Preterm Premature Rupture of Membranes (PPROM)Phase 3TREATNCT03060473
Treatment of ppROM With Erythromycin vs. Azithromycin Trial
A Phase 3 study testing Azithromycin, Erythromycin and Ampicillin in people with Preterm Premature Rupture of Membranes (PPROM), run by The University of Texas Medical Branch, Galveston at 3 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Preterm Premature Rupture of Membranes (PPROM)
- What is being tested?
- Azithromycin, Erythromycin and Ampicillin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 3 sitesUnited States
- Study dates
- 23 Feb 2017to 8 Dec 2023
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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.
Show all 14Show fewer
- 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.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
St. David's North Austin Medical Center
Austin, Texas, 78758
University of Texas Medical Branch
Galveston, Texas, 77555
University of Utah
Salt Lake City, Utah, 84132
About this study
Official title: 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.
Read the 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.
- Being tested
- Azithromycin, Erythromycin, Ampicillin, Amoxicillin
- Keywords
- PPROM, Azithromycin, Erythromycin
- Medical subject headings
- Preterm Premature Rupture of the Membranes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzithromycinDrug
Azithromycin 1 gm PO once
ErythromycinDrug
Erythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg PO every 8 hours for 5 days.
AmpicillinDrug
Ampicillin 2 gm IV every 6 hours for 2 days
AmoxicillinDrug
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 group | Role | What they receive |
|---|---|---|
| Azithromycin | Experimental | Ampicillin 2 gm IV every 6 hours followed by amoxicillin 500 mg PO every 8 hours with Azithromycin 1 gm PO once at randomization. Receives: Drug: Azithromycin; Drug: Ampicillin; Drug: Amoxicillin |
| Erythromycin | Active comparator | 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. Receives: Drug: Erythromycin; Drug: Ampicillin; Drug: Amoxicillin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 7 days
Secondary outcomes (1)
Latency Defined as Interval From PPROM to Delivery.
Number of days from diagnosis of PPROM to delivery
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2017
- Study start23 Feb 2017
- Primary completion8 Dec 2023
- Study completion8 Dec 2023
Why it stopped: Patient population that meets study criteria is insufficient to continue project in a reasonable amount of time. To continue is futile in resources, staff time, and effort.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Preterm Premature Rupture of Membranes (PPROM)Studies of the same condition, open and under way.
- More trials run by The University of Texas Medical Branch, GalvestonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Allocation: Randomized Intervention model: Parallel Assignment
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Nkechinyere Emezienna, MD, Principal investigator, University of Texas
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03060473
- Sponsor's protocol ID
- 16-0323
- Acronym
- TREAT
- Status last verified
- Jun 2024
- First submitted
- 10 Feb 2017
- Last updated
- 25 Jun 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- TREAT: Treatment of ppROM With Erythromycin vs. Azithromycin Trial
- ClinicalTrials.gov ID
- NCT03060473
- Acronym / sponsor ID
- TREAT / 16-0323
- Keywords
- PPROM, Azithromycin, Erythromycin
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Patient population that meets study criteria is insufficient to continue project in a reasonable amount of time. To continue is futile in resources, staff time, and effort.
- Enrolment
- 21 participants (actual)
- Lead sponsor
- The University of Texas Medical Branch, GalvestonUniversity, hospital or other
- Study start
- 23 Feb 2017 (actual)
- Primary completion
- 8 Dec 2023 (actual)
- Study completion
- 8 Dec 2023 (actual)
- First posted
- 23 Feb 2017 (actual)
- Results
- Posted 25 Jun 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- Allocation: Randomized Intervention model: Parallel Assignment
| Arm | Type | Receives |
|---|---|---|
| Azithromycin | Experimental | Drug: Azithromycin, Drug: Ampicillin, Drug: AmoxicillinAmpicillin 2 gm IV every 6 hours followed by amoxicillin 500 mg PO every 8 hours with Azithromycin 1 gm PO once at randomization. |
| Erythromycin | Active comparator | Drug: Erythromycin, Drug: Ampicillin, Drug: AmoxicillinAmpicillin 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (14 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzithromycinAzithromycin 1 gm PO once | Drug | Azithromycin |
| ErythromycinErythromycin 250 mg IV every 6 hours for 48 hours followed by 500 mg PO every 8 hours for 5 days. | Drug | Erythromycin |
| AmpicillinAmpicillin 2 gm IV every 6 hours for 2 days | Drug | Azithromycin, Erythromycin |
| AmoxicillinAmoxicillin 500 mg PO every 8 hours for 5 days (Azithromycin ARM) Amoxicillin 250 mg PO every 8 hours for 5 days (Erythromycin ARM) | Drug | Azithromycin, Erythromycin |
Primary outcome
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
1 secondary outcome
Latency Defined as Interval From PPROM to Delivery.
Time frame: 7 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jun 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nkechinyere Emezienna, MD principal investigator
University of Texas
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Azithromycin, Erythromycin and Ampicillin in people with Preterm Premature Rupture of Membranes (PPROM), run by The University of Texas Medical Branch, Galveston at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Jun 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of Women Still Pregnant by Day 7 (time frame: 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2024.