Conditions: Labor Onset and Length Abnormalities Induced; Birth
Keywords: Misoprostol Dilapan Induction of labor Aquacryl hydrogel
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 307
Healthy volunteers: yes

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Dilapan intervention 2: Misoprostol
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
Prot_002.pdf: 
        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 1 of 15  
  
  
  
The Columbia University Medical Center and New York-Presbyterian Hospital and   
The University of Texas Medical Branch (UTMB)  
  
ClinicalTrials.gov ID: NCT03670836 
  
Title:  
Comparison of Misoprostol Ripening Efficacy With Dilapan  
Version 3.1 dated September 4, 2020 
  
Prepared by:  
  
Rachana Gavara, MD  
Assistant Professor   
 Dept. of OBGYN  
Columbia University Medical Center  
5141 Broadway  
New York NY, 10034  
  
Ronald Wapner, MD  
Professor and Vice Chair of Research  
 Dept. of OBGYN  
Columbia University Medical center   
622 W. 168th St. Suite 16-66  
New York, NY 10032 
  
Antonio Saad, MD  
Assistant Professor   
 Dept. of OBGYN  
The University of Texas Medical Branch  
301 University Boulevard  
 Galveston, TX 77555-0144  
  
Funder:  
  
Medicem Technology s.r.o. Karlovarska trida 20  
Kamenne Zehrovice, 27301  
Czech Republic 
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 2 of 15  
  
Protocol Title:  
Dilapan vs Misoprostol for cervical ripening  
[COMRED – comparison of Misoprostol ripening efficacy with Dilapan]  
Protocol number:  
AAAR8566  
Version & date:  
Version 3.1  dated September 4, 2020   
Signature and Approval Section:  
Reviewer   
Signature and Date of last review & Approval   
Jan Waclav, MD  
Clinical & Medical Affairs Director 
Medicem Technology s.r.o.  
  
………………………………….             ………………………………  
(signature)                                                  (date: DD-MMM-YYYY)  
Jana Šubrtová  
QA, QC & Regulatory Director 
Medicem Technology s.r.o.  
  
………………………………….             ………………………………  
(signature)                                                  (date: DD-MMM-YYYY)  
Prof. Ronald Wapner, MD  
Chief Investigator  
Department of Ob and Gyn   
Columbia University Medical Center   
  
………………………………….             ………………………………  
(signature)                                                  (date: DD-MMM-YYYY)  
Regulatory Notice:   
This clinical study protocol is prepared in accordance with Helsinki Declaration and MEDDEV2.12 / 2 rev 2 January 2012 - Post 
Market Clinical Follow-up studies. This clinical study protocol and subsequent study report will become the part of technical 
product documentation and serves as proof of compliance with the requirements of the Directive and other related regulations. 
Investigator´s Signature Section:  
I hereby declare that I have read this Clinical Investigational Plan and I understand the information. With my signature, I agree to 
conduct this clinical investigation in accordance with the Clinical Investigational Plan, applicable Helsinki Declaration and  
MEDDEV2.12 / 2 rev 2 January 2012 - Post Market Clinical Follow-up studies, applicable local laws and regulatory requirements. 
Moreover, I will keep all information obtained from the participation in this clinical investigation confidential unless otherwise 
agreed in writing.  
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances that 
this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and ICH guidelines.  
Principal Investigator:  
Rachana Gavara, MD  
Department of Ob and Gyn   
Columbia University Medical center   
  
  
………………………………….             ………………………………  
(signature)                                                  (date: DD-MMM-YYYY)  
Co-Investigator:  
Antonio Saad, MD  
Department of Ob and Gyn  
University of Texas Medical Branch  
   
………………………………….             ………………………………  
(signature)                                                  (date: DD-MMM-YYYY) 
  


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 3 of 15  
  
PROTOCOL SYNOPSIS PAGE   
  
Background - In developed nations 25 % of pregnant women undergo induction of labor (IOL) 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-S® is an osmotic 
hygroscopic dilator of cervix commonly used for cervical preparation for mid trimester abortions. It has 
been proven safe for use for 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.  
  
Objective - To assess the efficacy of Dilapan-S® for cervical ripening compared to Misoprostol in 
women undergoing IOL at or more than 37 weeks gestation.  
  
Primary outcome - Proportion of women randomized to receive Dilapan-S® and Misoprostol for 
cervical ripening achieving vaginal delivery within 36 hours of intervention.  
  
Secondary outcomes - A composite of maternal and fetal outcomes including overall vaginal delivery 
rate, cesarean section rate, Bishop score after cervical ripening, infections, postpartum hemorrhage. 
Neonatal outcomes include Apgar scores, NICU admission and sepsis.   
  
Study design - Non Inferiority, unblinded randomized, controlled trial where 322 eligible participants 
undergoing IOL at >37 weeks gestation at CUMC and admitted to labor and delivery unit will be enrolled 
and randomly assigned in a ratio 1:1 to either receive Dilapan-S® or Misoprostol for cervical ripening. 
The study is powered at 85% for detecting the primary outcome with a type 1 error at 2.5% for one-
sided test.  
  
Procedures - After randomization all participants will undergo assessment as per the floor protocol 
including Bishop Score. Patients will have either Dilapan-S® 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. 
Patients will be examined after 12 hours, Dilapan-S® rods will be removed and Bishop Score will be 
reassessed. There will be a ±30 minute window for the removal of the Dilapan-S® rods and ±15 minutes 
for Misoprostol administration. Patients in both groups 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 AROM. 
Intrapartum management will be according to institutional guidelines. All study participants will be 
contacted by phone 2 weeks after delivery to find out if they needed any additional treatment following 
discharge. All study patients will be asked to fill out a questionnaire regarding their experience with the 
method of induction. Data will be collected by chart review and analyzed based on the outlined statistical 
plan.   
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 4 of 15  
  
Title  
Dilapan vs Misoprostol for cervical ripening  
[COMRED – comparison of Misoprostol ripening efficacy with Dilapan]  
  
Trial Objective  
To assess efficacy of Dilapan-S® [osmotic hygroscopic dilator] for cervical ripening compared to 
25mcg of oral Misoprostol   
  
Background  
In developed countries about 25% of the pregnant women are delivered by induction of labor annually 
[1]. A decision to proceed with induction of labor is made when continuation of pregnancy may worsen 
the condition of mother or her fetus. This number is expected to go up in the future as our 
understanding of pathophysiology of pregnancy improves. A recent landmark randomized controlled 
trial involving more than 6000 nulliparous women has proved that induction of labor at 39 weeks 
improves perinatal outcomes without increasing the cesarean section rate compared to expectant 
management [2].  
Induction of labor is one of the most common obstetric procedure [1]. Current practice in United States 
is to admit the patients to labor and delivery floor once a decision to proceed with induction of labor 
has been made. Majority of these women are candidates for cervical ripening as their cervix is found 
to be unfavorable for initiation of oxytocin based on the assessment of Bishop Score at the time of 
admission. Bishop score of 6 or more is a good predictor of likelihood of achieving vaginal delivery 
within 24 hours after initiation of labor induction. Cervical ripening is a process by which cervix 
undergoes enzymatic dissolution of collagen fibrils and changes in intercellular matrix, leading to 
increase in water content and softening [1]. These changes transform cervix to a soft, pliable structure 
that undergoes dilatation and effacement in response to uterine contractions. Two commonly methods 
used for cervical ripening are prostaglandins and mechanical devices.   
  
Misoprostol  
Misoprostol is a prostaglandin E1 analog approved for treatment and prevention of gastric ulcers. 
Misoprostol acts on the intracellular matrix of the cervix, causes breakdown of the collagen fibrils 
leading to cervical softening. It also induces uterine contractions. ACOG has indicated that use of 
Misoprostol appears to be safe and effective for induction of labor when used in low dose [2]. Despite 
a large number of trials of Misoprostol for cervical ripening there is no clear consensus as to the 
optimal oral dose, dosing interval and the maximum number of doses that can be given. In PROBAAT 
II, a non-inferiority trial comparing oral Misoprostol to Foley catheter for cervical ripening, Eikelder, 
Jozwiak et al. [3] used 50mcg of Misoprostol orally, dosed every 4 hours with a maximum of three 
times per day. Ibraheemi et al. [4] in their recent RCT - Misoprostol with Foley bulb compared with 
Misoprostol alone for cervical ripening, used 25 mcg of Misoprostol vaginally every 4 hours to a 
maximum 6 doses. Levine et al. [5] in their randomized clinical trial - Foley or Misoprostol for 
management of induction used 25 mcg of Misoprostol every 3 hours with a maximum of 6 doses over 
24 hours. WHO [10] has suggested using Misoprostol 25 mcg orally every 2 hours.   
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 5 of 15  
  
Weeks et al. [7] recommend use of oral misoprostol every 2 hours. This is supported by the 
pharmacokinetic studies that show that oral Misoprostol reaches its peak serum level in 30 minutes 
and its half-life is only 90 minutes. Misoprostol is rapidly metabolized by the liver and excreted by 
kidneys. This is also supported by a recent randomized trial of oxytocin versus oral misoprostol given 
every 2 hours which found no differences in major outcomes but reduced rates of hyperstimulation 
with Misoprostol.  
  
Dilapan-S®  
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. The rods are inserted into the 
cervical canal just above the internal os (see APPENDIX 1: Instructions for Use). Within 6-8 hours 
these rods expand up to 4 times of their original diameter and create a radial force inside the cervical 
canal causing it to dilate. In addition, an inflammatory process begins which activates endogenous 
prostaglandins leading to cervical softening and shortening. This response occurs at a predictable 
rate. Studies done in 1990s and recent ongoing, national and international trials [11, 12] have 
established safety of Dilapan-S® for use in pregnant women.  
  
Rationale for randomized clinical trial  
Misoprostol is one of the most commonly used methods for cervical ripening and labor induction in 
United States. It is safe and cost effective and shortens induction to delivery interval compared to 
other pharmacological and mechanical methods [5]. Dilapan-S® is a device that is FDA approved for 
cervical ripening. It has predictable response over time and lower risk of uterine tachysystole and 
hyperstimulation. Dilapan-S® has potential for use in outpatient setting among low risk patients due to 
its efficacy and predictable response. There are no studies comparing efficacy and safety of Dilapan-
S® to Misoprostol. We propose to do a well-designed randomized trial to assess if Dilapan-S® has a 
similar safety and efficacy profile compared to 25 mcg of oral Misoprostol.   
  
Study Design  
Non-inferiority unblinded randomized controlled trial where subjects will be randomized in a ratio of 
1:1 to Dilapan-S® and misoprostol groups. We decided to use the non-inferiority design as Misoprostol 
is considered as one of the accepted and standard treatments for induction of labor in United States. 
Our assumptions for the trial are based on results of PROBAAT-II trial, a large well designed 
randomized trial conducted in EU for studying efficacy of mechanical and pharmacological methods 
for labor induction. Assuming a rate of vaginal delivery within 36 hours to be 65% for Misoprostol and 
71% for mechanical method (based on data on transcervical Foley catheter in PROBAAT-II [3] and a 
recent trial comparing Foley catheter to Dilapan-S® for cervical ripening done by Saad et al. [12]), with 
a non-inferiority margin of 10 % and an expected screen failures rate of 5%, a total of 322 subjects will 
need to be randomized in ratio 1:1 to Dilapan-S® vs Misoprostol group. 153 eligible and assessable 
subjects are needed in Dilapan-S® group and 153 in Misoprostol group for analysis. The study is 
powered at 85% for detecting the primary outcome with a type 1 error at 2.5% for one-sided test.  
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 6 of 15  
  
Objective for the trial  
To assess efficacy of cervical ripening with Dilapan-S® or Misoprostol in women undergoing induction 
of labor.  
  
Primary research question (primary endpoint)  
Proportion of subjects achieving vaginal delivery within 36 hours after the initiation of the 
cervical ripening in Misoprostol and Dilapan-S® group.  
  
Rationale: The authors of PROBAAT-II study make the valid point that as an outcome of labor 
induction, giving birth vaginally is more important than how quickly it happens; therefore 24 hours may 
not be a long enough time for appropriate assessment. Indeed, the effect found in the PROBAAT-II 
study would have been reversed had the outcome been measured by assessing vaginal delivery 
within 36 hours. There is therefore a call to standardize the outcome measure in IOL trials to a vaginal 
delivery within 36 hours [6], particularly when mechanical methods are employed.  
  
Secondary research questions (secondary endpoints)  
● Bishop score at 12 hours after the intervention   
● Percentage of subjects delivering vaginally in 24 hours after the initiation of intervention   
● Overall vaginal delivery rate in each group   
● Rate of operative deliveries   
● Rate of cesarean deliveries in each group.  
● Total length of hospital stay   
Maternal outcomes:  
● Chorioamnionitis   
● Endometritis within 2 weeks after delivery ,   
● Postpartum hemorrhage (EBL>1000cc /and or drop in HCT by 10 points)  
Neonatal outcomes:  
● Apgar score <7 at 5 min  
● Cord Arterial blood pH <7  
● Base excess >12mmol/l  
● NICU admission within 2 weeks after delivery   
● Antibiotic use within 2 weeks after delivery   
  
Exploratory research questions (exploratory endpoints)  
There is paucity of clinical data in the literature obtained through well designed clinical trials for 
Dilapan-S® use for cervical ripening in women undergoing induction of labor. We would like to collect 
following information for assessing safety of Dilapan-S® use when compared to Misoprostol. Similar 
information was collected by Saad et al. [12] in their recent randomized trial comparing efficacy of 
Dilapan-S® to Foley catheter for cervical ripening. These are known potential complications of planned 
interventions and include (but are not limited to) the following:  
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 7 of 15  
  
Undesirable side effects  
● Fever, nausea, vomiting and diarrhea   
● Uterine tachysystole  
● Hyperstimulation  
● Uterine hypertonus  
● Failed induction of labor, arrest of first and second stage of labor  
Complications specific to dilator insertion  
● Vaginal bleeding   
● Rupture of membranes   
● Cervical laceration   
● Excessive pain causing need for analgesia during cervical ripening   
● Vasovagal reaction during insertion of the device   
● Entrapment of the device   
● Fragmentation of device during removal or insertion   
● Retraction of device into uterine cavity.   
  
Study subjects inclusion criteria   
1. Women undergoing labor induction with a gestation of ≥37 weeks determined by best clinical 
and/or ultrasound estimation   
2. Live fetus with in cephalic presentation   
3. Singleton pregnancy  
4. Able to provide informed consent for participation in the study.  
  
Study subjects 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  
  
Pre-randomization training  
Participating providers at Columbia University Medical Center will watch a video tutorial on insertion 
as part of their training and perform at least one Dilapan-S® insertion for patients undergoing induction 
of labor, prior to initiation of the trial. These will not be study participants and no data will be collected 
in these women. This will be done in the presence of the PI or other trained providers. The purpose of 
this training is to ensure that all participating providers follow the Dilapan-S® Instructions for use as 
per the manufacturer’s recommendation based on FDA approval for its use for cervical ripening. This 
will be documented in Training Log placed in Regulatory binder.  


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 8 of 15  
  
Participating providers at UTMB regularly perform Dilapan-S® insertion for patients undergoing 
induction of labor per standard of care, however any provider that has not previously performed 
Dilapan-S® insertion will watch a video tutorial on insertion as part of their training and perform at 
least one Dilapan-S® insertion for patients undergoing induction of labor, prior to placing Dilapan-S® 
for research study purposes. These will not be study participants and no data will be collected in these 
women. This will be done in the presence of the PI or other trained providers. The purpose of this 
training is to ensure that all participating providers follow the Dilapan-S® Instructions for use as per 
the manufacturer’s recommendation based on FDA approval for its use for cervical ripening. This will 
be documented in Training Log placed in Regulatory binder  
  
Study Procedures   
Screening for Eligibility and Consent   
All women admitted to labor and delivery at initiated sites within Columbia University Medical Center 
and at UTMB for induction of labor will be screened for eligibility for participation by trained research 
staff. Women who meet the criteria for inclusion in the trial will be assessed by the Attending 
physician, Resident or Midwife providing care to the patient and informed about the trial and they are 
candidates for cervical ripening. Patients who agree to participate in the trial will be required to sign 
and date an Informed Consent Form (ICF).   
  
Randomization  
Participants will be randomized in a ratio of 1:1 for Dilapan-S® insertion or oral Misoprostol, 
using stratification for:  
(A) parity (nulliparous vs. parous women) and   
(B) gestational age (≤39 weeks vs. >39 weeks).  
Due to the nature of intervention blinding of subjects or providers is not possible.  
Randomization plan will be generated based on computer program. Subjects will either undergo 
Dilapan-S® insertion or receive up to 6 oral doses of 25 mcg of Misoprostol based on their allocation 
to treatment groups.   
  
Baseline procedures  
Subject enrolled in the study will be evaluated by a care provider and a history and physical 
examination including a sterile speculum and digital vaginal exam will be done. Provider will also 
review maternal vital signs and indication for induction of labor. All enrolled subjects will have CTG 
monitoring for at least 20 minutes prior to the planned intervention and IV access and Type and 
Screen as per the labor and delivery standard procedure.   
  
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 9 of 15  
  
Pre-induction  
Arm A: Dilapan-S® group   
Patients who are randomized to receive Dilapan-S®, will have 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 [Appendix 1]. The Bishop score at 
the time of eligibility assessment and number of rods inserted will be recorded. Dilapan-S® will be left 
in cervix for 12 hours (±30 minutes). 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.  
Arm B: Misoprostol group  
For subjects randomized to Misoprostol group, after the baseline assessment and a reassuring CTG 
monitoring for 20 minutes, 25mcg of Misoprostol will be administered orally every 2 hours  
(±15 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.  
  
Subjects in both groups will remain on labor and delivery (L&D) floor and will have continuous fetal 
monitoring as per the institutional guidelines.   
All study participants will be examined after 12 hours of receiving intervention unless there is an 
indication for an exam prior to this period. Reasons for an exam earlier than 12 hours after the 
initiation of cervical ripening intervention include:   
1. Onset of spontaneous labor  
(defined as regular painful uterine contractions with a dilation of ≥ 4 cm and effacement of 75% or more)  
2. Vaginal bleeding  
3. Persistent Category 2 or Category 3 fetal heart tracing  
4. Spontaneous rupture of membranes  
5. Spontaneous expulsion of Dilapan-S® rods  
(if Bishop score is still <6, another set of rods may be placed and allowed to remain in situ for a maximum of 12 
hours cumulative based on clinical assessment made by the supervising provider)  
6. AROM is indicated  
  
Labor Induction  
Subjects in both groups will have an assessment of Bishop score 12 hours after the study intervention 
and evaluated for amniotomy and Oxytocin infusion. Oxytocin will be initiated as per the institutional 
guidelines. Amniotomy will be undertaken as soon as clinically feasible. If after 24 hours of amniotomy 
with Oxytocin the patient is not in active labor [cervical dilatation<6 cm], a diagnosis of failed induction 
will be made [Appendix 2] and a decision will be made to proceed with cesarean section. During labor, 
decision to proceed with operative delivery or cesarean section will be made by the attending 
physician supervising the care of the patient. All subjects will have the option to receive epidural 
during labor for pain management.   
  


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 10 of 15  
  
Oxytocin administration  
CUMC:  
Oxytocin will be administered for labor induction and augmentation as per the institutional 
guidelines [Appendix 2]. Oxytocin is supplied to L&D unit in prepared bags with 30 units of 
Oxytocin in 500 cc of Normal Saline. Oxytocin will be initiated at 1 milliunit/minute and increased 
every 15 minutes, till an optimal response is obtained.  
The maximum dose is limited to 40 milliunits/minute.  
UTMB:  
Oxytocin will be administered for labor induction and augmentation as per the institutional 
guidelines [Appendix 3]. Oxytocin is supplied to L&D unit in prepared bags with 20 units of 
Oxytocin in 1000 cc of Lactated Ringers. Oxytocin will be initiated at 2 milliunit/minute and 
increased every 20 minutes, till an optimal response is obtained.  
The maximum dose is limited to 40 milliunits/minute.  
  
Delivery period  
Data for date, time and mode of delivery and intra-partum complications (incl. those found 
during induction period) will be collected. The complications will include, but are not limited to 
following:  
● Uterine tachysystole   
(defined as > 5 contractions per 10 minutes averaged over 30 minutes.   
● Hyperstimulation  
(defined as > 5 contractions averaged over 20 min with abnormal fetal heart changes )[3]  
● Uterine hypertonus   
(defined as a single contraction lasting at least 2 minutes.   
● Failed induction of labor, arrest of first and second stage of labor (see Appendix 2)  
(defined according to the US NICHD, ACOG and SMFM workgroup guidelines [9] 
● Intrapartum fever   
(defined as body temperature (skin or oral) of 39°C  at one reading or as body temperature of 
38-38.9°C which persists when retaken after 30 minutes) [13]  
Intrapartum fever when present with any of the following indicates infection may be present.  
1. Purulent discharge on speculum exam from the cervical canal   
2. Fetal tachycardia lasting more than 10 minutes   
3. Maternal WBC count of more than 15 K   
4. Amniotic fluid analysis results indicative of an infection  
  
Postpartum and FU procedures  
All participants will receive routine postpartum care. They will be asked to fill out a questionnaire 
(Appendix 4) in the postpartum period regarding their experience with the cervical ripening 
method.  
All study participants will be contacted via phone two weeks after delivery to find out if they or 
their baby had any postpartum complication and received treatment at any health care entity 
other than the hospital where they were admitted for delivery.  
 
 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 11 of 15  
  
Safety reporting  
Scope  
In relation to the Dilapan-S®, the Clinical Trial is a post-market clinical follow-up study (PMCF) 
conducted using CE marked device 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 Funder will be informed about any SAE 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, incl. product defects, malfunctions or user errors.  
AEs not related to the study device are not to be reported to Funder. Borderline events should 
be handled conservatively and the Funder 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 study procedure.    
Serious Adverse Event (SAE) is any AE that:   
● Results in death;   
● Is Life-threatening;   
● Leads to Hospitalization   
● Causes Disability and/or Permanent impairment of a body function or structure;   
● 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 unquestionably 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.   


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 12 of 15  
  
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.   
Confidentiality of Study Data  
Data and research records will primarily be stored electronically in a study database. This study 
database will be developed and maintained with support from Columbia University’s Department 
of Obstetrics and Gynecology CORE Data Team. REDCap (Research Electronic Data Capture) 
is a secure, web-based application designed to support data capture for research studies [8]. 
The system was developed by a multi-institutional consortium initiated at Vanderbilt University. 
REDCap data collection projects rely on a thorough study-specific data dictionary defined in an 
iterative self- documenting process by all members of the research team with planning 
assistance from the OB/GYN Division of Research Informatics Support Team. The iterative 
development and testing process results in a well-planned data collection strategy for individual 
studies. With the assistance of the OB/GYN Division of Research Informatics, the research team 
work to maintain a software toolset and workflow methodology for electronic collection and 
management of research and clinical trial data. REDCap servers are securely housed in an 
onsite limited access data center and is managed by the OB/GYN IT Division. The data is all 
stored on a private, protected university managed server. All users are authenticated via the CU 
and NYP LDAP servers and their access is restricted on a role-specific basis. Access can only 
be granted by administrators of the system.  
REDCap@OBGYN was developed specifically around HIPAA-Security guidelines and is 
implemented and maintained according to Columbia University and New York Presbyterian 
guidelines. All collected data are backed up daily. REDCap@OBGYN system ID is 4283.   
Source data will be stored on encrypted, password protected servers maintained by OBGYN IT 
at the CUMC server farm; system id is 3959. Some data may be collected on paper case report 
forms, which will be stored in a locked file cabinet in the Study Investigators’ office and will be 
accessible only to named research personnel. Privacy Protections Patient information will be 
collected by trained research personnel in a private setting. Patient confidentiality will be 
maintained following HIPAA rules and regulations.  
Data Safety and Monitoring   
To ensure safety of the subjects, local monitoring will be completed by the Quality Assurance 
Monitor for the Department of Obstetrics and Gynecology for this Investigator/Peer study. At 
each scheduled monitoring visit, the QA will randomly select a representative number of study 
subject charts to be reviewed. Additional monitoring will be based on the initial monitoring 
review. An independent monitor appointed by the Funder {Medicem} will review the data 
periodically throughout the duration of trial to ensure the subject safety, data quality and protocol 
compliance.  
  
Biostatistics  
Primary/Null Hypothesis, to be rejected is as follows:  
Dilapan is inferior to Misoprostol in efficacy for cervical ripening for induction of labor.  
Basic principles for an evaluation of the study are presented in this section. It is concerned 
mostly about the study populations and evaluation of the study endpoints, more detailed 


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 13 of 15  
  
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.  
Additionally, the primary outcome will be analyzed on each stratification factor. Mantel-Haenzsel 
test will be used to test the difference between the subgroups. This testing will be done for 
exploratory purposes only.  
  
Study populations  
Safety Population  
The Safety population will be comprised of all subjects to whom Dilapan-S® was inserted or who 
received at least one dose of misoprostol. This population will be based on the actual treatment 
received if this differs from that to which the subject was randomized. This population will be used 
for the analysis of safety data.   
Intent-to-treat Population (ITT)  
ITT includes all patients that were randomized into the study. 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.  
Per Protocol Population (PP)  
PP is a subset of ITT patients who received study treatment. Following patients will be excluded 
from the PP population:  
1. Patients with major protocol violation affecting the efficacy endpoints. Major protocol 
violations include (but are not limited to): a. Treatment assignment error  
b. Violation of one or more inclusion/exclusion criteria  
c. Use of forbidden medication  
2. Patients who were prematurely withdrawn  
3. Patients with 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 evaluation of efficacy endpoints as a sensitivity analysis.  
 
Evaluation of the primary variable  
The primary endpoint of this study is:  
Proportion of subjects achieving vaginal delivery within 36 hours after the initiation of the 
cervical ripening in Misoprostol and Dilapan-S® group.  
Proportion of patients in each group and their difference will be calculated. 97.5% one-sided 
confidence interval adjusted for the stratification factors (parity and gestational age) will be 
calculated for the difference in the proportions and conclusion about non-inferiority will be drawn 
from it taking into consideration 10% non-inferiority margin. Unadjusted confidence interval will 
be calculated as well.   


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 14 of 15  
  
Evaluation of the secondary variables  
Bishop score at 12 hours after the intervention and total length of hospital stay will be 
summarized separately for each arm. Means of the two treatment arms will be compared by 
two-sample t-test.  
All secondary variables considering rates and percentages of patients will be calculated for both 
arms. Difference in proportions will be derived together with a 95% two-sided confidence 
interval. The difference between treatment groups will be concluded if the confidence interval 
does not include zero.  
Maternal and neonatal outcomes will be summarized as reported in the CRF.  
  
Exploratory variables  
Exploratory variables will be evaluated from the adverse event and device deficiency reports. 
Number of cases and proportion of patients will be presented.  
  
Potential Risks   
The potential foreseeable risks to the subjects are:   
● pain and discomfort during insertion of Dilapan-S®  
● vaginal bleeding   
● rupture of membranes and cervical lacerations.  
● entrapment of Dilapan-S®  rods inside cervix  
● retraction into uterine cavity necessitating additional procedures for removal.   
● infection leading to chorioamnionitis/endometritis  
● allergic reaction to the hydrogel  
● risk of improper release or misuse of personal information or specimens.   
(the chance of this happening is very small; the research team has many protections in 
place to lessen this risk)  
● unexpected unknown risk to mother and fetus (very unlikely)  
  
Potential Benefits   
This trial may show that Dilapan-S® is a safe and effective method for cervical ripening and may 
increase the likelihood of vaginal delivery. If subjects decide to participate in this research study, 
they (and/or their newborn) may or may not directly benefit from their participation. The data 
gathered on maternal and neonatal outcomes will serve to increase the general knowledge 
regarding safe and effective methods for cervical ripening in women undergoing induction of 
labor. The study may also provide information if Dilapan-S®  is cost effective for cervical ripening 
in terms of impact on length of stay and has a satisfactory safety profile for use in outpatient 
setting.  
  
Alternatives   
The alternative to this study is not to participate and to continue receiving standard care during 
delivery and postpartum period.  


        
   
  
  
Version 3.1  dated SEP 4, 2020   
COMRED  
Page 15 of 15  
  
References  
1. Grobman, W. Techniques for ripening the unfavorable cervix prior to induction. 
UpToDate [online]. Wolters Kluwer. Available at:  
https://www.uptodate.com/contents/techniques‐for‐ripening‐the‐unfavorable‐cervixprior‐to‐
induction [Accessed July 30, 2018].  
2. ACOG Committee on Practice Bulletins ‐ Obstetrics. ACOG Practice Bulletin No. 107: 
Induction of labor. Obstet Gynecol. 2009 Aug;114(2 Pt 1):386‐97.   
3. Ten Eikelder ML, et al. Induction of labour at term with oral misoprostol versus a Foley 
catheter (PROBAAT‐II): a multicentre randomised controlled non‐inferiority trial. Lancet. 
2016 Apr 16;387(10028):1619‐28.   
4. Al‐Ibraheemi Z, et al. Misoprostol With Foley Bulb Compared With Misoprostol Alone for 
Cervical Ripening: A Randomized Controlled Trial. Obstet Gynecol. 2018 Jan;131(1):23‐29.   
5. Levine LD, et al. Mechanical and Pharmacologic Methods of Labor Induction: A 
Randomized Controlled Trial. Obstet Gynecol. 2016 Dec;128(6):1357‐1364.  
6. Hofmeyr GJ, et al. Vaginal misoprostol for cervical ripening and induction of labour. 
Cochrane Database Syst Rev. 2010 Oct 6;(10):CD000941.  
7. Alfirevic Z, et al. Oral misoprostol for induction of labour. Cochrane Database Syst Rev. 
2014 Jun 13;(6):CD001338.  
8. Harris PA, et al. Research electronic data capture (REDCap) ‐ a metadata‐driven 
methodology and workflow process for providing translational research informatics 
support. J Biomed Inform. 2009 Apr;42(2):377‐81.  
9. Spong CY, et al. Preventing the first cesarean delivery: summary of a joint Eunice  
Kennedy Shriver National Institute of Child Health and Human Development, Society for  
Maternal‐Fetal Medicine, and American College of Obstetricians and Gynecologists 
Workshop. Obstet Gynecol. 2012 Nov;120(5):1181‐93.  
10. Tang J, et al. WHO recommendations for misoprostol use for obstetric and gynecologic 
indications. Int J Gynaecol Obstet. 2013 May;121(2):186‐9.  
11. An RCT of a Synthetic Osmotic Cervical Dilator for Induction of Labour in Comparison to 
Dinoprostone Vaginal insErt (SOLVE). ClinicalTrials.gov [online]. Available at: 
https://clinicaltrials.gov/ct2/show/NCT03001661 [Accessed July 30, 2018].  
12. Saad AF, et al. A randomized controlled trial of Dilapan-S® vs Foley balloon for 
preinduction cervical ripening (DILAFOL trial). Am J Obstet Gynecol. 2019;220(3):275.e1-
275.e9 
13. Committee on Obstetric Practice. Committee Opinion No. 712: Intrapartum Management 
of Intraamniotic Infection. Obstet Gynecol. 2017 Aug;130(2):e95‐e101.  
  

SAP_001.pdf: 
 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 1 of 10 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Title: 
Dilapan vs Misoprostol for cervical ripening [COMRED – comparison of Misoprostol ripening 
efficacy with Dilapan] 
Study Ref.: 
AAAR8566 
 
 
DOCUMENT HISTORY 
VERSION NO.: 
DATE 
PURPOSE OF REVIEW/UPDATE: 
0.1 
2021-01-06 Initial version 
1.0 
2021-04-11 Additional secondary endpoints added, final edits, V1.0 being FINAL 
 
  
 
  
 
 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 2 of 10 
DOCUMENT APPROVAL INFORMATION 
Author(s): 
Name: 
Pekka Heikkilä 
Date: 
 
 
Title: 
Statistician, 
Neox s.r.o. 
Signature: 
 
 
 
 
 
Signing this document indicates my approval. 
Approvals: 
Name: 
Jan Waclav, MD 
Date: 
 
Title: 
Clinical & Medical Affairs 
Director, 
Medicem Technology s.r.o. 
Signature: 
 
 
 
 
Signing this document indicates my approval. 
 
Name: 
Jakub Macháček 
Date: 
 
 
Title: 
Head of Clinical Operations, 
Neox s.r.o. 
Signature: 
 
 
 
 
 
Signing this document indicates my approval. 
 
Name: 
Rachana Gavara 
Date: 
04/12/2021 
 
Title: 
Principal Investigator, 
Dept. of OB/GYN  
Columbia University 
Medical Centre  
 
Rachana 
Gavara 
 
 
 
 
Signing this document indicates my approval. 
 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 3 of 10 
Contents 
1. 
Overview and Study Plan .......................................................................................................................... 4 
1.1. 
Study Design ..................................................................................................................................... 4 
2. 
Study Procedures ..................................................................................................................................... 4 
3. 
Objectives ................................................................................................................................................ 4 
3.1. 
Primary Outcome .............................................................................................................................. 4 
3.2. 
Secondary Outcomes ......................................................................................................................... 4 
3.3. 
Safety Endpoints ................................................................................................................................ 5 
3.3.1. 
Undesirable side effects .............................................................................................................. 5 
3.3.2. 
Complications specific to dilator insertion .................................................................................... 5 
4. 
Hypothesis ............................................................................................................................................... 6 
4.1. 
Interim Analysis ................................................................................................................................. 6 
5. 
Determination of Sample Size ................................................................................................................... 6 
6. 
Statistical Principles .................................................................................................................................. 6 
6.1. 
General Statistical Considerations ....................................................................................................... 6 
6.1.1. 
Measures to Adjust for Multiplicity, Confounders and Heterogeneity ............................................ 7 
6.1.2. 
Design Techniques to Avoid Bias ................................................................................................. 7 
6.1.3. 
Missing Values, Outliers and Other Data Conventions................................................................... 7 
6.2. 
Analysis Populations .......................................................................................................................... 7 
6.2.1. 
Safety Population ....................................................................................................................... 7 
6.2.2. 
Intent-to-treat Population (ITT) ................................................................................................... 7 
6.2.3. 
Per Protocol Population (PP) ....................................................................................................... 7 
7. 
Statistical Methods ................................................................................................................................... 8 
7.1. 
Analysis of Baseline Characteristics ..................................................................................................... 8 
7.2. 
Analysis of the Primary Endpoint ........................................................................................................ 8 
7.3. 
Analysis of Secondary Endpoints ......................................................................................................... 8 
7.4. 
Safety Analysis................................................................................................................................... 8 
Software Documentation .................................................................................................................................. 9 
Tables, Graphs and Listings ............................................................................................................................... 9 
Abbreviations ................................................................................................................................................. 10 
References ..................................................................................................................................................... 10 
 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 4 of 10 
1. OVERVIEW AND STUDY PLAN 
 
1.1. STUDY DESIGN 
This is a non-inferiority, unblinded, randomized, controlled trial where 322 eligible participants undergoing IOL at 
≥37 weeks gestation at CUMC and admitted to labor and delivery unit will be enrolled and randomly assigned in a 
ratio 1:1 to either receive Dilapan-S® or Misoprostol for cervical ripening. 
2. STUDY PROCEDURES  
After randomization all participants will undergo assessment as per the floor protocol including Bishop score. 
Patients will have either 1-5 Dilapan-S® 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. Patients will be examined after 12 hours, 
Dilapan-S® rods will be removed and Bishop score will be reassessed. Patients in both groups 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 AROM. 
Intrapartum management will be according to institutional guidelines. All study participants will be contacted by 
phone 2 weeks after enrollment to find out if they needed any additional treatment following discharge. All study 
patients will be asked to fill out a questionnaire regarding their experience with the method of induction. Data will 
be collected by chart review and analysed based on the outlined statistical plan. 
3. OBJECTIVES 
The objective of this study is to assess the efficacy of Dilapan-S® for cervical ripening compared to Misoprostol 
in women undergoing IOL at or more than 37 weeks gestation. 
3.1. PRIMARY OUTCOME 
Proportion of women achieving vaginal delivery within 36 hours of intervention. 
3.2. SECONDARY OUTCOMES 
Individual and composite maternal and fetal outcomes including overall vaginal delivery rate, cesarean section rate, 
Bishop score after cervical ripening, infections, postpartum hemorrhage. Neonatal outcomes include Apgar scores, 
NICU admission and sepsis. 
 
Secondary endpoints are: 
● Overall vaginal delivery rate in each group  
● Rate of caesarean deliveries in each group  
● Rate of operative deliveries (vaginal plus caesarean) 
● Bishop score at 12 hours after the intervention and change in Bishop score  
● Percentage of subjects who did not receive all 6 misoprostol doses  
● Percentage of subjects with failed Dilapan-S insertion 
● Percentage of subjects delivering vaginally in 24 hours after the initiation of intervention  


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 5 of 10 
● Delivery time 
● Initiation of cervical ripening to delivery time  
● Initiation of oxytocin to delivery time  
● Total length of hospital stay  
● Maternal outcomes: 
● Chorioamnionitis  
● Endometritis within 2 weeks after delivery 
● Postpartum haemorrhage (EBL>1000cc and/or drop in HCT by 10 points) 
● 3rd and 4th degree lacerations  
● Neonatal outcomes: 
● Apgar score <7 at 5 min 
● Cord arterial blood pH and Cord arterial blood pH <7 
● Cord arterial blood base excess and Cord arterial blood base excess > -12mmol/l 
● NICU admission within 2 weeks after study intervention  
● Antibiotic use within 2 weeks after study intervention 
 
3.3. SAFETY ENDPOINTS 
3.3.1. UNDESIRABLE SIDE EFFECTS 
● Fever, nausea, vomiting and diarrhoea  
● Uterine tachysystole 
● Hyperstimulation 
● Uterine hypertonus 
● Failed induction of labor, arrest of first and second stage of labor 
● Abnormal fetal heart tracing during cervical ripening  
● Intrapartum fever 
 
3.3.2. COMPLICATIONS SPECIFIC TO DILATOR INSERTION 
● Vaginal bleeding  
● Rupture of membranes  
● Cervical laceration  
● Excessive pain causing need for analgesia during cervical ripening  
● Vasovagal reaction during insertion of the device  
● Entrapment of the device  
● Fragmentation of device during removal or insertion  
● Retraction of device into uterine cavity. 
● Failure to insert Dilapan-S®  


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 6 of 10 
4. HYPOTHESIS 
The hypothesis is based on the primary objective and one primary outcome, which is proportion of women 
achieving vaginal delivery within 36 hours of intervention.  
Null hypothesis states that Dilapan-S is inferior to Misoprostol in efficacy for cervical ripening for induction of labor. 
𝐻0: 𝑝𝑀−𝑝𝐷≥𝛿   
Alternative hypothesis states that Dilapan-S is non-inferior to Misoprostol in efficacy for cervical ripening for 
induction of labor. 
𝐻𝐴: 𝑝𝑀−𝑝𝐷<  𝛿  
4.1. INTERIM ANALYSIS 
The data was reviewed by Data and Safety Monitoring Board (DSMB) to ensure the safety aspects of the study. Data 
was presented without revealing the randomization. 
5. DETERMINATION OF SAMPLE SIZE 
The study is powered at 85% for detecting the primary outcome with a type 1 error at 2.5% for one-sided test. 
6. STATISTICAL PRINCIPLES 
6.1. GENERAL STATISTICAL CONSIDERATIONS 
The statistical analyses will be performed in accordance with ICH E9 guideline (ICH E9, 1998) and is based on all 
collected data. Statistical analyses will be performed at the 5% significance level.  
The quantitative variables will be summarized using the following parameters: 
- 
Number of non-missing data, 
- 
Mean,  
- 
Standard deviation, 
- 
Median, 
- 
Minimum and Maximum (range), 
- 
First and Third quartiles (interquartile range). 
 
The categorical/qualitative variables will be summarized using the following parameters: 
- 
Number of non-missing data, 
- 
Frequencies and percentages. 
 
All collected data will be presented in data listings. 
 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 7 of 10 
6.1.1. MEASURES TO ADJUST FOR MULTIPLICITY, CONFOUNDERS AND HETEROGENEITY 
Only one primary objective, outcome and pair of hypotheses is set. Subgroup/Covariate analyses will be introduced 
as sensitivity analysis if appropriate. 
6.1.2. DESIGN TECHNIQUES TO AVOID BIAS 
This is a prospective, randomized, controlled, open-label clinical trial to assess the performance and safety. 
6.1.3. MISSING VALUES, OUTLIERS AND OTHER DATA CONVENTIONS 
The analysis will be conducted per protocol.  
Besides, for primary and secondary objectives that explore trends over time, in the case of intermediate or final 
missing data, these will be replaced in accordance with the "intention to treat" method (ITT) and in particular by 
using the LOCF (last observation carried forward) method.  
6.2. ANALYSIS POPULATIONS 
6.2.1. SAFETY POPULATION 
The Safety population will be comprised of all subjects in whom Dilapan-S® was inserted or who received at least 
one dose of misoprostol. This population will be based on the actual treatment received if this differs from that to 
which the subject was randomized. This population will be used for the analysis of safety data.  
6.2.2. INTENT-TO-TREAT POPULATION (ITT) 
ITT includes all patients that were randomized into the study. ITT subjects will be analysed 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. 
6.2.3. PER PROTOCOL POPULATION (PP) 
PP is a subset of ITT patients who received study treatment. Following patients will be excluded from the PP 
population: 
1. Patients with major protocol violation affecting the efficacy endpoints. Major protocol violations include 
(but are not limited to): 
a. Treatment assignment error 
b. Violation of one or more inclusion/exclusion criteria 
c. Use of forbidden medication 
2. Patients who were prematurely withdrawn 
3. Patients with 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 evaluation of efficacy endpoints as a sensitivity analysis. 
 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 8 of 10 
7. STATISTICAL METHODS 
7.1. ANALYSIS OF BASELINE CHARACTERISTICS 
Demographic data will be summarized.  
7.2. ANALYSIS OF THE PRIMARY ENDPOINT 
The primary outcome is the proportion of subjects achieving vaginal delivery within 36 hours after the initiation of 
the cervical ripening in Misoprostol and Dilapan-S® groups. Proportion of patients in each group and their difference 
will be calculated. One-sided 97.5% confidence interval1 adjusted for the stratification factors (parity and 
gestational age) will be calculated for the difference in the proportions and conclusion about non-inferiority will be 
drawn from it taking into consideration a 10% non-inferiority margin. Unadjusted confidence interval will be 
calculated as well.  
Additionally, the primary outcome will be analysed for each stratification factor. Mantel-Haenszel test will be used 
to test the difference between the subgroups. 
7.3. ANALYSIS OF SECONDARY ENDPOINTS 
All quantitative secondary variables will be summarized separately for each arm. Means of the two treatment arms 
will be compared with two-sample t-test and Wilcoxon rank-sum test as appropriate.  
All secondary variables involving rates and percentages, will be calculated for both arms. Difference in proportions 
will be derived together with a 95% two-sided confidence interval. The difference between treatment groups will 
be concluded if the confidence interval does not include zero. 
Maternal and neonatal outcomes will be summarized as reported in the CRF. 
Delivery time will be presented using Kaplan-Meier curves with censoring for caesarean delivery.  
7.4. SAFETY ANALYSIS 
Exploratory variables will be evaluated from the adverse event and device deficiency reports. Number of cases and 
proportion of patients will be presented. 
 
 
                                                           
1 Lower limit of two-sided 95% confidence interval is same as using one-sided 97.5% confidence interval. 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 9 of 10 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses, tables, figures and listings will be created with SAS® 9.4.  
TABLES, GRAPHS AND LISTINGS 
Baseline characteristics 
Table 14.1.1 Disposition summary 
Table 14.1.2 Summary statistics of Demographic data 
Table 14.1.3 Summary statistics of Baseline characteristics 
 
Efficacy data 
 
Table 14.2.1  
Summary of Delivery Characteristics 
Table 14.2.2.1 
Primary analysis for proportion of Vaginal Delivery within 36 hours 
Table 14.2.2.2 
Analysis for proportion of Vaginal Delivery within 24 hours 
Table 14.2.3.1 
Analysis for proportion of Mode of Delivery 
Table 14.2.3.2 
Analysis of Delivery Time 
Table 14.2.4.1 
Analysis of Bishop score 
Table 14.2.5.1 
Analysis of Total Length of Hospital Stay 
 
Table  14.2.6.1 
Summary statistics of Maternal Outcomes 
Table  14.2.7.1 
Summary statistics of Neonatal outcomes 
 
Safety data 
Table  14.3.1 Summary statistics of Undesirable Side Effects 
Table  14.3.2 Summary statistics of Complications Specific to Dilator Insertion 
 
Listings  
 
Listing 16.2.4.1 
Eligibility and Informed Concent 
Listing 16.2.4.2 
Treatment and Randomizatoin 
Listing 16.2.4.2 
Indication of Induction of Labor 
Listing 16.2.4.3 
Pre-Induction data 
Listing 16.2.4.4 
Delivery data 
Listing 16.2.4.5 
Postpartum data 


 
 
DOCUMENT TITLE: 
 
VERSION NO.: 
Final 1.0 
STATISTICAL ANALYSIS PLAN 
VERSION DATE: 
2022-07-06 
 
 
 
Neox Clinical Research 
Confidential 
Page 10 of 10 
Listing 16.2.4.6 
Maternal readmission data 
Listing 16.2.4.7 
Newborn data 
Listing 16.2.4.8 
Neonatal Post-Partum data 
ABBREVIATIONS 
AROM 
Artificial Rupture of Membranes 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case Report Form 
CUMC 
Columbia University Medical Center  
DSMB 
Data Safety Monitoring Board 
EBL 
Estimated Blood Loss 
EMA 
European Medicines Agency 
HCT 
Hematocrit  
ICH 
International Conference on Harmonization 
IOL 
Induction of Labour 
ITT 
Intent to Treat 
NICU 
Neonatal intensive care unit 
PP 
Per Protocol 
 
REFERENCES 
Committee for Proprietary Medicinal Products (CPMP). (2000). Points to Consider on Switching Between Superiority 
and Non-Inferiority Trials. European Medicinal Agency (EMA). 
ICH E3. (1996). ICH Topic E3 Structure and Content of Clinical Study Reports. The International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. 
ICH E9. (1998). Statistical Principles of Clinical Trials (E9). The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use. 
The Columbia University Medical Center and New York-Presbyterian Hospital. (2019). Dilapan vs Misoprostol for 
cervical ripening. Medicem Technology s.r.o.