Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 15, 2020

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.

Interventions

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

Arms, Groups and Cohorts

  • 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
  • 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
  • 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • Composite of foetal loss and neonatal mortality
    • Time Frame: 8 months
    • Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality
  • SGA-LBW-PT composite
    • Time Frame: 6 months
    • Composite of small for gestational age, low birth weight or preterm birth
  • SGA
    • Time Frame: 6 months
    • Small for gestational age using the new INTERGROWTH population reference’s 10th percentile
  • LBW
    • Time Frame: 6 months
    • Low birth weight defined as a corrected birth weight below 2.5 kg
  • PT
    • Time Frame: 6 months
    • Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks
  • Neonatal length and stunting
    • Time Frame: 8 months
    • Neonatal length and stunting
  • Clinical malaria during pregnancy
    • Time Frame: 6 months from randomisation
    • Incidence of clinical malaria during pregnancy
  • 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
  • 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
  • Placental malaria detected by microscopy
    • Time Frame: 6 months from randomisation
    • Prevalence of placental malaria detected in maternal placental blood by microscopy
  • Placental malaria detected by molecular methods (PCR)
    • Time Frame: 6 months from randomisation
    • Prevalence of placental malaria detected in maternal placental blood by PCR
  • Placental malaria detected by histology
    • Time Frame: 6 months from randomisation
    • Prevalence of placental malaria detected in full placental section by histology
  • Maternal nutritional status
    • Time Frame: 6 months from randomisation
    • Changes in maternal nutritional status by MUAC and BMI.
  • 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
  • Congenital anaemia
    • Time Frame: 6 months from randomisation
    • Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood
  • Congenital malaria infection
    • Time Frame: 6 months from randomisation
    • Prevalence of malaria infection by microscopy or PCR from newborn cord blood
  • 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.
  • Congenital malformations
    • Time Frame: 6 months from randomisation
    • Any visible external congenital abnormality on surface examination
  • 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.
  • Other SAEs and AEs
    • Time Frame: 8 months from randomisation
    • Incidence of AEs and SAEs
  • (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
  • Dizziness
    • Time Frame: 6 months from randomisation
    • Prevalence of dizziness after a course of IP
  • Gastrointestinal complaints
    • Time Frame: 6 months from randomisation
    • Prevalence of gastrointestinal complaints after a course of IP
  • 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
  • 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
  • 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
  • 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

Participating in This Clinical Trial

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

Gender Eligibility: Female

Pregnant female

Minimum Age: 16 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Liverpool School of Tropical Medicine
  • Collaborator
    • Kamuzu University of Health Sciences
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Simon K Kariuki, PhD, Principal Investigator, Kenya Medical Research Institute
    • Frank Mosha, PhD, Principal Investigator, Kilimanjaro Christian Medical University College
    • John Lusingu, PhD, Principal Investigator, National Institute for Medical Research

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