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Trial registered on ANZCTR


Registration number
ACTRN12619000859189
Ethics application status
Approved
Date submitted
23/05/2019
Date registered
17/06/2019
Date last updated
17/06/2019
Date data sharing statement initially provided
17/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of Artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in Eritrea
Scientific title
Efficacy and safety of Artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in Eritrea
Secondary ID [1] 298317 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 312954 0
Condition category
Condition code
Infection 311450 311450 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study aims to assess the efficacy and safety of artesunate-amodiaquine once daily dose for three days for the treatment of uncomplicated Plasmodium falciparum and Plasmodium viva malaria. administered based on body weight as follows: 1 tablet of 25+67.5 mg will be given to patient weighing 4.5 to <9 kg; 1 tablet of 50+135 mg to patient weighing 9 to <18 kg; 1 tablet of 100+270 mg to patient weighing 18 to <36 kg; 2 tablets of 100+270 mg. The target doses are 4mg/kg BW of Artesunate and 10mg/kg BW of Amodiaquine given once a day for three days. All treatments will be taken orally under direct supervision by the health worker and will be followed up for 28 days.
Intervention code [1] 314554 0
Treatment: Drugs
Comparator / control treatment
No comparator. It is a single arm prospective study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320165 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This was composite primary outcome.
Patient will be assessed clinically (axillary temperature and history of fever) and parasitologically by microscopy.
Below are the treatment failure definitions as per WHO protocol 2009
Early treatment failure
• danger signs or severe malaria on day 1, 2 or 3 in the presence of parasitaemia;
• parasitaemia on day 2 higher than on day 0, irrespective of axillary temperature;
• parasitaemia on day 3 with axillary temperature equal or above 37.5 degree centigrade ;
• parasitaemia on day 3 equal or above 25% of count on day 0.
Late clinical failure
• danger signs or severe malaria in the presence of parasitaemia on any day between day 4 and day 28 in patients who did not previously meet any of the criteria of early treatment failure;
• presence of parasitaemia on any day between day 4 and day 28 with axillary temperature
equal or above 37.5 degree centigrade or history of fever in patients who did not previously meet any of the criteria of early treatment failure.
Late parasitological failure
• presence of parasitaemia on any day between day 7 and day 28 with axillary temperature
below 37.5 degree centigrade in patients who did not previously meet any of the criteria of early treatment failure or late clinical failure.


Timepoint [1] 320165 0
Patients will be assed on days 0 (before treatment), 1, 2, 3, 7, 14, 21, 28.

The primary timepoint is day 28.
Secondary outcome [1] 370753 0
Proportion of patients with adverse event following treatment of artesunate+amodiaquine.

The known adverse events of artesunate+amodiaquine abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting and extrapyramidal reactions.

Patients or Parents/guardians will be asked routinely about previous symptoms and about symptoms that had emerged since the previous follow-up visit. When clinically indicated, patients will evaluated and treated appropriately. All adverse events will be recorded on the case report form.
Timepoint [1] 370753 0
Days 0, 1, 2, 3, 7, 14, 21, 28

Eligibility
Key inclusion criteria
1. age between 6 months and above;
2. infection with P. falciparum or P. vivax a parasites confirmed by positive blood smear (no mixed infection);
3. parasitaemia of 250-200, 000 asexual forms per microliter;
4. presence of axillary or tympanic temperature greater or equal to 37.5 degree 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 follow-up visit schedule;
7. informed consent from the patient or from a parent or guardian in the case of children aged less than 18;
8. informed assent from any minor participant aged from 12 to 18 years; and
9. Consent for pregnancy testing from female of child-bearing age (defined as age > 12 years and sexually active) and from their parent or guardian if under the age of 18.
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 12 years or signs of severe P. falciparum or P. vivax malaria according to the definitions of WHO;
2. weight under 5 kg;
3. haemoglobin < 8 g per deciliter;
4. presence of severe malnutrition defined as a child aged between 6-60 months whose weight-for-high is below –3 z-score, or has symmetrical oedema involving at least the feet or has a mid-upper arm circumference < 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; and
9. unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age (defined as age above 12 years and 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)
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
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample size
As the treatment failure rate to artesunate+amodiaquine in the study areas is estimated to 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be included for each species. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients per site per species will be included in the study.

Analysis of data
The WHO excel software programs will be used for data management and analysis. Data will be analyzed by two methods: the Kaplan-Meier method and per-protocol analysis. Patients was 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 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.

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] 21522 0
Eritrea
State/province [1] 21522 0
Gash Barka region

Funding & Sponsors
Funding source category [1] 302858 0
Government body
Name [1] 302858 0
Ministry of Health, Eritrea
Address [1] 302858 0
P.O. Box 212 Asmara,
Country [1] 302858 0
Eritrea
Primary sponsor type
Government body
Name
Ministry of Health of Eritrea
Address
P.O. Box 212 Asmara
Country
Eritrea
Secondary sponsor category [1] 302810 0
None
Name [1] 302810 0
None
Address [1] 302810 0
None
Country [1] 302810 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303433 0
WHO ERC
Ethics committee address [1] 303433 0
20, AV Appia, H-1211 Geneva 27
Ethics committee country [1] 303433 0
Switzerland
Date submitted for ethics approval [1] 303433 0
30/03/2019
Approval date [1] 303433 0
21/05/2019
Ethics approval number [1] 303433 0
Eritrea 2019

Summary
Brief summary
Title: Efficacy and safety of Artesunate-amodiaquine (ASAQ) for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Eritrea.
Purpose: To assess the efficacy of the existing first-line antimalarial drug and inform revision of the national malaria treatment guideline accordingly.
Objective: To assess the efficacy and safety of Artesunate-amodiaquine for the treatment of uncomplicated P. falciparum and P. vivax.
Study Sites: Tokombia, Shambuko, Goluj and Akordat.
Study Period: The study will run for five months from August-December, 2019.
Study Design: This surveillance study is a one-arm 28-day in-vivo prospective study.
Patient population: Febrile patients aged 6 months and above, with microscopically confirmed uncomplicated P. falciparum and P. vivax.
Sample Size: The study will enrol 88 patients per site to reach an overall sample size of 352 per species.
Treatment(s) and follow-up: Clinical and parasitological parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy of Artesunate-amodiaquine which is given for 3 days.
Primary endpoints: The proportion of patients with early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response will be measured as indicators of efficacy. Recrudescence will be distinguished from re-infection by polymerase chain reaction (PCR) analysis.
Secondary endpoints: The frequency and nature of adverse events will be recorded as part of monitoring safety of the drug.
Optional exploratory endpoints: To determine the polymorphism of molecular markers for artemisinin resistance (ASAQ).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93654 0
Dr Araia Berhane
Address 93654 0
CDC, Ministry of Health, Eritrea,
P. O. Box 212 Asmara
Country 93654 0
Eritrea
Phone 93654 0
+2911 117041
Fax 93654 0
Email 93654 0
araiabm@gmail.com
Contact person for public queries
Name 93655 0
Dr Araia Berhane
Address 93655 0
CDC, Ministry of Health, Eritrea,
P. O. Box 212 Asmara
Country 93655 0
Eritrea
Phone 93655 0
+2911 117041
Fax 93655 0
Email 93655 0
araiabm@gmail.com
Contact person for scientific queries
Name 93656 0
Dr Marian Warsame Yusuf
Address 93656 0
Dept Public Health and Community Medicine
Medicinaregatan 18A, 413 90 Göteborg
Country 93656 0
Sweden
Phone 93656 0
+46760525254
Fax 93656 0
Email 93656 0
dahan2004@hotmail.com

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?
Clinical study report
Ethical approval
Summary results
No Results