Improving PRegnancy Outcomes With PReVEntive Therapy in Africa-2 (IMPROVE-2)
Status:
Active, not recruiting
Trial end date:
2022-11-30
Target enrollment:
Participant gender:
Summary
2.3.3 Short technical protocol summary Background: Pregnant women represent a vulnerable
population for malaria. HIV-infected women are particularly at risk. In HIV-infected pregnant
women, WHO recommends daily cotrimoxazole (CTX), an antifolate drug, for malaria
chemoprevention and prophylaxis against opportunistic infection. However, there is
cross-resistance with sulphadoxine-pyrimethamine (SP), and high levels of antifolate
resistance threatens the antimalarial effect of CTX. Recent trials with intermittent
preventive therapy (IPT) with mefloquine in HIV-infected women on daily CTX, suggested that
chemoprevention with an effective antimalarial markedly improves the protection against
malaria compared to daily CTX alone. However, mefloquine was not well tolerated.
The long-acting combination of dihydroartemisinin-piperaquine (DP) is well tolerated and has
shown great promise as IPTp in HIV-negative women in East-Africa. Chemoprevention with
monthly DP has also been explored in HIV-infected pregnant women on daily CTX in Uganda.
Unfortunately, the study was inconclusive because malaria transmission was too low and a
clinically relevant drug interaction with efavirenz (EFV) was found reducing the exposure to
DP. WHO now recommends dolutegravir (DTG) based combination antiretroviral therapy (ARTs) as
the preferred firstline regimen including for pregnant women in the 2nd and 3rd trimester of
pregnancy for the prevention of mother-to-child transmission of HIV. As a result, many
countries in Africa are now transitioning to DTG-based combination antiretroviral therapy
(cARTs). No such drug-drug interaction is expected between DTG and DP. We will, therefore,
assess the safety and efficacy of malaria chemoprevention with monthly DP in HIV-infected
women on daily CTX and DTG-based cARTs.
Objectives and methods: This is a 2-arm, individually-randomized, multi-centre,
placebo-controlled superiority trial comparing the safety and efficacy of daily CTX plus
monthly DP ('CTX-DP') versus daily CTX plus monthly placebo-DP (i.e. 'CTX-alone', control
arm) to reduce malaria and the adverse effects of malaria in 898 (449 per arm) HIV-infected
pregnant women on DTG-based cARTs. The study will be conducted in 8 hospitals in Kenya and
Malawi in high SP-resistance areas with a high prevalence of malaria. These are the same
sites where the sister trial in HIV-uninfected women is being conducted in Kenya and Malawi
(IMPROVE trial). Both the mother and baby will be followed for 6-8 weeks after delivery. The
study is powered at 80% (alpha=0.05) to detect ≥50% relative risk reduction (RR=0.50) in the
primary outcome (cumulative incidence of malaria infection) from 12% in the CTX-alone arm
(control arm) to 6% in in the interventions arm allowing for 20% non-contributors. The trial
includes a pharmacokinetic assessment, cardiac monitoring for safety, assessment of
antimalarial drug and the impact on immune responses to malaria and other pathogens.
Phase:
Phase 3
Details
Lead Sponsor:
Liverpool School of Tropical Medicine
Collaborators:
CardiaBase Centers for Disease Control and Prevention KEMRI-Wellcome Trust Collaborative Research Program Kenya Medical Research Institute Kenya National AIDS & STI Control Programme University of Cape Town University of Copenhagen University of Malawi College of Medicine University of Massachusetts, Worcester University of Melbourne University of Toronto