonstrate increased concentrations of cell-free haemoglobin, and urinary F2-IsoPs, the investigators hypothesize that this novel inhibitory mechanism of paracetamol may provide renal protection in this population by reducing the hemoprotein-induced lipid peroxidation. As there is currently no consensus that exists concerning adequate medical treatment for blackwater fever, the potential application of this safe and extensively used drug would be of great benefit.


Condition Intervention
Malaria
Drug: Paracetamol
Drug: No Paracetamol

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Paracetamol Effect on Oxidative Stress and Renal Function in Severe Falciparum Malaria With Intravascular Haemolysis: A Randomised Controlled Clinical Trial

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • Effect of paracetamol concentrations [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    Compare the effect of therapeutic paracetamol concentrations compared with absent or low paracetamol concentration on renal function, peak creatinine levels or trough creatinine clearance, defined as the change at 72 hours compared to baseline, in patients with severe and moderately severe falciparum malaria stratified by the level of intravascular haemolysis (cell-free haemoglobin).


Secondary Outcome Measures:
  • Compare treatment arm with control arm with respect to duration of Acute Kidney Injury (AKI) and development of AKI. [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    Duration of AKI will be defined as the length of time elapsed until serum creatinine returns to normal (<1mg/dL) in the absence of renal replacement therapy. Development of AKI will be assessed using the Acute Kidney Injury Network (AKIN) criteria, and by a creatinine increase of >= 0.5mg/dl or 25%. Plasma paracetamol concentration will be measured daily by liquid chromatography-mass spectrometer (LC-MS/MS).

  • Compare between groups correlations between oxidative stress, cell-free hemoglobin and renal function [ Time Frame: 3 days ] [ Designated as safety issue: No ]
    Urine and plasma F2-isoprostanes and isofurans will be measured by gas chromatography-mass spectrometry. Cell-free haemoglobin measured as plasma concentration by enzyme linked immunosorbent assay (ELISA) on admission then daily for 72hours. Cell free haem measured in plasma using a chromogenic assay on admission then daily for 72hours. Haem-to-protein cross-links measured by high performance liquid chromatography (HPLC) on admission and daily for 72hours.

  • Assessment of Blackwater fever and association with renal function [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Blackwater fever assessed using a standardized urine colour chart and urine haemoglobin every 6 hours until clinical recovery between groups.

  • Mortality and hemodialysis trends [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    To compare mortality and hemodialysis trends between groups and evaluate if they correlate with level of oxidative stress, cell free haemoglobin and renal function.

  • Host factors of Intravascular Haemolysis [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Intravascular haemolysis according to G6PD status.

  • Fever clearance time [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Compared fever clearance time defined as the time taken for the tympanic temperature to fall below 37.5°C and remain there for at least 24hours); Fever time defined as the duration in hours of an individuals temperature above 37.5°C; Area above the 37.5°C temperature versus time curve (AUC-T°) within first 24hours of treatment. Aural temperature will be measured every 6 hours until fever clearance.

  • Parasite clearance time [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Parasite clearance time assessed by microscopy of peripheral blood films will be assessed every 6hours for the presence of asexual parasitaemia until negative on 2 consecutive blood films. Parasite half lives and clearance time will be compared between groups. Parasites will also be staged to assess if sequestration is inhibited due to temperature reduction.

  • Parasite sequestration [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Parasite sequestration assessed by capillary flow in the rectal microcirculation using Orthogonal Polarization Spectral (OPS) imaging will be compared between groups.

  • Assessment of Acute Kidney Injury [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Evaluation of pre-renal and acute tubular necrosis assessed by blood and urine biomarkers of pre-renal and renal injury including neutrophil gelatinase-associated lipocalcin (NGAL) and kidney injury molecule (KIM).

  • Urine scoring of dehydration and haemolysis [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    Urine colour will be assessed by standardized urine colour charts. Urine colour will be correlated with urine specific gravity, urine osmolality, urine haemoglobin and creatinine clearance.

  • Safety assessment [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    Safety assessed by the number of patients with serious adverse events (SAEs) and by changes from baseline in vital signs and laboratory measurements.

  • Assess the antimalarial drug sensitivity of patients treated with paracetamol [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    Preliminary in vitro studies suggest that paracetamol potentiates the anti-parasitic effect of artesunate as lower 50% inhibitory concentration of artesunate is observed when paracetamol is added to parasites in culture. We will investigate whether this effect is dependent on the infecting P. falciparum parasite strain

  • Paracetamol pharmacokinetics [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    Pharmacokinetic modelling of oral paracetamol in severe and moderately severe malaria

  • Paracetamol pharmacodynamics [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    Pharmacodynamics on variables including temperature and parasitemia.

  • Area under the plasma concentration versus time curve (AUC) [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    for paracetamol

  • The maximum concentration (Cmax) [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    for paracetamol


Enrollment: 62
Study Start Date: July 2012
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Paracetamol

>50kg: Paracetamol 1gm PO/NG q6hourly for 72 hours and febrile for 24 hours (maximum total dose 4g/24 hours) plus intravenous Artesunate

<50kg: Paracetamol 12.5-15mg/kg/dose q6hourly for 72 hours and febrile for 24 hours (maximum total dose 5 doses/24hours;75mg/kg) plus intravenous Artesunate

Drug: Paracetamol
>50kg: Paracetamol 1gm PO/NG q6hourly for 72hours and afebrile for 24h (maximum total dose 4g/24 hours) plus intravenous Artesunate <50kg: Paracetamol 12.5-15mg/kg/dose q6hourly for 72hours and afebrile for 24h (maximum total dose 5 doses/24hours;75mg/kg) plus intravenous Artesunate
Active Comparator: No Paracetamol

No paracetamol + Intravenous Artesunate

  • If temperature > 40°C, ibuprofen PO/PR will be administered in the absence of renal impairment and dehydration; 500mg paracetamol PO/PR will be administered in the presence of renal impairment or dehydration. Dengue testing will be done prior to the administration of ibuprofen.
Drug: No Paracetamol

No paracetamol + Intravenous Artesunate

  • If temperature > 40°C, ibuprofen PO/PR will be administered in the absence of renal impairment and dehydration; 500mg paracetamol PO/PR will be administered in the presence of renal impairment or dehydration. Dengue testing will be done prior to the administration of ibuprofen.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient age >12 years
  2. Presence of severe or moderately severe P. falciparum malaria, with and without blackwater fever, confirmed by positive blood smear with asexual forms of P. falciparum
  3. Temperature >38 degrees Celsius on admission or fever during the preceding 24hours
  4. Written informed consent from patient or attending relative able to and willing to give informed consent. Consent form and information sheets will be translated into Bangla and copies provided to the patient.

Exclusion Criteria:

  1. Patient or relatives unable or unwilling to give informed consent
  2. History of chronic liver disease
  3. History of alcohol use (>3drinks per day)
  4. Contraindication or allergy to paracetamol or artesunate therapy
  5. Contraindication to nasogastric tube insertion i.e. facial fracture, bleeding diathesis
  6. Pregnancy
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01641289

Locations
Bangladesh
Chittagong Medical College Hospital
Chittagong, Bangladesh
Ramu Upazilla Health Complex
Ramu, Bangladesh
Sponsors and Collaborators
University of Oxford
Investigators
Principal Investigator: Katherine Plewes, MD University of Oxford
  More Information

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT01641289     History of Changes
Other Study ID Numbers: BAKMAL1201 
Study First Received: May 23, 2012
Last Updated: March 16, 2016
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by University of Oxford:
Falciparum malaria
Paracetamol
Renal function
Oxidative stress

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Ibuprofen
Acetaminophen
Artesunate
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antipyretics
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials

ClinicalTrials.gov processed this record on December 09, 2016