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Trial registered on ANZCTR


Registration number
ACTRN12620000942954
Ethics application status
Approved
Date submitted
19/06/2020
Date registered
21/09/2020
Date last updated
21/09/2020
Date data sharing statement initially provided
21/09/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study investigating the efficacy of artemisinin combination therapy to prevent postpartum malaria and as a treatment for uncomplicated malaria in young infants.
Scientific title
A study investigating the efficacy of artemisinin combination therapy to prevent postpartum malaria and as a treatment for uncomplicated malaria in young infants.
Secondary ID [1] 295706 0
NHMRC1124130
Universal Trial Number (UTN)
U1111-1218-3680
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 309098 0
Condition category
Condition code
Infection 307968 307968 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Efficacy of ACT in preventing postpartum malaria (Main trial)
Recruited participants will be recruited 1:1 to no-treatment and intervention groups. Those women randomised to the no-treatment group will received standard labour and postnatal care, with no interventional drugs administered. For women allocated to an intervention group, a further 1:1 randomisation to treatment Arm 1 (artemether-lumefantrine) and Arm 2 (dihydroartemisinin-piperaquine) will occur.

Arm 1: Artemether-lumefantrine: Oral tablet administration as 1.7 mg/kg artemether and 10 mg/kg lumefantrine given twice-daily for 3 days with milk/food.
Arm 2: Dihydroartemisinin-piperaquine: Oral tablet administration as 7 mg/kg dihydroartemisinin and 58 mg/kg piperaquine phosphate (equivalent to 33 mg/kg piperaquine base for a 50 kg woman) given once daily for 3 days with water.
Allocated treatment will be administered within 24 hours of delivery, after lactation had been established and the infant had fed on first colostrum. All oral doses will be administered to the nearest full tablet with all morning doses directly observed by research staff, and evening artemether-lumefantrine doses taken at home if the mother is to be discharged. Women remaining in the labor ward over night will have their evening doses given under direct observation. Women vomiting within 30 minutes of dosing will be re-treated.

Pharmacokinetics of ACT drugs in breast milk study (Sub-study 1)
A randomly-selected subset of 40 of the 90 ACT-treated women enrolled in the Main trial (20 in each Arm) will be co-enrolled in Sub-study 1. Each participant will be exposed to the intervention as described above. Each participant will provide a 3-5mL fore- and hind-milk samples will be taken at 0.5-2 hours, 4-6 hours, 6-8 hours, 10-12 hours and on Days 1, 2, 3, 4, 7, 14 and 28 after drug administration

Infant pharmacokinetic and preliminary efficacy study (Sub-study 2)
Those of the 90 infants of mothers randomised to the no-treatment arm of the study who are found to have malaria at any time during the 6 months follow-up period will be randomised 1:1 by computer-generated schedule to:
i) Artemether-lumefantrine: Oral tablet suspension administered as 2.0 mg/kg artemether and 12 mg/kg lumefantrine given twice-daily for 3 days given with breast milk, or
ii) Dihydroartemisinin-piperaquine: Oral tablet suspension administered as 7 mg/kg dihydroartemisinin and 58 mg/kg piperaquine phosphate given once daily for 3 days with water or coconut milk (which is low in fat), as per manufacturer's recommendation.
Those of the 90 infants of mothers randomised to the treatment arms of the study who are found to have malaria at any time during the 6 months follow-up period will be given artemether-lumefantrine initially, but subsequent pharmacokinetic analyses from samples taken in the breast milk sub-study and from the ACT-treated infants of the untreated mothers may indicate that it is safe for full randomisation to artemether-lumefantrine or dihydroartemisinin-piperaquine. Doses will be to the nearest quarter-tablet. Infants vomiting with 30 minutes of drug treatment will re-treated.
Intervention code [1] 302027 0
Prevention
Intervention code [2] 302028 0
Treatment: Drugs
Comparator / control treatment
There will be a 2:1:1 randomisation to no treatment (comparator group) or either artemether-lumefantrine or dihydroartemisinin-piperaquine intervention groups.
Control group
Active

Outcomes
Primary outcome [1] 306950 0
Incidence of malaria infection in postpartum women will be assessed by malaria microscopy of blood smear samples (Main trial).
Timepoint [1] 306950 0
4, 8, 12, 16, 20 and 24 weeks (primary timepoint) after intervention commencement, or upon symptomatic presentation during the 6 month follow-up period.
Primary outcome [2] 324419 0
Incidence of malaria infection in postpartum women will be assessed by polymerase chain reaction (Main trial).
Timepoint [2] 324419 0
4, 8, 12, 16, 20 and 24 weeks (primary timepoint) after intervention commencement, or upon symptomatic presentation during the 6 month follow-up period.
Secondary outcome [1] 350213 0
Pharmacokinetics of artemether, and dihydroartemisinin in breast milk will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assay (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F) (composite outcome; Sub-study 1).
Timepoint [1] 350213 0
Baseline, 0.5 to 2 hours, 4 to 6 hours, 6 to 8 hours, 10 to 12 hours, Days 1, 2, 3, 4, 7, 14 and 28 after commencement of intervention.
Secondary outcome [2] 350214 0
Pharmacokinetics of lumefantrine and desbutyl-lumefantrine in breast milk will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assay (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F) (composite outcome; Sub-study 1).
Timepoint [2] 350214 0
Baseline, 0.5 to 2 hours, 4 to 6 hours, 6 to 8 hours, 10 to 12 hours, Days 1, 2, 3, 4, 7, 14 and 28 after commencement of intervention.
Secondary outcome [3] 350215 0
Pharmacokinetics of piperaquine in breast milk will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assay (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F) (Sub-study 1).
Timepoint [3] 350215 0
Baseline, 0.5 to 2 hours, 4 to 6 hours, 6 to 8 hours, 10 to 12 hours, Days 1, 2, 3, 4, 7, 14 and 28 after commencement of intervention.
Secondary outcome [4] 384587 0
Pharmacokinetics of artemether and dihydroartemisinin in dried blood spots from young infants will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assays (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F (composite outcome; Sub-study 1).
Timepoint [4] 384587 0
Baseline, 0.5 to 2 hours, 4 to 6 hours, 6 to 8 hours, 10 to 12 hours, Days 1, 2, 3, 4, 7, 14 and 28 after commencement of maternal intervention (corresponding with breast milk sample collection).
Secondary outcome [5] 384588 0
Pharmacokinetics of lumefantrine and desbutyl-lumefantrine in dried blood spots from young infants will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assays (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F) (composite outcome; Sub-study 1).
Timepoint [5] 384588 0
Baseline, 0.5 to 2 hours, 4 to 6 hours, 6 to 8 hours, 10 to 12 hours, Days 1, 2, 3, 4, 7, 14 and 28 after commencement of maternal intervention (corresponding with breast milk sample collection).
Secondary outcome [6] 384589 0
Pharmacokinetics of piperaquine in dried blood spots from young infants will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assays (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F) (Sub-study 1).
Timepoint [6] 384589 0
Baseline, 0.5 to 2 hours, 4 to 6 hours, 6 to 8 hours, 10 to 12 hours, Days 1, 2, 3, 4, 7, 14 and 28 after commencement of maternal intervention (corresponding with breast milk sample collection).
Secondary outcome [7] 384590 0
Pharmacokinetics of artemether, dihydroartemisinin, lumefantrine, desbutyl-lumefantrine and piperaquine in dried blood spots from young infants will be assessed by liquid chromatography mass spectroscopy (LC-MS/MS) assays (e.g. AUC, Cmax, elimination half-life, ka, VcF, CL/F, Vp/F and Q/F) (composite outcome; Sub-study 2).
Timepoint [7] 384590 0
Baseline, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, Days 7, 14, 28 and 42 after commencement of intervention.
Secondary outcome [8] 384591 0
Incidence of malaria infection in young infants will be assessed by polymerase chain reaction using filter paper spots (Main trial).
Timepoint [8] 384591 0
4, 8, 12, 16, 20 and 24 weeks after intervention commencement, or upon symptomatic presentation during the 6 month follow-up period.
Secondary outcome [9] 386014 0
Incidence of gametocytaemia in postpartum women will be assessed by malaria microscopy of blood smear samples (Main trial).
Timepoint [9] 386014 0
4, 8, 12, 16, 20 and 24 weeks after intervention commencement.
Secondary outcome [10] 386015 0
Change in maternal haemoglobin concentrations in postpartum women as assessed by HemoCue point of care monitoring (Main trial).
Timepoint [10] 386015 0
Baseline and 24 weeks post intervention.
Secondary outcome [11] 386016 0
Incidence of other non-malaria infections requiring health service intervention in postpartum women as per clinical assessment (Main trial).
Timepoint [11] 386016 0
4, 8, 12, 16, 20 and 24 weeks after intervention commencement, or upon symptomatic presentation during the 6 month follow-up period.
Secondary outcome [12] 386017 0
Incidence of malaria infection in young infants will be assessed by malaria microscopy of blood smear samples (Main trial).
Timepoint [12] 386017 0
4, 8, 12, 16, 20 and 24 weeks after intervention commencement, or upon symptomatic presentation during the 6 month follow-up period.

Eligibility
Key inclusion criteria
Postpartum study (Main trial)
i) >=18 years of age
ii) Peripheral blood slide negative for malaria at delivery (slide positive women will receive conventional artemether-lumefantrine treatment and are not eligible for recruitment).
ii) They have not received a study intervention in the previous 4 weeks.
iii) They have not required medical/surgical intervention for complications during delivery, other than an episiotomy and broad spectrum antibiotic treatment.
iv) They have no significant co-morbidity
v) They can attend follow-up assessments over the full 6 months

Infant study (Sub-study 2)
i) infant born to Main trial study mother within the last 6 months.
ii) positive blood slide or polymerase chain reaction positive for malaria during the 6 months' follow-up
Minimum age
No limit
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
i) < 18 years of age
ii) Husband/ father do not grant informed consent (as per Papua New Guinean custom)
iii) Participant has a positive malaria blood slide or rapid diagnostic test at time of delivery.
iv) Participant has a pre-term delivery
v) Neonate demonstrating signs of illness or low APGAR score at delivery
vi)Participant has received treatment with a study intervention in the past 4 weeks.
vii) Participant has signs of a significant concomitant disease including malnutrition, tuberculosis, and pneumonia.
viii) Surgical intervention was required during delivery.
vi) Participant residence is outside health centre catchment area.

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
Sample size: A sample of 180 women (90 allocated to no treatment, 45 to artemether-lumefantrine, and 45 to dihydroartemisinin-piperaquine) has been calculated from the following assumptions:
i) the cumulative incidence of slide-positive post-partum malaria parasitaemia during a 6-month follow-up period will be 15%. The 4-month cumulative incidence of slide-positive post-partum malaria in the Madang area in 1985-1987 of 28.2% for primigravidae and 22.8% for multigravidae despite chemo-prophylaxis, or an average of 25.5% given that, in a recent intermittent preventive treatment in pregnancy (IPTp) trial in the area, 50% of women delivering were primigravidae. Although most cases of post-partum malaria occur within 6 weeks, cases are recorded between 4 and 6 months. We have thus extrapolated the 25.5% average 4-month cumulative incidence to 30%, and reduced this by 50% down to 15% to allow for recent preventive interventions such as long lasting insecticide bed-nets. Given that >9% of women in the recent IPTp trial had blood smear positive and/or active placental malaria at delivery despite prophylaxis, this appears a conservative estimate of the current post-partum malaria risk in the Madang area.
ii) conventional adult doses of artemether-lumefantrine or dihydroartemisinin-piperaquine will reduce the incidence by more than, or equal to, 75%, down to 3.75%. Our recent 6-month follow-up of young children with uncomplicated malaria managed mainly at Alexishafen Health Centre in the intervention trial showed that those given artemether-lumefantrine or artemisinin-naphthoquine had a recurrence rate of 24.6% for P. falciparum or P. vivax, or a treatment success rate of >75%.
iii) there will be equal numbers in each arm (no treatment vs conventional doses of artemisinin combination therapy) and a 10% attrition rate that will not differ between the two arms. Recent long-term paediatric intervention and pregnancy pharmacokinetic studies conducted by our group have had greater than or equal to 8% attrition.
Under these assumptions and using a one-tailed a of 5% and at 80% power, a total of 180 (90 in treatment vs no treatment) will be required.

Data analysis: Statistical analysis will be by a priori plan. Per-protocol analyses will include
mothers with complete follow-up or a confirmed treatment failure, and will exclude those treated for malaria without confirmatory microscopy or who defaulted from follow-up despite repeated attempts at contact. These excluded patients will be retained in modified intention-to-treat analyses utilizing; i) a worst-case approach (all treatment failure) and ii) a best-case approach (all parasite negative). Kaplan-Meier estimates will be computed for each endpoint by treatment allocation (no treatment or ACT) and compared by log-rank test. Cox proportional hazards modelling will also be performed to assess independent predictors of postpartum outcomes including antimalarial treatment (mainly IPTp during pregnancy), allocated treatment at delivery including type of ACT, and maternal weight and haemoglobin. Blinded interim efficacy analyses and safety assessments including all serious adverse events (SAEs) will be performed by the DSMC and the trial terminated prematurely if ACT is superior. Kaplan-Meier analysis will be performed for slide- or PCR-positive infant malaria by maternal treatment allocation, the results of which will be interpreted with the breast milk drug data in Sub-study 1.. Comprehensive health care cost data will be collected for each patient as previously used in our paediatric treatment trials.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
21/08/2018
Date of last participant enrolment
Anticipated
30/09/2020
Actual
Date of last data collection
Anticipated
1/04/2021
Actual
Sample size
Target
180
Accrual to date
172
Final
Recruitment outside Australia
Country [1] 10720 0
Papua New Guinea
State/province [1] 10720 0
Madang

Funding & Sponsors
Funding source category [1] 300296 0
Government body
Name [1] 300296 0
National Health and Medical Research Council of Australia
Country [1] 300296 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] 299730 0
None
Name [1] 299730 0
Address [1] 299730 0
Country [1] 299730 0
Other collaborator category [1] 280275 0
University
Name [1] 280275 0
Curtin University
Address [1] 280275 0
Curtin University
Kent Street, Bentley, Perth
Western Australia, 6102
Country [1] 280275 0
Australia
Other collaborator category [2] 280276 0
Government body
Name [2] 280276 0
Papua New Guinea Institute of Medical Research
Address [2] 280276 0
Papua New Guinea Institute of Medical Research
Homate Street, Goroka
Papua New Guinea
Country [2] 280276 0
Papua New Guinea

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301106 0
University of Western Australia Human Research Ethics Committee
Ethics committee address [1] 301106 0
The University of Western Australia
M459, 35 Stirling Highway
Crawley WA 6009 Australia
Ethics committee country [1] 301106 0
Australia
Date submitted for ethics approval [1] 301106 0
20/03/2017
Approval date [1] 301106 0
24/11/2017
Ethics approval number [1] 301106 0
RA/4/20/1012
Ethics committee name [2] 301107 0
Papua New Guinea Institute of Medical Research Institutional Review Board
Ethics committee address [2] 301107 0
Papua New Guinea Institute of Medical Research
Homate Street, Goroka
Papua New Guinea
Ethics committee country [2] 301107 0
Papua New Guinea
Date submitted for ethics approval [2] 301107 0
16/05/2017
Approval date [2] 301107 0
10/08/2017
Ethics approval number [2] 301107 0
IRB 1710
Ethics committee name [3] 301108 0
Government of Papua New Guinea Medical Research Advisory Committee
Ethics committee address [3] 301108 0
Medical Research Advisory Committee
National Department of Health
PO Box 807
Waigani 131, NCD
Papua New Guinea
Ethics committee country [3] 301108 0
Papua New Guinea
Date submitted for ethics approval [3] 301108 0
14/08/2017
Approval date [3] 301108 0
13/03/2018
Ethics approval number [3] 301108 0
MRAC 17.43

Summary
Brief summary
Women in tropical countries are likely to be at significant risk of postpartum malaria. This could have implications for maternal health including anaemia. Malaria in infants in the first 6 months of life is under-recognised, can remain untreated, and have more serious consequences than previously thought. There is a need for studies that i) evaluate the efficacy of a maternal treatment course of artemisinin combination therapy (ACT) at delivery, ii) assess whether transfer of the component drugs into breast milk can lead to protection of the infant against malaria or, by contrast, toxicity especially if the infant is treated for malaria with ACT, and iii) characterise the pharmacokinetics and preliminary efficacy of ACT in infants with malaria so that appropriate treatment regimens can be developed. The proposed studies, to be carried out in north coastal Papua New Guinea (PNG), address these needs through i) a randomised trial of no treatment (current national policy) vs ACT in pregnant PNG women presenting in labour with a primary endpoint of any slide-positive malaria detected either from symptomatic presentation or on prospective monthly screening within 6 months of delivery, ii) a study of the pharmacokinetics of ACT component drugs in breast milk and in small volume blood samples in the suckling infants, and iii) a preliminary pharmacokinetic and efficacy evaluation of ACT in infants found to have malaria in the first 6 months of life. The data should prove valuable in informing prevention and treatment of malaria in mother and child in the postpartum period in PNG and other epidemiologically similar countries.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85890 0
Prof Timothy Davis
Address 85890 0
University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959
Country 85890 0
Australia
Phone 85890 0
+61 8 9431 3229
Fax 85890 0
+618 9431 2977
Email 85890 0
[email protected]
Contact person for public queries
Name 85891 0
Timothy Davis
Address 85891 0
University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959
Country 85891 0
Australia
Phone 85891 0
+61 8 9431 3229
Fax 85891 0
+618 9431 2977
Email 85891 0
[email protected]
Contact person for scientific queries
Name 85892 0
Timothy Davis
Address 85892 0
University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959
Country 85892 0
Australia
Phone 85892 0
+61 8 9431 3229
Fax 85892 0
+618 9431 2977
Email 85892 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



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