Comparison Between 25 µg Vaginal Misoprostol vs Slow Release Pessary PGE2 (CYTOPRO)

Comparison Between 25 µg Vaginal Misoprostol Versus Slow Release Pessary Prostaglandin-E2 (PGE2) : Could we Use Low Dose Vaginal Misoprostol as a First Line Treatment for Induction of Labor ?

For about 10% of pregnancies, it is necessary to induce delivery for medical reasons. Prostaglandins alone can be used to perform cervical ripening in cases of immature cervix. In France, dinoprostone is the own approved medication. It is in the form of gel or sustained release device whose effectiveness and side effects are comparable. The vaginal misoprostol has no marketing authorization in France, but is sometimes used. Some data in the scientific literature have showed that its use with low-dose (25 mcg) vaginally did not lead to more complications, was at least as effective and seems to be cost-effective compared with dinoprostone. Misoprostol with this dose and route of administration is now recommended by the American College of Obstetricians and Gynecologist (ACOG), Grade A (ACOG Practice Bulletin August 2009). This is not the case in France (French HAS 2008 Guidelines on induction of labor). According to HAS, the investigators still lack data on large samples to confirm the benefits of misoprostol 25 mcg vaginally, in terms of efficiency, rate of cesarean section, and lower cost compared to dinoprostone.

The primary objective is to demonstrate non-inferiority of vaginal misoprostol 25 mcg vs. dinoprostone in terms of cesarian section occurence with a non-inferiority margin of +5% difference.

Study Overview

• Status: Completed
• Conditions: Delivery Uterine
• Intervention / Treatment: Drug: Misoprostol; Drug: Dinoprostone

Detailed Description

To show if the experimental treatment (25μg of intravaginal misoprostol) used for induction of labor in singleton women ≥ 36 weeks gestation with an unfavorable cervix is not clinically and statistically inferior than the reference treatment , ie intravaginal dinoprostone sustained release (10mg), in terms of cesarian sectionto compare the cost-effectiveness and to assess the differential tolerance of the two strategies.

Non-inferiority will be demonstrated if the upper limit of the 90%-bilateral confidence interval of the difference between cesarian section rates (misoprostol - dinosprostone) is below 5% in the intention-to-treat analysis and the per-protocol analysis.

If non-inferiority is demonstrated, as a secondary analysis, superiority of misosprostol will be tested.

Orther secondary objectives are to assess the cost-effectiveness, the tolerance, maternal satisfaction and other efficacy endpoints of the two strategies.

• Study Type: Interventional
• Enrollment (Actual): 1700
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94000
    • Bicetre Hospital
  • Poissy, France, 78303
    • Hospital Poissy
  • Strasbourg, France, 67091
    • Hopitaux Universitaires de Strasbourg
  • Toulouse, France, 31059
    • University Hospital Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• singleton pregnancy
• Cephalic presentation
• Bishop ≤ 5
• ≤ 3 uterine contractions / 10 mn
• ≥ 36 weeks gestation
• Personally signed and dated informed consent document

Exclusion Criteria:

• History of cesarian-section
• uterine scar
• deceleration on Cardiotocogram (CTG)
• placenta praevia
• bleeding
• chorioamnionitis
• Fetal weight US ≥4500 g
• Contra-indication to vaginal delivery
• Hystory of myomectomy
• Herpes primoinfection or recurrence
• Allergy to prostaglandins

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Misoprostol; one 25 micrograms capsule all 4 hours by intravaginal route	Drug: Misoprostol; administration of Misoprostol 25 micrograms capsule by intravaginal route every 4 hours, up to 4 capsules; Other Names: CYTOTEC; 25 micrograms Misoprostol capsule by intravaginal route
ACTIVE_COMPARATOR: Dinoprostone; one unique intravaginal sustained released of 10 milligrams	Drug: Dinoprostone; administration of one sustained released pessary of 10 milligrams by intravaginal route; Other Names: PROPESS; one intravaginal sustained released capsule of 10 milligrams

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cesarean for all indications	Occurrence of cesarean section for all indications	Up to delivery

Secondary Outcome Measures

Outcome Measure	Time Frame
Cost-effectiveness of two strategies (direct medical cost differential efficiency strategies measured by the Cesarean rate	Up to discharge / end of study

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Summary description of all adverse events, related adverse events and serious adverse events by treatment using MedRA classification.	Up to discharge/end of study
Other specific safety assessments	Maternal hyperstimulation syndromes with or without changes of foetal heart rate, uterine hypertonus, rate, rate of postpartum hemorrhage, degree III/IV perineal tears, uterine rupture, neonatal rate of pH <7.05 and/or BDbase deficit> 12mmol / L, rates Apgar score <7 at 5 minutes, transfer rate in neonatal intensive-care unit (NICU), neonatal seizures	Up to discharge/end of study
Other efficacy assessments	Time from 1st treatment administration to delivery, ocytocine administration and dose, occurrence of instrumental delivery, occurrence of spontaneous delivery	Up to discharge/end of study
Participant satisfaction assessment	Maternal satisfaction using visual analog scale and questionnaire	Up to discharge/end of study

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Christophe Vayssière, MD PhD, University Hospital, Toulouse

Publications and helpful links

General Publications

• Mounie M, Costa N, Gaudineau A, Molinier L, Vayssiere C, Derumeaux H. Cost-effectiveness analysis of vaginal misoprostol versus dinoprostone pessary: A non-inferiority large randomized controlled trial in France. Int J Gynaecol Obstet. 2022 Aug;158(2):390-397. doi: 10.1002/ijgo.13999. Epub 2021 Nov 19.
• Gaudineau A, Senat MV, Ehlinger V, Gallini A, Morin M, Olivier P, Roth E, Orusco E, Javoise S, Fort J, Lavergne C, Arnaud C, Rozenberg P, Vayssiere C; Groupe de Recherche en Obstetrique rt Gynecologie. Induction of labor at term with vaginal misoprostol or a prostaglandin E2 pessary: a noninferiority randomized controlled trial. Am J Obstet Gynecol. 2021 Nov;225(5):542.e1-542.e8. doi: 10.1016/j.ajog.2021.04.226. Epub 2021 Apr 19.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): September 1, 2015

Study Registration Dates

• First Submitted: January 8, 2013
• First Submitted That Met QC Criteria: January 9, 2013
• First Posted (ESTIMATE): January 10, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): April 28, 2016
• Last Update Submitted That Met QC Criteria: April 26, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: misoprostol,; cost-effectiveness; Induction of labor; prostaglandin; cervical ripening
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Gastrointestinal Agents; Reproductive Control Agents; Anti-Ulcer Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Oxytocics; Misoprostol; Dinoprostone
• Other Study ID Numbers: 1014301; 2011-000933-35 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO