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

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

Tracking Information
First Submitted Date  ICMJE February 10, 2017
First Posted Date  ICMJE February 23, 2017
Last Update Posted Date August 22, 2022
Actual Study Start Date  ICMJE February 23, 2017
Estimated Primary Completion Date March 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Treatment of ppROM With Erythromycin vs. Azithromycin Trial
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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  ICMJE Preterm Premature Rupture of Membranes (PPROM)
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 17, 2017)
324
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2025
Estimated Primary Completion Date March 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
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  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Antonio F Saad, MD 8187311674 afsaad@utmb.edu
Contact: Fawzi Saoud, MD 4094579285 fasaoud@utmb.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03060473
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Current Responsible Party The University of Texas Medical Branch, Galveston
Original Responsible Party Same as current
Current Study Sponsor  ICMJE The University of Texas Medical Branch, Galveston
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Antonio F Saad, MD Assistant Professor Maternal Fetal Medicine
PRS Account The University of Texas Medical Branch, Galveston
Verification Date August 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP