Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria
NCT ID: NCT03056391
Last Updated: 2019-12-19
Study Results
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Basic Information
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COMPLETED
PHASE3
360 participants
INTERVENTIONAL
2016-10-31
2018-02-01
Brief Summary
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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
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
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.
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.
No interventions assigned to this group
Interventions
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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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
2. Contraindication or allergy to paracetamol or artesunate therapy
3. Known cirrhosis, or \>6 standard alcoholic drinks/day
4. Pregnancy
5 Years
ALL
No
Sponsors
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Menzies School of Health Research
OTHER
Responsible Party
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Principal Investigators
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Giri M Rajahram, MD
Role: PRINCIPAL_INVESTIGATOR
Clinical Research Center, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia
Bridget Barber, MBBS
Role: STUDY_DIRECTOR
Menzies School of Health Research
Nicholas Anstey, PhD
Role: STUDY_DIRECTOR
Menzies School of Health Research
Matthew Grigg, MBBS
Role: STUDY_DIRECTOR
Menzies School of Health Research
Timothy William, MBBS
Role: STUDY_DIRECTOR
Jesselton Medical Centre
Jayaram Menon, MBBS
Role: STUDY_DIRECTOR
Ministry of Health, Malaysia
Tsin Yeo, MBBS
Role: STUDY_DIRECTOR
Menzies School of Health Research
Katherine Plewes, MD
Role: STUDY_DIRECTOR
Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
Arjen Dondorp, MD
Role: STUDY_DIRECTOR
Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
Daniel Cooper, MBChB
Role: STUDY_DIRECTOR
Menzies School of Health Research
Locations
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Keningau District Hospital
Keningau, Sabah, Malaysia
Queen Elizabeth Hospital
Kota Kinabalu, Sabah, Malaysia
Kota Marudu District Hospital
Kota Marudu, Sabah, Malaysia
Ranau District Hospital
Ranau, Sabah, Malaysia
Countries
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References
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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.
Other Identifiers
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NMRR-16-356-29088
Identifier Type: -
Identifier Source: org_study_id