Balloon + Oxytocin Versus Oral Misoprostol to Induce Labor in Case of PROM (RUBAPRO2)

Sponsor

University Hospital, Clermont-Ferrand (Other)

Overall Status

Recruiting

CT.gov ID

NCT05568745

Collaborator

(none)

520

Enrollment

Locations

Arms

36.5

Anticipated Duration (Months)

104

Patients Per Site

2.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Premature rupture of membranes (PROM) at term complicates 6 to 22% of singleton pregnancies. Spontaneous labour occurs in 60-67% of these patients within 24h. If no effective uterine contraction occurs, induction of labour (IOL) is the strategy recommended by the French as well as the American College of Obstetricians and Gynecologists. The optimal strategy for IOL in case of PROM with an unfavourable cervix remains unknown and none of the studies conducted in nulliparous women showed the superiority of one induction method over another.

In the current project, we aimed to determine (1) if IOL with association of balloon catheter and oxytocin after 6 hours could increase the rate of delivery < 24h versus low dose of oral misoprostol (25 µg oral PGE1 every 2h) in case of PROM at term in nulliparous women and (2) patient satisfaction using EXIT survey assessed before hospital discharge.

Condition or Disease	Intervention/Treatment	Phase
Induction of Labor Cervical Ripening Premature Rupture of Fetal Membranes Nulliparous	Device: Balloon for cervical ripening (Teleflex French Dufour catheter CH20 reference 174000) Drug: Oxytocin Drug: Misoprostol Oral Tablet	Phase 4

Detailed Description

Context : Premature rupture of membranes (PROM) at term complicates 6 to 22% of singleton pregnancies. Spontaneous labour occurs in 60-67% of these patients within 24hours. If no effective uterine contraction occurs, induction of labour (IOL) is the strategy recommended by the French as well as the American College of Obstetricians and Gynecologists. The optimal strategy for IOL in case of PROM with an unfavourable cervix remains unknown and none of the studies conducted in nulliparous women showed the superiority of one induction method over another1. Oral misoprostol (ProstaglandinE1, PGE1) usually demonstrated the lowest rate of c-section after IOL in general population and balloon catheter was associated with the lowest rate of uterine hyperstimulation. Recently, a comparison 1 to 1 between these two methods was conducted in singletons with comparable results. Despite recent studies demonstrating no higher risk of infectious complications using mechanical device in the context of PROM, only prostaglandins and oxytocin are usually recommended. Recently, Devillard et al. demonstrated that the combination of balloon catheter plus oxytocin systematically infused after 6 hours increased the rate of delivery <24h compared to dinoprostone vaginal insert group (90% versus 57.5% respectively) and decreased the time between induction and delivery in nulliparous group (17.0hours versus 26.5hours).

In the current project, we aimed to determine (1) if IOL with association of balloon catheter and oxytocin after 6 hours could increase the rate of delivery < 24hours versus low dose of oral misoprostol (25 µg oral PGE1 every 2h) in case of PROM at term in nulliparous women and (2) patient satisfaction using EXIT (EXperience of Induction Tool) survey assessed before hospital discharge.

We hypothesized that the rate of delivery < 24hours will be 15% higher in the group induced with balloon + oxytocin (estimated around 85 %) compared to the misoprostol group (estimated around 70 %). Patient satisfaction concerning experience of IOL will be assessed using a validated survey- the EXperience of Induction Tool (EXIT) - translated in French language (Beckman et al., 2017). We aimed to demonstrate a difference greater than an effect-size of 0.25.

Objectives: The main objective is to demonstrate higher rate of vaginal birth <24hours by insertion of a balloon catheter + oxytocin after 6hours, versus low dose of oral misoprostol (25 µg oral PGE1 every 2hours) in case of unfavorable cervix beyond 12 hours of PROM in nulliparous and to compare patient satisfaction using EXIT survey translated in French language before hospital discharge.

The secondary objectives are:

To compare the rate of caesarean sections in the two groups.
To compare the safety related to women of both induction methods in terms of maternal morbidities, uterine hyperstimulation, maternal infections and other reported adverse events (AEs).
To compare the safety related to neonates of both induction methods in terms of neonatal morbidities, neonatal infections and other reported AEs.

Study type: Multi-center, randomized, controlled, open-label therapeutic trial with two parallel arms.

Number of centers: 5

Study Description:

The study group is the balloon catheter group with addition of oxytocin as early as 6h after the catheter insertion. After 12 hours of balloon insertion, induction of labour is continued by oxytocin alone. The control group corresponds to induction with misoprostol 25µg given orally (oral prostaglandin E1). The same dose is delivered every 2 hours until labour onset with a maximum of 8 administrations. Oxytocin can be started at least 4 hours after the last misoprostol administration.

Patients will be assigned by random allocation on a 1:1 basis in permuted blocks to either treatment group or control group using a dedicated, password-protected, SSL-encrypted website. To minimize the risk of imbalance between the study groups, the randomization will be stratified by trial site.

Primary endpoint: Hierarchical primary endpoint: (1) Proportion of patients vaginally delivered <24h and (2) patient satisfaction using EXIT survey assessed before hospital discharge.

Number of patients: 520

Study Design

Study Type:

Interventional

Anticipated Enrollment :

520 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Multi-center, randomized, controlled, open-label therapeutic trial with two parallel arms.Multi-center, randomized, controlled, open-label therapeutic trial with two parallel arms.

Masking:

None (Open Label)

Masking Description:

Masking is impossible because of the nature of the device studied.

Primary Purpose:

Treatment

Official Title:

Balloon + Oxytocin Versus Oral Misoprostol to Induce Labor in Case of Premature Rupture of Membranes (PROM) at Term in Nulliparous: a Randomized Controlled Trial (RUBAPRO2).

Actual Study Start Date :

Jan 18, 2023

Anticipated Primary Completion Date :

Feb 1, 2025

Anticipated Study Completion Date :

Feb 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Balloon+oxytocin Mecanical cervical ripening will be done by transcervical balloon (Teleflex French Dufour catheter CH20 reference 174000). Oxytocin will be started 6 hours after balloon insertion. At H12 balloon will be removed and induction continued by oxytocin alone.	Device: Balloon for cervical ripening (Teleflex French Dufour catheter CH20 reference 174000) Balloon catheter is inserted by a resident or a physician under visual control. The expected volume injected in the balloon probe is 60 mL. No traction is performed on the catheter. The catheter is left in place for a maximum of 12 hours. Drug: Oxytocin Intravenous oxytocin addition (preceded or followed by epidural analgesia on patient's request) will be performed 6 hours after insertion of balloon catheter. Oxytocin is administered as an intravenous infusion (5 IU of oxytocin in 49 mL of 5% glucose*) at the lowest possible dose with the aim of achieving a maximum of three to four contractions per ten minutes. After appropriate uterine activity has been achieved, the rate of the oxytocin infusion is decreased or stopped.
Active Comparator: Oral misoprostol Patients will receive misoprostol 25 micrograms given orally (oral prostaglandin E1). The same dose will be given every 2 hours until beginning of labor with a maximum of 8 administrations. (Oxytocin can be started at least 4 hours after the last misoprostol administration if patient remains not in labour.)	Drug: Misoprostol Oral Tablet Patients will receive misoprostol 25 micrograms given orally (oral prostaglandin E1). The same dose will be given every 2 hours until beginning of labor with a maximum of 8 administrations.

Arm

Intervention/Treatment

Experimental: Balloon+oxytocin

Mecanical cervical ripening will be done by transcervical balloon (Teleflex French Dufour catheter CH20 reference 174000). Oxytocin will be started 6 hours after balloon insertion. At H12 balloon will be removed and induction continued by oxytocin alone.

Device: Balloon for cervical ripening (Teleflex French Dufour catheter CH20 reference 174000)

Balloon catheter is inserted by a resident or a physician under visual control. The expected volume injected in the balloon probe is 60 mL. No traction is performed on the catheter. The catheter is left in place for a maximum of 12 hours.

Drug: Oxytocin

Intravenous oxytocin addition (preceded or followed by epidural analgesia on patient's request) will be performed 6 hours after insertion of balloon catheter. Oxytocin is administered as an intravenous infusion (5 IU of oxytocin in 49 mL of 5% glucose*) at the lowest possible dose with the aim of achieving a maximum of three to four contractions per ten minutes. After appropriate uterine activity has been achieved, the rate of the oxytocin infusion is decreased or stopped.

Active Comparator: Oral misoprostol

Patients will receive misoprostol 25 micrograms given orally (oral prostaglandin E1). The same dose will be given every 2 hours until beginning of labor with a maximum of 8 administrations. (Oxytocin can be started at least 4 hours after the last misoprostol administration if patient remains not in labour.)

Drug: Misoprostol Oral Tablet

Patients will receive misoprostol 25 micrograms given orally (oral prostaglandin E1). The same dose will be given every 2 hours until beginning of labor with a maximum of 8 administrations.

Outcome Measures

Primary Outcome Measures

Vaginal delivery <24hours [at birth]
Proportion of patients vaginally delivered <24hours (in %)
Patient satisfaction [up to 4 days]
Satisfaction of women concerning method of induction by the EXperience of Induction Tool (EXIT) validated in french language.

Secondary Outcome Measures

Duration from rupture to beginning of induction [at birth]
in hours
Duration between IOL and delivery [at birth]
in hours
Duration of balloon exposure or misoprostol exposure [at birth]
in hours
Misoprostol received [at birth]
Total dose of misoprostol received (in µg)
Bishop score on balloon removal [at birth]
(comprised between 0 and 13)
Balloon in place (yes/no) [at birth]
Rate of balloon in place (%) at 12 hours after the beginning of induction
Duration between induction and full cervical dilatation [at birth]
Duration (in hours)
Mode of delivery [at birth]
Rate in %
Post-partum hemorrhage [up to 4 days]
Rate in %
Rate of fever [during labor]
Rate in %
Rate of patients experiencing episode(s) of uterine hyperstimulation [during labor]
Rate of patients experiencing episode(s) of uterine hyperstimulation (%) during labour (defined by the necessity to interrupt oxytocin and/or to inject pharmacological agents in the context of excessive number of contractions with or without abnormal FHR),
Endometritis [up to 4 days]
Rate of endometritis in %
Duration of hospital stay [up to 4 days]
Duration (in days)
Birth weight of the newborn [at birth]
in grammes
Apgar score < 7 [5min after birth]
Neonatal endpoint (yes/no)
pH umbilical artery [at birth]
pH at the umbilical artery
Base defect and lactate (umbilical artery) [at birth]
mmol/L
Neonatal tranfer [up to 4 days]
Rate of neonatal transfer to intensive care unit or neonatology unit
maternal-fetal infection [up to 4 days]
Rate of maternal-fetal infection in %

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Age > 18 years old,
Pregnant, Gestational age ≥ 37 weeks
Singleton pregnancy with cephalic presentation
Nulliparous
PROM without labour beyond 12 hours
Unfavourable cervix (Bischop score < 6)
Able to give her informed consent
Ability to comply with the requirement of the study
Covered by the French Social Security welfare system

Exclusion Criteria:

Unable to understand French language
Contraindication for vaginal delivery
Loss of meconium amniotic fluid (LA)
Temperature > 38.2°C
Intrauterine infection
IUGR with Doppler anomaly
Fetus with expected polymalformative syndrome
Scarred womb
Suspicion of genital herpes
Known HIV seropositivity
Placenta praevia
Fetal death
Abnormal FHR (Fetal Heart Rate)
Contraindication to misoprostol:
Allergy or hypersensibility
Suspicion or confirmation of a scarred uterus following past surgical intervention
Renal insufficiency
Malformation of the uterus
Contraindication to balloon:
Vasa praevia, placenta praevia
Invasive cervical cancer
Contraindication to oxytocin
Allergy or hypersensibility
Dystocia
Fragility or excessive distension of the uterus
Uterine hypertonia or fetal distress when delivery is not imminent
Cardiovascular disorders and severe preeclampsia
Predisposition to amniotic embolism (in utero fetal demise, abruption).
Patient subject to a legal protection order (curatorship or tutorship)
Refusal to participate

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU de Bordeaux	Bordeaux	France	33000
2	CHU de Clermont-Ferrand	Clermont-Ferrand	France	63000
3	Assistance Publique Hôpitaux de Paris- CHU Bicêtre	Le Kremlin-Bicêtre	France	94275
4	CHU de Saint Etienne	Saint-Étienne	France	42270
5	CHU de Toulouse	Toulouse	France	31059