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Trial registered on ANZCTR


Registration number
ACTRN12620000426987
Ethics application status
Approved
Date submitted
31/10/2019
Date registered
30/03/2020
Date last updated
30/03/2020
Date data sharing statement initially provided
30/03/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Khyber district of Khyber Pakhtunkhwa and Zhob district of Balochistan Pakistan
Scientific title
Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Khyber district of Khyber Pakhtunkhwa and Zhob district of Balochistan Pakistan
Secondary ID [1] 299686 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 315039 0
Condition category
Condition code
Infection 313369 313369 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 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 are 5-24 mg/kg bw of artemether and 29-144 mg/kg bw of lumefantrine. All treatments will be given orally under direct supervision by the health worker. The patient will be followed up for 28 days
Intervention code [1] 315953 0
Treatment: Drugs
Comparator / control treatment
No control group as the study is a one arm cohort prospective study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321850 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. Treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 321850 0
On days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [1] 376471 0
Percent of adverse event following treatment.
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.

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] 376471 0
On days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 376472 0
Prevalence of mutations of K13 (molecular marker for artemisinin resistance).

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] 376472 0
On day 0 (before treatment)

Eligibility
Key inclusion criteria
1. Aged between 6 months and above with the exception of 12-17 years old female minors and unmarried females above 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 or tympanic temperature greater or equal to 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 18 years;
8. Informed assent from any minor participant aged from 12 to 17 years; and
9. Consent for pregnancy testing from married female aged 18 years and above
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. 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 below 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 of married women aged 18 years and above; and
9. Unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age and who are 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)
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
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size estimation
The assumed treatment failure rate to artemether/lumefantrine in the area is 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.

Data analysis
WHO excel software program 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 of the protocol, 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 282, 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
28/09/2019
Date of last participant enrolment
Anticipated
Actual
28/11/2019
Date of last data collection
Anticipated
Actual
26/12/2019
Sample size
Target
176
Accrual to date
Final
181
Recruitment outside Australia
Country [1] 21979 0
Pakistan
State/province [1] 21979 0
Khyber Pakhtunkhwa and Balochistan

Funding & Sponsors
Funding source category [1] 304164 0
Government body
Name [1] 304164 0
Ministry of National Health Services Regulations and Coordination
Country [1] 304164 0
Pakistan
Funding source category [2] 304165 0
Other
Name [2] 304165 0
World Health Organization
Country [2] 304165 0
Switzerland
Primary sponsor type
Government body
Name
Ministry of National Health Services Regulations and Coordination
Address
Ground Floor, National Influenza Control Program Building,
NIH Premises, Park Road Chak Shahzad,
Zip Code 44000, Islamabad, Pakistan
Country
Pakistan
Secondary sponsor category [1] 304392 0
None
Name [1] 304392 0
None
Address [1] 304392 0
None
Country [1] 304392 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304640 0
National Bioethics Committe (NBC) Pakistan
Ethics committee address [1] 304640 0
Pakistan Heaalh Research Council, Sharah-e-Jamhuriat
Off Constitution Avenue, Sector G-5/2, Islamabad, Pakistan
Ethics committee country [1] 304640 0
Pakistan
Date submitted for ethics approval [1] 304640 0
26/07/2019
Approval date [1] 304640 0
09/08/2019
Ethics approval number [1] 304640 0
No.4-87/NBC-101+255-Exten 2019-20/19/134

Summary
Brief summary
Febrile malaria patients aged 6 months and above will be recruited to assess efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum infection. Artemether-lumefantrine will be given based on weight bands: one tablet to those weighing 5-14kg; 2 tablets for 15-24 kg; 3 tablets for 25-34 kg and four tablets for equal to or greater than 35 kg. Clinical and parasitological parameters will be monitored for 28 days followed-up to establish proportion of patients with treatment failure, frequency of adverse events and polymorphism of molecular markers for artemisinin resistance (K13).
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 97686 0
Mr Mounir Ahmed Khan
Address 97686 0
Institute of Public Health, Quetta Balochistan province
Brewery Road. Provincial Malaria Reference Laboratory, IPH Quetta, Balochistan,
Pakistan
Country 97686 0
Pakistan
Phone 97686 0
+923337807644
Fax 97686 0
Email 97686 0
[email protected]
Contact person for public queries
Name 97687 0
Mounir Ahmed Khan
Address 97687 0
Institute of Public Health, Quetta Balochistan province
Brewery Road. Provincial Malaria Reference Laboratory, IPH Quetta, Balochistan,
Pakistan
Country 97687 0
Pakistan
Phone 97687 0
+923337807644
Fax 97687 0
Email 97687 0
[email protected]
Contact person for scientific queries
Name 97688 0
Marian Warsame
Address 97688 0
School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Country 97688 0
Sweden
Phone 97688 0
+46760525254
Fax 97688 0
Email 97688 0
[email protected]

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
5522Ethical approval  [email protected]
5523Clinical study report  [email protected]



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.