Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001429246
Ethics application status
Approved
Date submitted
20/08/2018
Date registered
27/08/2018
Date last updated
27/01/2022
Date data sharing statement initially provided
27/01/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
An open label study to assess the efficacy, safety and tolerability of pyronaridine-artesunate in the treatment of malaria infection caused by single or mixed species of Plasmodium falciparum, P. vivax, or P. malariae in Vietnam
Scientific title
An open label study to assess the efficacy, safety and tolerability of pyronaridine-artesunate (Pyramax) in the treatment of malaria infection caused by single or mixed species of Plasmodium falciparum, P. vivax, or P. malariae in Vietnamese patients living in Dak Nong Province, central west-highlands of Vietnam
Secondary ID [1] 295830 0
VNPA-01 Version 2.0 (9 Dec 2017)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 309274 0
Condition category
Condition code
Infection 308149 308149 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with blood smear positive malaria will be treated with the fixed dose combination of pyronaridine-artesunate (registered as Pyramax). 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 7.2 to 2.4 mg/kg/day of body weight to 13.8 to 4.6 mg/kg/day. Pyronaridine–artesunate will be administered orally, at about 24 hour intervals for the 3 consecutive days. Adherence to dosing will be by direct observation.
Intervention code [1] 312163 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307122 0
Parasite clearance time as assesses by blood smear microscopy.
Timepoint [1] 307122 0
Blood smears collected before treatment (day 0) with pyronaridne-artesunate. After commencement of treatment blood smears will then be collected twice daily (i.e. about 12 hours apart) up to day 7 until the participant’s blood smears are negative for malaria on two consecutive collections.
Primary outcome [2] 307175 0
Fever clearance time as assessed by oral temperature measured using either a mouth thermometer or digital ear thermometer.
Timepoint [2] 307175 0
Body temperature collected before treatment (day 0) with pyronaridne-artesunate.. 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] 307176 0
Determine the Adequate Clinical and Parasitologic Response (ACPR) for the treatment of mono-infections of P. falciparum, P. vivax and P. malariae or mixed infections of these Plasmodium species in participants after the commencement of treatment with pyronaridine-artesunate. This a composite primary outcome with a follow-up period of 42 days after starting pyronaridine-artesunate.treatment for recurrent malaria infection in participants.
Timepoint [3] 307176 0
On days 28 and 42 after the commencement of treatment with pyronaridine-artesunate filter paper blood samples from participants will be analysed by Polymerase Chain Reaction (PCR) to obtain corrected ACPR for the treatment of malaria infections.
Secondary outcome [1] 350765 0
Blood chemistries (biochemical and hematological indices) conducted on participants blood samples to assess the safety of pyronaridine-artesunate. The biochemical tests will be for Urea, Total Bilirubin, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase, Alkaline Phosphatase and Creatinine. The hematological tests will be for Hemoglobin, Hematocrit, Platelets, White Cell Count, Granulocyte, Lymphocyte and Monocyte Count and Red Blood Cell Count.
Timepoint [1] 350765 0
Blood samples collected from participants before treatment (day 0) with pyronaridine-artesunate and at days 7 and 28 after starting treatment.
Secondary outcome [2] 350977 0
Medical checks performed by the study doctor on participants to assess the tolerability of pyronaridine-artesunate. For each participant, the medical checks will consist of a physical examination (body weight, blood pressure, pulse rate, respiratory rate and body system assessment such as general appearance, heads and eyes, ears, nose and throats, chest and lungs, cardiovascular, abdomen, neurological, lymphatic and musculo-skeleton). Also, the medical history of the participant over the last 3 days will be obtained by the study doctor covering signs and symptoms such as rigors/chills, fever, cough, headache, abdominal pain, nausea, and vomiting.
Timepoint [2] 350977 0
Medical check performed by the study doctor on participants before treatment (day 0) with pyronaridine-artesunate and daily until the participant is without malaria symptoms such as fever, headache, fatigue and abdominal pain.
Secondary outcome [3] 350978 0
Genotypic assessment of P. falciparum resistance using PCR analysis as an exploratory outcome.
Timepoint [3] 350978 0
Filter paper blood samples collected from participants before treatment (day 0) with pyronaridne-artesunate using PCR analysis for genetic markers of P. falciparum resistance such as K13 mutations for artemisinin resistance.
Secondary outcome [4] 350979 0
Determine drug exposure by measuring participant's plasma artesunate and its active metabolite, dihydroartemisinin concentrations after starting treatment with pyronaridne-artesunate.
Timepoint [4] 350979 0
Plasma sample collected from participants at about 1 hour after the last dose of pyronaridne-artesunate on day 2 for measuring artesunate and dihydroartemisinin concentrations by liquid chromatography mass spectrometry.
Secondary outcome [5] 350980 0
Determine the in vitro drug susceptibility of participant’s falciparum parasites against standard antimalarial drugs.
Timepoint [5] 350980 0
Blood sample collected from participants before treatment (day 0) participants with pyronaridine-artesunate will be processed for in vitro drug susceptibility testing using hypoxanthine incorporation assay..
Secondary outcome [6] 351110 0
Determine drug exposure by measuring participant's blood pyronaridine concentrations after starting treatment with pyronaridne-artesunate.
Timepoint [6] 351110 0
Blood sample collected from participants at day 7 after the commencement of pyronaridne-artesunate for measuring pyronaridine concentrations by liquid chromatography mass spectrometry.

Eligibility
Key inclusion criteria
• Adults and children with a body weight greater than or equal to 20 kg
• Symptomatic of malaria infection (i.e. history of fever within 24 hours and/or presence of fever greater than 37.5°C for axillary temperature or greater than 38.0°C for tympanic temperature.
• Microscopic confirmation of asexual (i.e. blood) stages of mono-infections of P. falciparum, P. vivax and P. malariae or mixed infections of the Plasmodium species.
• Parasitemia between 250/µL and less than 100 000/µL of blood.
• Glucose-6-Phosphate Dehydrogenase (G6PD) normal participants with mono-infection of P. vivax or mixed infections of P. vivax will be treated with primaquine to kill liver hypnozoites.
• Ability to take oral medication. Written informed consent given to participate in the trial by the patient or in case of children up to 17 years old (assent for children aged 10 to 17 years old) with adult or guardian permission.
Minimum age
8 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Pregnancy or lactation (urine test for ß HCG to be performed on any woman of child bearing age 10 to 55 years old).
• Hematocrit less than 20%.
• Parasitemia less than 250/µL or greater than 100 000/µL of blood.
• Signs or symptoms indicative of severe/cerebral malaria (WHO, 2014).
• Liver function test (AST/ALT levels) more than 2.5 times the upper limit of normal (ULN) range.
• Total bilirubin greater than 2 ULN.
• Use of an antimalarial drug in the preceding 4 weeks.
• History of splenectomy, heavy alcohol use or injecting drugs of abuse.
• Any other condition, which in the judgment of the study physician would make participation in the study unsafe for the potential study 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
Safety/efficacy
Statistical methods / analysis
A sample size of 55 participants for the P. falciparum mono-infection arm has been selected. Allowing for a 10% lost to follow-up and withdrawal, 50 participants will still fulfil the minimum sample of 50 participants that is required for a study to be representative as a WHO (Methods for Surveillance of Antimalarial Drug Efficacy. Geneva, World Health Organization, 2009) P. falciparum therapeutic efficacy study, with sufficient numbers to cover for participants who are likely to be lost during follow-up, withdrawal, and PCR-corrected reinfections (Stephniewska and White, 2006, Malar. J. 5:127.). With regards to the P. vivax mono-infection arm, since the baseline rates of vivax and falciparum malaria in this region are essentially equal, the same sample size goal of 55 participants will be pursued. With the additional inclusions of P. malariae and/or mixed infections of the three Plasmodium species of about 10 participants, the overall sample size goal is 120 participants.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
29/07/2018
Date of last participant enrolment
Anticipated
16/06/2020
Actual
7/10/2019
Date of last data collection
Anticipated
28/07/2020
Actual
18/11/2019
Sample size
Target
120
Accrual to date
Final
110
Recruitment outside Australia
Country [1] 20785 0
Viet Nam
State/province [1] 20785 0
Dak Nong Province

Funding & Sponsors
Funding source category [1] 300426 0
Government body
Name [1] 300426 0
US Naval Medical Research Center-Asia and US Naval Medical Research Unit - Two
Country [1] 300426 0
Singapore
Primary sponsor type
Government body
Name
US Naval Medical Research Center-Asia and US Naval Medical Research Unit - Two
Address
US Navy Base, Port of Singapore Authority, Sembawang. Singapore
Country
Singapore
Secondary sponsor category [1] 299887 0
Government body
Name [1] 299887 0
Australian Defence Force Malaria and Infectious Disease Institute
Address [1] 299887 0
Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Brisbane, QLD, 4051
Country [1] 299887 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301229 0
Vietnam Ministry of Health IRB in Biomedical Research
Ethics committee address [1] 301229 0
Ethics committee country [1] 301229 0
Viet Nam
Date submitted for ethics approval [1] 301229 0
10/05/2018
Approval date [1] 301229 0
24/05/2018
Ethics approval number [1] 301229 0
40/CN-HDDD
Ethics committee name [2] 301230 0
Departments of Defence and Veterans’ Affairs Human Research Ethics Committee
Ethics committee address [2] 301230 0
Ethics committee country [2] 301230 0
Australia
Date submitted for ethics approval [2] 301230 0
30/09/2016
Approval date [2] 301230 0
30/11/2016
Ethics approval number [2] 301230 0
841-16

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2985 2985 0 0
/AnzctrAttachments/375812-171209-Pyramax Protocol-Final English Version-VNPA-01 Version2.0-9Dec2017.pdf (Protocol)
Attachments [2] 2986 2986 0 0
/AnzctrAttachments/375812-161130-ADHREC Protocol 841-16 Approval Letter for Pyramax Protocol-VNPA-01-Version 1.0-15Jul2016.pdf (Ethics approval)
Attachments [3] 2987 2987 0 0
/AnzctrAttachments/375812-180524-IRB MOH Approval for Pyramax Protocol-VNPA-01-Version 2.0-9Dec2017- English Version.pdf (Ethics approval)
Attachments [4] 2988 2988 0 0
/AnzctrAttachments/375812-180604-DDVAHREC Approval of Amendments to Pyramax Protocol-VNPA-01 Version 2.0-9Dec2017.pdf (Protocol)

Contacts
Principal investigator
Name 86306 0
Dr Nguyen Duc Manh
Address 86306 0
Military Institute of Preventive Medicine
T21-Trung Liet, Dong Da
Hanoi
Country 86306 0
Viet Nam
Phone 86306 0
+84943911247
Fax 86306 0
Email 86306 0
[email protected]
Contact person for public queries
Name 86307 0
Nguyen Duc Manh
Address 86307 0
Military Institute of Preventive Medicine
T21-Trung Liet, Dong Da
Hanoi
Country 86307 0
Viet Nam
Phone 86307 0
+84943911247
Fax 86307 0
Email 86307 0
[email protected]
Contact person for scientific queries
Name 86308 0
Michael Edstein
Address 86308 0
Australia Defence Force Malaria and Infectious Disease Institute
Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Brisbane
QLD, 4051
Country 86308 0
Australia
Phone 86308 0
61-403321689
Fax 86308 0
Email 86308 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14829Study protocol  [email protected]
14830Clinical study report  [email protected]
14831Informed consent form  [email protected]
14832Ethical approval  [email protected]
14833Other  [email protected] Publication of the study in a scientific peered-re... [More Details]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePyronaridine-artesunate (pyramax) for treatment of artemisinin- And piperaquine-resistant plasmodium falciparum in the central highlands of vietnam.2021https://dx.doi.org/10.1128/AAC.00276-21
N.B. These documents automatically identified may not have been verified by the study sponsor.