Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa

Pregnancy Clinical Trial

— IMPROVE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03208179
• Other study ID #: 16.049
• Status: Completed
• Phase: Phase 3
• Start date: March 29, 2018
• Est. completion date: March 15, 2020

Study information

• Verified date: June 2022
• Source: Liverpool School of Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4680
• Est. completion date: March 15, 2020
• Est. primary completion date: March 15, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 16 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malaria
• Malaria in Pregnancy
• Pregnancy

Intervention

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

Locations

Country	Name	City	State
Kenya	Ahero Sud-countyHospital	Ahero	Kisumu
Kenya	Homa Bay County Hospital	Homa Bay
Kenya	Rabour Sub-county Hospital	Kisumu
Malawi	Chikwawa District Hospital	Chikwawa
Malawi	Mangochi District Hospital	Mangochi
Tanzania	Handeni District Hospital	Handeni
Tanzania	Korogwe District Hospital	Korogwe

Sponsors (16)

Lead Sponsor

Collaborator

Liverpool School of Tropical Medicine

Centers for Disease Control and Prevention, Foundation for Innovative New Diagnostics, Switzerland, 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 Malawi College of Medicine, University of Massachusetts, Worcester, University of Melbourne, University of Toronto

Countries where clinical trial is conducted

Kenya,  Malawi,  Tanzania, 

Outcome

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