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

Tocolysis in the Management of Preterm Premature Rupture of Membranes Before 34 Weeks of Gestation: a Double-blinded Randomized Controlled Trial

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 Overview

• Status: Recruiting
• Conditions: Preterm Premature Rupture of Membrane
• Intervention / Treatment: Drug: Placebo of Nifedipine; Drug: Nifedipine

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
• Enrollment (Estimated): 850
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Gilles Kayem, MD, PhD; Phone Number: 00 33 1 44 73 51 18; Email: gilles.kayem@aphp.fr
• Study Contact Backup: Name: Nelly Briand, PhD; Phone Number: 00 33 1 44 38 18 62; Email: nelly.briand@aphp.fr

Study Locations

• France
  • Paris, France, 75012
    • Recruiting
    • Trousseau University Hospital
    • Contact: Gilles Kayem, MD, PhD; Phone Number: 0033 1 44 73 51 18; Email: gkayem@aphp.fr
    • Contact: Clémence Cabanne, RM; Phone Number: 0033 1 71 73 86 95; Email: clemencecabanne.tocoprom@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo of Nifedipine; Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43
Active Comparator: Nifedipine	Drug: Nifedipine; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to discharge from hospital, with a maximum of 24 weeks after birth.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prolongation of gestation	Latency duration (defined as the duration from PPROM to delivery)	Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Prolongation of gestation	Pregnancy prolongation beyond 48 hours after randomization	Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Prolongation of gestation	Pregnancy prolongation beyond 1 week after randomization	Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Prolongation of gestation	Gestational age at delivery	Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Prolongation of gestation	Delivery after 37 weeks of gestation	Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
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.	During the first 10 days postpartum
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.	At delivery
Fetal mortality	Fetal death	Up to delivery so up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Neonatal mortality	Neonatal death	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal severe morbidity	Mechanical ventilation ≥ 48 hrs	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal severe morbidity	Severe bronchopulmonary dysplasia	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal severe morbidity	Severe intraventricular hemorrhage	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal severe morbidity	Cystic periventricular leucomalacia	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal severe morbidity	Early-onset sepsis	From birth to Day 3 after birth.
Neonatal severe morbidity	Necrotizing enterocolitis	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal severe morbidity	Retinopathy of prematurity	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal morbidity	Severe fetal acidemia	At birth.
Neonatal morbidity	Respiratory distress syndrome	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal morbidity	Mild or moderate bronchopulmonary dysplasia	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal morbidity	Grades I-II intraventricular hemorrhage	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Neonatal morbidity	Late-onset sepsis.	From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth.
Vital status	Death between discharge and follow up at 2 years	At 22-26 months of corrected age
Frequency of Gross motor impairment among children alive at 2 years of corrected age	Cerebral palsy	At 22-26 months of corrected age
Frequency of Neurosensory impairment among children alive at 2 years of corrected age	Visual impairment	At 22-26 months of corrected age
Frequency of Neurosensory impairment among children alive at 2 years of corrected age	Hearing impairment	At 22-26 months of corrected age

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France; INSERM U1153; 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

Publications and helpful links

General 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.
• 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, 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2019
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2030

Study Registration Dates

• First Submitted: May 29, 2019
• First Submitted That Met QC Criteria: June 4, 2019
• First Posted (Actual): June 5, 2019

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Nifedipine; Tocolysis; Preterm birth; Latency; Preterm premature rupture of membranes; Neonatal outcome
• Additional Relevant MeSH Terms: Wounds and Injuries; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Rupture; Premature Birth; Fetal Membranes, Premature Rupture; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Calcium Channel Blockers; Tocolytic Agents; Nifedipine
• Other Study ID Numbers: P160917

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No