Project title: Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria
Project Coordinator(s): U. D’Alessandro (Belgium) and TK Mutabingwa (Tanzania)
European collaborators: Feiko ter Kuile and Jenny Hill (UK), Raffaella Ravinetto, Jean Pierre Van geertruyden, Joris Menten (Belgium), Henk Schallig and Peter De Vries (The Nederlands), Vera Ecser (Austria)
Site PIs: Halidou Tinto (Burkina Faso); Harry Tagbor (Ghana); Linda Kalilani (Malawi); Modest Mulenga (Zambia); Steven Rulisa (Rwanda)
This project aims to identify two treatment regimens that are at least 95% effective as first-line treatment of uncomplicated malaria in second and third trimester pregnancy, and one regimen for the second line (rescue) treatment.
The study is designed as a non-inferiority, multi-centre, randomized, open label trial to be conducted in four sites across Africa (Burkina Faso, Ghana, Malawi and Zambia) and comparing the fixed dose combinations of artemether-lumefantrine (AL); amodiaquine-artesunate (AQ-AS); mefloquine–artesunate (MQ-AS) and dihydroartemisinin-piperaquine (DQ-PPQ). Pregnant women attending the antenatal clinic at 16 weeks of gestation or above will be screened for P. falciparum malaria infection and, pending the informed consent, will be randomised to one of the above treatments. Each site will test three treatments, distributed in a way to allow a head-to-head comparison so that each treatment’s relative value according to a series of outcomes will be established. The primary analysis will use the combined data from all four centres together, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all six possible pair-wise treatment comparisons using all available data. Each pregnant woman will be actively followed for 63 days post treatment and then monthly until delivery. Birth weight and haemoglobin data will be collected as soon as possible after delivery. When possible, a placenta impression smear and a PCR spot will also be prepared. The newborn will be examined for congenital abnormalities. Both the mother and the newborn will be reassessed between four and six weeks after delivery for any adverse event.
Blood samples for population pharmacokinetics will be collected at established times, allowing the analysis of the relationship between drugs levels and response to treatment. In Burkina Faso, to test the sensitivity of the local parasite population to the study drugs, an additional blood sample for in vitro testing with the isotopic microtest technique will be collected from women with an initial parasitaemia of 4,000/.
A total of 870 patients will be recruited to each treatment; this corresponds to 290 patients in each treatment group in each centre (i.e. total centre sample size for the three arms: 870 patients) – and hence a total study sample size of 3480 patients.