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

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

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.

Study Overview

• Status: Completed
• Conditions: Pregnancy; Malaria; Malaria in Pregnancy
• Intervention / Treatment: Drug: sulphadoxine-pyrimethamine; Drug: dihydroartemisinin-piperaquine; Drug: dihydroartemisinin-piperaquine plus azithromycin

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.

• Study Type: Interventional
• Enrollment (Actual): 4680
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Homa Bay, Kenya
    • Homa Bay County Hospital
  • Kisumu, Kenya
    • Rabour Sub-county Hospital
  • Kisumu
    • Ahero, Kisumu, Kenya
      • Ahero Sud-countyHospital
• Malawi
  • Chikwawa, Malawi
    • Chikwawa District Hospital
  • Mangochi, Malawi
    • Mangochi District Hospital
• Tanzania
  • Handeni, Tanzania
    • Handeni District Hospital
  • Korogwe, Tanzania
    • Korogwe District Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: Eurartesim plus Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse pregnancy outcome	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.	8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of foetal loss and neonatal mortality	Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality	8 months
SGA-LBW-PT composite	Composite of small for gestational age, low birth weight or preterm birth	6 months
SGA	Small for gestational age using the new INTERGROWTH population reference's 10th percentile	6 months
LBW	Low birth weight defined as a corrected birth weight below 2.5 kg	6 months
PT	Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks	6 months
Neonatal length and stunting	Neonatal length and stunting	8 months
Clinical malaria during pregnancy	Incidence of clinical malaria during pregnancy	6 months from randomisation
Malaria infection during pregnancy detected by microscopy and PCR	Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR	6 months from randomisation
Composite placental malaria detected by microscopy, by molecular methods or by histology	Prevalence of placental malaria by microscopy, PCR and placental histology	6 months from randomisation
Placental malaria detected by microscopy	Prevalence of placental malaria detected in maternal placental blood by microscopy	6 months from randomisation
Placental malaria detected by molecular methods (PCR)	Prevalence of placental malaria detected in maternal placental blood by PCR	6 months from randomisation
Placental malaria detected by histology	Prevalence of placental malaria detected in full placental section by histology	6 months from randomisation
Maternal nutritional status	Changes in maternal nutritional status by MUAC and BMI.	6 months from randomisation
Maternal anaemia during pregnancy and delivery	Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery	6 months from randomisation
Congenital anaemia	Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood	6 months from randomisation
Congenital malaria infection	Prevalence of malaria infection by microscopy or PCR from newborn cord blood	6 months from randomisation
QTc-prolongation	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.	6 months from randomisation
Congenital malformations	Any visible external congenital abnormality on surface examination	6 months from randomisation
Maternal mortality	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.	8 months from randomisation
Other SAEs and AEs	Incidence of AEs and SAEs	8 months from randomisation
(History of) vomiting study drug	Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit	6 months from randomisation
Dizziness	Prevalence of dizziness after a course of IP	6 months from randomisation
Gastrointestinal complaints	Prevalence of gastrointestinal complaints after a course of IP	6 months from randomisation
Molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery	Prevalence and incidence of SP and artemisinin resistance markers from infection isolates after enrollment and at delivery	6 months from randomisation
Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis)	Prevalence and incidence of STIs/RTIs (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) at randomization and last antenatal visit prior to delivery	6 months from randomisation
Changes in macrolide resistance in Pneumococcus detected in maternal nasopharyngeal samples	Prevalence and incidence of carriage of macrolide resistant pneumococcus at randomization and delivery	6 months from randomisation
Changes in the colony composition of maternal vaginal microbiota, and intestinal microbiota of mother and infant.	Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota	6 months from randomisation

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Mtove G, Abdul O, Kullberg F, Gesase S, Scheike T, Andersen FM, Madanitsa M, Ter Kuile FO, Alifrangis M, Lusingu JPA, Minja DTR, Schmiegelow C. Weight change during the first week of life and a new method for retrospective prediction of birthweight among exclusively breastfed newborns. Acta Obstet Gynecol Scand. 2022 Mar;101(3):293-302. doi: 10.1111/aogs.14323. Epub 2022 Feb 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2018
• Primary Completion (Actual): March 15, 2020
• Study Completion (Actual): March 15, 2020

Study Registration Dates

• First Submitted: June 30, 2017
• First Submitted That Met QC Criteria: June 30, 2017
• First Posted (Actual): July 5, 2017

Study Record Updates

• Last Update Posted (Actual): June 27, 2022
• Last Update Submitted That Met QC Criteria: June 22, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Malaria in Pregnancy; Intermittent Preventive Treatment; IPTp
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Renal Agents; Pyrimethamine; Azithromycin; Piperaquine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Artenimol; Artemisinins
• Other Study ID Numbers: 16.049

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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
• IPD Sharing Time Frame: No later than 5 years after publication
• IPD Sharing Access Criteria: Open access
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No