Treatment of ppROM With Erythromycin vs. Azithromycin Trial (TREAT)

TREAT: Treatment of ppROM With Erythromycin vs. Azithromycin Trial

Preterm premature rupture of membranes (PPROM) complicates 4% of pregnancies annually. This pregnancy complication is a major contributor to preterm births and results in neonatal morbidity and mortality. The current standard of care for PPROM subjects between the gestational age of 24 weeks and 0 days and 33 weeks and 6 days, is to administer ampicillin and erythromycin for a total of 7 days. Erythromycin can cause GI upset and some subjects do not tolerate this regimen over the course of 7 days. In addition, there is a national shortage of erythromycin, and published expert opinion proposed to use a second-generation macrolide (azithromycin) instead of erythromycin. Azithromycin can be taken once daily, is cheaper than erythromycin and has less GI upset adverse effects. The investigators' objective is to compare the effectiveness of the 2 regimens in prolonging pregnancy after PPROM. The investigators' working hypothesis is that there is no measurable difference in the primary outcome between the group randomized to the azithromycin regimen versus the group randomized to the erythromycin regimen.

Study Overview

• Status: Recruiting
• Conditions: Preterm Premature Rupture of Membranes (PPROM)
• Intervention / Treatment: Drug: Azithromycin; Drug: Ampicillin; Drug: Amoxicillin; Drug: Erythromycin

Detailed Description

In the United States, preterm premature rupture of membranes (PPROM) complicates 4% of pregnancies annually. This pregnancy complication is a major contributor to preterm births and results in neonatal morbidity and mortality. Without treatment, 70-80% of women deliver within the 1st week following membrane rupture. Multiple trials have proven that antibiotics given to this population prolong the latency from time of PPROM to delivery, hence reducing maternal and neonatal morbidities.

According to the American College of Obstetrics and Gynecology, the current standard of care for PPROM subjects between the gestational age of 24 weeks and 0 days and 33 weeks and 6 days, is to administer ampicillin 2 gm IV every 6 hours for 48 hours followed by amoxicillin 250 mg orally every 8 hours for 5 days, with erythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg orally every 8 hours for 5 days. In this regimen, multiple doses of intravenous (IV) and oral (PO) doses of erythromycin are needed to achieve the desired outcome. Erythromycin can cause GI upset and some subjects do not tolerate this regimen over the course of 7 days. In addition, there is a national shortage of erythromycin, and published expert opinion proposed to use a second-generation macrolide (azithromycin) instead of erythromycin. This strategy was adopted nationwide including the maternal center at UTMB since 2014. Compared to erythromycin, advantages of azithromycin include:

• It is taken once orally (due to its long intracellular half-life).
• The entire regimen is much cheaper than the multiple does of erythromycin (23 doses).
• It has less gastrointestinal adverse effects.

As a result, azithromycin is now commonly being used as a substitute for erythromycin on many labor and delivery units around the country.

Despite its common use, there exists no level 1 evidence that azithromycin is equivalent to erythromycin. Haas and colleagues published a retrospective comparison of the two regimens in 2014 and concluded that the substitution of azithromycin for erythromycin in the recommended antibiotic regimen did not impact latency or any other measured maternal or fetal outcomes. This study, however, was limited by its non-randomized retrospective nature.

The investigators' objective is to compare the effectiveness of the 2 regimens in prolonging pregnancy after PPROM.

This trial will be a comparative effectiveness pragmatic randomized trial performed in singleton pregnancies with the diagnosis of PPROM between 24 weeks and 0 days - 32 weeks and 6 days. It will be comparing two well-accepted standardized treatments of care in this subject population: Erythromycin (FDA Category B) versus Azithromycin (FDA Category B). The investigators' primary outcome will be the proportion of women still pregnant by day 7 after the diagnosis of PPROM is made. The investigators' working hypothesis is that there is no measurable difference in the primary outcome between the group randomized to the azithromycin regimen versus the group randomized to the erythromycin regimen. The investigators' secondary outcome will be latency defined as interval from PPROM to delivery.

Data to be collected will consist of demographics, obstetrical history, relevant vital signs and laboratories. Examples of data to be collected but not limited to include: age, ethnicity/race, gravida, para, received tocolytics, received antenatal steroids, gestational age at rupture of membranes, reason for delivery, mode of delivery, gestational age at delivery, chorioamnionitis, date & time of initiation of antibiotics, date & time of delivery, placental abruption, hospital length of stay, number of women undelivered at day 7 of admission, NICU admission, infant intubation days, neonatal NEC and neonatal sepsis.

In addition, drug adverse effects profiles between the two will be assessed in a post treatment patient survey. The latter will be assessing the severity and incidence of diarrhea and other symptoms such as nausea and vomiting and their severity.

The investigators propose a total of 324 subjects will be needed to complete the study.

• Study Type: Interventional
• Enrollment (Estimated): 324
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fawzi Saoud, MD; Phone Number: 4094579285; Email: fasaoud@utmb.edu
• Study Contact Backup: Name: Nkechinyere Emezienna, MD; Phone Number: (409)772-1011; Email: nkemezie@utmb.edu

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78758
      • Recruiting
      • St. David's North Austin Medical Center
      • Contact: Richard T Hale, PhD; Phone Number: 512-821-2540; Email: Richard.Hale@stdavids.com
    • Galveston, Texas, United States, 77555
      • Recruiting
      • University of Texas Medical Branch
      • Contact: Nkechinyere Emezienna, MD; Phone Number: 409-772-1011; Email: nkemezie@utmb.edu
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah
      • Contact: Shannon Leigh Son, MD; Phone Number: 801-581-8425; Email: Shannon.Son@hsc.utah.edu
      • Contact: Kathy Harvey; Phone Number: 801.581.4128; Email: Kathy.Harvey@hsc.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Maternal age ≥ 18 years and <50 years
• Pregnant women between the gestational age 23 6/7 and 32 6/7 weeks
• Singleton pregnancy
• Preterm premature rupture of membranes, determined clinically
• Cervical dilation visually ≤ 5cm on sterile speculum exam.
• Planned delivery at John Sealy Hospital (JSH)

Exclusion Criteria:

• Intrauterine fetal demise (no fetal heart beat identified and documented by two physicians)
• Any contraindication to expectant management (e.g. fetal compromise, chorioamnionitis, placental abruption)
• Cervical cerclage in place
• Placenta previa or other known placental anomalies
• Contraindication to any of the antibiotics used (allergy to macrolides).
• Enrolled in another trial that may affect outcome.
• Clinical chorioamnionitis or any other active bacterial infection (e.g. pyelonephritis, pneumonia, abscess) at time of randomization: because standard antibiotic therapy for these conditions may confound trial intervention.
• No prenatal care (less than 2 prenatal visits)
• Non-resident subject who is unlikely to be followed-up after delivery
• Any fetal congenital anomaly.
• Significant liver disease defined as known cirrhosis or elevated transaminases of at least 3-fold upper limit of normal
• Significant renal disease defined as serum creatinine known to be >2.0 mg/dl or on dialysis.
• Active congestive heart failure (EF<45%) or pulmonary edema.
• Immunosuppressed subjects: i.e., taking systemic immunosuppressants or steroids (e.g. transplant subjects; not including steroids for lung maturity), HIV with CD4<200, or other.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azithromycin; Ampicillin 2 gm IV every 6 hours followed by amoxicillin 500 mg PO every 8 hours with Azithromycin 1 gm PO once at randomization.	Drug: Azithromycin; Azithromycin 1 gm PO once; Drug: Ampicillin; Ampicillin 2 gm IV every 6 hours for 2 days; Drug: Amoxicillin; Amoxicillin 500 mg PO every 8 hours for 5 days (Azithromycin ARM) Amoxicillin 250 mg PO every 8 hours for 5 days (Erythromycin ARM)
Active Comparator: Erythromycin; Ampicillin 2 gm IV every 6 hours followed by amoxicillin 250 mg PO every 8 hours for 5 days with erythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg PO every 8 hours for 5 days.	Drug: Ampicillin; Ampicillin 2 gm IV every 6 hours for 2 days; Drug: Amoxicillin; Amoxicillin 500 mg PO every 8 hours for 5 days (Azithromycin ARM) Amoxicillin 250 mg PO every 8 hours for 5 days (Erythromycin ARM); Drug: Erythromycin; Erythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg PO every 8 hours for 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of women still pregnant by day 7	Proportion of women still pregnant by day 7 after the diagnosis of PPROM is made. The investigators' working hypothesis is that there is no measurable difference in the primary outcome between the group randomized to the azithromycin regimen versus the group randomized to the erythromycin regimen	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Latency defined as interval from PPROM to delivery.	Number of days from diagnosis of PPROM to delivery	7 days

Collaborators and Investigators

• Sponsor: The University of Texas Medical Branch, Galveston
• Investigators: Principal Investigator: Nkechinyere Emezienna, MD, University of Texas

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2017
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: February 10, 2017
• First Submitted That Met QC Criteria: February 17, 2017
• First Posted (Actual): February 23, 2017

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Erythromycin; Azithromycin; PPROM
• Additional Relevant MeSH Terms: Wounds and Injuries; Pregnancy Complications; Obstetric Labor Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Rupture; Fetal Membranes, Premature Rupture; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin stearate; Ampicillin; Amoxicillin; Azithromycin
• Other Study ID Numbers: 16-0323

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes