| Protocol No: | ECCT/19/07/01 | Date of Protocol: | 17-05-2019 |
| Study 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).
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| Study Objectives: |
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.
SECONDARY OBJECTIVES
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| Laymans Summary: | Context of the research: In malaria-endemic Africa, HIV and malaria conspire to increase the risks of pregnancy loss, preterm delivery, and growth retardation resulting in small babies. HIV-negative women in these areas receive intermittent preventive therapy in pregnancy (IPTp) with the antimalarial sulphadoxine-pyrimethamine (SP) to mitigate these effects. HIV-infected women receive daily prevention with cotrimoxazole (CTX), an antibiotic which also has antimalarial activity. However, the malaria parasite is increasingly resistant to SP and CTX. Recent trials with IPTp with mefloquine, when provided in addition to daily CTX, suggested that chemoprevention with an effective antimalarial markedly improves the protection against malaria in HIV-infected women compared to daily CTX alone. However, mefloquine was not well tolerated and other antimalarials are needed.
The long-acting antimalarial dihydroartemisinin-piperaquine (DP) is well tolerated and has shown great promise in trials in HIV-negative women in Uganda and Kenya. Chemoprevention with monthly DP has also been explored in a small study (N=200) of HIV-infected women on daily CTX in Uganda. Unfortunately, the study was inconclusive because malaria transmission was low. It also showed a drug-drug interaction with the anti-retroviral efavirenz (EFV), which markedly reduced the protective drug levels of DP. Since this first trial, the preferred first-line combination antiretroviral therapy (cART) recommended by WHO for use in the 2nd and 3rd trimester changed to dolutegravir (DTG) based 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.
Aim: To determine whether monthly IPTp-DP in HIV-infected pregnant women on cARTs and daily CTX improves current policies to control malaria in areas with high resistance to CTX and high prevalence of malaria in East & Southern Africa.
Methods: This is a 2-arm multi-centre trial involving 898 (449 per arm) women in 8 hospitals in Kenya and Malawi comparing daily CTX alone versus daily CTX plus monthly DP. The primary outcome is the incidence of malaria infection. This study is conducted alongside a sister trial among HIV-negative women (IMPROVE trial) also evaluating monthly DP.
Potential benefits and risks to participants: CTX and DP are currently thought to be safe for the mother and foetus during the second and third trimesters of pregnancy. The drugs have not yet been given concurrently in HIV-infected women on DTG-based cARTs, and the study will, therefore, include a nested cardiac monitoring component and a pharmacokinetic component to ensure women have adequate and safe drug levels. Examinations will be non-invasive, except for blood sampling which may cause minor discomfort. Participants experiencing illness between visits will be seen and treated free of charge as part of the study.
Potential applications: The study is designed to inform WHO policy in countries experiencing high levels of malaria parasite resistance and may potentially pave the way for new strategies to combat malaria in HIV-infected pregnant women hopefully resulting in healthier pregnancies and newborns.
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| Abstract of Study: |
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.
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