Trial Review

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
ACTRN12616001422415
Ethics application status
Approved
Date submitted
27/08/2016
Date registered
12/10/2016
Date last updated
5/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum in Dolisie, Republic of Congo
Scientific title
Efficacy and safety of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum in Dolisie, Republic of Congo
Secondary ID [1] 290033 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 300075 0
Condition category
Condition code
Infection 299957 299957 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The efficacy and safety of artemether-lumefantrine (twice daily doses for 3 days) and artesunate-amodiaquine (one daily dose for 3 days) for the treatment of uncomplicated P. falciparum malaria will be evaluated. For artemether-lumefantrine, each tablet contains 20 mg artemether and 120 mg lumefantrine, A total target dose ranges 5-24 mg/kg bw of artemether and 29-144 mg/kg bw of lumefantrine. Artemether+lumefantrine will be given by weight bands: 1 tablet for children 5 to less than 15kg, 2 tablets per dose for children 15 to less than 25kg, 3 tablets for children 25 to less than 35 kg. For artesunate+amodiaquine treatment, a daily dose of 4 mg of artesunate/kg body weight and 10 mg of amodiaquine base/kg body weight will be given. The treatment will be given orally in tablets. Eligible children will be treated for three days and followed up for 28 days. The daily doses of the study medicines will be administered under direct supervision by the study team.

Patients will be enrolled sequentially. The first cohort of recruited patients will be treated with artesunate+amodiaquine. When 88 patients have been enrolled and treated with artesunate+amodiaquine, the recruitment of the second cohort will begin; patients in the second cohort will be treated with artemether+lumefantrine and recruitment will continue until the target number of patients was reached.
Intervention code [1] 295756 0
Treatment: Drugs
Comparator / control treatment
There is no comparison. Each drug will be studied separately in a cohort of patients. So for each drug it is one arm prospective study design
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299443 0
Percent of treatment failures (early treatment failure + late clinical failure + late parasitological failure). This is a composite primary outcome.

Enrolled children will be evaluated for parasitological (using microscopy) and clinical responses. Treatment outcomes will be classified according to the WHO protocol 2009
Timepoint [1] 299443 0
Primary outcome (treatment failures) will be assessed on days 1, 3, 7, 14, 21 and 28 following treatment of artesunate+amodiaquin or artemether+lumefantrine
Secondary outcome [1] 327158 0
Percent of adverse events

Known adverse events of the study drugs are:

1. Artemether-lumefantrine: Abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.
2.Artesunate-amodiaquine: abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.

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 assessed and treated appropriately. All adverse events will be recorded on the case report form.
Timepoint [1] 327158 0
Secondary outcome (adverse events) will be assessed on days days 1, 3, 7, 14, 21 and 28 following treatment of artesunate+amodiaquin or artemether+lumefantrine
Secondary outcome [2] 328185 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] 328185 0
At day 0 (prior initiation of treatments)

Eligibility
Key inclusion criteria
1. age between 6 months and 11 years.
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000–200000/microliter asexual forms;
4. presence of axillary temperature equal to or greater than 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 parent of children
Minimum age
6 Months
Maximum age
11 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 (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)
Allocation concealment. is not applicable as this is a single arm study,
Patients aged between 6 month and 11 years with uncomplicated falciparum malaria who meet the study inclusion criteria will be recruited and treated on site with artemether-lumefantrine or artesunate-amodiaquine. Patients will enrolled sequentially: patients will be enrolled first in the artesunate-amodiaquine study and when the sample size of 88 is reached, the subsequent patients will be enrolled in the artemether/lumefantrine arm. Patient will be monitored for 28 days at 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)
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 artesunate+amodiaquine, and artemether-lumefantrine in the study 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 the28/42-day follow-up period, 88 patients per per drug will be included in the study.

The WHO excel software programs will be used for data double entry and analysis. Data will be analysed using Kaplan-Meier method and per-protocol analysis. In addition to the other 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.

Guidelines on calculating the cumulative success or failure rate, the proportion of adequate clinical and parasitological response and treatment failure are given in the WHO protocol 2009.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/10/2016
Actual
17/01/2017
Date of last participant enrolment
Anticipated
30/11/2016
Actual
14/03/2017
Date of last data collection
Anticipated
30/12/2016
Actual
14/04/2017
Sample size
Target
176
Accrual to date
Final
121
Recruitment outside Australia
Country [1] 8146 0
Congo
State/province [1] 8146 0
Niari

Funding & Sponsors
Funding source category [1] 294399 0
Government body
Name [1] 294399 0
Ministry of Health and Population of Congo
Country [1] 294399 0
Congo
Primary sponsor type
Government body
Name
Ministry of Health and Population
Address
Rue Lucien Fourneau 9, Centre-ville, BP 2101, Brazzaville
Country
Congo
Secondary sponsor category [1] 293247 0
None
Name [1] 293247 0
Nil
Address [1] 293247 0
Nil
Country [1] 293247 0
Other collaborator category [1] 279182 0
Other Collaborative groups
Name [1] 279182 0
Institute Pasteur du Cambodge, Phnom Penh
Address [1] 279182 0
5 Blvd Monivong, BP 983
Phnom Penh
Country [1] 279182 0
Cambodia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295822 0
WHO ethics and research committee
Ethics committee address [1] 295822 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 295822 0
Switzerland
Date submitted for ethics approval [1] 295822 0
09/06/2016
Approval date [1] 295822 0
23/08/2016
Ethics approval number [1] 295822 0
ERC.0002769

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

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

Study Sites: study will be conducted in two public health facilities in Dolisie.

Study Period: The study period will cover October to December 2016.

Study Design: Single arm prospective study for each drug.

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

Sample Size: 88 patients will be enrolled in each treatment arm.

Treatments and follow-up: artemether-lumefantrine (twice daily doses for 3 days) and artesunate-amodiaquine (daily dose for 3 days) will be given under direct supervision. 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 68610 0
Dr Mathieu Ndounga
Address 68610 0
Programme National de Lutte contre le Paludisme (PNLP)
Rue Lucien Fourneau 9, Centre ville, BP 2101, Brazzaville
Country 68610 0
Congo
Phone 68610 0
+242 05 526 05 03
Fax 68610 0
Email 68610 0
[email protected]
Contact person for public queries
Name 68611 0
Dr Mathieu Ndounga
Address 68611 0
Programme National de Lutte contre le Paludisme (PNLP)
Rue Lucien Fourneau 9, Centre ville, BP 2101, Brazzaville
Country 68611 0
Congo
Phone 68611 0
+242 05 526 05 03
Fax 68611 0
Email 68611 0
[email protected]
Contact person for scientific queries
Name 68612 0
Dr Mathieu Ndounga
Address 68612 0
Programme National de Lutte contre le Paludisme (PNLP)
Rue Lucien Fourneau 9, Centre ville, BP 2101, Brazzaville
Country 68612 0
Congo
Phone 68612 0
+242 05 526 05 03
Fax 68612 0
Email 68612 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

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePrevalence of malaria among febrile patients and assessment of efficacy of artemether-lumefantrine and artesunate-amodiaquine for uncomplicated malaria in Dolisie, Republic of the Congo.2022https://dx.doi.org/10.1186/s12936-022-04143-4
N.B. These documents automatically identified may not have been verified by the study sponsor.