Clinical trial NCT03111316
Conditions: Cervical Ripening Induction of Labor
Keywords: Cervical Ripening Induction of Labor
Sponsor: University of Oklahoma
Start date: 2017-04-09; Completion date: 2020-07-24
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In term women presenting for labor induction, combined use of the controlled release dinoprostone vaginal insert and Foley catheter for cervical ripening will decrease the median time from induction to vaginal delivery by at least four hours compared to the Foley catheter alone.

Detailed description:
Those who provide informed consent will be allocated by an online randomization system either to placement of a transcervical Foley catheter and an intravaginal dinoprostone controlled release insert or a Foley catheter alone. Randomization will be stratified by parity (nulliparous or parous).

In both study groups, the balloon on the end of the Foley catheter will be inflated with 30 mL of sterile water, pulled back against the internal os of the cervix, and taped to the maternal thigh under minimal tension. Also in both groups, the Foley catheter will be removed if any of the following occurs: 1) expulsion, 2) fetal heart rate tracing mandating evaluation for membrane rupture and placement of internal monitors, 3) spontaneous membrane rupture, or 4) if 12 hours has elapsed since placement. The dinoprostone insert will be removed if: 1) the fetal heart rate tracing mandates evaluation for membrane rupture and placement of internal monitors, 2) tachysystole develops (more than 5 contractions per 10 minutes averaged over 30 minutes, 3) spontaneous membrane rupture, or 4) 12 hours has elapsed since placement. Though these are the criteria for insert removal, in keeping with the pragmatic design of this trial, the decision regarding removal will be left to the discretion of the attending physician.

Women will remain recumbent for 30 minutes after agent placement and, except for trips to the restroom, will undergo continuous monitoring of uterine contractions and fetal heart rate. Oxytocin, according to standard intravenous protocol, will be allowed only after removal of cervical ripening agent(s). After specified cervical ripening, labor management will be at the discretion of the attending obstetrician, in keeping with the pragmatic nature of the study design.

Antibiotics will be administered if indicated for prophylaxis against early-onset neonatal infection with group B streptococci or for treatment of chorioamnionitis. Cesarean delivery will be performed, per the discretion of the attending obstetrician, for standard maternal or fetal indications.

Medical records will be reviewed no less than 30 days after delivery. Demographic, intrapartum, and outcome data will be entered into a computerized database.

Arms: arm 1: transcervical Foley catheter and an intravaginal dinoprostone controlled release insert arm 2: a Foley catheter alone
Interventions: intervention 1: Cervidil 10 MG Vaginal Insert intervention 2: Foley Catheter
Intervention descriptions: intervention 1: Dinoprostone vaginal insert is a thin, flat, polymeric slab which is rectangular in shape with rounded corners contained within the pouch of an off-white knitted polyester retrieval system, an integral part of which is a long tape. Each slab is buff colored, semitransparent and contains 10 mg of dinoprostone in a hydrogel insert. An integral part of the knitted polyester retrieval system is a long tape designed to aid retrieval at the end of the dosing interval or earlier if clinically indicated. The finished product is a controlled release formulation which has been found to release dinoprostone in vivo at a rate of approximately 0.3 mg/hr. intervention 2: The balloon on the end of the Foley catheter will be inflated with 30 mL of sterile water, pulled back against the internal os of the cervix, and taped to the maternal thigh under minimal tension.

Protocol documents:
Prot_SAP_000.pdf: 
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Combined Use of the Controlled Release Dinoprostone Insert and Foley Catheter 
Compared to the Foley Catheter Alone for Cervical Ripening and Labor Induction 
in Term Women: A Randomized Controlled Trial
Investigator Initiated Trial in Women’s Health
Tracking Number IIt-2016-100752
Rodney K. Edwards, MD, MS
Professor and Section Chief, Maternal-Fetal Medicine
Chair of Perinatal Research
Director, MFM Fellowship Program
Department of Obstetrics and Gynecology
University of Oklahoma College of Medicine
Oklahoma City, OK, USA
Study Coordinator
Christy Zornes 
Christy-Zornes@ouhsc.edu 
Request Date July 26, 2016
IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017


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Background/Rationale
About 25% of pregnant women in the United States undergo labor induction (1). The rate has 
more than doubled in recent years, having been less than 10% in 1990 (2). Cervical ripening 
agents are used to start labor inductions in the setting of an unfavorable cervix. The reason for 
this fact is that administration of oxytocin is less successful in achieving vaginal delivery in the 
setting of an unfavorable cervix (3). 
Options for cervical ripening include mechanical agents, such as Foley catheter, and 
pharmacologic methods, primarily synthetic prostaglandins. In a recent systematic review and 
meta-analysis, it was concluded that the controlled release dinoprostone insert was superior to 
repeated prostaglandin administration (either dinoprostone or misoprostol) due to a lower 
cesarean delivery rate and less oxytocin use (4). 
The author of this application led a multicenter randomized controlled trial of Foley compared to 
the dinoprostone insert that demonstrated that, compared to the dinoprostone insert, starting 
labor inductions for women with unfavorable cervices with the Foley catheter leads to shorter 
times to delivery (median 21.6 vs. 26.6 hours; p=0.003) (5). Our findings differ from those of 
other authors (6,7), but those studies were underpowered and were conducted in populations 
that were thin, overwhelmingly Caucasian, and where a minority received epidural analgesia. 
Our findings are more generalizable to obstetric populations in the United States. 
There is a precedent for using multiple agents for cervical ripening. Misoprostol and Foley 
combined have been shown to result in shorter times to delivery than Foley alone (8). However, 
not all authors have found a decreased time to delivery with this combination and have seen 
more uterine tachysystole with the addition of misoprostol (9). This unwanted effect with 
misoprostol is what causes many to favor agents besides misoprostol, despite that drug’s low 
cost. The combination of the dinoprostone insert and Foley catheter for cervical ripening and 
labor induction has not been studied (Pubmed and clinicaltrials.gov searches using the terms 
“dinoprostone” AND “Foley” on July 23, 2016). 
Here, we propose a pilot randomized trial to estimate the parameters necessary to accomplish 
the power calculation for a multicenter randomized controlled trial to compare the combined use 
of the dinoprostone vaginal insert and Foley catheter with Foley catheter alone for cervical 
ripening and labor induction in term pregnant women. In both this pilot study and the larger 
multicenter trial to follow, both efficacy and safety outcomes will be evaluated.
Hypothesis
In term women presenting for labor induction, combined use of the controlled release 
dinoprostone vaginal insert and Foley catheter for cervical ripening will decrease the median 
time from induction to vaginal delivery by at least four hours compared to the Foley catheter 
alone.
Objectives/Specific Aims
1. To estimate the median times from placement of ripening agents to vaginal delivery in 
both of the following groups: 
IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017


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a. Dinoprostone vaginal insert and Foley catheter 
b. Foley catheter alone 
2. To evaluate the safety of the above combination by estimating in the above groups, 
stratified by parity (nulliparous or parous): 
a. Cesarean delivery rates 
b. Uterine tachysystole rates 
c. Puerperal infection rates 
d. Oxytocin use rates 
e. Neonatal ICU admission rates
Study Design Methodology
This is an open-label trial. The study will be approved by the local IRB. Women meeting 
enrollment criteria will be approached for enrollment. Those who provide informed consent will 
be allocated by an online randomization system either to placement of a transcervical Foley 
catheter and an intravaginal dinoprostone controlled release insert or a Foley catheter alone. 
Randomization will be stratified by parity (nulliparous or parous).
In both study groups, the balloon on the end of the Foley catheter will be inflated with 30 mL of 
sterile water, pulled back against the internal os of the cervix, and taped to the maternal thigh 
under minimal tension. Also in both groups, the Foley catheter will be removed if any of the 
following occurs: 1) expulsion, 2) fetal heart rate tracing mandating evaluation for membrane 
rupture and placement of internal monitors, 3) spontaneous membrane rupture, or 4) if 12 hours 
has elapsed since placement. The dinoprostone insert will be removed if: 1) the fetal heart rate 
tracing mandates evaluation for membrane rupture and placement of internal monitors, 2) 
tachysystole develops (more than 5 contractions per 10 minutes averaged over 30 minutes, 3) 
spontaneous membrane rupture, or 4) 12 hours has elapsed since placement. Though these 
are the criteria for insert removal, in keeping with the pragmatic design of this trial, the decision 
regarding removal will be left to the discretion of the attending physician. 
Women will remain recumbent for 30 minutes after agent placement and, except for trips to the 
restroom, will undergo continuous monitoring of uterine contractions and fetal heart rate. 
Oxytocin, according to standard intravenous protocol, will be allowed only after removal of 
cervical ripening agent(s). After specified cervical ripening, labor management will be at the 
discretion of the attending obstetrician, in keeping with the pragmatic nature of the study design. 
Antibiotics will be administered if indicated for prophylaxis against early-onset neonatal infection 
with group B streptococci or for treatment of chorioamnionitis. Cesarean delivery will be 
performed, per the discretion of the attending obstetrician, for standard maternal or fetal 
indications. 
Medical records will be reviewed no less than 30 days after delivery. Demographic, intrapartum, 
and outcome data will be entered into a computerized database.
IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017


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Primary Endpoint
Median time from placement of transcervical Foley catheter to vaginal delivery
Secondary Endpoints
1. Proportion of patients delivered by 12 hours 
2. Proportion of patients delivered by 24 hours 
3. Proportion of patients delivered vaginally by 12 hours 
4. Proportion of patients delivered vaginally by 24 hours 
5. Chorioamnionitis (defined as a temperature of 38C or higher and one or more of the 
following: maternal heart rate over 100, baseline fetal heart rate over 160, uterine 
tenderness, and/or purulent or foul-smelling cervical discharge) 
6. Endometritis (defined as a postpartum temperature of 38C or higher on 2 or more 
occasions and no other source of fever apparent) 
7. Wound infection (defined as a cesarean wound disruption and treatment with 
antibiotics for that indication); specifically excludes antibiotic treatment for “wound 
cellulitis” not associated with spontaneous or iatrogenic wound disruption
8. Puerperal infection (5, 6, or 7 above) 
9. Cesarean delivery rate 
10. Uterine tachysystole (defined as more than 5 contractions per 10 minutes, averaged 
over 30 minutes) 
11. Neonatal information at delivery and discharge status (birth weight, Apgar scores, 
cord pH, NICU admission, other complications, neonatal death)
Sample Size
N=100
Inclusion Criteria
1. Cervix ≤2 cm dilated; if 2 cm, <80% effaced 
2. Gestational age 37 weeks or more 
3. Singleton gestation 
4. Cephalic presentation 
5. Live fetus
Exclusion Criteria
1. Contractions more frequent than every 5 minutes 
2. Premature rupture of membranes 
3. Prior uterine incision 
4. Temperature 38C or higher 
5. Fetal anomalies 
6. Placenta previa 
7. Suspected abruption or undiagnosed bleeding more than spotting 
8. Fetal heart rate tracing prior to enrollment with no more than minimal variability, late 
decelerations, or more than two variable decelerations 
IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017


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9. HIV infection 
10. Allergy to Prostaglandins
11. Clinical suspicion or definite evidence of fetal distress
12. Unexplained vaginal bleeding during this pregnancy
13. Evidence or strong suspicion of marker cephalopelvic disproportion
14. Oxytocic drugs are contraindicated 
15. Already receiving intravenous oxytocic drugs
16. Multipara with 6 or more previous term pregnancies
Statistical Plan
This proposal is for a pilot study to estimate the parameters that will be used to inform the power 
calculation for a next-step multicenter randomized controlled trial. We will randomize, in a 1:1 
ratio, stratifying 1:1 nulliparous and parous patients, 100 total patients to receive either: 
1. Both the dinoprostone controlled release insert and a transcervical Foley catheter, or 
2. Foley catheter alone 
Patient characteristics and outcomes will be compared between the two study groups using two-
sample t-tests for continuous measures and chi-square tests of association for categorical 
measures. Since time to delivery is known to not be a normally distributed outcome, we will 
estimate that parameter with medians and its variance with interquartile ranges. 
Since this is a pilot study, we will estimate the outcomes to be evaluated in the planned next-
step multicenter trial. Not surprisingly, the proposed sample size for this pilot study has less 
than 50% power to detect a 4-hour difference between groups. The rationale for stratifying a 1:1 
ratio of nulliparous:parous patients is that doing so will maximize the precision with which the 
endpoints are estimated when stratified by parity. 
Planned Publications
Results will be submitted for presentation at a national meeting, probably SMFM. Also, will 
submit results for publication as a full-length original article--probably Obstetrics&Gynecology.
Gender/Minority/Pediatric Inclusion for Research
Since only women become pregnant and undergo labor induction, all subjects in this study will 
be pregnant woman and fetus/infant dyads. The inclusion of minorities is anticipated in keeping 
with the racial/ethnic distribution of our obstetric population. Therefore, we anticipate including 
about 15% African-Americans, 45% Caucasians, 29% Hispanics, and 11% of other ethnicities.
Human Participants
We will enroll women age 18-50 who meet the above enrollment criteria. No specimens will be 
collected. Clinical data will be recorded at the time of enrollment. Clinical data also will be 
abstracted later from the medical record. A data collection form is attached.
Women with scheduled labor inductions will be screened by study personnel for eligibility. If 
IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017


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potentially eligible and the plan from the medical team is to begin the labor induction with 
cervical ripening using a Foley catheter, women will be approached about participation when the 
present for their scheduled induction. Since these women will not be in labor and it will be 
emphasized that participation is not required, coercion should not be an issue. Those women 
agreeing to participate will be consented by trained study personnel in their preferred language. 
We will have both English and Spanish consent forms. Those women who agree to participate 
will have a transcervical Foley catheter placed according to standard clinical practice. Once the 
Foley is placed, they will be randomized to either also have a Cervidil placed in the posterior 
vaginal fornix (according to package insert instructions) or not. 
Because we will have consent forms in both English and Spanish, and since our patient 
population is 29% Hispanic, we anticipate enrolling non-English speaking participants. In 
addition to the Spanish consent form, hospital translation services will be utilized.
Since both Foley catheter and Cervidil are within the standard of care for starting labor 
inductions in the setting of an unfavorable cervix, risks associated with the study are anticipated 
to be no greater than the risks associated with pregnancy, labor induction and delivery. These 
include discomfort; abnormal labor progress, fetal heart rate tracing abnormalities, or other 
considerations leading to cesarean delivery; and postpartum complications such as hemorrhage 
or infection. Likelihood and seriousness should be no greater than similar patients not in the 
study who are undergoing labor induction.
To protect the privacy and confidentiality of research subjects, we will assign each participant a 
study ID number. This ID number will be linked to the patient’s name and medical record 
number only via a key that will be maintained in a locked file drawer in the research 
coordinator’s locked office. Once data collection is complete, the key will be destroyed, and the 
de-identified will not be able to be linked to participants.
The only potential benefit to subjects would be an increased likelihood of vaginal delivery or a 
shorter duration of labor induction if one of the treatment groups is superior. However, since this 
is a pilot study aimed at estimating the parameters needed for a next-step clinical trial, we do 
not anticipate a statistically significant difference in those outcomes in this study. The study, and 
participants’ inclusion is important, since obtaining the data needed to conduct the next-step 
study will get us closer to optimizing labor inductions for future patients. Despite lack of a high 
likelihood of direct benefit, subject inclusion is reasonable since the risks are essentially the 
same as a labor induction if not included in the study.
Data and Safety Monitoring Plan
All adverse events will be reviewed by the PI and co-investigators and reported to the IRB 
according to institutional guidelines. All research data will be stored on a password-protected 
computer in the administrative offices of the Section of Maternal-Fetal Medicine. Any paper 
records and CRFs will be stored in a locked file drawer in the locked office of the research 
coordinator that is also located in the administrative offices of the Section of Maternal-Fetal 
Medicine. Since this study is a pilot including only 100 participants, we are no assembling a data 
and safety monitoring board.  
IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017


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IRB NUMBER: 7491
IRB APPROVAL DATE: 07/21/2017