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Trial registered on ANZCTR


Registration number
ACTRN12618001274268
Ethics application status
Approved
Date submitted
19/07/2018
Date registered
27/07/2018
Date last updated
11/12/2019
Date data sharing statement initially provided
9/07/2019
Date results information initially provided
9/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Evaluation of the therapeutic efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated falciparum malaria in areas of artemisinin-resistant falciparum malaria in Viet Nam
Scientific title
Evaluation of the therapeutic efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated falciparum malaria in areas of artemisinin-resistant falciparum malaria in Viet Nam
Secondary ID [1] 292750 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria disease 304529 0
Condition category
Condition code
Infection 307799 307799 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To assess the therapeutic efficacy of pyronaridine-artesunate (Pyramax®) tablets 180mg/60mg
a) the dose administered:
Body weight (kg) Daily dose (mg) Number of tablets
PYR AS
20 - < 24 180 60 1
24 - < 45 360 120 2
45 - < 65 540 180 3
> 65 720 240 4

b) the duration of administration : 3 days.
c) Pyronaridine- artesunate will be taken orally with water, once daily for 3 days. Each dose will be administered under supervision in the clinic or if not possible by a home visitor to the patient’s home. A dose will be repeated in full if vomiting occurs within 30 minutes of administration of the first day of administration only. This event will be documented in the case record form (CRF).
Intervention code [1] 301888 0
Treatment: Drugs
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 306789 0
Clearance of P..falciparum as assessed by PCR corrected ACPR'
Timepoint [1] 306789 0
Assess weekly for 42 days after dose,
Secondary outcome [1] 338260 0
• The numbers of patients with a positive malaria slide 72 hours after treatment initiation
Timepoint [1] 338260 0
Assess every 12 hours for 72 hours after dose,
Secondary outcome [2] 350000 0
Assess fever clearance time by thermometer with axillary temperature
Timepoint [2] 350000 0
Assess every 12 hours up to fall below 37.5°C and remain there for at least 24 hours.
Secondary outcome [3] 350001 0
• Assess PCR uncorrected ACPR at 42 days for P. falciparum
Timepoint [3] 350001 0
Assess weekly for 42 days after dose,
Secondary outcome [4] 350002 0
• Kaplan Meier analysis over 42 days for recrudescences and reinfections
Timepoint [4] 350002 0
Assess 42 days after doses
Secondary outcome [5] 350003 0
• Documented AEs and SAEs and relationships to study drugs.
Patients will be screened for common adverse events using and will be recorded in a predefined list of events, with in addition an open text field for non-listed events. Changes in liver enzymes will be recorded.. Clinical signs typical of an acute malaria episode will not be considered Adverse Events unless the healthcare personnel considers these events as exceptional due to their evolution, their seriousness, or another factor related to these events.
Liver function test results that are codified as adverse events, and/or elevations that occur rapidly or exceed multiples of the upper limits of normal, merit further inquiry on the part of the investigator. The laboratory tests that are relevant in this regard include:
a. ALT (SGPT), AST (SGOT), Examples of elevations that may require more intensive inquiry on the part of the investigator include an ALT value that exceeds 5.0 times the upper limit of normal.
b. Total bilirubin value that exceeds 2 times the upper limit of normal (Hy’s law). With massive hepatic injury, the ability of the liver to excrete conjugated (or direct) bilirubin diminishes.
c. Therefore, the presence of ALT >3xULN and concomitant bilirubin >2xULN (>35% direct), suggests significant liver injury, mandating the need for specialist consultation, and follow up of liver chemistries twice weekly until values normalise or substantively improve.
Timepoint [5] 350003 0
Assess 42 days afer doses.
Liver function tes (ALT, ÁST and bilirubin) assessed at D0, D7 and D28..

Eligibility
Key inclusion criteria
• Adults less than or equal to 70 and children greater than or equal to 7 year old and greater than or equal to 20 kbw
• Symptomatic of malaria infection, i.e. history of fever within 24 hours and/or presence of fever >37.5°c.
• Microscopic confirmation of asexual stages of P.falciparum, parasite density greater than or equal to' 1000 and below 150 000/asexual per micro liter
• Microscopic confirmation of asexual stages of P.falciparum (mono P. falciparum infection )
• Capability of taking an oral medication
• Written informed consent given to participate in the trial
• Willingness and ability to adhere to follow-up visit schedule
Minimum age
7 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Children < 7 year old and < 20 kbw and Adults > 70 year old.
• Pregnancy or lactation (urine test for ß HCG to be performed on any woman of child bearing age that is 18 to 45 years).
• Unmarried female aged 12-18 years
• Signs or symptoms indicative of severe malaria:
• Impaired consciousness (Blantyre Coma Score <5)
• Severe anaemia (Hct<20 % or Hb < 8g/dl)
• Bleeding disorder –evidenced by epistaxis, bleeding gums, frank haematuria, bleeding from venepuncture sites
• Respiratory, Kidney distress
• Severe jaundice
• Known hypersensitivity to artemisinins - defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis to pyronaridine
• History of splenectomy
• Known history or evidence of clinically significant liver disorders, such as:
- Known active Hepatitis A, e.g. by detection of anti HAV-IgM.
- Known hepatitis B surface antigen (HBsAg) carrier.
- Known hepatitis C antibody (HCV Ab).
- Liver function test (AST and ALT levels) more than 2.5 times the upper limit of normal range.
• Total Bilirubin > 2 ULN

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)
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
The primary analysis will be on an ‘intention to treat’ basis, including all patients enrolled into the study. Primary outcome will be the Kaplan Meier analysis up to day 42 of follow-up. A per protocol analysis will be based on all enrolled patients complying with all inclusion criteria who received a full course of the study drugs. Secondary analyses will include the ‘adequate parasitological and clinical response’ (APCR) at day 42. Safety and tolerability measurements will be summarized for the ITT patient population.

Recruitment
Recruitment status
Completed
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] 10666 0
Viet Nam
State/province [1] 10666 0
Binh Phuoc, Dak Nong, Gia Lai, Ninh Thuan, Khanh Hoa

Funding & Sponsors
Funding source category [1] 297386 0
Government body
Name [1] 297386 0
Ministry of Health, Viet Nam
Address [1] 297386 0
138A Giang Vo Street, Ba Dinh, Hanoi, Viet Nam
Country [1] 297386 0
Viet Nam
Funding source category [2] 300167 0
Other
Name [2] 300167 0
world health organization
Address [2] 300167 0
Avenue Appia 20
CH-1211 Geneva 27, Switzerland
Country [2] 300167 0
Switzerland
Funding source category [3] 300168 0
Commercial sector/Industry
Name [3] 300168 0
Shin Poong Pharmaceutical Company Ltd
Address [3] 300168 0
161, Yeoksam-ro, Gangnam-gu, Seoul 06246, Korea
Country [3] 300168 0
Korea, Republic Of
Primary sponsor type
Government body
Name
Ministry of Health, Viet Nam
Address
138A Giang Vo Street, Ba Dinh, Hanoi, Viet Nam
Country
Viet Nam
Secondary sponsor category [1] 296370 0
Other
Name [1] 296370 0
world health organization
Address [1] 296370 0
Avenue Appia 20
CH-1211 Geneva 27, Switzerland
Country [1] 296370 0
Switzerland
Secondary sponsor category [2] 299576 0
Commercial sector/Industry
Name [2] 299576 0
Shin Poong Pharmaceutical Company Ltd
Address [2] 299576 0
161, Yeoksam-ro, Gangnam-gu, Seoul 06246, Korea
Country [2] 299576 0
Korea, Republic Of

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298486 0
National Ethics Committee for Health Research of the MoH of Vietnam
Ethics committee address [1] 298486 0
138A, Giang Vo, Ba Dinh, Ha Noi
Ethics committee country [1] 298486 0
Viet Nam
Date submitted for ethics approval [1] 298486 0
02/08/2016
Approval date [1] 298486 0
14/09/2016
Ethics approval number [1] 298486 0
4922/QD- BYT
Ethics committee name [2] 300999 0
Ethics Committee for Health Research of WHO regional office, Western Pacific Region.
Ethics committee address [2] 300999 0
United Nations Ave, Ermita, Manila, 1000 Metro Manila
Ethics committee country [2] 300999 0
Philippines
Date submitted for ethics approval [2] 300999 0
09/11/2016
Approval date [2] 300999 0
01/03/2017
Ethics approval number [2] 300999 0
2017/693826-2

Summary
Brief summary
Pyronaridine-artesunate is the most current efficacy of antimalarial drugs that has been used in some countries in Asia as Cambodia, Thailand… Pyronaridine-artesunate is a newer artemisinin combination therapy, and was recently approved by the European Medicine Agency for single time use in adults and children >20 kg in countries with documented artemisinin resistance. We here propose an open-labelled clinical trial to assess the efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated falciparum malaria or mixed infection in Khanh Hoa, Dak Nong, Binh Phuoc, Ninh Thuan and Gia Lai provinces in Central and Southern Viet Nam.
Interventional study for the assessment of drug efficacy and safety over 42 days Patients with acute uncomplicated P. falciparum malaria. Samples size: 170.patients.
The patients respond all Inclusion and exclusion criteria will be recruited into study. Pyronaridine-artesunate tablet (Pyramax®). One tablet contains 60mg artesunate+ 180mg pyronaridine. Dosing will be according to body weight. Pyronaridine-artesunate will be taken orally with water, once daily for 3 days. The patients will be assessed therapy efficacy and safety for 42 days
All patients will have a blood smear examined every 12 hours from D0 – D3 or during the first week by microscopy until parasite clearance (2 consecutive negative slides on two consecutive days; both asexual and sexual stages). A negative blood slide will be defined as parasite count negative per 1000 WBC in two consecutive days. The sample on day 3 will be taken as close as possible to 72h after the initial blood smear.
The primary endpoint of the study is day 42 PCR corrected ACPR ( Adequate clinical and parasitological response. It means: absence of parasitaemia on day 42, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure) . To assess therapeutic efficacy of pyronaridine - artesunatefor the treatment of uncomplicated falciparum malaria in an area where artemisinin resistant malaria is prevalent.
The secondary endpoints
• The numbers of patients with a positive malaria slide 72 hours after treatment initiation
• Fever clearance time, parasite clearance time.
• Kaplan Meier analysis over 42 days for recrudescence and reinfections.
• PCR uncorrected ACPR at 28 days or 42 days for P. falciparum infection..
• Gametocyte carriage rates and gametocyte clearance times.
• Documented AEs and SAEs and relationships to study drugs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77238 0
A/Prof Bui Quang Phuc
Address 77238 0
National Institute of Malariology, Parasitology and Entomology.
34 Trung Van, South Tu Liem. Ha Noi
Country 77238 0
Viet Nam
Phone 77238 0
0084 913 522 874
Fax 77238 0
0084 24 3854 0099
Email 77238 0
phucnimpe@yahoo.com
Contact person for public queries
Name 77239 0
A/Prof Tran Thanh Duong
Address 77239 0
National Institute of Malariology, Parasitology and Entomology.
34 Trung Van, South Tu Liem. Ha Noi
Country 77239 0
Viet Nam
Phone 77239 0
0084 916 895 919
Fax 77239 0
0084 24 38544326
Email 77239 0
tranthanhduong@hotmail.com
Contact person for scientific queries
Name 77240 0
A/Prof Ta Thi Tinh
Address 77240 0
National Institute of Malariology, Parasitology and Entomology.
34 Trung Van, South Tu Liem. Ha Noi
Country 77240 0
Viet Nam
Phone 77240 0
0084 912 684 889
Fax 77240 0
Email 77240 0
tinhnimpe@yahoo.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
approval from My director and sponsor
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 6031 0
Clinical Infectious Diseases
Received 16 April 2019; editorial decision 24 May 2019; accepted 26 June 2019;
published online June 28, 2019
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary