Optimal Chemopreventive Regimens to Prevent Malaria and Improve Birth Outcomes in Uganda
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 2,757
- 试验地点
- 1
- 主要终点
- Risk of Having a Composite Adverse Birth Outcome
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two drugs on day 1 (SP and placebo or DP and placebo or SP and DP) followed by one drug on days 2 and 3 (DP or placebo). Two placebos will be used, one that mimics the appearance of SP and one that mimics the appearance of DP. A randomization list will be computer generated by a member of the project who will not be directly involved in the conduct of the study. The randomization list will include consecutive treatment numbers with corresponding random treatment assignments. Randomized codes will correspond to the 3 treatment arms using permuted variable sized blocks of 6 and 9.
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Viable singleton pregnancy confirmed by ultrasound
- •Estimated gestational age between 12-20 weeks
- •Confirmed to be HIV- uninfected by rapid test
- •16 years of age or older
- •Residency within Busia District of Uganda
- •Provision of informed consent
- •Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol
- •Willing to deliver in the hospital
排除标准
- •History of serious adverse event to SP or DP
- •Active medical problem requiring inpatient evaluation at the time of screening
- •Intention of moving outside of Busia District Uganda
- •Chronic medical condition requiring frequent medical attention
- •Prior chemopreventive therapy or any other antimalarial therapy during this pregnancy
- •Early or active labor (documented by cervical change with uterine contractions)
- •Multiple pregnancies (i.e. twins/triplets)
研究组 & 干预措施
SP + DP placebo every 4 weeks
干预措施: Sulfadoxine-pyrimethamine (SP) (Drug)
DP + SP placebo every 4 weeks
干预措施: Dihydroartemisinin-piperaquine (DP) (Drug)
SP + DP given every 4 weeks
干预措施: Sulfadoxine-pyrimethamine (SP) (Drug)
SP + DP given every 4 weeks
干预措施: Dihydroartemisinin-piperaquine (DP) (Drug)
结局指标
主要结局
Risk of Having a Composite Adverse Birth Outcome
时间窗: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
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
Incidence of Serious Adverse Events (SAE) Per Time at Risk
时间窗: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk
时间窗: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
Grade 3 and 4 AEs or SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
次要结局
- Number of Participants With Spontaneous Abortion(Time of delivery)
- Incidence of Anemia Adverse Event Per Time at Risk(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(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(At the time of delivery)
- Incidence of Malaria During Pregnancy(Day study drugs first given until delivery, an average of 6 months)
- Microscopic Parasitemia During Pregnancy(Day study drugs first given until delivery, an average of 6 months)
- Prevalence of Anemia During Pregnancy(Day study drugs are first given until delivery)
- Stillbirth(Time of delivery)
- Low Birth Rate(Time of delivery)
- Preterm Delivery(Time of delivery)
- Small-for-gestational Age(Time of delivery)
- Neonatal Death(Time of delivery)
- Microscopic or Sub-microscopic Parasitemia During Pregnancy(Day study drugs first given until delivery, an average of 6 months)
- Prevalence of Severe Anemia During Pregnancy(Day study drugs are first given until delivery, an average of 6 months)
- Incidence of Stillbirth Adverse Event Per Time at Risk(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(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(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(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(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(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(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(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(Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months)
研究者
Grant Dorsey, M.D, Ph.D.
Principle Investigator
University of California, San Francisco