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Completed

NCT Number: NCT03208179

Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa

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-pyrimethamine (SP) for the prevention of malaria in pregnant women in the second and third trimester.

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Key information

Conditions

Pregnancy Infections Malaria Malaria in Pregnancy Mosquito-Borne Diseases Parasitic Diseases Protozoan Infections Vector Borne Diseases

Age range

16 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 3

Primary location

Ahero Sud-countyHospital, Ahero, Kisumu County, Kenya

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About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Dihydroartemisinin-Piperaquine

Drug

Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo

Other names: Eurartesim

Sulphadoxine-pyrimethamine

Drug

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 names: Fansidar

dihydroartemisinin-piperaquine plus azithromycin

Drug

Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)

Other names: Eurartesim plus Zithromax

Primary outcomes

  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 outcomes

  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 delivery

  15. Congenital anaemia

    Time frame: 6 months from randomisation

    Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood

  16. Congenital malaria infection

    Time frame: 6 months from randomisation

    Prevalence of malaria infection by microscopy or PCR from newborn cord blood

  17. QTc-prolongation

    Time frame: 6 months from randomisation

    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 randomisation

    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 pneumococcus 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

Sponsors and collaborators

Lead sponsor

Liverpool School of Tropical Medicine

Other

Collaborators

  • Centers for Disease Control and Prevention
  • Foundation for Innovative New Diagnostics, Switzerland
  • Kamuzu University of Health Sciences
  • Kenya Medical Research Institute
  • Kilimanjaro Christian Medical Centre, Tanzania
  • London School of Hygiene and Tropical Medicine
  • Malawi-Liverpool-Wellcome Trust Clinical Research Programme
  • National Institute for Medical Research, Tanzania
  • Tampere University
  • University College, London
  • University of Bergen
  • University of Copenhagen
  • University of Massachusetts, Worcester
  • University of Melbourne
  • University of Toronto

Registry information

Official study 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

Acronym: IMPROVE

Important dates

Study start
2018
Primary completion
2020
Study completion
2020
First posted
Jul 5, 2017
Registry last updated
Jun 27, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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