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Trial registered on ANZCTR


Trial ID
ACTRN12617000456358
Ethics application status
Approved
Date submitted
3/03/2017
Date registered
28/03/2017
Date last updated
28/03/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of the medications of first line treatment (artesunate+amodiaquine) and second line treatment (artemether+lumefantrine) for the treatment of uncomplicated Plasmodium falciparum in Malabo, Bata and Ebibey, Equatorial Guinee
Scientific title
Efficacy and safety of the medications of first line treatment (artesunate+amodiaquine) and second line treatment (artemether+lumefantrine) for the treatment of uncomplicated Plasmodium falciparum in Malabo, Bata and Ebibey, Equatorial Guinee
Secondary ID [1] 291341 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 302325 0
Condition category
Condition code
Infection 301909 301909 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study aims yo assess the efficacy and safety of the first line (artesunate+amodiaquine) and second line (artemether+lumefantrine) with the following dosages:
Artesunate-amodiaquine: 4 mg/kg artesunate + 10mg/kg amodiaquine once daily for 3 consecutive days will be given.
Artemether-lumefantrine containing 20 mg artemether+ 120 mg lumefantrine in each tablet will be given twice daily for three days according to the recommended weight bands as follows: 1 tablet to those weighing 5 to 14 kg; 2 tablets for 15 to 24 kg; 3 tablets for 25 to 34 kg and 4 tablets for equal or greater than 35 kg. The total target dose ranges are 5-24 mg/kg bw of artemether and 29-144 mg/kg bw of lumefantrine.

All treatments will be taken orally under direct supervision by the health worker. The two drugs will be tested sequentially. The patient will be given artesunate+amodiaquine or artemether+lumefantrine and will be followed up for 28 days.
Intervention code [1] 297369 0
Treatment: Drugs
Comparator / control treatment
No control group.
The study is one arm cohort prospective assessment for each drug.
Patients in each site will be enrolled first to artesunate+amodiaquine untill a sample of 88 is reached. Then the subsequent patients will be recruited to the artemether+lumefantrine untill the target sample size of 88 is reached.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301339 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 and clinical responses during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 301339 0
Days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [1] 332335 0
Percent of adverse event following treatment of each drugs will be documented.
The known adverse events of:
Artesunate+amodiaquine are abdominal pain, asthenia, cough, diarrhoea, dizziness, insomnia, loss of appetite, nausea, vomiting.
Atemether+lumefantrine are abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.

Parents or guardians of all enrolled children 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] 332335 0
Days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 332336 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] 332336 0
Day 0

Eligibility
Key inclusion criteria
1. age from 6 to 59 months;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000–200,000/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 parent/ guardian of children.
Minimum age
6 Months
Maximum age
59 Months
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. 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).

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)
Allocation is not concealed
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
Treatment failure for each drug is estimated 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients per drug and per site will be included in the study.
The WHO data analysis excel sheet 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 to the reasons for withdrawal listed in section 3.8, patients will be 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] 8707 0
Equatorial Guinea
State/province [1] 8707 0
Bioko Norte, Litoral and Kie-ntem provinces

Funding & Sponsors
Funding source category [1] 295813 0
Government body
Name [1] 295813 0
Ministry of Public Health of Equatorial Guinea
Address [1] 295813 0
Rue Rey Malabo S/N.
Malabo Bioko Norte
Country [1] 295813 0
Equatorial Guinea
Primary sponsor type
Government body
Name
Ministry of Public Health of Equatorial Guinea
Address
Rue Rey Malabo S/N.
Malabo Bioko Norte
Country
Equatorial Guinea
Secondary sponsor category [1] 294662 0
None
Name [1] 294662 0
Address [1] 294662 0
Country [1] 294662 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297100 0
WHO Research Ethics Review Committee
Ethics committee address [1] 297100 0
World Health Organization
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 297100 0
Switzerland
Date submitted for ethics approval [1] 297100 0
30/01/2017
Approval date [1] 297100 0
01/03/2017
Ethics approval number [1] 297100 0
ERC.0002867

Summary
Brief summary
The efficacy and safety of artesunate-amodiaquine and artemether+lumefantrine for the treatment of uncomplicated P. falciparum malaria will be assessed in three sites of Equatorial Guinea.
It is single prospective study for each drug and both drugs will be tested in each site. Patients will be enrolled sequentially starting with artesunate+amodiaquine and then artemether+lumefantrine.
Febrile patients aged 6 to 59 months with confirmed uncomplicated P. falciparum infection will be enrolled. A sample Size of 88 patients per drug per site will be targeted.
Patients will be treated with the WHO recommended standard doses of artesunate-amodiaquine (daily dose for 3 days) and artemether-lumefantrine (twice daily for 3 days).
Clinical and parasitological parameters will be monitored over a 28-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 72974 0
Dr Pedro Berzosa Diaz
Address 72974 0
National Centre of Tropical Medicine of the Institute of Health Carlos III
Carretera de Majadahonda - Pozuelo, Km. 2.200.
28220 - Majadahonda (Madrid).
Country 72974 0
Spain
Phone 72974 0
+34-918 222 223
Fax 72974 0
Email 72974 0
pberzosa@isciii.com
Contact person for public queries
Name 72975 0
Dr Pedro Berzosa Diaz
Address 72975 0
National Centre of Tropical Medicine of the Institute of Health Carlos III
Carretera de Majadahonda - Pozuelo, Km. 2.200.
28220 - Majadahonda (Madrid).
Country 72975 0
Spain
Phone 72975 0
+34-918 222 223
Fax 72975 0
Email 72975 0
pberzosa@isciii.com
Contact person for scientific queries
Name 72976 0
Dr Pedro Berzosa Diaz
Address 72976 0
National Centre of Tropical Medicine of the Institute of Health Carlos III
Carretera de Majadahonda - Pozuelo, Km. 2.200.
28220 - Majadahonda (Madrid).
Country 72976 0
Spain
Phone 72976 0
+34-918 222 223
Fax 72976 0
Email 72976 0
pberzosa@isciii.com