Azithromycin to Improve Latency in Exam Indicated Cerclage Control Trial (ALEC)

Azithromycin to Improve Latency in Exam Indicated Cerclage: a Randomized Control Trial

Azithromycin is an antibiotic that is effective against bacteria that been associated with preterm birth (PTB). The purpose of this study is to evaluate if the addition of azithromycin prior to exam indicated cerclage prolongs gestation. A cerclage is a suture placed in the cervix to prolong gestation.

Study Overview

• Status: Recruiting
• Conditions: Pregnancy Complications; Obstetric Labor Complications; Preterm Birth; Obstetric Labor, Premature; Uterine Cervical Incompetence; Anti-Bacterial Agents; Physiological Effects of Drugs; Azithromycin; Cefazolin
• Intervention / Treatment: Drug: Cefazolin and indomethacin; Drug: Azithromycin 1 gram IV

Detailed Description

Preterm birth (PTB) continues to be a leading cause of neonatal morbidity and mortality. The rate of spontaneous PTB (delivery before 37 weeks gestation) is one in ten pregnancies and a history of prior preterm birth remains a risk factor for recurrence. The pathophysiology of cervical insufficiency leading to PTB remains poorly understood.

While interventions for PTB prevention are limited, the American College of Obstetrics and Gynecology (ACOG) supports the use of cervical cerclage. A physical exam indicated cerclage may be placed in the setting of painless cervical dilation in the second trimester. The cerclage is believed to provide mechanical support to a weakened cervix and promote the cervical mucosal plug as a barrier to ascending infection.

While many aspects of cerclage use have been extensively studied, the use of antibiotics prior to placement remains under evaluated. While antibiotic use is recommended during cesarean section, preterm premature rupture of membranes (PPROM), and obstetric anal sphincter injuries (OASIS), ACOG currently does not recommend perioperative antibiotics or prophylactic tocolytics at the time of cerclage placement citing insufficient evidence.

Miller et al. performed a randomized controlled trial (RCT) showing an increased incidence of pregnancy prolongation by at least 28 days among women who received indomethacin and perioperative antibiotics in the setting of an exam indicated cerclage compared to those who received no perioperative medications (92.3% vs 62.5%, p=0.01). Participants in the experimental arm received cefazolin or clindamycin if they had a penicillin allergy. Cefazolin is a first generation cephalosporin that has activity against gram positive cocci and gram negative rods and is commonly used for surgical prophylaxis. Clindamycin is a protein synthesis inhibitor and covers gram positive organisms and anaerobic bacteria, making it an appropriate alternative in cases of penicillin allergy. The use of cefazolin specifically with indomethacin has been studied retrospectively and showed a significant improvement in gestational latency (adjusted relative risk [aRR] 1.21, 95% CI 1.05-1.40) and birth weight (+489.8 grams, 95% CI 64.6-915.0).

The use of prolonged azithromycin with cerclage has been studied in a prospective, non- randomized fashion. In this study, patients were given 500mg azithromycin for 3 days and this was repeated every 10 days until 34 weeks. Patients who received this regimen and a cerclage had lower PTB (65.7% vs 5.7%, p<0.001) and reduced immediate fetal mortality (37.1% vs 0%, p<0.001).

The aim of our study is to determine if the addition of azithromycin prior to exam indicated cerclage prolongs gestation. Azithromycin is a macrolide antibiotic that binds to the 50S subunit of the bacterial ribosome and inhibits transpeptidation. It is effective against a wide variety of bacteria, specifically mycoplasma which has been associated with preterm birth. Azithromycin is currently used in obstetrics for patients undergoing nonelective cesarean delivery and as part of latency antibiotics in the setting of PPROM.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Rupsa Boelig, MD; Phone Number: 2159555000; Email: Rupsa.boelig@jefferson.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Contact: Emily Miller, MD
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Rutgers Robert Wood Johnson
      • Contact: Justin Brandt, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Pregnant women with singleton pregnancies
• ≥18 years old
• Estimated gestational age less than 24 weeks
• Meet criteria for an exam indicated cerclage
• Patients must also be able to provide consent, demonstrate an understanding of the purpose of the study, and agree to the study protocol.

Exclusion Criteria:

• Human immunodeficiency virus (HIV) positive status
• Known prolonged QT syndrome
• Major fetal congenital anomalies
• Temperature of 100.4 F or higher
• Prior cerclage during the current pregnancy
• Contraindication to indomethacin
• Allergy to both penicillin and clindamycin
• Received indomethacin or any antibiotics within 7 days before their presentation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cefazolin and Indomethacin; Control arm- perioperative cefazolin and indomethacin	Drug: Cefazolin and indomethacin; Perioperative standard of care with cefazolin and indomethacin
Experimental: Azithromycin + control; perioperative azithromycin, cefazolin and indomethacin	Drug: Cefazolin and indomethacin; Perioperative standard of care with cefazolin and indomethacin; Drug: Azithromycin 1 gram IV; Perioperative addition of azithromycin at the time of physical exam indicated cerclage placement.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational Latency Achieved Between Cerclage Placement and Time of Delivery	Mean gestational latency achieved Between Cerclage Placement and Time of Delivery	24 weeks following cerclage placement

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preterm birth <37 weeks, <34 weeks, <32 weeks, <28 weeks, <24 weeks	Preterm delivery stratified by gestational age at delivery in weeks	at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.
Mean gestational age at delivery	Measured in weeks	at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.
chorioamnionitis	Histologic or clinical diagnosis	at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.
birth weight	measured in grams	at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.
Admission to neonatal intensive care unit	If admitted, measured in days	at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.
Neonatal Morbidity and Mortality	including apgars, Respiratory Distress Syndrome, Bronchopulmonary dysplasia, Retinopathy of prematurity, Intraventricular hemorrhage (IVH) (grade 3 or 4), patent ductus arteriosus, and neonatal death	within 28 days of delivery
Cervicovaginal cytokine analysis	Measurement of proinflammatory cytokines in pg/ml (IL-1B, IL-2, IL-4, IL-6, IL-8, IL-8, IL-10, G-CSF, GM-CSF, MCP-1, TNF-a, IFN-g, CCL5, VEGF, ICAM-1) from cervicovaginal fluid at the time of cerclage placement and at follow up 1-4 weeks after placement	Cerclage placement and 1-4 weeks after

Collaborators and Investigators

• Sponsor: Thomas Jefferson University
• Investigators: Principal Investigator: Jenani S Jayakumaran, MD, Thomas Jefferson University; Principal Investigator: Rupsa Boelig, MD, Thomas Jefferson University

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: October 25, 2021
• First Submitted That Met QC Criteria: November 12, 2021
• First Posted (Actual): November 24, 2021

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: June 23, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: preterm birth; antibiotics; cerclage; premature cervical dilation
• Additional Relevant MeSH Terms: Uterine Cervical Diseases; Uterine Diseases; Abortion, Habitual; Abortion, Spontaneous; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Premature Birth; Obstetric Labor Complications; Pregnancy Complications; Obstetric Labor, Premature; Uterine Cervical Incompetence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Anti-Bacterial Agents; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Cefazolin; Azithromycin; Indomethacin
• Other Study ID Numbers: 21D.746

Drug and device information, study documents

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