Protocol No: ECCT/19/06/02 Date of Protocol: 19-01-2019

Study Title:

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

Study Objectives:

1.1Primary Specific Aims

To test the effectiveness of a single dose of prophylactic intrapartum azithromycin compared to placebo in reducing the risk of the composite outcome of maternal death or sepsis. To separately test the effectiveness of a single oral dose of intrapartum azithromycin prophylaxis (2 g) compared to placebo in reducing the risk of the composite outcome of intrapartum/neonatal death or sepsis. Both groups will receive the routine or usual care provided at the facility during and after labor. This will be ensured through training of all nurses on maternal and newborn care using the National guidelines and protocols as provided for by the Ministry of Health viz Basic Paediatric Protocols 2016, National Guidelines for Quality Obstetrics and Perinatal Care and National Guidelines on Essential Newborn Care.


1.2Secondary Specific Aims

The single dose of intrapartum  azithromycin prophylaxis (2 g) will be compared to placebo to accomplish the following secondary aims:

  • Main Secondary Aim for Women at High Risk for Infection Cohort:
    1. To evaluate whether the risk of maternal death or sepsis differs among laboring women with and without high-risk for infection (high risk is defined as women with prolonged labor [≥18 hours] and/or prolonged membrane rupture [≥8 hours]).
  • Other secondary specific Aims:
  1. To evaluate the effectiveness in reducing the risk of individual components of the primary composite endpoints (i.e., maternal death, maternal sepsis, intrapartum/neonatal death, neonatal sepsis including specifically all-cause neonatal deaths and neonatal deaths due to sepsis).
  2. To evaluate the effectiveness on the risk of intrapartum/neonatal death or sepsis in infants of laboring women at high-risk for infection because of prolonged labor (≥18hours) and/or prolonged membrane rupture (≥8 hours).
  3. To evaluate the effectiveness on the risk of maternal infections including clinical chorioamnionitis, endometritis, wound infections (perineal or subsequent cesarean), abdominal or pelvic abscess, mastitis/breast abscess, pyelonephritis and pneumonia in all laboring women as well as in those at high-risk for infection.
  4. To evaluate the effectiveness in reducing the use of subsequent maternal antibiotic therapy from randomization to 6 weeks for any reason in all laboring women as well as in those at high-risk for infection.
  5. To compare the use of health care resources. Use of health care resources will be measured in terms of maternal and neonatal duration of hospital stay, unscheduled clinic or ER visits, readmissions, and admission to special care units/intensive care units in all laboring women and newborns as well as in those at high-risk for infection.
  6. To assess maternal GI symptoms (e.g., nausea, vomiting, and diarrhea) and other reported side effects, as well as infant pyloric stenosis and type of culture positive infections (antimicrobial resistance and maternal and infant microbiome diversity are compared in an ancillary study).
  7. To determine whether the effect on each of the primary outcomes differs by region (Africa, Latin America or Asia), any other antibiotic use during labor, and mode of delivery (cesarean or vaginal). Note that antibiotic use will not include use to treat any infections diagnosed after randomization as those will be outcomes.
Laymans Summary:

The purpose of the A-PLUS study is to learn whether an antibiotic, called azithromycin, given by mouth to pregnant women during labor can reduce the risk of infection for the woman and her baby. A total of 34,000 women will be enrolled in this study from eight sites in sub-Saharan Africa, South Asia, and Latin America.

The target population are pregnant women of legal age of consent who labor with one or more live fetuses and a pregnancy of ≥28 weeks, plan to deliver vaginally in a health facility, have no known infections that require antibiotics, have no known problems taking azithromycin or similar antibiotics (such as amoxicillin), and have not used azithromycin, erythromycin, or similar antibiotic in the past 3 days.

Before participating, participants will be provided with information about the study procedures and given an opportunity to ask questions. If they qualify and agree to participate, they will be asked to sign a form to indicate consent.

Participants will be assigned to either the treatment group or the control group randomly, like flipping a coin or choosing a grain of rice from a bag. The women in the treatment group will take four 500 mg azithromycin pills. For comparison, the women in the control group will take four pills called placebo that look identical to azithromycin but do not contain any medication. Neither participants nor the study staff will know whether they were assigned to the treatment or control group. Participants will receive care during your labor, delivery, and recovery from the health facility staff, according to the local standard of care.

While at the health facility for deliver, the study team will also collect: information about labor and delivery; information about the baby, such as birthweight and health status at the time of delivery. If study participants develop an infection before being discharged from the health facility, a sample will be taken from the site of the infection. Participants may also be asked to provide a blood sample.

After delivery, the study team will visit a total of three times at home at 3 days, 1 week and 6 weeks after delivery or in the hospital if the participant or the baby is in hospital. The study team will assess for signs of infection in the mother and baby and will collect a specimen to help identify the bacteria involved. This may be a sample of pus, urine, or blood.  The visits will take approximately 30 minutes.

The team will access and collect information from the medical records at the health facilities where care was received.  The information collected from medical records will be coded with a number to protect the identity of study participants. The local research staff has been selected because of their skills, knowledge, and familiarity with the community and should be contacted between visits if there are any questions or concerns.

Abstract of Study:

Background: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 certain maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality.

Hypotheses:The 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 Design Type:Randomized, placebo-controlled, parallel multicenter clinical trial. Women in labor will be randomized with one-to-one ratio to intervention/placebo.

Population:Pregnant women in labor at ≥28 weeks gestational age with a live fetus pregnancy who plan to deliver vaginally in a facility. Women with evidence of chorioamnionitis or other infection requiring antibiotic therapy (not prophylaxis) at time of eligibility, allergy to azithromycin, use of azithromycin, erythromycin or other macrolide within 3 days of enrollment, known arrhythmia or cardiomyopathy, or plan for cesarean section delivery prior to enrollment will be excluded.

Intervention:A single, prophylactic intrapartum oral dose of 2 g azithromycin.

Comparison:A single intrapartum oral dose of an identical appearing placebo


Primary outcomes:1) Incidence of maternal death or sepsis and 2) incidence of intrapartum/neonatal death or sepsis.

Secondary outcomes:Individual components of the primary outcomes (maternal death, maternal sepsis, intrapartum/neonatal death, neonatal sepsis), neonatal death/sepsis, neonatal deaths due to sepsis, and all-cause neonatal death; the primary maternal outcome in a high-risk for infection population; specific maternal infections; use of subsequent maternal antibiotic therapy; pyloric stenosis; health care resource utilization; culture-positive infections and resistance; in an ancillary surveillance study,  incidence of antimicrobial resistance and microbiome diversity.