Pregnancy; HIV; Malaria Clinical Trial
— IMPROVE-2Official title:
Chemoprevention With Monthly IPTp With Dihydroartemisinin-piperaquine for Malaria in HIV-infected Pregnant Participants on Daily Cotrimoxazole in Kenya and Malawi: a Multi-centre Placebo-controlled Trial
| Verified date | August 2023 |
| Source | Liverpool School of Tropical Medicine |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 898 |
| Est. completion date | August 30, 2022 |
| Est. primary completion date | April 15, 2022 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | Female |
| Age group | N/A and older |
| Eligibility | 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 |
| Country | Name | City | State |
|---|---|---|---|
| Kenya | Kenya Medical Research Institute | Kisumu |
| Lead Sponsor | Collaborator |
|---|---|
| Liverpool School of Tropical Medicine | CardiaBase, Centers for Disease Control and Prevention, Kamuzu University of Health Sciences, 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 Massachusetts, Worcester, University of Melbourne, University of Toronto |
Kenya,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Cumulative incidence of malaria infection | The primary outcome will be the cumulative incidence of malaria infection detected from 2 weeks after the first day of the first dose of the first course to delivery inclusive, defined as the presence of peripheral (maternal) or placental (maternal) Plasmodium infection detected by either molecular diagnostics (henceforth referred to as PCR), microscopy, RDT or placental histology (active infection). | Detected from 2 weeks after the first day of the first dose of the first course to delivery inclusive. The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months. | |
| Secondary | Efficacy of the intervention on the following listed secondary outcomes | Incidence of malaria infection
The individual components of the composite malaria infection endpoints Incidence of clinical malaria. Malaria infection at delivery Placental malaria by histology (active, past, and active and past infections pooled) Placental malaria by any measure Maternal peripheral malaria infection at delivery by any measure Placental inflammation or chorioamnionitis Adverse pregnancy outcome: the composite of foetal loss (spontaneous abortion or stillbirth), or singleton live births born small-for-gestational-age (SGA), or with low birthweight (LBW), or preterm (PT) (SGA-LBW-PT), or subsequent neonatal death by day 28. Composite of foetal loss and neonatal mortality. SGA-LBW-PT composite. The individual components of the above composites Neonatal length and stunting. Evidence of arboviral infections |
The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old | |
| Secondary | Safety: Cardiac safety, serious adverse events and MTCT of HIV | QTc-prolongation.
Congenital malformations. Maternal mortality Other SAEs and AEs. Mother to child transmission of HIV |
The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old | |
| Secondary | Tolerance | History of vomiting study drug (<30 min).
Dizziness. Gastrointestinal complaints. |
The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old | |
| Secondary | Antimicrobial activity and resistance | Frequency of molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery. | The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old | |
| Secondary | Pharmacokinetic parameters | Standard pharmacokinetic parameters for dolutegravir, piperaquine and CTX. | The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old |