Azithromycin and Ampicillin for Late PPROM

NCT ID: NCT07183462

Last Updated: 2025-12-18

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 311 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-10
• Study Completion Date: 2029-07-31

Brief Summary

The goal of this clinical trial is to learn whether adding azithromycin to the standard antibiotic treatment (ampicillin) improves newborn outcomes in women with preterm premature rupture of membranes (PPROM) between 34.0 and 36.6 weeks of pregnancy.

The main question it aims to answer is:

Does the combination of ampicillin and azithromycin lower the risk of serious neonatal health problems compared to ampicillin alone?

Researchers will compare two antibiotic regimens:

Ampicillin alone, which is the current standard care Ampicillin with azithromycin, a broader regimen that may better prevent infections and prolong pregnancy

Participants will:

Receive one of the two antibiotic treatments during hospitalization. Be monitored until delivery for signs of infection and labor

All participants will stay in the hospital until delivery. The study also looks at how the antibiotic choice may affect the time between membrane rupture and delivery, maternal infections, and the need for neonatal intensive care.

Detailed Description

Preterm premature rupture of membranes (PPROM) occurs in 1-3% of all pregnancies and accounts for approximately 30% of all preterm births. It is associated with significant maternal, fetal, and neonatal risks, including infections, respiratory complications, and adverse neurodevelopmental outcomes. The management of PPROM before 34 weeks is well established and includes corticosteroids and antibiotic therapy to prolong latency and reduce infectious complications. However, optimal management of PPROM in the late preterm period (34.0 to 36.6 weeks) remains under debate.

Historically, immediate delivery was recommended after PPROM at 34 weeks or later. More recent evidence, however, suggests that expectant management may reduce neonatal respiratory morbidity, mechanical ventilation, and NICU stays, even in the late preterm period. As a result, expectant management has become more accepted. In this setting, prophylactic antibiotics are commonly used to reduce maternal and neonatal infections. While ampicillin is the standard agent used for GBS prophylaxis, it is unclear whether broader antibiotic coverage might lead to better neonatal outcomes by delaying delivery or preventing ascending infections.

In early preterm PPROM (<32 weeks), a combination of ampicillin and erythromycin (or azithromycin) has demonstrated improved outcomes in large trials. However, few studies have addressed the benefits of such regimens in late PPROM, and no randomized controlled trials to date have compared different antibiotic regimens in this specific population.

This multicenter randomized controlled trial will compare two antibiotic regimens in women with PPROM between 34.0 and 36.6 weeks of gestation:

Control group (standard care): Intravenous ampicillin 2 g every 6 hours for 48 hours, followed by oral amoxicillin 500 mg every 8 hours for 5 days.

Intervention group: Same regimen as the control group, with the addition of a single dose of PO azithromycin 1 g administered at the start of treatment.

The primary outcome is a composite of neonatal adverse outcomes, including:

Use of respiratory support (CPAP, HFNC, mechanical ventilation, ECMO) Neonatal sepsis (confirmed by positive blood culture) Hypoglycemia requiring treatment Hyperbilirubinemia requiring phototherapy Stillbirth or neonatal death within 72 hours

Secondary neonatal outcomes include:

Components of the primary outcome analyzed individually RDS, need for resuscitation, surfactant use, TTN, IVH, NEC, NICU stay duration, pneumothorax, asphyxia, convulsions, placental pathology, and others Maternal outcomes include Latency from randomization to delivery Chorioamnionitis, fever, bacteremia, placental abruption, cesarean delivery Composite maternal morbidity Postpartum infections, need for ICU admission, wound complications Length of postpartum hospital stay and breastfeeding initiation

Participants will be hospitalized from diagnosis until delivery. Management will include:

Regular maternal vital signs and infection monitoring Twice-daily fetal heart rate monitoring Corticosteroids for fetal lung maturation (in selected patients) Ultrasound to assess fetal well-being No tocolysis will be administered Labor will be induced at 37 weeks or earlier if indicated

Inclusion criteria:

Women aged 18-50 years with singleton pregnancy PPROM diagnosed between 34.0 and 36.6 weeks No active labor or signs of infection at presentation

Exclusion criteria:

Multiple gestation, chorioamnionitis, abnormal fetal heart rate, cerclage, meconium-stained amniotic fluid, fetal malformations, or GBS macrolide allergy Diagnosis of PPROM will be based on history and physical exam, including pooling seen on sterile speculum exam. When necessary, AmniSure testing will confirm membrane rupture.

Eligible women will be approached within 24 hours of admission. After obtaining informed consent, participants will be randomized (1:1) and stratified by center and gestational age (<35 weeks or ≥35 weeks). Women will remain inpatients until delivery, and labor will be induced no later than 37.0 weeks, unless earlier delivery is indicated.

Placental pathology and culture will be performed in all participants after delivery.

The sample size is based on an expected 50% rate of the composite neonatal outcome in the control group. A total of 296 women will provide 80% power to detect a 33% relative reduction in the primary outcome (from 50% to 33.5%) with a 5% alpha level. Including a 5% loss to follow-up, 311 women will be enrolled.

Data will be collected using REDCap, and participant confidentiality will be maintained through study ID numbers. Results may be used in future research but will remain de-identified.

Ethics approval will be obtained at each participating site. All participants will provide written informed consent, and the study will be conducted under standard GCP (Good Clinical Practice) guidelines.

This trial aims to provide the first direct comparison of two antibiotic regimens in the setting of late preterm PPROM, potentially impacting future recommendations on latency antibiotic therapy and neonatal outcomes.

Conditions

Pregnancy Complications, Infectious; Premature Birth; Neonatal Diseases and Abnormalities; Antibiotic Prophylaxis; Latency Period; Prematurity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard antibiotic regimen (Ampicillin and Amoxicillin)

Participants in the control arm receive the standard antibiotic regimen for late PPROM, consisting of intravenous Ampicillin 2g every 6 hours for 48 hours, followed by oral Amoxicillin 500mg every 8 hours for 5 days, administered according to current clinical guidelines

Group Type: ACTIVE_COMPARATOR

Ampicillin/Amoxicillin plus single-dose PO Azithromycin

Intervention Type: DRUG

This intervention includes intravenous Ampicillin 2 grams every 6 hours for 48 hours, followed by oral Amoxicillin 500 mg every 8 hours for 5 days, plus a single dose of oral Azithromycin 1 gram administered once at the start of treatment

Intervention Arm - Standard Antibiotics with Azithromycin

Participants in this arm will receive the standard antibiotic regimen of intravenous Ampicillin followed by oral Amoxicillin, plus a single dose of 1 gram oral Azithromycin

Group Type: EXPERIMENTAL

Intravenous Ampicillin followed by Oral Amoxicillin

Intervention Type: DRUG

This intervention consists of intravenous Ampicillin 2 grams every 6 hours for 48 hours, followed by oral Amoxicillin 500 mg every 8 hours for 5 days

Interventions

Intravenous Ampicillin followed by Oral Amoxicillin

This intervention consists of intravenous Ampicillin 2 grams every 6 hours for 48 hours, followed by oral Amoxicillin 500 mg every 8 hours for 5 days

Intervention Type: DRUG

Ampicillin/Amoxicillin plus single-dose PO Azithromycin

This intervention includes intravenous Ampicillin 2 grams every 6 hours for 48 hours, followed by oral Amoxicillin 500 mg every 8 hours for 5 days, plus a single dose of oral Azithromycin 1 gram administered once at the start of treatment

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Maternal age 18-50
• Premature rupture of membranes
• Gestational age 34.0 and 36.4 weeks
• Singleton pregnancy

Exclusion Criteria

• Multiple gestations
• Individuals in active labor (defined as 3 cm dilatation and 80% effacement or more. or regular uterine construction of more than 4 in 10 minutes)
• Meconium stain amniotic fluid
• Non-reassuring fetal heart rate or status
• Maternal or fetal indication for labor:

• Suspected Chorioamnionitis
• Suspected placental abruption
• Any maternal morbidity requiring labor
• Cervical cerclage in place.
• Major fetal malformation or known chromosomal abnormalities.
• Stillbirth.
• Sensitivity to Macrolides Antibiotics

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Sheba Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Noa Gonen, MD

Role: STUDY_CHAIR

Sheba Medical Center

Locations

Sheba medical center

Ramat Gan, Israel, Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Noa Gonen, MD

Role: CONTACT

Phone: 972-54-3955584

Email: gonen.noa7@gmail.com

Michal Fishel - Bartal, MD

Role: CONTACT

Phone: 972-52-8087034

Email: michalbartal@gmail.com

Facility Contacts

noa gonen

Role: primary

Provided Documents

Document Type: Study Protocol

View Document

Other Identifiers

MOH_2025-04-30_014029

Identifier Type: OTHER

Identifier Source: secondary_id

SHEBA-05-1755-24-NG-CTIL

Identifier Type: -

Identifier Source: org_study_id