Pregnancy, Malaria in Pregnancy, Malaria
Conditions
Keywords
Malaria in Pregnancy, Intermittent Preventive Treatment, IPTp
Brief 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.
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
DRUGdihydroartemisinin-piperaquine
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
DRUGdihydroartemisinin-piperaquine plus azithromycin
Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)
Sponsors
Kamuzu University of Health Sciences
Kenya Medical Research Institute
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
National Institute for Medical Research, Tanzania
Kilimanjaro Christian Medical Centre, Tanzania
University of Copenhagen
Centers for Disease Control and Prevention
London School of Hygiene and Tropical Medicine
University College, London
Tampere University
University of Bergen
University of Massachusetts, Worcester
University of Toronto
University of Melbourne
Foundation for Innovative New Diagnostics, Switzerland
Liverpool School of Tropical Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study will be a partially placebo-controlled involving a single placebo for AZ. To further minimise bias, an objective primary outcome measure will be used and all staff will be masked to the treatment assignment of individual women. The trial statistician will also be masked in regard to the treatment code when he develops the statistical analysis plan and writes the statistical programmes, which will be validated and completed using dummy randomisation codes. The actual allocation will only be provided to the study team after locking of the database and approval of the statistical analysis plan by the independent Data Monitoring and Ethics Committee (DMEC) before they review any trial results. The study statistician conducting the interim analysis will remain masked throughout the analysis.
Eligibility
Sex/Gender
FEMALE
Age
16 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse pregnancy outcome | 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
| Measure | Time frame | Description |
|---|---|---|
| Congenital malaria infection | 6 months from randomisation | Prevalence of malaria infection by microscopy or PCR from newborn cord blood |
| Maternal anaemia during pregnancy and delivery | 6 months from randomisation | Prevalence and incidence of maternal anaemia (Hb \< 11g/dl) at enrolment, last antenatal visit and delivery |
| Composite of foetal loss and neonatal mortality | 8 months | Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality |
| SGA-LBW-PT composite | 6 months | Composite of small for gestational age, low birth weight or preterm birth |
| SGA | 6 months | Small for gestational age using the new INTERGROWTH population reference's 10th percentile |
| LBW | 6 months | Low birth weight defined as a corrected birth weight below 2.5 kg |
| PT | 6 months | Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks |
| Neonatal length and stunting | 8 months | Neonatal length and stunting |
| Clinical malaria during pregnancy | 6 months from randomisation | Incidence of clinical malaria during pregnancy |
| Malaria infection during pregnancy detected by microscopy and PCR | 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 | 6 months from randomisation | Prevalence of placental malaria by microscopy, PCR and placental histology |
| Placental malaria detected by microscopy | 6 months from randomisation | Prevalence of placental malaria detected in maternal placental blood by microscopy |
| Placental malaria detected by molecular methods (PCR) | 6 months from randomisation | Prevalence of placental malaria detected in maternal placental blood by PCR |
| Congenital anaemia | 6 months from randomisation | Prevalence of anaemia (Hb \< 13g/dl) from newborn cord blood |
| Maternal nutritional status | 6 months from randomisation | Changes in maternal nutritional status by MUAC and BMI. |
| QTc-prolongation | 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 | 6 months from randomisation | Any visible external congenital abnormality on surface examination |
| Maternal mortality | 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 | 8 months from randomisation | Incidence of AEs and SAEs |
| (History of) vomiting study drug | 6 months from randomisation | Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit |
| Dizziness | 6 months from randomisation | Prevalence of dizziness after a course of IP |
| Gastrointestinal complaints | 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 | 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) | 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 | 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. | 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 |
| Placental malaria detected by histology | 6 months from randomisation | Prevalence of placental malaria detected in full placental section by histology |
Countries
Kenya, Malawi, Tanzania
Outcome results
None listed