ALEC: Azithromycin to Improve Latency in Exam Indicated Cerclage Control Trial

Sponsor

Thomas Jefferson University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05132829

Collaborator

(none)

Enrollment

Locations

Arms

41.4

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Preterm Birth Obstetric Labor, Premature Obstetric Labor Complications Pregnancy Complications Physiological Effects of Drugs Uterine Cervical Incompetence Anti-Bacterial Agents Azithromycin Cefazolin	Drug: Azithromycin 1 gram IV Drug: Cefazolin and indomethacin	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 20, 2021

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

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: Azithromycin 1 gram IV Perioperative addition of azithromycin at the time of physical exam indicated cerclage placement. Drug: Cefazolin and indomethacin Perioperative standard of care with cefazolin and indomethacin

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: Azithromycin 1 gram IV

Perioperative addition of azithromycin at the time of physical exam indicated cerclage placement.

Drug: Cefazolin and indomethacin

Perioperative standard of care with cefazolin and indomethacin

Outcome Measures

Primary Outcome Measures

Gestational Latency Achieved Between Cerclage Placement and Time of Delivery [24 weeks following cerclage placement]
Mean gestational latency achieved Between Cerclage Placement and Time of Delivery

Secondary Outcome Measures

Preterm birth <37 weeks, <34 weeks, <32 weeks, <28 weeks, <24 weeks [at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.]
Preterm delivery stratified by gestational age at delivery in weeks
Mean gestational age at delivery [at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.]
Measured in weeks
chorioamnionitis [at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.]
Histologic or clinical diagnosis
birth weight [at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.]
measured in grams
Admission to neonatal intensive care unit [at delivery following cerclage placement. Latest will occur 26 weeks following cerclage placement.]
If admitted, measured in days
Neonatal Morbidity and Mortality [within 28 days of delivery]
including apgars, Respiratory Distress Syndrome, Bronchopulmonary dysplasia, Retinopathy of prematurity, Intraventricular hemorrhage (IVH) (grade 3 or 4), patent ductus arteriosus, and neonatal death
Cervicovaginal cytokine analysis [Cerclage placement and 1-4 weeks after]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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