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Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa (IMPROVE)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03208179
Recruitment Status : Unknown
Verified June 2017 by Liverpool School of Tropical Medicine.
Recruitment status was:  Not yet recruiting
First Posted : July 5, 2017
Last Update Posted : July 5, 2017
Sponsor:
Collaborators:
University of Malawi College of Medicine
Kenya Medical Research Institute
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
National Institute for Medical Research
Kilimanjaro Christian Medical Centre
University of Copenhagen
Centers for Disease Control and Prevention
London School of Hygiene and Tropical Medicine
University College, London
Tampere University
University of Bergen
University of Massachusetts, Worcester
University of Toronto
University of Melbourne
Intellectual Ventures Laboratory
Cardiabase, Banook Group
PATH
Foundation for Innovative New Diagnostics
Information provided by (Responsible Party):
Liverpool School of Tropical Medicine

Brief Summary:
This study evaluates the efficacy and safety of monthly intermittent preventive treatment using dihydroartemisinin piperaquine (DP) alone or in combination with azithromycin (AZ) compared to sulphadoxine-pyrimthamine (SP) for the prevention of malaria in pregnant women in the second and third trimester.

Condition or disease Intervention/treatment Phase
Pregnancy Malaria in Pregnancy Malaria Drug: dihydroartemisinin-piperaquine Drug: sulphadoxine-pyrimethamine Drug: dihydroartemisinin-piperaquine plus azithromycin Phase 3

Detailed Description:

Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is one of the pillars of malaria prevention in pregnancy in sub-Saharan Africa, in addition to prompt case management and use of long lasting insecticide treated bednets. However, mounting resistance to SP by Plasmodium falciparum increasing renders IPTP-SP ineffective.

Two exploratory trials in Uganda and Kenya demonstrated that IPTp with DP was superior to IPTp-SP for the prevention of malaria infection in pregnancy. However, neither study was adequately powered to look at adverse birth outcomes. This study is a confirmatory efficacy trial in Malawi, Tanzania and Kenya to determine the efficacy and safety of IPTp with DP alone or in combination with AZ.

This will be a 3-arm trial, superiority, partial blinded, placebo controlled, randomized trial comparing IPTp with SP, versus IPTp with DP alone, and IPTp with DP+AZ with the following hypotheses:

  • IPTp with DP is superior to IPTp with SP in preventing adverse pregnancy outcomes.
  • The combination of DP with AZ further reduces adverse pregnancy outcomes compared to IPTp with DP alone.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 4680 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The study will be a partially placebo-controlled involving a single placebo for AZ. To further minimise bias, an objective primary outcome measure will be used and all staff will be masked to the treatment assignment of individual women. The trial statistician will also be masked in regard to the treatment code when he develops the statistical analysis plan and writes the statistical programmes, which will be validated and completed using dummy randomisation codes. The actual allocation will only be provided to the study team after locking of the database and approval of the statistical analysis plan by the independent Data Monitoring and Ethics Committee (DMEC) before they review any trial results. The study statistician conducting the interim analysis will remain masked throughout the analysis.
Primary Purpose: Prevention
Official Title: IPTp With Dihydroartemisinin-piperaquine and Azithromycin for Malaria, Sexually Transmitted and Reproductive Tract Infections in Pregnancy in High Sulphadoxine-pyrimethamine Resistance Areas in Kenya, Malawi and Tanzania: an International Multi-centre 3-arm Placebo-controlled Trial
Estimated Study Start Date : September 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Active Comparator: IPTp-SP
Stat course of 3 tablets of quality-assured SP (tablets of 500 mg of sulphadoxine and 25 mg of pyrimethamine) at each scheduled antenatal visit
Drug: sulphadoxine-pyrimethamine
Women randomised to this intervention will receive stat dose of 3 tablets of 500 mg sulphadoxine and 25 mg of pyrimethamine each (total dose of 1,500mg sulphadoxine and 75mg pyrimethamine) on a single day of clinic visit
Other Name: Fansidar

Experimental: IPTp-DP
Dihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + placebo AZ at each scheduled antenatal visit
Drug: dihydroartemisinin-piperaquine
Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo
Other Name: Eurartesim

Experimental: IPTp-DPAZ
Dihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + AZ tablet [1.5g over 3 days as 500mg per day] at each scheduled antenatal visit.
Drug: dihydroartemisinin-piperaquine plus azithromycin
Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)
Other Name: Eurartesim plus Zithromax




Primary Outcome Measures :
  1. Adverse pregnancy outcome [ Time Frame: 8 months ]
    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.


Secondary Outcome Measures :
  1. Composite of foetal loss and neonatal mortality [ Time Frame: 8 months ]
    Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality

  2. SGA-LBW-PT composite [ Time Frame: 6 months ]
    Composite of small for gestational age, low birth weight or preterm birth

  3. SGA [ Time Frame: 6 months ]
    Small for gestational age using the new INTERGROWTH population reference's 10th percentile

  4. LBW [ Time Frame: 6 months ]
    Low birth weight defined as a corrected birth weight below 2.5 kg

  5. PT [ Time Frame: 6 months ]
    Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks

  6. Neonatal length and stunting [ Time Frame: 8 months ]
    Neonatal length and stunting

  7. Clinical malaria during pregnancy [ Time Frame: 6 months from randomisation ]
    Incidence of clinical malaria during pregnancy

  8. Malaria infection during pregnancy detected by microscopy and PCR [ Time Frame: 6 months from randomisation ]
    Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR

  9. Composite placental malaria detected by microscopy, by molecular methods or by histology [ Time Frame: 6 months from randomisation ]
    Prevalence of placental malaria by microscopy, PCR and placental histology

  10. Placental malaria detected by microscopy [ Time Frame: 6 months from randomisation ]
    Prevalence of placental malaria detected in maternal placental blood by microscopy

  11. Placental malaria detected by molecular methods (PCR) [ Time Frame: 6 months from randomisation ]
    Prevalence of placental malaria detected in maternal placental blood by PCR

  12. Placental malaria detected by histology [ Time Frame: 6 months from randomisation ]
    Prevalence of placental malaria detected in full placental section by histology

  13. Maternal nutritional status [ Time Frame: 6 months from randomisation ]
    Changes in maternal nutritional status by MUAC and BMI.

  14. Maternal anaemia during pregnancy and delivery [ Time Frame: 6 months from randomisation ]
    Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and deivery

  15. Congenital anaemia [ Time Frame: 6 months from randomistion ]
    Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood

  16. Congenital malaria infection [ Time Frame: 6 months from randomistion ]
    Prevalence of malaria infection by microscopy or PCR from newborn cord blood

  17. QTc-prolongation [ Time Frame: 6 months from randomistion ]
    QTcF-prolongation of more than 60ms between baseline DTcF prior to first dose of DP (+/- AZ) on day 0 and repeat QTcF 4 - 6 hrs after administration of 3rd dose of DP(+/- AZ) on day 2, or QTcF > 480ms, 4 - 6 hours after on day 2 treatment administration. Only on the DP containing arms.

  18. Congenital malformations [ Time Frame: 6 months from randomistion ]
    Any visible external congenital abnormality on surface examination

  19. Maternal mortality [ Time Frame: 8 months from randomisation ]
    The death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.

  20. Other SAEs and AEs [ Time Frame: 8 months from randomisation ]
    Incidence of AEs and SAEs

  21. (History of) vomiting study drug [ Time Frame: 6 months from randomisation ]
    Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit

  22. Dizziness [ Time Frame: 6 months from randomisation ]
    Prevalence of dizziness after a course of IP

  23. Gastrointestinal complaints [ Time Frame: 6 months from randomisation ]
    Prevalence of gastrointestinal complaints after a course of IP

  24. Molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery [ Time Frame: 6 months from randomisation ]
    Prevalence and incidence of SP and artemisinin resistance markers from infection isolates after enrollment and at delivery

  25. Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) [ Time Frame: 6 months from randomisation ]
    Prevalence and incidence of STIs/RTIs (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) at randomization and last antenatal visit prior to delivery

  26. Changes in macrolide resistance in Pneumococcus detected in maternal nasopharyngeal samples [ Time Frame: 6 months from randomisation ]
    Prevalence and incidence of carriage of macrolide resistant pneumoccocus at randomization and delivery

  27. Changes in the colony composition of maternal vaginal microbiota, and intestinal microbiota of mother and infant. [ Time Frame: 6 months from randomisation ]
    Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota



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 female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Pregnant women between 16-28 weeks' gestation
  • Viable singleton pregnancy
  • 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-positive
  • Known heart ailment
  • Severe malformations or non-viable pregnancy if observed by ultrasound
  • History of receiving IPTp-SP during this current pregnancy
  • 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): NCT03208179


Contacts
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Contact: Feiko O ter Kuile, PhD +447846377369 feiko.terkuile@lstmed.ac.uk
Contact: Mwayiwawo M Madanitsa, PhD +265999616537 mwayi.madanitsa@gmail.com

Locations
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Kenya
Ahero Sud-countyHospital Not yet recruiting
Ahero, Kisumu, Kenya
Contact: Simon Kariuki, PhD    + 254725389246    SKariuki@kemricdc.org   
Homa Bay County Hospital Not yet recruiting
Homa Bay, Kenya
Contact: Simon Kariuki, PhD    + 254725389246    SKariuki@kemricdc.org   
Rabour Sub-county Hospital Not yet recruiting
Kisumu, Kenya
Contact: Simon Kariuki, PhD    + 254725389246    SKariuki@kemricdc.org   
Malawi
Chikwawa District Hospital Not yet recruiting
Chikwawa, Malawi
Contact: Victor Mwapasa, PhD    +265999981496    vmwapasa@gmail.com   
Mangochi District Hospital Not yet recruiting
Mangochi, Malawi
Contact: Kenneth Maleta, PhD    +265888232202    ken.maleta@gmail.com   
Tanzania
Handeni District Hospital
Handeni, Tanzania
Korogwe District Hospital
Korogwe, Tanzania
Sponsors and Collaborators
Liverpool School of Tropical Medicine
University of Malawi College of Medicine
Kenya Medical Research Institute
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
National Institute for Medical Research
Kilimanjaro Christian Medical Centre
University of Copenhagen
Centers for Disease Control and Prevention
London School of Hygiene and Tropical Medicine
University College, London
Tampere University
University of Bergen
University of Massachusetts, Worcester
University of Toronto
University of Melbourne
Intellectual Ventures Laboratory
Cardiabase, Banook Group
PATH
Foundation for Innovative New Diagnostics
Investigators
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Principal Investigator: Simon K Kariuki, PhD Kenya Medical Research Institute
Principal Investigator: Frank Mosha, PhD Kilimanjaro Christian Medical University College
Principal Investigator: John Lusingu, PhD National Institute for Medical Research

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Responsible Party: Liverpool School of Tropical Medicine
ClinicalTrials.gov Identifier: NCT03208179     History of Changes
Other Study ID Numbers: 16.049
First Posted: July 5, 2017    Key Record Dates
Last Update Posted: July 5, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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 5 years after the publication of the trial a fully de-identified data set will be available for sharing purposes
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: No later than 5 years after publication
Access Criteria: Open access

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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
Pyrimethamine
Piperaquine
Sulfadoxine
Dihydroartemisinin
Artemisinins
Fanasil, pyrimethamine drug combination
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents