Induction of Labor in Women With Unfavorable Cervix: Randomized Controlled Trial Comparing Outpatient to Inpatient Cervical Ripening Using Dilapan-S® (HOMECARE)
Phase: NA
Conditions: Labor, Induced, Cervix Uteri-Diseases
Sponsor: The University of Texas Medical Branch, Galveston

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Research Protocol IRB # 18-0132 
 
 
 
Title: 
 
Induction of labor in women with unfavorable cervix: randomized controlled trial 
comparing outpatient to inpatient cervical ripening using Dilapan-S® 
(HOMECARE) 
 
 
 
 
Principal Investigator : 
 
Antonio Saad, MD, MFM 
The University of Texas Medical Branch 
301 University Blvd. 
Galveston TX, 77555 
 
Prepared by: 
 
George Saade, MD, MFM 
The University of Texas Medical Branch 
301 University Blvd. 
Galveston TX, 77555 
 
Rachana Gavara, MD  
Columbia University Medical Center  
Lawrence Hospital 
55 Palmer Ave 
Bronxville, NY 10708  
 
 
Sponsored by: 
 
Medicem Technology s.r.o. 
Karlovarska trida 20 
Kamenne Zehrovice, 27301 
Czech Republic 
 
 
 

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1. Introduction and Purpose 
Historically, mechanical methods were the first methods developed to ripen the cervix or to induce 
labor (1). Dilapan-S, a hygroscopic cervical dilator made of a patented hydrogel (AQUACRYL), 
works by absorbing fluid from the cells of the cervical canal, resulting in reversible cell wall 
dehydration and softening. The increase in volume of the rod(s) in turn, leads by mechanical stretch, to 
endogenous PG release with resultant cervical ripening. Dilapan-S is approved by the FDA for 
cervical ripening in the third trimester. Recently a non-inferiority randomized trial at our center 
comparing Dilapan-S to the most commonly used, but not FDA approved, mechanical dilator method 
(Foley balloon) was completed and results show that it is not inferior to the latter 
(https://clinicaltrials.gov/ct2/show/NCT02899689). The usual practice with mechanical ripening 
methods is to insert the mechanical dilator in the hospital and then await cervical ripening, which can 
take up to 12 hours. We believe that allowing the subject to go back home after insertion is a promising 
strategy that lowers in-hospital healthcare costs and improves subject satisfaction. Therefore, we 
propose a randomized controlled trial to compare the efficacy and safety of outpatient versus inpatient 
pre-induction cervical ripening with Dilapan-S in pregnant women greater than 37 weeks. 
 
2. Background 
Labor induction is a common obstetric procedure that is generally undertaken when the risks of 
continuing pregnancy outweigh the benefits (2). To maximize the success of induction of labor in 
women with an unfavorable cervix, various ripening methods are available. These include 
pharmacological agents such as prostaglandins and mechanical agents such as the Foley balloon 
cervical dilator, which has been used in labor delivery units for decades. Mechanical methods of labor 
induction are safe and cost effective. Recently, Dilapan-S was approved by the FDA as another form 
of mechanical dilators. The rates of labor induction continue to increase and a recently completed trial 
which showed that induction at 39 weeks decreases cesarean delivery compared with expectant 
management is expected to lead to even higher rates of induction (2). Currently, cervical ripening in 
the US is performed as inpatient. A few pilot studies and the mechanism of action of mechanical 
dilators support the safety of allowing women to go home after insertion. There have been multiple 
proposals to study outpatient cervical ripening (3-7), but none evaluated the role of Dilapan-S in the 
outpatient setting. Unlike the Foley balloon, Dilapan-S is FDA approved for labor induction and does 
not have any parts that protrude from the vagina, making it the ideal candidate for outpatient cervical 
ripening. However, data are lacking regarding the comparative effectiveness of inpatient versus 
outpatient Dilapan-S in labor induction. Trials are also needed to determine whether outpatient 
cervical ripening actually shortens length of hospital stay compared with inpatient cervical ripening. 
 
3. Concise Summary of Project 
The target population for our study is women who present for induction of labor. If there is a decision 
by the obstetrical team to place a mechanical dilator for cervical ripening, the obstetrical team will 
notify the research staff so that the patient may be screened for the study. If the subject is eligible for 
the trial, written informed consent will be obtained by person-to-person contact. The PI, study 
coordinator, or a collaborator will be responsible for the informed consent procedure. After informed 
consent is obtained and Dilapan-S is placed, the patient will be randomized to the Outpatient or the 
Inpatient group. Those randomized to the outpatient group will be asked to come back within 12 hours 
or sooner if contractions or other conditions arise. 
 

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Our primary objective will be to compare the hospital length of stay in the inpatient setting to the 
outpatient setting. 
Secondary objectives will be to compare other clinical outcomes such as composite maternal and 
neonatal outcomes, vaginal delivery rate within 24 and 36 hours after admission, time to reach active 
stage of labor defined as ≥ 6 cm, change in Bishop score, rates of spontaneous and operative vaginal 
delivery, rate of cesarean delivery, adverse events, healthcare cost impact and subject satisfaction.  
Healthcare cost impact will be assessed based on direct hospital costs or Medicaid charges, using cost 
minimization technique. In cost-minimization analysis, two or more interventions that have been 
assumed or shown to have the same effectiveness are compared for cost and the least expensive one is 
recommended from an economic perspective. The primary analysis will be performed for all those 
randomized including the costs/charges after randomization. A secondary analysis will be performed 
accounting separately for costs/charges before randomization. 
 
Secondary Analysis/ Metanalysis will be performed for all those randomized as individual participant 
data meta-analysis all data from respective randomized controlled trials in the different centers, 
including from UTMB, will be de-identified. All centers will be requested to send the raw data for 
secondary analysis in an individual participant data meta-analysis. Research groups who share data 
will get the opportunity of a co-authorship in relation to the size of their study. 
Data will be shared in a file that is encrypted and deidentified and password protected. 
 
Randomization will be performed using a computer-generated random list of numbers assigning 
subjects to the 2 groups of the study. This list of random number assignments will be kept secure in an 
opaque envelope until the end of the study. 2 randomization sequences will be required for UTMB and 
CUMC sites. 
No significant adverse effects are expected with the use of Dilapan-S® for mechanical dilation as an 
outpatient when compared to inpatient setting. The most common adverse events from cervical 
ripening with mechanical dilators such as the Foley balloon have been reported to be less than 1% (8), 
the most common being pain (0.26%), unintended amniotomy (0.04%), vaginal bleeding (0.07%), non-
reassuring fetal heart tracing (0.07%), and uterine tachysystole (too low to quantify). Our group also 
reported the following adverse effects with inpatient use of Dilapan-S® for cervical ripening in a group 
of 444 subjects (9): 
Maternal and neonatal adverse 
events 
Nr. of cases 
(%) 
Comments (n) 
Uterine tachysystole 
1 (0.2) 
 
Non reassuring fetal heart rate 
1 (0.2) 
 
Maternal complications/discomfort 
15 (3.4) 
Bleeding during insertion/extraction of dilators 
(12), Cramping/pain (1), Other (1) 
Uterine contractions 
111 (25) 
Tocography during cervical ripening showed 
low frequency and mild intensity contractions 
Maternal infection 
14 (3.2) 
Chorioamnionitis (9), Urinary tract infection 
(3), Endomyometritis (1), Wound infection (1) 

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NICU admission 
6 (1.4) 
Meconium aspiration (2), Growth restriction 
(2), Asphyxia (1), Congenital cardiac 
abnormality (1) 
Neonatal infection 
1 (0.2) 
Neonatal sepsis (maternal group B 
Streptococcus was not observed prior IOL) 
 
The most significant potential risks noted with Dilapan-S® occur during or shortly after insertion and 
include vaginal bleeding due to cervical trauma and incidental rupture of membranes, as well as pain 
or discomfort with placement. If these occur and are persistent (i.e. unresolved pain despite analgesia), 
subjects will be admitted for delivery (as they require maternal monitoring) and will not be 
randomized, since they do not fulfill the eligibility criteria to receive the outpatient intervention.  
 
 

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Similarly, in the case of inability to place Dilapan-S®, patients will not be randomized and will be 
considered a screening failure (please refer to section 4.7 for further details). Recent data reports that 
the risks associated with outpatient pre-induction are similar when compared to inpatient pre-induction 
cervical ripening (10). 
 
The study period will be between September 2018 and December 2021. The sample size will be up to 
376 consented subjects at UTMB and at CUMC (see section 12). 
 
The subject will be withdrawn from the study at any time, if she wishes to discontinue participation 
and withdraw her consent (refer to section 4.7 for details).  
 
The data collected will be kept on a password-secured UTMB or CUMC computer. An encrypted USB 
flash drive will be used to transfer data, if needed. The data will be linked to the patient by the patient's 
MRN number. This identifier is needed to access and analyze demographic data. After analysis of the 
data, all identifiers will be deleted.  
 
Data to be collected will consist of maternal age and ethnicity, gravida/para, gestational age, height, 
weight, estimated fetal weight, reason for induction, date and time of device placement, date and time 
of delivery, mode of delivery, Bishop score at eligibility assessment, Bishop score prior to dilator 
insertion, Bishop score after removal or expulsion of dilator, date and time of rupture of membranes, 
date and time of device expulsion/removal, hospital length of stay, other intrapartum and obstetrical 
interventions, complications in device placement and cervical ripening, during labor and delivery 
including but not limited to meconium, infections, hemorrhage, fetal decelerations and subject 
satisfaction. We will also collect the amount of analgesics subjects received during device placement, 
cervical ripening and induction time (includes acetaminophen or intravenous medications or regional 
anesthesia). Data will be abstracted from the medical records as well as from direct interview. We will 
also collect basic neonatal data including birth weight, Apgar scores, rate of admission to neonatal 
intensive care unit, infections, and other neonatal complications. The data collected will not be used for 
clinical diagnosis or treatment purposes. Additional economic data to be collected includes the 
following admission direct costs or charges from the following services/departments: Blood Bank 
Transfusion Operations, Chemistry Division, Hematopathology Division, JSH Labor & Delivery unit, 
Materials Management, Microbiology Division, Mother Baby Unit, Pharmacy, Respiratory Care 
Services, Surgical Operating Suite. 
 
4. Participating sites: 
 
The following sites are participating in this trial:  
 
The University of Texas Medical Branch (UTMB) site: 
301 University Blvd. 
Galveston TX, 77555 
UTMB is the leading site for this trial. There is no specific accrual number per site. Across multi-sites, 
randomization is centralized by sponsor.  
 
Columbia University Medical Center (CUMC) site. The study will be conducted on 2 clinics listed 
below: 
Clinic 1: Allen Hospital 
5141 Broadway, New York, NY 10034 

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Clinic 2: Lawrence Hospital 
55 Palmer Ave, Bronxville NY 10708 
Contact: Dr. Rachana Gavara, PI rg2460@cumc.columbia.edu 
 
 Each site will be having the protocol reviewed and approved independently by their local IRB before 
participating in this trial or recruiting. 
 
 
5. Study Procedures  
 
VISIT #1 
 
5.1. Screening, eligibility assessment, consenting and baseline data collection 
After institutional review board (IRB) approval, pregnant women who have a plan of care for induction 
of labor at term will be approached by the principal investigator or any of the co-investigators for 
participation in the study. Informed consent for this study can be obtained during several different 
phases of interaction with the patient:  
Phase 1: At any antenatal obstetrical office visit when decision is made to schedule subject for 
induction of labor. 
Phase 2: Potential subjects presenting for induction of labor at term in the “Labor and delivery” unit 
(L&D). 
Subjects willing to participate in the study will be evaluated for their eligibility including their Bishop 
score. The latter will be obtained from the medical record after the initial pelvic exam which is 
standard of care in our unit. Subjects will be reassured that participation in the study is voluntary and 
will not interfere with diagnosis or treatment of her condition. The subjects will receive the same care 
and expertise as any other subject treated in our unit. Subjects are approached in a private patient 
room, and written consent will be obtained by direct person-to-person contact. The principal 
investigator, study coordinator, or a collaborator will be responsible for the informed consent. Non-
English-speaking subjects are anticipated to be part of the study population and informed consent will 
be provided in their primary language. We will also be using the teach back method; briefly the 
potential subject will be asked to explain in their own words what they need to know or do, we will 
also ensure they understand the study and, whenever needed, re-explain to them about the study 
procedures and risk of participating in the trial. After obtaining informed consent, and Dilapan-S® is 
successfully placed (see section 4.2) and after 30 minutes period of observation, subjects who remain 
eligible will be randomized to management as inpatient versus outpatient (see section 4.3).  
 
5.2. Placement of synthetic osmotic cervical dilator  
Placement of the Dilapan-S® will be performed by trained medical personnel. After informed consent 
is obtained, Dilapan-S® will be placed as follows:  
Before the device placement, subjects will undergo continuous cardiotocography (CTG) monitoring for 
30 minutes while fetal condition and uterine activity are monitored. The cervix is visualized with a 
sterile vaginal speculum and cleaned with iodine or chlorohexidine. As many synthetic osmotic 
cervical dilators (Dilapan-S®, Medicem Technology s.r.o., Kamenne Zehrovice, Czech Republic) as 
possible are inserted into the cervical canal under direct visualization. Synthetic osmotic dilators are 
inserted into the cervical canal with special attention to cross through the internal os.  
The number of Dilapan-S® rods inserted will vary, depending on the status of the cervix for the 
particular subject. Synthetic osmotic dilators will be inserted as per manufacturer’s instructions (IFU – 

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Appendix 1). After insertion, the subject will be evaluated for excessive bleeding, pain or other 
concerns by the clinical providers (see section 4.4). The synthetic osmotic dilators will be left in place 
for at least 12 hours, and no longer than 24 hours. Subjects will be instructed, that under no 
circumstances they should try to remove Dilapan-S® themselves. If subject removes the device herself, 
such act will constitute protocol deviation and the subject will be assessed for cervical ripening within 
Intent-to-Treat analysis (see section 4.4 for details) but will not be included in the Per-Protocol-
Population analysis. 
In the rare event that the Dilapan-S® cannot be inserted or contraindications for outpatient management 
develop during insertion or during the observation period after the insertion but before randomization 
(subject changed her mind and desires to stay inpatient, significant vaginal bleeding during insertion, 
non-reassuring fetal heart rate, rupture of membrane, intractable pain or other concerns the providers or 
investigators feel that patient cannot be managed as an outpatient), then the subject will not be 
randomized nor included in the analyses. These subjects will be considered as screening failures and 
managed as inpatient according to standard practice and under the direction of the clinical team. Refer 
to section 4.8.1 for further details. 
 
5.3. Randomization  
After Dilapan-S® placement, and if the subject remains eligible, subject will be randomized to the 
outpatient group or the inpatient group. A confidential computer-generated simple randomization 
scheme will be prepared and provided by independent vendor (PharmTest, s.r.o., Czech Republic) to 
our study coordinator. The currently used randomization code will be replaced by 2 randomization 
codes, 1 of them for CUMC site (both clinics will use the same randomization sequence. The 
randomization envelopes to be use at CUMC will be provided by UTMB).  
A randomization log with group assignment, subject name, and medical record number will be used to 
track the randomization process. The subject will be included in the analysis by intent-to-treat once the 
randomization assignment has been made.  
 
5.4. Pre-Induction 
5.4.1. Group Assigned to Outpatient Cervical Ripening 
After Dilapan-S® placement, subject will be monitored for at least 30 minutes. If no contraindications, 
such as tachysystole, active vaginal bleeding, rupture of membranes or nonreassuring fetal testing 
(defined as minimal or absent variability, abnormal baseline, or presence of decelerations) evidence of 
labor, or other serious medical conditions deemed by the clinical staff or the attending physician to 
preclude outpatient cervical ripening develop after insertion, the subjects will be randomized. After 
randomization subject will record the pain she experienced during insertion in the patient’s survey (see 
Appendix 3). Those subjects randomized to outpatient ripening will be given the option to either stay 
in a hotel or, if they are able to reach the hospital within 60 minutes, return home. The cost for the 
hotel will be covered by the study budget. Subjects at CUMC will solely be given the option to stay at 
home. Subjects will be allowed to ambulate, shower and perform regular activity during that period. 
“Nothing per vagina” will be allowed (incl. intercourse, tampons etc.). Subjects will also be instructed 
to return to L&D unit 12 hours after insertion, or earlier if any excessive bleeding, rupture of 
membranes, pain or other concerns (contractions, decreased fetal movement) develop before the 12 
hours. Special leaflet (Appendix 2) will be provided to subjects leaving the hospital, with detailed 
instruction, emergency contacts to appropriate study/clinical staff and space to document of oral 
medication taken for pain relief (acetaminophen). Subject will also document the date and time of 
membrane rupture if applicable.  
 
Reasons for examining or removing dilators earlier include but are not limited to:  

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1) Spontaneous onset of labor  
(defined as regular, firm, uterine contractions with an effaced cervix >80% and a cervical dilatation > 3 cm)  
2) Other than category I fetal heart rate tracing  
(category I includes all: Baseline rate: 110–160 beats per minute, baseline FHR variability: moderate, absent late or 
variable decelerations, Early decelerations: present or absent and accelerations: present or absent) 
3) Spontaneous rupture of membranes or need for amniotomy  
4) Spontaneous expulsion of Dilapan-S® rods 
5) Subject removed the rods herself  
 
After the designated 12 hours’ time or earlier, if indicated, subjects are to return and to be admitted to 
L&D unit for standard protocol of labor induction. If the cervix remains unfavorable after extraction or 
spontaneous expulsion of the dilators (< 3cm and at most 60% effaced), additional mechanical or 
pharmacological cervical ripening may be provided at the provider’s discretion. The agent/type will be 
recorded into the data sheet.  
If subject does not return in the designated time and date as instructed (12 hours window), all attempts 
will be made to contact the subject by phone or supporting contact person. Subject will also be 
instructed that if she presents to another hospital, she needs to inform the clinical staff seeing her that 
she is participating in a trial and that Dilapan-S® was placed for cervical ripening, and to present the 
study card. We will also do our best to obtain our primary outcome through release of records. 
 
5.4.2. Group Assigned to Inpatient Cervical Ripening 
Subjects randomized to inpatient management will be admitted to L&D unit and standard clinical 
protocol will be initiated for cervical ripening and labor induction. During the period of 12 hours of 
cervical ripening subject is to remain “nothing per vagina” and undergo continuous fetal heart rate 
monitoring. During this period, clinical care will be left to the provider’s discretion (standard of care at 
the institution) including “nil per os” or “nothing per os” (NPO) status. No other interventions are to 
occur during this period of 12 hours, unless clinically indicated. Reasons to remove the dilators and 
management after 12 hours will be the same as for the outpatient group (see sec. 4.4.1.).  
 
VISIT #2 
5.5. Labor Induction and Labor 
Management of the subject after the initial 12 hours of pre-induction or following the earlier removal 
or spontaneous expulsion of the dilator will be the same for both groups and at the discretion of the 
clinical team. Additional ripening (mechanical or prostaglandins) and/or oxytocin may or may not be 
needed. If needed, duration, type and dose of additional ripening agents and oxytocin will be 
documented.  
Routine intrapartum care will be provided and relevant data collected by the subject’s managing 
obstetrical team.  
Trained and experienced research staff will be responsible for all research data abstraction.  
The PI and collaborators will review and validate the outcomes. If there is uncertainty, a second 
investigator will review the chart, discuss with the other investigators as needed, and make a final 
determination regarding the outcome. 
Subjective assessment data will be collected, using adequate validated tools either after Dilapan-S® 
extraction or any time prior labor or post-partum (Appendix 3) at the time point best suitable for both 
the subject and the study team. 
 
5.6. Post-partum data collection 

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Maternal and neonatal outcomes will be assessed following delivery, as detailed in section 5.  
Subjects will be encouraged to call the research team with any concerns. 
Data collection forms will be used during these processes and charts will be reviewed. 
Subjects’ direct participation will end after her discharge home from the hospital, however, data on 
postpartum infections or hospital readmission will be collected from medical charts 2 weeks after 
subject’s delivery. 
 
5.7. Follow-up  
No extra postpartum follow-up visits will be performed. Neonatal and maternal outcomes will be 
collected up to two weeks postpartum and documented in the relevant data collection forms. If these 
outcomes are not obtainable by chart review, all attempts will be made to obtain relevant outcomes 
from subject by phone. These will be reported as missing data, if unable to be reached by four weeks 
after delivery. 
 
5.8. Premature Terminations 
5.8.1 Screening failure  
A subject who is screened and consented, but Dilapan-S® isn’t placed will be considered a screen 
failure. 
 
5.8.2 Early (or premature) termination  
A study subject will be discontinued from participation in the study if any of the following occurs: 
• Medical condition or situation occurs such that continued participation in the study would not be 
in the best interest of the subject in the opinion of the treating investigator. 
• Subject wishes to end her study participation prematurely for any reason.  
• Lost to follow-up before reaching primary outcome (e.g. did not return from outpatient ripening). 
 
5.8.3 Rules for consent withdrawal 
If a subject withdraws her consent to participate in the study, all efforts will be made to discuss with 
the subject that despite the withdrawal, as many data as possible will be collected, such as safety data, 
AEs, SAEs. In such circumstances or situations, no data will be collected from the moment of her 
consent withdrawal, however, data collected before the withdrawal will be kept.  
The subject can still request the deletion of such data at any time, but the subject will need to request it 
in written for proper documentation. 
Subjects who will either withdraw their consent or end their participation in the study prematurely will 
not be replaced. Data obtained will be assessed within ITT population analysis. 
 
6. Study Outcomes 
6.1. Primary Outcomes 
Rate of hospital stay longer than 48 hours (from admission to discharge) 
6.2. Secondary Outcomes 
• Rate of vaginal deliveries (%) 
• Rate of vaginal deliveries within 24 hours since admission to hospital (%) 
• Rate of vaginal deliveries within 36 hours since admission to hospital (%) 
• Time from hospital admission to reach active stage of labor defined as ≥ 6 cm (mins) 
• Time from device placement to reach active stage of labor defined as ≥ 6 cm (mins) 

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• Change in Bishop score from insertion to extraction of device 
• Change in cervical dilation after Dilapan-S® 
• Rate of spontaneous vaginal deliveries after one round of cervical ripening (%)  
(no additional medical or mechanical interventions) 
• Rate of operative vaginal deliveries (%) 
• Rate of caesarean deliveries (%) 
• Rate of artificial rupture of membranes (AROM) (%) 
• Rate of epidural analgesia (%) 
• Total duration of Dilapan-S® application (insertion to removal/extraction) (mins) 
• Device placement to delivery interval (mins) 
• Induction (Oxytocin/Prostaglandin initiation) to delivery interval (mins) 
• Analgesia used during device placement (%), cervical ripening (%) and labor induction (%) 
• Rate of adverse neonatal outcomes (composite and individual) –Apgar score <7 at 1-5-10 minutes, 
Cord arterial pH <7.1, neonatal ICU admission (%) 
• Occurrence of maternal and neonatal complications within 2 weeks after delivery (%) 
• Total duration of maternal hospital stay (hours) 
• Subject reported clinical outcomes (sleep, rest, pain, activities of daily living, etc.) (Appendix 3) 
• Subject reported satisfaction with Dilapan-S® treatment (Appendix 3) 
• Medicaid charges for each hospitalized subject in both arms  
(Blood Bank Transfusion Operations, Chemistry Division, Hematopathology Division, JSH Labor 
& Delivery unit, Materials Management, Microbiology Division, Mother Baby Unit, Pharmacy, 
Respiratory Care Services, Surgical Operating Suite) 
 
7. Inclusion and Exclusion Criteria  
7.1. Criteria for Inclusion of Subjects:  
Subjects must meet all of the inclusion criteria in order to be eligible to participate in the study. 
Inclusion criteria are: 
1. Pregnant woman whose plan of care is induction of labor 
2. Maternal age between 18 and 45 years 
3. Understanding and capable to sign informed consent 
4. Singleton pregnancy 
5. Gestational age ≥ 37 0/7 weeks  
(based on a sure last menstrual period or a first trimester dating ultrasound)  
6. Live fetus in cephalic presentation 
7. Intact membranes 
8. Pelvic exam (sterile vaginal exam) of less than or equal to 3cm and at most 60% effaced 
 
7.2. Criteria for Exclusion of Subjects 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study participation. 
Exclusion Criteria are: 
1. Active labor  
2. Active genital herpes 
3. Chorioamnionitis  
4. Transfundal uterine or cervical surgery 
5. Previous cesarean delivery 

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6. Non-reassuring fetal status 
7. Need for continuous maternal or fetal monitoring during ripening 
8. Contraindication for vaginal delivery 
9. Active vaginal bleeding 
10. Abnormal placental location or adherence (placenta previa or unresolved low lying placenta) 
11. Estimated fetal weight > 5000 g (non diabetic) or > 4500 g (diabetic) 
12. Intrauterine growth restriction (estimated fetal weight <10 percentile)  
13. Oligohydramnios (amniotic fluid index < 5cm or deep vertical pocket of < 2 cm) 
14. Fetal anomaly 
15. Need for inpatient care (e.g. hypertension, insulin-dependent diabetes) 
16. Poor or no access to a telephone and cannot be placed in the hotel 
17. Absence of support person ( no adult accompanying the subject during outpatient cervical 
ripening period) 
 
8. Sources of Research Data 
Medical chart/records, charges for Medicaid services report forms and direct cost reports will be used 
as source for data collection. 
 
 
 

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9. Potential Risks 
9.1. Randomization risk 
Since the location of pre-induction management will be randomized, it is possible that the subject may 
be in a group with higher adverse outcomes.   
 
9.2. Loss of Confidentiality 
Any time information is collected, there is a potential risk for loss of confidentiality. Every effort will 
be made to keep subject’s information confidential; however, this cannot be guaranteed. 
 
9.3. Risks associated with mechanical dilator 
• Vaginal bleeding during/after device insertion 
• Subjective pain felt during insertion 
• Vaso-vagal reaction from manipulation of the cervix 
• Contamination of the device during insertion 
• Allergic reaction from hypersensitivity to the components 
• Rupture of membranes 
• Uterine tachysystole (> 5 contractions in 10 mins averaged over 30) 
• Cervical trauma during insertion or extraction. 
• Retraction of the device into the uterine cavity  
• Entrapment of the device 
• Fragmentation of the device  
 
10. Subject Safety and Data Monitoring 
10.1. Safety reporting 
Scope 
In relation to Dilapan-S®, the Clinical Trial is a post-market clinical follow-up study (PMCF) 
conducted using CE marked device ("Conformité Européenne") within its intended use. The provisions 
of Directive 93/42/EEC concerning information and notification of incidents occurring following 
placing devices on the market are fully applicable. Medical Device Reporting regulation (21 CFR 803) 
will be followed to report certain device related adverse events and product problems to the FDA.  
The Investigator shall ensure that Sponsor will be informed about any adverse events (AEs) that would 
be related to study device according to the definitions given below. Complaints about any product 
problem are within the scope of obligatory notification too, including product defects, malfunctions or 
user errors. 
AEs not related to the study device are not to be reported to sponsor. Borderline events should be 
handled conservatively and the sponsor should be notified in case of any doubt.  
Definitions 
Adverse Event (AE) is any untoward medical occurrence in a subject and that does not necessarily 
have a causal relationship to the study device and surgical procedure.   
Serious Adverse Event (SAE) is any AE that:  
• 
Results in death.  
• 
Is life-threatening.  
• 
Leads to hospitalization or prolongation of hospitalization.  
• 
Causes disability and/or permanent impairment of a body function or structure.  

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• 
Requires medical or surgical intervention to prevent permanent impairment of a body function or 
permanent damage to a body structure.  
• 
Leads to fetal demise, a congenital abnormality, or birth defect. 
Product Problem includes: 
• 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance. It also includes inadequate labelling.  
• 
Malfunction: failure of an investigational medical device to perform in accordance with its 
intended purpose when used in accordance with the instructions for use or Clinical Investigation 
Plan.  
• 
User error: act or omission of an act that results in a different medical device response than 
intended by the manufacturer or expected by the user. 
Evaluation of an AE 
When evaluating AEs, the Investigator must determine: 
• 
if the event is serious. Seriousness criteria are based on definition of an SAE (above). 
• 
if the event is related to the study device. The following rules are to be applied: 
a) Not Related: AE which are clearly and incontrovertibly due to causes other than the study 
device (e.g., concomitant disease).  
b) Related: AE which are felt with a reasonable degree of certainty to be related to the study 
device.  
c) Unknown: AEs for which a connection with the study device cannot be ruled-out with 
certainty, or not enough information is available to assess the relationship.  
Reporting 
The collection of AEs begins at the time the subject is enrolled into the study (eligible subject with 
signed informed consent). 
Reporting will be done in written via the attached Safety Report Form (Appendix 4).   
The Investigator is obligated to send the applicable report to the Sponsor within 24 hours of becoming 
aware of the event to ensure the safety of all participants in the study and to meet regulatory reporting 
requirements. 
Subsequent reporting to the IRB and the corresponding regulatory authorities will be organized by the 
Sponsor and in accordance with all applicable legal requirements of the concerned country. 
 
10.2. Data Monitoring 
The PI and collaborators will ensure all aspects of data quality, including monitoring for adherence to 
consent procedures, inclusion and exclusion criteria, valid abstraction, correct entry, timeliness and 
responsiveness to data queries.  
Data will be collected and stored with the participant ID code only. The master enrollment log linking 
subject identifiers with study ID numbers will be kept in a password-protected database on the 
OB/GYN department’s internal server separate from the data. Data collection forms will be used. Data 
on these forms devoid of personal identifiers will be securely stored at our perinatal research division. 
The research coordinator will be available to monitor the data and correct any discrepancies based on 
source documents if needed. 
 
Data quality and safety of subjects will be monitored also by sponsor’s representative to assure 
independent review. Any issue identified will be followed up closely to assure the subjects’ safety and 
adherence to protocol as well as data quality.  

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The sponsor’s monitor performs monitoring remotely; therefore, they only need to formally conduct in 
person monitoring visits to review the informed consents and other paper documents. One monitoring 
visit for approximately every 60 randomized subjects is sufficient. The monitoring visit frequency 
depends on enrollment, if enrollment increases, the frequency will increase as well. In conclusion, we 
expect approximately 2-4 monitoring visits per year.  
 
11. Procedures to Maintain Confidentiality 
Each subject will be assigned a study number (Subject ID) with personally identifiable information 
deleted or removed. This Subject ID will be unique for every subject and will not contain any study 
group identifier. Subjects' information will be de-identified and tagged with a number. Data will be 
collected and stored on a UTMB or CUMC password-protected computer in a locked room.  
 
12. Potential Benefit 
This study has the potential benefit to show that outpatient pre-induction cervical ripening with 
Dilapan-S® decreases length of hospital stay without affecting maternal and neonatal outcomes. 
Ultimately, this may reduce the health care costs and workload associated with induction of labor and 
improve maternal neonatal early bonding. 
 
13. Biostatistics/Sample Size 
Basic principles for an evaluation of the study are presented in this section, more detailed description 
of how to analyze collected data will be specified in statistical analysis plan (SAP) which will be 
written and approved before the database lock. The statistical analysis including the data from the 
additional site will be specified in the SAP. 
 
13.1. Study populations 
All Randomized population 
This will be comprised for all subjects who had Dilapan-S® inserted and were randomized. This includes 
patients who terminated participation for any reason (lost to follow-up or did not return to hospital for 
admission). We will perform a sensitivity analysis (worst case scenario), where we will consider these 
subjects to have reached the primary outcome. 
Safety Population 
The Safety population will be comprised of all subjects who had Dilapan-S® inserted and were 
randomized. This population will be used for the analysis of safety of the outpatient versus inpatient 
management. Subjects who were consented and had Dilapan-S® inserted, but not randomized, and had 
complications attributed to the device will be reported as AEs (detailed in section 9.1). 
Intent-to-treat Population (ITT) 
ITT includes all patients that were randomized into the study and primary outcome has been obtained. 
ITT subjects 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. Other 
predefined subgroup interaction analysis for cervical dilation at randomization, parity (P=0 vs P>0), or 
BMI > 30 kg/m2 will be also performed. 
Per Protocol Population (PP) 
PP is a subset of ITT patients without any major protocol violation affecting the efficacy endpoints. 
Major protocol violations include: 

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1. Treatment assignment error 
2. Violation of one or more inclusion/exclusion criteria 
3. Use of forbidden medication 
4. Premature withdrawal 
5. Missing data for the evaluation of the primary endpoint 
This list can be extended based on a knowledge of other serious issues appearing in the data. 
PP population will be used for assessment of primary endpoint. 
 
13.2. Analysis of primary outcome 
Primary outcome of the study is the rate of hospital stay longer than 48 hours. Proportion of patients in 
the outpatient and inpatient group will be calculated and their difference will be tested by chi-square 
test by ITT analysis. 
 
13.3. Analysis of secondary outcomes 
Nominal variables will be evaluated in the same manner as the primary outcome. Continuous variables 
will be summarized (minimum, maximum, mean, standard deviation, median, lower and upper 
quartile) and the difference between groups will be tested by t-test or Wilcoxon-Mann-Whitney test as 
appropriate. For time-to-event outcomes, Kaplan-Meier will be used to estimate the survival curves 
and log-rank test will be used to test the difference between groups by ITT analysis. 
 
13.4. Sample size  
Sample size was calculated based on the determination of superiority. The primary outcome is 
proportion of women with hospital stay >48 hours. For the sample size calculation, we assumed the 
proportion in the control arm would be 54% (pi = 0.54). This is based on current experience at UTMB 
and unpublished data from an international registry trial (9). We estimate that outpatient intervention 
would decrease this proportion by 30% (pii = 0.378). Based on 85% power and two-sided alpha of 
0.05, the total sample size per group required would be 169. Accounting for 10% of premature 
terminations or drop outs the sample size per group becomes 188, making the total sample size needed 
376.   
 
14. Clinical Trial Registration  
This trial will be registered with Clinical Trials Registry (www.clinicaltrials.gov), before recruitment is 
initiated after IRB approval. 
 

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References 
1. Thiery M, De Boever J, Merchiers E, Martens G. Hormones and cervical ripening. 
Am J Obstet Gynecol. 1989 May; 160(5 Pt 1):1251-3 
2. Grobman, W. A randomized trial of elective induction of labor at 39 weeks compared with 
expectant management of low-risk nulliparous women. AJOG 2018 Volume 218, Issue 1, 
Supplement, Page S601 
3. Wilkinson C, Adelson P, Turnbull D. A comparison of inpatient with outpatient balloon 
catheter cervical ripening: a pilot randomized controlled trial. BMC Pregnancy Childbirth 
2015;15:126.6 
4. Wilkinson C, Bryce R, Adelson P, Turnbull D. A randomised controlled trial of outpatient 
compared with inpatient cervical ripening with prostaglandin E(2) (OPRA study). BJOG 
2015;122:94–104 
5. Henry A, Madan A, Reid R, Tracy S, Austin K, Welsh A, et al. Outpatient Foley catheter 
versus inpatient prostaglandin E2 gel for induction of labour: a randomised trial. BMC 
Pregnancy Childbirth 2013;13:25.10 
6. Kruit H, Heikinheimo O, Ulander VM, Aitokallio-Tallberg A, Nupponen I, Paavonen J, et al. 
Foley catheter induction of labor as an outpatient procedure. J Perinatol 2016;36:618–22 
7. Sciscione AC, Muench M, Pollock M, Jenkins TM, Tildon-Burton J, Colmorgen GH. 
Transcervical Foley catheter for preinduction cervical ripening in an outpatient versus inpatient 
setting. Obstet Gynecol. 2001 Nov;98(5 Pt 1):751-6 
8. Diederen M, Gommers J, Wilkinson C, Turnbull D, Mol B. Safety of the balloon catheter for 
cervical ripening in outpatient care: complications during the period from insertion to expulsion 
of a balloon catheter in the process of labour induction: a systematic review. BJOG. 2018 
Aug;125(9):1086-1095. doi: 10.1111/1471-0528.15047. Epub 2018 Jan 10 
9. Saad AF, Gupta J, Maier J, Hruban L, Mehta P, Baev, O.  Synthetic Osmotic Dilator Prior to 
Induction of Labor: Outcomes From International Observational E-Registry [13C]. Obstetrics 
& Gynecology: May 2017 doi: 10.1097/01.AOG.0000514325.32536.c4 
10. Kuper SG, Jauk VC, George DM, Edwards RK, Szychowski JM, Mazzoni SE, Wang MJ, 
Files P, Tita AT, Subramaniam A, Harper LM. Outpatient Foley Catheter for Induction of 
Labor in Parous Women: A Randomized Controlled Trial. Obstetrics & Gynecology. 
132(1):94-101, 2018 Jul. 
 
 

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List of Appendices: 
1. Instructions for Use: DILAPAN - S® Hygroscopic Cervical Dilator  
(DSPIenus-Rev019/2021-04) 
2. Leaflet – instructions for patients on home-based ripening 
3. Patient questionnaire 
4. Safety Report Form 

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Appendix 1: Instructions for Use: DILAPAN - S® Hygroscopic Cervical Dilator (DSPIenus-
Rev019/2021-04) 

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Appendix 2:  
Leaflet – instructions for patients on home-based ripening 
 
 

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Appendix 3:  
Patient Satisfaction Survey 
 

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Appendix 4:  
Safety Report Form