Artemisinin-Based Combination Therapy: Clinical Trials in Cameroon

Study Overview
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Brief Summary
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This proposal aims to evaluate the safety and efficacy of artemisinin-based anti-malaria combination drugs (ACTs) for the treatment of children aged 6-120 months in different locations in Cameroon. Randomized clinical trials will provide local data on the safety of the test drugs, and on putative marker mutations of the development of resistance to ACT. The study will involve three centers, namely, Banso (Guinea-Savannah region), Limbe(Littoral Forest), and Garoua(Sahel-Savannah). The trial will compare the efficacy and safety of Amodiaquine(AQ)-Artesunate(Art) with Coartem®(Artemether-Lumefantrine). Drug efficacy will be determined using a WHO standardized 28-day protocol. Safety will be monitored through clinical examination and biochemical and hematological indices. Molecular markers of artemisinin resistance will be investigated by molecular sequencing and comparison of parasite profiles of the PfATP6 gene in drug failure cases, . Recrudescences or re-infections will be assessed by analysis of the msp1 and msp2 genes. The impact of these combinations on generation of gametocytes will be determined from gametocyte carriage rates measured by microscopy.

Detailed Description
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Outpatients will be screened for malaria by blood film examination Malaria-positive children will be examined by the physician for inclusion or exclusion(see below) Informed consent will be sought from the guardians of potential patients Patients or guardians will be interviewed and a case record form completed Patients will be randomized into one of the two arms in the ratio 4:1 AQ/Art: CoArtem and issued a study card Filter paper and 5ml venous blood samples will be collected Patients will be hospitalised for three days to allow completion of therapy under observation The patient will be asked to return on days 7, 14 and 28 for assessment of clearance or recrudescence of parasites Patient will be examined for parasites and evaluated for early treatment failure (ETF), late treatment failure (LTF), late parasitological failure (LPF) or adequate clinical and parasitological response.(ACPR). If a patient does not appear for follow up, a community health worker will try to trace them and will collect blood onto filter paper and a microscope slide should the patient have a temperature ≥ 37.5°C Patients whose parents opt out of the study will be administered quinine sulphate if parasitaemic Filter paper samples will be air dried and stored with dessicant until required. Whole blood samples collected into citrate as anticoagulant will be processed for plasma, aliquoted into 300µl lots and stored at -70°C. Patient information will be entered at the close of each day into laptops and collectively sent to Yaounde at the end of the first month of study and thereafter at the end of each week, along with the hard copies of the case report forms. Analysis will be performed on the samples within three months of collection for molecular markers of resistance, genetic structure of parasites and for blood drug levels of medications used in the trial

Official Title
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Phase III Clinical Trials of Artemisinin-based Combination Therapy in Cameroon

Conditions
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Malaria

Intervention / Treatment
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* Drug: 1. Artemether-Lumefantrine (AL)
* Drug: 2. Amodiaquine-Artesunate (AQ-AS)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: children aged 6-120 months; axillary temperature ≥ 37.5°C and/or history of fever within past 24 hours; P. falciparum asexual parasitemia between 1000 and 100000/µl; ability to attend follow-up visits. Exclusion criteria: co-infections; underlying chronic disease; severe malaria as indicated by hyperparasitemia, severe anemia (PCV 15%, Hb 5g/ml), respiratory distress, inability to drink, persistent vomiting in past 24 hours; recent history of multiple convulsions; jaundice; the inability to stand or sit; history of allergy to study drugs.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 120 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 Artemether-Lumefantrine (AL)<br>Study group 1. Subjects in this group received treatment with Artemether-Lumefantrine. Children received 2 mg/kg Artemether and 12 mg/kg Lumefrantrine with milk twice daily (or every 12 hours for 3 days. | Drug: 1. Artemether-Lumefantrine (AL)<br>* Artemether-Lumefantrine(Co-Artem)=Artemether, 2mg/kg x 2(12h apart) and Lumefantrine, 12mg/kgx2 (12h apart).<br>* Other names: CoArtem;|
| Active Comparator: 2 Amodiaquine-Artesunate (AQ-AS)<br>Study group 2. Subjects in this group received treatment with Amodiaquine-Artesunate. Children received a co-administered combination of 30 mg/kg Amodiaquine (AQ) plus 4 mg/kg Artesunate (AS) daily for 3 days. | Drug: 2. Amodiaquine-Artesunate (AQ-AS)<br>* Amodiaquine-Artesunate (0H),D1(24H),D2(48H)= Artesunate 4mg/kg and Amodiaquine at 10mg/kg<br>* Other names: Arsucam;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure Rate on Day 28 | To evaluate the safety and antimalarial efficacy of two drug combinations: Artemether-Lumefantrine (AL) and Amodiaquine-Artesunate (AQ - AS) in Camaroonian patients in Mutengene, Bangolan and Garoua | Day 0 - 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure Rate Day 14 | To evaluate antimalarial efficacy of AL and AQ-AS on day 14 post-treatment | Day 0-14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Efficacy, Safety, Children, Cameroon