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Trial registered on ANZCTR


Registration number
ACTRN12617000283370
Ethics application status
Approved
Date submitted
7/02/2017
Date registered
23/02/2017
Date last updated
6/05/2019
Date data sharing statement initially provided
6/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in two sites in Yemen.
Scientific title
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in two sites in Yemen.
Secondary ID [1] 291098 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 301914 0
Condition category
Condition code
Infection 301576 301576 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 containing 20 mg artemether+ 120 mg lumefantrine in each tablet will be 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 are 5-24 mg/kg bw of artemether and 29-144 mg/kg bw of lumefantrine.
All treatments will be taken orally under direct supervision by the health worker. The two drugs will be tested separately. The patient will be given artemether+lumefantrine and will be followed up for 28 days.
Intervention code [1] 297087 0
Treatment: Drugs
Comparator / control treatment
No control group.
This is a one arm cohort prospective study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300983 0
Percent 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 latest WHO protocol.
Timepoint [1] 300983 0
At days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [1] 331330 0
Percent of adverse event following treatment.
Atemether+lumefantrine are abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.

Parents or guardians of all enrolled children 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] 331330 0
At days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 331331 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] 331331 0
At day 0 (prior to initiation of the treatment.

Eligibility
Key inclusion criteria
1. age 6 months and above, excluding female minors 12-17 years old and unmarried females aged 18 years and above;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 500-200000 per microL asexual forms;
4. presence of axillary temperature greater or equal to 37.5 degrees C 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 18 years;
8. informed assent from any minor participant aged from 12 to 17 years; and
9. consent for pregnancy testing from female of child-bearing potential and from their parent or guardian if under the age of majority years.
Minimum age
6 Months
Maximum age
60 Weeks
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. 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);
8. a positive pregnancy test or breastfeeding; and
9. unable to or unwilling to take pregnancy test or to use contraception for married women.

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)
No concealment
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
None
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Minimum sample size
Treatment failure rate artemether-lumefantrine in the study areas is assumed to be 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients should be included in the study per site.

Analysis of data
The WHO Excel software programme for therapeutic efficacy 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 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
Not yet recruiting
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] 8661 0
Yemen
State/province [1] 8661 0
Ibb and Al Hudeida

Funding & Sponsors
Funding source category [1] 295538 0
Government body
Name [1] 295538 0
Ministry of Public Health and Population
Address [1] 295538 0
P.O. Box: 16544, Sana'a
Country [1] 295538 0
Yemen
Primary sponsor type
Government body
Name
Ministry of Public Health and Population
Address
P.O. Box: 16544, Sana'a
Country
Yemen
Secondary sponsor category [1] 294356 0
None
Name [1] 294356 0
Address [1] 294356 0
Country [1] 294356 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296859 0
WHO ERC
Ethics committee address [1] 296859 0
World Health Organization
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 296859 0
Switzerland
Date submitted for ethics approval [1] 296859 0
31/03/2019
Approval date [1] 296859 0
01/04/2019
Ethics approval number [1] 296859 0
ERC.0003177

Summary
Brief summary
Title: Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in two sites in Yemen.
Purpose: To assess the efficacy of the current first and/or second line treatment policy;
Objective: To assess the efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Al Udayn, Ibb governorate and in Bajil, Al Hudeida governorate.
Study Period: April to November 2017.
Study Design: One arm prospective study.
Patient population: Febrile patients aged 6 months and above, excluding female minors 12-17 years old and unmarried females aged 18 years and above, with confirmed uncomplicated P. falciparum infection. The female minors and unmarried females will be excluded as subjecting them to pregnancy testing is unacceptable according to the local customs and cultures.
Sample Size: 88 patients per site.
Treatment(s) and follow-up: Artemether/lumefantrine, Novartis, Basel Switzerland], a fixed combination of 20 mg of artemether and 120 mg of lumefantrine in a tablet)] will be administered according to the recommended weight bands as follows: One tablet to those weighing 5-14 kg; two tablets for 15-24 kg; three tablets for 25-34 kg and four tablets for greater or equal to 35 kg. The full course of treatment for all study patients consists of 6-doses given twice daily over 3 days. Clinical and parasitological parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy.
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.
Secondary endpoints: The frequency and nature of adverse events
to determine the polymorphism of molecular markers for name of the antimalarial drug(s) resistance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72250 0
Dr Methaq Abdulla Alssada
Address 72250 0
National Malaria Control Programme,
Ministry of Public Health & Population
PO Box: 16544, Sana'a, Yemen
Country 72250 0
Yemen
Phone 72250 0
+967700079668
Fax 72250 0
Email 72250 0
dr.mithak@gamil.com
Contact person for public queries
Name 72251 0
Dr Methaq Abdulla Alssada
Address 72251 0
National Malaria Control Programme,
Ministry of Public Health & Population
PO Box: 16544, Sana'a, Yemen
Country 72251 0
Yemen
Phone 72251 0
+967700079668
Fax 72251 0
Email 72251 0
dr.mithak@gamil.com
Contact person for scientific queries
Name 72252 0
Dr Marian Warsame
Address 72252 0

Dept Public Health and Community Medicine
Medicinaregatan 18A, 413 90 Göteborg
Country 72252 0
Sweden
Phone 72252 0
+46760525254
Fax 72252 0
Email 72252 0
dahan2004@hotmail.com

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?
Clinical study report
Ethical approval
Summary results
No Results