The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12616001600437
Ethics application status
Approved
Date submitted
5/11/2016
Date registered
18/11/2016
Date last updated
6/03/2020
Date data sharing statement initially provided
6/03/2020
Date results information initially provided
6/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated Palsmodium falciparum malaria in Lambarene, Gabon
Scientific title
Efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated Palsmodium falciparum malaria in Lambarene, Gabon
Secondary ID [1] 290470 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 300837 0
Condition category
Condition code
Infection 300663 300663 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 (given twice a day for 3 days) and artesunate-amodiaquine (given daily for 3 days) for the treatment of uncomplicated P. falciparum infection. Doses of artemether-lumefantrine (20/120) will be administered according to the recommended weight bands as follows: 1 tablet to those weighing 5 to 14kg; 2 tablets for 15 to 24 kg;3 tablets for 25 to34 kg and 4 tablets for equal or greater than 35 kg. For the artesunate-amodiaquine, 4 mg/kg artesunate and 10 mg/kg amodiaquine will be give daily. The treatment will be given in tablets by oral under direct supervision. Eligible subjects will be treated for three days and followed up for 28 days.
Intervention code [1] 296322 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300084 0
Percentage 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 WHO protocol 2009.
Timepoint [1] 300084 0
Primary outcome (treatment failures) will be assessed on Days 1, 3, 7, 14, 21, 28 following initiation of treatment.
Secondary outcome [1] 328986 0
Percentage of adverse event will be documented.

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.
Known adverse events for artesunate-amodiaquine include abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting

Patients or parents/guardians of children enrolled in the study 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] 328986 0
Secondary outcome (adverse events) will be assessed on Days 1, 2, 3, 7, 14, 21, 28 following initiation of treatment.
Secondary outcome [2] 328987 0
Prevalence of artemisinin resistance molecular markers (K13) among the study patients.

Parasite DNA extracted from the dried blood spots will be analyzed by PCR and sequencing for the presence of mutations of K13 (molecular marker for artemisinin resistance).
Timepoint [2] 328987 0
Day 0 (prior of treatment)

Eligibility
Key inclusion criteria
1. age 6 months to 12 years old
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000–100,000/microliter asexual forms;
4. presence of axillary temperature greater than or equal 37.5 degrees 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 the patient or from a 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 below 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 symmetrical oedema involving at least the).
6. presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea 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)
This a single arm study, no concealment.
Patients aged between 6 month and 12 years with uncomplicated falciparum malaria, who meet the study inclusion criteria will be enrolled, treated on site with either artemether-lumefantrine or artesunate-amodiaquine and monitored for 28 days. 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)
NA
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: they will enrolled first in the artesunate+amodiaquine until the sample size is reached and subsequent patients will be enrolled in the artemether+lumefantrine.
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
As the treatment failure rate to artemether+lumefantrine and artesunate+amodiaquine in the area is 5%. At a confidence level of 95% and a precision around the estimate of 10%, a minimum of 50 patients must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 60 patients per test drug will be included in the study.
Analysis of data
The WHO Excel software programs last version 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] 8373 0
Gabon
State/province [1] 8373 0
Moyan-Ogooue

Funding & Sponsors
Funding source category [1] 294883 0
Government body
Name [1] 294883 0
Ministry of Health and Population Gabon
Address [1] 294883 0
c/o Monsieur le Representant de l'OMS
Boite postale 820
Libreville
Gabon
Country [1] 294883 0
Gabon
Primary sponsor type
Government body
Name
Ministry of Health and Population Gabon
Address
c/o Monsieur le Representant de l'OMS
Boite postale 820
Libreville
Gabon
Country
Gabon
Secondary sponsor category [1] 293721 0
None
Name [1] 293721 0
Nil
Address [1] 293721 0
Nil
Country [1] 293721 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296261 0
Approved by WHO ERC
Ethics committee address [1] 296261 0
20 Av. Appia,
1211 Geneva 27
Ethics committee country [1] 296261 0
Switzerland
Date submitted for ethics approval [1] 296261 0
03/11/2016
Approval date [1] 296261 0
17/03/2017
Ethics approval number [1] 296261 0
ERC.0002834

Summary
Brief summary
Title: Efficacy and safety of artesunate+amodiaquine and artemether+lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Lambarene Gabon.
Purpose: To assess the efficacy and safety of the first-line and second-line treatments for uncomplicated malaria.
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 Lambarene in Gabon.
Study Period: The study will be conducted from December 2016 to July 2017.
Study Design: A one arm prospective study for each drug combination. The patients will be assigned to the drugs sequentially.
Patient population: Febrile patients aged 6 months to 12 years with confirmed uncomplicated P. falciparum infection will be enrolled.
Sample Size: 60 patients per drug.
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
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70182 0
Dr Adegnika Ayola Akim
Address 70182 0
Centre de Recherches Medicale de Lambarene
Fondation Internationale de l’Hopital Albert Schweitzer
B.P : 118 Lambarene
Country 70182 0
Gabon
Phone 70182 0
+24107406464
Fax 70182 0
Email 70182 0
aadegnika@gmail.com
Contact person for public queries
Name 70183 0
Dr Adegnika Ayola Akim
Address 70183 0
Centre de Recherches Medicale de Lambarene
Fondation Internationale de l’Hopital Albert Schweitzer
B.P : 118 Lambarene
Country 70183 0
Gabon
Phone 70183 0
+24107406464
Fax 70183 0
Email 70183 0
aadegnika@gmail.com
Contact person for scientific queries
Name 70184 0
Dr Adegnika Ayola Akim
Address 70184 0
Centre de Recherches Medicale de Lambarene
Fondation Internationale de l’Hopital Albert Schweitzer
B.P : 118 Lambarene
Country 70184 0
Gabon
Phone 70184 0
+24107406464
Fax 70184 0
Email 70184 0
aadegnika@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?
Yes
Journal publication details
Publication date and citation/details [1] 7261 0
Adegbite et al. Monitoring of efficacy, tolerability and safety of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Lambaréné, Gabon: an open-label clinical trial. Malar J. 2019 Dec 16;18(1):424. doi: 10.1186/s12936-019-3015-4.
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary