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Trial registered on ANZCTR


Registration number
ACTRN12617001064392
Ethics application status
Approved
Date submitted
27/06/2017
Date registered
21/07/2017
Date last updated
5/11/2019
Date data sharing statement initially provided
5/11/2019
Date results information initially provided
5/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of Artesunate+Amodiaquine and Artemether+Lumefatrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Saclepea-Mahn Comprehensive Health Center (Saclepea-Mahn District, Nimba County), Rennie Hospital (Kakata District, Margibi County) and Sinje Health Center (Garwula District, Cape Mount County and Bensonville Hospital-Montserrado County) in Liberia
Scientific title
Efficacy and safety of Artesunate+Amodiaquine and Artemether+Lumefatrine for the treatment of uncomplicated Plasmodium falciparum in children malaria in Saclepea-Mahn Comprehensive Health Center (Saclepea-Mahn District, Nimba County), Rennie Hospital (Kakata District, Margibi County) and Sinje Health Center (Garwula District, Cape Mount County and Bensonville Hospital-Montserrado County) in Liberia
Secondary ID [1] 292276 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 303796 0
Condition category
Condition code
Infection 303165 303165 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The aim of the study is to evaluates the efficacy and safety of artesunate+amodiaquine and artemether+lumefantrine with the following dosages:
Artesunate-amodiaquine: 4 mg/kg artesunate + 10mg/kg amodiaquine once daily for 3 consecutive days will be given.
Artemether-lumefantrine containing 20 mg artemether+ 120 mg lumefantrine in each tablet will be given twice daily for three days according to the recommended weight bands as follows: 1 tablet 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. The two drugs will be tested sequentially. The patient will be given artesunate+amodiaquine or artemether+lumefantrine and will be followed up for 28 days.
Intervention code [1] 298451 0
Treatment: Drugs
Comparator / control treatment
No control group.
The study is one arm cohort prospective assessment for each drug.
Patients in each site will be enrolled first to artesunate+amodiaquine untill a sample of 88 is reached. Then the subsequent patients will be recruited to the artemether+lumefantrine untill the target sample size of 88 is reached.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302536 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 and clinical responses during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 302536 0
On days 0,1,2,3,7,14,21 and 28
Secondary outcome [1] 336329 0
Percent of adverse event following treatment of each drugs will be documented.
The known adverse events of:
Artesunate+amodiaquine are abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.
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 on each visit 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] 336329 0
Days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 336330 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] 336330 0
On day 0 (prior to treatment)

Eligibility
Key inclusion criteria
1. age 6-59 months;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 2000–200000/µl asexual forms;
4. presence of axillary or tympanic temperature greater 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;
7. informed consent from a parent or guardian of children aged 6-59 months;
8. Patients living within 5 km radius of the health facility
Minimum age
6 Months
Maximum age
59 Months
Gender
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. Mixed or mono-infection with another Plasmodium species detected by microscopy;
4. Presence of severe malnutrition defined as a child aged 6-59 months whose mid-upper arm circumference less than 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)
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
Other
Other design features
Patients will be enrolled sequentially to the two drugs. Patients will be recruited to the artesunate+amodiaquine until the target sample size (n=88) is achieved. The subsequent patients will be enrolled in the artemether+lumefantrine until 88.
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample size
As the treatment failure rate to ASAQ and AL is assumed 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients per drug per site must be enrolled in the study. With an additional 20% to allow for lost to follow-up and withdrawal during the 28-day follow-up period, 88 patients per site should be enrolled in the study.

Analysis of data
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. 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
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] 9014 0
Liberia
State/province [1] 9014 0
Nimba, Margibi and Cape Mount Counties

Funding & Sponsors
Funding source category [1] 296820 0
Government body
Name [1] 296820 0
Ministry of Health of Liberia
Address [1] 296820 0
Congo Town,Tubman Blvd
Monrovia, Liberia.
Country [1] 296820 0
Liberia
Primary sponsor type
Government body
Name
Ministry of Health of Liberia
Address
Congo Town,Tubman Blvd
Monrovia, Liberia.
Country
Liberia
Secondary sponsor category [1] 295809 0
None
Name [1] 295809 0
None
Address [1] 295809 0
None
Country [1] 295809 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298055 0
WHO ERC
Ethics committee address [1] 298055 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 298055 0
Switzerland
Date submitted for ethics approval [1] 298055 0
29/03/2017
Approval date [1] 298055 0
16/06/2017
Ethics approval number [1] 298055 0
ERC.0002892

Summary
Brief summary
Title: Efficacy and safety of Artesunate +Amodiaquine and Artemether+Lumefatrine for the treatment of uncomplicated Plasmodium falciparum malaria in Saclepea-Mah Comprehensive Health Center (Saclepea-Mah District, Nimba County), Rennie Hospital (Kakata District, Margibi County) and Sinje Health Center (Garwula District, Cape Mount County) in Liberia.
Purpose: To assess the efficacy of the current first and/or second line treatment policy.
Objective: To assess the efficacy and safety of Artesunate +Amodiaquine and Artemether+Lumefatrine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Saclepea-Mah District in Nimba County, Kakata District in Margibi County and Garwula District, Cape Mount County.
Study Period: September 2017 to June 2018
Study Design: Two cohorts prospective study in sequential enrollments.
Patient population: Febrile patients aged 6 to 59 months with confirmed uncomplicated P. falciparum infection.
Sample Size: 88 patients per site for each drug.
Treatment(s) and follow-up: Artesunate+Amodiaquine (ASAQ) daily dose for three days and Artemether+Lumefatrine (AL) twice daily dose for three days will be administered. Clinical and parasitological parameters will be monitored over a 28-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
Exploratory endpoint: to determine the polymorphism of molecular markers for lumefantrine and artemisinin resistance.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 75838 0
Dr Benjamin Vonhm
Address 75838 0
Ministry of Health – Liberia
Congo Town,Tubman Blvd
Monrovia, Liberia.
Country 75838 0
Liberia
Phone 75838 0
+231777551561
Fax 75838 0
Email 75838 0
btvonhm@gmail.com
Contact person for public queries
Name 75839 0
Dr Benjamin Vonhm
Address 75839 0
Ministry of Health – Liberia
Congo Town,Tubman Blvd
Monrovia, Liberia.
Country 75839 0
Liberia
Phone 75839 0
+231777551561
Fax 75839 0
Email 75839 0
btvonhm@gmail.com
Contact person for scientific queries
Name 75840 0
Dr Benjamin Vonhm
Address 75840 0
Ministry of Health – Liberia
Congo Town,Tubman Blvd
Monrovia, Liberia.
Country 75840 0
Liberia
Phone 75840 0
+231777551561
Fax 75840 0
Email 75840 0
btvonhm@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary