Pregnancy; HIV; MalariaPhase 3IMPROVE-2NCT04158713
Improving PRegnancy Outcomes With PReVEntive Therapy in Africa-2 (IMPROVE-2)
A Phase 3 study testing Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine in people with Pregnancy; HIV; Malaria, run by Liverpool School of Tropical Medicine at 1 site in Kenya.
Trial 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… Read more about this study
- Who is it for?
- Any age, women onlyHealthy volunteers can take part
- Conditions the study is for
- Pregnancy; HIV; Malaria
- What is being tested?
- Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 898 participants
- Where
- 1 siteKenya
- Study dates
- 11 Nov 2019to 30 Aug 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- Women only
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official 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
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.
Read the detailed description
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.
- Conditions
- Pregnancy; HIV; Malaria
- Being tested
- Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intermittent Preventive Therapy with Dihydroartemisinin-PiperaquineDrug
Also called Monthly DP, D-artepp
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.
| Study group | Role | What they receive |
|---|---|---|
| CTX-alone | Placebo comparator | 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. Receives: Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine |
| CTX-DP | Experimental | 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. Receives: Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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 outcomes (5)
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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Nov 2019
- Study start11 Nov 2019
- Primary completion15 Apr 2022
- Study completion30 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Pregnancy; HIV; MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 898 participants (actual)
Sponsor and investigators
- Lead sponsor
- Liverpool School of Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Kenya Medical Research Institute, Kamuzu University of Health Sciences, Kenya National AIDS & STI Control Programme, KEMRI-Wellcome Trust Collaborative Research Program, Centers for Disease Control and Prevention, University of Copenhagen, University of Cape Town, University of Massachusetts, Worcester, University of Toronto, University of Melbourne, CardiaBase
- Responsible party
- Sponsor
- Investigators
- Feiko terKuile, MD-PhD, Principal investigator, Liverpool School of Tropical Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04158713
- Sponsor's protocol ID
- 17-005
- Acronym
- IMPROVE-2
- Status last verified
- Aug 2023
- First submitted
- 7 Nov 2019
- Last updated
- 22 Aug 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Biological samples and data will be shared using material and data transfer agreements with the collaborating institutions (see 2.2.4 Collaborators, page 9) to minimise the risk of unauthorised analysis beyond the scope of the agreed parameters.
Publications
Pons-Duran C, Wassenaar MJ, Yovo KE, Marin-Carballo C, Briand V, Gonzalez R. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women. Cochrane Database Syst Rev. 2024 Sep 26;9(9):CD006689. doi: 10.1002/14651858.CD006689.pub3.
PubMed 39324693Barsosio HC, Madanitsa M, Ondieki ED, Dodd J, Onyango ED, Otieno K, Wang D, Hill J, Mwapasa V, Phiri KS, Maleta K, Taegtmeyer M, Kariuki S, Schmiegelow C, Gutman JR, Ter Kuile FO. Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin-piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial. Lancet. 2024 Jan 27;403(10424):365-378. doi: 10.1016/S0140-6736(23)02631-4. Epub 2024 Jan 12.
PubMed 38224710
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT04158713
- Acronym / sponsor ID
- IMPROVE-2 / 17-005
- Conditions
- Pregnancy; HIV; Malaria
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 898 participants (actual)
- Lead sponsor
- Liverpool School of Tropical MedicineUniversity, hospital or other
- Collaborators
- Kenya Medical Research Institute, Kamuzu University of Health Sciences, Kenya National AIDS & STI Control Programme, KEMRI-Wellcome Trust Collaborative Research Program, Centers for Disease Control and Prevention, University of Copenhagen, University of Cape Town, University of Massachusetts, Worcester, University of Toronto, University of Melbourne, CardiaBase
- Study start
- 11 Nov 2019 (actual)
- Primary completion
- 15 Apr 2022 (actual)
- Study completion
- 30 Aug 2022 (actual)
- First posted
- 12 Nov 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| CTX-alone | Placebo comparator | Drug: Intermittent Preventive Therapy with Dihydroartemisinin-PiperaquineDaily, 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. |
| CTX-DP | Experimental | Drug: Intermittent Preventive Therapy with Dihydroartemisinin-PiperaquineDaily, 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. |
Who may qualify
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intermittent Preventive Therapy with Dihydroartemisinin-PiperaquineAlso: Monthly DP, D-arteppMonthly 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. | Drug | CTX-DP, CTX-alone |
Primary outcome
Cumulative incidence of malaria infection
Time frame: 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).
5 secondary outcomes
Efficacy of the intervention on the following listed secondary outcomes
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2023.
- Derived from this study: PubMed 39324693Pons-Duran C, Wassenaar MJ, Yovo KE, Marin-Carballo C, Briand V, Gonzalez R. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women. Cochrane Database Syst Rev. 2024 Sep 26;9(9):CD006689. doi: 10.1002/14651858.CD006689.pub3.
- Derived from this study: PubMed 38224710Barsosio HC, Madanitsa M, Ondieki ED, Dodd J, Onyango ED, Otieno K, Wang D, Hill J, Mwapasa V, Phiri KS, Maleta K, Taegtmeyer M, Kariuki S, Schmiegelow C, Gutman JR, Ter Kuile FO. Chemoprevention for malaria with monthly intermittent preventive treatment with dihydroartemisinin-piperaquine in pregnant women living with HIV on daily co-trimoxazole in Kenya and Malawi: a randomised, double-blind, placebo-controlled trial. Lancet. 2024 Jan 27;403(10424):365-378. doi: 10.1016/S0140-6736(23)02631-4. Epub 2024 Jan 12.
- Individual participant dataSharing planned: Yes. Biological samples and data will be shared using material and data transfer agreements with the collaborating institutions (see 2.2.4 Collaborators, page 9) to minimise the risk of unauthorised analysis beyond the scope of the agreed parameters.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Feiko terKuile, MD-PhD principal investigator
Liverpool School of Tropical Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine in people with Pregnancy; HIV; Malaria, run by Liverpool School of Tropical Medicine at 1 site in Kenya.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Kenya. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cumulative incidence of malaria infection (time frame: 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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04158713, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2023.