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Trial registered on ANZCTR


Registration number
ACTRN12617000664347
Ethics application status
Approved
Date submitted
7/03/2017
Date registered
8/05/2017
Date last updated
8/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Therapeutic Efficacy Of Artemether+Lumefantrine For The Treatment Of Uncomplicated Falciaprum Malaria In Papua New Guinea, 2017.
Scientific title
Therapeutic Efficacy Of Artemether+Lumefantrine For The Treatment Of Uncomplicated Falciaprum Malaria In Papua New Guinea, 2017.
Secondary ID [1] 291376 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 302378 0
Condition category
Condition code
Infection 301960 301960 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will evaluate the efficacy and safety of artemether-lumefantrine give twice daily for three days according to the recommended weight bands as follows: 1 tablet (20/120 mg) to those weighing 5 to 14 kg; 2 tablets for 15 to 24 kg; 3 tablets for 25 to 34 kg and 4 tablets for equal or greater than 35 kg. The total target dose ranges are 5-24 mg/kg bw of artemether and 29-144 mg/kg bw of lumefantrine.
All treatments will be taken orally under direct supervision by the health worker and will be taken with fatty food e.g. milk. The patient will be given artemether+lumefantrine and will be followed up for 28 days.
Intervention code [1] 297413 0
Treatment: Drugs
Comparator / control treatment
No control group.
This is a one arm cohort prospective study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301374 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This is a composite primary outcome.

Enrolled patients will be assessed for parasitological (using microscopy) and clinical responses and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 301374 0
At days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [1] 332484 0
Percent of adverse event following treatment.
Atemether+lumefantrine are abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.
Parents or guardians of all enrolled children will be asked routinely about previous symptoms and about symptoms that have emerged since the previous follow-up visit.

When clinically indicated, patients will be evaluated and treated appropriately. All adverse events will be recorded on the case report form
Timepoint [1] 332484 0
On days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 332485 0
Proportion of polymorphism of molecular markers for artemisinin resistance (K13).

Extracted total nucleic acid from day 0 filter paper blood spots will be subjected to nested PCR for the detection of K13 gene. Subsequently, PCR products will be further subjected to DNA sequencing using BigDye terminator chemistry. DNA sequences will be assembled and mutations will be verified by inspection of both forward and reverse strands using BioEdit software version 7.
Timepoint [2] 332485 0
On day 0 (before treatment)
Secondary outcome [3] 333839 0
Proportion of piperaquine resistance (pfplasmepsin 2)
Filter paper blood spots will be used to extract genetic materials and plasmepsin2 and 3 mutation will be determined by PCR and immunoblotting.
Timepoint [3] 333839 0
Day 0 (before treatment)

Eligibility
Key inclusion criteria
1. age between 6 months to 60 years;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 250–100,000/microliter asexual forms;
4. presence of axillary temperature greater than or equal to 37.5 degree centigrade or history of fever during the past 24 h;
5. ability to swallow oral medication;
6. ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; (weather the patient is a temporary or permanent resident to the area is important to note, i.e. to minimize loosing study cases); and
7. informed consent from the patient or from a parent or guardian of children aged less than age of majority .
8. informed assent from any minor participant aged from 12 to age of majority years; and
9. consent for pregnancy testing from female of child-bearing age (defined as age > 12 years and sexually active) and from their parent or guardian if under the age of majority years
Minimum age
6 Months
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO;
2. weight under 5 kg;
3. haemoglobin < 8 g/dl;
4. mixed or mono-infection with another Plasmodium species detected by microscopy;
5. presence of severe malnutrition defined as a child aged 6-60 months who has a mid-upper arm circumference <115mm.
6. 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);
7. regular medication, which may interfere with antimalarial pharmacokinetics;
8. history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s);
9. a positive pregnancy test or breastfeeding; and
10. unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age and who are sexually active.

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)
No concealment
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
None
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%, 5% has been chosen. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients should be included in the study.
A Microsoft excel database provided by WHO will be used for data management and analysis. Data will be analysed by two methods: the Kaplan-Meier method and per-protocol analysis. In addition to the reasons for withdrawal listed in section 3.8, patients will be considered withdrawn from the analysis if the PCR results are unclassifiable or if the results of PCR indicate that the failure is due to reinfection with P. falciparum or P. vivax.
The final analysis will include:
1. a description of all patients screened and the distribution of reasons for non-inclusion in the study;
2. a description of all the patients included in the study;
3. the proportion of adverse events and serious adverse events in all the patients included in the study;
4. the proportion of patients lost to follow-up or withdrawn, with 95% confidence intervals and a list of reasons for withdrawal;
5. the cumulative incidence of success and failure rates at day 28, PCR-uncorrected and PCR-corrected; and
6. the proportion of early treatment failure, late clinical failure, late parasitological failure and adequate clinical and parasitological response at day 28, with 95% confidence intervals, PCR-uncorrected and PCR-corrected.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
22/05/2017
Actual
Date of last participant enrolment
Anticipated
30/11/2017
Actual
Date of last data collection
Anticipated
28/12/2017
Actual
Sample size
Target
88
Accrual to date
Final
Recruitment outside Australia
Country [1] 8715 0
Papua New Guinea
State/province [1] 8715 0
Milne Bay

Funding & Sponsors
Funding source category [1] 295849 0
Government body
Name [1] 295849 0
Department of Health
Country [1] 295849 0
Papua New Guinea
Primary sponsor type
Government body
Name
Department of Health
Address
AOPI Centre,
Waigani Drive
P O Box 807
Waigani 131
Port Moresby
Country
Papua New Guinea
Secondary sponsor category [1] 294710 0
None
Name [1] 294710 0
Address [1] 294710 0
Country [1] 294710 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297130 0
Medical Research Advisory Committee
Ethics committee address [1] 297130 0
National Department of Health
Waigani Drive
P O Box 807
Waigani 131
Port Moresby
Ethics committee country [1] 297130 0
Papua New Guinea
Date submitted for ethics approval [1] 297130 0
02/01/2017
Approval date [1] 297130 0
30/01/2017
Ethics approval number [1] 297130 0
MRAC No. 16.38.

Summary
Brief summary
Title: Efficacy of Artemether-Lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Gurney Health Centre, Alotau, Milne Bay Province, Papua New Guinea.
Purpose: Ongoing therapeutic efficacy surveillance of current first line antimalarial treatment for uncomplicated falciparum malaria.
Objective: To assess the current efficacy and safety of Artemether-Lumefantrine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Gurney Health Centre, Alotau, Milne Bay Province, Papua New Guinea
Study Period: April to December 2017.
Study Design: One arm prospective study.
Patient population: Febrile patients aged between minimum 6 months and maximum 60 years, with confirmed uncomplicated P. falciparum infection. Within the defined age group, no particular age will be exempted. Both male and female will be recruited; however, pregnant women will be excluded from the study.
Sample Size: Target number of patients to be recruited is 88.
Treatment(s) and follow-up: Artemether-Lumefantrine is available as a fixed-dose formulation with dispersible or standard tablets containing 20 mg of artemether and 120 mg of lumefantrine. The recommended treatment is a 6-dose regimen over a 3-day period. The treatment dosage ranges from 1.4-4 mg/kg of artemether and 10-16 mg/kg of lumefantrine. Clinical and parasitological parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy. All artemether-lumefantrine are to be taken with fatty food.
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: The polymorphism of molecular markers for arteamisinin resistance (K13) and piperaquine resistance (plasmepsin-2).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73082 0
Dr Lucy John
Address 73082 0
Disease Control and Surveillance,
Department of Health
Waigani Drive
P O Box 807
Waigani 131
Port Moresby
Country 73082 0
Papua New Guinea
Phone 73082 0
+6753013736
Fax 73082 0
Email 73082 0
[email protected]
Contact person for public queries
Name 73083 0
Lucy John
Address 73083 0
Disease Control and Surveillance,
Department of Health
Waigani Drive
P O Box 807
Waigani 131
Port Moresby
Country 73083 0
Papua New Guinea
Phone 73083 0
+6753013736
Fax 73083 0
Email 73083 0
[email protected]
Contact person for scientific queries
Name 73084 0
Lucy John
Address 73084 0
Disease Control and Surveillance,
Department of Health
Waigani Drive
P O Box 807
Waigani 131
Port Moresby
Country 73084 0
Papua New Guinea
Phone 73084 0
+6753013736
Fax 73084 0
Email 73084 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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