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

NCT04158713 | Completed Phase 3 DMC

• 1 other identifier: 17-005
• Study Type: interventional
• Target: 898
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Pregnancy; HIV; Malaria

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• 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

Study Arms (2)

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.

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.

Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine

Interventions

Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine DRUG

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.

Also known as: Monthly DP, D-artepp

CTX-DP; CTX-alone

Eligibility Criteria

• Gender Eligibility Details: Pregnant women
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Liverpool School of Tropical Medicine: lead
• Kenya Medical Research Institute: collaborator
• Kamuzu University of Health Sciences: collaborator
• Kenya National AIDS & STI Control Programme: collaborator
• KEMRI-Wellcome Trust Collaborative Research Program: collaborator
• Centers for Disease Control and Prevention: collaborator
• University of Copenhagen: collaborator
• University of Cape Town: collaborator
• University of Massachusetts, Worcester: collaborator
• University of Toronto: collaborator
• University of Melbourne: collaborator
• CardiaBase: collaborator

Study Sites (1)

Kenya Medical Research Institute

Kisumu, 40100, Kenya

Location

Related Publications (2)

• 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.

  PMID: 39324693 DERIVED

• Barsosio 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.

  PMID: 38224710 DERIVED

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• Feiko terKuile, MD-PhD

  Liverpool School of Tropical Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: November 7, 2019
• First Posted: November 12, 2019
• Study Start: November 11, 2019
• Primary Completion: April 15, 2022
• Study Completion: August 30, 2022
• Last Updated: August 22, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Five years
• Access Criteria: The full protocol will be available on request to any interested professional and may be published in a peer reviewed journal or deposited in an online repository. Individual, de-identified participant data will be made available for meta-analyses as soon as the data analysis is completed, with the understanding that results of the meta-analysis will not be published prior to the results of the individual trial without prior agreement of the investigators. No later than five years after the publication of the trial a fully de-identified data set of the complete patient-level data will be available for sharing purposes, such as via the WWARN repository platform (http://www.wwarn.org/working-together/sharing-data/accessing-data). All requests for data for secondary analysis will be considered by a Data Access Committee to ensure that use of data is within the terms of consent and ethics approval.

Locations

KE (1)