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Trial registered on ANZCTR


Registration number
ACTRN12616001609448
Ethics application status
Approved
Date submitted
8/11/2016
Date registered
21/11/2016
Date last updated
21/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum in health units of the Agua Grande and Lobata districts of the Sao Tome Island, Sao Tome and Principe
Scientific title
Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum in health units of the Agua Grande and Lobata districts of the Sao Tome Island, Sao Tome and Principe
Secondary ID [1] 290485 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 300865 0
Condition category
Condition code
Infection 300686 300686 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 the three drugs, the following dosages will be give:
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 separately. The patient will be given artesunate+amodiaquine or artemether+lumefantrine and will be followed up for 28 days.
Intervention code [1] 296343 0
Treatment: Drugs
Comparator / control treatment
No control group.
This is a one arm cohort prospective study for each drug.
Artesunate+amodiaquine will be tested in four health facilities in the Agua Grande district and artemether+lumefantrine will evaluated in three health facilities in the Lobata district.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300106 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] 300106 0
At days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [1] 329066 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] 329066 0
At days 1, 2, 3, 7, 14, 21, 28
Secondary outcome [2] 329067 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] 329067 0
At day 0 (prior to treatment

Eligibility
Key inclusion criteria
1. age from 6 months to 60 years;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 500–100,000/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 the patient or parent/ guardian of children.
8. informed assent from any minor participant aged from 12 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 majority years.
Minimum age
6 Months
Maximum age
60 Years
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. Haemoglobin < 8g/dl;
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);
9. a positive pregnancy test or breastfeeding; and
10. 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)
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
The treatment failure rate of artesunate+amodiaquine and artemether+lumefantrine in the area is assumed 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients should be included in the study per district.
WHO excel software programme 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 28/42, 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 28/42, with 95% confidence intervals, PCR-uncorrected and PCR-corrected.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/11/2016
Actual
Date of last participant enrolment
Anticipated
30/09/2017
Actual
Date of last data collection
Anticipated
30/10/2017
Actual
Sample size
Target
176
Accrual to date
Final
Recruitment outside Australia
Country [1] 8378 0
Sao Tome and Principe
State/province [1] 8378 0
Island of Sao Tome

Funding & Sponsors
Funding source category [1] 294903 0
Government body
Name [1] 294903 0
Ministry of Health of Sao Tome and Principe
Country [1] 294903 0
Sao Tome and Principe
Primary sponsor type
Government body
Name
Ministry of Health of Sao Tome and Principe
Address
Rua Patrice Lumumba 433. BP 23.
Country
Sao Tome and Principe
Secondary sponsor category [1] 293740 0
None
Name [1] 293740 0
Nil
Address [1] 293740 0
Nil
Country [1] 293740 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296279 0
WHO ERC
Ethics committee address [1] 296279 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 296279 0
Switzerland
Date submitted for ethics approval [1] 296279 0
29/06/2016
Approval date [1] 296279 0
17/10/2016
Ethics approval number [1] 296279 0
ERC.0002782

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 two districts.
It is single prospective study where artesunate+amodiaquine will be tested in one district and artemether+lumefantrine will tested in the other district.
Febrile patients aged 6 months and above with confirmed uncomplicated P. falciparum infection will be enrolled. A sample Size of 88 patients per drug per site per district.
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 70250 0
Dr Herodes Sousa Pontes Sacramento Rompao
Address 70250 0
Centre National des Endemies
Rua Patrice Lumumba 433.
BP 23 . Sao Tome.
Country 70250 0
Sao Tome and Principe
Phone 70250 0
+ 239 98595553
Fax 70250 0
Email 70250 0
herodesrompao@gmail.com
Contact person for public queries
Name 70251 0
Herodes Sousa Pontes Sacramento Rompao
Address 70251 0
Centre National des Endemies
Rua Patrice Lumumba 433.
BP 23 . Sao Tome.
Country 70251 0
Sao Tome and Principe
Phone 70251 0
+ 239 98595553
Fax 70251 0
Email 70251 0
cruzc@who.int
Contact person for scientific queries
Name 70252 0
Herodes Sousa Pontes Sacramento Rompao
Address 70252 0
Centre National des Endemies
Rua Patrice Lumumba 433.
BP 23 . Sao Tome.
Country 70252 0
Sao Tome and Principe
Phone 70252 0
+ 239 98595553
Fax 70252 0
Email 70252 0
herodesrompao@gmail.com

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

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