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Trial registered on ANZCTR


Registration number
ACTRN12615001248550
Ethics application status
Approved
Date submitted
Date registered
16/11/2015
Date last updated
6/03/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of Dihydroartemisinin-Piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in District Headquarter Hospital Zhob of Balochistan province and Tehsil HQ Hospital Sadda Kurram Agency FATA, Pakistan
Scientific title
Efficacy and safety of Dihydroartemisinin-Piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in District Headquarter Hospital Zhob of Balochistan province and Tehsil HQ Hospital Sadda Kurram Agency FATA, Pakistan
Secondary ID [1] 287719 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 296554 0
Condition category
Condition code
Infection 296818 296818 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 Dihydroartemisinin+Piperaquine (4 mg/kg DHA and 18 mg/kg Piperaquine once a day for 3 days) for the treatment of uncomplicated P. falciparum infection. The treatment will be given in tablets by oral. Eligible subjects will be treated for three days and followed up for 42 days.

The daily doses of the study medicine will be administered under direct supervision.
Intervention code [1] 293107 0
Treatment: Drugs
Comparator / control treatment
No control group. It is a single arm study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296415 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This is 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] 296415 0
Primary outcome (treatment failures) will be assessed on Days 2, 3, 7, 14, 21, 28, 35, 42 following initiation of Dihydroartemisinin+piperaquine.
Secondary outcome [1] 318391 0
Percent of adverse event will be documented.

Known adverse events of Dihydroartemisinin+Piperaquine are asthenia, cough, diarrhoea, fever, loss of appetite, nausea, vomiting.

Parents or guardians of all enrolled patients 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] 318391 0
Secondary outcome (adverse events) will be assessed on Days 1, 2, 3, 7, 14, 21, 28, 35, 42 following initiation of Dihydroartemisinin+piperaquine.
Secondary outcome [2] 318392 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] 318392 0
At Day 0 (prior to initiation of the treatment.

Eligibility
Key inclusion criteria
1. age between six months and above with the exception of 12-17 years olde female minors and unmarried women above 18 years;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 500–200,000/microliter 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 married female aged 18 years and above.
Minimum age
6 Months
Maximum age
No limit
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
2. falciparum malaria according to the definitions of WHO;
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 6-60 months has a mid-upper arm circumference below 115 mm)
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 or breastfeeding of married women aged 18 years and above; and
10. 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)
Patients aged between 6 month and above with uncomplicated malaria who meet the study inclusion criteria will be enrolled, treated on site with Dihydroartemisinin and monitored for 42 days. The follow-up will consist of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations.
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
The assumed treatment failure rate to Dihydroartemisinin+Piperaquine 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 42-day follow-up period, 88 patients should be included in the study per site.

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 patients will be considered withdrawn from the analysis due to consent withdrawal, failure to complete treatment, enrolment violation, voluntary and involuntary protocol violation and 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 42, PCR-uncorrected and PCR-corrected; and

Recruitment
Recruitment status
Completed
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] 7265 0
Pakistan
State/province [1] 7265 0
Balochistan Balochistan and Sadda Kurram Agency FATA,

Funding & Sponsors
Funding source category [1] 292264 0
Government body
Name [1] 292264 0
Directorate of Malaria Control, Ministry of National Health Services Regulations and Coordination, NIH, Islamabad
Address [1] 292264 0
Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country [1] 292264 0
Pakistan
Primary sponsor type
Government body
Name
Directorate of Malaria Control, Ministry of National Health Services Regulations and Coordination, NIH, Islamabad
Address
Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country
Pakistan
Secondary sponsor category [1] 290937 0
None
Name [1] 290937 0
Nil
Address [1] 290937 0
Nil
Country [1] 290937 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293735 0
WHO ethics and research committee
Ethics committee address [1] 293735 0
20 Avenue Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 293735 0
Switzerland
Date submitted for ethics approval [1] 293735 0
31/08/2015
Approval date [1] 293735 0
03/10/2015
Ethics approval number [1] 293735 0
ERC.0002649

Summary
Brief summary
Title: Efficacy and safety of Dihydroartemisinin-Piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in District Headquarter Hospital Zhob of Balochistan province and Tehsil HQ Hospital Sadda Kurram Agency FATA, Pakistan

Purpose: To assess the efficacy and safety of Dihydroartemisinin-Piperaquine for treatment of uncomplicated falciparum malaria

Objective: To assess the efficacy and safety Dihydroartemisinin-Piperaquine for the treatment of uncomplicated P. falciparum malaria infections

Study Sites: study will be conducted in two hostpitals: health centres: District Headquarter Hospital Zhob of Balochistan province and Tehsil HQ Hospital Sadda Kurram Agency FATA

Study Period: The study will be conducted from October to December 2015

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

Sample Size: 88 patients per site. For the two sites a total of 176 subjects will be enrolled.

Treatments and follow-up: Dihydroartemisinin-Piperaquine (daily dose for 3 days) will be given.

Clinical and parasitological parameters will be monitored over a 42-day follow-up period to evaluate drug efficacy and safety.

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 determined.

Secondary endpoints:
1. The frequency of adverse events.
2. Frequency of molecular markers for artemisinin resistance (K13)
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 61110 0
Mr Mounir Ahmed Khan
Address 61110 0
National Malaria Control Programme,
Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country 61110 0
Pakistan
Phone 61110 0
+92 3337807644
Fax 61110 0
Email 61110 0
malaria.k@gmail.com
Contact person for public queries
Name 61111 0
Mr Mounir Ahmed Khan
Address 61111 0
National Malaria Control Programme,
Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country 61111 0
Pakistan
Phone 61111 0
+92 3337807644
Fax 61111 0
Email 61111 0
malaria.k@gmail.com
Contact person for scientific queries
Name 61112 0
Mr Mounir Ahmed Khan
Address 61112 0
National Malaria Control Programme,
Ground Floor, National Influenza Control Program Building,NIH, Chak Shahzad, Islamabad, Pakistan
Country 61112 0
Pakistan
Phone 61112 0
+92 3337807644
Fax 61112 0
Email 61112 0
malaria.k@gmail.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary