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

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

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.

Study Overview

• Status: Completed
• Conditions: Maternal Death; Maternal Infections Affecting Fetus or Newborn; Neonatal SEPSIS; Maternal Sepsis During Labor; Neonatal Death; Postpartum Sepsis
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

Detailed Description

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

1. 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;

2. Among a subset of 1000 randomly selected maternal-infant dyads:

   1. 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).
   2. Serial microbiome collection and storage of specimens for future testing to monitor maternal and newborn microbiome status of selected sites.

• Study Type: Interventional
• Enrollment (Actual): 58747
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh, 1212
    • ICDDRB
• Congo, The Democratic Republic of the
  • Kinshasa, Congo, The Democratic Republic of the
    • Kinshasa School of Public Health
• Guatemala
  • Guatemala City, Guatemala, 01011
    • Institute for Nutrition of Central America and Panama (INCAP)
• India
  • Belagam, India, 590 010
    • Jawaharlal Nehru Medical College
  • Nagpur, India
    • Lata Medical Research Foundation
• Kenya
  • Eldoret, Kenya, 30100
    • Moi University School of Medicine
• Pakistan
  • Karachi, Pakistan, 74800
    • The Aga Khan University
• Zambia
  • Lusaka, Zambia
    • University Teaching Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.	Maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.	Within 6 weeks (42 days)
Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 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. 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.	Within 4 weeks (28 days) post-delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal Sepsis	Maternal sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.	Within 42 days post-delivery
Maternal Death Due to Sepsis	Maternal death due to sepsis using the Global Network algorithm for cause of death	Within 42 days post-delivery
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.	Between date/time of randomization and date/time of delivery (up to 120 hours before delivery)
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
Cesarean Wound Infection	Wound infection (Purulent infection of a 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);	Within 42 days post-delivery
Perineal Wound Infection	Wound infection (Purulent infection of a perineal 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);	Within 42 days post-delivery
Other Infections	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). Other bacterial infection.	Within 42 days post-delivery
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. 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 until initial discharge after delivery (time may vary by site).	Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days)
Maternal Readmissions	Maternal readmissions after delivery discharge and within 42 days of delivery	After delivery discharge and within 42 days post-delivery
Maternal Admission to Special Care Units	Maternal admission to special care units	Within 42 days post-delivery (reported during study)
Maternal Unscheduled Visit for Care	Maternal unscheduled visit for care	Within 42 days post-delivery (reported during study)
Maternal GI Symptoms	Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects.	Within 42 days post-delivery (reported during study)
Neonatal Sepsis	Neonatal sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Within 28 days post-delivery
Neonatal Death Due to Sepsis	Neonatal death due to sepsis using the Global Network algorithm for causes of death. This outcome is measured among neonates with 28-day status available born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Within 28 days post-delivery
Other Neonatal Infections	Other neonatal infections (e.g. eye infection, skin infection). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Within 28 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). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Time from delivery to discharge from delivery hospital (0 to 62 days)
Neonatal Readmissions	Neonatal readmissions to facility after delivery discharge and within 42 days of delivery. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	After delivery discharge and within 42 days of delivery
Neonatal Admission to Special Care Units	Neonatal admission to special care units. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Within 42 days post-delivery (reported during study)
Neonatal Unscheduled Visit for Care	Neonatal unscheduled visit for care. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Within 42 days post-delivery (reported during study)
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. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.	Within 42 days post-delivery

Collaborators and Investigators

• Sponsor: NICHD Global Network for Women's and Children's Health
• Collaborators: Boston University; University of Colorado, Denver; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); University of Alabama at Birmingham; Columbia University; Bill and Melinda Gates Foundation; University of North Carolina, Chapel Hill; Aga Khan University; University of Virginia; International Centre for Diarrhoeal Disease Research, Bangladesh; Thomas Jefferson University; RTI International; Indiana University School of Medicine; University Teaching Hospital, Lusaka, Zambia; Kinshasa School of Public Health; Institute of Nutrition of Central America and Panama; Lata Medical Research Foundation, Nagpur; Moi Univeristy; Jawaharlal Nehru Medical College
• Investigators: Study Director: Marion Koso-Thomas, MD, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: March 5, 2019
• First Submitted That Met QC Criteria: March 11, 2019
• First Posted (Actual): March 12, 2019

Study Record Updates

• Last Update Posted (Actual): October 24, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19; Kenya; Bangladesh; India; azithromycin; Pakistan; Guatemala; Zambia; maternal sepsis; maternal death; neonatal sepsis; neonatal death; Democratic Republic of Congo
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Puerperal Disorders; Parental Death; Neonatal Sepsis; Sepsis; Infections; Toxemia; Death; Pregnancy Complications, Infectious; Puerperal Infection; Perinatal Death; Maternal Death; Anti-Bacterial Agents; Anti-Infective Agents; Azithromycin
• Other Study ID Numbers: CP Azithromycin; U24HD092094 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified participant data will be made available through the NICHD Data and Specimen Hub (N-DASH) system, a publicly accessible online archive, following publication of the primary paper.
• IPD Sharing Time Frame: No more than one year after publication of the primary paper. No end date.
• IPD Sharing Access Criteria: Deidentified participant data will be made available through the NICHD Data and Specimen Hub (N-DASH) system, a publicly accessible online archive. Investigators interested in data and access are required to submit their request through N-DASH, per the requirements of the DASH policy. This includes a brief description of the proposed use of the research data, a signed NICHD DASH Data Use Agreement, and IRB approval, exemption, or declaration that the research does not involve human subjects.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No