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Trial registered on ANZCTR


Registration number
ACTRN12616001451493
Ethics application status
Approved
Date submitted
5/10/2016
Date registered
17/10/2016
Date last updated
5/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated falciparum malaria in Bangui and Boali in Central African Republic
Scientific title
Efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated falciparum malaria in children in Bangui and Boali in Central African Republic
Secondary ID [1] 290276 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 300509 0
Condition category
Condition code
Infection 300366 300366 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 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 are based on weight bands: one tablet to those weighing 5 to14kg; 2 tablets for 15 to 24 kg; 3 tablets for 25 to 34 kg and 4 tablets for greater than or equal to 35 kg. The treatment will be taken orally under direct supervision by the health worker. Eligible subjects will be treated twice daily for three days and followed up for 28 days.
Intervention code [1] 296072 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299823 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 during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 299823 0
Days 1, 2, 3, 7, 14, 21 and 28 following initiation of artemether+lumefantrine treatment
Secondary outcome [1] 328201 0
Percent of adverse event will be documented.
The known adverse events of 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] 328201 0
Days 1, 2, 3, 7, 14, 21 and 28 following initiation of artemether+lumefantrine treatment
Secondary outcome [2] 328202 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] 328202 0
Day 0 (before treatment)

Eligibility
Key inclusion criteria
1. age between 6 month and 12 years;
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 cntigrade 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
12 Years
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. haemoglobin less than 8g/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 < 115 mm);
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)
Allocation is not concealed.
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
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The treatment failure rate to artemether+lumefantrine in the study areas 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 in the study. A total of 352 patients will be enrolled.
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, 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] 8295 0
Central African Republic
State/province [1] 8295 0
Bangui in Ombella-M'Poko and Boali

Funding & Sponsors
Funding source category [1] 294645 0
Government body
Name [1] 294645 0
Ministry of Health
Address [1] 294645 0
Avenue Gamal Abdel Nasser
BP: 883, Bangui

Country [1] 294645 0
Central African Republic
Primary sponsor type
Government body
Name
Ministry of Health
Address
Avenue Gamal Abdel Nasser
BP: 883, Bangui
Country
Central African Republic
Secondary sponsor category [1] 293509 0
None
Name [1] 293509 0
None
Address [1] 293509 0
None
Country [1] 293509 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296083 0
WHO Ethics Review Committee
Ethics committee address [1] 296083 0
20, AVENUE APPIA – CH-1211 GENEVA 27 – SWITZERLAND
Ethics committee country [1] 296083 0
Switzerland
Date submitted for ethics approval [1] 296083 0
14/07/2016
Approval date [1] 296083 0
30/09/2016
Ethics approval number [1] 296083 0
ERC.0002802

Summary
Brief summary
Title: Efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated Plasmodium falciparum will be evaluated.
Objective: To assess the efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated P. falciparum malaria infections in four sentinel sites.
Study Sites: study will be conducted in 4 sites: in Bangui: (i) Complex Pediatric of Bangui ; (ii) Centre de sante of Lakouanga and (iii) Centre de sante of Bede Combattant; and in Boali: (iv) Centre de sante de Boali.
Study Period: The study will be conducted from November 2016 to December 2017.
Study Design: A one arm prospective study.
Patient population: Febrile patients aged between 6 months and 12 years with confirmed uncomplicated P. falciparum infection will be enrolled.
Sample Size: 88 patients per site giving a total of 352 patients.
Treatments and follow-up: 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
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 69490 0
Dr Wilfried Sylvain NAMBEI
Address 69490 0
University of Bangui
Avenue des Martyrs, Bangui,
Country 69490 0
Central African Republic
Phone 69490 0
+23675599075
Fax 69490 0
Email 69490 0
wilfrid.nambei@gmail.com
Contact person for public queries
Name 69491 0
Dr Wilfried Sylvain NAMBEI
Address 69491 0
University of Bangui
Avenue des Martyrs, Bangui,
Country 69491 0
Central African Republic
Phone 69491 0
+23675599075
Fax 69491 0
Email 69491 0
wilfrid.nambei@gmail.com
Contact person for scientific queries
Name 69492 0
Dr Wilfried Sylvain NAMBEI
Address 69492 0
University of Bangui
Avenue des Martyrs, Bangui,
Country 69492 0
Central African Republic
Phone 69492 0
+23675599075
Fax 69492 0
Email 69492 0
wilfrid.nambei@gmail.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary