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.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
4,680
Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo
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
Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)
Ahero Sud-countyHospital
Ahero, Kisumu County, Kenya
Homa Bay County Hospital
Homa Bay, Kenya
Rabour Sub-county Hospital
Kisumu, Kenya
Chikwawa District Hospital
Chikwawa, Malawi
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.
Time frame: 8 months
Composite of foetal loss and neonatal mortality
Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality
Time frame: 8 months
SGA-LBW-PT composite
Composite of small for gestational age, low birth weight or preterm birth
Time frame: 6 months
SGA
Small for gestational age using the new INTERGROWTH population reference's 10th percentile
Time frame: 6 months
LBW
Low birth weight defined as a corrected birth weight below 2.5 kg
Time frame: 6 months
PT
Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks
Time frame: 6 months
Neonatal length and stunting
Neonatal length and stunting
Time frame: 8 months
Clinical malaria during pregnancy
Incidence of clinical malaria during pregnancy
Time frame: 6 months from randomisation
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Mangochi District Hospital
Mangochi, Malawi
Handeni District Hospital
Handeni, Tanzania
Korogwe District Hospital
Korogwe, Tanzania
Malaria infection during pregnancy detected by microscopy and PCR
Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR
Time frame: 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
Time frame: 6 months from randomisation
Placental malaria detected by microscopy
Prevalence of placental malaria detected in maternal placental blood by microscopy
Time frame: 6 months from randomisation
Placental malaria detected by molecular methods (PCR)
Prevalence of placental malaria detected in maternal placental blood by PCR
Time frame: 6 months from randomisation
Placental malaria detected by histology
Prevalence of placental malaria detected in full placental section by histology
Time frame: 6 months from randomisation
Maternal nutritional status
Changes in maternal nutritional status by MUAC and BMI.
Time frame: 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
Time frame: 6 months from randomisation
Congenital anaemia
Prevalence of anaemia (Hb \< 13g/dl) from newborn cord blood
Time frame: 6 months from randomisation
Congenital malaria infection
Prevalence of malaria infection by microscopy or PCR from newborn cord blood
Time frame: 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.
Time frame: 6 months from randomisation
Congenital malformations
Any visible external congenital abnormality on surface examination
Time frame: 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.
Time frame: 8 months from randomisation
Other SAEs and AEs
Incidence of AEs and SAEs
Time frame: 8 months from randomisation
(History of) vomiting study drug
Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit
Time frame: 6 months from randomisation
Dizziness
Prevalence of dizziness after a course of IP
Time frame: 6 months from randomisation
Gastrointestinal complaints
Prevalence of gastrointestinal complaints after a course of IP
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 6 months from randomisation