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Trial record 1 of 1 for:    NCT03056391
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Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria (PACKNOW)

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ClinicalTrials.gov Identifier: NCT03056391
Recruitment Status : Completed
First Posted : February 17, 2017
Last Update Posted : December 19, 2019
Sponsor:
Information provided by (Responsible Party):
Menzies School of Health Research

Tracking Information
First Submitted Date  ICMJE January 31, 2017
First Posted Date  ICMJE February 17, 2017
Last Update Posted Date December 19, 2019
Study Start Date  ICMJE October 2016
Actual Primary Completion Date February 1, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2017)
Effect of Paracetamol on kidney function [ Time Frame: 72 hours ]
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2017)
  • Longitudinal change in creatinine [ Time Frame: 72 hours ]
    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
  • Change in creatinine in severe malaria [ Time Frame: 72 hours ]
    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.
  • Development of AKI [ Time Frame: 72 hours ]
    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).
  • Duration of AKI [ Time Frame: 28 days ]
    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.
  • Longitudinal changes in haemolysis: plasma cell-free haemoglobin [ Time Frame: 72 hours ]
    Longitudinal changes in plasma cell-free haemoglobin over 72 hours.
  • Longitudinal changes in haemolysis: plasma cell-free haem [ Time Frame: 72 hours ]
    Longitudinal changes in plasma cell-free haem over 72 hours.
  • Longitudinal changes in haemolysis: haem-to-protein cross-links [ Time Frame: 72 hours ]
    Longitudinal changes in haem-to-protein cross-links over 72 hours.
  • Longitudinal changes in markers of oxidative stress: F2-IsoP [ Time Frame: 72 hours ]
    Longitudinal changes in plasma F2-isoprostanes [F2-IsoP] over 72 hours.
  • Longitudinal changes in markers of oxidative stress: IsoF [ Time Frame: 72 hours ]
    Longitudinal changes in plasma isofurans [IsoF]) over 72 hours.
  • Longitudinal changes in F2-IsoPs according to G6PD enzyme activity [ Time Frame: 72 hours ]
    Longitudinal changes in F2-IsoPs according to G6PD enzyme activity, assessed qualitatively by fluorescent spot test.
  • Longitudinal changes in IsoFs according to G6PD enzyme activity [ Time Frame: 72 hours ]
    Longitudinal changes in IsoFs and CFHb according to G6PD enzyme activity, assessed qualitatively by fluorescent spot test.
  • Longitudinal changes in CFHb according to G6PD enzyme activity [ Time Frame: 72 hours ]
    Longitudinal changes in CFHb according to G6PD enzyme activity, assessed qualitatively by fluorescent spot test.
  • Longitudinal changes in F2-IsoPs according to G6PD genotype [ Time Frame: 72 hours ]
    Longitudinal changes in F2-IsoPs according to G6PD genotype
  • Longitudinal changes in IsoFs according to G6PD genotype [ Time Frame: 72 hours ]
    Longitudinal changes in IsoFs according to G6PD genotype
  • Longitudinal changes in CFHb according to G6PD genotype [ Time Frame: 72 hours ]
    Longitudinal changes in CFHb according to G6PD genotype
  • Population pharmacokinetics of paracetamol: Cmax [ Time Frame: 72 hours ]
    Peak plasma concentration (Cmax)
  • Population pharmacokinetics of paracetamol: Tmax [ Time Frame: 72 hours ]
    Time to peak plasma concentration (Tmax)
  • Population pharmacokinetics of paracetamol: AUC [ Time Frame: 72 hours ]
    Area under the plasma drug concentration-time curve (AUC)
  • Population pharmacodynamics of paracetamol [ Time Frame: 72 hours ]
    Paracetamol dose-response curve
  • Fever clearance time [ Time Frame: 72 hours ]
    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
  • Fever duration [ Time Frame: 72 hours ]
    Defined as the duration in hours that an individual's temperature is above 37.5°C
  • Area above the fever versus time curve (AUC-T°) [ Time Frame: 72 hours ]
    Area above the 37.5°C temperature versus time curve (AUC-T°) within first 24 hours of treatment.
  • Parasite clearance time (hours) [ Time Frame: 72 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.
  • Blood and urine biomarkers of pre-renal and renal injury [ Time Frame: 72 hours ]
    Neutrophil gelatinase-associated lipocalcin (NGAL), kidney injury molecule (KIM), urinalysis, urine microscopy, urine electrolytes, and urine creatinine.
  • Longitudinal urine colour [ Time Frame: 72 hours ]
    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.
  • Longitudinal urine pH [ Time Frame: 72 hours ]
    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.
  • Longitudinal urine specific gravity [ Time Frame: 72 hours ]
    Longitudinal urinalysis dipstick test-strip: urine specific gravity
  • Longitudinal urine haemoglobin [ Time Frame: 72 hours ]
    Longitudinal urinalysis dipstick test-strip: urine haemoglobin
  • Change in creatinine (umol/L) between therapeutic concentrations of paracetamol vs those with absent or low. [ Time Frame: 72 hours ]
    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
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 28 days ]
    Reporting of any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with paracetamol administration
  • Longitudinal red cell deformability [ Time Frame: 72 hours ]
    Longitudinal red cell deformability, as measured by laser-assisted optical rotational red cell analyser (LORCA) elongation index.
  • Longitudinal changes in markers of endothelial dysfunction [ Time Frame: 72 hours ]
    Longitudinal changes in markers of weibel palade body exocytosis including angiopoietin-2
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria
Official Title  ICMJE Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria: A Randomised Controlled Clinical Trial
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malaria
Intervention  ICMJE 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 Name: acetaminophen
Study Arms  ICMJE
  • 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.

    Intervention: Drug: Paracetamol
  • 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.

Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2017)
360
Original Estimated Enrollment  ICMJE
 (submitted: February 14, 2017)
200
Actual Study Completion Date  ICMJE February 1, 2018
Actual Primary Completion Date February 1, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Malaysia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03056391
Other Study ID Numbers  ICMJE NMRR-16-356-29088
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Menzies School of Health Research
Study Sponsor  ICMJE Menzies School of Health Research
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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: 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
PRS Account Menzies School of Health Research
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP