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

Preterm Premature Rupture of Membrane Clinical Trial

— TOCOPROM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03976063
• Other study ID #: P160917
• Status: Recruiting
• Phase: Phase 3
• Start date: October 7, 2019
• Est. completion date: November 2030

Study information

• Verified date: February 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Gilles Kayem, MD, PhD
• Phone: 00 33 1 44 73 51 18
• Email: gilles.kayem[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 850
• Est. completion date: November 2030
• Est. primary completion date: November 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Fetal Membranes, Premature Rupture
• Premature Birth
• Preterm Premature Rupture of Membrane
• Rupture

Intervention

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)
• Placebo of Nifedipine
Oral Placebo of Nifedipine 20 mg, at T0, T0.5, T3, T11, T19, T27, T35 and T43

Locations

Country	Name	City	State
France	Trousseau University Hospital	Paris

Sponsors (4)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Groupe de Recherche en Obstétrique et Gynécologie, INSERM U1153, Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	Prolongation of gestation	Gestational age at delivery	Up to 20 weeks after PPROM (i.e. up to the maximum duration of a normal pregnancy)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	Neonatal mortality	Neonatal death	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal severe morbidity	Mechanical ventilation = 48 hrs	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal severe morbidity	Severe bronchopulmonary dysplasia	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal severe morbidity	Severe intraventricular hemorrhage	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal severe morbidity	Cystic periventricular leucomalacia	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal severe morbidity	Early-onset sepsis	From birth to Day 3 after birth.
Secondary	Neonatal severe morbidity	Necrotizing enterocolitis	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal severe morbidity	Retinopathy of prematurity	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal morbidity	Severe fetal acidemia	At birth.
Secondary	Neonatal morbidity	Respiratory distress syndrome	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal morbidity	Mild or moderate bronchopulmonary dysplasia	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal morbidity	Grades I-II intraventricular hemorrhage	From birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Neonatal morbidity	Late-onset sepsis.	From Day 3 after birth to discharge from hospital, with a maximum of 24 weeks after birth.
Secondary	Vital status	Death between discharge and follow up at 2 years	At 22-26 months of corrected age
Secondary	Frequency of Gross motor impairment among children alive at 2 years of corrected age	Cerebral palsy	At 22-26 months of corrected age
Secondary	Frequency of Neurosensory impairment among children alive at 2 years of corrected age	Visual impairment	At 22-26 months of corrected age
Secondary	Frequency of Neurosensory impairment among children alive at 2 years of corrected age	Hearing impairment	At 22-26 months of corrected age