Clinical trial NCT03056391: Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria
Official title: Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria: A Randomised Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: knowlesi malaria
paracetamol
renal function
haemolysis
oxidative stress
Lead sponsor: Menzies School of Health Research
Sponsor class: OTHER
First posted: 2017-02-17
Enrollment: 360
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Effect of Paracetamol on kidney function
timeFrame: 72 hours
Secondary outcomes:
measure: Longitudinal change in creatinine
timeFrame: 72 hours
measure: Change in creatinine in severe malaria
timeFrame: 72 hours
measure: Development of AKI
timeFrame: 72 hours
measure: Duration of AKI
timeFrame: 28 days
measure: Longitudinal changes in haemolysis: plasma cell-free haemoglobin
timeFrame: 72 hours
measure: Longitudinal changes in haemolysis: plasma cell-free haem
timeFrame: 72 hours
measure: Longitudinal changes in haemolysis: haem-to-protein cross-links
timeFrame: 72 hours
measure: Longitudinal changes in markers of oxidative stress: F2-IsoP
timeFrame: 72 hours
measure: Longitudinal changes in markers of oxidative stress: IsoF
timeFrame: 72 hours
measure: Longitudinal changes in F2-IsoPs according to G6PD enzyme activity
timeFrame: 72 hours
measure: Longitudinal changes in IsoFs according to G6PD enzyme activity
timeFrame: 72 hours
measure: Longitudinal changes in CFHb according to G6PD enzyme activity
timeFrame: 72 hours
measure: Longitudinal changes in F2-IsoPs according to G6PD genotype
timeFrame: 72 hours
measure: Longitudinal changes in IsoFs according to G6PD genotype
timeFrame: 72 hours
measure: Longitudinal changes in CFHb according to G6PD genotype
timeFrame: 72 hours
measure: Population pharmacokinetics of paracetamol: Cmax
timeFrame: 72 hours
measure: Population pharmacokinetics of paracetamol: Tmax
timeFrame: 72 hours
measure: Population pharmacokinetics of paracetamol: AUC
timeFrame: 72 hours
measure: Population pharmacodynamics of paracetamol
timeFrame: 72 hours
measure: Fever clearance time
timeFrame: 72 hours
measure: Fever duration
timeFrame: 72 hours
measure: Area above the fever versus time curve (AUC-T°)
timeFrame: 72 hours
measure: Parasite clearance time (hours)
timeFrame: 72 hours
measure: Blood and urine biomarkers of pre-renal and renal injury
timeFrame: 72 hours
measure: Longitudinal urine colour
timeFrame: 72 hours
measure: Longitudinal urine pH
timeFrame: 72 hours
measure: Longitudinal urine specific gravity
timeFrame: 72 hours
measure: Longitudinal urine haemoglobin
timeFrame: 72 hours
measure: Change in creatinine (umol/L) between therapeutic concentrations of paracetamol vs those with absent or low.
timeFrame: 72 hours
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 28 days
measure: Longitudinal red cell deformability
timeFrame: 72 hours
measure: Longitudinal changes in markers of endothelial dysfunction
timeFrame: 72 hours
Other outcomes:
Locations:
city: Keningau
country: Malaysia
facility: Keningau District Hospital
state: Sabah
city: Kota Kinabalu
country: Malaysia
facility: Queen Elizabeth Hospital
state: Sabah
city: Kota Marudu
country: Malaysia
facility: Kota Marudu District Hospital
state: Sabah
city: Ranau
country: Malaysia
facility: Ranau District Hospital
state: Sabah
Study officials:
affiliation: Clinical Research Center, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia
name: Giri M Rajahram, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Menzies School of Health Research
name: Bridget Barber, MBBS
role: STUDY_DIRECTOR
affiliation: Menzies School of Health Research
name: Nicholas Anstey, PhD
role: STUDY_DIRECTOR
affiliation: Menzies School of Health Research
name: Matthew Grigg, MBBS
role: STUDY_DIRECTOR
affiliation: Jesselton Medical Centre
name: Timothy William, MBBS
role: STUDY_DIRECTOR
affiliation: Ministry of Health, Malaysia
name: Jayaram Menon, MBBS
role: STUDY_DIRECTOR
affiliation: Menzies School of Health Research
name: Tsin Yeo, MBBS
role: STUDY_DIRECTOR
affiliation: Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
name: Katherine Plewes, MD
role: STUDY_DIRECTOR
affiliation: Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
name: Arjen Dondorp, MD
role: STUDY_DIRECTOR
affiliation: Menzies School of Health Research
name: Daniel Cooper, MBChB
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.