Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000944730
Ethics application status
Approved
Date submitted
23/05/2022
Date registered
4/07/2022
Date last updated
4/07/2022
Date data sharing statement initially provided
4/07/2022
Date results information initially provided
4/07/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety Study of Artesunate+Sulphadoxine/Pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria and Chloroquine for Plasmodium vivax malaria in health facilities of Nangarhar and Laghman provinces of Afghanistan
Scientific title
Efficacy and safety Study of Artesunate+Sulphadoxine/Pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria and Chloroquine for Plasmodium vivax malaria in health facilities of Nangarhar and Laghman provinces of Afghanistan
Secondary ID [1] 307186 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 326411 0
Condition category
Condition code
Infection 323696 323696 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study was a single-arm prospective trial to evaluate the efficacy and safety of artesunate + sulfadoxine/pyrimethamine (AS-SP) for the treatment of uncomplicated P. falciparum and chloroquine for the treatment of uncomplicated P. vivax. For treatment with artesunate + sulfadoxine/pyrimethamine, patients received 4mg/kg body weight artesunate once daily for three consecutive days plus a single dose of 25/1.25 mg/kg body weight sulfadoxine/pyrimethamine on the first day. For the P. vivax patients, chloroquine 25 mg/kg body weight for 3 days (10 mg/kg on day 1, 10 mg/kg on day 2, and 5 mg/kg on day 3) was given. Artesunate+sulfadoxine/pyrimethamine tablets (100 mg artesunate tablet and one tablet 25 mg/500 mg SP) manufactured by Guilin Pharmaceutical CO., Ltd. China, and chloroquine tablet (150 mg base) was manufactured by Medopharma, India, and was obtained from the World Health Organization (Headquarter). All treatments were administered orally under the direct supervision of medical personnel. All study patients were followed up for 28 days.
Intervention code [1] 323638 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331446 0
Percent of treatment failures (early treatment failure + late clinical failure+late parasitological failure). This is a composite primary outcome.

Enrolled patients were monitored for parasitological (microscopic) and clinical responses. To distinguish reucrudescence from reinfection, PCR analysis was performed on paired filter blood samples on day 0 and on the day of parasite recurrence. Treatment outcomes were classified according to the latest protocol of World Health Organization.
Timepoint [1] 331446 0
Days 0(before treatment), 1, 2,3, 7, 14, 21, 28 (primary endpoint)
Day 1,2 and 3: Early treatment failure is assessed
Days 7,14,21 and 28: Late treatment failure (late clinical or later parasitological failures) were assessed.
A composite primary outcome was estimated by adding early treatment failure + late clinical failure+late parasitological failure.
Secondary outcome [1] 409904 0
Percent of adverse event following treatment.
Known adverse events of artesunate+sulfadoxine/pyrimethamine are abdominal discomfort, nausea, headache and dizziness. These effects are usually minor and resolve quickly.

Parents or guardians of all enrolled children was asked routinely about previous symptoms and about 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] 409904 0
On days 1, 2 (during treatment) and 3, 7, 14, 21, 28 (post-treatment)

Eligibility
Key inclusion criteria
1. age above 6 months, excluding female minors aged 12-15 years and unmarried women for the falciparum study
2. mono-infection with P. falciparum or P. vivax detected by microscopy;
3. parasitaemia of 500-200,000 per microL asexual forms
4. presence of axillary 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 under 16 years of age
8. Informed assent from any minor participant in the P. falciparum study aged from 12 to 15 years
9. Consent for pregnancy testing from married female of child-bearing age for the P. falciparum sub-study
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 5 years and adults or signs of severe falciparum malaria according to the definitions of WHO
2. Weight under 5 kg
3. mono-infection of P. malariae or mixed with another Plasmodium species detected by microscopy
4. Presence of severe malnutrition (defined as a child who has a mid-upper arm circumference below 110 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 for potential participants in the P. falciparum group
9. unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age and who are sexually active for the falciparum group

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
The treatment failure rate to artesunate+sulfadoxine/pyrimethamine (AS+SP) and chloroquine (CQ) in the study areas was assumed at 5%. At a confidence level of 95% and a precision around the estimate of 10%, a minimum of 50 patients per site per drug were targeted. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, a minmum 60 patients was included in the study per test drugs and per site. A total of 120 patients (both sites) for AS+SP and 120 for CQ (both sites) were recruited. For the P. falciparum cases, prevalences of mutations in K13 gene, amplification in mdr-1 gene and amplification in pm2 gene for artemisinin, piperaquine and mefloquine resistance, respectively were

Data analysis
WHO excel software program was used for data management and analysis. Data was analysed by two methods: the Kaplan-Meier method and per-protocol analysis. A patient was considered withdrawn from the analysis if the PCR results were unclassifiable or if the results of PCR indicate that the failure is due to reinfection with P. falciparum..
The final analysis included:
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.
7. For P. falciparum cases, proportion of mutations in K13 gene, amplification in mdr-1 gene and amplification in pm2 gene for artemisinin, piperaquine and mefloquine resistance, respectively.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
6/09/2016
Date of last participant enrolment
Anticipated
Actual
17/01/2017
Date of last data collection
Anticipated
Actual
11/02/2017
Sample size
Target
240
Accrual to date
Final
243
Recruitment outside Australia
Country [1] 24782 0
Afghanistan
State/province [1] 24782 0
Laghman and Nanagarhar provices

Funding & Sponsors
Funding source category [1] 311493 0
Government body
Name [1] 311493 0
Ministry of Public Health Afghanistan
Country [1] 311493 0
Afghanistan
Primary sponsor type
Government body
Name
Ministry of Public Health Afghanistan
Address
Darul Aman Road Sanatorium Street, Kabul 25000
Country
Afghanistan
Secondary sponsor category [1] 312893 0
None
Name [1] 312893 0
None
Address [1] 312893 0
None
Country [1] 312893 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310953 0
Institutional Review Board (IRB) of Afghanistan
Ethics committee address [1] 310953 0
5&6 Floors of the Central Blood Bank, Maiwand Road, Kabul 25000
Ethics committee country [1] 310953 0
Afghanistan
Date submitted for ethics approval [1] 310953 0
06/06/2016
Approval date [1] 310953 0
06/08/2016
Ethics approval number [1] 310953 0
No. 355323

Summary
Brief summary
Febrile malaria patients aged above 6 months were recruited to evaluate the efficacy and safety of artesunate sulfadoxine/pyrimethamine (ASSP) for the treatment of uncomplicated P. falciparum infection and of chloroquine (CQ) for the treatment of uncomplicated P. vivax infection. Clinical and parasitological parameters were monitored for 28 days to determine the proportion of patients with treatment failure, prevalence of adverse events, and polymorphism of molecular markers for artemisinin (K13), piperaquine (pm2 amplification) and mefloquine (mdr-1 amplification) resistance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 119478 0
Dr Khalilahmad Kohestani
Address 119478 0

National Malaria and Leishmania Control Programme,
Darul Aman Road Sanatorium Street, Kabul 25000
Country 119478 0
Afghanistan
Phone 119478 0
+93700237629
Fax 119478 0
Email 119478 0
khalil_impd@yahoo.com
Contact person for public queries
Name 119479 0
Dr Khalilahmad Kohestani
Address 119479 0
National Malaria and Leishmania Control Programme, Darul Aman Road Sanatorium Street, Kabul 25000
Country 119479 0
Afghanistan
Phone 119479 0
+93700237629
Fax 119479 0
Email 119479 0
khalil_impd@yahoo.com
Contact person for scientific queries
Name 119480 0
Dr Marian Warsame
Address 119480 0
School of Public Health and Community Medicine, University of Gothenburg,
Box 463
40530 Göteborg
Country 119480 0
Sweden
Phone 119480 0
+46760525254
Fax 119480 0
Email 119480 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.