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Trial registered on ANZCTR


Registration number
ACTRN12616001423404
Ethics application status
Approved
Date submitted
3/09/2016
Date registered
12/10/2016
Date last updated
2/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of therapeutic efficacy and safety of artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinine-piperaquine for the treatment of uncomplicated Plasmodium falciparum in Democratic Republic of Congo
Scientific title
Evaluation of therapeutic efficacy and safety of artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinine-piperaquine for the treatment of uncomplicated Plasmodium falciparum in Democratic Republic of Congo
Secondary ID [1] 290087 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 300178 0
Condition category
Condition code
Infection 300062 300062 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 2o mg artemether+ 120 mg lumefantrine in each tablet (twice a day for 3 days) will be administered 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.
Dihydroartemisinin-piperaquine: 4 mg/kg dihydroartemisinin and 18 mg/kg piperaquine once a day for 3 days.

All treatments will be taken orally under direct supervision by the health worker. These three artemisinin-based combinations will be tested separately. The patient will be given either artesunate+amodiaquine, artemether+lumefantrine or dihydroartemisinin+piperaquine. enrolled patients will be followed up for 28 days (artesunate+amodiaquine, artemether+lumefantrine) for or 42 days (dihydroartemisinin+piperaquine).
Intervention code [1] 295826 0
Treatment: Drugs
Comparator / control treatment
This is a one arm cohort prospective study for each drug. Patients will be enrolled sequentially to each drugs: each site patients will be enrolled for artesunate+amodiquine until 88 patients are recruited; then patients will be enrolled into artemether-lumefantrine until 88 patients are recruited and lastly patients will be enrolled into dihydroartemisinin-piperaquine group. These is not a comparative study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299529 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 42 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 299529 0
At days 1, 2, 3, 7, 14, 21 and 28 following artesunate+amodiquine or artemether-lumefantrine treatments; and days 1, 2, 3, 7, 14, 21 and 28, 35 and 42 following dihydroartemisinin-piperaquine treatment.
Secondary outcome [1] 327459 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.
Dihydroartemisinine – piperaquine are Asthenia, cough, diarrhoea, fever, loss of appetite, 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] 327459 0
At days 1, 2, 3, 7, 14, 21 and 28 following artesunate+amodiquine or artemether-lumefantrine treatments; and days 1, 2, 3, 7, 14, 21 and 28, 35 and 42 following dihydroartemisinin-piperaquine treatment.
Secondary outcome [2] 327460 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] 327460 0
Day 0 (before treatment)

Eligibility
Key inclusion criteria
1. age between six to 59 months;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 2000–200,000/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 parent or guardian.
Minimum age
6 Months
Maximum age
59 Months
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 belo 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)
It is three arm cohorts sequential prospective evaluation of clinical and parasitological responses to directly observed treatment..
No concealment.

Patients will enrolled sequentially to the three drugs: patients will be enrolled for artesunate-amodiaquine until the sample size is reached, then into artemether-lumefantrine until required sample size is reached and finally in to dihydroartemisinin-piperaquine.
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
Other
Other design features
The three drugs will be tested sequentially: a cohort for each drugs.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
As the treatment failure rate to the study drugs are 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. With a 20% increase to allow loss to follow-up and withdrawals during the 42-day follow-up period, 88 patients per site will be included in the study.
The WHO excel software programs 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 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 42, with 95% confidence intervals, PCR-uncorrected and PCR-corrected.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/11/2016
Actual
11/04/2017
Date of last participant enrolment
Anticipated
30/01/2017
Actual
23/05/2017
Date of last data collection
Anticipated
28/02/2017
Actual
23/06/2017
Sample size
Target
534
Accrual to date
Final
564
Recruitment outside Australia
Country [1] 8185 0
Congo, The Democratic Republic Of The
State/province [1] 8185 0
Tshopo, Haut Katanga, North Kinu, Kasai Central, Equatorial, Kongo Central

Funding & Sponsors
Funding source category [1] 294457 0
Government body
Name [1] 294457 0
Ministry of Health
Country [1] 294457 0
Congo, The Democratic Republic Of The
Primary sponsor type
Government body
Name
Ministry of Health
Address
Av. du tourisme number 1
c/o Hopital de la rive
Ngaliema / Kinshasa
Country
Congo, The Democratic Republic Of The
Secondary sponsor category [1] 293323 0
None
Name [1] 293323 0
Nil
Address [1] 293323 0
Nil
Country [1] 293323 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295891 0
WHO ERC
Ethics committee address [1] 295891 0
20 Av. Appia,
1211 Geneva 27
Ethics committee country [1] 295891 0
Switzerland
Date submitted for ethics approval [1] 295891 0
14/07/2016
Approval date [1] 295891 0
23/08/2016
Ethics approval number [1] 295891 0
ERC.0002803

Summary
Brief summary
The efficacy and safety of artesunate-amodiaquine, artemether+lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated P. falciparum malaria infections will be assessed in 6 sites during September 2016 to January 2017.
It is 3 arms arm sequential prospective study for each drug combination.
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) and dihydroartemisinin-piperaquine ( daily dose for 3 days).
Clinical and parasitological parameters will be monitored over a 42-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 68818 0
Dr Gauthier MESIA KAHUNU
Address 68818 0
Unite de Pharmacologie Clinique et Pharmacovigilance
Facultes de Medecine et des Sciences Pharmaceutiques
Universite de Kinshasa
B.P. 212 Kinshasa XI
Country 68818 0
Congo, The Democratic Republic Of The
Phone 68818 0
+243 813 261 360
Fax 68818 0
Email 68818 0
[email protected]
Contact person for public queries
Name 68819 0
Gauthier MESIA KAHUNU
Address 68819 0
Unite de Pharmacologie Clinique et Pharmacovigilance
Facultes de Medecine et des Sciences Pharmaceutiques
Universite de Kinshasa
B.P. 212 Kinshasa XI
Country 68819 0
Congo, The Democratic Republic Of The
Phone 68819 0
+243 813 261 360
Fax 68819 0
Email 68819 0
[email protected]
Contact person for scientific queries
Name 68820 0
Gauthier MESIA KAHUNU
Address 68820 0
Unite de Pharmacologie Clinique et Pharmacovigilance
Facultes de Medecine et des Sciences Pharmaceutiques
Universite de Kinshasa
B.P. 212 Kinshasa XI
Country 68820 0
Switzerland
Phone 68820 0
+243 813 261 360
Fax 68820 0
Email 68820 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

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