Cervical Ripening, Labor, Induced
Conditions
Keywords
Cervical ripening, Induction of labor, Dinoprostone vaginal insert, Cervidil, Misoprostol vaginal insert, Modified Bishop's Score, PGE2, PGE1, Uterine Hyperstimulation, Cesarean section
Brief summary
The purpose of this study is to determine whether the misoprostol vaginal insert (50 mcg and 100 mcg) can safely and effectively speed time to vaginal delivery compared to Cervidil (R) in women who need to have cervical ripneing and induction of labor.
Detailed description
Induction of labor is required in approximately 20% of pregnant women. Although contractions can be brought on by oxytocin (pitocin), some women need help in softening the cervix, or mouth of the womb (uterus), before oxytocin can be started. Prostaglandins have been shown to ripen, or soften, the cervix; at present, the only prostaglandin approved for marketing by FDA for this purpose is dinoprostone. Dinoprostone can be delivered in several ways; one method is to use a polymer vaginal insert that slowly releases the dinoprostone directly to the cervical tissues. This product is called Cervidil (R) and has been marketed for more than 10 years in the United States. Misoprostol is another form of prostaglandin that is approved for protecting the stomach and intestinal lining for patients taking NSAIDs. Misoprostol has also been used by many obstetricians for cervical ripening and inducing contractions, but, it is not approved by FDA for this purpose. The same company that makes the Cervidil polymer insert has made an insert that will slowly release misoprostol. This study will determine whether this investigational insert containing misoprostol will decrease time to vaginal delivery compared to Cervidil. Two different doses of misoprostol will be tested (50 micrograms and 100 micrograms); each vaginal insert will gradually release a small, controlled amount of misoprostol over up to 24 hours. Comparator: The Cervidil (R) vaginal insert containing dinoprostone will be the comparator in this study.
Interventions
Hydrogel polymer intravaginal insert with retrieval system. One insert is to remain in the posterior fornix of the vagina until removed for one of the following conditions: onset of active labor; maternal/fetal complication, e.g. non-reassuring fetal heart rate. Record if the insert falls out prior to meeting one of the first two criteria. In no case is the insert to remain in place longer than 24h.
Hydrogel polymer intravaginal insert with retrieval system. One insert is to remain in the posterior fornix of the vagina until removed for one of the following conditions: onset of active labor; maternal/fetal complication, e.g. non-reassuring fetal heart rate. Record if the insert falls out prior to meeting one of the first two criteria. In no case is the insert to remain in place longer than 24h.
DRUGDinoprostone vaginal insert (Cervidil)
Hydrogel polymer intravaginal insert with retrieval system. One insert is to remain in the posterior fornix of the vagina until removed for one of the following conditions: onset of active labor; maternal/fetal complication, e.g. non-reassuring fetal heart rate. Record if the insert falls out prior to meeting one of the first two criteria. In no case is the insert to remain in place longer than 24h.
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pregnant women at least 36 weeks gestation requiring cervical ripening and induction of labor
Exclusion criteria
* No uterine scar (no previous delivery by cesarean section) * No multiple gestation * No condition that disallows use of prostaglandins for induction of labor * No more than 3 previous vaginal births beyond 24 weeks gestation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Minutes From Drug Insertion to Vaginal Delivery | 2880 minutes | Interval between time/date of insertion of study drug and time/date of neonate birth. This is a time-to-event analysis, there is no set time for the assessment. The endpoint occurs when the baby is born. 48 hours can be used as an approximate interval by which time most of the babies have been delivered. |
| Percentage of Participants With a Cesarean Section Delivery | 2880 minutes | Percentage of participants with cesarean delivery after study drug was administered. There is no set assessment time or date as the woman's labor may last hours or days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Cervical Ripening Success Based On Modified Bishop Score (mBS) 12 Hours After Administration of Vaginal Insert | 12 hours | Measured the percentage of participants who achieved success on the mBS. This composite score is based on the mBS and vaginal delivery and it is measured 12 hours after insertion of the study drug. The mBS has a score of 0 when the cervix is not ripe and a score of 12 when completely ripened. The 12 hour score is compared to baseline. Using the mBS, assess at 12 hours whether each subject has met any of the following three criteria: 1) has improved (increased) the mBS by at least 3 points from baseline; 2) has reached a score of at least 6 on the mBS; or 3) has acheived a vaginal delivery. |
| Minutes to Onset of Active Labor | 2880 minutes | Interval from insertion of study drug to onset of active labor, defined as at least three contractions in a ten-minute period of at least moderate intensity and resulting in cervical change such as dilatation or effacement; OR at least 4 cm cervical dilatation achieved after progressive change in dilatation. |
| Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | 96 hours | This outcome reports the percentage of adverse events in each treatment arm spontaneously reported or observed during the study. The intrapartum period (mother is still pregnant) is called the Maternal/Fetal period; once the baby has been born, adverse events are assessed separately for the mother (Post Partum) and the baby (Neonatal). The number of adverse events was assessed separately for each of the three periods. |
| Duration of Stay in Minutes in Labor and Delivery Suite | 5760 minuts | Minutes in Labor and Delivery (L & D) suite starting from insertion of the study drug to discharge from L & D to post partum care. |
| Days in Hospital for Mother and Neonate | 10 days | Duration of stay in hospital for mother and neonate starting with insertion of the study drug and ending with discharge from the hospital. |
| Minutes to Rupture of Membranes (ROM) | 2880 minutes | Interval from study drug insertion to ROM. |
| Percentage of Participants With Pre-Delivery Oxytocin Use | 2880 minutes | Incidence in each treatment group of need for oxytocin for pre-delivery induction or augmentation of labor. |
Countries
Canada, United States
Participant flow
Recruitment details
First subject entered 26 April 2006; last subject completed 07 August 2007; 49 hospitals entered subjects requiring cervical ripening prior to induction of labor.
Participants by arm
| Arm | Count |
|---|---|
| Misoprostol Vaginal Insert (MVI) 100 Misoprostol vaginal insert 100 mcg over a period of up to 24 h | 428 |
| Misoprostol Vaginal Insert (MVI) 50 Misoprostol vaginal insert 50 mcg over a period of up to 24 h | 444 |
| Cervidil 10 mg Vaginal Insert Cervidil 10 mg vaginal insert over a period of up to 24h | 436 |
| Total | 1,308 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Baby not born within 7 days of treatment | 1 | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Subject incarcerated, data not allowed | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Misoprostol Vaginal Insert (MVI) 100 | Misoprostol Vaginal Insert (MVI) 50 | Cervidil 10 mg Vaginal Insert | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 428 Participants | 444 Participants | 436 Participants | 1308 Participants |
| Age Continuous | 26.2 years STANDARD_DEVIATION 5.9 | 26.9 years STANDARD_DEVIATION 6.2 | 26.0 years STANDARD_DEVIATION 5.7 | 26.4 years STANDARD_DEVIATION 5.9 |
| modified Bishop score (mBS) | 2.69 Units on a scale of 0 (low) to 12 (most) STANDARD_DEVIATION 1.1 | 2.74 Units on a scale of 0 (low) to 12 (most) STANDARD_DEVIATION 1.1 | 2.73 Units on a scale of 0 (low) to 12 (most) STANDARD_DEVIATION 1.1 | 2.72 Units on a scale of 0 (low) to 12 (most) STANDARD_DEVIATION 1.1 |
| Parity Nulliparous | 267 participants | 275 participants | 270 participants | 812 participants |
| Parity Parous | 161 participants | 169 participants | 166 participants | 496 participants |
| Region of Enrollment Canada | 15 participants | 17 participants | 17 participants | 49 participants |
| Region of Enrollment United States | 413 participants | 427 participants | 419 participants | 1259 participants |
| Sex: Female, Male Female | 428 Participants | 444 Participants | 436 Participants | 1308 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 130 / 428 | 129 / 443 | 132 / 436 |
| serious Total, serious adverse events | 106 / 428 | 134 / 443 | 117 / 436 |
Outcome results
Primary
Minutes From Drug Insertion to Vaginal Delivery
Interval between time/date of insertion of study drug and time/date of neonate birth. This is a time-to-event analysis, there is no set time for the assessment. The endpoint occurs when the baby is born. 48 hours can be used as an approximate interval by which time most of the babies have been delivered.
Time frame: 2880 minutes
Population: This analysis is for time to vaginal delivery (interval from insertion of study drug into the vagina to the delivery of the neonate); patients delivered by cesarean section were censored from this time-to-event analysis using the longest interval for all participants from insertion of study drug to cesarean section delivery of neonate.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Minutes From Drug Insertion to Vaginal Delivery | 1595.5 minutes |
| Misoprostol Vaginal Insert (MVI) 50 | Minutes From Drug Insertion to Vaginal Delivery | 2127 minutes |
| Cervidil 10 mg Vaginal Insert | Minutes From Drug Insertion to Vaginal Delivery | 1649.5 minutes |
Comparison: Null hypothesis was that there would be no difference in time to vaginal delivery for MVI 100 compared to time to vaginal delivery for Cervidil.p-value: 0.974Log Rank
p-value: 0.01195% CI: [1977, 2253]Log Rank
Primary
Percentage of Participants With a Cesarean Section Delivery
Percentage of participants with cesarean delivery after study drug was administered. There is no set assessment time or date as the woman's labor may last hours or days.
Time frame: 2880 minutes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Percentage of Participants With a Cesarean Section Delivery | 28 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 50 | Percentage of Participants With a Cesarean Section Delivery | 28 Percentage of participants |
| Cervidil 10 mg Vaginal Insert | Percentage of Participants With a Cesarean Section Delivery | 26 Percentage of participants |
p-value: 0.6495% CI: [23.61, 32.31]Fisher Exact
p-value: 0.5995% CI: [23.86, 32.42]Fisher Exact
Secondary
Days in Hospital for Mother and Neonate
Duration of stay in hospital for mother and neonate starting with insertion of the study drug and ending with discharge from the hospital.
Time frame: 10 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Days in Hospital for Mother and Neonate | Mother | 4.5 days | Standard Deviation 1.24 |
| Misoprostol Vaginal Insert (MVI) 100 | Days in Hospital for Mother and Neonate | Neonate | 3.6 days | Standard Deviation 1.8 |
| Misoprostol Vaginal Insert (MVI) 50 | Days in Hospital for Mother and Neonate | Neonate | 3.5 days | Standard Deviation 1.2 |
| Misoprostol Vaginal Insert (MVI) 50 | Days in Hospital for Mother and Neonate | Mother | 4.7 days | Standard Deviation 1.1 |
| Cervidil 10 mg Vaginal Insert | Days in Hospital for Mother and Neonate | Neonate | 3.6 days | Standard Deviation 1.6 |
| Cervidil 10 mg Vaginal Insert | Days in Hospital for Mother and Neonate | Mother | 4.5 days | Standard Deviation 1.3 |
Secondary
Duration of Stay in Minutes in Labor and Delivery Suite
Minutes in Labor and Delivery (L & D) suite starting from insertion of the study drug to discharge from L & D to post partum care.
Time frame: 5760 minuts
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Duration of Stay in Minutes in Labor and Delivery Suite | 1683.6 minutes | Standard Deviation 811 |
| Misoprostol Vaginal Insert (MVI) 50 | Duration of Stay in Minutes in Labor and Delivery Suite | 2010 minutes | Standard Deviation 850 |
| Cervidil 10 mg Vaginal Insert | Duration of Stay in Minutes in Labor and Delivery Suite | 1729 minutes | Standard Deviation 862 |
Secondary
Minutes to Onset of Active Labor
Interval from insertion of study drug to onset of active labor, defined as at least three contractions in a ten-minute period of at least moderate intensity and resulting in cervical change such as dilatation or effacement; OR at least 4 cm cervical dilatation achieved after progressive change in dilatation.
Time frame: 2880 minutes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Minutes to Onset of Active Labor | 1032.5 minutes | Standard Deviation 627.2 |
| Misoprostol Vaginal Insert (MVI) 50 | Minutes to Onset of Active Labor | 1343.7 minutes | Standard Deviation 692 |
| Cervidil 10 mg Vaginal Insert | Minutes to Onset of Active Labor | 1005.2 minutes | Standard Deviation 667.1 |
Secondary
Minutes to Rupture of Membranes (ROM)
Interval from study drug insertion to ROM.
Time frame: 2880 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Minutes to Rupture of Membranes (ROM) | 1285.0 minutes |
| Misoprostol Vaginal Insert (MVI) 50 | Minutes to Rupture of Membranes (ROM) | 1364.0 minutes |
| Cervidil 10 mg Vaginal Insert | Minutes to Rupture of Membranes (ROM) | 1123 minutes |
Secondary
Percentage of Participants With Cervical Ripening Success Based On Modified Bishop Score (mBS) 12 Hours After Administration of Vaginal Insert
Measured the percentage of participants who achieved success on the mBS. This composite score is based on the mBS and vaginal delivery and it is measured 12 hours after insertion of the study drug. The mBS has a score of 0 when the cervix is not ripe and a score of 12 when completely ripened. The 12 hour score is compared to baseline. Using the mBS, assess at 12 hours whether each subject has met any of the following three criteria: 1) has improved (increased) the mBS by at least 3 points from baseline; 2) has reached a score of at least 6 on the mBS; or 3) has acheived a vaginal delivery.
Time frame: 12 hours
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Percentage of Participants With Cervical Ripening Success Based On Modified Bishop Score (mBS) 12 Hours After Administration of Vaginal Insert | 59 Percentage of Participants | 3.15 |
| Misoprostol Vaginal Insert (MVI) 50 | Percentage of Participants With Cervical Ripening Success Based On Modified Bishop Score (mBS) 12 Hours After Administration of Vaginal Insert | 50 Percentage of Participants | 2.8 |
| Cervidil 10 mg Vaginal Insert | Percentage of Participants With Cervical Ripening Success Based On Modified Bishop Score (mBS) 12 Hours After Administration of Vaginal Insert | 60 Percentage of Participants | 3.3 |
Secondary
Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events
This outcome reports the percentage of adverse events in each treatment arm spontaneously reported or observed during the study. The intrapartum period (mother is still pregnant) is called the Maternal/Fetal period; once the baby has been born, adverse events are assessed separately for the mother (Post Partum) and the baby (Neonatal). The number of adverse events was assessed separately for each of the three periods.
Time frame: 96 hours
Population: Analysis was based on intention to treat, i.e., all subjects who had the insert placed in the vagina.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Maternal/Fetal | 65 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 100 | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Neonatal | 29 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 100 | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Maternal (Post-Partum) | 29 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 50 | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Maternal/Fetal | 64 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 50 | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Maternal (Post-Partum) | 26 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 50 | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Neonatal | 24 Percentage of participants |
| Cervidil 10 mg Vaginal Insert | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Maternal (Post-Partum) | 27 Percentage of participants |
| Cervidil 10 mg Vaginal Insert | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Neonatal | 27 Percentage of participants |
| Cervidil 10 mg Vaginal Insert | Percentage of Participants With Maternal/Fetal, Maternal (Post-Partum), and Neonatal Adverse Events | Maternal/Fetal | 65 Percentage of participants |
Secondary
Percentage of Participants With Pre-Delivery Oxytocin Use
Incidence in each treatment group of need for oxytocin for pre-delivery induction or augmentation of labor.
Time frame: 2880 minutes
Population: This analysis included all participants exposed to study drug and for whom there was data available regarding whether oxytocin was used pre-delivery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Misoprostol Vaginal Insert (MVI) 100 | Percentage of Participants With Pre-Delivery Oxytocin Use | 68.5 Percentage of participants |
| Misoprostol Vaginal Insert (MVI) 50 | Percentage of Participants With Pre-Delivery Oxytocin Use | 80.8 Percentage of participants |
| Cervidil 10 mg Vaginal Insert | Percentage of Participants With Pre-Delivery Oxytocin Use | 69.0 Percentage of participants |