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

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ClinicalTrials.gov Identifier: NCT03976063
Recruitment Status : Recruiting
First Posted : June 5, 2019
Last Update Posted : October 21, 2019
Sponsor:
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  ICMJE May 29, 2019
First Posted Date  ICMJE June 5, 2019
Last Update Posted Date October 21, 2019
Actual Study Start Date  ICMJE October 7, 2019
Estimated Primary Completion Date August 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History Complete list of historical versions of study NCT03976063 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Preterm Premature Rupture of Membrane
Intervention  ICMJE
  • 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  ICMJE
  • Active Comparator: Nifedipine
    Intervention: Drug: Nifedipine
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo of Nifedipine
Publications *

*   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: June 4, 2019)
850
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2025
Estimated Primary Completion Date August 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03976063
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: Undecided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE
  • INSERM U1153
  • Ministry of Health, France
  • Groupe de Recherche en Obstétrique et Gynécologie
Investigators  ICMJE
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

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