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

Primary Purpose

Preterm Premature Rupture of Membrane

Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Nifedipine
Placebo of Nifedipine
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Preterm Premature Rupture of Membrane focused on measuring Preterm premature rupture of membranes, Tocolysis, Nifedipine, Latency, Neonatal outcome, Preterm birth, Randomized controlled trial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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
  • Tocolytic treatment with Nifedipine between PPROM diagnosis and randomization
  • 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

placebo drug components: lactose monohydrate, colloidal silica, microcrystalline cellulos

  • Coadministration of diltiazem or rifampicine
  • Hypotension (systolic pressure < 90 mmHg)
  • Participation to another interventional research (category 1)

Sites / Locations

  • Trousseau University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Nifedipine

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Perinatal morti-morbidity
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).

Secondary Outcome Measures

Prolongation of gestation
Latency duration (defined as the duration from PPROM to delivery)
Prolongation of gestation
Pregnancy prolongation beyond 48 hours after randomization
Prolongation of gestation
Pregnancy prolongation beyond 1 week after randomization
Prolongation of gestation
Gestational age at delivery
Prolongation of gestation
Delivery after 37 weeks of gestation
Maternal morbidity
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.
Maternal morbidity
Intra-uterine infection, defined as fever (maternal temperature ≥38 °C), with no alternative cause identified, associated with at least two of the following criteria: persistent fetal tachycardia > 160 bpm, uterine pain or painful uterine contractions or spontaneous labor, purulent amniotic fluid.
Fetal mortality
Fetal death
Neonatal mortality
Neonatal death
Neonatal severe morbidity
Mechanical ventilation ≥ 48 hrs
Neonatal severe morbidity
Severe bronchopulmonary dysplasia
Neonatal severe morbidity
Severe intraventricular hemorrhage
Neonatal severe morbidity
Cystic periventricular leucomalacia
Neonatal severe morbidity
Early-onset sepsis
Neonatal severe morbidity
Necrotizing enterocolitis
Neonatal severe morbidity
Retinopathy of prematurity
Neonatal morbidity
Severe fetal acidemia
Neonatal morbidity
Respiratory distress syndrome
Neonatal morbidity
Mild or moderate bronchopulmonary dysplasia
Neonatal morbidity
Grades I-II intraventricular hemorrhage
Neonatal morbidity
Late-onset sepsis.
Vital status
Death between discharge and follow up at 2 years
Frequency of Gross motor impairment among children alive at 2 years of corrected age
Cerebral palsy
Frequency of Neurosensory impairment among children alive at 2 years of corrected age
Visual impairment
Frequency of Neurosensory impairment among children alive at 2 years of corrected age
Hearing impairment

Full Information

First Posted
May 29, 2019
Last Updated
September 4, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
INSERM U1153, Ministry of Health, France, Groupe de Recherche en Obstétrique et Gynécologie
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1. Study Identification

Unique Protocol Identification Number
NCT03976063
Brief Title
Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation
Acronym
TOCOPROM
Official Title
Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation: a Double-blinded Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 7, 2019 (Actual)
Primary Completion Date
November 2024 (Anticipated)
Study Completion Date
October 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
INSERM U1153, Ministry of Health, France, Groupe de Recherche en Obstétrique et Gynécologie

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Preterm Premature Rupture of Membrane
Keywords
Preterm premature rupture of membranes, Tocolysis, Nifedipine, Latency, Neonatal outcome, Preterm birth, Randomized controlled trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
850 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nifedipine
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Nifedipine
Intervention Description
Loading dose: Oral Nifedipine 20 mg prolonged-release at T0 and T0.5 (i.e. 30 min), total=2x20 mg Maintenance dose: Oral Nifedipine 20 mg prolonged-release at T3, then 1 pill every 8 hr for 48 hr (i.e. T11, T19, T27, T35 and T43, total=6x20 mg)
Intervention Type
Drug
Intervention Name(s)
Placebo of Nifedipine
Intervention Description
Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43
Primary Outcome Measure Information:
Title
Perinatal morti-morbidity
Description
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).
Time Frame
Up to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary Outcome Measure Information:
Title
Prolongation of gestation
Description
Latency duration (defined as the duration from PPROM to delivery)
Time Frame
Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Title
Prolongation of gestation
Description
Pregnancy prolongation beyond 48 hours after randomization
Time Frame
Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Title
Prolongation of gestation
Description
Pregnancy prolongation beyond 1 week after randomization
Time Frame
Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Title
Prolongation of gestation
Description
Gestational age at delivery
Time Frame
Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Title
Prolongation of gestation
Description
Delivery after 37 weeks of gestation
Time Frame
Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Title
Maternal morbidity
Description
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.
Time Frame
During the first 10 days postpartum
Title
Maternal morbidity
Description
Intra-uterine infection, defined as fever (maternal temperature ≥38 °C), with no alternative cause identified, associated with at least two of the following criteria: persistent fetal tachycardia > 160 bpm, uterine pain or painful uterine contractions or spontaneous labor, purulent amniotic fluid.
Time Frame
At delivery
Title
Fetal mortality
Description
Fetal death
Time Frame
Up to delivery so up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Title
Neonatal mortality
Description
Neonatal death
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal severe morbidity
Description
Mechanical ventilation ≥ 48 hrs
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal severe morbidity
Description
Severe bronchopulmonary dysplasia
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal severe morbidity
Description
Severe intraventricular hemorrhage
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal severe morbidity
Description
Cystic periventricular leucomalacia
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal severe morbidity
Description
Early-onset sepsis
Time Frame
From birth to Day 3 after birth.
Title
Neonatal severe morbidity
Description
Necrotizing enterocolitis
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal severe morbidity
Description
Retinopathy of prematurity
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal morbidity
Description
Severe fetal acidemia
Time Frame
At birth.
Title
Neonatal morbidity
Description
Respiratory distress syndrome
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal morbidity
Description
Mild or moderate bronchopulmonary dysplasia
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal morbidity
Description
Grades I-II intraventricular hemorrhage
Time Frame
From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Neonatal morbidity
Description
Late-onset sepsis.
Time Frame
From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth.
Title
Vital status
Description
Death between discharge and follow up at 2 years
Time Frame
At 22-26 months of corrected age
Title
Frequency of Gross motor impairment among children alive at 2 years of corrected age
Description
Cerebral palsy
Time Frame
At 22-26 months of corrected age
Title
Frequency of Neurosensory impairment among children alive at 2 years of corrected age
Description
Visual impairment
Time Frame
At 22-26 months of corrected age
Title
Frequency of Neurosensory impairment among children alive at 2 years of corrected age
Description
Hearing impairment
Time Frame
At 22-26 months of corrected age

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 Tocolytic treatment with Nifedipine between PPROM diagnosis and randomization 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 placebo drug components: lactose monohydrate, colloidal silica, microcrystalline cellulose Coadministration of diltiazem or rifampicin Hypotension (systolic pressure < 90 mmHg) Participation to another interventional research (category 1) in which intervention could interfere with TOCOPROM's results (efficacy and safety)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gilles Kayem, MD, PhD
Phone
00 33 1 44 73 51 18
Email
gilles.kayem@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Nelly Briand, PhD
Phone
00 33 1 44 38 18 62
Email
nelly.briand@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilles Kayem, MD, PhD
Organizational Affiliation
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
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Elsa Lorthe, RM, PhD
Organizational Affiliation
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
Official's Role
Study Director
Facility Information:
Facility Name
Trousseau University Hospital
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gilles Kayem, MD, PhD
Phone
0033 1 44 73 51 18
Email
gkayem@aphp.fr
First Name & Middle Initial & Last Name & Degree
Clémence Cabanne, RM
Phone
0033 1 71 73 86 95
Email
clemencecabanne.tocoprom@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
24578236
Citation
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.
Results Reference
background
PubMed Identifier
28412086
Citation
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.
Results Reference
background
PubMed Identifier
23182704
Citation
Couteau C, Haumonte 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.
Results Reference
background
PubMed Identifier
30870741
Citation
Schmitz T, Sentilhes L, Lorthe E, Gallot D, Madar H, Doret-Dion M, Beucher G, Charlier C, Cazanave C, Delorme P, Garabedian C, Azria E, Tessier V, Senat 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.
Results Reference
background
PubMed Identifier
24901312
Citation
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;2014(6):CD002255. doi: 10.1002/14651858.CD002255.pub2.
Results Reference
background
PubMed Identifier
35947046
Citation
Wilson A, Hodgetts-Morton VA, Marson EJ, Markland AD, Larkai E, Papadopoulou A, Coomarasamy A, Tobias A, Chou D, Oladapo OT, Price MJ, Morris K, Gallos ID. Tocolytics for delaying preterm birth: a network meta-analysis (0924). Cochrane Database Syst Rev. 2022 Aug 10;8(8):CD014978. doi: 10.1002/14651858.CD014978.pub2.
Results Reference
derived
PubMed Identifier
34496799
Citation
Lorthe E, Kayem G; TOCOPROM Study Group and the GROG (Groupe de Recherche en Obstetrique et Gynecologie). Tocolysis in the management of preterm prelabor rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM). BMC Pregnancy Childbirth. 2021 Sep 8;21(1):614. doi: 10.1186/s12884-021-04047-2.
Results Reference
derived

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

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