Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria

NCT03056391 | Completed Phase 3 DMC

• 1 other identifier: NMRR-16-356-29088
• Study Type: interventional
• Target: 360
• Locations: 1 country
• Sites: 4

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.

Conditions

Malaria

Keywords

knowlesi malaria; paracetamol; renal function; haemolysis; oxidative stress

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (32)

• Longitudinal change in creatinine

  72 hours

• Change in creatinine in severe malaria

  72 hours

• Development of AKI

  72 hours

• Duration of AKI

  28 days

• Longitudinal changes in haemolysis: plasma cell-free haemoglobin

  72 hours

Study Arms (2)

Paracetamol

EXPERIMENTAL

\>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

No Paracetamol

NO INTERVENTION

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.

Interventions

Paracetamol DRUG

\>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.

Also known as: acetaminophen

Paracetamol

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient age ≥ 5 years
• Presence of P. knowlesi malaria, confirmed by positive blood smear with asexual forms of P. knowlesi.
• Temperature \>38C on admission or fever during the preceding 48 hours
• Enrolled within 18 hours of commencing antimalarial treatment
• 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.

You may not qualify if:

• Patient or relatives unable or unwilling to give informed consent
• Contraindication or allergy to paracetamol or artesunate therapy
• Known cirrhosis, or \>6 standard alcoholic drinks/day
• Pregnancy

Sponsors & Collaborators

• Menzies School of Health Research: lead

Study Sites (4)

Keningau District Hospital

Keningau, Sabah, 88200, Malaysia

Location

Queen Elizabeth Hospital

Kota Kinabalu, Sabah, 88200, Malaysia

Location

Kota Marudu District Hospital

Kota Marudu, Sabah, 89100, Malaysia

Location

Ranau District Hospital

Ranau, Sabah, 89300, Malaysia

Location

Related Publications (3)

• 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.

  PMID: 35732155 DERIVED

• 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.

  PMID: 35180298 DERIVED

• 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.

  PMID: 29690924 DERIVED

MeSH Terms

Conditions

Malaria; Hemolysis

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Study Officials

• Giri M Rajahram, MD

  Clinical Research Center, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia

  PRINCIPAL INVESTIGATOR

• 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

• Tsin Yeo, MBBS

  Menzies School of Health Research

  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

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2017
• First Posted: February 17, 2017
• Study Start: October 1, 2016
• Primary Completion: February 1, 2018
• Study Completion: February 1, 2018
• Last Updated: December 19, 2019

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will not share

Locations

MY (4)