This trial tests the hypothesis that intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) + dihydroartemisin-piperaquine (DP) will significantly reduce the risk of adverse birth outcomes compared to IPTp with SP alone or DP alone. This double-blinded randomized controlled phase III trial of 2757 HIV uninfected pregnant women enrolled at 12-20 weeks gestation will be randomized in equal proportions to one of three IPTp treatment arms: 1) SP given every 4 weeks, or 2) DP given every 4 weeks, or 3) SP+DP given every 4 weeks. SP or DP placebos will be used to ensure adequate blinding is achieved in the study and follow-up will end 28 days after giving birth.
Malaria in pregnancy remains a major challenge in Africa, where approximately 50 million women are at risk for P. falciparum infection during pregnancy each year. Among pregnant women living in malaria endemic areas symptomatic disease is uncommon, but infection with malaria parasites is associated with maternal anemia and adverse birth outcomes including abortions, stillbirth, preterm birth, low birth weight (LBW), and infant mortality. The World Health Organization (WHO) recommends the use of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for the prevention of malaria in pregnancy in endemic areas of Africa. However, there is concern for diminishing efficacy of these interventions due to the spread of vector resistance to the pyrethroid insecticides used in LLINs and parasite resistance to SP. Thus, there is an urgent need for new strategies for the prevention of malaria in pregnancy and improving birth outcomes. Artemisinin-based combination therapies (ACTs) are now the standard treatment for malaria in Africa. Dihydroartemisin-piperaquine (DP) is a fixed-dose ACT and an attractive alternative to SP for IPTp. DP is highly efficacious, and the long half-life of piperaquine provides at least 4 weeks of post-treatment prophylaxis. Recent randomized controlled trials showed that, compared to IPTp with SP, IPTp with DP dramatically reduced risks of malaria-specific outcomes but there were minimal differences between the SP and DP groups in risks of adverse birth outcomes. The key question for this study is why IPTp with either SP or DP is associated with similar risks of adverse birth outcomes despite the far superior antimalarial activity of DP. The likely explanation is that SP, a broad-spectrum antibiotic, protects against non-malarial causes of LBW and preterm birth. The central hypothesis is that SP improves birth outcomes independent of its antimalarial activity and that IPTp with a combination of SP+DP will offer antimalarial and non-antimalarial benefits, thus providing superior prevention of adverse birth outcomes compared to either drug used alone. To test this hypothesis, a double-blinded randomized clinical trial will conducted in a rural area of Uganda with very high malaria transmission intensity, where there is already an established infrastructure for clinical research. Specific aims will be (1) to compare the risk of adverse birth outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, (2) To compare safety and tolerability of IPTp regimens among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, and (3) to compare risks of malaria-specific and non-malarial outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP. This study will be the first to evaluate the efficacy and safety of a novel combination of well-studied drugs for improving birth outcomes and findings may well have important policy implications, with a change in standard practice for millions of pregnant women in Africa.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
2,757
SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.
DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days.
Infectious Diseases Research Collaboration Clinic - Masafu Hospital
Masafu, Busia, Uganda
Risk of Having a Composite Adverse Birth Outcome
Composite adverse birth outcome defined as the occurrence of any of the following: * Spontaneous abortion: Fetal loss at \< 28 weeks gestational age * Stillbirth: Infant born deceased at \> 28 weeks gestational age * Low Birth Weight (LBW): Live birth with birth weight \< 2500 gm * Preterm birth: Live birth at \< 37 weeks gestational age * Small-for-gestational age (SGA): Live birth with weight-for-gestational age \< 10th percentile of reference population * Neonatal death: Live birth with neonatal death within the first 28 days of life
Time frame: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Incidence of Serious Adverse Events (SAE) Per Time at Risk
SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk
Grade 3 and 4 AEs or SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Number of Participants With Spontaneous Abortion
Spontaneous abortion defined as fetal loss at \< 28 weeks gestational age
Time frame: Time of delivery
Incidence of Anemia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Grade 3-4 AEs Possibly Related to Study Drugs
Grade 3-4 AEs possibly or definitely related to study drug defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Risk of Placental Malaria
Detection of malaria parasites or pigment by histopathology
Time frame: At the time of delivery
Incidence of Malaria During Pregnancy
Episodes of symptomatic malaria (incidence per person year at risk following initiation of study drugs)
Time frame: Day study drugs first given until delivery, an average of 6 months
Microscopic Parasitemia During Pregnancy
Proportion of routine samples with asexual parasites detected by microscopy
Time frame: Day study drugs first given until delivery, an average of 6 months
Prevalence of Anemia During Pregnancy
Proportion of routine hemoglobin measurements \< 11 g/dL
Time frame: Day study drugs are first given until delivery
Stillbirth
Stillbirth defined as infant born deceased at \> 28 weeks gestational age
Time frame: Time of delivery
Low Birth Rate
Low birth weight defined as live birth with birth weight \< 2500 gm
Time frame: Time of delivery
Preterm Delivery
Preterm delivery defined as live birth at \< 37 weeks gestational age
Time frame: Time of delivery
Small-for-gestational Age
Small-for-gestational age defined as live birth with weight-for-gestational age \< 10th percentile of reference population
Time frame: Time of delivery
Neonatal Death
Neonatal death defined as live birth with neonatal death within the first 28 days of life
Time frame: Time of delivery
Microscopic or Sub-microscopic Parasitemia During Pregnancy
Proportion of routine samples with asexual parasites detected by microscopy or qPCR
Time frame: Day study drugs first given until delivery, an average of 6 months
Prevalence of Severe Anemia During Pregnancy
Proportion of routine hemoglobin measurements \< 8 g/dL
Time frame: Day study drugs are first given until delivery, an average of 6 months
Incidence of Stillbirth Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Congenital Anomaly Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Neutropenia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Proteinuria Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Thrombocytopenia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Pre-eclampsia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
Incidence of Elevated Temperature Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
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