Improving PRegnancy Outcomes With PReVEntive Therapy in Africa-2 (IMPROVE-2)

• Status: Active, not recruiting
• Trial end date: 2022-11-30
• Target enrollment: 0
• Participant gender: Female

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
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

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
• Treatments: Artemisinins; Artenimol; Dihydroartemisinin; Piperaquine; Sulfamethoxazole; Trimethoprim

Criteria

Inclusion Criteria:

• HIV-infected pregnant women between 16-28 weeks' gestation

• Viable singleton pregnancy

• On or eligible for cARTs and CTX

• A resident of the study area

• Willing to adhere to scheduled and unscheduled study visit procedures

• Willing to deliver in a study clinic or hospital

• Provide written informed consent

Exclusion Criteria:

• Multiple pregnancies (i.e. twin/triplets)

• HIV-negative or HIV status unknown

• Known heart ailment

• Severe malformations or non-viable pregnancy if observed by ultrasound

• Participants with advanced HIV-disease at WHO clinical stage 3 and 4

• Confirmed or suspected TB infection,

• Unable to give consent

• Known allergy or contraindication to any of the study drugs