Prevention of Maternal and Neonatal Death/Infections With a Single Oral Dose of Azithromycin in Women in Labor (in Low- and Middle-income Countries): a Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 58,747
- 试验地点
- 8
- 主要终点
- Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.
研究概览
简要总结
Maternal and neonatal infections are among the most frequent causes of maternal and neonatal deaths, and current antibiotic strategies have not been effective in preventing many of these deaths. Recently, a randomized clinical trial conducted in a single site in The Gambia showed that treatment with oral dose of 2 g azithromycin vs. placebo for all women in labor reduced selected maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. The A-PLUS trial includes two primary hypotheses, a maternal hypothesis and a neonatal hypothesis. First, a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labor will reduce maternal death or sepsis. Second, a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labor will reduce intrapartum/neonatal death or sepsis.
详细描述
The A-PLUS Trial is a randomized, placebo-controlled, parallel multicenter clinical trial. The study intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, with a comparison with a single intrapartum oral dose of an identical appearing placebo. For the A-PLUS randomized control trial (RCT), a total of 34,000 laboring women from eight research sites in sub-Saharan Africa, South Asia, and Latin America will be randomized with one-to-one ratio to intervention/placebo. In response to the global coronavirus pandemic, research sites will also collect data on COVID-19 signs/symptoms, diagnosis, and treatment in order to estimate the incidence of infection and evaluate the impact of the pandemic on the target population.
Prior to the initiation of the A-PLUS RCT, research sites will conduct an observational pilot study using the RCT's planned infrastructure in order to characterize the current practices at participating research facilities and optimize the identification of suspected infection for the RCT. The information obtained in the pilot study will be used to validate estimates of intrapartum deaths, maternal sepsis, and neonatal sepsis used in the sample size calculations for the RCT. Finally, the pilot study will allow the research sites to inventory and upgrade local capacity to conduct routine cultures during the RCT.
A maximum of 16,000 women, separate from the sample for the main trial, will be enrolled in the pilot, across all eight research sites, with no more than 2000 women enrolled at any individual site. Research sites will be eligible to transition to the RCT when a minimum of 600 participants have been enrolled in the pilot study with evidence of (a) high rates of follow-up; (2) acceptable data quality and completeness; and (3) there are no concerns about identification and reporting of infection.
Given the clinical benefits of intrapartum azithromycin so far reported in two trials and the likelihood that it may become the usual practice if the investigator's large RCT confirms the reported benefits, it is important to monitor antibiotic resistance to determine the safety of azithromycin prophylaxis. Therefore, the RCT will also include an ancillary study (referred to as the antimicrobial resistance (AMR) sub-study) to monitor antimicrobial resistance and maternal and newborn microbiome effects of the single dose of prophylactic azithromycin using the following methodology
- For all mothers enrolled in the RCT and their infants:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Both the azithromycin and placebo will be procured from the same manufacturer. The packaging will be standardized across sites and will be labeled as: "Azithromycin 2 g or Placebo", with the expiration data and a unique identifier.
Clinical and research staff as well as the women will be masked to treatment status unless there is a serious adverse event potentially related to the treatment modality that requires unmasking for safety reasons. There will be one pharmacist at each site who will monitor randomization, drug supply, and safety. If concerns about randomization or participant safety are identified, the data coordinating center will authorize and instruct the study pharmacist to apply un-masking procedures.
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Pregnant women in labor ≥28 weeks Gestational Age (GA) (by best estimate) with a pregnancy with one or more live fetuses who plan to deliver vaginally in a facility.
- •Admitted to health facility with clear plan for spontaneous or induced delivery.
- •Live fetus must be confirmed via a fetal heart rate by Doptone prior to randomization.
- •≥18 years of age or minors 14-17 years of age in countries where married or pregnant minors (or their authorized representatives) are legally permitted to give consent.
- •Have provided written informed consent.
- •Pregnant women in labor ≥28 weeks GA (by best estimate) with a pregnancy with one or more live fetuses who plan to deliver vaginally in a facility.
- •Admitted to health facility with clear plan for spontaneous or induced delivery.
- •Live fetus must be confirmed via presence of a fetal heart rate prior to randomization.
- •≥18 years of age or minors 14-17 years of age in countries where married or pregnant minors (or their authorized representatives) are legally permitted to give consent.
- •Have provided written informed consent [Note: written informed consent may be obtained during antenatal care, but verbal re-confirmation may be needed (per local regulations) at the time of randomization].
排除标准
- •Non-emancipated minors (as per local regulations)
- •Evidence of chorioamnionitis or other infection requiring antibiotic therapy at time of eligibility (however, women given single prophylactic antibiotics with no plans to continue after delivery should not be excluded).
- •Arrhythmia or known history of cardiomyopathy.
- •Allergy to azithromycin or other macrolides that is self-reported or documented in the medical record.
- •Any use of azithromycin, erythromycin, or other macrolide in the 3 days or less prior to randomization.
- •Plan for cesarean delivery prior to randomization.
- •Preterm labor undergoing management with no immediate plan to proceed to delivery.
- •Advanced stage of labor (>6 cm or 10 cm cervical dilation per local standards) and pushing or too distressed to understand, confirm, or give informed consent regardless of cervical dilation.
- •Are not capable of giving consent due to other health problems such as obstetric emergencies (for example, antepartum hemorrhage) or mental disorder.
- •Any other medical conditions that may be considered a contraindication per the judgment of the site investigator.
- •Previous randomization in the trial.
研究组 & 干预措施
Intervention
The study intervention is a single 2 g dose of directly observed oral azithromycin.
干预措施: Azithromycin (Drug)
Placebo
By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization.
干预措施: Placebo (Drug)
结局指标
主要结局
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.
时间窗: Within 6 weeks (42 days)
Maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.
Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group
时间窗: Within 4 weeks (28 days) post-delivery
Intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among stillbirths and neonates with 28-day status available born to women randomized. The study includes multiple births so there are more stillbirths and neonates than participants enrolled.
次要结局
- Maternal Sepsis(Within 42 days post-delivery)
- Maternal Death Due to Sepsis(Within 42 days post-delivery)
- Chorioamnionitis(Between date/time of randomization and date/time of delivery (up to 120 hours before delivery))
- Endometritis(Within 42 days post-delivery)
- Cesarean Wound Infection(Within 42 days post-delivery)
- Perineal Wound Infection(Within 42 days post-delivery)
- Other Infections(Within 42 days post-delivery)
- Use of Subsequent Maternal Antibiotic Therapy(After randomization to 42 days post-delivery. Randomization occurs between labor onset and delivery (0 to 120 hours before delivery). 42 participants were randomized >120 hours before delivery due to false labor.)
- Maternal Initial Hospital Length of Stay(Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days))
- Maternal Readmissions(After delivery discharge and within 42 days post-delivery)
- Maternal Admission to Special Care Units(Within 42 days post-delivery (reported during study))
- Maternal Unscheduled Visit for Care(Within 42 days post-delivery (reported during study))
- Maternal GI Symptoms(Within 42 days post-delivery (reported during study))
- Neonatal Sepsis(Within 28 days post-delivery)
- Neonatal Death Due to Sepsis(Within 28 days post-delivery)
- Other Neonatal Infections(Within 28 days post-delivery)
- Neonatal Initial Hospital Length of Stay(Time from delivery to discharge from delivery hospital (0 to 62 days))
- Neonatal Readmissions(After delivery discharge and within 42 days of delivery)
- Neonatal Admission to Special Care Units(Within 42 days post-delivery (reported during study))
- Neonatal Unscheduled Visit for Care(Within 42 days post-delivery (reported during study))
- Pyloric Stenosis Within 42 Days of Delivery(Within 42 days post-delivery)