Induced; Birth, Labor Onset and Length Abnormalities
Conditions
Keywords
Misoprostol, Dilapan, Induction of labor, Aquacryl hydrogel
Brief summary
The purpose of this study is to find out if Dilapan works as well as Misoprostol for preparing the mouth of the uterus (cervix) for inducing labor in women who need to undergo this procedure. The primary objective is to assess the efficacy of Dilapan for cervical ripening compared to Misoprostol in women undergoing Induction of labor (IOL) at or more than 37 weeks gestation.
Detailed description
In developed nations 25 % of pregnant women undergo labor induction for various indications. Likelihood of vaginal delivery depends on the degree of ripeness of cervix. Majority of women undergoing induction of labor are candidates for cervical ripening. Dilapan is an osmotic hygroscopic dilator of cervix commonly used for cervical preparation for mid trimester abortions. It has been proven safe for use for induction of Labor (IOL) at term. Misoprostol is a synthetic prostaglandin E1 analogue, widely used for cervical ripening and IOL in United States and is considered as standard of care. This is a non-inferiority, unblinded randomized, controlled trial where 322 eligible participants undergoing IOL at \>37 weeks gestation and admitted to labor and delivery unit will be enrolled and randomly assigned in a ratio 1:1 to either receive Dilapan or Misoprostol for cervical ripening. After randomization all participants will undergo assessment as per standard of care. Participants will have either 1-5 Dilapan rods inserted into their cervix by the providers or receive 25 mcg of misoprostol orally every 2 hours to a maximum of 6 doses over 12 hours. Participants will be evaluated for artificial rupture of membranes and initiation of oxytocin for inducing uterine contraction. A diagnosis of failed IOL will be made if patient does not go into active labor within 24 hours after initiation of Oxytocin and Artificial Rupture Of Membranes (AROM). Intrapartum management will be according to institutional guidelines. All participants will be followed up and contacted by phone 2 weeks after discharge regarding their experience with the method of induction.
Interventions
DEVICEDilapan
Dilapan-S® is a mechanical method for cervical ripening using rods made of a patented hydrogel Aquacryl, it is marketed in form of rods of 3 and 4 mm diameter. It is FDA approved for cervical ripening.
DRUGMisoprostol
25mcg of Misoprostol will be administered orally every 2 hours (maximum of 6 doses) Misoprostol is a prostaglandin E1 analog approved for treatment and prevention of gastric ulcers. The use of Misoprostol appears to be safe and effective for induction of labor when used in low dose.
Sponsors
Medicem International CR s.r.o.
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Women undergoing labor induction with a gestation of ≥37 weeks (based on a sure last menstrual period and an ultrasound done before 22 0/7 weeks) 2. Live fetus with in cephalic presentation 3. Singleton pregnancy 4. Able to provide informed consent for participation in the study
Exclusion criteria
1. Contraindication for vaginal delivery 2. Age less than 18 years 3. Prior uterine scar from a cesarean section or myomectomy 4. Patients who have HELLP syndrome or eclampsia 5. Active genital herpes at the time of labor induction 6. Complex medical problems that may require assistance with second stage of labor 7. Bishop score ≥ 6 8. Major fetal congenital anomalies (as assessed by investigator) 9. Premature rupture of membranes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in ITT Population | Up to 36 hours after intervention | This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening. Intent-to-treat Population (ITT) includes all patients that were randomized into the study. ITT participants will be analyzed in accordance with their randomized study treatment (i.e. in the treatment group they were originally allocated, regardless of treatment actually received). ITT will be used for evaluation of the baseline characteristics and as the primary population for efficacy assessments. |
| Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in PP Population | Up to 36 hours after intervention | This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Vaginal Delivery Rate | Approximately up to 48 hours | This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening |
| Number of Participants With Cesarean Deliveries | Start of cervical ripening to delivery, up to 36 hours | This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening |
| Total Length of Hospital Stay | Up to 4 days | This is to measure the cost-effectiveness of either Dilapan or Misoprostol for cervical ripening. Length will be measured in number of days from hospital admission until discharge. |
| Percentage of Women Who Developed Chorioamnionitis | From delivery until two weeks after discharge (approximately up to 3 weeks) | This is to measure the safety of either Dilapan or Misoprostol for cervical ripening |
| Change in Bishop Score | Baseline and 12 hours after intervention | The Bishop Score (also known as Pelvic Score) is the most commonly used method to rate the readiness of the cervix for induction of labor. The Bishop Score gives points to 5 measurements of the pelvic examination dilation, effacement of the cervix, station of the fetus, consistency of the cervix, and position of the cervix. It ranges from 0 to 13. Higher score is associated with increased likelihood of vaginal delivery. |
| Percentage of Newborns With Apgar Score <7 at 5 Min | 5 minutes following birth | This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns |
| Percentage of Newborns With Cord Arterial Blood Potential Hydrogen (pH) < 7.1 | From birth until two weeks after birth | This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns |
| Percentage of Newborns With Neonatal Intensive Care Unit (NICU) Admission Within 14 Days After Study Intervention | From birth until two weeks after birth | This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns |
| Percentage of Newborns With Antibiotic Use Within 14 Days After Study Intervention | From birth until two weeks after birth | This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns |
| Percentage of Women Who Developed Postpartum Hemorrhage | From delivery until two weeks after discharge (approximately up to 3 weeks) | This is to measure the safety of either Dilapan or Misoprostol for cervical ripening, postpartum hemorrhage is defined as estimated blood loss (EBL) \> 1000cc and/or drop in Hematocrit (HCT) by 10 points. |
| Percentage of Women Delivering Vaginally in 24 Hours After the Initiation of Intervention | Up to 24 hours after intervention | This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening |
Countries
United States
Participant flow
Recruitment details
A total of 1755 women presenting for Induction of labor to labor and delivery units were screened for eligibility at Columbia University Medical Center and UTMB Texas. 307 were enrolled and randomized, 154 to Dilapan and 153 to Oral Misoprostol group.
Pre-assignment details
A total of 306 participants were needed , 153 in each group, to evaluate the primary outcome with 85% power to confirm the noninferiority with one sided confidence level of 97.5%
Participants by arm
| Arm | Count |
|---|---|
| Dilapan Group Patients who are randomized to receive Dilapan, will have 3-5 rods of Dilapan-S® inserted in their cervix by the supervising provider, under aseptic precautions with a speculum exam, either digitally or using a sponge forceps, as per manufacturer's recommendations. The Bishop score at the time of eligibility assessment and number of rods inserted will be recorded. Dilapan will be left in cervix for 12 hours. Patients will be allowed to ambulate, shower and have light meals as long as they meet the criteria based on institutional guidelines for intermittent fetal heart monitoring. Nothing per vagina including douching and no bathing is allowed.
Dilapan: Dilapan-S® is a mechanical method for cervical ripening using rods made of a patented hydrogel Aquacryl, it is marketed in form of rods of 3 and 4 mm diameter. It is FDA approved for cervical ripening. | 151 |
| Misoprostol Group Patients who are randomized to Misoprostol group, after the baseline assessment and a reassuring cardiotocograms (CTG) monitoring for 20 minutes to a maximum of 6 doses. All subjects will have continuous fetal monitoring. A dose will be held if patient is noted to have uterine tachysystole, hyperstimulation, fetal heart tracing abnormalities or 3 or more painful uterine contractions over a period of 10 minutes (indicating onset of labor). Administration of Misoprostol will be done by the nurse assigned to the patient.
Misoprostol: 25mcg of Misoprostol will be administered orally every 2 hours (maximum of 6 doses)
Misoprostol is a prostaglandin E1 analog approved for treatment and prevention of gastric ulcers. The use of Misoprostol appears to be safe and effective for induction of labor when used in low dose. | 152 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intent-to-treat Population (ITT) | Withdrawal by Subject | 1 | 3 |
| Per Protocol Population (PP) | Incorrect stratification / inability to insert Dilapan | 1 | 1 |
| Per Protocol Population (PP) | Physician Decision | 9 | 10 |
Baseline characteristics
| Characteristic | Misoprostol Group | Dilapan Group | Total |
|---|---|---|---|
| Age, Continuous | 27.7 Years STANDARD_DEVIATION 5.9 | 27.2 Years STANDARD_DEVIATION 5.94 | 27.4 Years STANDARD_DEVIATION 5.9 |
| BMI at randomization | 33.1 kg/m^2 STANDARD_DEVIATION 4.83 | 33.1 kg/m^2 STANDARD_DEVIATION 5.02 | 33.1 kg/m^2 STANDARD_DEVIATION 5.9 |
| Cholestasis | 2 Participants | 1 Participants | 3 Participants |
| Elective induction | 32 Participants | 37 Participants | 69 Participants |
| Fetal growth restriction | 6 Participants | 9 Participants | 15 Participants |
| GBS positive status | 52 Participants | 60 Participants | 112 Participants |
| Gestational age at randomization < 39 weeks Gestational age ≤ 39 weeks | 55 Participants | 57 Participants | 112 Participants |
| Gestational age at randomization < 39 weeks Gestational age > 39 weeks | 97 Participants | 94 Participants | 191 Participants |
| Hypertensive disorders of pregnancy | 20 Participants | 14 Participants | 34 Participants |
| Indication for induction - Diabetes | 7 Participants | 15 Participants | 22 Participants |
| Oligohydramnios | 22 Participants | 14 Participants | 36 Participants |
| Parity at randomization- Nulliparous/ multiparous Multiparous | 71 Participants | 70 Participants | 141 Participants |
| Parity at randomization- Nulliparous/ multiparous Nulliparous | 81 Participants | 81 Participants | 162 Participants |
| Post term pregnancy | 40 Participants | 47 Participants | 87 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 152 Participants | 151 Participants | 303 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 | 0 / 151 | 0 / 152 |
| other Total, other adverse events | 39 / 151 | 81 / 152 |
| serious Total, serious adverse events | 1 / 151 | 3 / 152 |
Outcome results
Primary
Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in ITT Population
This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening. Intent-to-treat Population (ITT) includes all patients that were randomized into the study. ITT participants will be analyzed in accordance with their randomized study treatment (i.e. in the treatment group they were originally allocated, regardless of treatment actually received). ITT will be used for evaluation of the baseline characteristics and as the primary population for efficacy assessments.
Time frame: Up to 36 hours after intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in ITT Population | 93 Participants |
| Misoprostol Group | Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in ITT Population | 90 Participants |
Primary
Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in PP Population
This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening.
Time frame: Up to 36 hours after intervention
Population: The Per Protocol (PP) population is a subset of ITT population. PP population is comprised of participants who completed the treatment originally allocated with complete adherence to the protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in PP Population | 86 Participants |
| Misoprostol Group | Number of Women Achieving Vaginal Delivery Within 36 Hours After Initiation of Cervical Ripening in PP Population | 86 Participants |
Secondary
Change in Bishop Score
The Bishop Score (also known as Pelvic Score) is the most commonly used method to rate the readiness of the cervix for induction of labor. The Bishop Score gives points to 5 measurements of the pelvic examination dilation, effacement of the cervix, station of the fetus, consistency of the cervix, and position of the cervix. It ranges from 0 to 13. Higher score is associated with increased likelihood of vaginal delivery.
Time frame: Baseline and 12 hours after intervention
Population: Intent to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dilapan Group | Change in Bishop Score | 2 score on a scale |
| Misoprostol Group | Change in Bishop Score | 3 score on a scale |
Secondary
Number of Participants With Cesarean Deliveries
This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening
Time frame: Start of cervical ripening to delivery, up to 36 hours
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Number of Participants With Cesarean Deliveries | 41 Participants |
| Misoprostol Group | Number of Participants With Cesarean Deliveries | 42 Participants |
Secondary
Overall Vaginal Delivery Rate
This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening
Time frame: Approximately up to 48 hours
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Overall Vaginal Delivery Rate | 104 Participants |
| Misoprostol Group | Overall Vaginal Delivery Rate | 104 Participants |
Secondary
Percentage of Newborns With Antibiotic Use Within 14 Days After Study Intervention
This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns
Time frame: From birth until two weeks after birth
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Newborns With Antibiotic Use Within 14 Days After Study Intervention | 5 Participants |
| Misoprostol Group | Percentage of Newborns With Antibiotic Use Within 14 Days After Study Intervention | 4 Participants |
Secondary
Percentage of Newborns With Apgar Score <7 at 5 Min
This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns
Time frame: 5 minutes following birth
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Newborns With Apgar Score <7 at 5 Min | 0 Participants |
| Misoprostol Group | Percentage of Newborns With Apgar Score <7 at 5 Min | 1 Participants |
Secondary
Percentage of Newborns With Cord Arterial Blood Potential Hydrogen (pH) < 7.1
This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns
Time frame: From birth until two weeks after birth
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Newborns With Cord Arterial Blood Potential Hydrogen (pH) < 7.1 | 0 Participants |
| Misoprostol Group | Percentage of Newborns With Cord Arterial Blood Potential Hydrogen (pH) < 7.1 | 4 Participants |
Secondary
Percentage of Newborns With Neonatal Intensive Care Unit (NICU) Admission Within 14 Days After Study Intervention
This is to measure the safety of either Dilapan or Misoprostol for cervical ripening by studying the effect on newborns
Time frame: From birth until two weeks after birth
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Newborns With Neonatal Intensive Care Unit (NICU) Admission Within 14 Days After Study Intervention | 9 Participants |
| Misoprostol Group | Percentage of Newborns With Neonatal Intensive Care Unit (NICU) Admission Within 14 Days After Study Intervention | 8 Participants |
Secondary
Percentage of Women Delivering Vaginally in 24 Hours After the Initiation of Intervention
This is to measure the efficacy of either Dilapan or Misoprostol for cervical ripening
Time frame: Up to 24 hours after intervention
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Women Delivering Vaginally in 24 Hours After the Initiation of Intervention | 62 Participants |
| Misoprostol Group | Percentage of Women Delivering Vaginally in 24 Hours After the Initiation of Intervention | 58 Participants |
Secondary
Percentage of Women Who Developed Chorioamnionitis
This is to measure the safety of either Dilapan or Misoprostol for cervical ripening
Time frame: From delivery until two weeks after discharge (approximately up to 3 weeks)
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Women Who Developed Chorioamnionitis | 12 Participants |
| Misoprostol Group | Percentage of Women Who Developed Chorioamnionitis | 10 Participants |
Secondary
Percentage of Women Who Developed Postpartum Hemorrhage
This is to measure the safety of either Dilapan or Misoprostol for cervical ripening, postpartum hemorrhage is defined as estimated blood loss (EBL) \> 1000cc and/or drop in Hematocrit (HCT) by 10 points.
Time frame: From delivery until two weeks after discharge (approximately up to 3 weeks)
Population: Intent to treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dilapan Group | Percentage of Women Who Developed Postpartum Hemorrhage | 1 Participants |
| Misoprostol Group | Percentage of Women Who Developed Postpartum Hemorrhage | 3 Participants |
Secondary
Total Length of Hospital Stay
This is to measure the cost-effectiveness of either Dilapan or Misoprostol for cervical ripening. Length will be measured in number of days from hospital admission until discharge.
Time frame: Up to 4 days
Population: Intent to treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dilapan Group | Total Length of Hospital Stay | 80.5 hours | Standard Deviation 21.8 |
| Misoprostol Group | Total Length of Hospital Stay | 84.0 hours | Standard Deviation 22.6 |