Periodic Reporting for period 1 - ASAAP-plus (Clinical evaluation of AntimalarialS tri-therapy with AtovAquone-Proguanil for treatment of uncomplicated malaria in African children)
Período documentado: 2024-01-01 hasta 2024-12-31
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.
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.
WP1
• Monitoring of project activities
• Management of ethics and safety including the notification to regulatory authorities, ethics committees and the DSMB of the end of recruitment.
• Communication with EDCTP.
WP2
Enrolment and follow-up of study participants for the main trial: Recruitment of study participants for the Main Trial was completed in year one
Development of a clinical monitoring system: Clinical monitoring and safety data cleaning and close out were completed within reporting period 1.
WP3
The WP3 activities are Study monitoring, study logistics, data acquisition, data monitoring, and SOPs updates.
WP4
Assessing the inhibitory effect of AL+AP on the transmission of P. falciparum gametocytes to mosquito vectors by direct membrane feeding assays: This included the collection of data in field activities which was completed in 2024.
WP5
Preparation for comprehensive final analyses. Update of SAP.
Database cleaning and database lock has been completed, and preparation is ongoing for unblind and data analysis.
WP6
All Shortcourses have been performed including the paper and grant writing workshop which was completed in October 2024.
WP7
There has been an update and maintenance of the project website and this includes updates to the main study and inclusion of the ASAAP Plus.
WP8
Regular Supervision and support of financial and administrative activities within the project including disbursement of funds to the partner institutions. Funds were successfully disbursed during the first year to all partner institutions and beneficiaries for the successful implementation of the project.
• Monitoring of project activities
• Management of ethics and safety including the notification to regulatory authorities, ethics committees and the DSMB of the end of recruitment.
• Communication with EDCTP.
WP2
Enrolment and follow-up of study participants for the main trial: Recruitment of study participants for the Main Trial was completed in year one
Development of a clinical monitoring system: Clinical monitoring and safety data cleaning and close out were completed within reporting period 1.
WP3
The WP3 activities are Study monitoring, study logistics, data acquisition, data monitoring, and SOPs updates.
WP4
Assessing the inhibitory effect of AL+AP on the transmission of P. falciparum gametocytes to mosquito vectors by direct membrane feeding assays: This included the collection of data in field activities which was completed in 2024.
WP5
Preparation for comprehensive final analyses. Update of SAP.
Database cleaning and database lock has been completed, and preparation is ongoing for unblind and data analysis.
WP6
All Shortcourses have been performed including the paper and grant writing workshop which was completed in October 2024.
WP7
There has been an update and maintenance of the project website and this includes updates to the main study and inclusion of the ASAAP Plus.
WP8
Regular Supervision and support of financial and administrative activities within the project including disbursement of funds to the partner institutions. Funds were successfully disbursed during the first year to all partner institutions and beneficiaries for the successful implementation of the project.
The project has delivered a multicenter clinical evaluation of a triple combination therapy (AL+AP) in African children, targeting both treatment efficacy and transmission reduction. Harmonized entomological and molecular platforms across sites represent a significant innovation for clinical research capacity in sub-Saharan Africa.
ASAAP-Plus has advanced malaria treatment beyond the current state of the art through the clinical evaluation of a novel triple artemisinin-based therapy (TACT) combining artemether-lumefantrine (AL) with atovaquone-proguanil (AP) in African children. This represents the first large-scale Phase III assessment of a repurposed TACT regimen targeting both treatment efficacy and post-treatment prophylaxis in a high-burden paediatric population. In addition to standard clinical endpoints, the study generated evidence on transmission-blocking effects, pharmacokinetics and molecular resistance markers—areas insufficiently addressed by existing ACTs.
Preliminary results indicate that AL+AP may deliver added value through extended prophylaxis and reduced transmission potential, supporting its use as a resistance-management tool in settings threatened by emerging ACT resistance. The approach leverages already licensed drugs, creating a realistic path toward accelerated deployment.
If confirmed by final analyses, AL+AP could strengthen malaria control through improved treatment durability, reduced reinfection and possible reductions in community transmission. This would support global and EU health security priorities by slowing the spread of resistant P. falciparum strains.
ASAAP-Plus has advanced malaria treatment beyond the current state of the art through the clinical evaluation of a novel triple artemisinin-based therapy (TACT) combining artemether-lumefantrine (AL) with atovaquone-proguanil (AP) in African children. This represents the first large-scale Phase III assessment of a repurposed TACT regimen targeting both treatment efficacy and post-treatment prophylaxis in a high-burden paediatric population. In addition to standard clinical endpoints, the study generated evidence on transmission-blocking effects, pharmacokinetics and molecular resistance markers—areas insufficiently addressed by existing ACTs.
Preliminary results indicate that AL+AP may deliver added value through extended prophylaxis and reduced transmission potential, supporting its use as a resistance-management tool in settings threatened by emerging ACT resistance. The approach leverages already licensed drugs, creating a realistic path toward accelerated deployment.
If confirmed by final analyses, AL+AP could strengthen malaria control through improved treatment durability, reduced reinfection and possible reductions in community transmission. This would support global and EU health security priorities by slowing the spread of resistant P. falciparum strains.