Ulipristal Acetate for Use in Early Pregnancy Loss: A Phase 2 Pilot Feasibility Study
Phase: PHASE2
Conditions: Missed Abortion, Anembryonic Pregnancy, Non-Viable Pregnancy
Sponsor: University of North Carolina, Chapel Hill

Ulipristal Acetate for use in early pregnancy loss: A Phase 2 pilot feasibility study 
 
Protocol and Statistical Analysis Plan 
Version 8.0 Date: 6/2/22 
NCT: NCT05216952 
Date of Submission: 5/5/23 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
a 
 
 
Ulipristal acetate for use in early pregnancy loss: A 
Phase 2 pilot feasibility study 
UPA for EPL 
Protocol Number: 1.0 
National Clinical Trial (NCT) Identified Number:  N/A 
Principal Investigator: Jill M. Hagey, MD MPH 
Mentor: Amy Bryant, MD MSCR 
Funded by: UNC Chapel Hill, Division of Family Planning 
Version Number: 8.0 
2 June 2022 
 
 
Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.3, 2.2, 
4.1, 4.3, 
5.1, 5.2, 
5.4, 5.5, 
9.1, 9.2, 
9.4, 10.1 
See Track Changes 
SRC Revision 
4.1 
Updated Visit Days 
SRC Revision 
1.3, 4.1, 
5.2, 7.3, 
8.2, 8.3.5, 
8.3.6, 
10.1.2 
See Track Changes 
FDA IND Revision 
5.2, 5.5, 
7.2, 9.3, 
9.4.1, 9.4.3  
See Track Changes 
FDA IND Revision 
2.3.1, 5.2, 
8.3.6, 
10.1.9.1 
See Track Changes 
IRB Revision 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
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2.3.1, 4.1, 
5.5, 
10.1.9.1 
See Track Changes 
IRB Modification 
3, 4.1, 5.4, 
5.5, 8.1, 9.1 
Updated Outcome Measure 
IRB Modification 
5.5 
Updated Recruitment Methods 
IRB Modification 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................ 2 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 4 
2 
INTRODUCTION ........................................................................................................................................... 4 
2.1 
Study Rationale ................................................................................................................................... 4 
2.2 
Background .......................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment ................................................................................................................... 6 
2.3.1 
Known Potential Risks .................................................................................................... 6 
2.3.2 
Known Potential Benefits ............................................................................................... 7 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................... 7 
3 
OBJECTIVES AND OUTCOMES ................................................................................................................ 7 
4 
STUDY DESIGN ............................................................................................................................................ 8 
4.1 
Overall Design ..................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design ............................................................................................. 10 
4.3 
Justification for Dose ........................................................................................................................ 11 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 11 
5.1 
Inclusion Criteria ............................................................................................................................... 11 
5.2 
Exclusion Criteria .............................................................................................................................. 11 
5.3 
Lifestyle Considerations ................................................................................................................... 12 
5.4 
Screen Failures ................................................................................................................................. 12 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 13 
6 
STUDY INTERVENTION ............................................................................................................................ 14 
6.1 
Study Intervention(s) Administration .............................................................................................. 15 
6.1.1 
Study Intervention Description .................................................................................... 15 
6.1.2 
Dosing and Administration ........................................................................................... 15 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 15 
6.2.1 
Acquisition and accountability ..................................................................................... 15 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 15 
6.2.3 
Product Storage and Stability ...................................................................................... 16 
6.2.4 
Preparation ..................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 16 
6.4 
Study Intervention Compliance ....................................................................................................... 16 
6.5 
Concomitant Therapy ....................................................................................................................... 16 
6.5.1 
Rescue Medicine ........................................................................................................... 16 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 16 
7.1 
Discontinuation of Study Intervention ............................................................................................ 16 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 16 
7.3 
Lost to Follow-Up .............................................................................................................................. 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 17 
8.1 
Feasibility Assessments ................................................................................................................... 17 
8.2 
Safety and Other Assessments ...................................................................................................... 18 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 19 

  
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8.3.1 
Definition of Adverse Events (AE) ............................................................................... 19 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 19 
8.3.3 
Classification of an Adverse Event ............................................................................. 19 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 20 
8.3.5 
Adverse Event Reporting ............................................................................................. 21 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 21 
8.3.7 
Reporting Events to Participants ................................................................................. 21 
8.3.8 
Events of Special Interest ............................................................................................ 22 
8.3.9 
Reporting of Pregnancy ................................................................................................ 22 
8.4 
Unanticipated Problems ................................................................................................................... 22 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 22 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 22 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 23 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 23 
9.1 
Research Hypotheses ...................................................................................................................... 23 
9.2 
Sample Size rationale ...................................................................................................................... 23 
9.3 
Populations for Analyses ................................................................................................................. 23 
9.4 
Statistical Analyses ........................................................................................................................... 24 
9.4.1 
General Approach ......................................................................................................... 24 
9.4.2 
Analysis of the Primary feasibility outcome variable(s) ............................................ 24 
9.4.3 
Analysis of the Secondary outcome variable(s) ........................................................ 24 
9.4.4 
Safety Analyses ............................................................................................................. 25 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 25 
9.4.6 
Planned Interim Analyses ............................................................................................ 25 
9.4.7 
Sub-Group Analyses ..................................................................................................... 25 
9.4.8 
Tabulation of Individual participant Data .................................................................... 25 
9.4.9 
Exploratory Analyses .................................................................................................... 26 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 26 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 26 
10.1.1 
Informed Consent Process .......................................................................................... 26 
10.1.2 
Study Discontinuation and Closure ............................................................................. 26 
10.1.3 
Confidentiality and Privacy ........................................................................................... 27 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 27 
10.1.5 
Key Roles and Study Governance .............................................................................. 27 
10.1.6 
Safety Oversight ............................................................................................................ 28 
10.1.7 
Clinical Monitoring ......................................................................................................... 28 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 28 
10.1.9 
Data Handling and Record Keeping ........................................................................... 29 
10.1.10 
Protocol Deviations ....................................................................................................... 29 
10.1.11 
Publication and Data Sharing Policy .......................................................................... 30 
10.1.12 
Conflict of Interest Policy .............................................................................................. 30 
10.2 
Additional Considerations ................................................................................................................ 30 
10.3 
Abbreviations ..................................................................................................................................... 31 
10.4 
Protocol Amendment History ........................................................................................................... 33 
11 
REFERENCES ............................................................................................................................................. 34 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations (CFR). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the Investigational New Drug (IND) sponsor, funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Ulipristal Acetate for use in early pregnancy loss: A Phase 2 pilot feasibility 
study 
Study Description: 
We investigate the feasibility of using 90mg ulipristal acetate, a selective 
progesterone receptor agonist, as an adjunct to 800mcg vaginal 
misoprostol for the medical management of early pregnancy loss. Patients 
will be followed to assess effective treatment of early pregnancy loss, 
additional interventions needed, side effects, adverse events and patient 
acceptability. 
Objectives: 
 
Primary Objective:  
To assess if 90mg ulipristal acetate as an adjunct to 800mcg vaginal 
misoprostol is a feasible method for medical management of early 
pregnancy loss.  
Secondary Objectives:  
To evaluate if participants taking ulipristal acetate plus misoprostol 
achieve complete resolution of early pregnancy loss. 
To investigate if patients using ulipristal acetate plus misoprostol have side 
effects or adverse events when used for early pregnancy loss. 
To identify if patients find ulipristal acetate and misoprostol an acceptable 
treatment for early pregnancy loss.  
Outcomes: 
Primary Feasibility Outcome Variables: 
- 
Recruitment  
- 
Adherence  
- 
Retention  
Secondary Outcome Variables:  
- 
Absence of gestational sac on transvaginal ultrasound following 
study intervention 
- 
Side effects/adverse events following study intervention 
- 
Patient acceptability of study intervention 

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Study Population: 
Participants eligible for the study include women over age 18 presenting 
with a non-viable pregnancy between 5- and 12-weeks gestation or an 
anembryonic gestation and desiring medical management. Participants 
will be excluded if they are hemodynamically unstable, desire non-medical 
management, present with an incomplete or inevitable abortion, 
contraindication or allergy to the study medications, evidence of a viable 
intrauterine pregnancy, ectopic pregnancy or pregnancy with an IUD in 
place, evidence of a pelvic infection, anemia with a hemoglobin less than 
9.5g/dL, known cardiovascular disease or known clotting or bleeding 
disorder.  
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
All study activities will take place at University of North Carolina-Chapel 
Hill. Participants will be recruited from OBGYN clinics and the Emergency 
Department following diagnosis of early pregnancy loss on viability scan. 
All follow up study activities will take place at UNC Chapel Hill Family 
Planning Clinic.  
Description of Study 
Intervention: 
Ulipristal acetate is a selective progesterone receptor modulator that is 
currently FDA approved for the use of emergency contraception. Three 
30mg tablets will be administered orally for a total dose of 90mg. 
Participants will be instructed to self-administer 800mcg of misoprostol 6 
to 18 hours after receiving ulipristal acetate as per the standard of care for 
early pregnancy loss management. Participants will be followed for 
resolution of their early pregnancy loss.  
Study Duration: 
2 years 
Participant Duration: 
1 month 
 
 
1.2 
SCHEMA 
 
UPA for EPL Flow Diagram  
 
 

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Prior to  
Enrollment 
 
 
 
Visit 1 
Day 0 
 
 
 
Visit 2 
Day 3 
 
 
Visit 3 
Day 8  
 
 
 
Lab Visit 
Day 14 
 
 
 
Visit 4 
Day 30 
 
 
 
 
 
 
 
Eligibility Screening  
Informed Consent 
Liver function baseline testing 
Demographic Questionnaire 
Provide UPA 90mg PO 
 Patients instructed to take Misoprostol 800mcg vaginally 6-18 hours after initial 
medication 
Phone call with study participants 
Additional treatment questionnaire 
Side effects and adverse events questionnaire 
Patient acceptability questionnaire 
Follow up visit with ultrasound to confirm absence of gestational sac for those 
with sac still present on day 3 
If gestational sac still present, offer expectant management, medical 
management or surgical management 
Data cleaning 
Data analysis 
Dissemination of results 
Follow up visit with ultrasound to confirm absence of gestational sac 
If gestational sac still present, offer expectant management, medical 
management or surgical management 
Liver function testing 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Visit 1, Day 0 
Enrollment/Baseline 
Visit 1, Day 0 
At Home 
Day  0 
Study Visit 2 
Day 3 +/- 1day 
Study Visit 3 
Day 8 +/- 1 day 
Lab Testing 
Day 14 +/- 1 day 
Study Visit 4 
Day 30 +/- 7 days 
Eligibility criteria 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics questionnaire 
X 
 
 
 
 
 
 
Administer UPA 
 
X 
 
 
 
 
 
Patient self-administers 
misoprostol 
 
 
X 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
Vital signs 
X 
 
 
X 
X 
 
 
Hemoglobin and ABO/Rh 
testing 
X 
 
 
 
 
 
 
Liver function testing 
X 
 
 
 
 
X 
 
Adverse event review and 
evaluation 
X 
 
 
X 
X 
 
X 
Radiologic/Imaging assessment 
X 
 
 
X 
X 
 
 
Treatment success 
questionnaire completed by 
MD 
 
 
 
X 
X 
 
 
Offer additional intervention if 
needed if gestational sac still 
present 
 
 
 
X 
X 
 
 
Additional treatment 
questionnaire 
 
 
 
 
 
 
X 
Side effects and adverse events 
questionnaire 
 
 
 
X 
X 
 
X 
Patient acceptability 
questionnaire 
 
 
 
 
 
 
X 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Early pregnancy loss affects approximately 10% of women throughout their reproductive lives [1]. 
Options for management of early pregnancy loss include expectant management, medical management, 
or surgical management. Data from two large randomized controlled trials suggests that pretreatment 
with mifepristone 200mg, a selective progesterone receptor modulator, prior to administration of 
misoprostol 800mcg increases effectiveness of medical management of early pregnancy loss and 
decreases the need for subsequent surgical management [2,3]. However, mifepristone is subject to 
regulations based on the FDA Risk Evaluation and Mitigation Strategy (REMS) restrictions that have 
remained in place for more than 20 years despite extensive safety data for mifepristone and evidence-
based protocols for its use. Many OBGYN and non-OBGYN providers do not prescribe mifepristone due 
to these logistical barriers. Ulipristal acetate (UPA) is another selective progesterone receptor modulator 
that may allow for similar priming of the endometrium and sensitization of the myometrium to the 
prostaglandins to improve effectiveness of misoprostol in medical management of early pregnancy loss. 

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Ulipristal acetate is not subject to the FDA REMS restrictions and is available as a prescription 
medication through commercial pharmacies, with approximately 72% of pharmacies able to fill the 
prescription within 24 hours [4]. Thus, utilizing UPA plus misoprostol for early pregnancy loss may 
improve access to patients who otherwise may not be prescribed mifepristone. We propose a pilot 
feasibility study of UPA plus misoprostol for medical management of early pregnancy loss to assess if a 
larger clinical trial would be possible.  
 
2.2 
BACKGROUND  
Early pregnancy loss (EPL), defined as a nonviable intrauterine pregnancy, occurs in approximately 10% 
of clinically recognized pregnancies [1]. Early pregnancy loss encompasses both anembryonic gestations 
(presence of an empty gestational sac without embryo or fetus, previously known as a “blighted ovum”) 
and embryo or fetus without fetal cardiac activity before the 13th week of gestation [1]. Often, early 
pregnancy loss is diagnosed on viability ultrasound, and specific radiologic criteria have been laid out by 
the Society of Radiologists in Ultrasound Multispecialty Consensus Conference (so called “Doubilet 
criteria”, see Appendix A) [5]. When faced with this diagnosis, women are offered expectant 
management, medical management, or surgical management to allow expulsion of the pregnancy. 
Misoprostol, a prostaglandin analogue, has long been the standard of care for medical management of 
EPL; however, recent randomized controlled trials of mifepristone use prior to misoprostol illustrated 
increased rates of pregnancy expulsion with medication alone and decreased need for surgical 
intervention to complete evacuation of the pregnancy [2,3]. As a selective progesterone receptor 
modulator (SPRM) with antagonist effects on the endometrium and myometrium, mifepristone 
increases uterine contractility and sensitizes the myometrium to prostaglandin use, allowing for a lower 
dose of misoprostol to cause uterine emptying and shorter time to pregnancy expulsion. Following 
treatment with mifepristone, endometrial cells exhibit an increase in decidual prostaglandin release and 
decreased activity of prostaglandin dehydrogenase to prevent metabolism of prostaglandins [6]. 
Further, mifepristone downregulates progesterone receptor signaling in the endometrium, prompting 
antiproliferative effects that halt secretory changes to the endometrium and decrease endometrial 
receptivity [7,8]. 
 
While mifepristone exhibits many benefits when used for EPL, availability of mifepristone is limited by 
the Risk Evaluation and Mitigation Strategy (REMS) FDA restrictions [9]. This program restricts 
mifepristone administration to certified providers, requires a patient agreement form to be signed prior 
to administration, and requires administration of the medication in the presence of the certified 
provider [10]. These restrictions have been in place since mifepristone was FDA-approved in 2000 
despite excellent safety data and evidence-based protocols; even with extensive legislative appeals to 
remove the REMS restrictions [11]. Particularly as many women diagnosed with EPL are seen in non-
OBGYN settings such as the emergency department or primary care, these restrictions often prevent 
patients from accessing appropriate evidence-based medical management. Indeed, in a large qualitative 
survey of primary care clinicians, two thirds of providers were unable to dispense mifepristone in their 
clinics for medication abortion or EPL care, with most citing logistical difficulties with the REMS 
restrictions and resistance from health center leadership as rationale [12]. Logistical barriers to 
prescribing mifepristone for medication abortion has also been well documented among both OBGYN 
and non-OBGYN providers [13,14]. 
 
Ulipristal acetate (UPA, Ella®) is another substituted steroid synthetic progesterone agonist/antagonist 
commonly used for emergency contraception with a similar molecular weight, structural formula, and 
molecular formula to mifepristone [15-17]. As a class, progesterone receptor modulators are utilized in 

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similar clinical scenarios ranging from contraception to treatment of fibroids, endometriosis, and other 
causes of heavy or irregular bleeding. In the normal menstrual cycle, progesterone from the corpus 
luteum transforms the proliferative endometrium to the secretory endometrium for implantation. In 
contrast, the presence of SPRMs causes the endometrium to undergo glandular dilation and 
antiproliferative effects [18]. Like other SPRMs, UPA induces changes in the endometrium including a 
significant increase in glandular dilation and architecture and decrease in endometrial thickness similar 
to the effects noted following administration of mifepristone [19,20]. UPA’s effect on endometrial cells 
is also responsible for similar changes in receptivity markers when compared to mifepristone [21,22]. 
With the similarities between UPA and mifepristone, a recent pilot study investigated UPA in place of 
mifepristone for cervical preparation prior to dilation and evacuation for termination of pregnancy 
between 16- and 18-weeks’ gestation and found that UPA was a feasible and acceptable alternative 
[23]. 
  
While mifepristone is an effective medication for EPL, prescribing restrictions limit the ability of patients 
to use this medication to increase the efficacy of medical management of EPL. Thus, alternative 
regimens are needed to increase access to effective medical management of EPL for women choosing 
medical management. Given similarities between UPA and mifepristone, we propose utilizing UPA prior 
to misoprostol for medical management of EPL. As no prior studies have investigated UPA for this use, 
we propose a pilot feasibility study of UPA plus misoprostol for medical management of EPL to inform a 
subsequent larger clinical trial if successful. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Ulipristal acetate is a 30mg tablet progesterone receptor agonist/antagonist that was FDA approved for 
emergency contraception in 2010. Adverse events noted from an open-label multicenter trial and a 
randomized, single-blind multicenter trial include headache (18%), nausea (12%), and abdominal pain 
(12%). Other less common side effects include dysmenorrhea, fatigue and dizziness. Post marketing 
experience has also shown an increase in acne among users of the medication [16].  
 
This study will be utilizing a dosage of UPA 90mg to most closely match the effects of mifepristone 
200mg, which is the dosage studied for EPL based on a study of endometrial histology showing similar 
effects of UPA 100mg to mifepristone 200mg [2,19]. FDA approval indicated that experience with single 
dose equivalent of up to four times the standard UPA dose were administered to a limited number of 
subjects without any adverse reactions, suggesting that UPA 90mg may be used safely in this patient 
population [16]. In a pilot study of ulipristal acetate 90mg at the dose that would be used for this study, 
no significant adverse events were noted [23].  
 
Additionally, there will be two blood draws required for the study to monitor liver function testing. 
Possible risks of these blood draws include mild risks of pain, bruising and fainting. These risks are 
infrequent, and all lab draws will be completed by clinic nurses or the study coordinator, who have been 
trained in phlebotomy.  
 
Possible psychologic risks of the study include consequences of breach of confidentiality. All study 
materials will be kept solely with research staff. All medical care will be documented in the UNC EPIC 
system, which has safeguards to reduce the risk of confidentiality breaches. 
 

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Possible social risk includes the risk of stigmatization of UPA if used in the context of EPL. Just as 
mifepristone is known as the “abortion pill”, making it less likely to be used in other settings, UPA may 
undergo similar stigmatization, which may change prescribing patterns of UPA. 
 
Possible economic risks include loss of income and time for follow up appointments, as patients 
undergoing medication management of EPL generally are followed up with a phone call as opposed to 
an in-person appointment. Patients will be compensated for their travel time and will not have to pay 
for their follow up visits. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
There are no direct benefits to patients enrolling in this study. Participants will receive care for their EPL 
with appropriate follow up over the course of the study.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
While there are no direct benefits of UPA to study participants, UPA is very well tolerated with minimal 
side effects or adverse events noted from FDA pre-marketing and post marketing analysis. Further, all 
participants will also get misoprostol, which in clinical environments that do not prescribe mifepristone, 
is the standard of care for medical management of EPL.  
 
Societally, demonstration of feasibility of UPA for EPL may improve access to effective medical 
management for EPL. While mifepristone has been shown to increase effectiveness of medical 
management of EPL and decrease need for additional intervention for pregnancy expulsion, challenges 
with access to mifepristone limit its use. Thus, if UPA were to be a feasible alternative to mifepristone 
pretreatment, patients desiring medical management of EPL would have an effective option for 
treatment that can be more easily obtained.    
 
3 
OBJECTIVES AND OUTCOMES 
 
OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR 
OUTCOMES 
Primary 
 
 
To assess whether it is 
feasible to study UPA plus 
misoprostol as an 
intervention for medical 
management of EPL for 
larger future studies.   
Recruitment: number of participants 
in study/number of patients screened 
for participation  
Adherence: number of participants 
adhering to study intervention (UPA 
+ misoprostol vaginally after 6-18 
hours)/number of participants in 
study 
Retention: number of participants 
attending all study visits (day 0, 3/8, 
30)/number of participants in study 
Study outcomes of interest 
for feasibility based on 
outcomes of interest 
appropriate for pilot studies 
[24-26]. 
Secondary 
 
 

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OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR 
OUTCOMES 
To evaluate if participants 
taking UPA plus misoprostol 
achieve complete resolution 
of EPL.  
 
 
 
To investigate if UPA plus 
misoprostol is associated 
with side effects or adverse 
events when used for EPL. 
 
To identify if UPA plus 
misoprostol is acceptable to 
patients for treatment for 
EPL. 
Absence of gestational sac on 
transvaginal ultrasound examination 
on Day 3 follow up 
 
 
 
 
Participants self-report of side effects 
or adverse events following UPA and 
misoprostol.  
 
 
Participants willing to use this 
combination of medication again for 
another early pregnancy loss or 
recommend this combination of 
medications to a friend.  
Same outcome was used in 
randomized controlled trial 
of mifepristone plus 
misoprostol for early 
pregnancy loss to calculate 
effective intervention [2]. 
 
Study outcomes of interest 
for feasibility based on 
outcomes of interest 
appropriate for pilot studies 
[24-26]. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This is a phase 2 single site pilot study of UPA for use in medical management of early pregnancy loss. 
Our hypothesis is that UPA will be a feasible option for women desiring medical management. 
Specifically, we estimate that over 60% of participants screened for participation will enroll in the study 
(based on a recruitment rate of 75% in a prior study of mifepristone plus misoprostol for EPL) [2]. 
Additionally, we estimate that greater than 50% of participants will be able to adhere to the study 
protocol in taking UPA and misoprostol at the designated times and greater than 90% of participants will 
be able to complete follow up for the study. This is a pilot study with a small sample size and thus our 
secondary aims will only be for hypothesis generating activities, not hypothesis testing activities.  
 
The study will be conducted at UNC Chapel Hill. Patients will be approached as a convenience sample 
from patients diagnosed with EPL on viability scan at UNC Chapel Hill OBGYN clinics and UNC Chapel Hill 
Emergency Department between 5- and 12-weeks’ gestation desiring medical management. Participants 
will be provided counseling regarding their EPL by their OBGYN physician and subsequently screened for 
eligibility by a research coordinator. Based on prior data on recruitment in this setting and number of 
patients seen desiring medical management for EPL at UNC Chapel Hill, we anticipate 40 women will be 
eligible for participation and desire participation in the study after recruitment for 12 months.   
 
After providing informed consent, participants will complete a demographic questionnaire and ensure 
that they have appropriate baseline lab work (hemoglobin, ABO/Rh status, liver function testing). 
Participants will all receive the study intervention of 90mg UPA and will be instructed to self-administer 
800mcg misoprostol vaginally 6 to 18 hours after the study drug is administered. Self-administration of 
misoprostol is the standard of care for medical management of EPL. As all participants will receive the 
same intervention, no randomization or blinding will take place. Participants will receive an 

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appointment card with their follow up appointment date that also provides space for participants to 
document their misoprostol timing at home.  
 
Follow up of medical management of EPL generally consists of confirmation of pregnancy expulsion by 
ultrasound examination or serial beta-hCG measurements in settings where ultrasound is not available 
[1]. There is no standard of care regarding specific intervals when ultrasonography or laboratory follow 
up assessment should take place. Study follow up schema for our study is based on participant follow up 
design from a similar study of mifepristone and misoprostol for EPL [2].   
 
Participants will follow up with the UNC Family Planning Division for a transvaginal ultrasound on study 
day 3 to ensure expulsion of the gestational sac. Women generally experience cramping and vaginal 
bleeding 1 to 4 hours following misoprostol administration and pass their pregnancy within 24 hours of 
starting to bleed. Thus, follow up on day 3 will assess participants who are able to pass their pregnancy 
with a single dose of UPA and misoprostol. 
 
For those who still have a pregnancy in the uterus, they will be offered an additional dose of 800mcg 
misoprostol, expectant management, or surgical management. Those who did not have expulsion of the 
pregnancy on day 3 and elect for an additional dose of misoprostol or expectant management will follow 
up with the UNC Family Planning Division for another transvaginal ultrasound on study day 8 to ensure 
expulsion of the gestational sac. As some studies of EPL assess for response 7 days after medication 
administration, we will be able to compare our data to similar studies through our day 8 follow up 
results [3]. Further, twenty-five to thirty percent of EPL will pass with expectant management alone one 
week after diagnosis [27].  
 
Participants will be assessed for possible liver toxicity on study day 14 through a laboratory test of ALT, 
AST and total bilirubin. 
 
All study participants will receive a phone call on study day 30 to what additional treatment patients 
needed for their early pregnancy loss, investigate any side effects or adverse events, and identify 
acceptability of the treatment. Most symptoms of bleeding and abdominal cramping following medical 
management of EPL occur in the first two to four weeks following medication administration; thus, 30 
days is an adequate time to assess for side effects and acceptability of treatment while not being too 
remote from the time of the pregnancy passing. 
 
A detailed description of all study visits is provided below:  
 
Visit 1 (Day 0): 
• 
Participant is screened for eligibility by the study coordinator and offered admission to study if 
eligible 
o Review of radiologic imaging to confirm early pregnancy loss based on eligibility criteria 
o Review of physical exam findings and vital signs (heart rate, blood pressure, 
temperature) to ensure that patient is hemodynamically stable and not having an 
inevitable or incomplete abortion based on eligibility criteria 
• 
Participant reviews and signs informed consent and HIPAA authorization form 
• 
Participant completes paper baseline demographic questionnaire 
• 
Participant will have hemoglobin, ABO/Rh status and liver function testing (ALT, AST, total 
bilirubin) if not already performed by primary OBGYN 

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• 
Participant takes 90mg ulipristal acetate with study team; given prescription for 800mcg 
misoprostol to take at home 
 
Visit 2 (Day 3 ± 1 day):  
• 
Participant returns to UNC Family Planning Clinic 
• 
Participant has vital signs checked by RN at clinic 
• 
Participant fills out questionnaire regarding bleeding symptoms and any side effects or adverse 
events after taking the ulipristal acetate and misoprostol, including reporting time and route of 
administration of misoprostol at home 
• 
Participant has a transvaginal ultrasound completed by the principal investigator to ensure that 
the pregnancy has passed (no gestational sac visualized on ultrasound) 
• 
If pregnancy is still in the uterus, patient will be offered surgical management, medical 
management (an additional dose of misoprostol 800mcg), or expectant management 
 
Visit 3 (Day 8 ± 1 day): 
• 
Participant will only attend this visit if a gestational sac was still present on ultrasound on Visit 
2 and patient opted for medical management or expectant management. If gestational sac is 
absent at Visit 2, participant will not need Visit 3. All participants will complete Visit 4.  
• 
Participant returns to UNC Family Planning Clinic 
• 
Participant has vital signs checked by RN at clinic 
• 
Participant fills out questionnaire regarding bleeding symptoms and any side effects or adverse 
events after taking the ulipristal acetate and misoprostol 
• 
Participant has transvaginal ultrasound completed by the principal investigator to ensure that 
the pregnancy has passed (no gestational sac visualized on ultrasound) 
• 
If pregnancy is still in the uterus, patient will be offered surgical management, medical 
management (if patient did not receive additional misoprostol at Visit 2), or expectant 
management 
o If patient has medical management or expectant management, patient will be followed 
with weekly transvaginal ultrasounds until pregnancy has passed. No study 
questionnaires will be administered at these visits. Patient may elect for surgical 
management at any follow up visit as per the standard of care.  
 
Lab Visit (Day 14 ± 1 day):  
• 
Participant will have liver function testing (ALT, AST, total bilirubin) performed at outpatient 
laboratory 
 
Visit 4 (Day 30 ± 7 days): 
• 
Participant will be called by the principal investigator to administer a follow up questionnaire 
about any additional treatments taken to help pass the pregnancy, any side effects experienced 
with the medication and participant acceptability 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
As this is the first study utilizing UPA for this indication, a pilot feasibility study is warranted to ensure 
that patients are willing to take part in a research study of this kind, be adherent to the study protocol, 
monitor the effectiveness of the study medication for this use, and evaluate for any possible side effects 
or adverse events. As such, we will be employing a convenience sample of patients presenting with early 
pregnancy loss. No comparison group will be utilized.  

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4.3 
JUSTIFICATION FOR DOSE 
UPA 90mg will be utilized for this study based on multiple factors. As this is the first use of UPA for this 
indication, no prior dosage data is available. Safety of UPA has been well-documented at dosages over 
90mg, both from the FDA package insert that notes a lack of adverse events at dosages up to four times 
the standard dose of UPA (thus up to 120mg) as well as from phase 1 dose determination studies that 
showed that a single dose of UPA up to 100mg was well tolerated [16, 28]. Further, similar endometrial 
changes have been noted between UPA 100mg and mifepristone 200mg, suggesting that UPA may be 
effective at a dose of approximately one half that of mifepristone [19]. In clinical practice, when 
mifepristone is used for emergency contraception, which is the FDA-approved indication for UPA, 
mifepristone most effective at doses of 25-50mg compared to UPA 30mg [29], again suggesting that 
mifepristone may be effective at between one to two times the dosage of UPA. Lastly, UPA 90mg was 
the dosage used when UPA was studied in place of mifepristone 200mg for cervical preparation prior to 
dilation and evacuation for termination of pregnancy between 16- and 18-weeks’ gestation [23, 
https://clinicaltrials.gov/ct2/show/NCT03802149]. We further wanted a dosage of UPA that would be 
easily accessible based on the current packaging of UPA, which is in 30mg tablets for ease of use among 
participants. Given that mifepristone 200mg is used in early pregnancy loss, we propose a dose of UPA 
90mg for this study. No dose adjustments will be made for UPA, although further study could examine 
the effectiveness of a lower dosage of UPA on pregnancy expulsion.  
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. English or Spanish-speaking 
4. Female, age 18 years or older 
5. Ultrasound examination showing a non-viable intrauterine pregnancy between 5- and 12-weeks’ 
gestation as indicated by the Doubilet criteria or anembryonic gestation [5], see Appendix A 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 

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1. Desire for non-medical management of early pregnancy loss (either expectant management or 
surgical management) 
2. Hemodynamically unstable 
3. Women with incomplete or inevitable abortion (due to high efficacy of misoprostol alone) 
4. Contraindication or allergy to ulipristal acetate or misoprostol (glaucoma, mitral stenosis, sickle 
cell anemia, chronic glucocorticoid use) 
5. Evidence of a viable intrauterine pregnancy, ectopic pregnancy, or pregnancy with IUD in place 
6. Evidence of pelvic infection 
7. Hemoglobin <9.5g/dL  
8. Known cardiovascular disease (arrhythmia, cardiac failure, valvular disease, angina) 
9. Known clotting or bleeding disorder, or on anticoagulation therapy 
10. Use of the following medications that may influence metabolization of the study medications: 
barbituates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, 
rifampin, St. John’s Wort, topiramate [16] 
11. Use of CYP3A4 inhibitors within five elimination half-lives of ulipristal acetate 
12. Chronic adrenal failure (risk of acute renal insufficiency) 
13. Concurrent long-term corticosteroid therapy (risk of acute renal insufficiency) 
14. Any history of underlying liver disorder, including hepatitis 
15. Elevation of any or all liver enzymes (ALT, AST, total bilirubin) above the upper limit of normal 
(ULN) at baseline testing prior to enrollment 
16. A family history of hepatitis or currently living with a person who has been given a diagnosis of 
hepatitis 
17. A history of or currently working as a sex worker 
18. A history of or currently using intravenous (IV) drugs 
19. A self-reported history of alcohol dependency or abuse  
 
Of note, exclusion criteria 1 and 2 will be evaluated by the OBGYN provider assessing the patient for EPL. 
No discussion of options for management of EPL will take place by the research team prior to inclusion 
in the study to avoid any potential bias towards medical management if the patient desires expectant or 
surgical management.  
 
5.3 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
• 
Abstain from intercourse until expulsion of gestational sac is noted via transvaginal 
ultrasonography 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the study but are not 
administered the study intervention (ulipristal acetate) due to either participant withdrawal from the 
study or change in exclusion criteria following informed consent. A minimal set of information will be 
kept on all screen failure participants including eligibility screening checklist, informed consent 
documentation, demographic questionnaire (if completed), screen failure details and any severe 
adverse event (SAE). This information may be used in study reports, published materials, or to respond 
to regulatory authorities.  
 
Additionally, a minimal set of information will be kept for patients screened for enrollment who do not 
meet eligibility criteria or who do not consent to participate in the study on the study screening register. 

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This information includes name, date of birth, referring physician, date of referral, date of contact with 
patient, and patient outcome (e.g. screen out, decline to participate, enroll in study). Following 
completion of enrollment of study participants, this information will be de-identified with just the 
number of patients in each outcome (screen out, decline to participate, enroll in study) for use in study 
reports, published materials, or to respond to regulatory authorities.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
We propose a convenience sample as this is a pilot feasibility study. We propose enrolling 40 patients in 
the study based on an average of two patients presenting with early pregnancy loss per week at viability 
ultrasounds at UNC Chapel Hill OBGYN clinics over a year of recruitment. We estimate that 100 patients 
will be diagnosed with EPL to enroll these 40 patients given prior recruitment rates from studying 
mifepristone and misoprostol for early pregnancy loss (800 EPL patients for a total of 300 participants) 
[2]. 
 
This will be a single site study at UNC Chapel Hill. Participants will be recruited from OBGYN clinics at 
their viability scan upon diagnosis of EPL. Recruitment will take place at UNC Chapel Hill OBGYN clinics 
and UNC Chapel Hill Emergency Department. To aid providers in recruitment efforts, the study 
coordinator and principal investigator will pre-screen patient visits at the UNC Chapel Hill OBGYN clinics 
to identify those patients presenting for an early pregnancy ultrasound based on their visit type. 
Providers at the UNC Chapel Hill OBGYN clinics will be notified via secure EPIC message which of their 
patients may be eligible for recruitment to the study if they are diagnosed with an early pregnancy loss 
on that ultrasound. No additional patient information will be obtained until after a diagnosis of early 
pregnancy loss has been confirmed and the patient has been referred to the study team from the 
primary medical team.   
 
Once early pregnancy loss has been diagnosed on ultrasound, patients are referred back to their primary 
OBGYN provider for counseling on the diagnosis and discussion of management options, often on the 
same day as the ultrasound. Patients desiring medical management of EPL are referred to the GYN 
consultation team at UNC via a telephone call for more information regarding medical management and 
prescription of the requisite medications. The GYN consultation team will offer patients the standard of 
care of mifepristone and misoprostol versus admission into the study for ulipristal acetate and 
misoprostol. Patients interested in the study will then be approached by the research staff. Patients who 
initially elect for expectant management of their early pregnancy loss but desire medical management 
at a later date may be offered admission into the study as well within the first two weeks following 
diagnosis, as over 50% of patients will pass their pregnancy after two weeks following diagnosis [27].  
 
Thus, patients approached for participation will meet the following criteria:  
• 
Diagnosed with early pregnancy loss or anembryonic gestation between 5- and 12-weeks’ 
gestation on viability ultrasound at UNC Chapel Hill OBGYN clinics and UNC Chapel Hill 
Emergency Department 
• 
Desire medical management of early pregnancy loss and are clinically stable to do so (not 
hemodynamically unstable or with active vaginal bleeding) 
• 
Interested in learning more about the study from research team 
 
To aid in recruitment efforts, flyers will be placed in each of the two recruitment locations and 
brochures will be offered to patients if they are considering admission to the study but need time to 
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patients can reach out to the research team directly. Provider flyers will also be placed in the provider 
workspaces at both recruitment locations and in the GYN workspace at UNC Chapel Hill where the GYN 
consultation team is based to provide detailed information on the study and eligibility requirements. All 
study materials will be written to an appropriate reading level to ensure comprehension among all 
potential participants. 
 
All counseling on the diagnosis of early pregnancy loss and options for management of early pregnancy 
loss will take place prior to patient being approached by the research staff. Research staff will reach out 
to potential participants via telephone call to schedule an eligibility screening at the UNC Same Day 
Clinic. Research staff will then assess patients for study eligibility and proceed with study activities if the 
patients are eligible for participation.  
 
Participants will enroll in the study once they are screened for inclusion and exclusion criteria from the 
study team and the study team has been able to review laboratory tests (hemoglobin, hepatic function 
tests) to ensure the patient is an appropriate candidate for enrollment. Patients will be offered 
enrollment into the study and then complete their baseline visit including the demographic 
questionnaire and administration of UPA.   
 
Spanish-speaking patients make up a key demographic seeking OBGYN care at UNC Chapel Hill, with 
approximately 10% of individuals identifying as Latinx in the surrounding catchment area. As such, we 
will include Spanish speaking patients within our study population. All consent and data collection forms 
will be translated into Spanish for use with this patient population. Additionally, all patient interactions 
will take place with a Spanish-certified research staff member or with a certified Spanish interpreter 
(either in person or via telephone). 
 
All women recruited to the study will be pregnant but have already been diagnosed with an early 
pregnancy loss and thus do not have any risks to an ongoing pregnancy by participating in the study. 
Participants will be offered psychological support for their loss as part of their standard care for early 
pregnancy loss. No other vulnerable patients will be included in the patient population including minors 
under 18 years of age, prisoners, or patients unable to provide informed consent.  
 
UNC-Chapel Hill students and employees may seek OBGYN care at UNC-Chapel Hill and will not be 
excluded from the study. Any information regarding medical care for UNC-Chapel Hill students or 
employees will be documented appropriately in their medical charts, which are confidential from UNC-
Chapel Hill faculty or employers. Additionally, as with all other patients, all research materials relating to 
the study will be kept confidential and will not be shared with UNC-Chapel Hill faculty or employers. 
 
As part of the study, participants will receive compensated medical care for management of their EPL 
including no cost medication for the study intervention and follow up visit with transvaginal ultrasound 
to confirm resolution of the pregnancy. Subjects will also receive a gift card of USD $20 for their travel 
and time to their follow up visit(s) on day 3 and day 8, as often outside the context of this study these 
follow ups are completed via phone call. They will also receive parking vouchers to park at the UNC 
Chapel Hill campus for follow up. As this reimbursement is nominal, the risk for coercion is low. Further, 
all study procedures are in line with the standard of care for treatment of EPL at UNC such that patients 
do not risk receiving different care by completing the study. 
 
6 
STUDY INTERVENTION 

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6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The study intervention will involve administration of 90mg UPA (three 30mg oral tablets) followed by 
800mcg misoprostol (four 200mcg tablets) vaginally 6 to 18 hours after.  
• 
Information regarding UPA 30mg oral tablet is detailed in the full prescribing information from 
the FDA. Use of UPA for this purpose is being studied under an IND (pending).  
• 
Information regarding misoprostol 200mcg tablet is detailed in the full prescribing information 
from the FDA. While the FDA approves misoprostol for treatment of gastric ulcers, the dose and 
route of 800mcg misoprostol vaginally for medication abortion or medication treatment of early 
pregnancy loss has been studied extensively and is the most successful regimen to date [30, 31].  
6.1.2 DOSING AND ADMINISTRATION 
Participants will be given 90mg UPA (three 30mg oral tablets) in the presence of research staff on 
baseline/enrollment visit 1 (day 0) after determining eligibility and giving informed consent. Patients will 
be prescribed 800mcg misoprostol (four 200mcg tablets) and instructed to self-administer misoprostol 
vaginally 6 to 18 hours after administration of UPA. Participants will be given oral medications to 
manage pain and symptoms during their EPL from their OBGYN provider prior to discharge home.  
 
Medication timing of misoprostol administration will be based on post-hoc analysis of misoprostol 
administration following mifepristone for early pregnancy loss. These data suggest that patients have 
the highest likelihood of success when misoprostol is administered 7 to 20 hours after mifepristone [32]. 
Pharmacokinetic data suggest that peak concentrations of ulipristal acetate and its active metabolite are 
0.9 hours and 1 hour respectively, compared to mifepristone that reaches peak concentrations after 90 
minutes; thus we propose earlier times when compared with those recommended with mifepristone 
[16,17]. Further, extensive data has studied vaginal misoprostol 6 hours after mifepristone for 
medication abortion with good success [33].  
 
If a gestational sac is still present on transvaginal ultrasound on visit 2 (day 3), expectant management, 
medical management or surgical management will be offered to patients. Patients desiring additional 
medical management will be instructed to administer 800mcg misoprostol vaginally or buccally within 
24 hours of their appointment. Patients may not be eligible for additional dosage of misoprostol if they 
are hemodynamically unstable and necessitate urgent or emergent surgical intervention.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
UPA 90mg will be dispensed by study coordinators at visit 1. Prescription for misoprostol will be sent to 
the UNC Chapel Hill pharmacy for patients to pick up prior to discharge.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
UPA tablets are supplied as 30mg white, round, curved tablets marked with “ella” on both sides. Three 
tablets will be administered to patients at one time. UPA is manufactured by Osny Pharma in France and 
is under license from Laboratoire HRA Pharma. UPA is distributed by Watson Pharma, Inc [16].  

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6.2.3 PRODUCT STORAGE AND STABILITY 
UPA tablets are supplied in a PVC-PE-PVDC-aluminum blister. The medication should be stored at 68-77 
degrees F and the blisters will be kept in the outer carton to protect from light [16].  
 
6.2.4 PREPARATION 
No further preparation of UPA is needed for the study intervention.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
As UPA has not been studied for this indication, we propose a pilot study without randomization or 
blinding to assess the feasibility and effectiveness of this intervention. Once feasibility has been 
demonstrated, a subsequent randomized controlled trial may be undertaken.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Patients will take UPA in the presence of study staff prior to discharge from visit 1. Participants will 
report the time that they self-administered misoprostol vaginally on their return for their day 3 
transvaginal ultrasound.  
 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Patients will be advised to not take certain medications that 
affect CYP450 metabolism pathways as detailed in exclusion criteria (5.2) as these medications may 
influence metabolism of UPA. Otherwise, no recording of concomitant medication therapy will be 
collected from patients.  
 
6.5.1 RESCUE MEDICINE 
Not applicable.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from taking UPA will constitute discontinuation from the study protocol and 
participants may receive any option of EPL management (expectant management, medical 
management, or surgical management) from their OBGYN.  If a clinically significant finding is identified 
(including, but not limited to changes from baseline) after enrollment but before UPA administration, 
the investigator or qualified designee will evaluate if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance  

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• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant presents for enrollment >2 weeks following diagnosis of early pregnancy loss as over 
50% of participants will have complete miscarriage with expectant management alone at this 
time point [27]. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.   
Participants who discontinue or withdraw from the study will not be replaced. Instead, additional 
enrollment will commence to reach the targeted sample size of 40 study participants.  
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 1 day and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
Similarly, the following actions will be taken if a participant fails to return for her laboratory visit (Day 14 
± 1 day):  
• 
The site will attempt to contact the participant and reschedule the laboratory visit within 1 day 
and counsel the participant on the importance of maintaining the laboratory visit and ascertain 
if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file. 
• 
 Should the participant continue to be unreachable, she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
FEASIBILITY ASSESSMENTS  

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At the time of recruitment to the study, participants’ medical charts will be utilized to confirm the 
diagnosis of early pregnancy loss by ultrasound diagnosis. A HIPAA authorization form will be obtained 
from patients at the time of enrollment into the study, as EPL care will be documented in the UNC EPIC 
electronic medical record as well as in the study documentation. Any adverse events noted in the UNC 
EPIC electronic medical record during the study follow up time that are not associated with a study visit 
will be abstracted into the study documentation to appropriately follow up adverse events.  
 
Once study participants have been approached, administration of UPA should occur within 14 days of 
diagnosis of early pregnancy loss, as over 50% of patients will have completion of their miscarriage with 
expectant management alone 14 days after diagnosis of early pregnancy loss [27]. Following 
administration of ulipristal acetate 90mg PO, participants will place misoprostol 800mcg vaginally 6 to 
18 hours after ulipristal acetate. Study participants will note the time of misoprostol administration on 
their appointment card and report the time of misoprostol administration at their subsequent visit to 
ensure adherence to the study protocol. 
 
Patients will return to clinic on day 3 for a transvaginal ultrasound to confirm absence of a gestational 
sac. Transvaginal ultrasound will be performed by an obstetrician/gynecologist (fellow or attending) in 
the UNC Family Planning Clinic to confirm absence of the gestational sac. These physicians have training 
in transvaginal ultrasound in early pregnancy. If participants are still noted to have a pregnancy in the 
uterus, they will be offered expectant management, medical management with an additional dose of 
800mcg misoprostol, or surgical management with manual or electric uterine aspiration based on 
gestational age. Those patients with a pregnancy still in the uterus will return to clinic again on day 8 for 
an additional transvaginal ultrasound and again be offered options if pregnancy is still present. All 
patients will receive a phone call 30 days following misoprostol administration to assess for additional 
treatments needed, side effects, adverse events, and patient acceptability. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
At the time of diagnosis of EPL, the research coordinator will utilize the medical chart to review 
ultrasound images to confirm the diagnosis. Research personnel will then complete an eligibility 
questionnaire based on the inclusion and exclusion criteria as laid out above (5.1). Participants must be 
hemodynamically stable to take part in the study, which will be assessed by the OBGYN provider 
assessing the patient for their diagnosis.  
 
On day 3 follow up, participants will provide information regarding the time and route they took their 
misoprostol medication to ensure compliance with the study activities. Patients will be informed in real 
time regarding their follow up transvaginal ultrasound results at their follow up visits, as they will be 
able to decide how they want to proceed with management (expectant management, additional 
medical management with second dose of misoprostol, or surgical management) if ultrasound still 
confirms the presence of an intrauterine pregnancy. Similarly, any patients who necessitated any 
additional care as part of their treatment of EPL (e.g. genetic studies on products of conception, 
infectious disease testing) will have those results shared in the standard manner for all patients seeking 
care with the Family Planning Division. Participants will report all adverse events (both pregnancy and 
non-pregnancy related) at each clinical visit. 
 
During the two weeks post-treatment period, if women develop fatigue, malaise, abdominal pain or 
jaundice, a workup for liver injury should be performed. All patients with elevated LFTs (ALT, AST or total 
bilirubin) will be followed until resolution. For patients whose LFTs have not returned to normal within 

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one month, these patients will be referred to a specialist (e.g. hepatologist) for further workup and 
treatment if necessary.  
 
The study sponsor will evaluate the first 20 patients for their post-treatment LFTs prior to expanding 
enrollment to the subsequent 20 patients.   
 
Patients identified to have more severe medical adverse events or side effects will be advised to contact 
the UNC Family Planning Division. Based on the symptomatology and severity, patients will be instructed 
to seek care through the emergency department/urgent care or through the Family Planning Clinic. All 
medical adverse events or side effects will be managed based on the standard of care. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
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The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
The study sponsor will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study sponsor will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
All participants in the study will have notation on their UNC EPIC chart to alert the research staff if the 
patient is seen for any possible adverse event. Patients will be assessed for adverse events at their 
telephone follow up 30 days after study intervention. Solicited information on adverse events will 
include increased bleeding requiring hospital admission or blood transfusion and infection requiring 
hospital admission or IV antibiotics. All other adverse events will be identified based on unsolicited 
questioning during this telephone visit.  

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8.3.5 ADVERSE EVENT REPORTING  
Adverse event reporting by patient self-report will take place at each study visit, both in person and via 
telephone. Additionally, any adverse event that happens between study visits for which the participant 
seeks care at UNC Chapel Hill will be abstracted from the UNC EPIC electronic medical record. All 
adverse events will be recorded on case report forms (CRF) and will be reviewed by the principal 
investigator and mentor. Case report forms should be documented within 24 hours of the event, and 
review of the case report forms will occur on a weekly basis. 
 
 Likely mild medication side effects as detailed for UPA include headache (18%), nausea (12%), 
abdominal pain (12%). Other infrequent mild side effects include dysmenorrhea, fatigue and dizziness 
[14]. All patients may experience pain and discomfort during the process of pregnancy expulsion; 
however, this pain and discomfort are not different than what a patient would experience not in the 
study. Assessment of adverse events will include symptoms possibly related to the study medication and 
pregnancy expulsion, but will also include any additional adverse events experienced by the study 
participants. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
Based on prior studies of mifepristone and misoprostol, the rate of severe adverse event in this 
population is extremely low (approximately 1%). The study clinician will immediately report to the 
sponsor any serious adverse event, whether the adverse event is considered study intervention related, 
including those listed in the protocol and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study outcomes that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the study sponsor and should be provided as soon as possible. 
 
Upon the first severe adverse event that occurs among study participants, the study will be stopped 
temporarily until review of the event by the UNC IRB. Following review of the severe adverse event, a 
decision will be made if the entire study will need to be stopped prematurely or if it is safe to continue 
the study.  
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor identifies that the information qualifies for reporting. 
 
Any serious liver injury case consistent with Hy’s law will be reported as an expedited report to the FDA.  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  

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Participants will be notified at an aggregate level about any AEs or SAEs affecting >5% of the study 
population.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
There are no additional events of special interest beyond those that have already been described.  
 
8.3.9 REPORTING OF PREGNANCY  
As patients are being admitted to the study with early pregnancy loss, no new pregnancies will be 
assessed during the study period.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 UNANTICIPATED PROBLEM REPORTING  
Research personnel will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the principal investigator (PI). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study sponsor 
within 7 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the study sponsor within 30 days of the 
investigator becoming aware of the problem.  

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• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 7 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Not applicable.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
RESEARCH HYPOTHESES 
• 
Primary Outcome Variable(s):  
o Feasibility: 
§ 
Recruitment: >60% participants screened for participation enrolled in study 
§ 
Adherence: >50% participants took study medications at the appropriate time 
and route 
§ 
Retention: >90% participants had complete follow up for all study visits 
• 
Secondary Outcome Variable(s): This is a pilot study with a small sample size and thus our 
secondary aims will only be for hypothesis generating activities, not hypothesis testing activities. 
9.2 
SAMPLE SIZE RATIONALE 
As this is a feasibility pilot study, no formal power calculation is required. We anticipate recruiting a 
convenience sample of 40 participants over the course of 12 months recruitment based on prior 
information from UNC Chapel Hill where approximately two patients with EPL are diagnosed per week at 
our two study locations after accounting for eligibility criteria and desire participation in the study. We 
estimate that of the approximately 100 patients diagnosed with EPL over the year, 40 patients will enroll 
given prior recruitment rates from studying mifepristone and misoprostol for early pregnancy loss (800 
EPL patients for a total of 300 participants) [2]. 
 
9.3 
POPULATIONS FOR ANALYSES 
As no randomization will take place in this analysis, all participants will be analyzed as part of the same 
population using univariate statistics. For the primary endpoint of feasibility, all patients screened for 
study participation will be included in the sample size. For the secondary endpoints of resolution of EPL, 
side effects/adverse events and patient acceptability, only participants adherent to study medication 
and completing all study visits will be analyzed. A sensitivity analysis will be conducted for the secondary 
endpoints that will include all participants enrolled in the study population for which data is available, 
regardless of adherence to study medication or completion of all study visits.   
 
Patient disposition in the study will be reported, including the following:  
• 
Number (%) of patients screened for study participation 
• 
Number (%) of patients enrolled in study population 
• 
Number (%) of participants adherent to study medication (UPA + misoprostol after 6 to 18 
hours) 
• 
Number (%) of participants non-adherent to study medication (any other route or timing of 
taking study medications) 
• 
Number (%) of participants completing all study visits (day 0, day 3/8, day 30) 

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• 
Number (%) of participants completing some of study visits 
 
Patient disposition will be reported as a flow chart and in tabular format in any future study 
communication and manuscript.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
Continuous variables will be summarized using mean and standard deviation or median and range 
depending on the distribution and categorical variables will be described as frequency and percentage. 
All statistics will be reported with 95% confidence intervals. Where applicable, missing data will be 
reported as an individual category. As this is a pilot feasibility study with a small sample size, no formal 
statistical testing will be completed. The principal investigator will be responsible for all data 
management and data analysis. Statistical calculations will be performed in Stata 15.1.  
 
9.4.2 ANALYSIS OF THE PRIMARY FEASIBILITY OUTCOME VARIABLE(S) 
• 
Recruitment (%): number of participants in study/number of patients screened for participation  
• 
Adherence (%): number of participants adhering to study intervention (UPA + misoprostol 
vaginally after 6 to 18 hours)/number of participants in study 
• 
Retention (%): number of participants attending all study visits (day 0, 3/8, 30)/number of 
participants in study 
 
9.4.3 ANALYSIS OF THE SECONDARY OUTCOME VARIABLE(S) 
• 
Resolution of EPL 
o Binomial outcome: Absence of gestational sac on transvaginal ultrasound examination 
on Day 3 follow up 
o Binomial outcome: Need for additional dose of misoprostol within 30 days of treatment 
o Binomial outcome: Need for uterine aspiration within 30 days of treatment 
• 
Side Effects/Adverse Events 
o Side Effects Binomial Outcomes (N, %) 
§ 
Fatigue 
§ 
Headache 
§ 
Dizziness or lightheadedness 
§ 
Chills 
§ 
Nausea 
§ 
Diarrhea 
§ 
Vomiting 
§ 
Severe cramping 
§ 
Fever 
§ 
Other 
o Adverse Events Binomial Outcomes (N, %) 
§ 
Excess bleeding requiring blood transfusion 
§ 
Pelvic infection requiring antibiotics 
• 
Patient Acceptability 
o Likert Scale Ordinal Outcomes (Median, Counts) 

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§ 
Would you use this combination of medications again if you had another early 
pregnancy loss? 
§ 
Would you recommend this combination of medications to a friend with early 
pregnancy loss? 
§ 
If it was possible to take the first medication at home (versus in clinic), would 
you be more or less likely to use this combination of medications again? 
§ 
If it were possible to take the first medication at a different time (versus during 
your appointment), would you be more or less likely to use this combination of 
medications again? 
 
9.4.4 SAFETY ANALYSES 
AEs will be reported by frequency and percentage of participants presenting with the outcomes. Specific 
side effects and adverse events of interest are listed with secondary outcomes (9.4.3). All other side 
effects and adverse events outside of those listed in 9.4.3 will also be reported by frequency and 
percentage. Other AEs will be reported by severity of the adverse events (mild, moderate or severe) and 
related or not related to the study protocol. AEs will be grouped by Medical Dictionary for Regulatory 
Activity (MedDRA) System Organ Class (SOC).  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Descriptive statistics will be reported for patient demographics based on the demographic questionnaire 
collected at the time of participant enrollment into the study. As there is only one study group, no 
statistical comparisons will be made. The following demographic information will be collected: 
• 
Age (mean, SD) 
• 
Race/ethnicity (N, %) 
• 
Education (N, %) 
• 
Marital status (N, %) 
• 
Insurance type (N, %) 
• 
Gravidity (median, IQR) 
• 
Parity (median, IQR) 
• 
Vaginal deliveries (median, IQR) 
• 
Cesarean deliveries (median, IQR) 
• 
Living children (N, %) 
• 
Previous miscarriage (N, %) 
• 
Previous abortion (N, %) 
• 
Gestational age (mean, SD) 
 
9.4.6 PLANNED INTERIM ANALYSES  
Given the small size and short duration of the study, no interim analysis will be completed.  
 
9.4.7 SUB-GROUP ANALYSES 
Given the small sample size and lack of randomization, no sub-group analysis will be performed.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
All data will be aggregated for the purpose of reporting results from the study. No individual patient 
data will be listed.  
 

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9.4.9 EXPLORATORY ANALYSES 
No additional exploratory analyses will be completed.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol (Appendix A – Informed Consent).  
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, the Investigational 
New Drug (IND) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 

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Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
A life-threatening medical situation with determined study procedure causality 
• 
Persistent or significant incapacity as a result of study drug(s) or procedure(s) 
• 
A study participant with hepatic enzyme elevation greater than 3 times the upper limit of 
normal seen on laboratory testing on day 14 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, research 
personnel, and the sponsor and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored in a 21 CFR Part 11-compliant database through UNC. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by research staff will be secured and password 
protected. At the end of the study, all study databases will be disposed of 2 years following study 
termination.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
No future use of any data related to this study will be conducted.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Mentor 
Jill Melissa Hagey, MD MPH 
Amy Bryant, MD MSCR 
University of North Carolina, 
Chapel Hill 
University of North Carolina, 
Chapel Hill 

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101 Manning Drive 
Chapel Hill, NC 27514 
101 Manning Drive 
Chapel Hill, NC 27514 
919-966-5280 
 
jill.hagey@unchealth.unc.edu  
amy_bryant@med.unc.edu  
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a medical monitor with appropriate expertise given the 
small number of participants in the study. The medical monitor should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived conflict of 
interest.  The medical monitor will review this project at least semiannually to assess safety and efficacy 
data of the study. At this time, each data element that the medical monitor needs to assess will be 
clearly defined. The medical monitor will provide its input to the study sponsor and study team.  
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
On-site monitoring will occur for initial assessment and training of sites prior to study participant 
enrollment. The principal investigator will provide an overview of study activities and participant 
eligibility criteria to all OBGYN clinical staff at UNC Chapel Hill during a weekly departmental meeting. 
The principal investigator will also provide an overview of study activities to all key clinical staff 
members who may come in contact with study participants at the sites for patient recruitment as well as 
at UNC Chapel Hill Family Planning Clinic where follow up visits will take place. Targeted data verification 
will be performed by the principal investigator for the first 10 participants approached for recruitment 
to the study (approximately 10%) to ensure appropriate data collection from the research coordinator. 
As possible, most transvaginal ultrasounds will be performed by the principal investigator to ensure 
consistency between imaging findings. Of those not performed by the principal investigator, 20% will be 
randomly reviewed. 
 
Independent audits will not be conducted. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the 21 CFR Part 11-compliant database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 

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The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the research personnel at the site under the supervision of the 
principal investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents will be completed via paper and pencil and then transcribed into an electronic 21 
CFR Part 11-compliant database to ensure accurate interpretation of data. All patient questionnaires will 
require an answer to each question with an option to select “Prefer not to answer” to improve data 
completeness. “Prefer not to answer” will be coded as “99” to denote this value during data analysis. All 
provider questionnaires will be filled out by consistent study staff, with enrollment visits completed by 
the study coordinator and all follow up visits completed by the principal investigator.  
 
A data “codebook” will be created for each question of the source documents to ensure that all data is 
being entered into the electronic database in the same way.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the same 21 CFR Part 11-compliant data capture 
system provided by UNC. Any missing data from the clinical data abstracted from the EPIC chart will be 
denoted as “Missing” and will be coded as “98” to denote this value during data analysis. Any missing 
data will be reviewed in the EPIC chart by the principal investigator to ensure that this data value is not 
present.  
 
The data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 

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These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents, 
reported to the UNC IRB.  Protocol deviations must be sent to the reviewing Institutional Review Board 
(IRB) per their policies. The site investigator is responsible for knowing and adhering to the reviewing 
IRB requirements. Further details about the handling of protocol deviations will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 2 years after the 
completion of the primary outcome by contacting the principal investigator.   
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the UNC IRB has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
None 
 
 

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
EPL 
Early Pregnancy Loss 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
UPA 
Ulipristal Acetate 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
24 Aug 2021 Initial protocol 
 
2.0 
20 Sept 
2021 
Updated protocol per SRC comments  
3.0 
3 Dec 2021 
Updated protocol per FDA IND 
comments 
 
4.0 
10 Jan 2022 
Updated protocol per FDA IND 
comments 
 
5.0 
15 Feb 2022 
Updated protocol per IRB comments 
 
6.0 
3 Mar 2022 
IRB Modification 
 
7.0 
22 Apr 2022 
IRB Modification 
 
8.0 
2 June 2022 
IRB Modification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: DOUBILET CRITERIA [5]