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Trial registered on ANZCTR


Registration number
ACTRN12616001006437
Ethics application status
Approved
Date submitted
19/07/2016
Date registered
29/07/2016
Date last updated
5/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemisinin-based combinations: artesunate+amodiaquine and artemether+lumefantrine for the treatment of uncomplicated Plasmodium falciparum in the sites of BUHIGA, KAZIRABAGENI and KIGOBE MUTOYI in KARUZI , MAKAMBA, BUJUMBURA MAIRIE et GITEGA provinces, respectively, BURUNDI
Scientific title
Efficacy and safety of artemisinin-based combinations: artesunate+amodiaquine and artemether+lumefantrine for the treatment of uncomplicated Plasmodium falciparum in the sites of BUHIGA, KAZIRABAGENI and KIGOBE MUTOYI in KARUZI , MAKAMBA, BUJUMBURA MAIRIE et GITEGA provinces, respectively, BURUNDI
Secondary ID [1] 289716 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 299537 0
Condition category
Condition code
Infection 299518 299518 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 artesunate+amodiaquine (artesunate 4 mg/kg body weight + amodiaquine 10mg/kg body weight once daily for 3 consecutive days) and artemether+lumefantrine (20 mg artemether and 120 mg lumefantrine in a tablet) for the treatment of uncomplicated P. falciparum infection. The doses of artemether+lumefantrine is based on weight bands: 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; once daily for 3 consecutive days.. The treatment will be taken orally under direct supervision by the health worker. These two artemisinin-based combinations will be tested separately. The patient will be given either artesunate+amodiaquine or artemether+lumefantrine. Artesunate+amodaiquine will tested in all sites while artemether+lumefantrine will evaluated in two sites. Eligible subjects will be treated for three days and followed up for 28 days.
Intervention code [1] 295349 0
Treatment: Drugs
Comparator / control treatment
Not applicable.
This is a two arm cohort prospective study for each drug (in each site patients will be enrolled for artesunate+amodiquine until the target sample size is reached and then patients will be enrolled into artemether-lumefantrine) study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298997 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This is composite primary outcome.

Enrolled patients will be assessed for parasitological (using microscopy) and clinical responses during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 298997 0
At day 28 following initiation of treatments
Secondary outcome [1] 325842 0
Percent of adverse event will be documented.
The known adverse events of:
a. artesunate+amodiaquine are abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.

b. artemether+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 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] 325842 0
At day 28 following initiation of treatments
Secondary outcome [2] 325843 0
Prevalence of artemisinin resistance molecular markers (K13).

Parasite DNA extracted from the dried blood spots will be analyzed by PCR and sequencing for the presence of K13 (molecular marker for artemisinin resistance).
Timepoint [2] 325843 0
At day 0 (prior initiation of treatment)

Eligibility
Key inclusion criteria
1. age between 6 and 120 months;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000 - 200000/mocroliter asexual forms;
4. presence of axillary temperature greater than or equal 37.5 degrees 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;
7. informed consent from the parent or guardian;
Minimum age
6 Months
Maximum age
120 Months
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 (Appendix 1);
2. weight under 5 kg;
3. mixed or mono-infection with another Plasmodium species detected by microscopy;
4. presence of severe malnutrition (defined as a child aged 6-60 months who has a mid-upper arm circumference < 115 mm);
5. 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);
6. regular medication, which may interfere with antimalarial pharmacokinetics;
7. 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 between 6 and 120 months with uncomplicated malaria who meet the study inclusion criteria will be enrolled, treated on site with artesunate+amodiaquine or artemether+lumefantrine and monitored for 28 days. The follow-up will consist of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations.

Patients will be enrolled sequentially to the two drugs: in each site patients will be enrolled for artesunate+amodiaquine until the sample size is reached and then patients will be enrolled into artemether-lumefantrine.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable.
This is a two-arm cohorts sequential prospective (in each site patients will be enrolled for artesunate+amodiaquine until the sample size is reached and then patients will be enrolled into artemether-lumefantrine) evaluation of clinical and parasitological responses to directly observed treatment.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Where the two drugs will be studied, sequential:recruitment will be used: eligible patients will be enrolled in the artesunate+amodiaquine first and when the target sample is reached, the subsequent patients will be enrolled in the artemether+lumefantrine group
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
As the treatment failure rate to artesunate+amodiaquine or artemether-lumefantrine. in the area is estimated to 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients per site will be included for each drug and per site. A total of 528 patients [352 (88 x 4 sites)] for artesunate+amodiaquine group and 176 [(88 x 2 sites)] for artemether-lumefantrine will be enrolled.
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
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
The study could not be conducted at the planned period due to civil unrest.
Date of first participant enrolment
Anticipated
29/07/2016
Actual
Date of last participant enrolment
Anticipated
28/02/2017
Actual
Date of last data collection
Anticipated
30/03/2017
Actual
Sample size
Target
528
Accrual to date
Final
Recruitment outside Australia
Country [1] 8041 0
Burundi
State/province [1] 8041 0
KARUZI , MAKAMBA, BUJUMBURA MAIRIE and GITEGA

Funding & Sponsors
Funding source category [1] 294095 0
Government body
Name [1] 294095 0
Ministry of Health of Burundi
Country [1] 294095 0
Burundi
Primary sponsor type
Government body
Name
Ministry of Health of Burundi
Address
Avenue of the Hospital, N0. 05
Bujumbura
Country
Burundi
Secondary sponsor category [1] 292927 0
None
Name [1] 292927 0
Nil
Address [1] 292927 0
Nil
Country [1] 292927 0
Other collaborator category [1] 279090 0
Other
Name [1] 279090 0
World health Organization country Office
Address [1] 279090 0
UNICEF House
3813-3817 UPRONA Boulevard
Bujumbura.
Country [1] 279090 0
Burundi

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295511 0
WHO ethics and research committee
Ethics committee address [1] 295511 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 295511 0
Switzerland
Date submitted for ethics approval [1] 295511 0
04/04/2016
Approval date [1] 295511 0
15/06/2016
Ethics approval number [1] 295511 0
ERC.0002739

Summary
Brief summary
Title: Efficacy and safety of artemisinin-based combinations: artesunate+amodiaquine and artemether+lumefantrine for the treatment of uncomplicated Plasmodium falciparum in the sites of BUHIGA, KAZIRABAGENI and KIGOBE MUTOYI in KARUZI , MAKAMBA, BUJUMBURA MAIRIE et GITEGA provinces, respectively, BURUNDI.

Purpose: To assess the efficacy and safety of the first-line and second-line treatments.

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

Study Sites: study will be conducted in 4 sites: Buhiga, Kazirabageni, Kigobe and Mutoyi located in Karuzi , Makamba, Bujumbura Mairie and Gitega provinces, respectively.

Study Period: The study will be conducted from July 2016 to March 2016.

Study Design: A one arm prospective study for each drug combination.

Patient population: Febrile patients aged between 6 months and 11 years with confirmed uncomplicated P. falciparum infection will be enrolled.

Sample Size: 88 patients per drug per site. Artesunate+amodiaquine will be tested in all the 4 sites (352 patients) while artemether+lumefantrine will be evaluated in two sites (176 patients)

Treatments and follow-up: artesunate+amodiaquine (daily dose for 3 days) and artemether+lumefantrine (twice daily for 3 days) will be given. Clinical and parasitological parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy and safety.

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. Day 3 malaria positivity rate will determined.

Secondary endpoints:
1. The frequency of adverse events.
2. Frequency of molecular markers for artemisinin resistance (K13)
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 67554 0
Dr Claudette NDAYIKUNDA
Address 67554 0
Centre Hospitalier Universitaire de KAMENGE,
Boulevard du 28 novembre
Bujumbura
Country 67554 0
Burundi
Phone 67554 0
+25777721631
Fax 67554 0
Email 67554 0
[email protected]
Contact person for public queries
Name 67555 0
Claudette NDAYIKUNDA
Address 67555 0
Centre Hospitalier Universitaire de KAMENGE,
Boulevard du 28 novembre
Bujumbura
Country 67555 0
Burundi
Phone 67555 0
+25777721631
Fax 67555 0
Email 67555 0
[email protected]
Contact person for scientific queries
Name 67556 0
Claudette NDAYIKUNDA
Address 67556 0
Centre Hospitalier Universitaire de KAMENGE,
Boulevard du 28 novembre
Bujumbura
Country 67556 0
Burundi
Phone 67556 0
+25777721631
Fax 67556 0
Email 67556 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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No documents have been uploaded by study researchers.

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