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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Overview Study Design: This multi-centre trial will be conducted in antenatal clinics in 8 hospitals in Kenya and Malawi located in areas with high prevalence of HIV and malaria and with high anti-folate resistance of the malaria parasite. These are the same sites where the sister trial in HIV-uninfected women (all gravidae) is being conducted in Kenya and Malawi (IMPROVE trial: NCT03208179). Overall, 898 (449 per arm) HIV-infected pregnant women who are 16 to 28 weeks pregnant assessed by ultrasound dating, will be randomised to receive one of the two interventions. Permuted block randomisation stratified by site (i.e. hospital) and HIV-status (known-positive and newly-diagnosed) will be used. Allocation concealment will be ensured by using sequentially numbered, sealed, opaque envelopes. The study will include pharmacokinetic studies and cardiac monitoring in a sub group of women. Other components include molecular marker studies of antimalarial resistance. We will also look at the impact on biomarkers of placental function and trans-placental antibody transfer and multi-pathogen neonatal cell mediated immune responses. Study Interventions: Daily CTX for all trial participants receiving cARTs in addition to: a) monthly-DP ('CTX-DP'), or b) monthly DP-placebo ('CTX-alone') (control). Follow-up procedures: Monthly visits during pregnancy, and then at delivery. Mother and newborn follow-up at 7 days and 6-8 weeks post-partum. Primary outcome: 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). Sample size: 898 (449 per arm), allowing for 20% loss to follow-up. Data Analysis: Log-binomial regression will be used to analyse the primary outcome, controlled for site and gravidity. Primary partner institutions: KEMRI, Kenya; College of Medicine, University of Malawi, Malawi; Liverpool School of Tropical Medicine (LSTM); London School of Hygiene and Tropical Medicine (LSHTM); US Centers for Disease Control and Prevention (CDC); University of Bergen, Norway. Funding: Joint Global Health Trials Scheme, Medical Research Council/Wellcome Trust/DFID, UK; and the European and Developing Countries Clinical Trials Partnership (EDCTP). Sponsor: Liverpool School of Tropical Medicine (LSTM); Pembroke Place, Liverpool L3 5QA, UK, Phone: +44 0151 7053794; Email: lstmgov@lstmed.ac.uk.

Official Title
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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

Conditions
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Pregnancy; HIV; Malaria

Intervention / Treatment
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* Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Allocation: randomised; intervention model: parallel assignment; arms: 2; allocation ratio: 1:1; stratified by site (hospital) and HIV-status (known-positive and newly-diagnosed). Masking: Placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: CTX-alone<br>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. | Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine<br>* Monthly DP fixed dose of 3 tablets (40 mg of dihydroartemisinin and 320 mg of piperaquine) daily for three days until delivery. All participants will (continue to) receive daily cotrimoxazole (CTX) (one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim) and anti-retroviral drugs.<br>* Other names: D-artepp;|
| Experimental: CTX-DP<br>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. | Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine<br>* Monthly DP fixed dose of 3 tablets (40 mg of dihydroartemisinin and 320 mg of piperaquine) daily for three days until delivery. All participants will (continue to) receive daily cotrimoxazole (CTX) (one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim) and anti-retroviral drugs.<br>* Other names: D-artepp;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |