MalariaPhase 3PACKNOWNCT03056391
Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria
A Phase 3 study testing Paracetamol in people with Malaria, run by Menzies School of Health Research at 4 sites in Malaysia.
Trial 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… Read more about this study
- Who is it for?
- Ages 5 years and older
- Conditions the study is for
- Malaria
- What is being tested?
- Paracetamol
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 360 participants
- Where
- 4 sitesMalaysia
- Study dates
- Oct 2016to 1 Feb 2018
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
4 sites in 1 country.
Malaysia4 sites
Keningau District Hospital
Keningau, Sabah, 88200
Queen Elizabeth Hospital
Kota Kinabalu, Sabah, 88200
Kota Marudu District Hospital
Kota Marudu, Sabah, 89100
Ranau District Hospital
Ranau, Sabah, 89300
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Malaria
- Being tested
- Paracetamol
- Keywords
- knowlesi malaria, paracetamol, renal function, haemolysis, oxidative stress
- Medical subject headings
- Malaria, Hemolysis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ParacetamolDrug
Also called acetaminophen
>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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 72 hours
Secondary outcomes (32)
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
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 28 days
Longitudinal changes in haemolysis: plasma cell-free haemoglobin
Longitudinal changes in plasma cell-free haemoglobin over 72 hours.
Measured: 72 hours
Longitudinal changes in haemolysis: plasma cell-free haem
Longitudinal changes in plasma cell-free haem over 72 hours.
Measured: 72 hours
Longitudinal changes in haemolysis: haem-to-protein cross-links
Longitudinal changes in haem-to-protein cross-links over 72 hours.
Measured: 72 hours
Longitudinal changes in markers of oxidative stress: F2-IsoP
Longitudinal changes in plasma F2-isoprostanes [F2-IsoP] over 72 hours.
Measured: 72 hours
Longitudinal changes in markers of oxidative stress: IsoF
Longitudinal changes in plasma isofurans [IsoF]) over 72 hours.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 72 hours
Longitudinal changes in F2-IsoPs according to G6PD genotype
Longitudinal changes in F2-IsoPs according to G6PD genotype
Measured: 72 hours
Longitudinal changes in IsoFs according to G6PD genotype
Longitudinal changes in IsoFs according to G6PD genotype
Measured: 72 hours
Longitudinal changes in CFHb according to G6PD genotype
Longitudinal changes in CFHb according to G6PD genotype
Measured: 72 hours
Population pharmacokinetics of paracetamol: Cmax
Peak plasma concentration (Cmax)
Measured: 72 hours
Population pharmacokinetics of paracetamol: Tmax
Time to peak plasma concentration (Tmax)
Measured: 72 hours
Population pharmacokinetics of paracetamol: AUC
Area under the plasma drug concentration-time curve (AUC)
Measured: 72 hours
Population pharmacodynamics of paracetamol
Paracetamol dose-response curve
Measured: 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
Measured: 72 hours
Fever duration
Defined as the duration in hours that an individual's temperature is above 37.5°C
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 72 hours
Longitudinal urine specific gravity
Longitudinal urinalysis dipstick test-strip: urine specific gravity
Measured: 72 hours
Longitudinal urine haemoglobin
Longitudinal urinalysis dipstick test-strip: urine haemoglobin
Measured: 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
Measured: 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
Measured: 28 days
Longitudinal red cell deformability
Longitudinal red cell deformability, as measured by laser-assisted optical rotational red cell analyser (LORCA) elongation index.
Measured: 72 hours
Longitudinal changes in markers of endothelial dysfunction
Longitudinal changes in markers of weibel palade body exocytosis including angiopoietin-2
Measured: 72 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Feb 2017
- Study startOct 2016
- Primary completion1 Feb 2018
- Study completion1 Feb 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 360 participants (actual)
Sponsor and investigators
- Lead sponsor
- Menzies School of Health Research
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Giri M Rajahram, MD, Principal investigator, Clinical Research Center, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, MalaysiaBridget Barber, MBBS, Study director, Menzies School of Health ResearchNicholas Anstey, PhD, Study director, Menzies School of Health ResearchMatthew Grigg, MBBS, Study director, Menzies School of Health ResearchTimothy William, MBBS, Study director, Jesselton Medical CentreJayaram Menon, MBBS, Study director, Ministry of Health, MalaysiaTsin Yeo, MBBS, Study director, Menzies School of Health ResearchKatherine Plewes, MD, Study director, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03056391
- Sponsor's protocol ID
- NMRR-16-356-29088
- Acronym
- PACKNOW
- Status last verified
- Dec 2019
- First submitted
- 31 Jan 2017
- Last updated
- 19 Dec 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
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.
PubMed 35732155Cooper 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.
PubMed 35180298Cooper 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.
PubMed 29690924
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Paracetamol on Renal Function in Plasmodium Knowlesi Malaria: A Randomised Controlled Clinical Trial
- ClinicalTrials.gov ID
- NCT03056391
- Acronym / sponsor ID
- PACKNOW / NMRR-16-356-29088
- Conditions
- Malaria
- Keywords
- knowlesi malaria, paracetamol, renal function, haemolysis, oxidative stress
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 360 participants (actual)
- Lead sponsor
- Menzies School of Health ResearchUniversity, hospital or other
- Study start
- Oct 2016
- Primary completion
- 1 Feb 2018 (actual)
- Study completion
- 1 Feb 2018 (actual)
- First posted
- 17 Feb 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Paracetamol | Experimental | 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. |
| 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. |
Who may qualify
- Ages
- 5 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ParacetamolAlso: acetaminophen>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 |
Primary outcome
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).
32 secondary outcomes
Longitudinal change in creatinine
Time frame: 72 hours
Change in creatinine in severe malaria
Time frame: 72 hours
Development of AKI
Time frame: 72 hours
Duration of AKI
Time frame: 28 days
Longitudinal changes in haemolysis: plasma cell-free haemoglobin
Time frame: 72 hours
Longitudinal changes in haemolysis: plasma cell-free haem
Time frame: 72 hours
Longitudinal changes in haemolysis: haem-to-protein cross-links
Time frame: 72 hours
Longitudinal changes in markers of oxidative stress: F2-IsoP
Time frame: 72 hours
Longitudinal changes in markers of oxidative stress: IsoF
Time frame: 72 hours
Longitudinal changes in F2-IsoPs according to G6PD enzyme activity
Time frame: 72 hours
Longitudinal changes in IsoFs according to G6PD enzyme activity
Time frame: 72 hours
Longitudinal changes in CFHb according to G6PD enzyme activity
Time frame: 72 hours
Longitudinal changes in F2-IsoPs according to G6PD genotype
Time frame: 72 hours
Longitudinal changes in IsoFs according to G6PD genotype
Time frame: 72 hours
Longitudinal changes in CFHb according to G6PD genotype
Time frame: 72 hours
Population pharmacokinetics of paracetamol: Cmax
Time frame: 72 hours
Population pharmacokinetics of paracetamol: Tmax
Time frame: 72 hours
Population pharmacokinetics of paracetamol: AUC
Time frame: 72 hours
Population pharmacodynamics of paracetamol
Time frame: 72 hours
Fever clearance time
Time frame: 72 hours
Fever duration
Time frame: 72 hours
Area above the fever versus time curve (AUC-T°)
Time frame: 72 hours
Parasite clearance time (hours)
Time frame: 72 hours
Blood and urine biomarkers of pre-renal and renal injury
Time frame: 72 hours
Longitudinal urine colour
Time frame: 72 hours
Longitudinal urine pH
Time frame: 72 hours
Longitudinal urine specific gravity
Time frame: 72 hours
Longitudinal urine haemoglobin
Time frame: 72 hours
Change in creatinine (umol/L) between therapeutic concentrations of paracetamol vs those with absent or low.
Time frame: 72 hours
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 28 days
Longitudinal red cell deformability
Time frame: 72 hours
Longitudinal changes in markers of endothelial dysfunction
Time frame: 72 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2019.
- Derived from this study: PubMed 35732155Longley 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.
- Derived from this study: PubMed 35180298Cooper 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.
- Derived from this study: PubMed 29690924Cooper 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.
- Individual participant dataSharing planned: No
Related trials for Malaria
Recruiting
The Effects of Iron Treatment on Vaccine Immunogenicity in Kenyan Infants With Iron Deficiency
Iron Deficiencies
Not yet recruiting
Positron Emission Tomography and Organ-Specific Changes in Participants Co-Enrolled in NIH Studies of Plasmodium Vivax Controlled Human Malaria Infection
Healthy Volunteer, Malaria
RecruitingObservational study
Host and Parasite Factors That Influence Susceptibility to Malaria Infection and Disease During Pregnancy and Early Childhood in Ouelessebougou and Bamako, Mali
Malaria
RecruitingPhase 1
Safety, Tolerability and Efficacy of PfSPZ-LARC2 Vaccine Against CHMI in Malaria-Naïve Adults
Malaria Falciparum
Not yet recruiting
Three-arm Cluster Randomised Control Trial Evaluation of Guardian Spatial Emanator as a Complimentary Vector Control Tool in Papua New Guinea
Malaria
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Giri M Rajahram, MD principal investigator
Clinical Research Center, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia
Bridget Barber, MBBS study director
Menzies School of Health Research
Nicholas Anstey, PhD study director
Menzies School of Health Research
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Paracetamol in people with Malaria, run by Menzies School of Health Research at 4 sites in Malaysia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Malaysia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effect of Paracetamol on kidney function (time frame: 72 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03056391, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2019.