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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 898
- 试验地点
- 1
- 主要终点
- Cumulative incidence of malaria infection
研究概览
简要总结
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.
详细描述
2.3.4 Long technical protocol summary 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(IMPROVE-2).
Background and rationale: In malaria-endemic Africa, HIV and malaria conspire to increase the risks of adverse pregnancy outcomes. For HIV-infected pregnant women, WHO recommends daily cotrimoxazole (CTX) for chemoprevention for malaria and prophylaxis against opportunistic infection. However, there is cross-resistance with SP, and high levels of antifolate resistance threaten the antimalarial effect of CTX. Recent trials in HIV-infected pregnant women who received daily CTX plus IPTp with mefloquine, suggested that chemoprevention with an effective antimalarial markedly reduces the risk of 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 women on daily CTX in Uganda. Unfortunately, the study was inconclusive as malaria transmission was too low. Furthermore, a clinically relevant drug-drug interaction between DP and efavirenz (EFV) was found to reduce DP drug levels. Following the recommendation from WHO, many countries in Africa are transitioning from EFV-based to dolutegravir (DTG) based combination antiretroviral therapy (cARTs). WHO now recommends DTG-based cARTS as the preferred first-line cART regimen in the 2nd and 3rd trimester of pregnancy. 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. We will therefore assess the safety and efficacy of malaria chemoprevention with monthly IPTp with DP in women on daily CTX and DTG-based cARTs and daily CTX.
Overall aim: To provide WHO with evidence on whether monthly IPTp-DP can improve current policies to control malaria in HIV-infected pregnant women on daily CTX in areas with high levels of parasite resistance and malaria in East and Southern Africa.
Primary objective: To determine if monthly IPTp-DP in HIV-infected pregnant women receiving daily CTX is safe and superior to daily CTX-alone for controlling malaria infection in areas with high antifolates resistance to SP and CTX in Malawi and Kenya.
Hypotheses: Monthly IPTp-DP in women receiving daily CTX is superior to daily CTX-alone in controlling malaria infection during pregnancy in HIV infected women on antiretroviral therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
CTX-alone
Daily, one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim plus monthly placebo-DP, given as a fixed dose of 3 placebo-DP tablets daily for three days until delivery.
干预措施: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine (Drug)
CTX-DP
Daily, one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim plus monthly DP, given as a fixed dose of 3 tablets (40 mg of dihydroartemisinin and 320 mg of piperaquine) daily for three days until delivery.
干预措施: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine (Drug)
结局指标
主要结局
Cumulative incidence of malaria infection
时间窗: 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.
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).
次要结局
- Efficacy of the intervention on the following listed secondary outcomes(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)
- Safety: Cardiac safety, serious adverse events and MTCT 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)
- Tolerance(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)
- Antimicrobial activity and resistance(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)
- Pharmacokinetic parameters(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)