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Trial registered on ANZCTR


Registration number
ACTRN12622001243707
Ethics application status
Approved
Date submitted
18/08/2022
Date registered
14/09/2022
Date last updated
14/09/2022
Date data sharing statement initially provided
14/09/2022
Date results information initially provided
14/09/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether- lumefantrine and artesunate - amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mainland Tanzania
Scientific title
Efficacy and safety of artemether- lumefantrine and artesunate - amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mainland Tanzania
Secondary ID [1] 307659 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 327176 0
Condition category
Condition code
Infection 324312 324312 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
It is a one arm prospective study to assess the efficacy and safety of artemether-lumefantrine or artesunate-amodiaquine. Artemether-lumefantrine tablets (containing 20 mg artemether+ 120 mg lumefantrine in each tablet) is being 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. Artesunate-amodiaquine is being given a daily dose of approximately artesunate 4 mg/kg and amodiaquine 10mg/kg for 3 consecutive days will be administered. All treatments was given orally under direct supervision by the health worker. The patients were followed up for 28 days.

Patients will be sequentially enrolled: first to artemether-lumefantrine until a sample of 88 is reached. Then the subsequent patients will be enrolled to the Artesunate-amodiaquine until the target sample of 88 patients is reached.
Intervention code [1] 324118 0
Treatment: Drugs
Comparator / control treatment
No control group.
The efficacy and safety of artemether-lumefantrine (recommended first-line treatment for the Mainland Tanzania) and artesunate-amodiaquine (recommended first-line treatment for Island Zanzibar) will be assessed separately.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332118 0
Percent of treatment failures (early treatment failure + late clinical failure+late parasitological failure). This is a composite primary outcome.

Enrolled patients was monitored for parasitological (using microscopy) and clinical responses. Treatment outcomes was classified according to the latest WHO protocol.
Timepoint [1] 332118 0
Days 0 (before treatment), 1, 2 (during treatment),3, 7, 14, 21, 28 (post-treatment)
Secondary outcome [1] 412292 0
Percent of adverse event following treatment of artemether-lumefantrine will be investigated.

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.

Patients or care takers of children was asked on each visit about previous symptoms that have emerged since the previous follow-up visit. When clinically indicated, patients was evaluated and treated appropriately. All adverse events was recorded on the case report form.
Timepoint [1] 412292 0
Days 0 (pre-treatment, 1, 2 (during treatment), 3, 7, 14, 21, 28 (post-treatment)
Secondary outcome [2] 412293 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] 412293 0
Day 0 (before treatment)
Secondary outcome [3] 412294 0
Prevalence of amplification in mdr-1 gene associated with mefloquine resistance.
Parasite DNA extracted from dried blood spots will be analyzed by PCR for copy number variations in mdr-1 gene.
Timepoint [3] 412294 0
Day 0 (before treatment)
Secondary outcome [4] 413109 0
Parasite clearance rates
Thick and thin blood smears will be taken from study subject through finger prick every 8hrs over the first 72 hours post-treatment, Giemsa stained and examined for the presence of parasites using microscopy.
Timepoint [4] 413109 0
Day 0 (before treatment) and every 8 hours over the first 72 hours pos-treatment
Secondary outcome [5] 413110 0
prevalence of histidine rich protein 2 and 3 (hrp2/3) gene deletion

Suspected malaria cases are systematically tested using HRP2 malaria Rapid Diagnostic Test (mRDT) and a confirmatory test (microscopy) to estimate the frequency of suspected false-negative HRP2 mRDT results in symptomatic patients with P. falciparum malaria. In addition, dried blood spots (DBS) will be collected on a filter paper to perform molecular testing on the DBS of presumptive false-negative HRP2 mRDT results to determine the prevalence of pfhrp2/3 gene deletions in the HRP2 mRDT cohort with false-negative results and in the cohort of all symptomatic, confirmed P. falciparum cases. From DBS, ultrasensitive HRP2, Aldose and pLDH detection by multiplex bead immunoassay will be done and used to support genotyping results and particularly to resolve discordance between mRDT and PCR results.
Timepoint [5] 413110 0
Day 0 (before treatment)

Eligibility
Key inclusion criteria
• age from six months to 10 years
• malaria Rapid Diagnostic Test (mRDT) positive
• mono-infection with P. falciparum confirmed by positive blood smear (i.e. no mixed infection);
• parasitaemia of 500–200,000 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
10 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• presence of general danger signs in children aged between 6 months and 10 years or signs of severe falciparum malaria according to the definitions of WHO (Appendix 1);
• mRDT negative results
• 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 or equal 59 months; or BMI of below 16 in children aged 5 years and above)
• 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
Sequentional recruitment will be done, where patients will be enrolled in the artemether-lumefantrin group first until the target sample of 88 is reached. The subsequent patients will be enrolled in artesunate-amodiaquine group until the target sample of 88 is reached.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Minimum sample size
As the treatment failure rate to AL or ASAQ in the area is estimated to 5%, and at a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be included for each drug. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients will be included in the study per drug.

Analysis of data
Data entry will be done using a Microsoft Access database by two independent data clerks, which will be followed by validation and cleaning before analysis. The WHO excel software/Microsoft access database 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 censored or excluded 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:
• 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
1/05/2022
Date of last participant enrolment
Anticipated
Actual
4/08/2022
Date of last data collection
Anticipated
Actual
1/09/2022
Sample size
Target
176
Accrual to date
Final
176
Recruitment outside Australia
Country [1] 24963 0
Tanzania, United Republic Of
State/province [1] 24963 0
Kagera region

Funding & Sponsors
Funding source category [1] 311921 0
Government body
Name [1] 311921 0
National Institute for Medical Research
Country [1] 311921 0
Tanzania, United Republic Of
Primary sponsor type
Government body
Name
National Institute for Medical Research
Address
3 Barack Obama Drive, 11101 Dar es Salaam
Country
Tanzania, United Republic Of
Secondary sponsor category [1] 313404 0
None
Name [1] 313404 0
Address [1] 313404 0
Country [1] 313404 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311355 0
Tanzania Medical Research Coordinating Committee (MRCC).
Ethics committee address [1] 311355 0
3 Barack Obama Drive, 11101 Dar es Salaam
Ethics committee country [1] 311355 0
Tanzania, United Republic Of
Date submitted for ethics approval [1] 311355 0
10/09/2021
Approval date [1] 311355 0
29/11/2021
Ethics approval number [1] 311355 0
NIMR/HQ/R.8a/Vol.IX/3778

Summary
Brief summary
Febrile children aged 6 months to 10 years were recruited to evaluate the efficaxy and safety of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated P. falciparum malaria infections in Tanzania. Artemether-lumefantrine or artesunate-amodiaquine was given under direct supervision and clinical and parasitological parameters were monitored for 28 days follow-up to establish proportion of patients with PCR corrected treatment failure and frequency of adverse events. Polymorphism of molecular markers for artemisinin and partner drug resistance resistance as well hrp2/3 deletion were investigated on day 0 samples.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120826 0
Dr Deusdedith S. Ishengoma
Address 120826 0
National Institute for Medical Research
Address: 3 Barack Obama Drive, 11101 Dar es Salaam
Country 120826 0
Tanzania, United Republic Of
Phone 120826 0
+255754528891
Fax 120826 0
7496668572
Email 120826 0
deusdedith.ishengoma@nimr.or.tz
Contact person for public queries
Name 120827 0
Dr Deusdedith S. Ishengoma
Address 120827 0
National Institute for Medical Research
Address: 3 Barack Obama Drive, 11101 Dar es Salaam
Country 120827 0
Tanzania, United Republic Of
Phone 120827 0
+255754528891
Fax 120827 0
7496668572
Email 120827 0
deusdedith.ishengoma@nimr.or.tz
Contact person for scientific queries
Name 120828 0
Dr Marian Warsame
Address 120828 0
School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg
Box 463, 405 30 Göteborg, Sweden
Country 120828 0
Sweden
Phone 120828 0
+46760525254
Fax 120828 0
Email 120828 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
No additional documents have been identified.