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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
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
Secondary ID [1] 301579 0
NHMRC1130301
Universal Trial Number (UTN)
U1111-1253-8492
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 317951 0
Condition category
Condition code
Infection 315984 315984 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
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).
Intervention code [1] 317871 0
Prevention
Intervention code [2] 317873 0
Treatment: Drugs
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).
Control group
Active

Outcomes
Primary outcome [1] 324187 0
Incidence of malaria re-infection in PNG children will be assessed by malaria microscopy of blood smear samples.
Timepoint [1] 324187 0
Days 1, 2, 3, 7, 14, 15, 16, 28, 42, 56, 70 and 84 days after commencement of artemether-lumefantrine treatment.
Primary outcome [2] 324188 0
Incidence of malaria re-infection in PNG children will be assessed by polymerase chain reaction of dried blood spot samples.
Timepoint [2] 324188 0
Days 1, 2, 3, 7, 14, 15, 16, 28, 42, 56, 70 and 84 days after commencement of artemether-lumefantrine treatment.
Primary outcome [3] 324426 0
Incidence of gametocyte carriage in PNG children will be assessed by malaria microscopy of blood smear samples.
Timepoint [3] 324426 0
Days 1, 2, 3, 7, 14, 15, 16, 28, 42, 56, 70 and 84 days after commencement of artemether-lumefantrine treatment.
Secondary outcome [1] 383967 0
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).
Timepoint [1] 383967 0
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.
Secondary outcome [2] 384605 0
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).
Timepoint [2] 384605 0
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.
Secondary outcome [3] 384606 0
Determine the CYP2D6 genotype status of each participant from whole blood samples using
the AmpliChip CYP450 Test.
Timepoint [3] 384606 0
Baseline sample.

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.
Minimum age
6 Months
Maximum age
12 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed in sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computer sequence generation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
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.

Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
Actual
13/08/2018
Date of last participant enrolment
Anticipated
30/09/2020
Actual
29/07/2020
Date of last data collection
Anticipated
31/07/2021
Actual
Sample size
Target
220
Accrual to date
218
Final
Recruitment outside Australia
Country [1] 22684 0
Papua New Guinea
State/province [1] 22684 0
Madang Province

Funding & Sponsors
Funding source category [1] 306005 0
Government body
Name [1] 306005 0
National Health and Medical Research Council of Australia
Country [1] 306005 0
Australia
Primary sponsor type
University
Name
The University of Western Australia
Address
The University of Western Australia
35 Stirling Highway
Perth WA 6009
Australia
Country
Australia
Secondary sponsor category [1] 306468 0
University
Name [1] 306468 0
Curtin University
Address [1] 306468 0
Curtin University
Kent Street, Bentley, Perth
Western Australia, 6102
Country [1] 306468 0
Australia
Secondary sponsor category [2] 306469 0
University
Name [2] 306469 0
Papua New Guinea Institute of Medical Research
Address [2] 306469 0
Papua New Guinea Institute of Medical Research
Homate Street, Goroka
Country [2] 306469 0
Papua New Guinea

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306241 0
University of Western Australia Human Research Ethics Committee
Ethics committee address [1] 306241 0
The University of Western Australia
M459, 35 Stirling Highway
Crawley WA 6009 Australia
Ethics committee country [1] 306241 0
Australia
Date submitted for ethics approval [1] 306241 0
24/02/2017
Approval date [1] 306241 0
01/10/2017
Ethics approval number [1] 306241 0
RA/4/1/8970
Ethics committee name [2] 306242 0
Papua New Guinea Institute of Medical Research Institutional Review Board
Ethics committee address [2] 306242 0
Papua New Guinea Institute of Medical Research
Homate Street, Goroka
Ethics committee country [2] 306242 0
Papua New Guinea
Date submitted for ethics approval [2] 306242 0
11/07/2017
Approval date [2] 306242 0
10/08/2017
Ethics approval number [2] 306242 0
IRB 1709
Ethics committee name [3] 306243 0
Government of Papua New Guinea Medical Research Advisory Committee
Ethics committee address [3] 306243 0
Medical Research Advisory Committee
National Department of Health
PO Box 807
Waigani 131, NCD
Ethics committee country [3] 306243 0
Papua New Guinea
Date submitted for ethics approval [3] 306243 0
14/08/2017
Approval date [3] 306243 0
13/03/2018
Ethics approval number [3] 306243 0
MRAC 17.44

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103218 0
A/Prof Laurens Manning
Address 103218 0
University of Western Australia, Medical School
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive Murdoch WA 6150
Country 103218 0
Australia
Phone 103218 0
+61 8 6151 1156
Fax 103218 0
Email 103218 0
[email protected]
Contact person for public queries
Name 103219 0
Laurens Manning
Address 103219 0
University of Western Australia, Medical School
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive Murdoch WA 6150
Country 103219 0
Australia
Phone 103219 0
+61 8 6151 1156
Fax 103219 0
Email 103219 0
[email protected]
Contact person for scientific queries
Name 103220 0
Laurens Manning
Address 103220 0
University of Western Australia, Medical School
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive Murdoch WA 6150
Country 103220 0
Australia
Phone 103220 0
+61 8 6151 1156
Fax 103220 0
Email 103220 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data underlying published results.
When will data be available (start and end dates)?
Beginning 3 months following main results publication, no end date determined.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
IPD meta-analyses.
How or where can data be obtained?
Access subject to approvals by Principal Investigator ([email protected]).


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
SourceTitleYear of PublicationDOI
EmbaseAntimalarials for children with Plasmodium vivax infection: Current status, challenges, and research priorities.2022https://dx.doi.org/10.1016/j.parint.2021.102512
N.B. These documents automatically identified may not have been verified by the study sponsor.