Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000930785
Ethics application status
Approved
Date submitted
27/05/2022
Date registered
29/06/2022
Date last updated
29/06/2022
Date data sharing statement initially provided
29/06/2022
Date results information initially provided
29/06/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of Artemether-Lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel site in Sudan
Scientific title
Efficacy and safety of Artemether-Lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel site in Sudan
Secondary ID [1] 307225 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Malaria 326470 0
Condition category
Condition code
Infection 323744 323744 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This was a one arm prospective study to assess the efficacy and safety of artemether-lumefantrine (containing 20 mg artemether+ 120 mg lumefantrine in each tablet) 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. All treatments was given orally under direct supervision by the health worker. The patients were followed up for 28 days
Intervention code [1] 323668 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331488 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] 331488 0
Days 0 (before treatment), 1, 2 (during treatment),3, 7, 14, 21, 28 (post-treatment)
Secondary outcome [1] 410109 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] 410109 0
Days 0 (pre-treatment, 1, 2 (during treatment), 3, 7, 14, 21, 28 (post-treatment).
Secondary outcome [2] 410110 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] 410110 0
Day 0 (before treatment)
Secondary outcome [3] 410111 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] 410111 0
Day 0 (before treatment)
Secondary outcome [4] 411077 0
Prevalence of amplifications in plasmepsin 2 gene associated with piperaquine

Parasite DNA extracted from dried blood spots will be analyzed by PCR for variations of plamsepsin2 copy numbers.
Timepoint [4] 411077 0
Day 0 (before treatment)

Eligibility
Key inclusion criteria
1. Age above six months excluding unmarried females of child bearing age (from 12 years).
2. mono-infection with P. falciparum confirmed by positive blood smear (i.e. no mixed infection);
3. parasitaemia of 1000–100000 asexual parasite per microliter forms;
4. presence of axillary temperature equal 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 patient or from a parent or guardian in the case of children aged less than age of majority;
8. informed assent from any minor participant aged from 12 to 17 years; and
9. consent for pregnancy testing from married female of child-bearing age
Minimum age
6 Months
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. presence of general danger signs in children aged under 12 years or signs of severe falciparum malaria according to the definitions of WHO;
2. unmarried female in the child bearing age
3. weight under 5 kg;
4. mixed or mono-infection with another Plasmodium species detected by microscopy;
5. presence of severe malnutrition defined as a child aged between 6-60 months whose weight-for-high is below –3 z-score
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);
9. a positive pregnancy test.
10. Unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age (defined as age above 12 years and sexually active)

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
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size estimation
Treatment failure rate to artemether-lumefantrine in the study areas was assumed as 5%. At a confidence level of 95% and a precision around the estimate of 5%, gave a minimum of 73 patients. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients per site was targeted. The total target sample for the three sites were 264 patients.

Analysis of data
The WHO excel software programs was used for data management and analysis. Data was analyzed by both Kaplan-Meier method and per-protocol methods. Subjects were 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 other species. 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
7/12/2017
Date of last participant enrolment
Anticipated
Actual
26/02/2018
Date of last data collection
Anticipated
Actual
25/03/2018
Sample size
Target
264
Accrual to date
Final
212
Recruitment outside Australia
Country [1] 24807 0
Sudan
State/province [1] 24807 0
Blue Nile, Sennar, Masala states

Funding & Sponsors
Funding source category [1] 311523 0
Government body
Name [1] 311523 0
Ministry of Health
Country [1] 311523 0
Sudan
Primary sponsor type
Government body
Name
Ministry of Health
Address
Nile street, Zip code 1111 Khartoum
Country
Sudan
Secondary sponsor category [1] 312937 0
None
Name [1] 312937 0
None
Address [1] 312937 0
None
Country [1] 312937 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310982 0
National Health Research Ethis Committee
Ethics committee address [1] 310982 0
Nile street, 1111, P. O. box 303, Khartoum
Ethics committee country [1] 310982 0
Sudan
Date submitted for ethics approval [1] 310982 0
01/08/2017
Approval date [1] 310982 0
28/09/2017
Ethics approval number [1] 310982 0

Summary
Brief summary
Title: To assess the efficacy and safety of Artemether-Lumefantrine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Blue Nile, Kassale and Sennar state.
Study Period: September/2017 to March 2018.
Study Design: This surveillance study was a one arm prospective study.
Patient population: Febrile patients aged above six months, with confirmed uncomplicated P. falciparum infection. Female minors aged 12-17 years and unmarried females in child-bearing age were excluded as subjecting them to pregnancy testing is unacceptable according to the local customs and cultures.
Sample Size: A total of 88 patients was enrolled at each site. Clinical and parasitological parameters were monitored over a 28 days follow-up period to evaluate drug efficacy of artemether 20mg /lumefantrine120mg six-dose course over 3 days according to weight bands (1 tab: 5-14kg, 2 tabs: 15-24kg, 3 tabs: 25-34kg and 4 tabs: greater than or equal to 35kg). All treatment doses were administered under direct observation.
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 was distinguished from re-infection by polymerase chain reaction (PCR) analysis.
Secondary endpoints: (i) The frequency and nature of adverse events and (ii) the polymorphism of molecular markers for artemisinin (K13), piperaquine (amplification of plasmepsin 2) and mefloquine (amplification of mdr-1)
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119582 0
Dr Mariam Adam Babiker
Address 119582 0
CNCDCD, Ministry of Health
Algassar street junction with Army Road, Zib code 1111, Khartoum.
Country 119582 0
Sudan
Phone 119582 0
+249915202560
Fax 119582 0
Email 119582 0
mariamadam484@gmail.com
Contact person for public queries
Name 119583 0
Dr Mariam Adam Babiker
Address 119583 0
CNCDCD, Ministry of Health
Algassar street junction with Army Road, Zib code 1111, Khartoum
Country 119583 0
Sudan
Phone 119583 0
+249915202560
Fax 119583 0
Email 119583 0
mariamadam484@gmail.com
Contact person for scientific queries
Name 119584 0
Dr Marian Warsame
Address 119584 0
University of Gothenburg,
Medicinaregatan 16
405 30 Gothenburg
Country 119584 0
Sweden
Phone 119584 0
+46760525254
Fax 119584 0
Email 119584 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.