Cervical Ripening, Induction of Labor
Conditions
Keywords
Misoprostol vaginal insert, Induction of labor, Cervical ripening, Rate of cesarean section
Brief summary
The purpose of this study is to assess the efficacy and safety of the 100, 150 and 200 mcg Misoprostol Vaginal Insert (MVI 100, MVI 150 and MVI 200) for women requiring cervical ripening and induction of labor.
Interventions
DRUGMVI 100
Dose reservoir of 100 mcg of misoprostol in a hydrogel polymer vaginal insert within a retrieval system. The MVI 100 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.
DRUGMVI 150
Dose reservoir of 150 mcg of misoprostol in a hydrogel polymer vaginal insert within a retrieval system. The MVI 150 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.
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.
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 pharmacologic 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
* Nulliparous women participating in the pharmacokinetic (PK) arm of the study: women with hemoglobin level \< 11.0 grams per deciliter (g/dL) (confirmed within one week of study drug insertion); * 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 fetal abnormalities; * Any evidence of fetal compromise at baseline (e.g., non-reassuring fetal heart rate pattern or meconium staining); * 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, other prostaglandins or any of the excipients; * Any condition urgently requiring delivery; * Unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of Women Delivering Vaginally | Interval from study drug administration to 24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. These assessments were deemed as accurate and appropriate for the reporting of all serious and non serious adverse events. |
| Proportion of Cesarean Delivery | Interval from study drug administration to cesarean delivery (average 24 hours) | — |
| Cervical Ripening Using Composite Measure of Success | 12 hours after insertion of drug | Cervical ripening success was defined by achievement of one or more of the following by 12 hours after study drug administration: * Increase from baseline in modified Bishop score ≥3; or * Achievement of modified Bishop score of ≥6; or * Vaginal delivery. |
| Time to Vaginal Delivery | Interval from study drug administration to delivery (average 24 hours) | — |
| Time of Maximum Plasma Concentration (Tmax), Maximum Plasma Concentration (Cmax), Area Under the Curve (AUC) and Terminal Half Life of Misoprostol Acid. | From study drug insertion up to 2 hours post study drug removal | The timepoints over which the pharmacokinetic measurements were assessed, and deemed as accurate and appropriate, were as follows: 0 hours (baseline), 2, 4, 6, 8, 10 and 14 hours after insertion of the study drug, immediately prior to removal of the study drug and 0.5, 1 and 2 hours after removal of the study drug. |
| Time to Onset of Active Labor | Interval from study drug administration to active labor (average 12 hours) | — |
| Use of Oxytocin | At least 30 minutes after study drug removal | Percentage of participants in receipt of Oxytocin for induction after study drug removal is accurate and appropriate for this outcome measure. |
Countries
United States
Participant flow
Recruitment details
Pregnant women who required to be induced were recruited at 11 sites in the US
Participants by arm
| Arm | Count |
|---|---|
| MVI 100 MVI 100 mcg vaginal insert
Dose reservoir of 100 mcg of misoprostol in a hydrogel polymer vaginal insert within a retrieval system. The MVI 100 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. | 117 |
| MVI 150 MVI 150 mcg vaginal insert
Dose reservoir of 150 mcg of misoprostol in a hydrogel polymer vaginal insert within a retrieval system. The MVI 150 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. | 125 |
| MVI 200 MVI 200 mcg vaginal insert
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. | 131 |
| Total | 373 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | MVI 150 | MVI 200 | MVI 100 | 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 | 125 Participants | 131 Participants | 117 Participants | 373 Participants |
| Age, Continuous | 25.8 years STANDARD_DEVIATION 5.92 | 25.5 years STANDARD_DEVIATION 5.93 | 26.0 years STANDARD_DEVIATION 6.24 | 25.8 years STANDARD_DEVIATION 6.01 |
| Region of Enrollment United States | 125 participants | 131 participants | 117 participants | 373 participants |
| Sex: Female, Male Female | 125 Participants | 131 Participants | 117 Participants | 373 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 | 100 / 118 | 107 / 125 | 117 / 131 |
| serious Total, serious adverse events | 43 / 118 | 48 / 125 | 42 / 131 |
Outcome results
Primary
Proportion of Women Delivering Vaginally
Time frame: Interval from study drug administration to 24 hours
Population: Analysis based on Modified Intention-to-Treat (MITT) population who delivered vaginally. Percentage of subjects who delivered vaginally is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 100 | Proportion of Women Delivering Vaginally | 63.75 percentage of participants |
| MVI 150 | Proportion of Women Delivering Vaginally | 66.67 percentage of participants |
| MVI 200 | Proportion of Women Delivering Vaginally | 76.00 percentage of participants |
Comparison: The primary objective of this study is to compare the efficacy of MVI 100 and MVI 200 based on the proportion of vaginal deliveries within 24 hours. A minimum sample size of approximately 120 subjects per arm would provide 84 subjects per arm with vaginal delivery, which would ensure \>80% power (with two-sided alpha of 5%) to detect a 20% improvement in the proportion of women delivering vaginally within 24 hoursp-value: 0.057Cochran-Mantel-Haenszel
Secondary
Cervical Ripening Using Composite Measure of Success
Cervical ripening success was defined by achievement of one or more of the following by 12 hours after study drug administration: * Increase from baseline in modified Bishop score ≥3; or * Achievement of modified Bishop score of ≥6; or * Vaginal delivery.
Time frame: 12 hours after insertion of drug
Population: Percentage of subjects with cervical ripening success at 12 hours is presented (Modified Intention-to-Treat population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 100 | Cervical Ripening Using Composite Measure of Success | 77.78 percentage of participants |
| MVI 150 | Cervical Ripening Using Composite Measure of Success | 77.60 percentage of participants |
| MVI 200 | Cervical Ripening Using Composite Measure of Success | 80.15 percentage of participants |
p-value: 0.65Cochran-Mantel-Haenszel
Secondary
Proportion of Cesarean Delivery
Time frame: Interval from study drug administration to cesarean delivery (average 24 hours)
Population: Percentage of subjects who had a cesarean delivery during the first hospitalization (safety population) is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 100 | Proportion of Cesarean Delivery | 31.36 percentage of participants |
| MVI 150 | Proportion of Cesarean Delivery | 30.40 percentage of participants |
| MVI 200 | Proportion of Cesarean Delivery | 22.90 percentage of participants |
p-value: 0.153Fisher 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. These assessments were deemed as accurate and appropriate for the reporting of all serious and non serious adverse events.
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 100 | Rate of Adverse Events | Subjects with Maternal Postpartum Adverse Events | 28.0 percentage of participants |
| MVI 100 | Rate of Adverse Events | Subjects with Neonatal Adverse Events | 39.8 percentage of participants |
| MVI 100 | Rate of Adverse Events | Subjects with Intrapartum Adverse Events | 81.4 percentage of participants |
| MVI 150 | Rate of Adverse Events | Subjects with Intrapartum Adverse Events | 80.0 percentage of participants |
| MVI 150 | Rate of Adverse Events | Subjects with Maternal Postpartum Adverse Events | 27.2 percentage of participants |
| MVI 150 | Rate of Adverse Events | Subjects with Neonatal Adverse Events | 42.4 percentage of participants |
| MVI 200 | Rate of Adverse Events | Subjects with Neonatal Adverse Events | 48.9 percentage of participants |
| MVI 200 | Rate of Adverse Events | Subjects with Maternal Postpartum Adverse Events | 32.1 percentage of participants |
| MVI 200 | Rate of Adverse Events | Subjects with Intrapartum Adverse Events | 79.4 percentage of participants |
Secondary
Time of Maximum Plasma Concentration (Tmax), Maximum Plasma Concentration (Cmax), Area Under the Curve (AUC) and Terminal Half Life of Misoprostol Acid.
The timepoints over which the pharmacokinetic measurements were assessed, and deemed as accurate and appropriate, were as follows: 0 hours (baseline), 2, 4, 6, 8, 10 and 14 hours after insertion of the study drug, immediately prior to removal of the study drug and 0.5, 1 and 2 hours after removal of the study drug.
Time frame: From study drug insertion up to 2 hours post study drug removal
Population: The plan was to enrol 24 subjects to the pharmacokinetic (PK) arm of the study. Only 3 subjects enrolled in the PK arm; there were too few subjects and too few samples available. Due to insufficient data, no statistical analysis was possible. Only misoprostol acid levels for each blood sampling timepoint for each subject was determined.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 100 | Time of Maximum Plasma Concentration (Tmax), Maximum Plasma Concentration (Cmax), Area Under the Curve (AUC) and Terminal Half Life of Misoprostol Acid. | NA PK Parameters |
| MVI 150 | Time of Maximum Plasma Concentration (Tmax), Maximum Plasma Concentration (Cmax), Area Under the Curve (AUC) and Terminal Half Life of Misoprostol Acid. | NA PK Parameters |
Secondary
Time to Onset of Active Labor
Time frame: Interval from study drug administration to active labor (average 12 hours)
Population: Kaplan-Meier Estimates for Time to Onset of Active Labor presented (Modified Intention-to-Treat population). Subjects who never went into active labor during the first hospitalization were censored using the longest time interval from study drug administration to delivery (Censored subjects = MVI 100: 5; MVI 150: 7; MVI 200: 8)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MVI 100 | Time to Onset of Active Labor | 1069.00 minutes |
| MVI 150 | Time to Onset of Active Labor | 775.00 minutes |
| MVI 200 | Time to Onset of Active Labor | 701.00 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 withdraw consent prior to delivery will be censored using the longest time interval from study drug administration to labor and delivery discharge, independent of treatment group.p-value: 0.007Log Rank
Secondary
Time to Vaginal Delivery
Time frame: Interval from study drug administration to delivery (average 24 hours)
Population: Kaplan-Meier Estimates are based on Modified Intention-to-Treat (MITT) population.Subjects who had a cesarean, discharged prior to delivery or withdrew consent during first hospitalization were censored (MVI 100: 37, MVI 150: 39, MVI 200: 31) using the longest time interval from study drug administration to cesarean or to Labor \& Delivery discharge
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MVI 100 | Time to Vaginal Delivery | 1744 minutes |
| MVI 150 | Time to Vaginal Delivery | 1535 minutes |
| MVI 200 | Time to Vaginal Delivery | 1181 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: 0.018Log Rank
Secondary
Use of Oxytocin
Percentage of participants in receipt of Oxytocin for induction after study drug removal is accurate and appropriate for this outcome measure.
Time frame: At least 30 minutes after study drug removal
Population: Percentage of subjects who required pre-delivery oxytocin is presented (Modified Intention-to-Treat population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVI 100 | Use of Oxytocin | 70.94 percentage of participants |
| MVI 150 | Use of Oxytocin | 60.00 percentage of participants |
| MVI 200 | Use of Oxytocin | 48.85 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel