Treatment of ppROM With Erythromycin vs. Azithromycin Trial

NCT ID: NCT03060473

Last Updated: 2024-06-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-23
• Study Completion Date: 2023-12-08

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.

Conditions

Preterm Premature Rupture of Membranes (PPROM)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Azithromycin

Intervention Type: DRUG

Azithromycin 1 gm PO once

Ampicillin

Intervention Type: DRUG

Ampicillin 2 gm IV every 6 hours for 2 days

Amoxicillin

Intervention Type: DRUG

Amoxicillin 500 mg PO every 8 hours for 5 days (Azithromycin ARM) Amoxicillin 250 mg PO every 8 hours for 5 days (Erythromycin ARM)

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.

Group Type: ACTIVE_COMPARATOR

Erythromycin

Intervention Type: DRUG

Erythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg PO every 8 hours for 5 days.

Ampicillin

Intervention Type: DRUG

Ampicillin 2 gm IV every 6 hours for 2 days

Amoxicillin

Intervention Type: DRUG

Amoxicillin 500 mg PO every 8 hours for 5 days (Azithromycin ARM) Amoxicillin 250 mg PO every 8 hours for 5 days (Erythromycin ARM)

Interventions

Azithromycin

Azithromycin 1 gm PO once

Intervention Type: DRUG

Erythromycin

Erythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg PO every 8 hours for 5 days.

Intervention Type: DRUG

Ampicillin

Ampicillin 2 gm IV every 6 hours for 2 days

Intervention Type: 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)

Intervention Type: DRUG

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.

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

Sponsors

The University of Texas Medical Branch, Galveston

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nkechinyere Emezienna, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Locations

St. David's North Austin Medical Center

Austin, Texas, United States

University of Texas Medical Branch

Galveston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

16-0323

Identifier Type: -

Identifier Source: org_study_id