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Trial registered on ANZCTR


Registration number
ACTRN12621001085864
Ethics application status
Approved
Date submitted
17/06/2021
Date registered
17/08/2021
Date last updated
17/08/2021
Date data sharing statement initially provided
17/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Therapeutic efficacy surveillance of malaria treatment and drug resistance monitoring in Gia Lai and Phu Yen provinces of Central Vietnam
Scientific title
Therapeutic efficacy surveillance of malaria treatment and drug resistance monitoring in Gia Lai and Phu Yen provinces of Central Vietnam
Secondary ID [1] 304431 0
VDCP01 Version 2 (24 June 2021)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 322247 0
Condition category
Condition code
Infection 319936 319936 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with blood film positive Plasmodium falciparum malaria will be treated with the fixed dose combination of pyronaridine-artesunate (registered as Pyramax) to kill the blood asexual stages. Each tablet of pyronaridine-artesunate contains 60 mg artesunate + 180 mg pyronaridine. The dose of pyronaridine-artesunate will be in accordance to the participant's body weight with the target dosage range for pyronaridine–artesunate of 15.0 to 8.3 mg/kg/day of body weight for pyronaridine and 5.0 to 2.5 mg/kg/day of body weight for artesunate. Pyronaridine–artesunate will be administered orally, at about 24 hour intervals for the 3 consecutive days. Also, on the first day of treatment patients will be coadministered a single oral dose of primaquine (0.5 mg/kg) to kill sexual stages of falciparum malaria to prevent transmission. Each tablet of primaquine contains 7.5 mg of primaquine base. Adherence to dosing with Pyramax and primaquine will be by direct observation. This regimen is the first-line treatment for falciparum malaria infections in Vietnam.

Patients who are infected with P. vivax malaria and are Glucose-6-Phosphate Dehydrogenase (G6PD) normal will be treated with a standard oral course of chloroquine (25 mg/kg daily over 3 days) and primaquine (0.25 mg/kg) daily for 14 days. Each tablet of chloroquine contains 150 mg of chloroquine base and each tablet of primaquine contains 7.5 mg of primaquine base. Chloroquine has blood stage activity against vivax malaria whereas primaquine acts against the sexual and dormant liver stages of vivax malaria. Adherence to dosing with chloroquine and primaquine for the first 3-days will be by direct observation and the remaining 11 daily doses of primaquine will be unsupervised.

Initially, for the treatment of vivax malaria we were planning to use a new regimen of chloroquine (25 mg/kg) over 3 days and a single oral dose of tafenoquine (300 mg). Tafenoquine is a similar drug to primaquine but has a much longer half-life in the blood (15 days versus 6 hours). However, because we have experienced a problem in sourcing tafenoquine from GlaxoSmithKline due to extenuating pandemic circumstances, we have decided to use the alternative intervention treatment of chloroquine (3 days ) plus primaquine (daily for 14 days). Chloroquine plus primaquine is registered as first-line treatment of vivax malaria in Vietnam and worldwide. Ethics approval from the Vietnam Ministry of Health has been obtained to replace chloroquine plus tafenoquine with chloroquine plus primaquine.
Intervention code [1] 320784 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327806 0
Parasite clearance time as assessed by blood film microscopy
Timepoint [1] 327806 0
Blood films collected before treatment (day 0) with pyronaridne-artesunate plus primaquine for treating P. falciparum and chloroquine plus primaquine for treating P. vivax malaria. After commencement of treatment blood films will then be collected twice daily (i.e. about 12 hours apart) up to day 7 until the participant’s blood films are negative for malaria on two consecutive collections.
Primary outcome [2] 327807 0
Fever clearance time as assessed by oral temperature measured using either a mouth thermometer or digital ear thermometer.
Timepoint [2] 327807 0
Body temperature collected before treatment (day 0) with pyronaridne-artesunate plus primaquine or chloroquine plus primaquine. After commencement of treatment body temperature will then be collected twice daily (i.e. about 12 hours apart taken twice daily) for 7 days until axillary temperature remains <37.5ºC/tympanic temperature remains <38.0ºC for more than 24 hours.
Primary outcome [3] 327808 0
Determine the Adequate Clinical and Parasitologic Response (ACPR) for the treatment of mono-infections of P. falciparum and P. vivax in participants after the commencement of treatment with pyronaridine-artesunate plus primaquine or chloroquine plus primaquine. This is a composite primary outcome with a follow-up period of 42 days after starting pyronaridine-artesunate plus primaquine or chloroquine plus primaquine treatment for recurrent malaria infection in participants.
Timepoint [3] 327808 0
On days 28 and 42 after the commencement of treatment with pyronaridine-artesunate plus primaquine or chloroquine plus primaquine filter paper blood samples from participants will be analysed by Polymerase Chain Reaction (PCR) to obtain adjusted ACPR for the treatment of falciparum malaria infections and unadjusted ACPR for vivax malaria.
Secondary outcome [1] 396658 0
Determine drug exposure by measuring participant's blood chloroquine and pyronaridine concentrations using liquid chromatography mass spectrometry.
Timepoint [1] 396658 0
Blood samples collected from participants at days 7 and 42 after commencing of treatment.
Secondary outcome [2] 396659 0
Determine the in vitro drug susceptibility of participant’s falciparum parasites against standard antimalarial drugs.
Timepoint [2] 396659 0
Blood sample collected from adult (18 yrs and older) participants before treatment (day 0) with pyronaridine-artesunate plus primaquine for in vitro drug susceptibility and survival assay testing.
Secondary outcome [3] 396663 0
Characterize molecular markers of drug resistance of P. falciparum (e..g., polymorphism of the Pfkelch13 gene and the Pfcrt gene, point mutation in the Exo-E415G gene, and amplification in the plasmepsins 2/3 genes and Pfmdr1 gene) and P. vivax (e.g., potentially polymorphism in the Pvkelch12 gene and Pvcrt-o gene and amplification in the Pvmdr1 gene and plasmepsin 4 gene) in parasites collected from the patients before treatment.
Timepoint [3] 396663 0
Blood samples (venous blood and finger prick capillary blood) collected from participants before treatment (day 0) with pyronaridne-artesunate plus primaquine using PCR analysis for genetic markers of P. falciparum resistance such as K13 mutations and increase copy number for plasmepsin 2/3 for artemisinin and piperaquine resistance, respectively. For patients infected with P. vivax their day 0 blood samples will also be used for PCR analysis to identify genetic markers of P. vivax resistance to chloroquine plus primaquine.
Secondary outcome [4] 396761 0
Analyze genetic diversity/relatedness, polymorphism, and genetic origin of P. falciparum and P. vivax parasites.
Timepoint [4] 396761 0
DNA genome parasite sequencing will be performed on blood samples collected from malaria patients before drug treatment (day 0) to determine the diversity of var genes associated with malaria pathogenesis and erythrocyte surface antigenic variation.
Secondary outcome [5] 396762 0
Evaluate the decline in hemozoin concentration in malaria patients after treatment using the Gazelle (Hemex) device to predict the presence of either drug sensitive or resistant strains of malaria infections.
Timepoint [5] 396762 0
Hemozoin concentrations will be determined in finger prick blood samples collected from malaria patients before treatment and at 12 hourly intervals for 3 days and at day 7 post commencement of treatment.
Secondary outcome [6] 396763 0
Investigate microscopically positive and rapid diagnostic test (RDT) negative symptomatic infections for possible histidine-rich protein 2 and 3 (hrp2/hrp3) gene deletions.
Timepoint [6] 396763 0
Blood samples collected from malaria patients before drug treatment (day 0).
Secondary outcome [7] 399749 0
Assess how well participants adhere to daily primaquine for the treatment of P. vivax malaria without supervision by the IMPE-QN/MIPM study team
Timepoint [7] 399749 0
Participants to complete an eight-item Morisky Medication Adherence Scale questionnaire on their taking of daily primaquine at days 7 and 14 after starting primaquine treatment with chloroquine.

Eligibility
Key inclusion criteria
• People infected with uncomplicated mono-infections of P. falciparum and uncomplicated mono-infections of P. vivax;
• Malaria parasite density of P. falciparum (= 500 to < 100,000 parasites/µL);
• Malaria parasite density of P. vivax (= 250 parasites/µL);
• Children (=5 years and =20 kg to <18 years old) and adults (=18 to <60 years old) infected with P. falciparum, children (=5 to <18 years old) and adults (=18 to <60 years old) infected with P. vivax malaria;
• Gender: Males and females;
• Working or residing at the study commune;
• Able to provide information and capillary finger prick blood samples;
• Written informed consent given to participate in the study by the adult or in case of children up to <18 years old (Assent form for children aged 12 to <18 years old) with parent or guardian permission;
• Normal G6PD enzyme activity levels (>70%) of the site median value for G6PD normals for participants to be treated with primaquine for the radical cure of P. vivax malaria.

Minimum age
5 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• People not infected with malaria infections;
• Children (<5 years old and <20 kg)infected with P. falciparum and less than 5 years of age infected with P. vivax malaria;
• Unwilling to provide consent, information, and capillary finger prick blood sample;
• Inability to communicate well with the study staff (poor mental development or evidence of psychiatric disorder);
• People with P. vivax malaria who have G6PD deficient enzyme activity;
• Pregnant or lactating females;
• Any condition that in the judgment of the IMPE-QN/MIPM doctor would make participation in the study unsafe for the potential participant.


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This efficacy surveillance study is designed to monitor the effectiveness of Pyramax plus primaquine for the treatment of P. falciparum and chloroquine plus primaquine for the radical cure of P. vivax malaria. Both regimens are registered for use in Vietnam, For this purpose a representative number of patients is required to be monitored for parasite clearance and treatment outcome. For conventional therapeutic efficacy drug studies of single-arm investigations, the World Health Organization (2009) has set a minimum of 50 patients is required to detect less than 90% drug efficacy.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 23759 0
Viet Nam
State/province [1] 23759 0
Gia Lai province and Phu Yen province

Funding & Sponsors
Funding source category [1] 308795 0
Government body
Name [1] 308795 0
Australian Defence Force Malaria and Infectious Disease Institute
Address [1] 308795 0
Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Brisbane, QLD, 4051
Country [1] 308795 0
Australia
Funding source category [2] 308827 0
Government body
Name [2] 308827 0
U.S. Naval Medical Research Center-Asia and U.S. Naval Medical Research Unit - Two
Address [2] 308827 0
U.S. Navy Base, Port of Singapore Authority, Sembawang.
Country [2] 308827 0
Singapore
Primary sponsor type
Government body
Name
Australian Defence Force Malaria and Infectious Disease Institute
Address
Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Brisbane, QLD, 4051
Country
Australia
Secondary sponsor category [1] 309711 0
Government body
Name [1] 309711 0
U.S. Naval Medical Research Center-Asia and U.S. Naval Medical Research Unit - Two
Address [1] 309711 0
U.S. Navy Base, Port of Singapore Authority, Sembawang.
Country [1] 309711 0
Singapore

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308707 0
Viet Nam Ministry of Health Institute of Malariology, Parasitology, and Entomology Quy Nhon Institutional Review Board
Ethics committee address [1] 308707 0
Zone 8, Nhon Phu Ward, Quy Nhon city, Binh Dinh province.
Ethics committee country [1] 308707 0
Viet Nam
Date submitted for ethics approval [1] 308707 0
04/07/2021
Approval date [1] 308707 0
09/07/2021
Ethics approval number [1] 308707 0
No.: 276/VSR-QLKH

Summary
Brief summary
This is an open-label study in Central Vietnam to monitor the first-line artemisinin based combination therapy, Pyramax® (pyronaridine-artesunate) plus primaquine for the treatment of uncomplicated P. falciparum malaria and to evaluate chloroquine plus primaquine for the treatment of P. vivax malaria. Drug exposure will be determined by measuring patient’s blood drug concentrations after treatment. The prevalence of drug resistant parasites will be determined in blood samples collected from the patients before drug treatment using in vitro (phenotypic) drug susceptibility testing and molecular (genotypic) assays with validated molecular markers of drug resistance. The P. falciparum and P. vivax parasite populations will be genetically characterized. The new point-of-care hemozoin detection device (Gazelle) will be used to measure hemozoin concentration decline in patient’s blood samples after starting treatment to determine its feasibility in predicting either drug sensitive or resistant strains of malaria infections.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111634 0
Dr Huynh Hong Quang
Address 111634 0
Institute of Malariology, Parasitology, and Entomology Quy Nhon (IMPE Quy Nhon)
611B Nguyen Thai Hoc street, Quy Nhon city.
Country 111634 0
Viet Nam
Phone 111634 0
+84 905103496
Fax 111634 0
Email 111634 0
huynhquangimpe@yahoo.com
Contact person for public queries
Name 111635 0
Dr Huynh Hong Quang
Address 111635 0
Institute of Malariology, Parasitology, and Entomology Quy Nhon (IMPE Quy Nhon)
611B Nguyen Thai Hoc street, Quy Nhon city.
Country 111635 0
Viet Nam
Phone 111635 0
+84 905103496
Fax 111635 0
Email 111635 0
huynhquangimpe@yahoo.com
Contact person for scientific queries
Name 111636 0
Dr Michael Edstein
Address 111636 0
Australian Defence Force Malaria and Infectious Disease Institute
Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Brisbane, QLD 4051
Country 111636 0
Australia
Phone 111636 0
+61 403321689
Fax 111636 0
Email 111636 0
mike.edstein@defence.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
At this stage permission for IPD will need to be requested from the PI
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 12118 0
Study protocol
Citation [1] 12118 0
Link [1] 12118 0
Email [1] 12118 0
Other [1] 12118 0
Type [2] 12119 0
Informed consent form
Citation [2] 12119 0
Link [2] 12119 0
Email [2] 12119 0
Other [2] 12119 0
Type [3] 12120 0
Ethical approval
Citation [3] 12120 0
Link [3] 12120 0
Email [3] 12120 0
Other [3] 12120 0
Summary results
No Results