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Trial registered on ANZCTR


Registration number
ACTRN12623000239662p
Ethics application status
Submitted, not yet approved
Date submitted
14/01/2023
Date registered
6/03/2023
Date last updated
6/03/2023
Date data sharing statement initially provided
6/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Measurement of the level of performance of two malaria medicines (artemether-lumefantrine and dihydroartemisinin-piperaquine) for the treatment of uncomplicated malaria caused by malaria parasite called Plasmodium falciparum in Alikadam Upazila (sub-district) and Lama Upazila (subdistrict) of Bandarban district and Baghaichari Upazila (subdistrict) of Rangamati district, Bangladesh.
Scientific title
Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Alikadam Upazila and Lama Upazila of Bandarban district and Baghaichari Upazila of Rangamati districts, Bangladesh.
Secondary ID [1] 308754 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Febrile malaria patients aged more than 6 months with confirmed uncomplicated P. falciparum infection. 328701 0
Condition category
Condition code
Public Health 325713 325713 0 0
Epidemiology
Infection 325884 325884 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Clinical and parasitological efficacy of artemether-lumefantrine and dihydro-artemisinin piperaquine in patients aged more than 6 months, suffering from uncomplicated falciparum malaria, by determining the proportion with early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response as indicators of efficacy.
The study drugs will be Artemether-lumefantrine and Dihydroartemisinin-piperaquine. Artemether-lumefantrine will be administered orally for 6 doses over 3 days and Dihydroartemisinin-piperaquine will be administered orally daily for 3 days (total 3 doses).
Artemether-lumefantrine tablets will contain 20 mg artemether and 120 mg lumefantrine (detail provided in the attached protocol). In addition, Tab Primaquine (0.25mg/kg) will be given orally with the first dose of ACT.

Dihydroartemisinin-piperaquine will contain 40 mg dihydroartemisinin and 320 mg piperaquine phosphate (Detail provided in the attached protocol). Like Artemether-lumefantrine group Tab Primaquine (0.25mg/kg) will be given with the first dose of ACT.
Both the study drugs will be provided orally. For monitoring adherence to the interventions the subjects will be hospitalised for initial 3 days and will be provided Directly Observed treatment by the Senior Staff Nurse.
The choice of treatment either by the artemether-lumefantrine or dihydroartemesinin-piperaquine will be dependent on both the research assistant and the subject as this is not at randomised trial. As the dihydroartemisinin-peperaquine tablets are not available at this moment (for which procurement is under process), the study will be started with the tablet artemether-lumefantrine. When tablet dihydroartemisinin-peperaquine will be available (we are expecting it will be available soon) then the treatment choice will be dependent upon discussion between patients and research assistant.

Intervention code [1] 325212 0
Treatment: Drugs
Comparator / control treatment
The study will not compare the efficacy between the artemether-lumefantrine and dihydroartemisinin-peperaquine rather efficacy artemether-lumefantrine and dihydroartemisinin-peperaquine will be independently assessed. There will be no control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 333561 0
To measure the clinical and parasitological efficacy of artemether-lumefantrine in patients aged more than 6 months, suffering from uncomplicated falciparum malaria.
The outcome will be measured by both clinical examination of the subjects and malaria microscopy and Genotyping of patients' blood.
Timepoint [1] 333561 0
Adequate Clinical and Parasitological Response.
The patients will be followed daily for initial 3 days and then weekly upto 28 days for Artemether-lumefantrine group.
Primary outcome [2] 333742 0
To differentiate recrudescence from new infection by polymerase chain reaction (PCR) analysis.
The outcome will be measured through genotyping using patients blood.
Timepoint [2] 333742 0
The patients will be followed daily for initial 3 days and then weekly upto 28 days for Artemether-lumefantrine group and 42 days for Dihydro-artemisinin group. During this period if failure is reported then genotyping will be carried out.
Primary outcome [3] 333838 0
To determine the proportion with early treatment failure. This will be assessed based on the data/information recorded in the case record form.
Timepoint [3] 333838 0
Early Treatment Failure. This will be measured based on the presence of one or more of the following criterion/criteria.
• 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 greater than or equal to 37.5 ºC;
• parasitaemia on day 3 = 25% of count on day 0.
Secondary outcome [1] 417525 0
To evaluate the incidence of adverse events.
The outcome will be assessed through clinical examination of the patients.
Possible adverse events of Artemether-lumefantrine:
Abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.
Possible adverse events of Dihydroartemisinin-piperaquine:
Asthenia, cough, diarrhoea, fever, loss of appetite, nausea, vomiting.
The adverse events will be assessed using queationnaire.
Timepoint [1] 417525 0
The adverse events for artemether-lumefantrine groups patients will be measured throughout the 4 weeks of follow up period.
The adverse events for dihydro-artemisinin-piperaquine groups patients will be measured throughout the 6 weeks of follow up period.
Secondary outcome [2] 418118 0
To determine the polymorphism of molecular markers (K13) for Artemisinin resistance.
Timepoint [2] 418118 0
Will be measured through PCR testing of blood sample when there will be reported early treatment failure, late clinical failure and late parasitological failure.
Secondary outcome [3] 418445 0
To determine late treatment failure. The outcome will be measured through data linkage to medical records.
Timepoint [3] 418445 0
Late Treatment Failure that includes a) Late Clinical Failure; b) Late Parasitological failure.
Secondary outcome [4] 419205 0
To measure the clinical and parasitological efficacy of dihydro-artemisinin piperaquine in patients aged more than 6 months, suffering from uncomplicated falciparum malaria.
The outcome will be measured by both clinical examination of the subjects and malaria microscopy and Genotyping of patients' blood. This will be assessed as a primary outcome.
Timepoint [4] 419205 0
Adequate Clinical and Parasitological Response.
The patients will be followed daily for initial 3 days and then weekly up to 42 days for Dihydro-artemisinin group.

Eligibility
Key inclusion criteria
• age more than 6 months;
• mono-infection with P. falciparum detected by microscopy;
• parasitaemia of 1000/µl to 100,000 asexual forms;
• presence of tympanic temperature greater than or equal to 37.5 °C or history of fever during the past 48 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;
• informed consent from the patient or from a parent or guardian in the case of children aged less than 18 years;
• informed assent from any minor participant aged from 12 to 18 years; and
• consent for pregnancy testing from female of child-bearing potential and from their parent or guardian if under the age of majority years.
Minimum age
6 Months
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO;
• weight under 5 kg;
• any mixed or mono-infection with other Plasmodium species detected by microscopy;
• presence of severe malnutrition defined as a child aged 6-60 months who has symmetrical edema involving at least the feet and/or has a mid-upper arm circumference < 115 mm)
• presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhea 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);
• a positive pregnancy test or breastfeeding; and
• unable to or unwilling to take pregnancy test or to use contraception for married women of child-bearing age.
• minors (below 18 years of age) who have achieved menarche will be excluded from the study.
• Unmarried women

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
As the treatment failure rate to artemether-lumefantrine in the area is 5% has been chosen. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 50 patients must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day/42-day follow-up period, 60 patients should be included in the study per site.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/03/2023
Actual
Date of last participant enrolment
Anticipated
15/11/2023
Actual
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
360
Accrual to date
Final
Recruitment outside Australia
Country [1] 25209 0
Bangladesh
State/province [1] 25209 0
Bandaban and Rangamati Districts

Funding & Sponsors
Funding source category [1] 312978 0
Government body
Name [1] 312978 0
Ministry of Health and Family Welfare, Bangladesh
Country [1] 312978 0
Bangladesh
Primary sponsor type
Government body
Name
Ministry of Health and Family Welfare, Bangladesh
Address
Complete postal address:
National Malaria Elimination Program, CDC, Directorate General of Health Services, Mohakhali, Dhaka-1212 (under Ministry of Health and Family Welfare - 1000)
Country
Bangladesh
Secondary sponsor category [1] 314665 0
None
Name [1] 314665 0
Address [1] 314665 0
Country [1] 314665 0
Other collaborator category [1] 282525 0
Government body
Name [1] 282525 0
Directorate General of Health Services
Address [1] 282525 0
Complete postal address:
National Malaria Elimination Program, CDC, Directorate General of Health Services, Mohakhali, Dhaka-1212 (under Ministry of Health and Family Welfare - 1000)
Country [1] 282525 0
Bangladesh

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 312244 0
Bangladesh Medical Research Council
Ethics committee address [1] 312244 0
Bangladesh Medical Research Council, Mohakhali, Dhaka-1212, Bangladesh
Ethics committee country [1] 312244 0
Bangladesh
Date submitted for ethics approval [1] 312244 0
09/01/2023
Approval date [1] 312244 0
Ethics approval number [1] 312244 0

Summary
Brief summary
Title: Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Alikadam Upazila and Lama Upazila of Bandarban district and Baghaichari Upazila of Rangamati districts, Bangladesh.
Purpose: To assess the efficacy of the current first line and second line treatment policy
Objective: To assess the efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Alikadam Upazila of Bandarban district, Lama Upazila of Bandarban district and Baghaichari Upazila of Rangamati district.
Study Period: 30 January 2023 to 31 December 2023.
Study Design: This surveillance study is two arm prospective study.
Patient population: Febrile patients aged more than 6 months with confirmed uncomplicated P. falciparum infection.
Exclusion: pregnancy, breast feeding mother, young girls aged 12-18 years old and contraindication to Artemether-Lumefantrine.
Sample Size: A total of 360 patients (180 patients for each drug combination to be tested) will be enrolled from 3 upazilas, 120 patients of each upazila (60 patients for each drug combination).
Treatment(s) and follow-up: Clinical and parasitological parameters will be monitored over a 28-day follow-up period for artemether-lumefantrine and 42-day follow up period for dihydroartemisinin-piperaquine to evaluate drug efficacy of both the drug combinations.
Primary endpoints: The proportion of patients with early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response as indicators of efficacy. Recrudescence will be distinguished from re-infection by polymerase chain reaction (PCR) analysis.
Secondary endpoints: The frequency and nature of adverse events.
Optional exploratory endpoints:
• to determine the polymorphism of molecular markers (K13) for Artemisinin resistance
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123970 0
Prof Prof Dr. Md. Nazmul Islam
Address 123970 0
Institution: Director, Disease Control and Line Director, CDC
Address: DGHS, Mohakhali, Dhaka-1212, Bangladesh
Country 123970 0
Bangladesh
Phone 123970 0
+8801711269170
Fax 123970 0
Email 123970 0
[email protected]
Contact person for public queries
Name 123971 0
Dr Md Mushfiqur Rahman
Address 123971 0
Institution: Programme Operations Advisor, National Malaria Elimination and ATDs Control Programme
Address: DGHS, Mohakhali, Dhaka-1212, Bangladesh
Country 123971 0
Bangladesh
Phone 123971 0
+8801741889393
Fax 123971 0
Email 123971 0
[email protected]
Contact person for scientific queries
Name 123972 0
Dr Md Mushfiqur Rahman
Address 123972 0
Institution: Programme Operations Advisor, National Malaria Elimination and ATDs Control Programme
Address: DGHS, Mohakhali, Dhaka-1212, Bangladesh
Country 123972 0
Bangladesh
Phone 123972 0
+8801741889393
Fax 123972 0
Email 123972 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?
Individual participant data collected during the study.
When will data be available (start and end dates)?
Start date: 30 January 2023
End date: 31 December 2023
Available to whom?
Only researchers
Available for what types of analyses?
Only to achieve objectives of the proposal
How or where can data be obtained?
Access subject to approvals by Principal Investigator.
Director, Disease Control and Line Director, CDC
Address: DGHS, Mohakhali, Dhaka-1212, Bangladesh
Tel: +8801711269170
Email: [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
18046Study protocol  [email protected] 385228-(Uploaded-14-01-2023-16-21-25)-Study-related document.docx
18047Informed consent form    Consent form already included in the study protoco... [More Details]
18048Ethical approval    Waiting for ethical approval.
18049Other  [email protected] 1) Definition of severe malaria 2) Medications (w... [More Details]
18050Clinical study report  [email protected]



Results publications and other study-related documents

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