Latency Antibiotics in Previable PPROM, 18 0/7- 22 6/7 WGA

NCT04047849 | Recruiting Phase 4 FDA Drug

• 1 other identifier: RP-19-001
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a non-blinded, prospective, randomized controlled trial designed to compare the effect of outpatient oral antibiotics (i.e., amoxicillin and azithromycin) on the length of time (days) that pregnancy continues after a patient's water bag has ruptured prematurely. If a patient has been diagnosed with rupture of their water bag between 18 0/7 weeks and 22 6/7 weeks and there are no other associated complications with the pregnancy, the patient is eligible for initial consideration for this study. Patients will be admitted to the hospital for a 24-hour monitoring period. If the patient remains without further complications during this monitoring period, the patient will be eligible for enrollment. If enrollment is desired, the patient will be randomly assigned to receive either antibiotics (treatment arm of the study) or no antibiotics (control arm of the study). The treatment arm will receive an outpatient, 7-day course of oral antibiotics (azithromycin and amoxicillin) with the first dose given in the hospital to ensure no side effects. The control arm will not receive outpatient antibiotics. Both groups will have weekly, office follow-up visits with high-risk pregnancy specialists to ensure no further complications. Both groups will be admitted to the hospital if the patients reach 23 0/7 weeks without complications. At this time the patients will receive all medications and therapies recommended by the governing board of OBGYNs. Subjects of both groups will also be admitted before 23 0/7 weeks if further complications noted either at their clinic follow up visits or anytime outside of the hospital. The duration of time that the patient remains pregnant after breaking of the water bag will be compared in each group. The investigators will also see if there is a difference in the number of patients able to reach 23 0/7 weeks between each group (treatment versus control).

Conditions

Rupture of Membranes; Delayed Delivery (Following Spontaneous Rupture); Rupture of Membranes; Premature; Rupture of Membranes; Premature, Affecting Fetus; Preterm Birth; Preterm PROM (Pregnancy); Preterm Labor

Keywords

Previable; PPROM; Premature prelabor rupture of membranes; Preterm; Preterm birth; Latency antibiotics

Outcome Measures

Primary Outcomes (1)

• Latency period

  The number of days from diagnosis of previable prelabor rupture of membranes to the date of delivery

  Patient will be monitored from the date of diagnosis of previable prelabor rupture of membranes until date of delivery. This could vary from a duration of less than 1 day to 112 days.

Secondary Outcomes (1)

• Viability

  Number of days from the time of rupture of membranes (earliest 18 0/7 weeks) to viability (23 0/7 weeks), max 35 days.

Study Arms (2)

Antibiotics

EXPERIMENTAL

This will include those subjects randomized into the treatment arm, receiving the outpatient antibiotic course of azithromycin and amoxicillin prior to re-admission at viability (23 0/7 weeks gestation). They will receive a single, 500mg dose of Azithromycin given prior to discharge to home, followed by 250mg daily for 4 more days, and Amoxicillin 500mg orally TID for 7 days (first dose also being given prior to discharge home).

Drug: Antibiotics, oral Azithromycin and oral Amoxicillin

No antibiotics

NO INTERVENTION

This will include those subjects randomized into the control arm and will not receive outpatient antibiotics prior to re-admission at viability (23 0/7 weeks gestation).

Interventions

Antibiotics, oral Azithromycin and oral Amoxicillin DRUG

Azithromycin (500mg day one followed by 250mg per day for 4 more days) and amoxicillin (500mg orally three times daily for 7 days) for a total course of seven days of antibiotic therapy

Also known as: Z-pack

Antibiotics

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Singleton gestation
• Gestational age of greater than 18 0/7 but less than or equal to 22 6/7
• Diagnosis of prelabor premature rupture of membranes as determined by clinical examination noting either/or 1) visualization of amniotic fluid passing from the cervical canal and pooling in the vagina via sterile speculum examination, 2) a basic pH (i.e., positive nitrazine) test of vaginal fluid, 3) arborization (ferning) of dried vaginal fluid identified via microscopic examination, or 4) an amniotic fluid index (AFI) of less than 4cm
• Greater than or equal to 18 years of age
• Those with no known drug allergies or significant adverse reactions to azithromycin or amoxicillin
• Afebrile at the time of presentation and throughout 24-hour observation period
• Patient must be able to provide informed consent

You may not qualify if:

• Fetal anomalies in current pregnancy
• Diabetes mellitus, including both pre-gestational and gestational
• Abnormal placentation
• Poor dating with dating ultrasound performed later than or equal to 20 0/7 weeks
• Current subchorionic hemorrhage or current vaginal bleeding on presentation
• Hypertensive disease, including pre-gestational chronic hypertension, gestational hypertension and pre-eclampsia/eclampsia
• History of amniocentesis during this pregnancy
• History of cervical incompetence, history of cerclage in previous pregnancy or current cerclage in place
• Current documented urinary tract infection or bacteriuria
• Current documented genital tract infection (Chlamydia, gonorrhea, or trichomonas)
• Immunocompromised (i.e., HIV positive, daily steroid use, or a history of autoimmune disease for which the patient is currently undergoing treatment with immunotherapy medication)

Sponsors & Collaborators

• Woman's: lead

Study Sites (1)

Woman's Hospital

Baton Rouge, Louisiana, 70817, United States

RECRUITING

Related Publications (25)

• Kilbride HW, Thibeault DW. Neonatal complications of preterm premature rupture of membranes. Pathophysiology and management. Clin Perinatol. 2001 Dec;28(4):761-85. doi: 10.1016/s0095-5108(03)00076-9.

  PMID: 11817188 BACKGROUND

• Yeast JD. Preterm premature rupture of the membranes before viability. Clin Perinatol. 2001 Dec;28(4):849-60. doi: 10.1016/s0095-5108(03)00082-4.

  PMID: 11758532 BACKGROUND

• Cunningham, F. G., MD, Leveno, K. J., MD, Dashe, J. S., MD, Hoffman, B. L., MD, Bloom, S. L., MD, Casey, B. M., MD, Spong, C. Y., MD (Eds.). (2014). Preterm Labor. In Williams Obstetrics(24th ed., pp. 848-849). New York, NY: McGraw Hill Education.

  BACKGROUND

• Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, Rabello YA, Meis PJ, Moawad AH, Iams JD, Van Dorsten JP, Paul RH, Bottoms SF, Merenstein G, Thom EA, Roberts JM, McNellis D. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA. 1997 Sep 24;278(12):989-95.

  PMID: 9307346 BACKGROUND

• Mercer BM, Goldenberg RL, Das AF, Thurnau GR, Bendon RW, Miodovnik M, Ramsey RD, Rabello YA; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. What we have learned regarding antibiotic therapy for the reduction of infant morbidity after preterm premature rupture of the membranes. Semin Perinatol. 2003 Jun;27(3):217-30. doi: 10.1016/s0146-0005(03)00016-8.

  PMID: 12889589 BACKGROUND

• American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine. Obstetric Care consensus No. 6: Periviable Birth. Obstet Gynecol. 2017 Oct;130(4):e187-e199. doi: 10.1097/AOG.0000000000002352.

  PMID: 28937572 BACKGROUND

• Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement. 2000 Aug 17-18;17(2):1-18.

  PMID: 11725806 BACKGROUND

• Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD004661. doi: 10.1002/14651858.CD004661.pub3.

  PMID: 19160238 BACKGROUND

• Mercer BM, Crocker LG, Boe NM, Sibai BM. Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a randomized trial. Am J Obstet Gynecol. 1993 Oct;169(4):775-82. doi: 10.1016/0002-9378(93)90004-3.

  PMID: 8238131 BACKGROUND

• Broekhuizen FF, Gilman M, Hamilton PR. Amniocentesis for gram stain and culture in preterm premature rupture of the membranes. Obstet Gynecol. 1985 Sep;66(3):316-21.

  PMID: 2410839 BACKGROUND

• Cotton DB, Hill LM, Strassner HT, Platt LD, Ledger WJ. Use of amniocentesis in preterm gestation with ruptured membranes. Obstet Gynecol. 1984 Jan;63(1):38-43.

  PMID: 6691016 BACKGROUND

• Zlatnik FJ, Cruikshank DP, Petzold CR, Galask RP. Amniocentesis in the identification of inapparent infection in preterm patients with premature rupture of the membranes. J Reprod Med. 1984 Sep;29(9):656-60.

  PMID: 6492031 BACKGROUND

• Mercer BM, Moretti ML, Prevost RR, Sibai BM. Erythromycin therapy in preterm premature rupture of the membranes: a prospective, randomized trial of 220 patients. Am J Obstet Gynecol. 1992 Mar;166(3):794-802. doi: 10.1016/0002-9378(92)91336-9.

  PMID: 1550145 BACKGROUND

• Romero R, Emamian M, Quintero R, Wan M, Hobbins JC, Mazor M, Edberg S. The value and limitations of the Gram stain examination in the diagnosis of intraamniotic infection. Am J Obstet Gynecol. 1988 Jul;159(1):114-9. doi: 10.1016/0002-9378(88)90503-0.

  PMID: 2456013 BACKGROUND

• Oh KJ, Lee KA, Sohn YK, Park CW, Hong JS, Romero R, Yoon BH. Intraamniotic infection with genital mycoplasmas exhibits a more intense inflammatory response than intraamniotic infection with other microorganisms in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 2010 Sep;203(3):211.e1-8. doi: 10.1016/j.ajog.2010.03.035. Epub 2010 Aug 3.

  PMID: 20678747 BACKGROUND

• DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzun E, Relman DA. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2010 Jul 1;64(1):38-57. doi: 10.1111/j.1600-0897.2010.00830.x. Epub 2010 Mar 21.

  PMID: 20331587 BACKGROUND

• Svigos, John M, et al. "Chapter 63: Prelabor Rupture of Membranes." High Risk Pregnancy: Management Options - Expert Consult, by David K. James et al., Saunders, 2010, pp. 1321-132.

  BACKGROUND

• Amsden GW. Erythromycin, clarithromycin, and azithromycin: are the differences real? Clin Ther. 1996 Jan-Feb;18(1):56-72; discussion 55. doi: 10.1016/s0149-2918(96)80179-2.

  PMID: 8851453 BACKGROUND

• Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. BJOG. 2000 Jun;107(6):770-5. doi: 10.1111/j.1471-0528.2000.tb13339.x.

  PMID: 10847234 BACKGROUND

• Esteves JS, de Sa RA, de Carvalho PR, Coca Velarde LG. Neonatal outcome in women with preterm premature rupture of membranes (PPROM) between 18 and 26 weeks. J Matern Fetal Neonatal Med. 2016;29(7):1108-12. doi: 10.3109/14767058.2015.1035643. Epub 2015 Jul 3.

  PMID: 26138545 BACKGROUND

• Manuck TA, Eller AG, Esplin MS, Stoddard GJ, Varner MW, Silver RM. Outcomes of expectantly managed preterm premature rupture of membranes occurring before 24 weeks of gestation. Obstet Gynecol. 2009 Jul;114(1):29-37. doi: 10.1097/AOG.0b013e3181ab6fd3.

  PMID: 19546755 BACKGROUND

• Schucker JL, Mercer BM. Midtrimester premature rupture of the membranes. Semin Perinatol. 1996 Oct;20(5):389-400. doi: 10.1016/s0146-0005(96)80006-1.

  PMID: 8912993 BACKGROUND

• Linehan LA, Walsh J, Morris A, Kenny L, O'Donoghue K, Dempsey E, Russell N. Neonatal and maternal outcomes following midtrimester preterm premature rupture of the membranes: a retrospective cohort study. BMC Pregnancy Childbirth. 2016 Jan 29;16:25. doi: 10.1186/s12884-016-0813-3.

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• Deutsch A, Deutsch E, Totten C, Downes K, Haubner L, Belogolovkin V. Maternal and neonatal outcomes based on the gestational age of midtrimester preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2010 Dec;23(12):1429-34. doi: 10.3109/14767051003678069. Epub 2010 Mar 17.

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• Moore T, Hennessy EM, Myles J, Johnson SJ, Draper ES, Costeloe KL, Marlow N. Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. BMJ. 2012 Dec 4;345:e7961. doi: 10.1136/bmj.e7961.

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Related Links

• Werth, Brian. "Macrolides - Infectious Diseases." Merck Manuals Professional Edition, July 2018
• Hologic. (2018). Aptima Combo 2. Retrieved December 30, 2018
• Hologic. (2018). Aptima® Trichomonas vaginalis Assay (Panther® System). Retrieved December 30, 2018
• LabCorp. (2018). Wet Prep. Retrieved December 30, 2018
• LabCorp. (2018). Complete Blood Count (CBC) with Differential. Retrieved December 30, 201
• LabCorp. (2018). Group B Streptococcus Colonization Detection Culture. Retrieved December 30, 2018

MeSH Terms

Conditions

Fetal Membranes, Premature Rupture; Premature Birth; Obstetric Labor, Premature; Preterm Premature Rupture of the Membranes

Interventions

Anti-Bacterial Agents; Azithromycin; Amoxicillin

Condition Hierarchy (Ancestors)

Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Ampicillin; Penicillin G; Penicillins; beta-Lactams; Lactams; Amides; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Robert C Moore, MD

  Woman's Hospital, Louisiana

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Felicia LeMoine, MD

CONTACT

2252768164; fvenab@lsuhsc.edu

Robert C Moore, MD

CONTACT

2252153883; robert.moore@womans.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The treatment group will include those subjects randomized to the antibiotic arm versus the control arm, no antibiotics. The antibiotic arm will receive a single, 500mg dose of Azithromycin given prior to discharge to home, followed by 250mg daily for 4 more days, and Amoxicillin 500mg orally TID for 7 days (first dose also being given prior to discharge home). Both arms will receive patient pamphlets with study contacts, precautions, and graphs for daily temperature/symptom tracking. Weekly follow up with Maternal-Fetal Medicine, for both arms, will include history and physical exam, vital signs, and ultrasound for fetal well-being and measurement of AFI. Both arms will be re-admitted to the hospital either at 1) viability (23 0/7 weeks) or 2) clinical signs of placental abruption, preterm labor, chorioamnionitis or fetal demise. Re-admission of both arms at viability will include latency antibiotics, neuroprotective magnesium sulfate, and corticosteroids for fetal lung maturity.

Study Record Dates

• First Submitted: July 10, 2019
• First Posted: August 7, 2019
• Study Start: August 28, 2019
• Primary Completion: July 1, 2021
• Study Completion: July 1, 2021
• Last Updated: January 11, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: IPD will become available beginning 6 months after study publication and will be available indefinitely.
• Access Criteria: Requests for data are available to all researchers; however, approval for access to data will be granted by primary investigator.

Locations

US (1)