Project: IPTp with dihydroartemisinin-piperaquine and azithromycin for Malaria, sexually transmitted and reproductive tract infections in pregnancy in high sulphadoxine-pyrimethamine resistance areas in Kenya, Malawi and Tanzania (HIV-positive component)

Acronym	IMPROVE-2 (Reference Number: TRIA2015-1076b)
Duration	01/07/2017 - 30/11/2020
Project Topic	In some regions of malaria-endemic Africa, nearly 12% of women are co-infected with HIV and malaria during pregnancy. Co-infection with HIV and malaria during pregnancy individually increase the risks of pregnancy loss, preterm delivery, and growth retardation of the foetus resulting in small babies. In women not infected with HIV, these harmful effects can be partially mitigated by intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), recommended by WHO throughout sub-Saharan Africa. IPTp with SP is not recommended in HIV-infected women, taking daily prevention with cotrimoxazole (CTX), an antibiotic which also has antimalarial activity and which is presumed to provide adequate if not equivalent protection against pregnancy malaria as SP. Recent trials in East and Southern Africa where resistance by the malaria parasite to both SP CTX is high suggest the need for enhanced chemoprevention. Two exploratory trials showed that DP for IPTp in HIV-uninfected pregnant women was well tolerated and much more effective in preventing malaria than the current drug SP. A subsequent exploratory study showed that DP was also well tolerated and safe in HIV-infected women already taking cotrimoxazole and anti-retroviral drugs. None of these three trials were big enough to be able to evaluate the impact on pregnancy outcomes and health of the newborn. We propose a multi-national, 3-arm, parallel, placebo-controlled, individually randomised, phase-3, superiority trial to compare the efficacy of monthly IPTp with DP, alone or combined with AZ, against placebo-IPTp (i.e. CTX alone) in 1,335 (445 per arm) HIV-infected pregnant women receiving daily cotrimoxazole. The study will be conducted in six to eight sites in high malaria endemic and high HIV endemic areas in southern Malawi and western Kenya. These are the same sites in Malawi and Kenya where the trial in HIV-uninfected women will be conducted (TRIA2015-1076). HIV-infected pregnant women attending for antenatal care (ANC) between 16 and 28 weeks’ gestation will be eligible. Women will be seen monthly until delivery. Mothers and infants will be followed-up for 6 to 8 weeks post-partum. Sub-studies of cardiac-safety and pharmacokinetics, feasibility and cost-effectiveness will also be conducted. The trial is powered at 90% (alpha 0.05) to detect a 50% reduction in malaria, and at 80% to detect a 32.6% reduction in adverse pregnancy outcomes. The trial will take 3 years to complete. The Consortium consists of a highly experienced network of 4 institutions from Africa, Europe and the US with extensive experience in pregnancy trials.
Network	EDCTP2
Call	Research and Innovation Actions: Improved treatment and clinical management of poverty-related diseases

Project partner

Number	Name	Role	Country
1	Liverpool School of Tropical Medicine	Coordinator	United Kingdom
2	Kenya Medical Research Institute	Partner	Kenya
3	London School of Hygiene and Tropical Medicine	Partner	United Kingdom
4	University of Malawi, College of Medicine	Partner	Malawi