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Trial registered on ANZCTR


Registration number
ACTRN12618001630202
Ethics application status
Approved
Date submitted
24/08/2018
Date registered
3/10/2018
Date last updated
3/10/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Therapeutic efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and chloroquine for P. vivax in Myanmar
Scientific title
Efficacy and safety artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria and chloroquine for P. vivax in Buthidaung, Rakhine State
Secondary ID [1] 295768 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
malaria 309168 0
fever 309169 0
Condition category
Condition code
Infection 308046 308046 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treating malaria patients with standard dose and course of antimalarials as follow;

Artemether 2mg/Kg and lumefantrine 12 mg/Kg two times a day for three days course in one group (each tablet containing artemether 20 mg and lumefantrine 120mg)usually 2 tablets stat orally, another 2 tablets after 8 hrs on day 1, two tablets twice daily on day2 and 3.
Dihydroartemisinin 2-2.4 mg/Kg & piperaquine phosphate 16-19.2 mg/Kg combination on Day 0,1 & 2 in one group and were used for P. falciparum cases.Each tablet containing 40mg dihydroartemisinin and 320 mg piperaquine phosphate was administered at the dosage of 3 tabs given daily for 3 days.
Chloroquine 10 mg , 10 mg and 5 mg per Kg on day 0,1 and 2 days was given for P. vivax cases. Chloroquine containing 150mg base of chloroquine was given 4 tablets on day 1, and day 2, 2 tablets on day 3.
Every first dose was given by directly observed treatment (DOT) by trained Medical Officer and following doses by malaria volunteers.
To check the compliance, malaria volunteers visited the patient's home and recollected the empty blister cards.
Artemether-lumefantrine trial was started to enroll all criteria matched falciparum cases up to proposed study sites and followed by Dihydroartemisinine-piperquine trial. Falciparum malaria case enrollment for artemether-lumefantrine took place first to get proposed sample size and case enrollment for dihydroartemisinine-piperquine. Vivax malaria case enrollment took place in parallel to falciparum.
Intervention code [1] 312095 0
Treatment: Drugs
Comparator / control treatment
no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307038 0
Efficacy of artemether lumefantrine combination treatment (ACT) against Plasmodium falciparum will be either treatment success or failure.
Treatment outcome was categorized according to WHO classification as follow;
Early treatment failure
• danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia;
• parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature;
• parasitaemia on day 3 with axillary temperature equal to or greater than 37.5 ºC;
• parasitaemia on day 3 equal to or greater than 25% of count on day 0.
Late treatment failure
Late clinical failure
• danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 in patients who did not previously meet any of the criteria of early treatment failure;
• presence of parasitaemia on any day between day 4 and day 28 with axillary temperature equal to or greater than 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure
Late parasitological failure
• presence of parasitaemia on any day between day 7 and day 28 with axillary temperature less than 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure
Adequate clinical and parasitological response
• absence of parasitaemia on day 28, 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

Timepoint [1] 307038 0
Follow up period of 28 days after treatment with artemether-lumefantrine combination
Primary outcome [2] 307441 0
Efficacy of chloroquine in the treatment of vivax malaria will be either treatment success or failure
Treatment outcome was categorized according to WHO classification as follow;
Early treatment failure
• danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia;
• parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature;
• parasitaemia on day 3 with axillary temperature equal to or greater than 37.5 ºC;
• parasitaemia on day 3 equal to or greater than 25% of count on day 0.
Late treatment failure
Late clinical failure
• danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 in patients who did not previously meet any of the criteria of early treatment failure;
• presence of parasitaemia on any day between day 4 and day 28 with axillary temperature equal to equal to or greater than 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure
Late parasitological failure
• presence of parasitaemia on any day between day 7 and day 28 with axillary temperature < 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure
Adequate clinical and parasitological response
• absence of parasitaemia on day 28, 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

Timepoint [2] 307441 0
Follow up period of 28 days after treatment with chloroquine
Primary outcome [3] 307622 0
Efficacy of dihydroartemisinin-pipraquine combination treatment (DHA) against Plasmodium falciparum will be either treatment success or failure.
Treatment outcome was categorized according to WHO classification as follow;
Early treatment failure
• danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia;
• parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature;
• parasitaemia on day 3 with axillary temperature equal to or greater than 37.5 ºC;
• parasitaemia on day 3 equal to or greater than 25% of count on day 0.
Late treatment failure
Late clinical failure
• danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 42 in patients who did not previously meet any of the criteria of early treatment failure;
• presence of parasitaemia on any day between day 4 and day 42 with axillary temperature equal to or greater than 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure
Late parasitological failure
• presence of parasitaemia on any day between day 7 and day 42 with axillary temperature less than 37.5 ºC in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure
Adequate clinical and parasitological response
• 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

Timepoint [3] 307622 0
At the end of day 42 follow up after treating the patients with DHA combination
Secondary outcome [1] 350456 0
Safety of artemisinin-based combination treatment in Plasmodium falciparum and chloroquine in Plasmodium vivax.
Frequency of reports on adverse events (eg; head ache, dizziness,) submitted by team leader of field trial to Principal Investigator, were reviewed.
Timepoint [1] 350456 0
Follow-up period of 28 days for artemether-lumefantrine trial and chorquine trial and 42 days for dihydriartemisinine-piperaquine.

Eligibility
Key inclusion criteria
• age between 6 years and above ;
• mono-infection with P. falciparum detected by microscopy (parasitaemia of 500-100,000/µl asexual forms) or P. vivax detected by microscopy (parasitaemia > 250/µl asexual forms);
• presence of axillary temperature greater than or equal to 37.5 °C or history of fever during the past 24 h;
• ability to swallow oral medication;
• ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; and
• informed consent from the patient or from a parent or guardian in the case of children.
Minimum age
6 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• presence of signs of severe falciparum malaria according to the definitions of WHO
• mixed or mono-infection with another Plasmodium species detected by microscopy;
• presence of severe malnutrition (defined as a child whose growth standard is below –3 z-score, has symmetrical oedema involving at least the feet or has a mid-upper arm circumference < 110 mm);
• presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS);
• regular medication, which may interfere with antimalarial pharmacokinetics;
• history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s); and
• a positive pregnancy test or breastfeeding;
• unable to or unwilling to take a pregnancy test or contraceptive (for women of child-bearing age)

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
Other
Other design features
Enroll the patients for first drug combination to fulfill the proposed sample size and then enroll for the second drug combination
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Treatment failure to Dihydroartemesinin-piperaquine in the area being unknown, 5% has been chosen as the estimated therapeutic failure rate of the medicine. At a confidence level of 95% and with a precision around the estimate of 5%, 73 patients need to be included. With a 20% increase to allow losses to follow-up and withdrawals during the 42-day follow-up period, 80 patients in each arm need to be included in the study.
For treatment outcome analysis, excel sheet provided by WHO will be applied.

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] 20737 0
Myanmar
State/province [1] 20737 0
Rakhine State

Funding & Sponsors
Funding source category [1] 300356 0
Other
Name [1] 300356 0
WHO/GMS (World Health Organization/Greater Mekong Subregion)
Address [1] 300356 0
WHO/GSC/GPL
BLOCK 3510
JALAN TEKNOKRAT 6
CYBERJAYA 63000
Country [1] 300356 0
Malaysia
Primary sponsor type
Government body
Name
Ministry of Health and Sports
Address
Office number (4), Zaya HtaNy Road, Ministry Zone, Pobba Thiri , Nay Pyi Taw, 15011,
Country
Myanmar
Secondary sponsor category [1] 300016 0
None
Name [1] 300016 0
Address [1] 300016 0
Country [1] 300016 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301170 0
Ethics Review Committee, Department of Medical Research, Ministry of Health & Sports
Ethics committee address [1] 301170 0
No. 5, Ziwaka Road, Dagon Township, 11191
Ethics committee country [1] 301170 0
Myanmar
Date submitted for ethics approval [1] 301170 0
Approval date [1] 301170 0
31/10/2013
Ethics approval number [1] 301170 0

Summary
Brief summary
Purpose of the study was to determine efficacy and safety of artemether -lumefantrine, and dihydroartemisinine-pipraquine for the treatment of uncomplicated Plasmodium falciparum malaria and chloroquine for Plasmodium vivax in Buthitaung, Rakhine state, Myanmar. The study was conducted during June 2016 to December 2016. Total 199 patients were enrolled (, 70 falciparum malaria cases for artemether-lumefantrine trial, 71 falciparum malaria cases for dihyddroartemisinin-piperaquine trial and 57 vivax malaria cases for chloroquine trial.
Clinical and parasitological parameters were monitored over 28-days follow-up period for artemether-lumefantrine trial and chloroquine trial group, and 42 days for dihyddroartemisinin-piperaquine trial group to evaluate drug efficacy and safety
Trial website
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 86086 0
Dr KAY THWE HAN
Address 86086 0
Department of Medical Research
No. 5, Ziwaka Road, Dagon Township, 11191 Yangon
Country 86086 0
Myanmar
Phone 86086 0
95 9 5169228
Fax 86086 0
95 1 251514
Email 86086 0
drkaythwehan@yahoo.com
Contact person for public queries
Name 86087 0
Dr KAY THWE HAN
Address 86087 0
Department of Medical Research
No.5, Ziwaka Road, Dagon Township, Yangon 11191
Country 86087 0
Myanmar
Phone 86087 0
95 9 5169228
Fax 86087 0
95 1 251514
Email 86087 0
drkaythwehan@yahoo.com
Contact person for scientific queries
Name 86088 0
Dr Pascal Ringwald
Address 86088 0
Global Malaria Programme
World Health Organization
20 Avenue Appia
1211 Geneva 27
Switzerland
Country 86088 0
Switzerland
Phone 86088 0
+41 22 791 2533
Fax 86088 0
+41 22 791 4824
Email 86088 0
ringwaldp@who.int

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary