Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria. (PREGACT)

Overall Goal: To identify artemisinin-based combination treatments (ACT) that can be safely and efficaciously used to treat women with malaria in their second and third trimester of pregnancy. This will be attained through the following strategies: 1. Research: To determine the safety and efficacy of 4 ACTs when administered to pregnant women during the second and the third trimester with P. falciparum infection and collect explanatory variables for treatment failure (PCR-corrected) and for recurrent parasitaemia. 2. Capacity Development: To develop disease endemic country research capacity through training and professional development of scientists, building of infrastructure and transfer of technology. 3. Networking: To coordinate research efforts on treatment and prevention tools of malaria in pregnancy and, by doing so, finalise a common research agenda and promote the rational use of available resources. Rationale:Although malaria is the most important human parasitic disease, few studies on antimalarial drugs have been carried out in pregnant women. Pregnant women are a high-risk group requiring effective antimalarials but they are systematically excluded from clinical trials for fear of teratogenicity and embryotoxicity. This has complicated evidence-based recommendations for the prevention and treatment of malaria during pregnancy. There is insufficient information on the safety and efficacy of most antimalarials in pregnancy, including exposure in the first trimester. The World Health Organization (WHO) recommends effective ACT in the second and the third trimester and several African countries are already implementing it. Though the experience on the use of ACTs and on their safety and efficacy in pregnancy is increasing (over 1,000 documented pregnancies, mainly in South East Asia), this information is still limited, particularly in Africa. Therefore, we propose to test 4 potential candidates, the fixed dose combinations of artemether-lumefantrine (AL), amodiaquine-artesunate (AQ-AS), mefloquine-artesunate (MQ-AS) and dihydroartemisinin-piperaquine (DHA-PQ). This choice of candidate drugs was based on the target drug profile for case-management consisting of a range of criteria including known efficacy in children (cure), safety in pivotal phase-3 trials in children and adults; practicality of the dosing regimen (duration [e.g. 3 vs 7 days]; formulation (co-formulated tablets requires less tablets]), tolerance, current availability in the population, and cost. By contemporaneously testing several drug regimens, we will shorten the time of data collection and determine the relative ‘value’ of each treatment, providing the basis for an informed choice by programs and policy makers. In addition, PK data and in vitro parasite’s drug sensitivity will be related to treatment outcome and will help in understanding the drugs’ pharmacodynamic. The capacity building component has been formulated taking into account the individual needs of the participating African institutions and the complementary expertise between European and African partners. The investigators involved in this proposal recently held a meeting (in Barcelona under the umbrella of the MIPC) where the respective African research institutions where classified according to the criteria at page 7 of the guidelines for the applicants. Most institutions involved in this proposal where at level 3 or 4 for most but not all components. An African sister institution was identified and will benefit for a substantial share of the capacity building component of this proposal. Networking will be carried out under the umbrella of the MIPC, an initiative of 23 African and European institutions interested in contributing to the control of malaria in pregnancy. Considering that the Consortium comprises most groups involved in research on malaria in pregnancy, from the most biological questions (immunology, parasitology) to operational research, e.g. effectiveness of a given intervention, it represents a powerful body within which south-south and north-south interactions and exchanges can and will occur. The Consortium can also facilitate linkages with other MIP stakeholders so that new and efficient ways of preventing and treating MiP in Africa are found and implemented as speedily and effectively as possible. Specific research objectives 1. To compare the efficacy of AL, AQ-AS, MQ-AS and DHA-PQ on outcomes occurring during the 63-day active follow up post-treatment (parasitological failure and haematological recovery) and at delivery (birth weight and placenta malaria); 2. To determine the safety profile of AL, AQ-AS, MQ-AS and DHA-PQ in terms of tolerability and adverse events from treatment until 6 weeks post partum; 3. To determine the relation between drug pharmacokinetics (Day 7 levels of the partner drug) and response to treatment; 4. To asses the in vitro susceptibility of P. falciparum isolates collected before treatment to several drugs, including the partner drug tested, and to correlate their IC50 to treatment response; Specific capacity development objectives 1) To develop the capacity of southern partner institutions for conducting GCP-compliant multicentre trials in Africa 2) To standardise short-term training on key methodologies across all Consortium-led MiP trials through cost effective approaches and centralised training where appropriate 3) To develop sustainable strategies for the long term training of future generations of African scientists. Specific networking objectives 1. To agree upon and produce standard operating procedures for all project-related activities, from data collection, laboratory procedures to data analysis and dissemination strategies; 2. To interact with the larger MIPC, present and discuss the results obtained in the light of other ongoing research activities, e.g. malaria prevention; 3. To coordinate capacity building activities and create a common training program tailored to the participati