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

• ClinicalTrials.gov Identifier: NCT03060473
• Recruitment Status: Recruiting
• First Posted: February 23, 2017
• Last Update Posted: August 22, 2022
• Sponsor: The University of Texas Medical Branch, Galveston
• Information provided by (Responsible Party): The University of Texas Medical Branch, Galveston

Tracking Information

• First Submitted Date: February 10, 2017
• First Posted Date: February 23, 2017
• Last Update Posted Date: August 22, 2022
• Actual Study Start Date: February 23, 2017
• Estimated Primary Completion Date: March 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2017)

Proportion of women still pregnant by day 7 [ Time Frame: 7 days ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 3, 2018)

Latency defined as interval from PPROM to delivery. [ Time Frame: 7 days ]

Number of days from diagnosis of PPROM to delivery

• Original Secondary Outcome Measures (submitted: February 17, 2017): Latency defined as interval from PPROM to delivery. [ Time Frame: 7 days ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of ppROM With Erythromycin vs. Azithromycin Trial
• Official Title: TREAT: Treatment of ppROM With Erythromycin vs. Azithromycin Trial
• Brief Summary: 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.

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
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Allocation: Randomized Intervention model: Parallel Assignment

Masking: Single (Outcomes Assessor)
Masking Description:

Single Blind

Primary Purpose: Treatment

• Condition: Preterm Premature Rupture of Membranes (PPROM)

Intervention

• Drug: Azithromycin
  Azithromycin 1 gm PO once
• Drug: Erythromycin
  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)

Study Arms

• 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.
  Interventions:

  • Drug: Azithromycin
  • Drug: Ampicillin
  • Drug: Amoxicillin
• 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.
  Interventions:

  • Drug: Erythromycin
  • Drug: Ampicillin
  • Drug: Amoxicillin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 17, 2017): 324
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: March 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Study is to be carried out on pregnant patients with diagnosis of PPROM.

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Antonio F Saad, MD; 8187311674; afsaad@utmb.edu

Contact: Fawzi Saoud, MD; 4094579285; fasaoud@utmb.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03060473
• Other Study ID Numbers: 16-0323
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: The University of Texas Medical Branch, Galveston
• Original Responsible Party: Same as current
• Current Study Sponsor: The University of Texas Medical Branch, Galveston
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Antonio F Saad, MD; Assistant Professor Maternal Fetal Medicine

• PRS Account: The University of Texas Medical Branch, Galveston
• Verification Date: August 2022