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Trial registered on ANZCTR
Registration number
ACTRN12620000855921
Ethics application status
Approved
Date submitted
19/06/2020
Date registered
27/08/2020
Date last updated
27/08/2020
Date data sharing statement initially provided
27/08/2020
Type of registration
Retrospectively registered
Titles & IDs
Public title
Investigating the efficacy of early vs. late primaquine treatment for children with uncomplicated malaria due to infection with either Plasmodium vivax or Plasmodium falciparum
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Scientific title
Investigating the efficacy of early vs. late primaquine treatment for children with uncomplicated malaria due to infection with either Plasmodium vivax or Plasmodium falciparum
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Secondary ID [1]
301579
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NHMRC1130301
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Universal Trial Number (UTN)
U1111-1253-8492
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Malaria
317951
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Condition category
Condition code
Infection
315984
315984
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0
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Other infectious diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Using computer generated randomisation, children will be allocated 1:1 to either treatment Arm 1 or 2 of the study.
Arm 1 (comparator arm): Artemether-lumefantrine: Oral administration as 1.7 mg/kg artemether and 10 mg/kg lumefantrine given twice-daily for 3 days (Day 0 to 2) with food, with oral administration of 1.0 mg/kg primaquine (given as 7 doses every 12 hours over 3.5 days) starting the day following completion of all artemether-lumefantrine doses (Day 3).
Arm 2: Artemether-lumefantrine: Oral administration as 1.7 mg/kg artemether and 10 mg/kg lumefantrine given twice-daily for 3 days (Day 0 to 2) with food, with oral administration of 1.0 mg/kg primaquine (given as 7 doses every 12 hours over 3.5 days) starting three weeks after completion of all artemether-lumefantrine doses (Day 24).
All treatments will be administered as oral tablets, with combinations of full, half- or quarter-tablets swallowed whole or crushed lightly and given with milk to improve absorption of the lumefantrine component and reduce primaquine adverse effects.
All morning doses will be given under direct observation, with evening doses of artemether-lumefantrine and primaquine given to the parents each day to administer at home. Treatment compliance will be demonstrated by pharmacokinetic analysis of Day 7 drug assay samples. For the first 60 children recruited into the trial (pharmacokinetic study subset), all primaquine doses will be administered under direct observation (morning and evening).
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Intervention code [1]
317871
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Prevention
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Intervention code [2]
317873
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Treatment: Drugs
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Comparator / control treatment
Primaquine early treatment group.
Oral tablet administration of 1.0 mg/kg primaquine (given as 7 doses every 12 hours over 3.5 days) starting immediately after completion of all artemether-lumefantrine doses (Day 3).
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Control group
Active
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Outcomes
Primary outcome [1]
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Incidence of malaria re-infection in PNG children will be assessed by malaria microscopy of blood smear samples.
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Assessment method [1]
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Timepoint [1]
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Days 1, 2, 3, 7, 14, 15, 16, 28, 42, 56, 70 and 84 days after commencement of artemether-lumefantrine treatment.
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Primary outcome [2]
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Incidence of malaria re-infection in PNG children will be assessed by polymerase chain reaction of dried blood spot samples.
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Assessment method [2]
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Timepoint [2]
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Days 1, 2, 3, 7, 14, 15, 16, 28, 42, 56, 70 and 84 days after commencement of artemether-lumefantrine treatment.
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Primary outcome [3]
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Incidence of gametocyte carriage in PNG children will be assessed by malaria microscopy of blood smear samples.
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Assessment method [3]
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Timepoint [3]
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Days 1, 2, 3, 7, 14, 15, 16, 28, 42, 56, 70 and 84 days after commencement of artemether-lumefantrine treatment.
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Secondary outcome [1]
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Pharmacokinetics of lumefantrine and desbutyl-lumefantrine in dried blood spots in children as assessed by high performance liquid chromatography mass spectroscopy (LC-MS/ms) assays (e.g. AUC, Cmax, Ka, elimination half-life, VcF, CL/F. VpF and Q/F).
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Assessment method [1]
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Timepoint [1]
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The first 60 children recruited into the study will follow a frequent sampling protocol. Children will have 7 finger-prick samples allocated using a balanced randomisation schedule from time-points at 1, 2, 3, 4, 6, 9, 12 (pre-dose), 13, 14, 15, 16, 18, 21 and 24 hours after commencement of primaquine treatment. Further finger-prick samples will be collected on Days 2, 3, 7, 14, 15, 16 and 28 after commencement of artemether-lumefantrine treatment.
A sparse sampling protocol will be employed in the remaining 160 participants, with three finger-prick samples collected within the first 28 hours after commencement of primaquine treatment (from a possible 9 time points: 1, 2, 3, 4, 24, 25, 26, 27 and 28 hours) at time-points selected using a balanced randomisation schedule. Further finger-prick samples will be collected on Days 2, 3, 7, 14, 15, 16 and 28 after commencement of artemether-lumefantrine treatment.
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Secondary outcome [2]
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Pharmacokinetics of primaquine, carboxy-primaquine and 5,6-ortho-quinone in dried blood spots in children as assessed by high performance liquid chromatography mass spectroscopy (LC-MS/ms) assays (e.g. AUC, Cmax, Ka, elimination half-life, VcF, CL/F. VpF and Q/F).
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Assessment method [2]
384605
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Timepoint [2]
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The first 60 children recruited into the study will follow a frequent sampling protocol. Children will have 7 finger-prick samples allocated using a balanced randomisation schedule from time-points at 1, 2, 3, 4, 6, 9, 12 (pre-dose), 13, 14, 15, 16, 18, 21 and 24 hours after commencement of primaquine treatment. Further finger-prick samples will be collected on Days 2, 3, 7, 14, 15, 16 and 28 after commencement of artemether-lumefantrine treatment.
A sparse sampling protocol will be employed in the remaining 160 participants, with three finger-prick samples collected within the first 28 hours after commencement of primaquine treatment (from a possible 9 time points: 1, 2, 3, 4, 24, 25, 26, 27 and 28 hours) at time-points selected using a balanced randomisation schedule. Further finger-prick samples will be collected on Days 2, 3, 7, 14, 15, 16 and 28 after commencement of artemether-lumefantrine treatment.
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Secondary outcome [3]
384606
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Determine the CYP2D6 genotype status of each participant from whole blood samples using
the AmpliChip CYP450 Test.
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Assessment method [3]
384606
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Timepoint [3]
384606
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Baseline sample.
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Eligibility
Key inclusion criteria
i) Children aged 0.5 to 12 years
ii) Axillary temperature >37.5 degrees Celcius (or self-reported fever during previous 24 hours)
iii) Positive for malaria by on-site microscopy, or rapid diagnostic test, or polymerase chain reaction
iv) Have not received a study intervention in the previous 4 weeks
v) They have no significant co-morbidity
vi) they can attend follow-up assessments over the full duration of the study.
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Minimum age
6
Months
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Maximum age
12
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
i) Clinical signs or symptoms consistent with severe malaria
ii) History of allergy to artemether-lumefantrine or primaquine
iii) A proven history of G6PD deficiency
iv) Severe malnutrition
v) Haemoglobin <50 g/L
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed in sealed opaque envelopes.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computer sequence generation.
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
Primary Aims: Sample size calculations are based the lower CI95 estimate of P. vivax relapse rate in the relapse control group at the same field site (29% and 46% for P. falciparum and P. vivax, respectively). At Alexishafen, P. vivax accounts for 20% of uncomplicated malaria episodes and the attrition rate is ~10%. We also assume that, based on recent studies in adults from Indonesia, a course of primaquine will reduce P. vivax relapse by greater than or equal to 80% . For the superiority study, >60 children in each group are required demonstrate superiority with 90% power and a two-tailed alpha=0.01 for the primary outcome (P. vivax relapse following either species [34% vs 7%]). For non-inferiority comparisons between early versus late primaquine therapy, the same primary and secondary endpoints are planned, but applying a non-inferiority margin of 15%. In this scenario, a sample size of >76 in each group has a power of 90% and a two-tailed alpha=0.01. The planned non-inferiority margin is less than half the lower CI95 of the estimated effect size. The assessment of the smallest clinically relevant difference, the non-inferiority margin and 90% power are all consistent with published recommendations for this type of trial. The justification for 110 children in each group is to enrich the study with primary P. vivax infections that will enable species specific secondary outcomes to be explored and be adequately powered.
Secondary aims: To determine the pharmacokinetic interaction, via cytochrome P450 2D6 inhibition, between lumefantrine and primaquine the first thirty children recruited into the early and delayed treatment groups of the main trial will undergo an intensive pharmacokinetic sampling protocol. To detect a difference of 20% in relative metabolic conversion, >26 children in each group will be required with 90% power and alpha=0.05.
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Recruitment
Recruitment status
Suspended
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Date of first participant enrolment
Anticipated
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Actual
13/08/2018
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Date of last participant enrolment
Anticipated
30/09/2020
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Actual
29/07/2020
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Date of last data collection
Anticipated
31/07/2021
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Actual
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Sample size
Target
220
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Accrual to date
218
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Final
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Recruitment outside Australia
Country [1]
22684
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Papua New Guinea
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State/province [1]
22684
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Madang Province
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Funding & Sponsors
Funding source category [1]
306005
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Government body
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Name [1]
306005
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National Health and Medical Research Council of Australia
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Address [1]
306005
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National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
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Country [1]
306005
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Australia
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Primary sponsor type
University
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Name
The University of Western Australia
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Address
The University of Western Australia
35 Stirling Highway
Perth WA 6009
Australia
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Country
Australia
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Secondary sponsor category [1]
306468
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University
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Name [1]
306468
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Curtin University
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Address [1]
306468
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Curtin University
Kent Street, Bentley, Perth
Western Australia, 6102
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Country [1]
306468
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Australia
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Secondary sponsor category [2]
306469
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University
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Name [2]
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Papua New Guinea Institute of Medical Research
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Address [2]
306469
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Papua New Guinea Institute of Medical Research
Homate Street, Goroka
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Country [2]
306469
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Papua New Guinea
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
306241
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University of Western Australia Human Research Ethics Committee
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Ethics committee address [1]
306241
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The University of Western Australia
M459, 35 Stirling Highway
Crawley WA 6009 Australia
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Ethics committee country [1]
306241
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Australia
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Date submitted for ethics approval [1]
306241
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24/02/2017
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Approval date [1]
306241
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01/10/2017
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Ethics approval number [1]
306241
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RA/4/1/8970
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Ethics committee name [2]
306242
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Papua New Guinea Institute of Medical Research Institutional Review Board
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Ethics committee address [2]
306242
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Papua New Guinea Institute of Medical Research
Homate Street, Goroka
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Ethics committee country [2]
306242
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Papua New Guinea
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Date submitted for ethics approval [2]
306242
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11/07/2017
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Approval date [2]
306242
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10/08/2017
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Ethics approval number [2]
306242
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IRB 1709
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Ethics committee name [3]
306243
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Government of Papua New Guinea Medical Research Advisory Committee
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Ethics committee address [3]
306243
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Medical Research Advisory Committee
National Department of Health
PO Box 807
Waigani 131, NCD
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Ethics committee country [3]
306243
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Papua New Guinea
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Date submitted for ethics approval [3]
306243
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14/08/2017
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Approval date [3]
306243
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13/03/2018
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Ethics approval number [3]
306243
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MRAC 17.44
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Summary
Brief summary
There is a clear need for an abbreviated dosing schedule for primaquine, provided as early as possible to prevent reactivation of latent forms of P. vivax and to clear gametocytes following infection with either Plasmodium species. The purpose of this trial is to advance the treatment of paediatric malaria in areas with intense transmission of multiple Plasmodium species. The proposed studies, to be carried out in north coastal Papua New Guinea (PNG), address these needs through i) a randomised comparative study of early versus delayed primaquine treatment for the prevention of P. vivax and gametocyte carriage in PNG children with uncomplicated malaria, and ii) a pharmacokinetic study to define whether there is a possible pharmacokinetic interaction, via cytochrome P450 2D6 inhibition, between lumefantrine and primaquine. The primary clinical endpoints for superiority and non-inferiority will be the appearance of any P. vivax parasitaemia within 42 days following treatment for uncomplicated malaria.
We hypothesise that these studies will demonstrate:
i) There is no clinically relevant pharmacokinetic interaction when primaquine is administered directly following treatment with artemether-lumefantrine
ii) A short, high-dose primaquine regimen given directly after artemether-lumefantrine is non-inferior to delayed primaquine treatment in the prevention of post-treatment vivax malaria and gametocyte carriage in children with uncomplicated malaria due to either species.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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A/Prof Laurens Manning
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Address
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University of Western Australia, Medical School
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive Murdoch WA 6150
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Country
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Australia
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Phone
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+61 8 6151 1156
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Fax
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Email
103218
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[email protected]
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Contact person for public queries
Name
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A/Prof Laurens Manning
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Address
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University of Western Australia, Medical School
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive Murdoch WA 6150
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Country
103219
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Australia
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Phone
103219
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+61 8 6151 1156
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Fax
103219
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Email
103219
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[email protected]
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Contact person for scientific queries
Name
103220
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A/Prof Laurens Manning
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Address
103220
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University of Western Australia, Medical School
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive Murdoch WA 6150
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Country
103220
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Australia
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Phone
103220
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+61 8 6151 1156
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Fax
103220
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Email
103220
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
De-identified individual participant data underlying published results.
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When will data be available (start and end dates)?
Beginning 3 months following main results publication, no end date determined.
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Available to whom?
Researchers who provide a methodologically sound proposal.
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Available for what types of analyses?
IPD meta-analyses.
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How or where can data be obtained?
Access subject to approvals by Principal Investigator (
[email protected]
).
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Antimalarials for children with Plasmodium vivax infection: Current status, challenges, and research priorities.
2022
https://dx.doi.org/10.1016/j.parint.2021.102512
N.B. These documents automatically identified may not have been verified by the study sponsor.
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