Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation (TOCOPROM)

• ClinicalTrials.gov Identifier: NCT03976063
• Recruitment Status: Recruiting
• First Posted: June 5, 2019
• Last Update Posted: October 21, 2019
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: INSERM U1153; Ministry of Health, France; Groupe de Recherche en Obstétrique et Gynécologie
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: May 29, 2019
• First Posted Date: June 5, 2019
• Last Update Posted Date: October 21, 2019
• Actual Study Start Date: October 7, 2019
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 4, 2019)

Perinatal morti-morbidity [ Time Frame: Up to discharge from hospital, with a maximum of 24 weeks after birth. ]

Composite outcome including fetal death, neonatal death and/or neonatal severe morbidity (mechanical ventilation ≥ 48 hrs, severe bronchopulmonary dysplasia, severe intraventricular hemorrhage, cystic periventricular leucomalacia, neonatal early-onset sepsis, necrotizing enterocolitis, retinopathy of prematurity).

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT03976063 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 4, 2019)

• Prolongation of gestation [ Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) ]
  Latency duration (defined as the duration from PPROM to delivery)
• Prolongation of gestation [ Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) ]
  Pregnancy prolongation beyond 48 hours after randomization
• Prolongation of gestation [ Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) ]
  Pregnancy prolongation beyond 1 week after randomization
• Prolongation of gestation [ Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) ]
  Gestational age at delivery
• Prolongation of gestation [ Time Frame: Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) ]
  Delivery after 37 weeks of gestation
• Maternal morbidity [ Time Frame: During the first 10 days postpartum ]
  Endometritis, based on clinical diagnosis associating fever (temperature ≥ 38.0°C) with uterine tenderness, purulent or foul-smelling lochia, and in the absence of any other cause.
• Fetal mortality [ Time Frame: Up to delivery so up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy) ]
  Fetal death
• Neonatal mortality [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Neonatal death
• Neonatal severe morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Mechanical ventilation ≥ 48 hrs
• Neonatal severe morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Severe bronchopulmonary dysplasia
• Neonatal severe morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Severe intraventricular hemorrhage
• Neonatal severe morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Cystic periventricular leucomalacia
• Neonatal severe morbidity [ Time Frame: From birth to Day 3 after birth. ]
  Early-onset sepsis
• Neonatal severe morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Necrotizing enterocolitis
• Neonatal severe morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Retinopathy of prematurity
• Neonatal morbidity [ Time Frame: At birth. ]
  Severe fetal acidemia
• Neonatal morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Respiratory distress syndrome
• Neonatal morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Mild or moderate bronchopulmonary dysplasia
• Neonatal morbidity [ Time Frame: From birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Grades I-II intraventricular hemorrhage
• Neonatal morbidity [ Time Frame: From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth. ]
  Late-onset sepsis.
• Vital status [ Time Frame: At 22-26 months of corrected age ]
  Death between discharge and follow up at 2 years
• Frequency of Gross motor impairment among children alive at 2 years of corrected age [ Time Frame: At 22-26 months of corrected age ]
  Cerebral palsy
• Frequency of Neurosensory impairment among children alive at 2 years of corrected age [ Time Frame: At 22-26 months of corrected age ]
  Visual impairment
• Frequency of Neurosensory impairment among children alive at 2 years of corrected age [ Time Frame: At 22-26 months of corrected age ]
  Hearing impairment

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation
• Official Title: Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation: a Double-blinded Randomized Controlled Trial
• Brief Summary: The purpose of this study is to assess whether short-term (48 hr) tocolysis reduces perinatal morti-morbidity in cases of PPROM at 22 to 33 completed weeks' gestation.

Detailed Description

Preterm premature rupture of membranes (PPROM) complicates 3% of pregnancies and accounts for one-third of preterm births. It is a leading cause of neonatal mortality and morbidity and increases the risk of maternal infectious morbidity. In cases of early PPROM (22 to 33 completed weeks' gestation), expectant management is recommended in the absence of labor, chorioamnionitis or fetal distress. Antenatal steroids and antibiotics administration are recommended by international guidelines. However, there is no recommendation regarding tocolysis administration in the setting of PPROM. In theory, reducing uterine contractility should delay delivery and reduce risks of prematurity and neonatal adverse consequences. Likewise, a prolongation of gestation may allow administering a corticosteroids complete course that is associated with a two-fold reduction of morbidity and mortality. However, tocolysis may prolong fetal exposure to inflammation and be associated with higher risk of materno-fetal infection, potentially associated with neonatal death or long-term sequelae, including cerebral palsy.

The purpose of this study is to assess whether short-term (48 hr) tocolysis reduces perinatal morti-morbidity in cases of PPROM at 22 to 33 completed weeks' gestation.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Preterm Premature Rupture of Membrane

Intervention

• Drug: Nifedipine
  Loading dose: Oral Nifedipine 20 mg LP at T0 and T0.5 (i.e. 30 min), total=2x20 mg Maintenance dose: Oral Nifedipine 20 mg LP at T3, then 1 pill every 8 hr for 48 hr (i.e. T11, T19, T27, T35 and T43, total=6x20 mg)
• Drug: Placebo of Nifedipine
  Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43

Study Arms

• Active Comparator: Nifedipine
  Intervention: Drug: Nifedipine
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo of Nifedipine

Publications *

• Mackeen AD, Seibel-Seamon J, Muhammad J, Baxter JK, Berghella V. Tocolytics for preterm premature rupture of membranes. Cochrane Database Syst Rev. 2014 Feb 27;(2):CD007062. doi: 10.1002/14651858.CD007062.pub3. Review.
• Lorthe E, Goffinet F, Marret S, Vayssiere C, Flamant C, Quere M, Benhammou V, Ancel PY, Kayem G. Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis. Am J Obstet Gynecol. 2017 Aug;217(2):212.e1-212.e12. doi: 10.1016/j.ajog.2017.04.015. Epub 2017 Apr 13.
• Couteau C, Haumonté JB, Bretelle F, Capelle M, D'Ercole C. [Management of preterm and prelabour rupture of membranes in France]. J Gynecol Obstet Biol Reprod (Paris). 2013 Feb;42(1):21-8. doi: 10.1016/j.jgyn.2012.10.008. Epub 2012 Nov 24. French.
• Schmitz T, Sentilhes L, Lorthe E, Gallot D, Madar H, Doret-Dion M, Beucher G, Charlier C, Cazanave C, Delorme P, Garabédian C, Azria E, Tessier V, Sénat MV, Kayem G. Preterm premature rupture of the membranes: Guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol. 2019 May;236:1-6. doi: 10.1016/j.ejogrb.2019.02.021. Epub 2019 Mar 2. Review.
• Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014 Jun 5;(6):CD002255. doi: 10.1002/14651858.CD002255.pub2. Review.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 4, 2019): 850
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2025
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Preterm premature rupture of membranes (PPROM) between 220/7 - 336/7 weeks of gestation, as diagnosed by obstetric team
• Singleton gestation
• Fetus alive at the time of randomization (reassuring fetal heart monitoring)
• 18 years of age or older
• French speaking
• Affiliated to social security regime or an equivalent system
• Informed consent and signed

Exclusion Criteria:

• PPROM ≥ 24 hours before diagnosis
• Ongoing tocolytic treatment at the time of PPROM
• Any tocolytic treatment after PPROM diagnosis, including during in utero transfer
• Fetal condition contraindicating expectant management including chorioamnionitis, placental abruption, intrauterine fetal demise, non-reassuring fetal heart rate at the time of randomization
• Cervical dilation > 5 cm
• Iatrogenic rupture caused by amniocentesis or trophoblast biopsy
• Major fetal anomaly

• Maternal allergy or contra-indication to Nifedipine or placebo drug components:

  • Myocardial infarction
  • Unstable angina pectoris
  • Hepatic insufficiency
  • Cardiovascular shock
  • Beta blockers
• Coadministration of diltiazem or rifampicine
• Hypotension (systolic pressure < 90 mmHg)
• Participation to another interventional study

Sex/Gender

• Sexes Eligible for Study: Female

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

Contacts

Contact: Gilles Kayem, MD, PhD; 00 33 1 44 73 51 18; gilles.kayem@aphp.fr

Contact: Nelly Briand, PhD; 00 33 1 44 38 18 62; nelly.briand@aphp.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT03976063
• Other Study ID Numbers: P160917
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• Study Sponsor: Assistance Publique - Hôpitaux de Paris

Collaborators

• INSERM U1153
• Ministry of Health, France
• Groupe de Recherche en Obstétrique et Gynécologie

Investigators

• Principal Investigator: Gilles Kayem, MD, PhD; INSERM UMR 1153, Obstetrical, Perinatal and PEdiatric Epidemiology (EPOPé) Research Team, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), DHU Risks in Pregnancy, Paris Descartes University, Trousseau University Hospital
• Study Director: Elsa Lorthe, RM, PhD; INSERM UMR 1153, Obstetrical, Perinatal and PEdiatric Epidemiology (EPOPé) Research Team, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), DHU Risks in Pregnancy, Paris Descartes University

• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: October 2019