In Vivo and In Vitro Efficacy of Artemisinin Combination Therapy

Study Overview
=================
Brief Summary
-----------------
This study aims to assess the degree of artemisinin resistance in adult and pediatric subjects presenting with uncomplicated falciparum malaria in Western Kenya. The study treatments will be Artemether Lumefantrine (AL) and Artesunate Mefloquine (ASMQ).

Detailed Description
-----------------
Data generated by this study will provide a snapshot of the current situation regarding P. falciparum sensitivity to ACTs in Western Kenya. By having subjects in one of the study arms receive artesunate and then the partner drug after completion of the artemisinin phase will enable the accurate evaluation of the artemisinin derivative without the confounding influence of the partner drug. Sequential administration of the components of an ACT drug is recognized by the WHO as one of the ways in which ACTs can be administered. There will be close follow-up of the subjects throughout the duration of the study, and as such, subjects who fail to respond adequately will receive prompt rescue treatment. Since it is largely expected that most subjects in Western Kenya will have satisfactory responses to ACTs, data from this study will provide baseline information regarding parasite characteristics when compared to data from Thailand, an area that has reported resistance to ACTs. This, in turn, will potentially enable the identification of key markers, both in the host and the parasite, that may assist in the early detection of resistance, and also to better understand the development of resistance to ACTs. As such, the data generated from this study, both on its own and when compared to and pooled with data from similar studies that will be conducted in Peru and Thailand, will potentially inform both local and international policy regarding ACT use for the treatment of uncomplicated P. falciparum malaria.

Official Title
-----------------
In Vivo and In Vitro Efficacy of Artemisinin Combination Therapy in Kisumu County, Western Kenya

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Drug: Artesunate
* Drug: Artemether Lumefantrine
* Drug: Mefloquine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult/child aged between 6 months and 65 years inclusive (minimum weight 11kg), presenting with a measured temperature of ≥37.5 C, or history of fever within 24 hours prior to presentation Mono-infection with Plasmodium falciparum Baseline parasitemia of 2000 - 200,000 asexual parasites/µl Ability to provide informed consent Willingness and ability to comply with the study protocol for the duration of the study Willingness to remain in the hospital for 3 days Exclusion Criteria: Presence of signs of severe malaria as defined by WHO Presence of severe anemia, defined as hemoglobin level below 6 g/dl Presence of mixed Plasmodium infection, or mono-infection of non-falciparum Plasmodium Inability to take oral medication History of allergy or contraindications to the study treatments Lactating or pregnant females Any condition that the investigator feels will result in an unfavorable outcome should the potential subject participate in the study

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AS/MQ<br>Treatment of P.falciparum mono-infection with 4 mg/kg of Artesunate daily for three days followed by 25mg/kg of Mefloquine split over two days. | Drug: Artesunate<br> <br> * Other names: AS;Drug: Mefloquine<br> <br> * Other names: MQ;|
| Active Comparator: AL<br>Treatment of P. falciparum mono-infection with Artemether Lumefantrine administered at the standard dosage according to pre-defined weight bands (5-14 kg: 1 tablet; 15-24 kg: 2 tablets; 25-34 kg: 3 tablets; and > 34 kg: 4 tablets) given twice a day for 3 days. | Drug: Artemether Lumefantrine<br> <br> * Other names: AL;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasitological clearance rates by microscopy | Clearance rates for the first 72 hour period after first ACT dose in patients with uncomplicated P. falciparum malaria | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasitological clearance rates by quantitative Polymerase Chain Reaction (PCR) | PCR adjusted clearance rates for the first 72 hours after first ACT dose in patients with uncomplicated P. falciparum malaria | 72 hours | 
| PCR-adjusted treatment efficacy of AL and AS/MQ |  | 42 days | 
| Antimalarial drug sensitivity responses and molecular genotyping | Correlate clinical outcomes with results of above tests | 42 days | 
| Identify common specific genetic determinants of artemisinin resistance derived from parasite populations |  | 42 days | 
| Gametocyte carriage in patients with uncomplicated malaria after treatment |  | 42 days | 
| Catalog parasite samples | Correlated to clinical datasets to longitudinally track resistance trends | 42 days | 
| Pharmacokinetic parameters associated with ACT failure |  | 42 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Malaria, P. falciparum mono infection, Early Treatment Failure, Late Treatment Failure