Paracetamol Effect on Oxidative Stress and Renal Function in Severe Malaria

NCT01641289 | Completed

• 1 other identifier: BAKMAL1201
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Malaria

Keywords

Falciparum malaria; Paracetamol; Renal function; Oxidative stress

Outcome Measures

Primary Outcomes (1)

• Effect of paracetamol concentrations

  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).

  72 hours

Secondary Outcomes (16)

• Compare treatment arm with control arm with respect to duration of Acute Kidney Injury (AKI) and development of AKI.

  14 days

• Compare between groups correlations between oxidative stress, cell-free hemoglobin and renal function

  3 days

• Assessment of Blackwater fever and association with renal function

  7 days

• Mortality and hemodialysis trends

  4 weeks

• Host factors of Intravascular Haemolysis

  4 weeks

Study Arms (2)

Paracetamol

EXPERIMENTAL

\>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

No Paracetamol

ACTIVE COMPARATOR

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

Interventions

Paracetamol DRUG

\>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

Paracetamol

No Paracetamol DRUG

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.

No Paracetamol

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient age \>12 years
• 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
• Temperature \>38 degrees Celsius on admission or fever during the preceding 24hours
• 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.

You may not qualify if:

• Patient or relatives unable or unwilling to give informed consent
• History of chronic liver disease
• History of alcohol use (\>3drinks per day)
• Contraindication or allergy to paracetamol or artesunate therapy
• Contraindication to nasogastric tube insertion i.e. facial fracture, bleeding diathesis
• Pregnancy

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (2)

Chittagong Medical College Hospital

Chittagong, Bangladesh

Location

Ramu Upazilla Health Complex

Rāmu, Bangladesh

Location

Related Publications (1)

• Plewes K, Kingston HWF, Ghose A, Wattanakul T, Hassan MMU, Haider MS, Dutta PK, Islam MA, Alam S, Jahangir SM, Zahed ASM, Sattar MA, Chowdhury MAH, Herdman MT, Leopold SJ, Ishioka H, Piera KA, Charunwatthana P, Silamut K, Yeo TW, Lee SJ, Mukaka M, Maude RJ, Turner GDH, Faiz MA, Tarning J, Oates JA, Anstey NM, White NJ, Day NPJ, Hossain MA, Roberts Ii LJ, Dondorp AM. Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial. Clin Infect Dis. 2018 Sep 14;67(7):991-999. doi: 10.1093/cid/ciy213.

  PMID: 29538635 DERIVED

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Katherine Plewes, MD

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2012
• First Posted: July 16, 2012
• Study Start: July 10, 2012
• Primary Completion: September 13, 2014
• Study Completion: September 21, 2014
• Last Updated: June 14, 2018

Record last verified: 2018-06

Locations

BA (2)