Clinical trial NCT02620904
Conditions: Intrauterine Fetal Demise Fetal Death
Keywords: mifepristone randomized controlled trial vaginal delivery progesterone receptor modulator induction of labor
Sponsor: Montefiore Medical Center
Start date: 2016-07-14; Completion date: 2020-01-01
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Methods: Double blinded, randomized controlled trial with 1:1 allocation of mifepristone or placebo at initiation of induction of labor for fetal demise 20 weeks estimated gestational age or greater.

Hypothesis: Mifepristone will expedite time to delivery of fetus among demise patients, when compared to placebo, and in conjunction with other pharmacologic methods for induction of labor.

Expected outcomes: The addition of a progesterone receptor modulator will expedite time to delivery of the fetus and ultimately improve the experience associated with induction of labor for fetal demise.

Detailed description:
The investigators propose a double blinded, randomized, placebo-controlled clinical trial at the time of initiation of induction of labor for fetal demise at 20 weeks gestational age or greater.

1. Diagnose fetal demise: confirm absence of fetal heart motion by attending physician as per the institutional standards and protocols.
2. Confirm gestational age at presentation to labor and delivery based on available medical records and/or ultrasonography as per standard practice and institutional protocols.
3. Based on inclusion and exclusion criteria potential participants will be informed about the research, offered the opportunity to contribute, and trained research staff will complete the informed consent process. After documentation of consent and discussion of the research as indicated the participants will be randomized to the intervention or control arm. Both groups will receive emotional and physical support with induction of labor as per practice guidelines and standard of care by Montefiore physicians, faculty and staff irrespective of participation or assignment.
4. Interventional Arm: Ingest 200mg tab of mifepristone orally. This will coincide with or be implemented prior to the initiation of the induction of labor plan as delineated by the attending physician. The timing will be sensitive to the needs of the participant and the labor and delivery room staff.
5. Control Arm: Ingest a placebo tab orally with similar physical properties. This will coincide with or be implemented prior to the initiation of the induction of labor plan as delineated by the attending physician. The timing will be sensitive to the needs of the participant and the labor and delivery room staff.
6. Montefiore protocol for induction of labor: will follow institutional standards.
7. Data: Patient data will be collected by the Labor and Delivery staff via electronic medical record or paper record that will be scanned into the electronic medical record. The investigators will use data abstraction tools to collect information such as time of medication administration, medications administered, time of delivery of fetus, duration of admittance to labor and delivery, and postpartum course, or complications from the electronic medical record.

Arms: arm 1: following informed consent women will be randomized and the mifepristone group will take 200 mg by mouth immediately prior to induction of labor for fetal demise on labor and delivery arm 2: following informed consent women will be randomized and the placebo group will take a placebo pill by mouth (similar in properties to the mifepristone group, but it will lack any active drug) immediately prior to induction of labor for fetal demise on labor and delivery
Interventions: intervention 1: Mifepristone intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Version date 1/29/16 
Page 1 
 
 
Mifepristone Induction forFetal Demise 
(MIFD) 
 
A Randomized Control Trial 
 
Final Study and Analysis Protocol 
 
 
Principal Investigator JessicaAtrio, MD MSc 
Co-Investigator Nerys Benfield MD 
Saila Moni MD 
Faina Gelman MD 
 
 
 
 
Funded by the Department of Family Planning 
Department of Obstetrics & Gynecology  
Montefiore Medical Center  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 2 
 
 
I Introduction 
 
1.1 Background 
The diagnosis of an intrauterine fetal demise is in itself a challenging moment. A patient can tell, 
almost immediately, that something is gravely wrong as the medical team is working to confirm the 
diagnosis and gather more information. Once diagnosed, a provider’s goals are two-fold: first to provide 
appropriate emotional grievance support to the patient and her family; the second is to deliver the fetus in 
the safest and most expeditious matter [1, 2].  
 
Current methods applied to the management of a late second and third trimester fetal demise 
incorporate similar techniques and pharmaceuticals that are utilized for the induction of a term viable 
pregnancy such as prostaglandin analogues, dilute oxytocin, mechanical cervical dilation with foley 
balloon, and amniotomy [3]. Despite the need for a safe and swift delivery, there have been few 
innovations that focus on the delivery of a non-viable fetus or practices that see to enhance the standard 
management of these patients over the last several decades [4, 5].  New research involving mifepristone 
has shown to be a promising addition to third trimester labor augmentation [6].  
 
Mifepristone is a progesterone receptor modulator that is currently recommended by ACOG for 
use in management of first and second trimester medical abortions [27, 28]. Numerous publications have 
demonstrated the safety of this competitive progesterone receptor antagonist when utilized to induce labor 
in the second trimester or for cervical ripening and preparation prior to surgical dilation and evacuation[7-
9]. The use of mifepristone, in addition to misoprostol, in second trimester medical abortions has shown 
that the addition of mifepristone decreases time to completion of abortion by 8 hours compared to 
misoprostol alone (p<0.01) [26].   Mifepristone has been shown to augment the effects of misoprostol not 
only in the first and second trimesters, but in the third trimester as well [26].  
 
A recent study in India randomized women at a gestational age of 28weeks and greater, with 
diagnosed intrauterine fetal demise, to either receiving 200mg of mifepristone 24hours prior to initiation 
of induction with 100mcg of misoprostol every 4 hours or to receiving the misoprostol induction regimen 
alone. Results showed that induction to delivery in the combination group was 6.54 hours shorter than in 
the misoprostol group (p<0.001) and that significantly fewer doses of misoprostol were required for 
delivery completion in the combination group [30].  
 
The delayed dosage intervals of >24 hours between mifepristone and misoprostol in previous publications 
does not reflect the care implemented at most United States hospitals [6, 13].  At the time of diagnosis of 
fetal demise, a woman is typically offered and requests same-day admission to the hospital and definitive 
management via an induction of labor.  Utilization of mifepristone at the time of admission and initiation 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 3 
 
of induction has not been studied in a prospective randomized trail. This is clinically relevant for the 
typical and practical management of fetal demise in the late second and third trimester where the standard 
of care in the United States is to ascertain the diagnosis and then implement management during that 
same day or admission. The information gained from physical exam and ultrasound are rarely able to 
identify exactly at what point in time thefetal death had occurred.  However, ultrasound is a powerful and 
specific diagnostic tool, which can assure the veracity of the diagnosis when made.  Women are 
offeredinduction of labor at the time of diagnosis to minimize their suffering, and mitigate potential 
complications such as: coagulopathy, sepsis, and hemorrhage [22].  
 
In July of 2015, the CDC released the most updated statistical report on fetal and perinatal 
mortality.  There were 23,595 documented fetal deaths in the year 2013, gestational age 20weeks and 
greater. Minority and marginalized women are disproportionately affected; with 
blackwomencomprising26% and Hispanic women comprising20% of the reported cases [34]. Our Bronx 
population includes these vulnerable populations, who stand to gain the most from evidence based 
protocols and improvements in the management of fetal demise.  The community surrounding our 
Montefiore Weilerand Wakefield labor and delivery is identified as 45.3% Black and 58.4% Hispanic by 
US Census data [35]. Safely shortening the length of labor induction can greatly benefit the emotional and 
medical safety of our patients.  A prolonged induction puts a woman at increased risk for:coagulopathy, 
sepsis, hemorrhage, and complications that require surgical intervention [22]. Mifepristone has a well-
tested and known safety profile and has been proven to optimizethe effects of misoprostol, which is the 
standard medication for induction of labor in the setting of fetal demise [6].  
 
 
1.2 Hypothesis: 
The addition of mifepristone, when compared to placebo, to the standard accepted methods of induction 
of laborwill expedite time to delivery of the fetus in womenwith intra-uterine fetal demise at 20 weeks 
gestational age and greater. 
 
1.3 Objectives: 
1. To compare time to delivery of fetus after administration of mifepristone or placebo at the onset of 
labor induction. 
2. To calculate the duration of induction and hospitalization time among the two groups including time to 
delivery of placenta, duration of time on labor and delivery, time as an inpatient, and number of nights in 
the hospital.  
3.  To determine the number of women, in each arm of the study, who require surgical interventions due 
to a failed induction or retained products of conception. 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 4 
 
4. To determine if administration of mifepristone augments misoprostol, oxytocin and mechanical 
cervical dilation. 
5. To explore the overall incidence of complications and their association with mifepristone use, such as 
febrile morbidity, infection requiring antibiotics, or transfusion. 
6. To assess whether simultaneous start of induction of labor with misoprostol after mifepristone 
administration versus subsequent administration or delays in the administration of misoprostol after 
mifepristone administration makes a difference in the time to delivery of the fetus and to assess the 
optimal lag time between the two medications.   
 
1.4 Expected Outcomes: 
 
It is expected that the addition of mifepristone will allow for more an expeditious delivery of the 
fetus among women who present with fetal demise greater than 20 weeks gestation age.  It is the intention 
of the researchers that our results will be submitted for internal quality improvement assessment, 
scientific meeting presentation and peer review publication.  We hope to impact our institutional practice 
as well as regional and national guidelines regarding the management of second and third trimester fetal 
demise.   
 
 
II Study Design  
 
2.1 Proposed Protocol: 
 
We propose a double blinded, randomized, placebo-controlled clinical trial at the time of initiation of 
induction of labor for fetal demise at 20 weeks gestational age or greater. 
1. Diagnose fetal demise: confirm absence of fetal heart motion by attending physician as per the 
institutional standards and protocols.  
2. Confirm gestational age at presentation to labor and delivery based on available medical records 
and/or ultrasonography as per standard practice and institutional protocols.  
3. Based on inclusion and exclusion criteria potential participants will be informed about the 
research, offered the opportunity to contribute, and trained research staff will complete the 
informed consent process.  After documentation of consent and discussion of the research as 
indicated the participants will be randomized to the intervention or control arm.  Both groups will 
receive emotional and physical support with induction of labor as per practice guidelines and 
standard of care by Montefiore physicians, faculty and staff irrespective of participation or 
assignment. 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 5 
 
4. Interventional Arm: Ingest 200mg tab of mifepristone orally.  This will coincide with or be 
implemented prior to the initiation of the induction of labor plan as delineated by the attending 
physician.  The timing will be sensitive to the needs of the participant and the labor and delivery 
room staff.  
5. Control Arm: Ingest a placebo tab orally with similar physical properties.  This will coincide with 
or be implemented prior to the initiation of the induction of labor plan as delineated by the 
attending physician.  The timing will be sensitive to the needs of the participant and the labor and 
delivery room staff.  
6. Montefiore protocol for induction of labor:  
a. 12w0d-23w6d: Misoprostol 400 micrograms vaginally every 3 hours for 5 doses.  
b. 24w0d-28w6d: Misoprostol 400micrograms vaginally every 6 hours for 5 doses. 
c. 29w0d and older: Misoprostol 25-50mcg vaginally every 4 hours for 4 doses OR 100mcg 
vaginally every 12 hours for 4 doses.   
d. Induction methods and protocols will be at the discretion of the physician team and 
tailored to the clinical context. 
7. Data: Patient data will be collected by the Labor and Delivery staff via electronic medical record 
or paper record that will be scanned into the electronic medical record. The investigators will use 
data abstraction tools to collect information such astime of medication administration, 
medications administered, time of delivery of fetus,duration of admittance to labor and delivery, 
and postpartum course, or complications from the electronic medical record.  
 
2.2 Definitions: 
1. Intrauterine Demise: Absence of fetal heart motion on bedside ultrasound; confirmed by two 
separate providers and the attending physician. 
2. Mifepristone: A19-nor-steroid derivative of norethindrone that competitively binds to 
progesterone and glucocorticoid receptors, with antagonist effect. Mifepristone administration is 
the standard of care when providing medical management for first and second trimester 
terminations/abortions as per the American Congress of Obstetricians and Gynecologists. 
3. Induction of Labor: The use of medications and other techniques to induce contractions and 
cervical change with the goal of effecting delivery and evacuation of all uterine contents. 
 
2.3 Protocol Amendments: 
 
 
All amendments to the protocol by the primary research team will be delineated on handouts and 
distributed at participating Labor and Delivery Units at 8AM the following day. The same information 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 6 
 
will be electronically mailed to resident physicians, attending physicians, physician assistants and nurse 
managers currently staffing the participating Labor and Delivery units.  
 
III Drug Information 
 
3.1 Study Drug Information 
Mifepristone is a 19-nor-steroid derivative of norethindrone that competitively binds to 
progesterone and glucocorticoid receptors, with antagonist effect.  The majority of the drug is absorbed 
through the gut (70%), it then undergoes demethylation and hydroxylation in P-450 microenzyme 
systems, namely CYP3A4 [18].  Subsequent monodemethylated, didemethylated and hydroxylated 
metabolites all maintain significant receptor activity[19].  Mifepristone and its metabolites are bound to 
alpha 1 acid glycoprotein in serum (AAG); saturation is reached with 100 mg of mifepristone. Peak 
plasma concentrations are reached within 1-2 hours of ingestion, with rapid distribution, alpha half-life of 
1.4 hours, and a long beta half-life, elimination time of 20-30 hours [18].  Dosage regimens of 200 mg or 
more quickly saturate AAG and with the elaboration of metabolites nonlinear pharmacokinetics results in 
a large pool of biologically active substrates [19].   The physiologic effects of mifepristone include 
decidual detachment, necrosis, capillary regression, cervical softening and potentiation of myometrial 
contractions through the loss of progesterone’s inhibitory effects [20].  This profile lends compelling 
support that mifepristone can confer tissue changes and procedural benefit within hours of 
administration.Of note, since Mifepristone is mainly metabolized by microenzyme CP3A4, the study will 
thoroughly review patients’ medications/substances that may have the potential to induce/inhibit this 
enzyme. The safety and toxicity profiles of mifepristone are excellent.  The FDA approved regimens for 
medication abortion in the US includes a dose of 800 mg and does not require any consideration or 
contraindication for women who are taking cytochrome inducing or inhibiting agents.  It is not anticipated 
that many young, pregnant patients will be on such drugs; however, if a significant difference of patients’ 
intake of such medications is noticed among the study arm compared to the control arm, the analysis of 
the outcomes will take that into account as a possible confounder, ie. exclude such patients in sub-analysis 
or control for this as a confounder.      
 
The American Congress of Obstetricians and Gynecologists recommends the use of mifepristone 
in the management of labor induction for a woman with a first or second trimester fetal demise [27,28]. 
Clinical trials have proven mifepristone to be effective for cervical ripening for labor induction, 
shortening operative time in dilation and curettage procedures, decreasing length of completion of 
induced abortions, and augmenting the effects of misoprostol [26, 30-33].  These effects of mifepristone 
have not yet been studied in a real-time practical management of second and third trimester fetal demise. 
There is a dearth of information on how quickly the mifepristone augments the effects of cervidil, 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 7 
 
oxytocin, and mechanical cervical dilation – all methods currently known to be safe and effective in 
augmentation of late second and third trimester fetal demise in medical institutions. The following 
proposed study will investigate if administration of mifepristone at the time of induction of labor will 
expedite delivery of a demised fetus.  This finding would be a significant improvement to the existing 
management of fetal demise and a compelling surrogate for the potential morbidity associated with a 
protracted or failed induction of labor.  
 
3.2 Study Drug Side Effects 
The side effects of misoprostol are similar to those one would experience during a labor course: 
bleeding, abdominal cramping, diarrhea, nausea, vomiting, headache, dizziness, back pain, and tiredness. 
Any drug can cause an allergic reaction, which could be mild or more serious and can even result in 
death. Common symptoms of an allergic reaction are rash, itching, skin problems, swelling of the face 
and throat or trouble breathing.  
 
IV Participant Selection 
4.1 Recruitment 
Patients will be recruited at the time of admission to the Labor and Delivery units at the Montefiore 
Hospitals – Einstein Campus at Weiler and Montefiore North, at which there are approximately 60 and 
30, respectively, fetal demises diagnosed annually. Firstly the diagnosis of fetal death will be ascertained 
as per the standards of the unit by the attending physician.  The medical team will counsel the patient on 
the induction of labor plan.  Based on inclusion and exclusion criteria potential participants will be 
informed about the research, offered the opportunity to voluntarily contribute, and trained research staff 
will complete the informed consent process.The timing of consent will be sensitive to the needs of the 
participant. The research and therefore voluntary aspect of care will be clearly delineated.  After 
documentation of consent and discussion of the research as indicated the participants will be randomized 
to the intervention or control arm.  Both groups will receive emotional and physical support with 
induction of labor as per practice guidelines and standard of care by Montefiore physicians, faculty and 
staff irrespective of participation or assignment. 
Patients in the interventional arm will ingest 200mg tab of mifepristone orally.  This will coincide with or 
be implemented prior to the initiation of the induction of labor plan as delineated by the attending 
physician.  The timing will be sensitive to the needs of the participant and the labor and delivery room 
staff.  
Similarly, patients in the control arm will ingest a placebo tab orally with similar physical properties 
without the active ingredient.  This will coincide with or beimplemented prior to the initiation of the 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 8 
 
induction of labor plan as delineated by the attending physician.  The timing will be sensitive to the needs 
of the participant and the labor and delivery room staff.  
In an effort to optimize recruitment, participation and the diversity of the participants, no parental 
consent will be obtained. This is consistent with other research that involves youth and addresses 
reproductive health needs, with the goal of protecting privacy and eliminating a potential sampling 
bias (Martinez-Garcia 2014, Reed 2008). The National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research and the Society of Adolescent Medicine have 
advised that parental consent can be waived for minimal risk research that involves care that is 
legally rendered in the state (reproductive health services) and it is difficult to obtain parental 
consent (National Commission 1997, Santelli 2003).  Pregnant teens are emancipated in New York 
State and are often faced with socially complex and unstable home environments (Alperen 2013, 
Malee 2013). They may not have a guardian who accompanies them to their clinic visits or 
accompany is present with them in the hospital during the admission for management of fetal 
demise. 
4.2 Inclusion Criteria 
1. Women ages 16-50 
2. Women whose primary language is English 
3. Intrauterine fetal death as confirmed by absence of cardiac motion on ultrasound by 
Attending physician at the time of admission to the hospital. 
4. Estimated gestational age greater than 20 weeks  
5. Hemodynamically stable 
6. Women with one prior low transverse cesarean delivery 
 
4.3 Exclusion Criteria  
1. History of 2 or more low transverse cesarean deliveries 
2. Prior classical cesarean delivery 
3. History of abdominal myomectomy   
4. Known or suspected allergic reaction to mifepristone  
5. Known or suspected adrenal gland disease 
6. Known or suspected bleeding diatheses or coagulopathies   
7. Known or suspected use of QTc-prolonging medication  
8. Known maternal medical or physical conditions that prohibits vaginal delivery  
9. Patients in active labor, with cervical dilation greater than 6 cm. 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 9 
 
4.4 Participant Timeline 
1. The patient receives a diagnosis of intrauterine fetal demise at 20 weeks gestational age or 
greater. 
2. Patient must meet inclusion and exclusion criteria of study. 
3. Patient verbally consents to the delivery plan and is a candidate for induction at a Montefiore 
labor and delivery (Wakefield or Weiler-Einstien Hospitals). 
4. Participants will be informed about the research, offered the opportunity to contribute, and trained 
research staff will complete the informed consent process.   
5. After documentation of consent and discussion of the research as indicated the participants will 
be randomized to the intervention or control arm.  Both groups will receive emotional and 
physical support with induction of labor as per practice guidelines and standard of care by 
Montefiore physicians, faculty and staff irrespective of participation or assignment. 
6.  With prior assignment based on the randomization scheme medications will be maintained in 
secure medical dispensing equipment consistent with Montefiore standards (labor and delivery Pyxis 
will be used).  Medications will be individually placed in sequentially numbered, sealed opaque 
containers.   Research team will source and dispense medication to participants. 
6. Patient’s labor course is routinely monitored and documented in EMR by all participating 
providers. 
 
V Randomization  
Allocation methods will be variable block randomization (blocks of 2&6, by computer generated random 
number sequence.  Best practices will be implemented to assure the maintenance of randomization and 
blinding.  The randomization scheme will be kept at a separate secure research site and researchers will 
not have access to this scheme until the analysis phase, following completion of the data collection 
process and enrollment.  The Montefiore research pharmacy will be involved in the storage, packaging, 
monitoring and utilization of both placebo and study medications.  The placebo and study medications 
will be maintained in secure medical dispensing equipment consistent with Montefiore standards (labor 
and delivery Pyxis).  Medications will be individually placed in sequentially numbered, sealed opaque 
containerswith a unique participant identifier that will correspond with the patient identifier the 
participant receives upon enrollment.  Participants, research staff, and the data collection and analysis 
teamswill be blinded to contents of each pill. The mifepristone and placebo tablets will be obtained from 
Danco pharmacies where the placebo has been specifically developed to have similar physical properties 
to the mifepristone tablet. 
 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 10 
 
 
VI Data Collection 
The hospital staff will maintain medical records as per standard of care.   The research team will assigna 
unique numerical participant identifier with enrollment and allocation of participants.  As previously 
mentioned this identifier will correspond with the information on the sealed medication envelop.  Case 
report forms (CRF) will capture relevant data such as: medication administration time points, clinical 
events and secondary outcomes.  Nursing, pharmacy and medical records will be reviewed to assure 
accuracy and completeness.   Data proofing and collection will be completed by persons blinded to 
treatment assignment.  Intake measures will include: age, socio-economic status, gestational age, method 
of attainment of gestational age, insurance, gravidity and parity, previous cesarean deliveries, medical 
history, most recent hemoglobin and hematocrit.  Admission data will include cervical exam, membrane 
intact or rupture status, and vital signs.  Secondary outcomes, additional interventions, and adverse events 
will be captured on the CRF.  Due to the fact that participants will be inpatient for the duration of their 
induction and post-partum course, we do not anticipate any significant withdrawals, deviations or 
incomplete data sets.   Patient identifiers will be secured in locked and protected environments.  The CRF 
and abstracted data will not have any patient identifiers. 
 
VII Statistical Guidelines 
7.1 Sample Size:  
 
Based on a review of the literature, institutional charts and clinician experience, the mean time to 
delivery of fetus is projected to be 24 hours with a standard deviation of 6 hours.  To detect a change in 4 
hours, with a two-sided alpha of 0.05 and power of 0.8: 37 persons would be needed in each group for a 
total of 74 persons enrolled in the study.The effect of 4-hour reduction is chosen because it is considered 
a clinically significant reduction. 
 
7.2 Analysis: 
 
An intention to treat analysis will be completed.  Two sample t-test and Wilcoxon rank sum test 
will be calculated for the primary outcome of time to delivery of fetus. Other secondary outcomes will be 
described with descriptive statistics and compared with ANOVA or Chi square analysis.  
 
VIII Ethical Consideration 
8.1 Confidentiality:  
 
The participants, providers, and research team will all be blinded for the duration of the study. 
The patients’ medical information is protected under HIPAA, therefore only staff directly involved in the 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 11 
 
patients’ care and the primary research team will access the participants’ medical records. All personal 
identify information will be removed from CRF.  A unique participant identifier will be utilized for all 
data collection and analysis.  In a separate locked and secured location the consent forms will be secured 
with a log of participants enrolled in the research.  
 
8.2 Dissemination Policy:  
 
Data collected during the study by labor and delivery team is confidential and protected by 
HIPPA. Abstracted data without patient identifier will be entered into CRF. The data will then be 
analyzed and reported. 
 
8.3Declaration of Interest:  
 
The investigatorshave nothing to declare. Our purpose is to enrich the current body of knowledge 
on induction of labor for an intrauterine fetal demise in the second and third trimester.  
 
8.4 Potential Benefits: 
If Mifepristone expedites the delivery of the demised fetus, women in the control of the arm of the study 
will benefit tremendously from participating in the study as their induction will be shorter. This outcome 
has important consequences as it will avoid secondary complications from long inductions such as 
maternal infections and surgery. Additionally, a quicker induction time may ameliorate the emotional 
suffering of the patients.  
 
8.5Adverse Event and Safety Monitoring Board: 
 
A safety monitoring board will be identified consisting of two clinician scientists who are 
familiar with scope of clinical practice but are not directly involved in the research.  These 
physicians will review adverse events and work closely with the principle investigator and research 
team to assure that safety and reporting standards are maintained at a high level.  The principle 
investigator will also actively review all outcomes for the patients throughout the course of the 
study, and will remained blinded to their treatment.Data will be abstracted within 72 hours of 
enrollment from the electronic medical record onto case report forms for the majority of 
participants.  Timing regarding abstraction of serious adverse events onto case report forms is 
delineated below.  The PI will review all CRFs and cross check to the medical record for accuracy 
every 6 weeks.  There will be quarterly communications between the PI and monitoring board 
regarding adverse events and a written annual reports of these communications will be compiled 
regarding the review and assessments by the monitoring board.  The PI and research team will 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 12 
 
convene weekly for the first few months and then monthly thereafter to assure that the application 
of the protocol, recruitment and data collection practices are all in compliance.  All adverse event 
and case report forms will be available to the monitoring board, and reports of this information will  
 
An adverse event is any symptoms, sign, illness or experience that develops or worsens in 
severity during the course of the study.  A number of adverse events are expected in the course of the 
management of fetal demise and induction of labor including, painand bleeding.  Information as noted in 
the medical records will be abstracted in the CRF and compiled as secondary outcomes.  Events that are 
determined to be both unexpected and related to the study medication will be entered into the CRF as well 
as a separate adverse event form.  All serious adverse events will be reviewed by the PI, data safety 
monitoring board and submitted to the IRB within 48 hours.  Other adverse events will be reviewed by 
the PI, data safety monitoring board, and submitted within one week.  Events that meet International 
Conference on Harmonization (ICH) criteria for a serious adverse event include volunteers who 
experience any of the following during the course of their enrollment: death, life-threatening event, 
inpatient hospitalization or prolongation of existing hospitalization, occurrence that results in persistent or 
significant disability in capacity, congenital anomaly/birth defect, or other important medical event (may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the events listed above).An important medical event is one that 
may not be immediately life threatening, but is clearly of major medical significance. It may jeopardize 
the subject, and may require intervention to prevent one of the other serious outcomes noted above. All 
serious adverse events will be reviewed by the PI, regardless of causality assessment. Serious adverse 
events will be reported to Montefiore Medical Center, the FDA, and Danco Laboratories, Inc.   All 
information related to data and adverse events will be monitored by the principle investigator, Jessica 
Atrio.   
 
 
XI Consent 
 Following diagnosis, counseling and support patients will be offered the opportunity to go through the 
informed consent. Physician researchers will be sensitive to the context for some women this may be a 
relatively short interval (closer to 30 minutes) and for others who need time to process the diagnosis with 
family and in consultation with other persons they may be offered participation after a more lengthy 
counseling process (closer to several hours). Women will be approached during their admission for their 
induction while in the obstetric triage area or in labor and delivery. Standard of care will be maintained. 
When women are given this diagnosis, the standard recommendation is to admit to the hospital for 
induciton of labor. All physician researchers will respect the emotional needs of women and will offer 
participation and informed consent after women have received counseling and support. 
 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 13 
 
XII References 
 
1.  
MacDorman MF, Kirmeyer S. Fetal and perinatal mortality, United States, 2005. Natl Vital Stat Rep 
2009,57:1-19. 
2. 
Perinatal Moratality 2007: United Kingdom. In: CEMACH. Edited by Health CEiMaC; 2009. 
3. 
Gawron LM, Kiley JW. Labor induction outcomes in third-trimester stillbirths. Int J Gynaecol Obstet 
2013,123:203-206. 
4. 
Gregory EC, MacDorman MF, Martin JA. Trends in fetal and perinatal mortality in the United States, 
2006-2012. NCHS Data Brief 2014:1-8. 
5. 
Macdorman MF, Kirmeyer S. The challenge of fetal mortality. NCHS Data Brief 2009:1-8. 
6. 
Hapangama D, Neilson JP. Mifepristone for induction of labour. Cochrane Database Syst Rev 
2009:Cd002865. 
7. 
Borgatta L, Kapp N. Clinical guidelines. Labor induction abortion in the second trimester. Contraception 
2011,84:4-18. 
8. 
Perritt JB, Burke A, Edelman AB. Interruption of nonviable pregnancies of 24-28 weeks' gestation using 
medical methods: release date June 2013 SFP guideline #20133. Contraception 2013,88:341-349. 
9. 
Perritt JB, Edelman AB, Burke AE. Controversies in family planning: management of lethal fetal 
anomalies in the third trimester. Contraception 2012,86:93-95. 
10. 
Wagaarachchi PT, Ashok PW, Narvekar NN, Smith NC, Templeton A. Medical management of late 
intrauterine death using a combination of mifepristone and misoprostol. Bjog 2002,109:443-447. 
11. 
Vayrynen W, Heikinheimo O, Nuutila M. Misoprostol-only versus mifepristone plus misoprostol in 
induction of labor following intrauterine fetal death. Acta Obstet Gynecol Scand 2007,86:701-705. 
12. 
Jannet D, Aflak N, Abankwa A, Carbonne B, Marpeau L, Milliez J. Termination of 2nd and 3rd trimester 
pregnancies with mifepristone and misoprostol. Eur J Obstet Gynecol Reprod Biol 1996,70:159-163. 
13. 
Fairley TE, Mackenzie M, Owen P, Mackenzie F. Management of late intrauterine death using a 
combination of mifepristone and misoprostol--experience of two regimens. Eur J Obstet Gynecol Reprod 
Biol 2005,118:28-31. 
14. 
Panda S, Jha V, Singh S. Role of Combination OF Mifepristone and Misoprostol Verses Misoprostol alone 
in Induction of Labour in Late Intrauterin Fetal Death: A Prospective Study. J Family Reprod Health 
2013,7:177-179. 
15. 
ACOG Practice Bulletin No. 102: management of stillbirth. Obstet Gynecol 2009,113:748-761. 
16. 
The combination of mifepristone and misoprostol for the termination of pregnancy. Int J Gynaecol Obstet 
2011,115:1-4. 
17. 
Late intrauterine fetal death and stillbirth. In: Green-top guidelines. Edited by (RCOG) RCoOaG; 2010. 
18. 
Sarkar NN. Mifepristone: bioavailability, pharmacokinetics and use-effectiveness. Eur J Obstet Gynecol 
Reprod Biol 2002,101:113-120. 
19. 
Heikinheimo O. Clinical pharmacokinetics of mifepristone. Clin Pharmacokinet 1997,33:7-17. 
20. 
Im A, Appleman LJ. Mifepristone: pharmacology and clinical impact in reproductive medicine, 
endocrinology and oncology. Expert Opin Pharmacother 2010,11:481-488. 
21. 
Administration FaD. New Drug Application Approval Letter Mifeprex (Mifepristone). In. United States; 
2000. 
22. 
Lawn JE, Blencowe H, Pattinson R, Cousens S, Kumar R, Ibiebele I, et al. Stillbirths: Where? When? 
Why? How to make the data count? Lancet 2011,377:1448-1463. 
23. 
Community Needs Assessment of Maternal and Infant Health in the Bronx 2013. In: Bronx Health Link; 
2013. 
24. 
County Health Rankings. In. Edited by Institute UoWPh; 2014. 
25. 
Summary of Vital Statistics New York City. In. Edited by Hygiene DoHaM; 2010. 
26.  
Kapp N, Borgatta L, Stubblefield P, Vragovic O, Morena N. Mifepristone in Second-Trimester Medical 
Abortion. Obstet Gynecol 2007, 110: 1304-1310.  
27. 
ACOG Practice Bulletin No. 143: Medical Management of First-Trimester Abortion. Obstet Gynecol2014, 
123: 676-692. 
28.  
ACOG Practice Bulletin No. 135: Second-Trimester Abortion. Obstet Gynecol 2013, 121:1394-1406 
29.  
Mifepristone U.S. Postmarketing Adverse Events Summary through 4/30/2011. 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016


 
 
Version date 1/29/16 
Page 14 
 
30.  
Panda S, Jha V, Singh S. Role of Combination of Mifepristone and Misoprostol verses  Misoprostol alone 
in Induction of Labour in Late Intrauterine Fetal Death: A Prospective Study. Journal of Family and 
Reproductive Health 2013, 7: 177-179. 
31.  
Fox, MC, Creinin, MD, Harwood B. Mifepristone and vaginal misoprostol on the same day for abortion 
from 50-63days gestation. Contraception 2002, 66: 225-229. 
32.  
Ashok PW, Flett GMM, Templeton A. Mifepristone versus vaginally administered misorpsotol for cervical 
ripening before first-trimester termination of pregnancy: A randocmized control study. Am J Obstet 
Gynecol 2000, 183:998-1002. 
33. 
Shaw KA, Shaw JG, Hugin M, Velasquez G, Hopkin FW, Blumenthal PD. Adjunct mifepristone for 
cervical preparation prior to dilation and evacuation: a randomized trial. Contraception 2015, 91: 313-319. 
34.  
MacDorman MF, Gregory ECW. Fetal and Perinatal Mortality: United States, 2013. National Vital Statitics 
Reports2015, 64: 1-23. 
35.  
United States Census Bureau, Bronx County, NY. August 2015. 
 
 
 
 
 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016

ICF_001.pdf: 
1/30/16 
Page 1 of 6 
ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIVERSITY 
MONTEFIORE MEDICAL CENTER 
 
DOCUMENTATION OF INFORMED CONSENT AND HIPAA AUTHORIZATION 
 
 
Introduction 
You are being asked to participate in a research study called Mifepristone Induction for Fetal 
Demise. Your participation is voluntary -- it is up to you whether you would like to participate. It 
is fine to say “no” now or at any time after you have started the study. If you say “no,” your 
decision will not affect any of your rights or benefits or your access to care. 
 
The researcher in charge of this project is called 
the “Principal Investigator.” Her name is Dr. 
Jessica Atrio. You can reach Dr. Atrio at:  
1695 Eastchester Rd, suite 505 
Bronx, NY, 10461 
718-405-8260 
For questions about the research study, or if you 
believe you have an injury, contact the Principal 
Investigator or the IRB. 
The Institutional Review Board (IRB) of 
the Albert Einstein College of Medicine 
and Montefiore Medical Center has 
approved this research study. The IRB # 
is in the stamp in the upper right hand 
corner. If you have questions regarding 
your rights as a research subject you may 
contact the IRB office at 718-430-2253 or 
by mail: 
 
Einstein IRB  
Albert Einstein College of Medicine 
1300 Morris Park Ave., Belfer Bldg #1002 
Bronx, New York 10461 
Support for this research study is provided by 
Montefiore Medical Center, Department of Family 
Planning.  
The study drugs, Mifepristone and Placebo are 
provided by Danco Pharmacies. 
 
Why is this study being done?  
 This research study is being done so that we can find out if using one more medication 
(mifepristone) will help your procedure happen more quickly. If you agree to participate in this 
research study, you will receive all the standard medications (misoprostol) and hospital care for 
women who have a fetus that passes away in the uterus, plus as a study participant you will 
receive an additional pill (mifepristone or placebo).  A placebo is a pill with no active medication.  
Researchers use placebos to see if the study drug works better than receiving nothing at all.  
Neither you nor your study doctor will be able to decide which pill you receive, mifepristone or 
placebo.      
 
Mifepristone and misoprostol are used together for pregnancy termination (abortions) in early 
pregnancy (20 weeks or less).  Most women, like yourself, who have a fetus that passes away 
in the uterus are given one medication (misoprostol) to bring on contractions and delivery for a 
pregnancy at 13 weeks gestational age or greater.      
 
The U.S. Food and Drug Administration (FDA) has approved Mifepristone for pregnancy 
termination, but the FDA has not approved mifepristone to bring on contractions after a fetus 
has passed away.  The reason for this research study is to learn if Mifepristone will help women 
deliver faster than without mifepristone. 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016
IRB EXPIRATION DATE: 01/12/2017


1/30/16 
Page 2 of 6 
We are not sure which is the best way to help women deliver a pregnancy that has passed 
away and no longer alive.  We are asking women who are experiencing this condition to 
volunteer for this research study. Our goal is to improve treatment options for women in the 
future by understanding which method is most effective. 
 
 
  
Why am I being asked to participate?  
 
You are being asked to participate in this study because you are a healthy woman between 16 
to 50 years of age, with a pregnancy that passed away or died in the uterus after about 20 
weeks or five months.  
 
How many people will take part in the research study? 
 
You will be one of about 74 people who will be participating in this study at Montefiore Medical 
Center.   
 
How long will I take part in this research? 
 
You will be involved in the research during your admission to the hospital. You will be asked to 
schedule a routine post-partum follow up with a Montefiore provider anywhere between 2-6 
weeks postpartum depending on the type of procedure you have.  
 
What will happen if I participate in the study?   
 
Before any study-related procedures are performed, you will be asked to read and sign this 
consent document.  If you agree to take part in the study, you will be assigned, by chance, to 
either one of two study groups, the mifepristone group or the placebo (pill without any  
medication) group, prior to the start of the induction of labor. You and the study doctor cannot 
choose your study group.  You will have an equal chance of being assigned to either study 
group. The rest of your care will be the same as any other patient in your situation. 
 
Mifepristone Group 
 
If you are assigned to the Mifepristone group, you will be asked to take one mifepristone pill by 
mouth prior to additional medications as indicated by the doctors in charge of your care. 
 
Placebo Group 
 
If you are assigned to the placebo group, you will be asked to take one placebo pill by mouth 
prior to additional medications as indicated by the doctors in charge of your care. 
 
Both study groups 
 
In addition, if you agree to be a part of this research study, we will review your medical record to 
collect demographic data such as age, ethnicity, education, household,  and health information 
about you and your delivery, such as your treatments on labor and delivery and how long you 
have been  pregnant. 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016
IRB EXPIRATION DATE: 01/12/2017


1/30/16 
Page 3 of 6 
 
 
 
Will I be paid for being in this research study?  
 
You will not receive any payment or other compensation for taking part in this study 
 
Will it cost me anything to participate in this study?  
 
 
Taking part in this study will not involve any added costs to you. All study drugs will be given 
free of charge by the sponsor, company or the drug makers. You and/or your insurance 
company will have to pay for any costs that are part of your regular medical care.  
 
 
What will happen if I am injured because I took part in this study? 
 
If you are injured as a result of this research, only immediate, essential, short-term medical 
treatment as determined by the participating hospital, will be available for the injury without 
charge to you personally.  
 
 
No monetary compensation will be offered.  
 
You are not waiving any of your legal rights by signing this informed consent document.  
 
If additional treatment is required as a result of a physical injury related to the research, 
necessary medical treatment will be provided to you and billed to your insurance 
company or to you as part of your medical expenses.  
 
Immediately report any discomforts, problems or injuries you experience during the course of 
your participation in the study to Dr. Atrio at 718-405-8082. 
 
 
Are there any risks to me?  
 
Confidentiality 
We will keep your information confidential, however, a risk of taking part in this study is that your 
confidential information might be shared accidentally with someone who is not on the study 
team and is not supposed to see or know about your information. This is very unlikely, because 
the study team takes confidentiality of your information seriously. Your research records will be 
kept confidential and your name will not be used in any written or verbal reports. Your 
information will be given a code number and separated from your name or any other information 
that could identify you. The form that links your name to the code number will be kept in a 
locked file cabinet and only the investigator and study staff will have access to the file. All 
information will be kept in a secure manner and computer records will be password protected. 
Your study information and specimens will be kept as long as they are useful for this research. 
 
The only people who can see your research records are: 
 the research team and staff who work with them 
 clinicians and staff at Montefiore who review your records for your care 
 the organization that funded the research 
 organizations and institutions involved in this research: The Einstein School of Medicine. 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016
IRB EXPIRATION DATE: 01/12/2017


1/30/16 
Page 4 of 6 
 groups that review research (the Einstein IRB, and the Office for Human Research 
Protections, and the US Food and Drug Administration) 
 
These people, who receive your health information, may not be required by privacy laws to 
protect it and may share your information with others without your permission, if permitted by 
laws governing them.  All of these groups have been asked to keep your information 
confidential. 
 
Risks of Taking Mifepristone 
 
Mifepristone may cause bleeding, cramping, diarrhea, nausea, vomiting, headache, 
dizziness, back-pain, and tiredness.  These are also common side effects of the medication 
misoprostol and of the process of induction of labor. Therefore, if you develop any of the above 
listed side effects - it will be difficult to determine if they are cause by the other medications 
used to induce labor, the labor process itself or the study medication (mifepristone).   The 
medical team can offer medications to help you with these side effects.  Very rarely, the amount 
of blood loss may be life-threatening and it may be necessary for you to receive a blood 
transfusion. You may occasionally experience some discomfort during the pelvic exams and 
with delivery of the pregnancy or placenta. 
 
Occasionally, the medications and induction of labor treatment may not cause all of the 
pregnancy or placenta to come out of the uterus.  In that case you may need an exam in the 
operating room for emptying of the uterus by a clinician, or to complete a dilation and 
evacuation procedure (or dilation and curettage); this is a procedure that empties the uterus of 
pregnancy tissue. Very rarely, it is also possible that a woman may need a surgery like a 
cesarean section to remove the pregnancy from her uterus.   
 
Additionally, there is small chance that during the induction process you may get an infection in 
your uterus or develop sepsis (the body’s overwhelming response to infection).   Sepsis is a 
known risk related to any type of spontaneous or induced abortion or intrauterine pregnancy 
demise. There have been reports of deaths due to sepsis in women who have had induced 
abortion with mifepristone and misoprostol. Most of these women were infected with the same 
type of bacteria, known as Clostridium sordellii. The symptoms in these cases of infection were 
not the usual symptoms of sepsis. We do not know whether using mifepristone and misoprostol 
caused these deaths. Reports of fatal sepsis in women undergoing medical abortion are very 
rare (approximately 1 in 100,000).  
 
Other Risks 
 
The other risks include symptoms and situations similar to what was mentioned above 
and are expected to happen in women who are inducing labor because of pregnancy demise, 
many of which you would likely experience whether or not you chose to participate in the study.  
It is normal to feel very sad and distressed when faced with this situation.  The hospital staff has 
experience taking care of women in your situation and can offer support.  
 
 
Allergic Reaction to Study Drug 
Any drug can cause an allergic reaction which could be mild or more serious and can even 
result in death.  Common symptoms of an allergic reaction are rash, itching, skin problems, 
swelling of the face and throat, or trouble breathing.  There is hospital staff available throughout 
your time in the hospital, who will be checking in on you often. If you are experiencing any of 
these symptoms – alert a member of the staff immediately. 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016
IRB EXPIRATION DATE: 01/12/2017


1/30/16 
Page 5 of 6 
Unknown Risks 
We have described the risks we know about. However, because this is research, there a 
possibility that you will have a reaction that we do not know about yet and is not expected.  The 
unknown risks of participation could be permanent, severe or life threatening. If we learn about 
other risks, we will let you know what they are so that you can decide whether or not you want 
to continue to be in the study. 
  
Are there possible benefits to me?  
 
You may or may not receive personal, direct benefit from taking part in this study.  If you are 
enrolled into the Mifepristone group, the possible benefit of taking part in this study includes the 
possibility of safely shortening the length of labor induction and therefore a faster time to 
delivery of the fetus.  We hope you will participate because the study will generate important 
information about which labor induction medications have the greatest chance of success and 
fewest side effects in women who have a pregnancy that passes away in the uterus after 20 
weeks or 5 months.   
 
 
What choices do I have other than participating in this study? 
 
You can refuse to participate in the study. If you decide not to participate, the medical care 
providers at this facility will still give you all of the standard care and treatment that is 
appropriate for you. 
 
Your other choices are: 
- 
To receive treatment with misoprostol only and not participate in the study 
 
 
Are there any consequences to me if I decide to stop participating in this study? 
 
No. If you decide to take part, you are free to stop participating at any time without giving a 
reason. This will not affect your care and you will continue to be treated at this facility.  
 
Can the study end my participation early? 
 
We will not let you participate in the study any more if the Primary Investigator feels it is 
necessary for your health or safety, or if you have not followed study instructions. In addition, 
your participation will end if the investigator or study sponsor stops the study earlier than 
expected. 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016
IRB EXPIRATION DATE: 01/12/2017


1/30/16 
Page 6 of 6 
Information Banking (Future Use and Storage) 
 
 
       We will store information about you in a “bank”, which is a library of information from 
many studies. This information can be linked to you. In the future, researchers can apply 
for permission to use the information for new studies to prevent, diagnose or treat disease, 
including genetic research. If you agree to the future use, some of your de-identified 
genetic and health information (not linked to you) may be placed into one or more scientific 
databases. These may include databases maintained by the federal government. Your 
information may be kept for a long time, perhaps longer than 50 years. You may remove 
your consent for future research at any time by contacting the Principal Investigator named 
on the first page of the consent or the IRB office at 718-430-2237. If you do, we will destroy 
the information in the bank but if the information was already shared with other 
researchers, we cannot get it back. 
 
You can choose not to participate in the bank and still be part of the main study and this will 
not affect your treatment at this facility. 
 
INITIAL ONE (1) OF THE FOLLOWING OPTIONS 
_______ I consent to have my information used for future research studies. 
_______ I do NOT consent to have my information used for future research studies. The 
information will be destroyed at the end of the study. 
 
INITIAL YOUR CHOICE BELOW 
I consent to be contacted in the future to learn about: 
_______ New research protocols that I may wish to join. 
_______ General information about research findings. 
 
Some researchers may develop tests, treatments or products that are worth money. You 
will not receive payment of any kind for your information or for any tests, treatments, 
products or other things of value that may result from the research. 
 
 
 
CONSENT TO PARTICIPATE 
I have read the consent form and I understand that it is up to me whether or not I participate. I 
know enough about the purpose, methods, risks and benefits of the research study to decide 
that I want to take part in it. I understand that I am not waiving any of my legal rights by signing 
this informed consent document. I will be given a signed copy of this consent form. 
 
Printed name of participant 
Signature of participant 
Date 
Time 
Printed name of the person 
conducting the consent 
process 
Signature 
Date 
Time 
 
 
IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016
IRB EXPIRATION DATE: 01/12/2017