Clinical trial NCT05568745: Balloon + Oxytocin Versus Oral Misoprostol to Induce Labor in Case of PROM (RUBAPRO2)
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).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Induction of Labor
Cervical Ripening
Premature Rupture of Fetal Membranes
Nulliparous
Keywords: premature rupture of membranes
labour induction
unfavourable cervix
cervical ripening balloon
pharmacological cervical ripening
misoprostol
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2022-10-06
Enrollment: 520
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-center, randomized, controlled, open-label therapeutic trial with two parallel arms.
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Vaginal delivery <24hours
timeFrame: at birth
measure: Patient satisfaction
timeFrame: up to 4 days
Secondary outcomes:
measure: Duration from rupture to beginning of induction
timeFrame: at birth
measure: Duration between IOL and delivery
timeFrame: at birth
measure: Duration of balloon exposure or misoprostol exposure
timeFrame: at birth
measure: Misoprostol received
timeFrame: at birth
measure: Bishop score on balloon removal
timeFrame: at birth
measure: Balloon in place (yes/no)
timeFrame: at birth
measure: Duration between induction and full cervical dilatation
timeFrame: at birth
measure: Mode of delivery
timeFrame: at birth
measure: Post-partum hemorrhage
timeFrame: up to 4 days
measure: Rate of fever
timeFrame: during labor
measure: Rate of patients experiencing episode(s) of uterine hyperstimulation
timeFrame: during labor
measure: Endometritis
timeFrame: up to 4 days
measure: Duration of hospital stay
timeFrame: up to 4 days
measure: Birth weight of the newborn
timeFrame: at birth
measure: Apgar score < 7
timeFrame: 5min after birth
measure: pH umbilical artery
timeFrame: at birth
measure: Base defect and lactate (umbilical artery)
timeFrame: at birth
measure: Neonatal tranfer
timeFrame: up to 4 days
measure: maternal-fetal infection
timeFrame: up to 4 days
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand
city: Le Kremlin-Bicêtre
country: France
facility: Assistance Publique Hôpitaux de Paris- CHU Bicêtre
city: Saint-Étienne
country: France
facility: CHU de Saint Etienne
city: Toulouse
country: France
facility: CHU de Toulouse
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Denis Gallot
role: PRINCIPAL_INVESTIGATOR
References: