Susceptibility to Artemisinin-based combination therapies (ACTs) currently remains high among the African
Plasmodium falciparum population, but resistant mutants have been detected recently. To mitigate the risk of resistance leading to a dramatic increase in malaria related mortality, more efficient ACTs need to be urgently explored for quick deployment in Africa.
Artemether-lumefantrine (AL) is widely used and shows high efficacy and favourable safety in Africa but needs to be protected to increase its useful lifespan. Atovaquone-proguanil (AP) is highly efficacious, safe and resistant parasites that do not circulate in any endemic area. AP targets multiple parasite stages -liver and blood in human host, and mosquito through an independent mode of action, limiting the risk of cross-resistance with current ACTs.
Overall aim
To develop new antimalarial treatments by combining existing, efficacious medicines for treatment of uncomplicated malaria in African children by promoting African and European research collaboration and strengthening the capacity of 30 of African institutions to conduct clinical research.
Objectives
• To assess, through a non-inferiority comparator-controlled trial in four sub-Saharan
African countries, the efficacy of associating AL and AP (id est, AL+AP) for the treatment of uncomplicated P. falciparum malaria in African children.
• To compare AL+AP with AL regarding 1) post-treatment prophylactic efficacy, 2) transmission-blocking activity, 3) safety and tolerability, 4) pharmacokinetics, and 5) drug resistance selection.
Project Pathway to impact
• Likelihood to result in major advances in the field
• Advancing the clinical development of new and improved products, accelerating the adaption of treatment for use in children in the sub-Saharan Africa
• Contribution to strengthening the capacity in sub-Saharan Africa to conduct clinical trials of malaria interventions
• Contribution to the development of infrastructure to support assessment of transmission reduction potential of new malaria interventions including diagnostics, drug, and vaccines
• Scientific/academic dissemination
• Broad-Based Dissemination
• Country-level dissemination
• Internal/institutional-level dissemination
• communication
The main outcome will be cure rate at day-42, excluding reinfections. Antimalarial pharmacokinetic parameters and post-treatment prophylactic efficacy will be estimated for the two treatments and compared. Sub-studies will look at transmission-blocking efficacy through membrane-feeding assays and gametocyte dynamics, drug resistance selection.
By proofing that AL+AP has safety and cure rate similar to AL, this project will lead to important public health-level benefits by provision of a first candidate regimen to be deployed when ACT resistance spreads throughout Africa and by decreasing human to mosquito transmission.
Currently, Recruitment at the study sites has ended, with a total of 1,664 participants enrolled. The Last Patient Last Visit occurred on 30 March 2024, and the Database Lock has been completed in November 2024.
Clinical study report writing is underway and will be available by November 2025
Interim analysis of the entomological study shows the superiority of AL+AP to AL+placebo in terms of transmission blocking effect.
