Conditions: Uterine Fibroids
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
To determine the safety of extended treatment with Proellex® in women who have successfully completed either study ZPV-201 \[NCT02323646\] or ZPU-203 \[NCT02301897\] and meet eligibility criteria.

Detailed description:
This study will be for participants who had completed either ZPV-201 or ZPU-203.

Arms:
arm 1: Telapristone acetate 12 milligrams (mg), orally, once daily for two 18-weeks courses (Treatment Courses 1 and 2) separated by an off-drug interval (ODI).

Interventions: intervention 1: Telapristone acetate
Intervention descriptions: intervention 1: Telapristone acetate, orally, once daily for three 18-weeks courses separated by an ODI.

Protocol document:
Prot_SAP_000.pdf: 
*Any inconsistent numbering or deletion of pages is due to the removal of a full protocol due to its 
summary of changes being supplied.  
NCT02811159 
 
Study ID: ZPU-203EXT 
 
Title: An Open-Label Extension Study of 12 mg Proellex® (Telapristone Acetate) 
Administered Orally in the Treatment of Premenopausal Women with 
Confirmed Symptomatic Uterine Fibroids 
 
Protocol Amendment 1 Date: 13 July 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


T H E. R '' P E U T I 
• 5 
I 
~. C 
Protocol Number: ZPU-203EXT 
An Open-Label Extension Study of 12 mg Proellex® (Telapristone Acetate) 
Administered Orally in the Treatment of Premenopausal Women with 
Confirmed Symptomatic Uterine Fibroids 
Original Protocol: June 22, 2016 
Amendment 1: July 13,2016 
SPONSOR: 
Repros Therapeutics Inc.® 
2408 Timberloch Place, B-7 
The Woodlands, TX 77380 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or consultant for 
review by you, your staff and the applicable Institutional Review Board I Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information contained 
herein to others without written authorization from the Sponsor, Repros Therapeutics Inc.~ 
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TABLE OF CONTENTS 
 
COVER PAGE .................................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................................... 2 
3. PROTOCOL SYNOPSIS ............................................................................................................. 4 
4. PROCEDURES AND LABORATORY TABLES ..................................................................... 7 
5. LIST OF ABBREVIATIONS .................................................................................................... 10 
6. BACKGROUND INFORMATION .......................................................................................... 11 
6.1 
RATIONALE FOR CURRENT STUDY .................................................................................. 11 
6.2 
NON-CLINICAL DATA ...................................................................................................... 12 
6.3 
CLINICAL DATA/HUMAN EXPERIENCE ............................................................................ 13 
6.4 
SAFETY DATA .................................................................................................................. 14 
6.5 
ETHICAL CONDUCT OF THE STUDY .................................................................................. 16 
6.6 
DRUG SAFETY MONITORING BOARD (DSMB) ................................................................ 16 
7. TRIAL OBJECTIVES AND PURPOSE .................................................................................. 17 
8. TRIAL DESIGN ......................................................................................................................... 18 
8.1 
STUDY ENDPOINTS ........................................................................................................... 18 
8.2 
STUDY DESIGN ................................................................................................................. 18 
8.2.1 Overview of Study Design ............................................................................................. 18 
8.2.2 Study Drug Accountability ............................................................................................ 19 
8.2.3 Randomization and Blinding ......................................................................................... 19 
8.2.4 Study Medication ........................................................................................................... 19 
 
 
 
 
 
 
 
 
8.3.1 Inclusion Criteria ........................................................................................................... 22 
8.3.2 Exclusion Criteria .......................................................................................................... 22 
10. ASSESSMENT OF SAFETY ..................................................................................................... 29 
10.1 
ADVERSE EVENTS ............................................................................................................ 29 
10.1.1 
Reporting Adverse Experiences ............................................................................ 29 
10.1.2 
Definitions ............................................................................................................. 29 
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10.1.3 
Serious Adverse Events (SAEs) ............................................................................ 30 
11. CONCOMITANT MEDICATIONS ......................................................................................... 32 
11.1 
PROHIBITED MEDICATIONS .............................................................................................. 32 
11.2 
OTHER MEDICATIONS TAKEN DURING THE STUDY ........................................................ 32 
12. STATISTICAL METHODS ...................................................................................................... 33 
12.1 
DETERMINATION OF SAMPLE SIZE ................................................................................... 33 
12.2 
STATISTICAL AND ANALYTICAL PLAN ............................................................................ 33 
12.3 
GENERAL STATISTICAL ISSUES ........................................................................................ 34 
13. ETHICS ....................................................................................................................................... 36 
13.1 
SUBJECT INFORMATION AND CONSENT ........................................................................... 36 
13.2 
INSTITUTIONAL REVIEW BOARD ...................................................................................... 36 
13.3 
MONITORING CASE REPORT FORMS ................................................................................ 36 
13.4 
STUDY RECORD RETENTION ............................................................................................ 36 
13.5 
DATA QUALITY ASSURANCE ........................................................................................... 36 
13.6 
CONFIDENTIALITY............................................................................................................ 37 
13.7 
PUBLICATIONS ................................................................................................................. 37 
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3. 
PROTOCOL SYNOPSIS 
Test Drugs: 
Proellex® (Telapristone Acetate): 12 mg gelatin capsules 
Protocol Number: 
ZPU-203EXT  
Study Purpose: 
To determine the safety of extended treatment with Proellex in 
women who have successfully completed either study ZPV-201 or 
ZPU-203 and meet eligibility criteria. 
Study Design and 
Duration 
Of Treatment: 
This study is an open-label, multi-center extension study to evaluate 
the safety of continued treatment with Proellex in subjects who 
successfully completed either study ZPV-201 or ZPU-203.   The 
study requires 16 visits and is approximately 13 months in duration 
(up to 15 months for selected sites).   Subjects will be treated orally 
with 12 mg Proellex/day for three 18-week courses, each separated 
by an ODI.  Throughout the study women will record study 
information in the diary, PBAC, and questionnaires as outlined in the 
study procedures. 
The start of the first 18-week course of treatment (Course 1) should 
commence no later than 4 days after the end of bleeding, i.e. at visit 
24 (or Visit 19, see Study Procedures below) of the previous study.  
Once dosing for Course 1 is stopped, subjects will be followed until 
menses returns.  The start of the second and third 18 week courses of 
treatment (Courses 2 and 3) will commence no later than 4 days after 
the end of bleeding in the subject’s menses following withdrawal of 
drug after the previous course has been completed.   
At selected sites subjects will commence dosing on the first day of 
bleeding in their next menstrual cycle after Visit 19 or Visit 24 (about 
3 weeks after V19 or 24).  The start of the second and third courses of 
treatment will start on the first day of bleeding in the subject’s second 
menses following withdrawal of study drug. 
During the ODI, subjects will continue to record study information in 
the daily paper diary and PBAC charts. 
Any subject who has any 28-day period during treatment (not 
including the ODIs) without a bleeding score >1 will be deemed to 
have achieved amenorrhea.  Subjects who do not achieve amenorrhea 
after 8 weeks of treatment will exit the study.  After completion of 3 
courses of treatment, subjects will be followed through the 
subsequent menstrual event (recovery menses). 
A DSMB will review any liver safety events (LFTs ≥3 x ULN or 
bilirubin ≥2 x ULN). 
Subject Population: 
The study will enroll women who have successfully completed either 
study ZPV-201 or ZPU-203 and meet eligibility criteria. 
Number of Subjects: 
Up to about 60 subjects 
Number of Sites 
Approximately 10 sites  
Study Duration:  
Total participation in the study is approximately 13 months. 
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:  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
Study Endpoints 
Endpoints will be:  
• Percentage of subjects who become amenorrheic 
• Change in UFS-QOL Symptom Severity score comparing to the 
previous study baseline and study baseline 
• Change in the individual UFS-QOL sub scores 
• Change in PBAC scores 
• Percentage change from parent study baseline and study baseline 
in total uterine fibroid volume measured by MRI  
• Incidence of significant adverse events 
• Changes in physical examination results 
• Changes in clinical laboratory results  
• Changes in liver function to values  
• Unexpected or excessive vaginal bleeding 
• Endometrial thickness assessed using vaginal ultrasounds 
• Change in number and intensity of bleeding days over the course 
of the treatment and ODI periods 
 
 
• Pathology of the endometrium assessed by biopsies. 
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Statistical Methods: 
Summaries for quantitative variables include the sample size, mean, 
median, standard deviation, minimum, and maximum.  Summaries 
for categorical variables include the number and percent of patients 
for each outcome.    
Continuous efficacy endpoints, such as the change from baseline in 
uterine tumor volumes  will assess treatment effect using a within-
group t-test or appropriate non-parametric technique. The percentage 
of subjects becoming amenorrheic will be determined. 
 
 
 
 
 
 
   
 
 
 
 
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5. 
LIST OF ABBREVIATIONS 
 
AE 
 
Adverse event 
CRF 
 
Case report form 
DHEA  
Dehydroepiandrosterone 
dL 
 
Deciliter 
FSH 
 
Follicle-stimulating hormone 
GCP 
 
Good Clinical Practice 
GnRH  
Gonadotrophin releasing hormone 
g 
 
Grams 
ICH 
 
International Conference on Harmonization    
IRB 
 
Institutional Review Board 
IND 
 
Investigational new drug 
IUD 
 
Intra-uterine device 
kg  
 
Kilogram(s) 
LD50  
Median lethal dose 
LH 
 
Luteinizing hormone 
m 
 
Meters 
MBL  
Menstrual Blood Loss 
mg 
 
Milligram(s) 
mL 
 
Milliliter 
ng 
 
Nanograms 
OC 
 
Oral Contraceptive 
ODI 
 
Off-Drug Interval 
PBAC  
Pictorial Blood Loss Assessment Chart 
PCOS  
Polycystic Ovarian Syndrome 
PK 
 
Pharmacokinetic 
RBC  
Red blood cell 
SAE 
 
Serious adverse event 
UFSQOL 
Uterine Fibroid Symptom Quality of Life Survey 
UFS-QOL 
Uterine Fibroid Symptom Quality of Life Survey 
WBC  
White blood cell 
 
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6. 
BACKGROUND INFORMATION 
6.1 
Rationale for Current Study 
Repros believes telapristone offers the potential to provide significant 
symptomatic relief to women that suffer from a variety of reproductive 
disorders in which progesterone may be implicated. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
Based on findings from the recently completed ZP-204 low dose study of oral 
Proellex, doses from 1 mg up to 12 mg daily were administered for 
10 consecutive weeks with no observed elevations of liver enzymes or even 
trends towards increasing liver enzymes with increasing dose.  At the same 
time induction of amenorrhea was seen in a consistent fashion starting at a 3 
mg daily dose as long as trough levels of the drug were observed.  The 
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sponsor believes there is a direct correlation of symptomatic relief for uterine 
fibroids and endometriosis with induction of amenorrhea. 
 
 
 
 
 
  Typically women are 
dosed for 4 months (120 days) after which time the drug is withdrawn to allow 
for menses to return.  Once menses has occurred women may resume 
treatment for another dosing period. In this fashion the drug can be used to 
control the symptoms of endometriosis and fibroids until the onset of 
menopause.    
6.2 
Non-Clinical Data 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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6.3 
Clinical Data/Human Experience 
In addition to the preclinical studies, a Phase I/II study of orally administered 
Proellex in pre-menopausal women with symptomatic leiomyomata had been 
completed.  The objectives of this study were to test the safety, efficacy, and 
pharmacokinetics of three doses of Proellex (12.5 mg, 25 mg, and 50 mg) 
administered as a once daily dose for 90 days, with study visits at one-month 
intervals.  The safety and effectiveness of Proellex was compared to placebo 
and the active control leuprolide acetate for depot suspension (Lupron Depot).  
At the conclusion of this study, exploratory analyses showed statistically 
significant efficacy differences between treatment groups (overall and pair-
wise). 
 
  
  
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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FDA Guidance For Liver Enzyme 
Elevation Characterization as SAE
• 1.
LFTs ≥ 8 x ULN
• 2.
LFTs ≥ 5 x ULN for 2 consecutive weeks
• 3.
LFTs ≥ 3 x ULN + Bilirubin 2 x ULN
• 4.
LFTs ≥ 3 x ULN + clinical signs or 
symptoms (nausea; jaundice; etc.)
 
 
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6.5 
Ethical Conduct of the Study 
This trial will be conducted in strict compliance with the protocol and all 
applicable FDA regulations and GCP guidelines to insure Good Clinical 
Practice standards.  IntegReview, 3815 S. Capital of Texas Highway, Suite 
320, Austin, TX 78704, will serve as an Institutional Review Board (IRB) for 
clinical sites who will accept their review.  
6.6 
Drug Safety Monitoring Board (DSMB) 
A DSMB will review the data from any subject who has elevation of LFTs ≥3 
x ULN and/or a bilirubin level ≥2 x ULN.   
 
 
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7. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to determine the safety of orally administered 
Proellex administered at 12 mg/day for up to 3 courses of treatment (18 weeks each), 
each separated by an Off-Drug Interval (ODI), to women who have completed either 
ZPV-201 or ZPU-203.   
To further investigate the effect of the timing of start of dosing upon the onset of 
amenorrhea, at selected sites the start of dosing in each cycle will be on the first day 
of bleeding rather than 0-4 days after stopping bleeding. 
 
 
 
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8. 
TRIAL DESIGN 
8.1 
Study Endpoints 
• Percentage of subjects who become amenorrheic over the course of the 
study 
• Change in UFS-QOL Symptom Severity Score comparing to the previous 
study baseline and study baseline 
• Change in the individual UFS-QOL subscores over the course of the study 
• Change in PBAC scores over the course of the study 
• Percentage change from parent study baseline and study baseline in total 
uterine fibroid volume measured by MRI  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
8.2 
Study Design 
8.2.1 Overview of Study Design 
This study is an open-label, multi-center extension study to evaluate 
the safety of continued treatment with Proellex in subjects who 
successfully completed either study ZPV-201 or ZPU-203.  The study 
requires 16 visits and is approximately 13 months in duration.   
Subjects will be treated orally with 12 mg Proellex/day for three 18-
week courses, each separated by an ODI.  Subjects will use only 
sanitary supplies provided by the sponsor.  Throughout the study 
women will record study information in the diaries and questionnaires 
as outlined in the study procedures. 
Any subject who has any 28-day period during treatment (not 
including the ODIs) without a bleeding score >1 will be deemed to 
have achieved amenorrhea (in both the current or the previous study).  
Visit 1 of this study will also be Visit 24 of the previous study unless 
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the subject failed to achieve amenorrhea in the previous study.  Such 
subjects may enroll at Visit 19 (after first recovery menses) in the 
previous study.  Subjects who do not achieve amenorrhea after 8 
weeks of treatment in this study will exit the study. 
The start of the first 18-week course of treatment (Course 1) should 
commence no later than 4 days after the end of bleeding in the last 
menses, which should coincide with Visit 19 or 24 of the previous 
study.  Once dosing for Course 1 is stopped, subjects will be followed 
until menses returns.  The start of the second and third 18 week 
courses of treatment (Courses 2 and 3) will commence no later than 4 
days after the end of bleeding following withdrawal of drug after the 
previous course has been completed.   
At selected sites subjects will commence dosing on the first day of 
bleeding in their next menstrual cycle after Visit 19 or Visit 24 (about 
3 weeks after V19 or 24).  The start of the second and third courses of 
treatment will start on the first day of bleeding in the subject’s second 
menses following withdrawal of drug. 
During the ODI, subjects will continue to record study information in 
the daily paper diary. 
After completion of 3 courses of treatment, subjects will be followed 
through the subsequent menstrual event (recovery menses). 
A DSMB will review any liver safety events (LFTs ≥3 x ULN or bilirubin 
≥2 x ULN) . 
8.2.2 Study Drug Accountability 
The designee assigned by the Principal Investigator at each site will 
maintain accurate records of receipt of all study drugs, including dates 
of receipt.  Reasons for deviation from the expected dispensing 
regimen must also be recorded.  A Drug Dispensing Form will be 
provided for this purpose.  To satisfy regulatory requirements 
regarding drug accountability and destruction, the Principal 
Investigator at each site will return all used, unused, empty, and 
partially used study medication with dispensing records to the Sponsor 
for final accountability and disposal, after accountability has been 
verified by the study monitor.  
8.2.3 Randomization and Blinding 
As the study is open-label there will be no randomization or blinding. 
8.2.4 Study Medication 
All study drugs will be supplied by Repros Therapeutics Inc. Test 
drug, Proellex will be supplied in 40 count bottles and will be 
packaged by a clinical supplies contract vendor designated by Repros 
Therapeutics Inc.  
 
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and 
instructions to take 1 capsule daily in the morning with breakfast.  
Subjects will take one capsule with approximately 8 ounces of water 
and study medication should be taken roughly at the same time every 
day.  Subjects will record study medication date and time on subject 
drug diary cards.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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8.3.1 Inclusion Criteria 
Subjects must meet the following criteria: 
• Completed either study ZPV-201 or ZPU-203  
• Agreement not to attempt to become pregnant during the trial 
• Agreement to use alcohol in moderation and record the daily 
consumption (note: elevated liver enzymes may result in 
discontinuation from the study) 
• Ability to complete a daily subject diary and study procedures in 
compliance with the protocol 
• Agreement to use only sanitary supplies provided by the sponsor 
throughout the study 
• Women of child-bearing potential must be willing to use double-
barrier contraception during the study and off-drug intervals.  
Acceptable double-barrier methods are: male condom with 
spermicide; male condom with diaphragm; diaphragm containing 
spermicide plus additional intra-vaginal spermicide 
• Has a negative pregnancy test at Visit 1 
• Subject is available for all treatment and follow-up visits 
8.3.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from 
the study: 
• Subject had a significant decrease in bone mineral density while 
participating in ZPV-201 or ZPU-203 (total hip or spine 
measurement decreased by more than 5%) 
• Subject 
has 
undergone 
hysterectomy 
and/or 
bilateral 
oophorectomy since enrollment in ZPV-201 or ZPU-203. 
• Subject is pregnant or lactating or is attempting or expecting to 
become pregnant during the entire study period 
•  Subjects with abnormally high liver enzymes or liver disease. 
(ALT or AST exceeding 2 x ULN AND total bilirubin exceeding 
1.5 x ULN at Visit 1 and confirmed on repeat). 
• Subject has a hemoglobin of <7.5 g/dL at Visit 1 
• At sponsor discretion, subject had poor compliance in study ZPV-
201 or ZPU-203 
• Concurrent use of any testosterone, progestin, androgen, estrogen, 
anabolic steroids, DHEA or hormonal products for at least 2 weeks 
prior to Visit 1  
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• Use of oral contraceptives in the 30 days preceding screening.  Use 
of Depo-Provera® in the preceding 10 months. 
• Use of GnRHas (e.g. Lupron Depot) within 3 months prior to 
screening (Lupron Depot must have a wash-out period of 3 months 
prior to screening)  
• Has an IUD in place 
• Current cervical dysplasia classified as Atypical Squamous Cells 
of Undetermined Significance (ASCUS) associated with high-risk 
human papilloma virus (HPV) 
• Current diagnosis of Low/High Grade Squamous Intraepithelial 
Lesion (LGSIL or HGSIL), endometrial polyps or hyperplasia 
• Observation or history of abnormal endometrial biopsy including 
the presence of EIN 
• Recent history (within past 6 months) of alcoholism or drug abuse 
• Endometrial stripe ≥18 mm in thickness at Visit 1 (subject may be 
enrolled with sponsor approval) 
• Subject is currently taking cimetidine or spironolactone or has 
taken them in the last 30 days 
• Clinically significant abnormal findings on Visit 1 examination 
and laboratory assessments or any condition which in the opinion 
of the investigator would interfere with the participant’s ability to 
comply with the study instructions or endanger the participant if 
she took part in the study. 
 
 
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10. 
ASSESSMENT OF SAFETY 
 
 
10.1 
Adverse Events 
10.1.1 Reporting Adverse Experiences 
Any AE (clinical sign, symptom, or disease) temporally associated 
with the use of this investigational drug, whether or not considered 
related to the investigational product, shall be documented on the CRF 
and eDC.  All SAEs and AEs reported by the subject or observed by 
the Principal Investigator for up to 30 days after the last dose of study 
medication will be individually listed.  The signs and symptoms, time 
of onset (24-hour clock), duration, action taken and follow-up 
procedures will be reported.   
10.1.2 Definitions 
Adverse Event – Any untoward medical occurrence in a clinical 
investigation subject administered a drug and does not necessarily 
have a causal relationship with this treatment.  An AE can therefore, 
be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not related to the 
investigational product. 
Serious Adverse Event (SAE) – An adverse drug experience that 
results in any of the following outcomes:  death, a life-threatening 
experience, requires or prolongs subject hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital 
anomaly or birth defect.   
Cases of liver transaminases that increase above 3 times the upper 
limit of normal must be reported as SAEs regardless of whether the 
above defined SAE criteria are met. 
Unexpected Adverse Event: Any adverse event that is not identified in 
nature, severity, or frequency in the current Investigator’s Brochure. 
Additionally, the Principal Investigator will evaluate all AEs as 
follows: 
Action taken:  whether or not the AE caused the subject/patient to 
discontinue the study medication. 
 
 
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Intensity, to be graded as: 
DEGREE 
DESCRIPTION 
Mild 
Awareness of signs and symptoms; easily tolerated 
Moderate 
Discomfort sufficient to interfere, but not prevent 
daily activity 
Severe 
Unable to carry out usual activity 
 
Relationship to study medication, to be graded as: 
DEGREE 
DESCRIPTION 
Definitely 
There is evidence of exposure to the study drug, 
for example, reliable history or acceptable 
compliance assessment; the temporal sequence of 
the AE onset relative to the medication is 
reasonable; the AE is most likely to be explained 
by the treatment than by another cause; the AE 
shows a pattern consistent with previous 
knowledge of the treatment. 
Probably 
There is evidence of exposure to the study drug; 
the temporal sequence of the AE onset relative to 
medication administration is reasonable; the AE is 
more likely explained by the treatment than by 
another cause. 
Possibly 
There is evidence of exposure to the study drug; 
the temporal sequence of the AE relative to the 
medication administration is reasonable; the AE 
could have been due to another equally likely 
cause. 
Probably 
not 
There is evidence of exposure to the study drug; 
there is another more likely cause of the AE. 
Definitely 
not 
The subject/patient did not receive the study drug; 
or temporal sequence of the AE onset relative to 
administration of the study drug is not reasonable; 
or there is another obvious cause of the AE. 
10.1.3 Serious Adverse Events (SAEs) 
The Principal Investigator shall document all SAEs in a subject 
receiving study drug until completion of the study and must be 
reported to the Repros Therapeutics Inc. Safety Monitor within 24 
hours by Fax or telephone, even if the SAE does not appear to be drug-
related.  This report should include all available information at the 
time of notification.  This notification should be followed with 
submitting a SAE Report Form provided by Repros Therapeutics Inc, 
and notifying the IRB.    
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All additional follow-up reports must be reported to the Repros 
Therapeutic Inc. monitor as soon as available. 
Cases of liver transaminases that increase above 3 times the upper 
limit of normal must be reported as SAEs regardless of whether the 
above defined SAE criteria are met. 
 
 
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11. 
CONCOMITANT MEDICATIONS 
11.1 
Prohibited Medications 
The following medications are prohibited during the study: 
• Testosterone 
• Progestin 
• Androgen 
• Estrogen 
• Anabolic steroids 
• DHEA 
• Other hormonal products 
• Any other treatment for uterine fibroids 
11.2 
Other Medications Taken During the Study 
Any other prescription or over-the-counter medication taken during the study 
will be recorded in the appropriate section of the CRF.  Subject must be on a 
stable dosage of approved concomitant medications at least 48 hours prior to 
drug administration. 
 
 
 
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12. 
STATISTICAL METHODS 
12.1 
Determination of Sample Size 
This is a extension study and the number of subjects will be dependent on the 
number of subjects completing the parent studies.  No more than 60 subjects 
are expected to enroll.  
12.2 
Statistical and Analytical Plan 
Analyses in this study will focus on comparison to two baseline assessments.  
One baseline is associated with the original parent study baseline and the other 
is associated with the 28-day period prior to the start of this extension study.  
Reference to baseline in this section refers to each baseline definition. 
12.2.1 Demographics and Subject Characteristics 
For all subjects included in this study, subject disposition and 
demographic data will be summarized.  Summaries for quantitative 
variables include the sample size, mean, median, standard deviation, 
minimum, and maximum.  Summaries for categorical variables include 
the number and percent of patients for each outcome.   
12.2.2 Incidence of Amenorrhea 
The percentage of subjects who become amenorrheic during the 28 
days leading up to the last day of dosing in each course will be 
determined.  The incidence of amenorrhea during the entire course and 
after the 11th day of the course will also be investigated. 
A subject is deemed amenorrheic if they have no bleeding intensity 
score greater than 1 using the Daily Diary Card in Appendix 2 
(spotting not requiring hygiene products) during the period.   
12.2.3 Percentage Change in PBAC Scores 
The percentage change in PBAC scores over each 28 day period of the 
course will be recorded and compared to baseline to determine onset 
of benefit. Additionally PBAC scores will be used to monitor the level 
of vaginal bleeding during the ODI. 
Within treatment group paired t-tests will evaluate treatment effect.  
While the primary assessment will be after each 18 week treatment 
course, summaries will be prepared for each of the other visits.  If data 
are missing, a last observation carried forward procedure will be used, 
including the baseline, if necessary. Non-parametric methods will be 
employed as appropriate.   
12.2.4 Percentage Change in Total and Individual Symptom Severity Scores 
for the UFSQOL 
The UFSQOL  has been validated as a three month look back 
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questionnaire.  The survey will be administered at baseline and at the 
end of each course.  Within group paired tests will be used to assess 
treatment effect.  Non-parametric methods will be employed as 
appropriate.  If data are missing, a last observation carried forward 
procedure will be used, including the baseline, if necessary. 
12.2.5 Percentage Change in Uterine Fibroid Volume by MRI 
The percent change from baseline in total uterine fibroid volume will 
be determined at the end of treatment.  This study will assess up to 3 
fibroids present at baseline in each subject.  The volume of these 3 
fibroids will be summed to determine the total uterine fibroid volume 
at each assessment.   
Within group paired tests will be used to assess treatment effect.  Non-
parametric methods will be employed as appropriate.  If data are 
missing, a last observation carried forward procedure will be used, 
including the baseline, if necessary. 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
  
 
 
 
    
12.3 
General Statistical Issues 
A Statistical Analysis Plan (SAP) will be finalized prior to unblinding the 
study. For the efficacy variables a last observation forward approach will be 
used to impute missing data to generate a complete ITT data.  If there are no 
post-baseline efficacy data then a value of no change will be imputed for the 
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missing efficacy measure.  Statistical significance will be declared if the two-
sided p-value is ≤ 0.05.  
 
 
 
 
 
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13. 
ETHICS 
13.1 
Subject Information and Consent 
A properly executed, written informed consent in compliance with Food and 
Drug Administration (FDA) regulations and Good Clinical Practice (GCP) 
guidelines will be obtained from each subject prior to entering the study or 
performing any unusual or non-routine procedure that involve a risk to the 
subject.  The Principal Investigator will submit a copy of the informed consent 
document to the Institutional Review Board for review and approval before 
research subjects are enrolled.  The Principal Investigator will provide a copy 
of the signed informed consent to the subject and the original will be 
maintained in the subject's medical record. 
13.2 
Institutional Review Board 
The Principal Investigator will provide the Institutional Review Board with all 
requisite material, including a copy of the informed consent.  The study will 
not be initiated until the IRB provides written approval of the protocol and the 
informed consent and until approved documents have been obtained by the 
Principal Investigator and copies received by the Sponsor.  Appropriate 
reports on the progress of this study by the Principal Investigator will be made 
to the Institutional Review Board and the Sponsor in accordance with the 
applicable government regulations and in agreement with the policy 
established by the Sponsor. 
13.3 
Monitoring Case Report Forms 
Repros Therapeutics Inc. or their designee will monitor all aspects of the 
study with respect to current GCP and standard operating procedures for 
compliance with applicable federal regulations.  These individuals will have 
access to all records necessary to ensure integrity of the data and will 
periodically review progress of the study with the Principal Investigator. 
13.4 
Study Record Retention 
In accordance with FDA regulations and GCP guidelines, all study-related 
documentation shall be retained by the Principal Investigator for a minimum 
of 2 years after FDA approval of telapristone acetate or clinical development 
has been terminated.  At that time, the Principal Investigator will contact 
Repros Therapeutics Inc. regarding further disposition of the study records 
and comply with instructions. 
13.5 
Data Quality Assurance 
All data recorded during the study will be available for audit against source 
data and for compliance with GCP and specific protocol requirements.  
Monitoring of the study progress and conduct will be ongoing.  The Principal 
Investigator will be responsible for the following: 
 
1. Monitoring study conduct to ensure that the rights of subjects are 
protected; 
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2. Monitoring study conduct to ensure trial compliance with GCP guidelines; 
and 
3. Monitoring accuracy, completion and verification from source documents 
of study data. 
13.6 
Confidentiality 
All information provided to the Principal Investigator by Repros Therapeutics 
Inc. or their designees including non-clinical data, protocols, CRFs and verbal 
and written information will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study.  It is recognized that this 
information may be released in confidence to the IRB.  In addition, no reports 
or information about the study or its progress will be provided to anyone not 
involved in the study other than to Repros Therapeutics Inc. or their designees 
or in confidence to the IRB, except if required by law. 
13.7 
Publications 
Following completion of the study, the data from the entire study or from 
subsets of the study may be considered for reporting at a scientific meeting or 
for publication in a scientific journal, in which case Repros Therapeutics Inc. 
will be responsible for these activities and will work with the Principal 
Investigator to determine how the manuscript is written and edited, the 
number and order of authors, the publication to which it will be submitted and 
other related issues. 
 
 
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14. 
INVESTIGATOR'S STATEMENT 
I have reviewed the ZPU-203EXT protocol and Investigator Brochure and agree to 
conduct this study as outlined in the protocol and in compliance with ICH/GCP 
Guidelines. 
 
 
_________________________________ 
 
______________________ 
Investigator 
 
 
 
 
 
Date 
 
________________________________ 
Printed name 
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ZPU-203EXT Amendment 1 Protocol Summary of Changes 
ZPU-203EXT Amendment 1 Summary of Changes 
Page 1 of 9 
Protocol Title:  
An Open-Label Extension Study of 12 mg Proellex® (Telapristone Acetate) Administered Orally in the 
Treatment of Premenopausal Women with Confirmed Symptomatic Uterine Fibroids  
Changes From: 
From Original Protocol dated June 22, 2016 To: Protocol Amendment 1 dated July 13, 2016 
Reason for Amendment: 
To add a different start of dosing date for selected sites 
Changes to Protocol:  
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
PROTOCOL 
SYNOPSIS: Study 
Design and 
Duration of 
Treatment 
 
The study requires 16 visits and is 
approximately 13 months in duration 
Statement added: 
The study requires 16 visits and is approximately 13 
months in duration (up to 15 months for selected 
sites). 
 
At selected sites subjects will commence dosing on the 
first day of bleeding in their next menstrual cycle after 
Visit 19 or Visit 24 (about 3 weeks after V19 or 24).  
The start of the second and third courses of 
treatment will start on the first day of bleeding in 
the subject’s second menses following withdrawal 
of study drug. 
Change in 
design to 
investigate 
change in 
start of 
dosing 
PROTOCOL 
SYNOPSIS 
Study Endpoints 
• Changes 
in 
clinical 
laboratory 
results to values significantly outside 
of normal range  
• Changes in liver function to values 
outside the normal range 
• Change in Endometrial thickness 
assessed using vaginal ultrasounds 
• Changes in the endometrium over the 
• Changes in clinical laboratory results 
 
  
• Changes in liver function values  
• Endometrial thickness assessed using vaginal 
ultrasounds 
• 
Pathology of the endometrium assessed by biopsies. 
Corrections 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
course of the treatment and ODI period 
(half of the subjects will be assigned to 
biopsy on the last day of treatment and 
half will undergo a biopsy after 
recovery menses). 
PROTOCOL 
SYNOPSIS 
Statistical Methods 
Continuous efficacy endpoints, such as 
the change from baseline in uterine 
tumor volumes  will assess treatment 
effect using a within-group t-test or 
appropriate non-parametric technique. 
Other continuous efficacy variables will 
be treated similarly. The percentage of 
subjects becoming amenorrheic will be 
determined. 
Safety and tolerability will be assessed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Continuous efficacy endpoints, such as the change 
from baseline in uterine tumor volumes will assess 
treatment effect using a within-group t-test or 
appropriate non-parametric technique. The percentage 
of subjects becoming amenorrheic will be determined. 
 
 
 
 
 
 
 
  
Corrections 
7. TRIAL 
OBJECTIVES 
 
Statement added: 
To further investigate the effect of the timing of 
Change in 
design to 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
AND PURPOSE 
start of dosing upon the onset of amenorrhea, at 
selected sites the start of dosing in each cycle will 
be on the first day of bleeding rather than 0-4 days 
after stopping bleeding.  
investigate 
change in 
start of 
dosing 
8. TRIAL DESIGN 
8.1 Study 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
Corrections 
8.2.1 Overview of 
Study Design 
 
Statement added: 
At selected sites subjects will commence dosing on the 
first day of bleeding in their next menstrual cycle after 
Visit 19 or Visit 24 (about 3 weeks after V19 or 24).  
The start of the second and third courses of 
treatment will start on the first day of bleeding in 
the subject’s second menses following withdrawal 
of drug. 
Change in 
design to 
investigate 
change in 
start of 
dosing 
 
 
 
 
 
 
 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
8.3.2 Exclusion 
Criteria 
• Subject had a significant decrease in 
bone mineral density while participating 
in ZPV-201 or ZPU-203 (total hip or 
spine measurement decreased by 5% or 
more) 
• Subject had a significant decrease in bone mineral 
density while participating in ZPV-201 or ZPU-203 (total 
hip or spine measurement decreased by more than 5%) 
Correction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 5 of 9 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
10.1.1 Reporting 
Adverse 
Experiences 
After Visit 20, all SAEs and any adverse 
events that the investigator considers to 
be due to the study drug (e.g. 
hepatotoxicity) and not those considered 
to be due to withdrawal of the drug (e.g. 
vaginal bleeding), will be collected. 
 
Correction 
12. STATISTICAL 
METHODS 
12.2 Statistical and 
Analytical Plan 
 
Statement added: 
Analyses in this study will focus on comparison to 
two baseline assessments.  One baseline is 
associated with the original parent study baseline 
and the other is associated with the 28-day period 
prior to the start of this extension study.  Reference 
to baseline in this section refers to each baseline 
definition. 
Clarification 
12.2.2 Incidence of 
Amenorrhea 
The percentage of subjects who become 
amenorrheic during the 28 days leading 
up to the last day of dosing in each 
course will be determined. 
The percentage of subjects who become amenorrheic 
during the 28 days leading up to the last day of dosing 
in each course will be determined.  The incidence of 
amenorrhea during the entire course and after the 
11th day of the course will also be investigated. 
Clarification 
12.2.3 Percentage 
Change in PBAC 
scores 
The percentage change in PBAC scores 
over each 28 day period for each 
menstrual cycle will be recorded …. 
 
…..and the time to return to baseline 
vaginal bleeding to determine duration 
The percentage change in PBAC scores over each 28 
day period of the course will be recorded …. 
 
 
 
Correction 
 
 
 
Correction 
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Page 8 of 9 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
of benefit during the five menstrual 
cycle follow-up after dosing Course 2. 
 
Within treatment group paired t-tests 
will evaluate treatment effect.  Pairwise 
comparisons of the treatment groups 
will be made using a two-sample t test 
as well to compare the pooled Proellex 
doses to placebo.  While the primary 
assessment will be after 18 week of 
treatment, summaries will be prepared 
for each of the other visits.   
 
 
Within treatment group paired t-tests will evaluate 
treatment effect.  While the primary assessment will be 
after each 18 week treatment course, summaries will 
be prepared for each of the other visits.   
 
 
 
Correction 
12.2.5 Percentage 
Change in Uterine 
Fibroid Volume by 
MRI 
The percent change from baseline in 
total uterine fibroid volume will be 
determined at the end of each 18 week 
dosing course 
The percent change from baseline in total uterine 
fibroid volume will be determined at the end of 
treatment 
Correction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
12.3 General 
Statistical Issues 
A Statistical Analysis Plan (SAP) will 
be finalized prior to unblinding the 
study. 
A Statistical Analysis Plan (SAP) will be finalized 
prior to database lock. 
Correction 
 
 
 
 
   
 
 
 
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