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Trial registered on ANZCTR


Registration number
ACTRN12618000353291
Ethics application status
Approved
Date submitted
2/11/2017
Date registered
8/03/2018
Date last updated
8/03/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of Artesunate and Amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in four sentinel sites of Gash Barka Zone, Eritrea
Scientific title
Efficacy and safety of Artesunate and Amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in four sentinel sites of Gash Barka Zone, Eritrea
Secondary ID [1] 293270 0
None
Universal Trial Number (UTN)
None
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 305331 0
Condition category
Condition code
Infection 304623 304623 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The aim of the study was to evaluates the efficacy and safety of artesunate+amodiaquine among patients suffering from uncomplicated falciparum malaria treated with a daily oral tablet dose of artesunate 4 mg/kg bw + amodiaquine 10mg/kg for 3 consecutive days. The patients were treated under direct supervision and followed up for 28 days.
Intervention code [1] 299528 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303855 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This is composite primary outcome.

Enrolled patients was assessed for parasitological and clinical responses during the 28 days days follow-up and treatment outcomes was classified according to the latest WHO protocol.
Timepoint [1] 303855 0
Baseline: days 0
End point assessment at: days,1,2,3 (early treatment failure) 7,14,21 and 28 (late clinical and late parasitological failures). Primary timepoint is Day 28
Secondary outcome [1] 340279 0
Percent of adverse event following treatment of each drugs was assessed.
The known adverse events of artesunate+amodiaquine include abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.
Patients or parents/ guardians of the enrolled children were asked routinely on each visit about previous symptoms and about symptoms that have emerged since the previous follow-up visit. When clinically indicated, patients were evaluated and treated appropriately. All adverse events were recorded on the case report form.
Timepoint [1] 340279 0
Day 28
Secondary outcome [2] 343309 0
Prevalence of K13 mutations
DNA of day 0 (baseline) was extracted and were tested for the presence of mutations in the propeller domain in the pfK13 gene, which are associated with artemisinin resistance, whereby a portion of the pfK13 gene was amplified in a nested PCR assay (codons 440–680, 720 bp). DNA sequences were analysed to identify specific single nucleotide polymorphisms (SNPs) related to artemisinin resistance (Menard et al., 2016). Briefly, electrophoregrams were visualized and analysed with CEQ2000 genetic analysis system software (Beckman Coulter, Villepinte, France). The amino acid sequences were compared with the 3D7 wild-type amino acid sequences PF3D7_1343700. The presence of SNPs was confirmed by reading both the forward and the reverse strands. Parasites with mixed alleles were considered mutants.
Timepoint [2] 343309 0
At baseline (day0)

Eligibility
Key inclusion criteria
1. age 6 months and above;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 250–200,000/µl asexual forms;
4. presence of axillary temperature greater or equal to 37.5 degrees centigrade or history of fever within the last 24 hours;;
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 between 12 and 18 to age of majority years; and
9. consent for pregnancy testing from female of child-bearing potential and from their parent or guardian if under the age of 18 years.
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 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 < 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 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
A minimum sample size of 73 was calculated assuming 5% treatment failure of the study medicines, a confidence level of 95% and a precision level of 5%. With a loss to follow-up of 20% by day D28, 88 patients per site was calculated. The total target sample for the 4 sites is 352 patients.
All clinical and laboratory data were recorded in standardized case record forms for each patient. Data were validated. Demographic, clinical and laboratory data were double-entered independently and analysed with an Excel® database specifically designed by WHO for studies of anti-malarial drug efficacy (http://www.who.int/malaria/publications/atoz/9789241597531/en/). Baseline patient characteristics (age, temperature, parasitaemia) were compared across the study sites and antimalarial medicines using STATA. Patients were excluded from the per-protocol analysis of treatment outcomes if they were lost to follow-up, withdrawn, had reinfections or had unknown PCR. For the Kaplan-Meier analysis, all patients were included until the day of exclusion from the study. Chi-square test was used to compare categorical data. Fisher’s exact test was used where cell counts were less than 5. Differences in the mean were evaluated using the t-test. Confidence intervals were calculated for binomial proportions. Student’s t test was used to compare means

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
8/09/2016
Date of last participant enrolment
Anticipated
Actual
12/11/2016
Date of last data collection
Anticipated
Actual
3/12/2016
Sample size
Target
352
Accrual to date
Final
280
Recruitment outside Australia
Country [1] 9332 0
Eritrea
State/province [1] 9332 0
Gash Barka zone

Funding & Sponsors
Funding source category [1] 297898 0
Government body
Name [1] 297898 0
Ministry of health of Eritrea
Country [1] 297898 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] 296952 0
None
Name [1] 296952 0
Address [1] 296952 0
Country [1] 296952 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298948 0
Health Research Proposal Review and Ethical Committees
Ethics committee address [1] 298948 0
Ararib 174,Asmara,
Ethics committee country [1] 298948 0
Eritrea
Date submitted for ethics approval [1] 298948 0
12/06/2016
Approval date [1] 298948 0
14/07/2016
Ethics approval number [1] 298948 0

Summary
Brief summary
A study was conducted in 2016 to assess the efficacy of artesunate+amodiaquine (ASAQ) and patterns of molecular markers for artemisinin resistance. The study was conducted in 4 sentinel sites (Tesseney Hospital, Goluj Health Center, Tekombia Health Center, Shambuko Health Center). It was one-arm prospective assessment of clinical and parasitological outcomes to directly observed standard therapeutic regimen of ASAQ for the treatment of uncomplicated falciparum malaria. Patients aged 6 months and above were followed up 28 days following treatment. Prevalence of K13 mutations was investigated.
A total of 280 were recruited from the four sites. The laboratory analysis for differentiating recrudescence from new infection as well as for K13 mutations are underway.
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 78750 0
Dr Araia Berhane
Address 78750 0
Communicable Disease Control Division
Ministry of Health
P. O. Box 212, Asmara
Country 78750 0
Eritrea
Phone 78750 0
+2911117041
Fax 78750 0
Email 78750 0
[email protected]
Contact person for public queries
Name 78751 0
Araia Berhane
Address 78751 0
Communicable Disease Control Division
Ministry of Health
P. O. Box 212, Asmara
Country 78751 0
Eritrea
Phone 78751 0
+2911117041
Fax 78751 0
Email 78751 0
[email protected]
Contact person for scientific queries
Name 78752 0
Araia Berhane
Address 78752 0
Communicable Disease Control Division
Ministry of Health
P. O. Box 212, Asmara
Country 78752 0
Eritrea
Phone 78752 0
+2911117041
Fax 78752 0
Email 78752 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseIncreasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea.2023https://dx.doi.org/10.1056/NEJMoa2210956
N.B. These documents automatically identified may not have been verified by the study sponsor.