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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04158713
Recruitment Status : Recruiting
First Posted : November 12, 2019
Last Update Posted : February 5, 2020
Sponsor:
Collaborators:
Kenya Medical Research Institute
University of Malawi College of Medicine
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
Information provided by (Responsible Party):
Liverpool School of Tropical Medicine

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.


Condition or disease Intervention/treatment Phase
Pregnancy; HIV; Malaria Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 898 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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
Actual Study Start Date : November 11, 2019
Estimated Primary Completion Date : March 15, 2021
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Malaria

Arm Intervention/treatment
Placebo Comparator: 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.
Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine
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.
Other Names:
  • Monthly DP
  • D-artepp

Experimental: 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.
Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine
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.
Other Names:
  • Monthly DP
  • D-artepp




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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 ]
    1. Incidence of malaria infection
    2. The individual components of the composite malaria infection endpoints
    3. Incidence of clinical malaria.
    4. Malaria infection at delivery
    5. Placental malaria by histology (active, past, and active and past infections pooled)
    6. Placental malaria by any measure
    7. Maternal peripheral malaria infection at delivery by any measure
    8. Placental inflammation or chorioamnionitis
    9. 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.
    10. Composite of foetal loss and neonatal mortality.
    11. SGA-LBW-PT composite.
    12. The individual components of the above composites
    13. Neonatal length and stunting.
    14. Evidence of arboviral infections

  2. 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 ]
    1. QTc-prolongation.
    2. Congenital malformations.
    3. Maternal mortality
    4. Other SAEs and AEs.
    5. Mother to child transmission of HIV

  3. 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 ]
    1. History of vomiting study drug (<30 min).
    2. Dizziness.
    3. Gastrointestinal complaints.

  4. 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 ]
    Frequency of molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery.

  5. 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 ]
    Standard pharmacokinetic parameters for dolutegravir, piperaquine and CTX.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pregnant women
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04158713


Contacts
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Contact: Feiko C terKuile, MD-PhD +447846377369 feiko.terkuile@lstmed.ac.uk
Contact: Hellen Barsosio, MBChB-Msc +254724464507 hellen.barsosio@lstmed.ac.uk

Locations
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Kenya
Kenya Medical Research Institute Recruiting
Kisumu, Kenya, 40100
Contact: Hellen C Barsosio, MBChB    +254724464507    hellen.barsosio@lstmed.ac.uk   
Sponsors and Collaborators
Liverpool School of Tropical Medicine
Kenya Medical Research Institute
University of Malawi College of Medicine
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
Investigators
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Principal Investigator: Feiko terKuile, MD-PhD Liverpool School of Tropical Medicine
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Responsible Party: Liverpool School of Tropical Medicine
ClinicalTrials.gov Identifier: NCT04158713    
Other Study ID Numbers: 17-005
First Posted: November 12, 2019    Key Record Dates
Last Update Posted: February 5, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: 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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Malaria
Protozoan Infections
Parasitic Diseases
Piperaquine
Dihydroartemisinin
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents