Cervical Ripening, Induction of Labor, Reducing Time to Vaginal Delivery
Conditions
Keywords
Misoprostol vaginal insert, Dinoprostone vaginal insert, Cervidil, Cervical ripening, Induction of labor, Rate of cesarean section
Brief summary
The purpose of this study is to determine whether the Misoprostol Vaginal Insert (MVI) 200 microgram (mcg) can decrease the time to vaginal delivery compared to the Dinoprostone Vaginal Insert (DVI) 10 milligram (mg) in pregnant women requiring cervical ripening and induction of labor.
Interventions
DRUGMVI 200
Dose reservoir of 200 mcg of misoprostol in a hydrogel polymer vaginal insert within a retrieval system. The MVI 200 will be kept in place for up to 24 hours or will be removed earlier if one of the following occur: onset of active labor, intrapartum adverse event necessitating discontinuation of the study drug, other reasons including maternal request.
DRUGDinoprostone Vaginal Insert (DVI)
Dose reservoir of 10 mg of dinoprostone in a hydrogel polymer vaginal insert within a retrieval system. The DVI will be kept in place for up to 24 hours or will be removed earlier if one of the following occur: onset of active labor, intrapartum adverse event necessitating discontinuation of the study drug, other reasons including maternal request.
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
* Provide written informed consent; * Pregnant women at ≥ 36 weeks 0 days inclusive gestation; * Women aged 18 years or older; * Candidate for pharmacological induction of labor; * Single, live vertex fetus; * Baseline modified Bishop score ≤ 4; * Parity ≤ 3 (parity is defined as one or more births live or dead after 24 weeks gestation); * Body Mass Index (BMI) ≤ 50 at the time of entry to the study.
Exclusion criteria
* Women in active labor; * Presence of uterine or cervical scar or uterine abnormality e.g., bicornate uterus. Biopsies, including cone biopsy of the cervix, are permitted; * Administration of oxytocin or any cervical ripening or labor inducing agents (including mechanical methods) or a tocolytic drug within 7 days prior to enrollment. Magnesium sulfate is permitted if prescribed as treatment for pre-eclampsia or gestational hypertension; * Severe pre-eclampsia marked by Hemolytic anemia, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome, other end-organ affliction or Central Nervous System (CNS) findings other than mild headache; * Fetal malpresentation; * Diagnosed congenital anomalies, not including polydactyly; * Any evidence of fetal compromise at baseline (e.g., non-reassuring fetal heart rate pattern or meconium staining); * Amnioinfusion or other treatment of non-reassuring fetal status at any time prior to the induction attempt; * Ruptured membranes ≥ 48 hours prior to the start of treatment; * Suspected chorioamnionitis; * Fever (oral or aural temperature \> 37.5°C); * Any condition in which vaginal delivery is contraindicated e.g., placenta previa or any unexplained genital bleeding at any time after 24 weeks during this pregnancy; * Known or suspected allergy to misoprostol, dinoprostone, other prostaglandins or any of the excipients; * Any condition urgently requiring delivery; * Unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to Vaginal Delivery During the First Hospital Admission | Interval from study drug administration to vaginal delivery (average 24 hours) |
| Incidence of Cesarean Delivery During the First Hospital Admission | Interval from study drug administration to cesarean delivery (average 24 hours) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Active Labor During the First Hospital Admission | Interval from study drug administration to active labor (average 12 hours) | Active labor was defined as progressive cervical dilatation to 4 cm with any frequency of contractions OR rhythmic, firm, adequate quality uterine contractions causing progressive cervical change occurring at a frequency of 3 or more in 10 minutes and lasting 45 seconds or more. |
| Incidence of Pre-delivery Oxytocin During the First Hospital Admission | At least 30 minutes after study drug removal | Percentage of participants in receipt of Oxytocin for induction after study drug removal. |
| Incidence of Any Delivery Within 24 Hours | Interval from study drug administration to delivery of neonate within 24 hours | — |
| Incidence of Vaginal Delivery Within 12 Hours | Interval from study drug administration to vaginal delivery within 12 hours | — |
| Incidence of Vaginal Delivery Within 24 Hours | Interval from study drug administration to vaginal delivery within 24 hours | — |
| Incidence of Vaginal Delivery | Interval from study drug administration to vaginal delivery (average 24 hours) | — |
| Rate of Adverse Events | From study drug administration to hospital discharge (approximately 48-72 hours) | All adverse events were rated by the Investigator as mild, moderate or severe and classified as having no relationship, possible relationship or a probable relationship to the study drug. |
| Incidence of Any Delivery Within 12 Hours | Interval from study drug administration to delivery of neonate within 12 hours | — |
| Time to Any Delivery (Vaginal or Cesarean) During the First Hospital Admission | Interval from study drug administration to neonate delivery (average 24 hours) | — |
Countries
United States
Participant flow
Recruitment details
Pregnant women who required to be induced were recruited at 35 sites in the US.
Participants by arm
| Arm | Count |
|---|---|
| MVI 200 MVI 200 mcg vaginal insert
MVI 200: Dose reservoir of 200 mcg of misoprostol in a hydrogel polymer vaginal insert within a retrieval system. The MVI 200 will be kept in place for up to 24 hours or will be removed earlier if one of the following occur: onset of active labor, intrapartum adverse event necessitating discontinuation of the study drug, other reasons including maternal request. | 678 |
| Dinoprostone Vaginal Insert (DVI) 10 mg Dinoprostone vaginal insert
Dinoprostone vaginal insert: Dose reservoir of 10 mg of dinoprostone in a hydrogel polymer vaginal insert within a retrieval system. The DVI will be kept in place for up to 24 hours or will be removed earlier if one of the following occur: onset of active labor, intrapartum adverse event necessitating discontinuation of the study drug, other reasons including maternal request. | 680 |
| Total | 1,358 |
Baseline characteristics
| Characteristic | Dinoprostone Vaginal Insert (DVI) | MVI 200 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 680 Participants | 678 Participants | 1358 Participants |
| Age, Continuous | 25.9 years STANDARD_DEVIATION 5.95 | 26.2 years STANDARD_DEVIATION 5.99 | 26.0 years STANDARD_DEVIATION 5.96 |
| Region of Enrollment United States | 680 participants | 678 participants | 1358 participants |
| Sex: Female, Male Female | 680 Participants | 678 Participants | 1358 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 520 / 678 | 533 / 680 |
| serious Total, serious adverse events | 130 / 678 | 107 / 680 |
Outcome results
Primary
Incidence of Cesarean Delivery During the First Hospital Admission
Time frame: Interval from study drug administration to cesarean delivery (average 24 hours)
Population: Analysis was based on a between-treatment-group difference in the safety population. Subjects discharged prior to delivery, withdrew early without having a cesarean delivery or were lost-to-follow up were classified as not having the event.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Cesarean Delivery During the First Hospital Admission | 25.96 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Cesarean Delivery During the First Hospital Admission | 27.06 percentage of participants |
Comparison: The analysis of the cesarean delivery rates during the first hospitalization was based on a between-treatment-group difference. If the upper limit of the asymptotic two-sided 95% confidence interval of the difference in event rates (MVI minus DVI) was less than the calculated non-inferiority margin (10% relative to the DVI rate, i.e., 0.1 times DVI rate), then MVI 200 would be considered non-inferior to DVI.95% CI: [-5.79, 3.59]Chi-squared
Primary
Time to Vaginal Delivery During the First Hospital Admission
Time frame: Interval from study drug administration to vaginal delivery (average 24 hours)
Population: Subjects who underwent a cesarean delivery during the first hospitalization were censored using the longest time interval from study drug administration to cesarean delivery, independent of treatment assignment. Subjects who were discharged prior to delivery or withdrew consent prior to delivery were also censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MVI 200 | Time to Vaginal Delivery During the First Hospital Admission | 1292.00 minutes |
| Dinoprostone Vaginal Insert (DVI) | Time to Vaginal Delivery During the First Hospital Admission | 1968.50 minutes |
Comparison: Subjects who underwent a cesarean delivery during the first hospitalization were censored using the longest time interval from study drug administration to cesarean delivery during the first hospitalization, independent of treatment group. Subjects who, in their first hospitalization, were discharged prior to delivery or withdrew consent prior to delivery were censored using the longest time interval from study drug administration to labor and delivery discharge, independent of treatment group.p-value: <0.001Log Rank
Secondary
Incidence of Any Delivery Within 12 Hours
Time frame: Interval from study drug administration to delivery of neonate within 12 hours
Population: Intention-to-Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Any Delivery Within 12 Hours | 23.16 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Any Delivery Within 12 Hours | 9.26 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Incidence of Any Delivery Within 24 Hours
Time frame: Interval from study drug administration to delivery of neonate within 24 hours
Population: Intention-to-Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Any Delivery Within 24 Hours | 67.70 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Any Delivery Within 24 Hours | 40.74 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Incidence of Pre-delivery Oxytocin During the First Hospital Admission
Percentage of participants in receipt of Oxytocin for induction after study drug removal.
Time frame: At least 30 minutes after study drug removal
Population: Analysis population includes subjects who delivered during the first hospitalization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Pre-delivery Oxytocin During the First Hospital Admission | 48.1 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Pre-delivery Oxytocin During the First Hospital Admission | 74.1 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Incidence of Vaginal Delivery
Time frame: Interval from study drug administration to vaginal delivery (average 24 hours)
Population: The Intention-to-Treat (ITT) population was used for all secondary efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Vaginal Delivery | 73.30 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Vaginal Delivery | 71.62 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Incidence of Vaginal Delivery Within 12 Hours
Time frame: Interval from study drug administration to vaginal delivery within 12 hours
Population: Intention-to-Treat (ITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Vaginal Delivery Within 12 Hours | 19.76 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Vaginal Delivery Within 12 Hours | 8.38 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Incidence of Vaginal Delivery Within 24 Hours
Time frame: Interval from study drug administration to vaginal delivery within 24 hours
Population: Intention-to-Treat (ITT) Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 200 | Incidence of Vaginal Delivery Within 24 Hours | 54.57 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Incidence of Vaginal Delivery Within 24 Hours | 33.97 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Rate of Adverse Events
All adverse events were rated by the Investigator as mild, moderate or severe and classified as having no relationship, possible relationship or a probable relationship to the study drug.
Time frame: From study drug administration to hospital discharge (approximately 48-72 hours)
Population: The percentage of subjects with adverse events are presented for the Intrapartum (before delivery), postpartum (maternal) and neonatal periods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVI 200 | Rate of Adverse Events | Subjects with Neonatal Adverse Events | 53.4 percentage of participants |
| MVI 200 | Rate of Adverse Events | Subjects with an Intrapartum Adverse Events | 55.5 percentage of participants |
| MVI 200 | Rate of Adverse Events | Subjects with Maternal Postpartum Adverse Events | 21.4 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Rate of Adverse Events | Subjects with Neonatal Adverse Events | 58.1 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Rate of Adverse Events | Subjects with Maternal Postpartum Adverse Events | 21.2 percentage of participants |
| Dinoprostone Vaginal Insert (DVI) | Rate of Adverse Events | Subjects with an Intrapartum Adverse Events | 54.6 percentage of participants |
Secondary
Time to Active Labor During the First Hospital Admission
Active labor was defined as progressive cervical dilatation to 4 cm with any frequency of contractions OR rhythmic, firm, adequate quality uterine contractions causing progressive cervical change occurring at a frequency of 3 or more in 10 minutes and lasting 45 seconds or more.
Time frame: Interval from study drug administration to active labor (average 12 hours)
Population: Intention-to-Treat (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MVI 200 | Time to Active Labor During the First Hospital Admission | 726.50 minutes |
| Dinoprostone Vaginal Insert (DVI) | Time to Active Labor During the First Hospital Admission | 1116.50 minutes |
Comparison: Subjects who never went into active labor during the first hospitalization were censored using the longest time interval from study drug administration to delivery during the first hospitalization, independent of treatment group. Subjects who, in their first hospitalization, were discharged prior to delivery or withdrew consent prior to delivery were censored using the longest time interval from study drug administration to labor and delivery discharge, independent of treatment group.p-value: <0.001Log Rank
Secondary
Time to Any Delivery (Vaginal or Cesarean) During the First Hospital Admission
Time frame: Interval from study drug administration to neonate delivery (average 24 hours)
Population: Subjects who did not deliver during the first hospitalization were censored at the time of labour and delivery discharge.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MVI 200 | Time to Any Delivery (Vaginal or Cesarean) During the First Hospital Admission | 1096.50 minutes |
| Dinoprostone Vaginal Insert (DVI) | Time to Any Delivery (Vaginal or Cesarean) During the First Hospital Admission | 1639.50 minutes |
Comparison: Subjects who did not deliver during the first hospitalization were censored using the longest time interval from study drug administration to labor and delivery discharge without delivery, independent of treatment group.p-value: <0.001Log Rank