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Trial registered on ANZCTR


Registration number
ACTRN12622001476729
Ethics application status
Approved
Date submitted
14/10/2022
Date registered
23/11/2022
Date last updated
23/11/2022
Date data sharing statement initially provided
23/11/2022
Date results information initially provided
23/11/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine among children 6 to 59 months for the treatment of uncomplicated Plasmodium falciparum in Chad
Scientific title
Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine among children 6 to 59 months for the treatment of uncomplicated Plasmodium falciparum in Chad
Secondary ID [1] 308165 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 327886 0
Condition category
Condition code
Infection 324972 324972 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This was one arm prospective study to assess the efficacy and safety of artesunate-amodiaquine or artemether-lumefantrine. For the artesunate-amodiaquine treated patients, a daily dose of approximately artesunate 4 mg/kg and amodiaquine 10mg/kg was given for 3 consecutive days. Artemether-lumefantrine tablets (containing 20 mg artemether+ 120 mg lumefantrine in each tablet) was 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 were 5-24 mg/kg body weight (bw)of artemether and 29-144 mg/kg bw of lumefantrine.
Patients will be sequentially enrolled: first to artesunate-amodiaquine until a sample of 90 participants is reached (30 patients per site). Then the subsequent patients will be enrolled to artemether-lumefantrine until the target sample of 90 patients (30 patients per site) is reached. All treatments was given orally under direct supervision by the health worker and patients were followed up for 28 days.
Intervention code [1] 324611 0
Treatment: Drugs
Comparator / control treatment
No control group.
The efficacy and safety of artesunate-amodiaquine (recommended first-line treatment) and artemether-lumefantrine (recommended second-line treatment) for Chad were assessed sequentially in each site. Sequential enrolment was used where patients were enrolled first in artesunate-amodiaquine and when the target sample is reached, the subsequent patients were treated with artemether-lumefantrine. The treatment outcomes of each drug was assessed separately.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332773 0
Proportion of treatment failures (early treatment failure + late clinical failure+late parasitological failure). This is a composite primary outcome.

Enrolled patients were monitored for clinical and parasitological (using microscopy) responses. Treatment outcomes was classified according to the latest WHO protocol.
Timepoint [1] 332773 0
Days 0 (prior to treatment), 1, 2 (during treatment),3, 7, 14, 21, 28 (post-treatment)
Secondary outcome [1] 414669 0
Proportion of adverse event following treatment of artesunate-amodiaquine or artemether-lumefantrine

The known adverse events of atemether-lumefantrine are abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting. The known adverse events of artesunate-amodiaquine are Abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.

Care takers of children were asked on each visit about previous symptoms that have emerged since the previous follow-up visit. When clinically indicated, patients were evaluated and treated appropriately. All adverse events were recorded on the case report form.
Timepoint [1] 414669 0
Days 0 (pre-treatment, 1, 2 (during treatment), 3, 7, 14, 21, 28 (post-treatment)
Secondary outcome [2] 414670 0
Prevalence of mutations in k13 gene associated with partial artemisinin resistance.

Parasite DNA extracted from dried blood spots was analyzed by PCR and sequenced for the presence of mutations in k13 gene (molecular marker for artemisinin resistance)
Timepoint [2] 414670 0
Day 0 (before treatment)
Secondary outcome [3] 414671 0
Prevalence of mdr-1 gene mutation suspected to be associated with lumefantrine and amodiaquine resistance.

Parasite DNA extracted from dried blood spots was analyzed by PCR for mutations in mdr-1 gene.
Timepoint [3] 414671 0
Day 0 (before treatment)
Secondary outcome [4] 414672 0
Prevalence of P. falciparum art gene mutation suspected to be associated with amodiaquine resistance.

Parasite DNA extracted from dried blood spots was analyzed by PCR for art gene mutations.
Timepoint [4] 414672 0
Day 0 (before treatment)
Secondary outcome [5] 415586 0
Prevalence of crt gene mutation suspected to be associated with amodiaquine resistance.

Parasite DNA extracted from dried blood spots was analyzed by PCR for mutations in crt gene.
Timepoint [5] 415586 0
Day 0 (prior to treatment)
Secondary outcome [6] 415587 0
Prevalence of mutations in dhfr and dhps genes linked to sulfadoxine/pyrimethamine resistance.. This is a composite primary outcome.

Parasite DNA extracted from dried blood spots was analyzed by PCR for mutations in dhfr and dhps genes.
Timepoint [6] 415587 0
Day 0 (before treatment)

Eligibility
Key inclusion criteria
• age from six to 59 months
• mono-infection with P. falciparum confirmed by positive blood smear (i.e. no mixed infection);
• parasitaemia of 1000–200,000 per micrometer asexual forms;
• Presence of axillary or tympanic temperature greater or equal to 37.5 degrees centigrade or history of fever during the past 24 h;;
• ability to swallow oral medication;
• ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule;
• informed consent from parent or guardian.
Minimum age
6 Months
Maximum age
59 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• presence of general danger signs in children aged between 6 to 59 months or signs of severe falciparum malaria according to the definitions of WHO.
• weight under 5 kg;
• haemoglobin below 8 g per dl;
• mixed or mono-infection with another Plasmodium species detected by microscopy;
• presence of severe malnutrition defined as a child who has symmetrical oedema involving at least the feet or has a mid-upper arm circumference below 110 mm in children greater.
• 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);
• regular medication, which may interfere with antimalarial pharmacokinetics;
• 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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Sequential recruitment was done, where patients were enrolled in the artemether-lumefantrin group first until the target sample was reached. The subsequent patients were enrolled in artesunate-amodiaquine group until the target sample was reached. The target sample was 90 patients per drug for the three sites (30 patients per site).
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data was double entered by two independent data clerks using WHO database Excel programme, Data was analysed by both Kaplan-Meier and per-protocol methods. In addition to the reasons for withdrawal, patients were censored or excluded from the analysis if they were withdrawn or lost to follow-up or PCR results were 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:
• a description of all patients screened and the distribution of reasons for non-inclusion in the study;
• a description of all the patients included in the study;
• the proportion of adverse events and serious adverse events in all the patients included in the study;
• the proportion of patients lost to follow-up or withdrawn, with 95% confidence intervals and a list of reasons for withdrawal;
• the cumulative incidence of success and failure rates at day 28, PCR-uncorrected and PCR-corrected; and
• 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
2/11/2020
Date of last participant enrolment
Anticipated
Actual
21/01/2021
Date of last data collection
Anticipated
Actual
20/02/2021
Sample size
Target
180
Accrual to date
Final
215
Recruitment outside Australia
Country [1] 25058 0
Chad
State/province [1] 25058 0
Logone Oriental, Mayo Kebbi Est, Tandjilé

Funding & Sponsors
Funding source category [1] 312424 0
Government body
Name [1] 312424 0
Ministry of Public Health
Country [1] 312424 0
Chad
Primary sponsor type
Government body
Name
Ministry of Public Health
Address
Avenue Sahoulba Gontchomé
BP 440 N'Djaména
Country
Chad
Secondary sponsor category [1] 313996 0
None
Name [1] 313996 0
Address [1] 313996 0
Country [1] 313996 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311769 0
World Health Organization Research Ethics Review Committee
Ethics committee address [1] 311769 0
Avenue Appia 20, 1211 Geneva
Ethics committee country [1] 311769 0
Switzerland
Date submitted for ethics approval [1] 311769 0
15/05/2020
Approval date [1] 311769 0
16/06/2020
Ethics approval number [1] 311769 0
ERC_0005167

Summary
Brief summary
Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria infections in children aged 6 to 59 months in Chad. Artemether-lumefantrine or artesunate-amodiaquine was given under direct supervision and clinical and parasitological parameters were monitored for 28 days to establish proportion of patients with PCR corrected treatment failure and frequency of adverse events. Mutations in K13, mdr1, crt, dhfr an dhps genes were investigated on day 0 samples.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122302 0
Dr Issa Mahamat Souleymane
Address 122302 0
National Malaria Programme,
Avenue Sahoulba Gontchomé
P.O. Box 440 N'Djaména
Country 122302 0
Chad
Phone 122302 0
+23593371937
Fax 122302 0
Email 122302 0
issa.mahamatsoul@gmail.com
Contact person for public queries
Name 122303 0
Dr Issa Mahamat Souleymane
Address 122303 0
National Malaria Programme,
Avenue Sahoulba Gontchomé
P.O. Box 440 N'Djaména
Country 122303 0
Chad
Phone 122303 0
+23593371937
Fax 122303 0
Email 122303 0
issa.mahamatsoul@gmail.com
Contact person for scientific queries
Name 122304 0
Dr Marian Warsame
Address 122304 0
School of Public Health and Community Medicine
Medicinaregatan 18A
41390 Göteborg
Sweden
Country 122304 0
Chad
Phone 122304 0
+46760525254
Fax 122304 0
Email 122304 0
marian.warsame@gu.se

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
Dimensions AITherapeutic efficacy of artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Chad: clinical and genetic surveillance2023https://doi.org/10.1186/s12936-023-04644-w
N.B. These documents automatically identified may not have been verified by the study sponsor.