Conditions: Premature Rupture of Fetal Membranes
Keywords: Premature Rupture of Membrane (Pregnancy) PROM Cervical Ripening Induced Labor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
The CRB study is designed to study the safety and effectiveness of the Cook Cervical Ripening Balloon (CRB) for the induction of labor in term and near-term patients with premature rupture of membranes (PROM).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: CRB intervention 2: Pitocin
Intervention descriptions: intervention 1: Labor induction using the CRB intervention 2: Labor induction using Pitocin

Protocol document:
Prot_SAP_000.pdf: 
Cook Research Incorporated 
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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
 
 Study protocol 09-014-07  
STUDY PROTOCOL  
 
 
 
 
Randomized study to compare the Cook Cervical Ripening Balloon plus 
Pitocin to Pitocin alone in PROM patients 
 
 
 
 
Global Clinical Number 09-014 
 
 
 
 
Sponsor: 
 
 
 
 
 
Jennifer Kerr, President 
Cook Research Incorporated 
  
 
 
1 Geddes Way 
 
 
 
West Lafayette, IN 47906 
 
 
 
USA 
 
 
 
765.463.7537 
 
 
 
Jennifer.Kerr@CookMedical.com 
 
Data Coordinating Center and Monitor: 
Cook Research Incorporated 
 
 
 
 
 
 
 
1 Geddes Way 
 
 
 
 
 
 
 
West Lafayette, IN 47906 
 
 
 
 
 
 
 
USA 
 
 
 
 
 
 
 
765-463-7537 
 
Coordinating Clinical Investigator:  
 
Hugh Miller, MD 
 
 
 
 
 
 
 
Tucson Medical Center 
 
 
 
 
 
 
 
5301 E. Grant Road 
 
 
 
 
 
 
 
Tucson, AZ 85712 
 
 
 
 
 
 
 
USA 
 
 
 
 
 
 
 
520-881-9662 
 
 
 
 
 
 
 
 


Cook Research Incorporated 
Evaluation of CRB in PROM Patients 
STUDY PROTOCOL SIGNATURE PAGE 
Page 2 of 22 
This clinical investigation will be conducted in accordance with the study protocol, 
21 CFR 812, ICH-GCP, and other applicable requirements as appropriate. The 
protocol will be revised, as appropriate, based on new information. 
Signatures: 
Sponsor Contact 
ftt:>/.l>EA.J / 
Printed Name 
Title 
Principal Investigator 
I hereby confirm that I approve of this Study Protocol and agree to comply with its 
terms as laid out in this document. 
Signature 
Printed Name 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 · 27 Apr 2018 
DD/MM/YYYY 
Title 


Cook Research Incorporated 
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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
CONFIDENTIALITY STATEMENT 
 
 
 
 
 
 
 
 
This document shall be treated as a confidential 
document for the sole information and use of the clinical 
investigation team and the Institutional Review Board 
(IRB). 


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Evaluation of CRB in PROM Patients 
 
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Protocol 09-014-07 ∙ 27 Apr 2018 
Introduction:  
Cervical ripening and induction of labor continues to be a significant problem for 
patients with premature rupture of membranes (PROM) at term and near term with 
an unfavorable cervix. Despite the fact that some chemical means of effecting 
cervical ripening exist, their effectiveness is unpredictable in PROM patients. The 
purpose of this study is to compare the Cook Cervical Ripening Balloon (CRB) 
plus Pitocin to Pitocin alone in term and near term PROM patients not in labor.  
 
Objectives: 
To evaluate the safety and effectiveness of the CRB to expedite labor in term and 
near term PROM patients not in labor in conjunction with Pitocin compared to 
Pitocin alone.  
 
 
 
The primary effectiveness endpoint is the time from start of labor induction to 
delivery. 
 
The primary safety endpoint is the incidence of protocol-defined chorioamnionitis.  
 
Study Design:  
This is a prospective, controlled, randomized, multicenter study to compare the 
safety and effectiveness of the CRB plus Pitocin to Pitocin alone in term and near 
term PROM patients not in labor. 
 
This study intends to enroll up to 200 patients, randomized 1:1 into two treatment 
groups, at up to five investigational sites. 
 
Inclusion Criteria:  
1. 
Intrauterine pregnancy ≥ 34 0/7 and ≤ 42 0/7 weeks 
2. 
PROM not in labor  
3. 
Bishop score ≤ 6 
4. 
Maternal age ≥ 18 years old 


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Evaluation of CRB in PROM Patients 
 
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Protocol 09-014-07 ∙ 27 Apr 2018 
Exclusion Criteria: 
1. 
Patient unwilling or unable to provide informed consent 
2. 
Evidence of chorioamnionitis at enrollment 
3. 
Malpresentation (e.g., transverse fetal orientation, breech presentation) 
4. 
History of prior cesarean section or uterine surgery 
5. 
Major fetal anomaly or aneuploidy (anomalies that require immediate 
medical or surgical intervention) 
6. 
Significant vaginal bleeding 
7. 
Multiple gestation  
8. 
Contraindication to vaginal delivery (e.g., placenta previa, vasa previa, 
placenta percreta, prolapsed umbilical cord, active genital herpes 
infection, invasive cervical cancer) 
9. 
Contraindication to labor induction 
10. Abnormal (Category III) fetal heart rate patterns 
11. Maternal heart disease requiring medication or resulting in significant 
cardiac dysfunction 
12. Severe maternal hypertension (chronic or preeclampsia) 
13. Patient receiving or planning to undergo exogenous prostaglandin 
administration 
14. Polyhydramnios 
15. Pelvic structural abnormality that would preclude labor 
16. Presenting part above the pelvic inlet (i.e., - 4 station and above) 
 
 
Study Considerations: 
The CRB is indicated for mechanical dilation of the cervical canal prior to labor 
induction at term when the cervix is unfavorable for induction. The CRB is cleared 
for commercial use and is routinely used in labor and delivery patients at many 
institutions for cervical ripening. It has been adopted over the past several years 
as an important method of ripening the cervix in nulliparous and multiparous 
women who have an indication for delivery.  
 


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Protocol 09-014-07 ∙ 27 Apr 2018 
Although it has been used more frequently in term or near term patients, the CRB 
has also been used at other gestational ages where delivery is sought in a patient 
who has an unfavorable cervical exam, i.e., the cervix is not ripe or is unlikely to 
respond to the normal labor stimulants. In many of these circumstances the 
contraindications to the use of this device are discounted because of the inherent 
benefits the device affords in achieving labor in a reasonable time period. One of 
these conditions is the event of rupture of membranes (ROM), which is listed as a 
contraindication in the CRB Instructions for Use (IFU). This contraindication is 
based on the idea that anything that breeches the cervix might increase a 
woman’s risk for infection. Several devices that impose the same risk and are 
approved for this indication are already in use: the fetal scalp electrode, which 
actually attaches to the fetus, and the intrauterine pressure catheter. Both of these 
devices have been part of clinical practice for over 30 years. In each of these 
cases the device is being used during labor to improve the quality of monitoring or 
safety of labor. 
 
It is known that a longer latency period, the period from ROM to delivery, 
increases the chance for infection in the form of chorioamnionitis, neonatal sepsis, 
or postpartum endometritis. It is for this reason that once ROM has occurred in the 
term or near term pregnancy, it is important to expedite the course of labor to 
avoid this infectious outcome. In the current clinical environment there are 
approved products and products used off-label to achieve delivery. The use of 
Pitocin, Cytotec®, Cervidil® and the CRB have been the primary methods to 
achieve this goal.  
 
Risks and Foreseeable Adverse Device Effects: 
Please reference the CRB IFU for a list of adverse events that may be considered 
potential risks to patients participating in this study. Additional risks unique to the 
use of the CRB in term and near term PROM patients include intrapartum 
infection, adverse material reaction and entanglement of the umbilical cord. 


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Evaluation of CRB in PROM Patients 
 
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Protocol 09-014-07 ∙ 27 Apr 2018 
Appropriate obstetric care and standard procedures will be used to manage the 
risks unique to the use of the CRB in term and near term PROM patients. 
 
Study Procedure Initiation: 
Patients meeting all inclusion criteria and no exclusion criteria will be invited to 
participate in the study. Patient eligibility for enrollment will be based on known 
information at the time of enrollment; information obtained at a later date may 
contradict this information but will not be considered a noncompliance with the 
study protocol. Patients will have the study procedures, risks and benefits 
explained to them and will have the opportunity to ask questions. Point of 
enrollment occurs when the patient is randomized into the study.   
 
For patients who have not received any prenatal care or who, for any other 
reason, have not been assessed for abnormal placentation, it is recommended 
that an ultrasound be performed prior to study enrollment to assess the location of 
the placenta. Enrolled patients will be randomized 1:1 to treatment with the CRB 
plus Pitocin (Group A) or Pitocin alone (Group B). Randomization will utilize a 
computer generated randomization assignment that is stratified for parity, i.e., 
nulliparous and multiparous women will be accounted for in the randomization 
assignment. Approximately 200 pregnant women who meet the eligibility criteria 
will be enrolled into the study. 
 
Both groups A and B will receive Pitocin in accordance with ACOG 
recommendations to be started within 90 minutes of study enrollment. Limit 
ambulation per site’s standard of care following administration of Pitocin. 
 
Patients randomized to Group A will undergo CRB placement within 90 minutes of 
study enrollment. Please reference the CRB IFU for a description of patient 
preparation and suggested instructions for use.  In this study, the intrauterine 
balloon should be inflated with 60 cc of saline, and the vaginal balloon should be 
inflated with 30 cc of saline.  


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Protocol 09-014-07 ∙ 27 Apr 2018 
Pitocin Administration: 
Pitocin will be administered in accordance with current ACOG recommendations 
and following institutional protocols. Details of Pitocin administration, including the 
maximum amount of Pitocin administered, amount of Pitocin administered at the 
time of delivery (prior to post-delivery bolus) and total amount of Pitocin infused, 
will be recorded for each patient. Providers are permitted to suspend Pitocin for 
periods of time at their discretion for maternal or fetal indications. 
 
Intrapartum Procedure Management: 
The CRB will remain in situ for up to 12 hours or until it falls out of the vagina or 
when it is determined that the intrauterine balloon has descended past the cervix; 
please reference the IFU for a description of device removal. The removal of the 
CRB will have no impact on the use of Pitocin, its dosage, or its continued use. 
Those decisions will be made based on progress of labor and institutional 
standard of care, and in accordance with the Pitocin Administration guidelines 
described above.  
 
All other aspects of labor management will be at the discretion of the primary 
obstetrical provider. Patients known to be group B streptococcus (GBS) positive 
will receive prophylaxis in accordance with CDC guidelines. A cervical exam 
including Bishop score should be completed at baseline (i.e., within 90 minutes of 
point of enrollment and prior to start of labor induction) and every 6 hours until 
delivery.  
 
The use of fetal scalp electrodes and intrauterine pressure catheters will also be at 
the discretion of the obstetrical provider. Women will be able to choose analgesia 
or regional anesthesia depending on their preference. If a spontaneous delivery is 
not possible the ultimate decision to deliver by an operative vaginal procedure 
versus cesarean section will be made by the obstetrical provider using institutional 
and national criteria. 
 


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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
Uterine activity relative to contraction frequency and cervical change will be 
monitored along with fetal wellbeing (e.g., fetal heart tones assessment) per the 
discretion of the obstetrical provider. 
 
Statistical Considerations: 
Primary Effectiveness Hypothesis 
The primary effectiveness endpoint, the time from start of labor induction to 
delivery, will be analyzed on a per-patient basis based on the intent-to-treat 
population. The primary effectiveness hypothesis is that patients treated with the 
CRB and Pitocin will experience decreased time from start of labor induction to 
delivery than patients treated with Pitocin alone. 
 
  
H0: tCRB + PITOCIN > tPITOCIN   
 
  
H1: tCRB + PITOCIN ≤ tPITOCIN  
Where:  
 
tCRB + PITOCIN: Mean time from start of labor induction to delivery in patients 
treated with the CRB and Pitocin  
 
tPITOCIN: Mean time from start of labor induction to delivery in patients treated 
with Pitocin alone 
 
The null hypothesis will be rejected in favor of the alternate hypothesis indicating 
that the treatment with the CRB and Pitocin is more effective than Pitocin alone at 
a p-value < 0.025.  
 
Primary Safety Hypothesis 
The primary safety endpoint, the incidence of protocol-defined chorioamnionitis, 
will be analyzed on a per-patient basis based on the per-protocol population. The 
primary safety hypothesis is that patients treated with the CRB and Pitocin will 
experience non-inferior rates of protocol-defined chorioamnionitis than patients 
treated with Pitocin alone. 
 
  
H0: πCRB + PITOCIN > πPITOCIN + δ 
 
  
H1: πCRB + PITOCIN ≤ πPITOCIN + δ 


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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
Where: 
 
πCRB + PITOCIN: Incidence of protocol-defined chorioamnionitis in patients treated 
with the CRB and Pitocin  
 
πPITOCIN: Incidence of protocol-defined chorioamnionitis in patients treated with 
Pitocin alone 
 
δ: Margin of non-inferiority, set at 10% for this study 
 
The null hypothesis will be rejected in favor of the alternate hypothesis indicating 
that the treatment with the CRB and Pitocin is as safe as Pitocin alone at a p-value 
< 0.025.  
 
Secondary Endpoints 
The following secondary endpoints will be analyzed on a per-patient basis based 
on the per-protocol population: 
• Incidence of failed induction, 
• Incidence of cesarean section, 
• Incidence of post-partum endometritis, and 
• Incidence of cord prolapse. 
 
For each outcome, the CRB and Pitocin will be compared to Pitocin alone, to 
assess for a significantly reduced rate. P-values will be adjusted using the Holm 
method controlling the family-wide Type I error rate at 0.05. 
 
Additional Measures 
The following additional measures will be reported: 
• Time from PROM to delivery, 
• Length of each stage of labor, 
• Amount of Pitocin used, 
• Incidence of post-partum hemorrhage, 
• 1 minute, 5 minute, and 10 minute Apgar scores, 


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COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
• Time from start of labor induction to delivery in patients with vaginal births, 
• NICU admission rate, 
• Total maternal hospital stay, 
• Total newborn hospital stay, 
• General cost analysis based on service utilization, and 
• Maternal and newborn resource allocation. 
 
Sample Size Calculations 
Sample size calculations for the primary effectiveness hypothesis were performed 
using data from Sanchez-Ramos, et al.1 using a one-tailed t-test with α=0.025, 
power=0.80 and a pooled standard deviation of 300. The expected mean time 
from start of labor induction to delivery was 416 minutes for the CRB and Pitocin 
and 539 minutes for Pitocin alone. This resulted in a required sample size of 
190 patients, or 95 per group. 
 
Sample size calculations for the primary safety hypothesis were performed using 
an expected rate of 4% for each group, derived from the rate of chorioamnionitis 
observed in the literature. 1,2,3,4,5,6,7 A one-sided exact test, α=0.025, power=0.80 
and non-inferiority margin of 10% resulted in a required sample size of 
124 patients, or 62 per group. 
                                                 
1 Sanchez-Ramos L, Chen AH, Kaunitz AM, Gaudier FL, Delke I. Labor induction with intravaginal misoprostol 
in term premature rupture of membranes: a randomized study. Obstet Gynecol. 1997;89(6): 909-912. 
2 Guinn DA, Davies JK, Jones RO, Sullivan L, Wolf D. Labor induction in women with an unfavorable Bishop 
score: randomized controlled trial of intrauterine Foley catheter with concurrent oxytocin infusion versus 
Foley catheter with extra-amniotic saline infusion with concurrent oxytocin infusion. Am J Obstet Gynecol. 
2004;191(1): 225-229. 
3 Hannah ME, Ohlsson A, Farine D, Hewson SA, Hodnett ED, Myhr TL, et al. Induction of labor compared with 
expectant management for prelabor rupture of the membranes at term. TERMPROM Study Group. N Engl J 
Med. 1996;334(16):1005-1010. 
4 Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional 
delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 
2006;19(3):177-187. 
5 Heinemann J, Gillen G, Sanchez-Ramos L, Kaunitz AM. Do mechanical methods of cervical ripening 
increase infectious morbidity? A systematic review. Am J Obstet Gynecol. 2008;199(2):177-188. 
6 Kehl S, Ehard A, Berlit S, Spaich S, Sutterlin M, Siemer J. Combination of misoprostol and mechanical 
dilation for induction of labour: a randomized controlled trial. Eur J Obstet Gynecol Reprod Biol. 
2011;159(2):315-319. 
7 Wolff K, Swahn ML, Westgren M. Balloon catheter for induction of labor in nulliparous women with prelabor 
rupture of the membranes at term. A preliminary report. Gynecol Obstet Invest. 1998;46(1):1-4. 


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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
Cook intends to enroll 200 patients to account for those patients who might 
withdraw. 
 
General Statistical Analyses 
Statistical analyses will be performed using SAS® for Windows® (release 9.3 or 
higher) or other widely accepted statistical software. Clinically relevant baseline 
variables will be tabulated and compared between the treatment groups. 
Categorical variables will be assessed using appropriate contingency table 
analyses (chi-square test or Fisher's exact test) and logistic regression to assess 
the importance of covariates. Continuous variables will be tested using appropriate 
tests such as ANOVA, unpaired Student's t-test, or Wilcoxon rank-sum test, 
depending on variable distribution, and linear regression and repeated measure 
where appropriate. Survival analysis techniques such as Kaplan-Meier or Cox 
Proportional Hazards will be incorporated if censoring of data occurs. 
 
Measures to be Taken to Avoid or Minimize Bias 
This study is designed as a prospective, randomized, controlled clinical trial to 
minimize bias in both assigning patients to treatments and in analyzing the results. 
 
Randomization 
Assignment of patients to a treatment group will be by block randomization within 
each site and stratum. Sites will not be informed of the block size. 
 
Missing Data 
Due to the short-term follow-up of this study, a minimal amount of missing primary 
safety and effectiveness data is expected. Ten additional patients have been 
added to the required sample size to account for missing data. If necessary, 
multiple imputation will be used where the imputed values will be samples from the 
empirical distribution of the separate treatment groups.  
 


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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
The intent-to-treat population is defined as all patients who are randomized. The 
per-protocol population is defined as those patients who received the treatment as 
specified in their randomization.   
 
Site-level Poolability 
Poolability of data from multiple sites will be verified by examining the interaction 
between treatment arm and study site for the primary effectiveness and safety 
endpoints. Site-level poolability will be considered appropriate provided that these 
results are non-significant at the 0.05 level. 
 
Adverse Event Definitions and Reporting: 
Adverse events (AEs) are to be reported to the Data Coordinating Center using 
the appropriate case report form. In case of adverse device effects, completed 
forms will be submitted to the Data Coordinating Center as soon as possible upon 
knowledge of the event. 
 
The Data Coordinating Center will review the information submitted for possible 
reporting to the Sponsor. The Sponsor shall, if required according to applicable 
regulations, report the event to the appropriate Regulatory Authority. The Principal 
Investigator (PI) or designee will notify his/her IRB of applicable events according 
to institutional guidelines.  
 
Device Identification and Tracking: 
Devices under investigation will be tracked throughout the course of the study 
through use of a Product Log, upon which lot numbers, quantity and disposition of 
devices will be recorded. Product Logs will be maintained in the site’s Investigator 
File. Additionally, the lot number of each device used in a subject will be recorded 
on the case report forms. 


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Protocol 09-014-07 ∙ 27 Apr 2018 
Deviations from the Study Protocol: 
Investigators are not allowed to deviate from this protocol without prior 
authorization by the Sponsor except under emergency situations when necessary 
to preserve the rights, safety and well-being of human subjects. 
 
Deviations and noncompliances will be recorded together with an explanation. 
Deviations or noncompliances that impact the rights, welfare, or safety of patients 
shall be reported to the Sponsor and IRBs as required and as soon as possible. 
 
Data Collection: 
All primary, secondary and tertiary data will be collected and entered by the 
investigative site into an electronic case report form (eCRF) system. This is a 
secure, web-based system, allowing those with permission to access data from 
any location at any time.  
 
The eCRFs will reflect maternal events until the mother is discharged from the 
hospital and newborn events until the newborn is discharged from the hospital. If 
the newborn remains hospitalized at 60 days after birth, the eCRFs will reflect all 
events in the first 60 days of life. The data to be collected will include, but not be 
limited to: 
1. Prenatal history, 
2. Relevant medical and surgical history, 
3. Antimicrobial medications administered during the course of the study 
and Pitocin from start of induction to delivery, 
4. Basic biometric markers such as weight and height, 
5. Intrapartum events, times and treatments, and 
6. Maternal and newborn adverse events, duration of stay and treatments. 
 
Research Staff: 
All investigators and research staff will observe 21 CFR regulations and Good 
Clinical Practices (GCP) guidelines in the securing of patient consent, the 


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COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
documentation of the consent process, data recording, security of protected health 
information, entry of data in the eCRF system and maintenance of clinical data in 
general. It is the PI’s obligation to ensure that documentation of all relevant data 
such as relevant medical history, date of study enrollment, visit dates, results of 
examinations or tests and adverse events are correctly entered in each 
participant’s file. 
 
Case Report Forms and Source Documentation:  
Every effort will be made to enter the data accurately and in a timely manner. 
Source data are to be retained for data entered into the eCRF system. Instances 
of missing or uninterpretable data will be discussed with the investigator and 
research staff for resolution. Checking the eCRF entries for completeness and 
clarity, and cross-checking with source documents, will be required to monitor the 
progress of the study. Moreover, the FDA, IRBs, and/or the Sponsor and its 
designees may wish to carry out such source data checks and/or onsite audit 
inspections. Direct access to source data may be required for these inspections 
and audits; the audits will be carried out giving due consideration to data 
protection and medical confidentiality. The investigator agrees to give the auditor 
access to all relevant documents for review. The same applies in case of an 
inspection by the Regulatory Authority. 
 
Data Management and Monitoring: 
The study will be monitored through a combination of onsite and remote 
monitoring and in accordance with the International Conference on Harmonization 
(ICH)-GCP and 21 CFR 812.46. Written procedures for monitoring the study are 
maintained by the Data Coordinating Center. Data will be reviewed for missing 
data, data consistency and reasonableness of responses. Discrepancies will be 
resolved through a formal query process involving direct contact with investigators 
or research coordinators. Standard operating procedures maintained by the Data 


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Protocol 09-014-07 ∙ 27 Apr 2018 
Coordinating Center will be followed for database management, data verification 
and data archiving and retention. 
 
Archiving Study Records: 
According to ICH guidelines and FDA regulations, essential documents should be 
retained for a minimum of 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. However, 
these documents should be retained for a longer period if required by the 
applicable legal requirements and/or local IRB/institutional requirement. 
 
Good Clinical Practice: 
The procedures set out in this study protocol are designed to ensure that the 
Sponsor and investigator abide by the principles of the GCP guidelines of the ICH, 
the Declaration of Helsinki (2000, with clarification in 2004) and all applicable FDA 
regulations. The study also will be carried out in keeping with local legal 
requirements. 
 
The PI is responsible for obtaining approval of this study by the relevant IRB for 
his/her institution; the investigation will not begin at a site until a favorable opinion 
of the relevant IRB has been obtained. The PI is responsible for complying with 
requirements imposed by his/her IRB. Furthermore, the investigator will ensure 
that local regulations concerning data protection are followed. 
 
Informed Consent: 
Prior to the administration of any study-specific tests or procedures required in this 
protocol, the investigator or designee will obtain informed consent in writing from 
all study participants. Each participant, investigator or designee and witness (as 


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COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
applicable) must personally sign and date the informed consent form (ICF). Copies 
of the signed ICF for each patient will be retained at the investigative site. 
 
A copy of the signed ICF will be given to the participant for her records. The ICF 
will explain the nature of the study, its objectives and its potential risks. 
Furthermore, it will detail the requirements of the participant, all trial procedures, 
alternative procedures and the fact that the participant is free to withdraw her 
consent at any time without reason. Details of indemnity and insurance may also 
be stated. 
 
As required by ICH-GCP the participant will give in writing her authorization that 
the study data may be given for review to the responsible authorities and that 
Sponsor representatives may view the participant’s medical records for verification 
of clinical data. The ICF will be available in a language understandable to the 
participant. 
 
If a protocol amendment is required, the ICF will be revised if applicable to reflect 
the changes to the protocol. After the ICF is revised, it must be reviewed and 
approved by the appropriate IRBs, and signed by all participants subsequently 
enrolled in the study. Upon request of the IRBs, the revised ICF may also be 
signed by those previously enrolled in the study. 
 
Criteria and Procedures for Withdrawal: 
A patient may decide to withdraw from the study at any time either before or after 
undergoing the procedure without prejudice or loss of care. The PI may also 
decide to withdraw the patient from the study at any time based on medical 
judgment. In these instances, the appropriate study visit and study termination 
data will be submitted to the Data Coordinating Center, and will include the reason 
why the patient has been withdrawn from the study.  


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Patients who withdraw consent after study enrollment will be followed until the time 
of their withdrawal. Any data collected on the patient up to the point of withdrawal 
may be used in the study. No patient will be removed from the study unless the 
patient has withdrawn his/her consent before treatment or no treatment was ever 
attempted. 
 
Confidentiality: 
All study findings and documents will be regarded as confidential. The investigator 
and members of his/her research team must not disclose such information without 
prior written approval from the Sponsor. The anonymity of participants must be 
maintained. Participants will be identified in the eCRF system and on other 
documents submitted to the Sponsor by their participant number, initials and/or 
birth date, not by name.  
 
Publication: 
At the conclusion of the study, the primary study outcomes will be published in a 
reputable scientific journal. Publication policy, rights and obligations for this study 
have been negotiated, detailed and defined in the study’s contractual documents 
with the research sites and investigators.  
 
Definitions: 
Apgar score8 – An objective scoring system used to evaluate the condition of a 
newborn after birth.  
                                                 
8 Apgar V, Holaday DA, James LS, Weisbrot IM, Berrien C. Evaluation of the newborn infant: second report. 
JAMA. 1958;168:1985-1988. 


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Score Appearance 
(coloration) 
Pulse 
(heart rate) 
Grimace 
(reflex irritability) 
Activity 
(muscle tone) 
Respiration 
(breathing effort) 
0 
Blue or pale  
all over 
Absent 
No response  
Limp 
Absent 
1 
Blue or pale 
 at extremities < 100 bpm Grimace or feeble cry Weak, some 
movement Weak or irregular 
2 
Pink all over > 100 bpm 
Cry or pull away 
Active 
movement 
Strong cry 
 
Arrest of descent – Failure of the presenting fetal part to continue to descend 
during the second stage of labor despite uterine contractions and maternal effort 
(pushing). 
 
Arrest of dilation – Failure of the cervix to progressively dilate despite active 
labor. 
 
Bishop score9 – A scoring system used to help predict the success of labor 
induction. For this study, a standard Bishop score will be calculated using the 
scoring system below. No additional modifiers will be used in the calculation of the 
Bishop score. 
Score 
Dilatation 
Effacement 
Station 
Position 
Consistency 
0 
closed 
0 – 30% 
-3 
Posterior 
Firm 
1 
1 – 2 cm 
40 – 50% 
-2 
Mid-position 
Medium 
2 
3 – 4 cm 
60 – 70% 
-1, 0 
Anterior 
Soft 
3 
5+ cm 
80+% 
+1, +2 
- 
- 
 
                                                 
9 Bishop E. Pelvic scoring for elective induction. Obstet Gynecol. 1962;24:266-268. 
 


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COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
Chorioamnionitis10 – A complication of pregnancy caused by bacterial infection 
of the fetal amnion and chorion membranes. A diagnosis of chorioamnionitis will 
include maternal fever > 100.4°F (38.0°C) plus at least two of the following 
symptoms with no other documented source of infection: 
• Sustained maternal tachycardia with heart rate > 100 bpm, 
• Fetal tachycardia with fetal heart rate > 160 bpm for at least 10 minutes, 
• Foul smelling amniotic fluid, 
• White blood cell (WBC) count > 15,000, 
• C-reactive protein more than 2 mg/dL, or  
• Uterine tenderness. 
 
Cord prolapse – A condition that occurs when the umbilical cord descends 
alongside or beyond the fetal presenting part.  
 
Dystocia – Pathologic or difficult labor, which may be caused by an obstruction or 
constriction of the birth passage or abnormal size, shape, position, or condition of 
the fetus. 
 
Febrile – Temperature > 100.4˚F (38.0˚C). 
 
Labor – A patient will be considered in labor if she is having regular, painful 
uterine contractions > 6/hr resulting in progressive cervical effacement and 
dilatation. 
 
                                                 
10 Tita A, Andrews W. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol. 2010;37(2):339-
354. 
 


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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
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Non-reassuring fetal heart tones (NR FHT)11 – For this study, only Category III 
NR FHT will be considered adverse events. NR FHT are considered Category III 
(abnormal) when the fetal heart rate tracing shows EITHER of the following:  
• Sinusoidal pattern or 
• Absent variability with recurrent late decelerations, recurrent variable 
decelerations, or bradycardia. 
 
Postpartum endometritis12 – An infection of the decidua (i.e., pregnancy 
endometrium). Evidence of postpartum endometritis will include maternal fever 
> 100.4°F (38.0°C) on any two of the first 10 days postpartum, exclusive of the first 
24 hours, with no other documented source of infection; symptoms generally 
include foul-smelling uterine discharge and uterine tenderness. A positive 
laboratory result may be obtained for verification of the diagnosis.  
 
Postpartum hemorrhage13 – The loss of greater than 500 mL of blood following 
vaginal delivery or 1000 mL of blood following cesarean section.  
 
Premature rupture of membranes (PROM) – Ruptured membranes prior to the 
onset of labor will be confirmed by one of the following methods: 
• Non-invasive fetal membranes rupture diagnostic test (e.g., AmniSure), 
• Amniocentesis with indigo carmine instillation, or 
                                                 
11 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 106: Intrapartum fetal 
heart rate monitoring: nomenclature, interpretation and general management principles. Obstet Gynecol. 
2009;114(1):192-202. 
12 Chen, Katherine T. Postpartum endometritis. UpToDate. Available at 
http://www.uptodate.com/contents/postpartum-endometritis. Accessed July 9, 2013. 
13 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 76. Clinical management 
guidelines for obstetricians-gynecologists: postpartum hemorrhage. Obstet Gynecol. 2006;108(4):1039-1047. 
 


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Evaluation of CRB in PROM Patients 
 
COMPANY CONFIDENTIAL 
Protocol 09-014-07 ∙ 27 Apr 2018 
• Clinical indication of ruptured membranes, which will include at least two of 
the following symptoms:  
− Ferning, 
− Pooling, or 
− Visible leaking of amniotic fluid through the cervix. 
 
Tachysystole14 – More than five uterine contractions in 10 minutes, sustained 
> 30 minutes. 
                                                 
14 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 107: Induction of labor. 
Obstet Gynecol. 2009;114:386-397.