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Trial registered on ANZCTR


Registration number
ACTRN12616000526471
Ethics application status
Approved
Date submitted
2/03/2016
Date registered
22/04/2016
Date last updated
22/04/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of artesunate in treatment of malaria caused by Plasmodium falciparum parasite in Guyana
Scientific title
Efficacy and safety of artesunate in treatment of malaria caused by Plasmodium falciparum parasite in Guyana
Secondary ID [1] 288657 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 297841 0
Condition category
Condition code
Infection 298017 298017 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 artesunate (4 mg/kg body weight) once daily for 7 consecutive days) for the treatment of uncomplicated P. falciparum infection.. The treatment was taken orally under direct supervision by the health worker. The drug was tested in one site. Eligibile subjects were treated for 7 days days and followed up for 28 days.
Intervention code [1] 294071 0
Treatment: Drugs
Comparator / control treatment
No control group.
This was a one arm cohort prospective study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297530 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure) and adequate clinical and parasitological responses. This was composite primary outcome.

Enrolled patients were assessed for parasitological (using microscopy) and clinical (axillary temperature equal or more 37.5 centigrade) responses during the 28 days follow-up. Standard physical examination was performed and axillary temperature was measured at baseline, during the treatment and post-treatment over 28 days. Thick and thin blood films were collected and examined at baseline, during the treatment and post-treatment over 28 days.
Treatment outcomes was classified according to the latest WHO protocol (WHO 2009:.World Health Organization. Methods for surveillance of antimalarial drug efficacy).
Timepoint [1] 297530 0
At days 1, 2, 3, 7, 14, 21 and 28 following initiation of artesunate.
Primary outcome [2] 297531 0
Day 3 positivity rate and parasite clearance time with blood sampling for parasite counts 8 hourly until patient became negative
Timepoint [2] 297531 0
Day 3 positivity rate: at day day 3
Parasite clearance time: 8 hourly on days 1, 2, 3 until the patient became negative.
Secondary outcome [1] 321338 0
Percent of adverse event was documented.
The known adverse events of artesunate are abdominal pain, diarrhoea, dizziness, nausea, vomiting.

Parents or guardians of all enrolled patients 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] 321338 0
At day 28 following inititation of artesunate
Secondary outcome [2] 321339 0
Prevalence of artemisinin resistance molecular markers (K13).

Parasite DNA extracted from the dried blood spots was analyzed by PCR and sequencing for the presence of K13 (molecular marker for artemisinin resistance.
Timepoint [2] 321339 0
At Day 0 (prior initiation of treatment)

Eligibility
Key inclusion criteria
1. age greater or equal to 2 years;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000–100,000/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 patients or parent or guardian of children.
Minimum age
2 Years
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 5 years or signs of severe falciparum malaria according to the definitions of WHO;
2. mixed or mono-infection with another Plasmodium species detected by microscopy;
3. presence of severe malnutrition defined as a child aged 6-60 months has a mid-upper arm circumference belo 115 mm)
4. 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);
5. regular medication, which may interfere with antimalarial
pharmacokinetics;
6. history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s);
7. a positive pregnancy test or breastfeeding (include this criterion only if adults are included);
8. unable to or unwilling to take a pregnancy test or contraceptives (for women of child-bearing age);
9. previous antimalarial drug intake in the past 48 hours;
10. Patients presenting with splenectomy.


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)
Not applicable
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 estimated prevalence of patients positive at day 3 after Artesunate in the area was below 15%. At a confidence level of 95% and a precision around the estimate of 15%, a minimum of 40 must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, a number of 50 patients was targeted in the study.

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. In addition patients was 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 was unclassifiable or if the results of PCR indicate that the failure was due to reinfection with P. falciparum or P. vivax.

The final analysis included:
* 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 proportion of patients positive on day 3 (72 hours after treatment)
* the cumulative incidence of success and failure rates at day 28, PCR-uncorrected and PCR-corrected; and
* Proportion of patients carrying K13 mutations

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] 7632 0
Guyana
State/province [1] 7632 0
Demerara-Mahaica

Funding & Sponsors
Funding source category [1] 293014 0
Government body
Name [1] 293014 0
Ministry of Health
Address [1] 293014 0
Lot 1, Brickdam Street,
Georgetown
Country [1] 293014 0
Guyana
Primary sponsor type
Other
Name
Regional Office for the Americas of the World Health Organization
Address
525 Twenty-third Street, N.W., Washington, D.C. 20037,
Country
United States of America
Secondary sponsor category [1] 291791 0
None
Name [1] 291791 0
Nil
Address [1] 291791 0
Nil
Country [1] 291791 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294525 0
Institutional Review Board, Ministry of Health
Ethics committee address [1] 294525 0
Lot 1, Brickdam Street,
Georgetown
Ethics committee country [1] 294525 0
Suriname
Date submitted for ethics approval [1] 294525 0
20/02/2014
Approval date [1] 294525 0
08/01/2015
Ethics approval number [1] 294525 0
FWA00014641

Summary
Brief summary
Title: Assessment of parasite clearance rate in Plasmodium falciparum malaria induced by Artesunate in Guyana.

Purpose: To assess the efficacy, including parasite clearance time, and safety of artesunate 7 day treatment for uncomplicated falciparum malaria

Objective: To assess the efficacy, including parasite clearance time, and safety 7 days artesunate for the treatment of uncomplicated P. falciparum malaria infections

Study Sites: study was conducted in Malaria Clinic, Georgetown, Guyana

Study Period: The study was conducted from March to December 2014

Study Design: Single arm prospective study.

Patient population: Febrile patients aged 2 years and above with confirmed uncomplicated P. falciparum infection

Sample Size: 50 patients.

Treatments and follow-up: Artesunate (daily dose for 7 days) was be given.

Clinical and parasitological parameters was monitored over a 28-day follow-up period to evaluate drug efficacy and safety.

Primary endpoints: (i) 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; (ii) the proportion of patients positive on day 3 and parasite clearance time; Recrudescence was to be distinguished from re-infection by polymerase chain reaction (PCR) analysis.

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 64014 0
Dr Reyaud Rahman
Address 64014 0
Vector Control Services, Malaria Control Programme
Lot 1, Brickdam Street,
Georgetown

Country 64014 0
Guyana
Phone 64014 0
+592-2274752
Fax 64014 0
Email 64014 0
reyaudrahman@gmail.com
Contact person for public queries
Name 64015 0
Dr Reyaud Rahman
Address 64015 0
Vector Control Services, Malaria Control Programme
Lot 1, Brickdam Street,
Georgetown
Country 64015 0
Guyana
Phone 64015 0
+592-2274752
Fax 64015 0
Email 64015 0
reyaudrahman@gmail.com
Contact person for scientific queries
Name 64016 0
Dr Reyaud Rahman
Address 64016 0
Vector Control Services, Malaria Control Programme
Lot 1, Brickdam Street,
Georgetown
Country 64016 0
Guyana
Phone 64016 0
+592-2274752
Fax 64016 0
Email 64016 0
reyaudrahman@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