Azithromycin-Prevention in Labor Use Study (A-PLUS)

Study Overview
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Brief Summary
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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.

Detailed Description
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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: a. Routine clinical monitoring at baseline and three post-partum time points (3 days, 7 days, and 42 days), with culture and sensitivity testing in cases of suspected bacterial infections; Among a subset of 1000 randomly selected maternal-infant dyads: Serial susceptibility monitoring of antimicrobial resistance patterns (including azithromycin resistance) from selected maternal and newborn flora through culture and sensitivity testing. Serial monitoring will be conducted at baseline and three post-partum time points (1 week, 6 weeks, and 3 months). Serial microbiome collection and storage of specimens for future testing to monitor maternal and newborn microbiome status of selected sites.

Official Title
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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

Conditions
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Maternal Death, Maternal Infections Affecting Fetus or Newborn, Neonatal SEPSIS, Maternal Sepsis During Labor, Neonatal Death, Postpartum Sepsis

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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]. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled, parallel multicenter clinical trial. Women in labor will be randomized with one-to-one ratio to intervention/placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>The study intervention is a single 2 g dose of directly observed oral azithromycin. | Drug: Azithromycin<br>* The study intervention is a single 2 g dose of directly observed oral azithromycin, to be administered as four 500 mg pills or tablets directly after randomization. By random allocation, participants will receive 2 g of oral azithromycin.<br>|
| Placebo Comparator: Placebo<br>By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization. | Drug: Placebo<br>* Identical appearing placebo, administered as a single oral dose directly after randomization.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal: Incidence of maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group. | Incidence of maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group. | within 6 weeks (42 days) | 
| Neonatal: Incidence of intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group | Incidence of intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group | 4 weeks (28 days) post-delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of chorioamnionitis | Fever (>100.4°F/38°C) in addition to one or more of the following: fetal tachycardia ≥160 bpm, maternal tachycardia >100 bpm, tender uterus between contractions, or purulent/foul smelling discharge from uterus prior to delivery. | prior to delivery | 
| Incidence of endometritis | Fever (>100.4°F/38°C) in addition to one or more of maternal tachycardia >100 bpm, tender uterine fundus, or purulent/foul smelling discharge from uterus after delivery. | within 42 days post-delivery | 
| Incidence of other infections | Wound infection (Purulent infection of a perineal or Cesarean wound with or without fever. In the absence of purulence, requires presence of fever >100.4°F/38°C and at least one of the following signs of local infection: pain or tenderness, swelling, heat, or redness around the incision/laceration); Abdominopelvic abscess (Evidence of pus in the abdomen or pelvis noted during open surgery, interventional aspiration or imaging); Pneumonia (Fever >100.4°F/38°C and clinical symptoms suggestive of lung infection including cough and/or tachypnea >24 breaths/min or radiological confirmation); Pyelonephritis (Fever >100.4°F/38°C and one or more of the following: urinalysis/dip suggestive of infection, costovertebral angle tenderness, or confirmatory urine culture); Mastitis/breast abscess or infection (Fever >100.4°F/38°C and one or more of the following: breast pain, swelling, warmth, redness, or purulent drainage). | within 42 days post-delivery | 
| Incidence of use of subsequent maternal antibiotic therapy | Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason. | after randomization to 42 days post-delivery | 
| Maternal initial hospital length of stay | Time from drug administration until initial discharge after delivery (time may vary by site). | within 42 days post-delivery | 
| Incidence of maternal readmissions | Maternal readmissions within 42 days of delivery | within 42 days post-delivery | 
| Incidence of maternal admission to special care units | Maternal admission to special care units | within 42 days post-delivery | 
| Incidence of maternal unscheduled visit for care | Maternal unscheduled visit for care | within 42 days post-delivery | 
| Incidence of maternal GI symptoms | Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects. | within 42 days post-delivery | 
| Incidence of maternal death due to sepsis | Maternal death due to sepsis using the Global Network algorithm for cause of death | within 42 days post-delivery | 
| Incidence of other neonatal infections (e.g. eye infection, skin infection) | Incidence of other neonatal infections. | within 42 days post-delivery | 
| Neonatal initial hospital length of stay | Neonatal initial hospital length of stay, defined as time of delivery until initial discharge (time may vary by site). | within 28 days of delivery | 
| Incidence of neonatal readmissions | Neonatal readmissions within 42 days of delivery | within 42 days of delivery | 
| Incidence of neonatal admission to special care units | Neonatal admission to special care units | within 28 days of delivery | 
| Incidence of neonatal unscheduled visit for care | Neonatal unscheduled visit for care | within 42 days post-delivery | 
| Incidence of neonatal death due to sepsis | Neonatal death due to sepsis using the Global Network algorithm for causes of death | within 28 days of delivery | 
| Incidence of pyloric stenosis within 42 days of delivery | Pyloric stenosis within 42 days of delivery, defined as clinical suspicion based on severe vomiting leading to death, surgical intervention (pyloromyotomy) as verified from medical records, or radiological confirmation. | within 42 days of delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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maternal sepsis, maternal death, neonatal sepsis, neonatal death, azithromycin, Democratic Republic of Congo, Zambia, Guatemala, Bangladesh, India, Pakistan, Kenya, COVID-19