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Trial registered on ANZCTR


Registration number
ACTRN12617001025325
Ethics application status
Approved
Date submitted
27/06/2017
Date registered
14/07/2017
Date last updated
14/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of Artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Zhob of Balochistan province and Khyber Agency of FATA, Pakistan
Scientific title
Efficacy and safety of Artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Zhob of Balochistan province and Khyber Agency of FATA, Pakistan
Secondary ID [1] 292275 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 303795 0
Condition category
Condition code
Infection 303164 303164 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 given orally under direct supervision by the health worker. The patient will be followed up for 28 days
Intervention code [1] 298450 0
Treatment: Drugs
Comparator / control treatment
No control group.
This is a one arm cohort prospective study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302535 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] 302535 0
On days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [1] 336327 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] 336327 0
On days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 336328 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] 336328 0
On day 0 (before treatment)

Eligibility
Key inclusion criteria
1. Age 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
60 Years
Gender
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
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.

Analysis of data
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, 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
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] 9013 0
Pakistan
State/province [1] 9013 0
Balochistan and FATA

Funding & Sponsors
Funding source category [1] 296818 0
Government body
Name [1] 296818 0
Ministry of National Health Services Regulations and Coordination
Address [1] 296818 0
Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country [1] 296818 0
Pakistan
Funding source category [2] 296819 0
Other
Name [2] 296819 0
World Health Organization
Address [2] 296819 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Country [2] 296819 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, Chak Shahzad, Islamabad, Pakistan
Country
Pakistan
Secondary sponsor category [1] 295808 0
None
Name [1] 295808 0
Nil
Address [1] 295808 0
Nil
Country [1] 295808 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298054 0
WHO ERC
Ethics committee address [1] 298054 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 298054 0
Switzerland
Date submitted for ethics approval [1] 298054 0
19/10/2016
Approval date [1] 298054 0
19/06/2017
Ethics approval number [1] 298054 0
ERC0002831

Summary
Brief summary
Title: Efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Zhob of Balochistan province and Khyber Agency of FATA, Pakistan

Purpose: To assess the efficacy and safety of new alternate First line treatment policy
Objective: To assess the efficacy and safety of artemether+lumefantrine for the treatment of uncomplicated P. falciparum malaria infections.

Study Sites: District Headquarter Hospital in district Zhob of Balochistan province and Rural Health Centre Ali Masjid in Khyber Agency FATA, Pakistan

Study Period: From September 2017 to June 2018

Study Design: Single arm prospective study.

Patient population: Febrile patients aged 6 months and above excluding 12-17 old female minors and unmarried females aged 18 years and above, with confirmed uncomplicated P. falciparum infection. The female minors and unmarried females will be excluded as it is culturally inappropriate to ask this group pregnancy test.

Sample Size: 88 patients will be enrolled in each site, totally 176 patients for both sites.

Treatment(s) and follow-up: artemether+lumefantrine (20/120) oftwice daily dose for three days , administered under direct observation, will be evaluated. 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. Day 3 malaria positivity rate will be determined.

Secondary endpoints: (i) the frequency of adverse events, (ii) proportion of polymorphism of molecular markers for Sulfadoxine /pyrimethamine and artemisinin resistance (K13).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75834 0
Mr Mr. Mounir Ahmed Khan
Address 75834 0
National Malaria Control Programme, Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country 75834 0
Pakistan
Phone 75834 0
+92 3337807644
Fax 75834 0
Email 75834 0
malaria.k@gmail.com
Contact person for public queries
Name 75835 0
Mr Mr. Mounir Ahmed Khan
Address 75835 0
National Malaria Control Programme, Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country 75835 0
Pakistan
Phone 75835 0
+92 3337807644
Fax 75835 0
Email 75835 0
malaria.k@gmail.com
Contact person for scientific queries
Name 75836 0
Dr Marian Warsame
Address 75836 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Country 75836 0
Switzerland
Phone 75836 0
+41227915076
Fax 75836 0
Email 75836 0
warsamem@who.int

No data has been provided for results reporting
Summary results
Not applicable