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Trial registered on ANZCTR


Registration number
ACTRN12615000107527
Ethics application status
Approved
Date submitted
22/12/2014
Date registered
5/02/2015
Date last updated
5/02/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in three provinces in Angola
Scientific title
Efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in three provinces in Angola
Secondary ID [1] 285888 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 293811 0
Condition category
Condition code
Infection 294112 294112 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To assess the efficacy and safety of (i) artemether/lumefantrine (20 mg of artemether and 120 mg of
lumefantrine in a tablet) with dose regimen (one tablet to those weighing 5-14kg; two tablets for 15-24 kg; three tablets for 25-34 kg and four tablets for greater than or equal to 35 kg); (ii) artesunate+amodiaquine with dose regimen(4.5-8.9 kg:1 tablet of 25 mg AS/67.5 mg AQ), 9-17.9 kg: 1 tablet 50 mg AS/135 mg AQ, 18-35.9kg: 1 tablet 100 mg AS/270 mg AQ, greater than or equal to 36 kg: 2 tablets 100 mg AS/270 mg AQ);and (iii) dihydroartemisinin-piperaquine (40mg/320mg) with dose regimen of for the treatment of 5-9.9 kg: 0.5 tablet, 10-19.9 kg:1 tablet, 20-39.9 kg: 2 tablets, greater than or equal to 40 Kg: 3 tablets) for uncomplicated P. falciparum infection. The treatment will be taken orally. Eligibile subjects
will be treated for three days (daily dose for
artesunate+amodiaquine and dihydroartemisinin and twice daily dose for artemether lumefantrine).

All treatment was given under observation of the health worker who is administering the drug.
Intervention code [1] 290870 0
Treatment: Drugs
Comparator / control treatment
It is not a comparative study. It will be a sequential enrolment as follows:

Benguela site:the first 100 participants to be enrolled will receive AL.

Lunda SUl site:the first 100 participants will receive DP, and the next 100 participants will receive ASAQ.

Zaire: the first 100 participants will receive DP, and the next 100 participants will receive AL
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293910 0
Artesunate+amodiaquine:
Percent of treatment failures (early treatment failure + late clinical failure + late parasitological failure) for artesunate+amodiaquine. It is composite primary outcome.

Enrolled patients will be assessed for parasitological (using microscopy), clinical responses during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 293910 0
At day 28 following initiation of treatment of artesunate+amodiaquine treatment.
Primary outcome [2] 294086 0
Artemether+lumefantrine:
Percent of treatment failures (early treatment failure + late clinical failure + late parasitological failure) for artemether+lumefantrine. It is composite primary outcome.


Enrolled patients will be assessed for parasitological (using microscopy), clinical responses during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [2] 294086 0
At day 28 following initiation of artemether+lumefantrine treatment.
Primary outcome [3] 294087 0
Dihydroartemisinin+piperaquine:
Percent of treatment failures (early treatment failure + late clinical failure + late parasitological failure) for dihydroartemisinin+piperaquine. It is composite primary outcome.

Enrolled patients will be assessed for parasitological (using microscopy), clinical responses during the 42 days and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [3] 294087 0
At day 42 following initiation of dihydroartemisinin+piperaquine treatment.
Secondary outcome [1] 312139 0
Artesunate+amodiaquine:
Percent of adverse event will be documented. abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.

Patients or parents/guardians of enrolled patients 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] 312139 0
At day 28 following initiation of artesunate+amodiaquine treatment.
Secondary outcome [2] 312495 0
Artemether+lumefantrine:
Percent of adverse event will be documented. The known adverse events of artemether/lumefantrine are abdominal discomfort, nausea, headache and dizziness.

Patients or parents/guardians of enrolled patients 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 [2] 312495 0
At day 28 following initiation of artemether+lumefantrine treatment.
Secondary outcome [3] 312496 0
Dihydroartemisinin+piperaquine:
Percent of adverse event will be documented. The known adverse events of dihydroartemisinin/piperaquine are abdominal discomfort, nausea, headache and dizziness.

Patients or parents/guardians of enrolled patients 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 [3] 312496 0
At day 42 following initiation of dihydroartemisinin+piperaquine treatment.
Secondary outcome [4] 312497 0
Prevalence of artemisinin resistance molecular markers (K13). Parasite DNA will be extracted from the dried blood spots and will be analyzed by PCR and sequencing for the presence of molecular markers of resistance to artemisinin specifically to K13-propeller.
Timepoint [4] 312497 0
At Day 0 (prior of initiation of treatment)

Eligibility
Key inclusion criteria
1. age between 6 months to 9 years;
2. weight greater than or equal to 5 kg;
3. mono-infection with P. falciparum detected by microscopy;
4. parasitaemia of 2000 - 100000 asexual forms per microliter;
5. presence of axillary or tympanic temperature greater than or equal to 37.5 degree centigrade or history of fever during the past 24 h;
6. hemoglobin greater than 5.0g/dl;
7. ability to swallow oral medication;
8. easy access to the health facility and ability/willingness to return to the health facility over the course of the four weeks (six weeks for DP) of follow-up;
9. informed consent from the parent or guardian.
Minimum age
6 Months
Maximum age
9 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. pneumonia or bronchopneumonia;
3. history of taking antimalarials (or antibiotics with antimalarial activity such as cotrimoxazol, tetracycline or doxycycline) in the last 14 days;
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 whose weight-for-height is below –3 z-score
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);

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)
Patients aged 6 months to 9 years with uncomplicated falciparum malaria who meet the study inclusion criteria will be enrolled, treated on site with either artesunate/amodiaquine, artemether/lumefantrine or dihydroartemisinin and monitored for 28 days (artesunate/amodiaquine, artemether/lumefantrine ) or 42 dyas (dihydroartemisinin+piperaquine). The follow-up will consist of a fixed schedule of check-up visits
and corresponding clinical and laboratory examinations.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This is surveillance study of 3 drugs x one-arm prospective evaluation of clinical and parasitological responses to directly observed treatment for uncomplicated falciparum malaria with either artesunate/amodiaquine, artemether/lumefantrine or dihydroartemisinin+piperaquine.

Benguela site:the first 100 participants to be enrolled will receive AL and the next 100 patients will receive artesunate/amodiaquine

Lunda SUl site:the first 100 participants will receive dihydroartemisinin+piperaquine, and the next 100 participants will receive artesunate/amodiaquine.

Zaire: the first 100 participants will receive dihydroartemisinin+piperaquine, and the next 100 participants will receive artemether/lumefantrine.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We assume the treatment failure rate to all the three test drugs in the area is 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included. Allowing for a 25% loss to follow-up and withdrawal rate during the 28/42-day follow-up period, 100 patients should be included in the study per site per test drug. Two drugs will be tested in each of the three sites.

The WHO excel software programs will be used for data management and analysis. Data will be analysed by two methods: the Kaplan-Meier method and per-protocol analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/03/2015
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
600
Accrual to date
Final
Recruitment outside Australia
Country [1] 6565 0
Angola
State/province [1] 6565 0
Bengue, Zaire and Lund Sul

Funding & Sponsors
Funding source category [1] 290471 0
Other
Name [1] 290471 0
World Health Organization
Country [1] 290471 0
Switzerland
Primary sponsor type
Government body
Name
Ministry of Health
Address
Ministry of Health,
Rua 17 de Setembro,
P.O. Box 1201
Luanda, ANGOLA
Country
Angola
Secondary sponsor category [1] 289173 0
Government body
Name [1] 289173 0
National Malaria Control Centre
Address [1] 289173 0
National Malaria Control Centre
Avenida 10 de Dezembro,
Building of National Directorate of Public Health,
Maianga, Luanda-Angola
Country [1] 289173 0
Angola

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292140 0
WHO Ethical Research Committee
Ethics committee address [1] 292140 0
20 Av. Appia
1211 Geneva 27 Switzerland
Ethics committee country [1] 292140 0
Switzerland
Date submitted for ethics approval [1] 292140 0
11/11/2014
Approval date [1] 292140 0
18/12/2014
Ethics approval number [1] 292140 0
RPC691

Summary
Brief summary
Title: Efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in three provinces in Angola.

Purpose: 1) To assess the efficacy of the current first and/or second line treatment policy; 2) To assess the efficacy of a new antimalarial drug to support updating of the national policy

Objective: To assess the efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine for the treatment of uncomplicated P. falciparum malaria infections.

Study Sites: Benguela in Benguela Province, M'Banza Congo in Zaire Province, and Saurimo in Lunda Sul Province.

Study Period: January to April 2015.

Study Design: Two cohorts prospective study in each site in sequential enrolment.

Patient population: Febrile patients aged between 6 months to 9 years with confirmed uncomplicated P. falciparum infection.

Sample Size: 600 patients.

Treatment(s) and follow-up: artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine. Clinical and parasitological parameters will be monitored over a 28 (for artemether-lumefantrine, artesunate-amodiaquine) and 42 (for dihydroartemisinin-piperaquine)-day follow-up period to evaluate drug efficacy.

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 for resistance
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 53702 0
Dr Mateusz Plucinski
Address 53702 0
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329 USA
Country 53702 0
United States of America
Phone 53702 0
+1800-232-4636
Fax 53702 0
Email 53702 0
[email protected]
Contact person for public queries
Name 53703 0
Mateusz Plucinski
Address 53703 0
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329 USA
Country 53703 0
United States of America
Phone 53703 0
+1800-232-4636
Fax 53703 0
Email 53703 0
[email protected]
Contact person for scientific queries
Name 53704 0
Mateusz Plucinski
Address 53704 0
Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329 USA
Country 53704 0
United States of America
Phone 53704 0
+1800-232-4636
Fax 53704 0
Email 53704 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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