Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria (PACKNOW)

Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria: A Randomised Controlled Clinical Trial

Acute kidney injury is a common complication of severe Plasmodium knowlesi malaria, and an important contributor to mortality.

The exact pathogenic mechanisms of AKI in knowlesi malaria are not known, however it is hypothesised that haemolysis of red blood cells and subsequent release of cell-free haemoglobin leads to oxidative stress and lipid peroxidation in the renal tubules.

A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol acts as a potent inhibitor of hemoprotein-catalyzed lipid peroxidation. In a proof of concept trial, paracetamol at therapeutic levels was shown to significantly decrease oxidative kidney injury and improve renal function by inhibiting the hemoprotein-catalyzed lipid peroxidation in a rat model of rhabdomyolysis-induced renal injury.

The investigators hypothesize that this novel inhibitory mechanism of paracetamol may provide renal protection in adults with knowlesi malaria by reducing the hemoprotein-induced lipid peroxidation that occurs in haemolytic conditions. 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 paracetamol would be of benefit, especially as it is safe and widely available.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: Paracetamol

Detailed Description

Plasmodium knowlesi is the most common cause of malaria, and malaria deaths, in Sabah, Malaysia. Acute kidney injury (AKI) is a common feature of severe knowlesi malaria; however the mechanisms of AKI in knowlesi malaria are unknown. In falciparum malaria, recent evidence suggests that oxidative stress from haemolysis-related cell-free haemoglobin (CFHb) may contribute to pathogenesis of AKI.

Cell-free haemoglobin and oxidative stress: CFHb is released during intravascular haemolysis, and when exceeding the binding capacity of plasma haptoglobin, is filtered by the glomeruli and enters the renal tubules. CFHb is pathogenic as the ferrous heme can be oxidized to the ferric state, conferring peroxidase activity to the hemoglobin. Consequently, the hemoglobin can reduce hydroperoxides, such as hydrogen peroxide (H2O2) and lipid hydroperoxides, which generate the ferryl state of heme (FeIV=O) and a protein radical. The ferryl heme and protein radical can then generate lipid radicals by oxidation of free and phospholipid-esterified unsaturated fatty acids. The arachidonic side chains of membrane phospholipids are particularly vulnerable to this free radical-mediated damage in the complex cascade of lipid oxidation leading to the generation of F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs). F2-IsoPs and IsFs are increased in severe falciparum malaria, and have been shown to induce vasoconstriction associated with renal injury in other haemolytic conditions including rhabdomyolysis, sepsis and post-operatively.

Paracetamol and oxidative stress: A novel mechanism of paracetamol was recently demonstrated, showing that paracetamol acts as a potent inhibitor of hemoprotein-catalyzed lipid peroxidation by reducing ferryl heme to its less toxic ferric state and quenching globin radicals. In a proof of concept trial, paracetamol at therapeutic levels was shown to significantly decrease oxidative kidney injury and improve renal function by inhibiting the hemoprotein-catalyzed lipid peroxidation in a rat model of rhabdomyolysis-induced renal injury. In a retrospective study of patients with sepsis, receiving paracetamol in the setting of raised CFHb was associated with reduced lipid peroxidation, and reduced risk of death. More recently, in a randomized placebo-controlled trial, paracetamol was associated with a reduction in F2-IsoPs and improved renal function in adults with sepsis and detectable CFHb.

Rationale: The investigators hypothesize that paracetamol may provide renal protection in patients with severe knowlesi malaria by reducing the hemoprotein-induced lipid peroxidation that occurs in haemolytic conditions. 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 paracetamol would be of great benefit, especially as it is safe and widely available.

Proposed activities: The main activity proposed is a randomised, open label, controlled trial of regularly-dosed paracetamol, versus no paracetamol, in patients with knowlesi malaria, to assess the effect of paracetamol on renal function and oxidative stress.

• Study Type: Interventional
• Enrollment (Actual): 360
• Phase: Phase 3

Contacts and Locations

Study Locations

• Malaysia
  • Sabah
    • Keningau, Sabah, Malaysia, 88200
      • Keningau District Hospital
    • Kota Kinabalu, Sabah, Malaysia, 88200
      • Queen Elizabeth Hospital
    • Kota Marudu, Sabah, Malaysia, 89100
      • Kota Marudu District Hospital
    • Ranau, Sabah, Malaysia, 89300
      • Ranau District Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient age ≥ 5 years
2. Presence of P. knowlesi malaria, confirmed by positive blood smear with asexual forms of P. knowlesi.
3. Temperature >38C on admission or fever during the preceding 48 hours
4. Enrolled within 18 hours of commencing antimalarial treatment
5. 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 Malay and copies provided to the patient.

Exclusion Criteria:

1. Patient or relatives unable or unwilling to give informed consent
2. Contraindication or allergy to paracetamol or artesunate therapy
3. Known cirrhosis, or >6 standard alcoholic drinks/day
4. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paracetamol; >50kg: Paracetamol 1gm PO/NG 6 hourly for 72 hours (maximum dose 4g/24h) plus IV artesunate or oral artemether/lumefantrine. <50kg: Paracetamol 12.5-15mg/kg/dose 6 hourly for 72 hours (maximum total dose 5doses/24hours;75mg/kg) plus IV artesunate or oral artemether/lumefantrine.	Drug: Paracetamol; >50kg: Paracetamol 1gm PO/NG 6 hourly for 72 hours (maximum dose 4g/24h) plus IV artesunate or oral artemether/lumefantrine. <50kg: Paracetamol 12.5-15mg/kg/dose 6 hourly for 72 hours (maximum total dose 5doses/24hours;75mg/kg) plus IV artesunate or oral artemether/lumefantrine.; Other Names: acetaminophen
No Intervention: No Paracetamol; No Paracetamol plus IV artesunate or oral artemether/lumefantrine. If temperature >39.5°C, tepid sponging and mechanical antipyresis will be performed by research staff and/or relatives.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Paracetamol on kidney function	Change in creatinine concentration (umol/L) at 72 hours from enrolment in patients receiving regularly-dosed paracetamol compared to those not receiving regular paracetamol, stratified by the level of intravascular haemolysis (cell-free haemoglobin).	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longitudinal change in creatinine	Longitudinal change in creatinine, as measured by the area under the creatinine-time curve, with creatinine measured 12 hourly from enrolment to 72 hours; and the effect of enrolment cell-free haemoglobin on longitudinal change in creatinine	72 hours
Change in creatinine in severe malaria	Change in creatinine at 72 hours and longitudinal change in creatinine over 72 hours, including the effect of enrolment CFHb, in patients with severe knowlesi malaria.	72 hours
Development of AKI	Development of AKI over 72 hours: i) an absolute increase in serum creatinine of >26.5 umol/L from enrolment creatinine; ii) a percentage increase in serum creatinine of >50% from enrolment; iii) post-enrolment onset of oliguria of less than 0.5ml/kg/hour for more than 6 hours; iv) 24 hour urine output of <400ml after rehydration and urinary obstruction excluded. AKI on enrolment will also be described by the Kidney Disease Improving Global Outcomes (KDIGO) criteria (with baseline creatinine estimated using the MDRD equation).	72 hours
Duration of AKI	Length of time elapsed until serum creatinine returns to normal (estimated using MDRD equation) in the absence of renal replacement therapy in those with AKI on enrolment and those that develop AKI after enrolment.	28 days
Longitudinal changes in haemolysis: plasma cell-free haemoglobin	Longitudinal changes in plasma cell-free haemoglobin over 72 hours.	72 hours
Longitudinal changes in haemolysis: plasma cell-free haem	Longitudinal changes in plasma cell-free haem over 72 hours.	72 hours
Longitudinal changes in haemolysis: haem-to-protein cross-links	Longitudinal changes in haem-to-protein cross-links over 72 hours.	72 hours
Longitudinal changes in markers of oxidative stress: F2-IsoP	Longitudinal changes in plasma F2-isoprostanes [F2-IsoP] over 72 hours.	72 hours
Longitudinal changes in markers of oxidative stress: IsoF	Longitudinal changes in plasma isofurans [IsoF]) over 72 hours.	72 hours
Longitudinal changes in F2-IsoPs according to G6PD enzyme activity	Longitudinal changes in F2-IsoPs according to G6PD enzyme activity, assessed qualitatively by fluorescent spot test.	72 hours
Longitudinal changes in IsoFs according to G6PD enzyme activity	Longitudinal changes in IsoFs and CFHb according to G6PD enzyme activity, assessed qualitatively by fluorescent spot test.	72 hours
Longitudinal changes in CFHb according to G6PD enzyme activity	Longitudinal changes in CFHb according to G6PD enzyme activity, assessed qualitatively by fluorescent spot test.	72 hours
Longitudinal changes in F2-IsoPs according to G6PD genotype	Longitudinal changes in F2-IsoPs according to G6PD genotype	72 hours
Longitudinal changes in IsoFs according to G6PD genotype	Longitudinal changes in IsoFs according to G6PD genotype	72 hours
Longitudinal changes in CFHb according to G6PD genotype	Longitudinal changes in CFHb according to G6PD genotype	72 hours
Population pharmacokinetics of paracetamol: Cmax	Peak plasma concentration (Cmax)	72 hours
Population pharmacokinetics of paracetamol: Tmax	Time to peak plasma concentration (Tmax)	72 hours
Population pharmacokinetics of paracetamol: AUC	Area under the plasma drug concentration-time curve (AUC)	72 hours
Population pharmacodynamics of paracetamol	Paracetamol dose-response curve	72 hours
Fever clearance time	Defined as the time taken for the aural temperature to fall below 37.5°C, and the time taken for the temperature to fall below 37.5°C and remain there for at least 24hours	72 hours
Fever duration	Defined as the duration in hours that an individual's temperature is above 37.5°C	72 hours
Area above the fever versus time curve (AUC-T°)	Area above the 37.5°C temperature versus time curve (AUC-T°) within first 24 hours of treatment.	72 hours
Parasite clearance time (hours)	Parasite clearance time, defined as (i) the time from commencement of antimalarial treatment to the first of 2 consecutive negative blood films, with blood films assessed by microscopy every 6 hours for the presence of asexual parasitaemia, and (ii) the linear portion of the slope of the log-parasitemia versus time relationship.	72 hours
Blood and urine biomarkers of pre-renal and renal injury	Neutrophil gelatinase-associated lipocalcin (NGAL), kidney injury molecule (KIM), urinalysis, urine microscopy, urine electrolytes, and urine creatinine.	72 hours
Longitudinal urine colour	Longitudinal urine colour (assessed by standardized urine colour charts). The proportion of patients with enrolment urine pH less than 6 together with a urine color of 6 or greater who develop AKI will be compared between groups.	72 hours
Longitudinal urine pH	Longitudinal urinalysis dipstick test-strip: urine pH. The proportion of patients with enrolment urine pH less than 6 together with a urine color of 6 or greater who develop AKI will be compared between groups.	72 hours
Longitudinal urine specific gravity	Longitudinal urinalysis dipstick test-strip: urine specific gravity	72 hours
Longitudinal urine haemoglobin	Longitudinal urinalysis dipstick test-strip: urine haemoglobin	72 hours
Change in creatinine (umol/L) between therapeutic concentrations of paracetamol vs those with absent or low.	Change in creatinine at 72 hours and longitudinal change in creatinine over 72 hours in patients with therapeutic concentrations of paracetamol, compared to patients with absent or low concentrations of paracetamol	72 hours
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Reporting of any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with paracetamol administration	28 days
Longitudinal red cell deformability	Longitudinal red cell deformability, as measured by laser-assisted optical rotational red cell analyser (LORCA) elongation index.	72 hours
Longitudinal changes in markers of endothelial dysfunction	Longitudinal changes in markers of weibel palade body exocytosis including angiopoietin-2	72 hours

Collaborators and Investigators

• Sponsor: Menzies School of Health Research
• Investigators: Principal Investigator: Giri M Rajahram, MD, Clinical Research Center, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia; Study Director: Bridget Barber, MBBS, Menzies School of Health Research; Study Director: Nicholas Anstey, PhD, Menzies School of Health Research; Study Director: Matthew Grigg, MBBS, Menzies School of Health Research; Study Director: Timothy William, MBBS, Jesselton Medical Centre; Study Director: Jayaram Menon, MBBS, Ministry of Health, Malaysia; Study Director: Katherine Plewes, MD, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand; Study Director: Arjen Dondorp, MD, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand; Study Director: Daniel Cooper, MBChB, Menzies School of Health Research

Publications and helpful links

General Publications

• Longley RJ, Grigg MJ, Schoffer K, Obadia T, Hyslop S, Piera KA, Nekkab N, Mazhari R, Takashima E, Tsuboi T, Harbers M, Tetteh K, Drakeley C, Chitnis CE, Healer J, Tham WH, Sattabongkot J, White MT, Cooper DJ, Rajahram GS, Barber BE, William T, Anstey NM, Mueller I. Plasmodium vivax malaria serological exposure markers: Assessing the degree and implications of cross-reactivity with P. knowlesi. Cell Rep Med. 2022 Jun 21;3(6):100662. doi: 10.1016/j.xcrm.2022.100662.
• Cooper DJ, Grigg MJ, Plewes K, Rajahram GS, Piera KA, William T, Menon J, Koleth G, Edstein MD, Birrell GW, Wattanakul T, Tarning J, Patel A, Wen Yeo T, Dondorp AM, Anstey NM, Barber BE. The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial. Clin Infect Dis. 2022 Oct 12;75(8):1379-1388. doi: 10.1093/cid/ciac152.
• Cooper DJ, Plewes K, Grigg MJ, Rajahram GS, Piera KA, William T, Chatfield MD, Yeo TW, Dondorp AM, Anstey NM, Barber BE. The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial. Trials. 2018 Apr 24;19(1):250. doi: 10.1186/s13063-018-2600-0.

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: January 31, 2017
• First Submitted That Met QC Criteria: February 14, 2017
• First Posted (Actual): February 17, 2017

Study Record Updates

• Last Update Posted (Actual): December 19, 2019
• Last Update Submitted That Met QC Criteria: December 18, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: oxidative stress; renal function; paracetamol; knowlesi malaria; haemolysis
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: NMRR-16-356-29088

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No