Efficacy and Safety of Artemisinin-based Combination Treatments in the Democratic Republic of the Congo

Study Overview
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Brief Summary
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The Democratic Republic of the Congo (DRC) is among the countries most affected by malaria in Sub-Saharan Africa. Condidering its size and the geographic position, the DRC is meant to play a major role in the malaria control in the region. The National Malaria Control program recommends artemisinin-based combination treatments (ACTs), in particular artesunate-amodiaquine or artemether-lumefrantrine for the treatment of uncomplicated malaria. Previous studies indicated that ACTs are still effective, with efficacy above the required threshold of 90%. It is required to assess regularly the efficacy of antimalarial drugs, in order to ascertain the relevance of treatment guidelines such that, in case of increasing failure rates, alternative options can be decided ontime. The purpose of this trial is to assess efficacy and safety of artesunate-amodiaquine (ASAQ Winthrop®), artemether-lumefantrine (Coartem Dispersible®) and dihydro-artemisinin-piperaquine (Eurartesim®) at day 42 in the treatment of uncomplicated Plasmodium falciparum malaria in six surveillance sites around DRC.

Detailed Description
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This is a phase 4, randomized, open labelled clinical trial, aiming to assess efficacy and safety of 3 ACTs in the treatment of uncomplicated malaria in the Democratic Republic of the Congo. Children diagnosed with uncomplicated Plasmodium falciparum uncomplicated malaria will be randomized and followed-up during 42 days.

Official Title
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Efficacy and Safety of Artesunate-amodiaquine, Artemether-lumefantrine and Dihydroartemisinine-piperaquine in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Democratic Republic of Congo: a Randomized Controlled Trial

Conditions
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Malaria

Intervention / Treatment
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* Drug: artesunate-amodiaquine
* Drug: artemether-lumefantrine
* Drug: Dihydroartemisinine-piperaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: children aged 6 to 59 months axillary temperature ≥ 37.5 °C or history of fever during the 24 h before recruitment monoinfection with Plasmodium falciparum with asexual parasite count of 2,000 to 200,000/µL ability to swallow oral medication ability and willingness to comply with the protocol for the duration of the study and to comply with the study visit schedule informed consent from a parent/guardian absence of general danger signs or signs of severe falciparum malaria according to the definitions of WHO (2000) absence of severe malnutrition according to WHO child growth standards absence of febrile condition due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal or hepatic diseases, HIV/AIDS) absence of regular medication, which might interfere with antimalarial pharmacokinetics absence of history of hypersensitivity reactions or contraindication to any medicine being tested or used as alternative treatment Exclusion Criteria: presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO body weight < 5kg hemoglobin level < 5g/ dL mixed or monoinfection with another Plasmodium species detected by microscopy presence of severe malnutrition presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS) regular medication, which may interfere with antimalarial pharmacokinetics; history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: artesunate-amodiaquine<br>Tablets containing 25 mg of artesunate and 67.5 mg of amodiaquine: one tablet daily for three days children weighing 4.5 to 8 kg, and tablets containing 50 mg of artesunate and 135 mg of amodiaquine: one tablet daily for three days for children weighing 9 to 17 kg. | Drug: artesunate-amodiaquine<br>* Tablets containing 25 mg of artesunate and 67.5 mg of amodiaquine: one tablet daily for three days children weighing 4.5 to 8 kg, and tablets containing 50 mg of artesunate and 135 mg of amodiaquine: one tablet daily for three days for children weighing 9 to 17 kg.<br>* Other names: artesunate-amodiaquine Winthrop®;|
| Experimental: artemether-lumefantrine<br>Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine. Each dose to be taken with high-fat food or drinks (for example milk). One tablet twice daily for children weighing 5 to <15 kg, two tablets twice daily for those weighing 15 to <25 kg and three tablets twice daily for those weighing 25 to < 35 kg, for three days. | Drug: artemether-lumefantrine<br>* Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine. Each dose to be taken with high-fat food or drinks (for example milk). One tablet twice daily for children weighing 5 to <15 kg, two tablets twice daily for those weighing 15 to <25 kg and three tablets twice daily for those weighing 25 to < 35 kg, for three days.<br>* Other names: Coartem®;|
| Experimental: Dihydroartemisinine-piperaquine<br>Tablets containing 20 mg of dihydroartemisinine and 160 mg of piperaquine. Half a tablet once daily for children weighing 5 to <7 kg, one tablet once daily for those weighing 7 to <13 kg, and two tablets once daily for those weighing 13 to <24 kg, for three days. | Drug: Dihydroartemisinine-piperaquine<br>* Tablets containing 20 mg of dihydroartemisinine and 160 mg of piperaquine. Half a tablet once daily for children weighing 5 to <7 kg, one tablet once daily for those weighing 7 to <13 kg, and two tablets once daily for those weighing 13 to <24 kg, for three days.<br>* Other names: Eurartesim®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-adjusted efficacy | the proportion of children with PCR adequate clinical and parasitological response | day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-unadjusted efficacy | the proportion of children with treatment failure: all treatment failures detected during the follow-up, regardless of genotyping | day 42 | 
| K-13 propeller polymorphisms | the proportion of mutations in portions of P. falciparum gene encoding kelch(K-13)-propeller domains (confering resistance to artemisinin) | day 42 | 
| incidence of adverse events | monitoring of all adverse events experienced by participants | day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, efficacy, safety, ACT, DR Congo