Clinical trial NCT02323646
Conditions: Uterine Fibroids
Keywords: uterine fibroids leiomyoma fibroid tumor fibroma
Sponsor: Repros Therapeutics Inc.
Start date: 2015-02-12; Completion date: 2017-04-06
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to determine the safety and efficacy of two vaginal doses of Proellex® administered for up to 2 courses of treatment (18 weeks each), each separated by an Off-Drug Interval (ODI), to premenopausal women with symptomatic uterine fibroids.

Detailed description:

Arms: arm 1: Following the baseline assessment no treatment period, matching placebo, vaginally, once daily for 18 weeks (Course 1) and repeated for an additional 18 weeks (Course 2) following the ODI. arm 2: Following the baseline assessment no treatment period, telapristone acetate 6 milligrams (mg), vaginally, once daily for 18 weeks (Course 1) and repeated for an additional 18 weeks (Course 2) following the ODI. arm 3: Following the baseline assessment no treatment period, telapristone acetate 12mg, vaginally, once daily for 18 weeks (Course 1) and repeated for an additional 18 weeks (Course 2) following the ODI.
Interventions: intervention 1: Placebo intervention 2: Telapristone Acetate
Intervention descriptions: intervention 1: Matching placebo, vaginally, once daily for 18 weeks (Course 1) and repeated for an additional 18 weeks (Course 2) following the ODI. intervention 2: Telapristone acetate, vaginally, once daily for 18 weeks (Course 1) and repeated for an additional 18 weeks (Course 2) following the ODI.

Protocol documents:
Prot_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.  
NCT02323646 
 
Study ID: ZPV-201 
 
Title: A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate 
the Safety and Efficacy of 6 and 12 mg Proellex® (Telapristone Acetate) Administered 
Vaginally in the Treatment of Premenopausal Women with Confirmed Symptomatic Uterine 
Fibroids 
 
Protocol Amendment 4 Date: 20 June 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ZPV-201 Amendment 1 Summary of Changes 
ZPV201 Protocol Amendment 1 Summary of Changes 
 
Protocol Title:  
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Vaginally in the Treatment of Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Original protocol, dated December 12, 2014 To: Protocol Amendment 1 dated February 24, 2015 
Reason for Amendment: 
Change procedures, make corrections, add clarifications and change eligibility criteria 
Changes to Protocol:  
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR 
CHANGE 
PROTOCOL 
SYNOPSIS: Study 
Population  
 
Subjects with evidence of prior heavy 
blood loss may be enrolled at the sponsor’s 
discretion. 
Change in 
eligibility 
requirements 
PROTOCOL 
SYNOPSIS: Study 
Procedures 
An infectious disease screen will be 
conducted and a vaginal ultrasound will be 
performed 
 
 
 
and MRI to confirm presence and 
size of uterine fibroids.  Sanitary products 
and instructions for their collection will be 
provided and study questionnaires will be 
administered.  
  
Subjects who meet the inclusion and 
exclusion criteria will be scheduled for Visit 
2.  
 
 
 
 
An infectious disease screen will be 
conducted and a vaginal ultrasound will be 
performed 
 
 
 
 and to confirm presence of uterine 
fibroids.  Sanitary products and instructions 
for their collection will be provided and 
study questionnaires will be administered.  
  Subjects who 
meet the inclusion and exclusion criteria will 
be scheduled for Visit 2.  At visit 2, 
 
 
 
 an 
MRI to confirm the presence and size of 
uterine fibroids. 
Correction 
PROCEDURES 
AND 
MRI of Uterine Fibroids 
MRI of Uterine Fibroids (no contrast) 
Correction 
 
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ZPV-201 Amendment 1 Summary of Changes 
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LABORATORY 
TABLES: Table 1 
3.. Also in the event of a finding of 
abnormal LFT 
7. A historical PBAC looking back over the 
last 28 days will be used to determine 
eligibility (must be >120 mL, and verified 
by Alkaline Hematin as ≥80mL). 
 
11.  For subjects who had finished bleeding 
5 days or less before Visit 1, Visit 2 
will occur within +4 days after end of 
bleeding in their first menstrual event after 
Visit 1.  For everyone else Visit 2 will 
occur within + 4 days after end of bleeding 
in the second menstrual event after Visit 1. 
3. Also as necessary to evaluate possible 
hepatic abnormalities 
7. A historical PBAC looking back over the 
last 28 days will be used to determine 
eligibility (must be >120 mL, unless 
approved by sponsor, and verified by 
Alkaline Hematin as ≥80mL). 
 
11.  A complete menstrual event must be 
collected before Visit 2.  If subject is 
bleeding at Visit 1, she must wait until 
the last day of bleeding of this cycle, 
then 
start 
collecting 
pads 
the 
following day until the last day of 
bleeding in the next menstrual event.  
Visit 2 will occur within +4 days after end 
of bleeding in the first complete menstrual 
event after Visit 1.   
Change in 
procedure 
 
 
 
 
 
 
 
 
 
PROCEDURES 
AND 
LABORATORY 
TABLES: Table 3 
 
Hypotension Questions 
…. 
The investigator should report any of the 
above as adverse events. 
Clarification 
 
 
 
 
 
 
 
 
 
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ZPV-201 Amendment 1 Summary of Changes 
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8. TRIAL DESIGN 
8.2.1 Overview of 
study Design 
In the first stage, women will undergo a 
baseline 
assessment 
period, 
with 
no 
treatment, until 15-20 days after the start of 
their second or third menstrual event.  
 
 
 
 
 
 
 
  
 
 
 
 
  
In the first stage, women will undergo a 
baseline 
assessment 
period, 
with 
no 
treatment, until 15-20 days after the start of 
their second complete menstrual event.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Change in 
procedures 
8.3 Selection and 
Withdrawal of 
Subjects 
• A need arises for concomitant medication 
prohibited by the protocol 
• A need arises for concomitant medication 
prohibited by the protocol, unless use of 
such medication is approved by the 
sponsor 
 
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ZPV-201 Amendment 1 Summary of Changes 
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8.3.1 Inclusion 
Criteria 
• Subject has a history of at least 3 regular 
menstrual cycles in which menorrhagia 
is due to uterine fibroids 
 
 
 
 
 
 
 
 
 
 
• 
 
 
MBL of at least 80 mL by Alkaline 
Hematin Assay (during the baseline 
assessment period).   
• Subject has a history of at least 3 regular 
menstrual cycles in which menorrhagia is 
due to uterine fibroids (a past or 
concurrent diagnosis of uterine fibroids 
is acceptable). 
 
 
 
 
 
 
 
• 
 
 
 MBL of at least 
80 mL by Alkaline Hematin Assay (during 
the baseline assessment period).  Subjects 
with evidence of prior heavy blood loss 
may be enrolled at the sponsor’s 
discretion. 
Clarification 
 
 
 
 
 
 
 
8.3.2 Exclusion 
Criteria 
•  Use of oral contraceptives in the 
preceding 30 days.  Use of Depo-Provera® 
in the preceding 10 months. 
•  Use of GnRHas (e.g. Lupron Depot) 
within 3 months of the first dose of study 
drug (Lupron Depot must have a wash-out 
period of 3 months)  
•  Known or suspected carcinoma of the 
breast or reproductive organs 
• 
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)  
 
• 
History 
or 
current 
diagnosis 
of 
Change in 
Exclusion Criteria 
 
 
Clarification 
 
 
 
 
 
Clarification 
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ZPV-201 Amendment 1 Summary of Changes 
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malignancy 
other 
than 
curatively 
treated basal cell carcinoma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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ZPV-201 Amendment 1 Summary of Changes 
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their next cycle (first cycle after 
Visit 1).   
 
 
    
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
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ZPV-201 Amendment 1 Summary of Changes 
SECTION 
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.   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZPV-201 Amendment 1 Summary of Changes 
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12. Statistical 
Methods 
12.2 Statistical and 
Analytical Plan 
 
A Statistical Analysis Plan (SAP) will be 
prepared prior to unblinding the data.  
The 
first 
efficacy 
analysis 
will 
be 
conducted when all subjects complete the 
first cycle of treatment.  A second analysis 
will summarize the subject’s additional 
treatment cycles which will be conducted 
after all subjects complete study treatment 
and follow-up in Stage 2. In this Phase 2 
study 
there 
will 
be 
no 
statistical 
corrections 
for 
interim 
analyses 
or 
multiple comparisons.   
For the statistical analysis at the end of the 
first course of treatment, only statistical 
staff will be unblinded.  All clinical 
operations staff and staff at investigative 
sites will remain blinded until completion 
of the study. 
Clarification 
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ZPV-201 Amendment 1 Summary of Changes 
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ZPV-201 Amendment 1 Summary of Changes 
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ZPV-201 Amendment 2 Summary of Changes 
ZPV-201 Amendment 2 Protocol Summary of Changes 
 
Protocol Title:  
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Vaginally in the Treatment of Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Protocol Amendment 1 dated February 24, 2015 
To: Protocol Amendment 2 dated September 4, 
2015 
Reason for Amendment: 
Changes study requirements for endometrial stripe ≥18mm. 
Changes to Protocol:  
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
8.3 Selection and 
Withdrawal of 
Subjects 
• 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
• Any subject who experiences heavy 
bleeding (bleeding intensity of 4 or more 
per the Daily Diary Card in Appendix 4) 
for 7 consecutive days or more will be 
discontinued from the study.  This does not 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZPV-201 Amendment 2 Summary of Changes 
SECTION 
CHANGED FROM 
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FOR 
CHANGE 
apply if heavy bleeding occurs in the first 
recovery menses after withdrawal of drug 
at the end of Course 1 or Course 2, or is no 
heavier than bleeding was prior to 
treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
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ZPV-201 Amendment 3 Summary of Changes 
ZPV-201 Amendment 3 Protocol Summary of Changes 
 
Protocol Title:  
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Vaginally in the Treatment of Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Protocol Amendment 2 dated September 4, 2015 
To: Protocol Amendment 3 dated April 8, 2016 
Reason for Amendment: 
Addition of Alkaline Hematin Assay at the end of Course 2 
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 
Subjects will collect and return used sanitary 
materials for alkaline hematin assay for their 
first menstrual event during screening, for the 
recovery menses following Courses 1 and 2 
and for the 2nd, 4th and 6th menstrual cycles 
after end of treatment in Course 2. 
Subjects will collect and return used sanitary 
materials for alkaline hematin assay for their 
first menstrual event during screening, for the 
recovery menses following Course 1, for the 
28 days leading up to the end of treatment 
in Course 2, and for the 1st, 2nd, 4th and 6th 
menstrual cycles after end of treatment in 
Course 2. 
Addition 
of 
Alkaline 
Hematin assay 
at the end of 
Course 2 
8.2.1 Overview of 
Study Design 
 
Statement added: 
Sanitary products will be collected for alkaline 
hematin assay during the following timepoints: 
• From the 28 days leading up to end of 
treatment in Course 2 (Visit 18) 
Addition of 
Alkaline 
Hematin assay 
at the end of 
Course 2 
8.2.6 Endometrial 
Biopsies 
 
Statement added: 
 
 
 
 
 
Clarification 
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ZPV-201 Amendment 3 Summary of Changes 
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FOR 
CHANGE 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
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ZPV-201 Amendment 3 Summary of Changes 
SECTION 
CHANGED FROM 
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REASON 
FOR 
CHANGE 
 
 
 
 
 
 
 
 
 
 
Charts and footnotes were updated to reflect the changes above. 
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Repros Therapeutics Inc. 
 
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TABLE OF CONTENTS 
 
1. COVER PAGE 
............................................................................................................................... 1 
2. TABLE OF CONTENTS .............................................................................................................. 2 
3. PROTOCOL SYNOPSIS 
.............................................................................................................. 4 
4. PROCEDURES AND LABORATORY TABLES 
...................................................................... 8 
5. LIST OF ABBREVIATIONS ..................................................................................................... 13 
6. BACKGROUND INFORMATION ........................................................................................... 14 
6.1 
RATIONALE FOR CURRENT STUDY ................................................................................... 14 
6.2 
NON-C
LINICAL DATA ....................................................................................................... 15 
6.3 
CLINICAL DATA/H
UMAN EXPERIENCE 
............................................................................. 21 
6.4 
SAFETY DATA 
................................................................................................................... 22 
6.5 
DATA FROM ZPV-200 
....................................................................................................... 24 
6.6 
ETHICAL CONDUCT OF THE STUDY 
................................................................................... 25 
7. TRIAL OBJECTIVES AND PURPOSE 
................................................................................... 26 
8. TRIAL DESIGN .......................................................................................................................... 27 
8.1 
STUDY ENDPOINTS 
............................................................................................................ 27 
8.1.1 
Primary Efficacy Endpoint 
............................................................................................. 27 
8.1.2 
Secondary Endpoints 
...................................................................................................... 27 
8.1.3 
Safety Endpoints 
............................................................................................................. 27 
8.2 
STUDY DESIGN 
.................................................................................................................. 28 
8.2.1 
Overview of Study Design 
.............................................................................................. 28 
8.2.2 
Study Drug Accountability 
............................................................................................. 29 
8.2.3 
Randomization and Blinding 
.......................................................................................... 30 
8.2.4 
Study Medication 
............................................................................................................ 30 
 
ELECTION AND ITHDRAWAL OF UBJECTS
 
8.3.1 
Inclusion Criteria 
............................................................................................................ 32 
8.3.2 
Exclusion Criteria 
........................................................................................................... 33 
10. ASSESSMENT OF SAFETY 
...................................................................................................... 42 
10.1 ADVERSE EVENTS 
............................................................................................................. 42 
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10.1.1 
Reporting Adverse Experiences ............................................................................. 42 
10.1.2 
Definitions .............................................................................................................. 42 
10.1.3 
Serious Adverse Events (SAEs) ............................................................................. 43 
11. CONCOMITANT MEDICATIONS .......................................................................................... 45 
11.1 
PROHIBITED MEDICATIONS ............................................................................................... 45 
11.2 
OTHER MEDICATIONS TAKEN DURING THE STUDY ......................................................... 45 
12. STATISTICAL METHODS ....................................................................................................... 46 
12.1 
DETERMINATION OF SAMPLE SIZE .................................................................................... 46 
12.2 
STATISTICAL AND ANALYTICAL PLAN ............................................................................. 46 
12.3 
GENERAL STATISTICAL ISSUES ......................................................................................... 49 
13. ETHICS ........................................................................................................................................ 50 
13.1 
SUBJECT INFORMATION AND CONSENT ............................................................................ 50 
13.2 
INSTITUTIONAL REVIEW BOARD ....................................................................................... 50 
13.3 
MONITORING CASE REPORT FORMS ................................................................................. 50 
13.4 
STUDY RECORD RETENTION ............................................................................................. 50 
13.5 
DATA QUALITY ASSURANCE ............................................................................................ 50 
13.6 
CONFIDENTIALITY............................................................................................................. 51 
13.7 
PUBLICATIONS .................................................................................................................. 51 
14. INVESTIGATOR'S STATEMENT ........................................................................................... 52 
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3. 
PROTOCOL SYNOPSIS 
 
Test Drugs: 
Proellex® (Telapristone Acetate): 6 and 12 mg vaginal capsules and 
matching placebo 
Protocol Number: 
ZPV-201  
Study Purpose: 
To determine the safety and efficacy of two doses of Proellex in 
premenopausal women with symptomatic (menorrhagia) uterine 
fibroids confirmed by MRI. 
Study Design and 
Duration of 
Treatment: 
This study is a phase 2 3-arm-study with two 18-week dosing 
courses.  The study will be conducted in two stages.   
In the first stage, women will undergo a baseline assessment period 
with no treatment, until 15-20 days after the start of their second 
complete menstrual event.  During this phase a pictorial blood loss 
assessment chart will be utilized as well as sanitary products 
collected from their first menstrual event, for alkaline hematin assay, 
to determine menstrual blood loss and confirm eligibility.   
In the second stage, subjects will be randomized into one of 3 arms in 
a 1-1-1 fashion and receive two 18-week courses of treatment at their 
randomized dose (6 mg, 12 mg or placebo), separated by an off-drug 
interval (ODI).  The start of the first 18-week course of treatment 
(Course 1) should commence 15-20 days after the start of their 
previous menses. Subjects should be instructed to continue vaginal 
dosing during their menses throughout the study and not to have sex 
or insert anything in the vagina for at least 1 hour after the capsule is 
inserted. Once dosing for Course 1 is stopped, subjects will be 
followed until menses return.  The start of the second 18 week course 
of treatment (Course 2) will commence 15-20 days after the start of 
their menses following withdrawal of drug after Course 1 has been 
completed.  During the ODI, subjects will continue to record study 
information in the daily paper diary and PBAC charts as well as 
collect sanitary products for alkaline hematin assay. 
After completion of stage 2 dosing (Courses 1 and 2), subjects will be 
followed through the subsequent 6 menses (recovery menses plus an 
additional 5 menstrual events),  the subject may be offered the 
opportunity to enroll in an open-label extension study.  Subjects who 
fail to achieve amenorrhea may enroll in the extension study at Visit 
19.  Amenorrhea is defined as any 28-day period during treatment 
(not including the ODIs) without a bleeding score >1. Throughout the 
study women will record study information in the diary, PBAC, and 
questionnaires as outlined in the study procedures.  
Subjects will collect and return used sanitary materials for alkaline 
hematin assay for their first menstrual event during screening, for the 
recovery menses menses following Course 1, for the 28 days leading 
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up to the end of treatment in Course 2, and for the 1st, 2nd, 4th and 6th 
menstrual cycles after end of treatment in Course 2. 
Subject Population: 
The study will enroll healthy adult, pre-menopausal women with 
confirmed uterine fibroids via MRI and confirmed menorrhagia 
(>120 mL blood loss per menstrual cycle by historical PBAC 
assessment, nominal 28 days to ensure a MBL of at least 80 mL by 
Alkaline Hematin Assay).  Subjects with evidence of prior heavy 
blood loss may be enrolled at the sponsor’s discretion. 
Number of Subjects: 
Up to 45 female subjects, 15 per dose arm 
Number of Sites 
Approximately 10 sites  
Study Duration:  
Total participation in the study is approximately 18 months. 
:  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
   
 
 
 
 
 
Study Endpoints 
The primary endpoint will be:  
• Percentage of subjects who become amenorrheic after one course 
of treatment 
Secondary endpoints will be: 
• Percentage of subjects who become amenorrheic after 2 courses 
of treatment 
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• Change and percentage change in PBAC score over the course of 
the study.  Specifically comparing the baseline menstrual cycle to 
the matching end-of-study period leading up to Week 18 and the 
end of treatment as well as comparing the baseline PBAC to the 
ODI time periods. 
• Percentage change in UFSQOL Symptom Severity score (UFS-
SSS) comparing Week 18 to Baseline (three month look back) 
and for the ODI. 
• Percentage change in the individual UFS-SSS sub scores 
• Percentage change from baseline in total uterine fibroid volume 
measured by MRI  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Statistical Methods: 
A Statistical Analysis Plan (SAP) will be developed prior to 
unblinding of the data that will outline all planned analyses and 
analysis populations.  The first efficacy analysis will be conducted 
when all subjects complete the first cycle of treatment.  A second 
analysis will summarize the subject’s additional treatment cycles 
which will be conducted after all subjects complete study treatment 
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and follow-up in Stage 2. 
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.  All summaries will be prepared for each treatment 
group.  
Continuous efficacy endpoints, such as the change from baseline in 
the alkaline hematin assay will assess treatment effect using a t-test 
or appropriate non-parametric technique.  Pairwise comparisons 
between treatment groups will also be conducted with the same 
methods.  Other continuous efficacy variables will be treated 
similarly. The percentage of subjects becoming amenorrheic within 
each treatment and dose group will be compared by Chi-square test 
or appropriate non-parametric method. 
Safety and tolerability will be assessed by evaluating physical exams, 
colposcopy findings and reported AEs as well as changes in values 
from baseline of clinical chemistry variables, hematology variables, 
hormone variables, and liver function variables.  No formal 
hypothesis testing will be performed to compare the treatment 
groups.  For the quantitative physical exam variables, laboratory 
variables and bone mineral density the statistical significance of the 
change from baseline to each of the post-baseline visits will be 
determined using a paired t-test.   
 
 
 
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Repros Therapeutics Inc. 
 
 
 
 
 
 
 
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1. Any LFT >ULN will be repeated.   
Subjects must be discontinued if any of the following occur: 
• ALT or AST >8xULN  
• ALT or AST >5xULN for more than 2 weeks  
• ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
• ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, jaundice (skin or sclera) and/or eosinophilia 
(>5%)  
Cases of liver transaminases that increase above 3 times the upper limit of normal must be 
reported as SAEs regardless of whether the SAE criteria specified in Section 10.1.2 are met.   
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Repros Therapeutics Inc. 
 
 
 
 
 
 
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5. 
LIST OF ABBREVIATIONS 
 
AE 
 
Adverse event 
Cavg 
 
Average concentration 
Cmax 
 
Maximum concentration 
CRF 
 
Case report form 
DHEA  
Dehydroepiandrosterone 
dL 
 
Deciliter 
ECG  
Electrocardiogram 
FSH 
 
Follicle-stimulating hormone 
GCP 
 
Good Clinical Practice 
GnRH  
Gonadotrophin releasing hormone 
g 
 
Grams 
hCG 
 
Human chorionic gonadotrophin 
ICH 
 
International Conference on Harmonization    
IGF-1  
Insulin-like growth factor-1 
IRB 
 
Institutional Review Board 
IND 
 
Investigational new drug 
IUD 
 
Intra-uterine device 
kg  
 
Kilogram(s) 
LD50  
Median lethal dose 
LH 
 
Luteinizing hormone 
LSC 
 
Least Significant Change 
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-SSS 
Uterine Fibroid Symptom Quality of Life Survey Symptom Severity 
Score (first 8 questions) 
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 recent findings in rabbit and dog studies the sponsor believes 
vaginal administration of Telapristone will bypass the liver, achieve higher 
local concentrations and better effects in utero while significantly reducing 
safety margin.  
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Page 15 of 65 
 
 
 
 
 
  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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Endometrial Proliferation 
BioQual also used a scoring system that assessed several uterine sections from 
the  five  rabbits  in  each  dose  group.   
 
 
 
 
 
 
 
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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 has 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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6.4  Safety Data 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Data From ZPV-200 
This study included an initial two week exposure of vaginal administration of 
12mg telapristone acetate in six women with uterine fibroids to determine the 
length of time it takes for the drug to reach steady state and the overall 
systemic exposure of both the parent compound and the primary metabolite. 
The purpose of this first cohort was to determine whether the systemic 
exposure of 12mg vaginal for both the parent molecule and primary 
metabolite was less than that which had been safely tested in the previously 
completed low dose oral study ZP-204. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.6 
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, 3001 S. Lamar Blvd., Suite 210, Austin, 
Texas 78704, will serve as an Institutional Review Board (IRB) for clinical 
sites who will accept their review.  
 
 
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7. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to determine the safety and efficacy of two 
vaginal doses of Proellex administered for up to 2 courses of treatment (18 weeks 
each), each separated by an Off-Drug Interval (ODI), to premenopausal women with 
symptomatic uterine fibroids.   
 
 
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8. 
TRIAL DESIGN 
8.1 
Study Endpoints 
8.1.1 Primary Efficacy Endpoint 
• Percentage of subjects who become amenorrheic after one course 
of treatment 
8.1.2 Secondary Endpoints 
• Percentage of subjects who become amenorrheic after 2 courses of 
treatment 
• Change and percentage change in PBAC score over the course of 
the study.  Specifically comparing the baseline menstrual cycle to 
the matching end-of-study period leading up to Week 18 and the 
end of treatment as well as comparing the baseline PBAC to the 
ODI time periods. 
• Percentage change in UFSQOL Symptom Severity score (UFS-
SSS) comparing Week 18 to Baseline (three month look back) and 
for the ODI. 
• Percentage change in the individual UFS-SSS subscores 
• Percentage change from baseline in total uterine fibroid volume 
measured by MRI  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.2 
Study Design 
8.2.1 Overview of Study Design 
This study is a phase 2 3-arm-study with a 36 week active dosing 
period.  The study will be conducted in two stages.   
In the first stage, women will undergo a baseline assessment period, 
with no treatment, until 15-20 days after the start of their second 
complete menstrual event.  During this phase a pictorial blood loss 
assessment chart and daily diaries will be utilized.  Used sanitary 
products from the first menstrual event will be collected and returned 
to the clinic for alkaline hematin assay.  This assay will confirm 
subject eligibility (MBL must be 80 mL or greater by alkaline hematin 
assay for subjects to qualify). 
In the second stage, subjects will be randomized into one of 3 arms in 
a 1-1-1 fashion.  The start of the 18 week dosing period (Course 1) in 
this stage of the study should commence 15-20 days after the start of 
their first menses after Visit 2.  Once active dosing is stopped, subjects 
will be followed until menses returns.  The start of the second 18 week 
dosing period (Course 2) will commence 15-20 days after the start of 
their menses following withdrawal of drug after Course 1 has been 
completed.  During the non dosing off-drug interval (ODI), subjects 
will continue to record study information in the daily paper diary and 
PBAC charts. 
After end of dosing in Course 2, subjects will be followed through the 
subsequent recovery menses and for an additional 5 menstrual events, 
after which the subject may be offered the opportunity to enroll in an 
extension study.  Subjects who fail to achieve amenorrhea may enroll 
in the extension study at Visit 19.  Amenorrhea is defined as any 28-
day period during treatment (not including the ODIs) without a 
bleeding score >1.  Throughout the study women will record study 
information in the diary, PBAC and questionnaires as outlined in the 
study procedures.  
In addition to the diary information, endometrial thickness will be 
recorded at screening and every month thereafter.  Assessment of 
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trough levels of drug will be determined at every office visit during the 
first and second 18 week dosing periods. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The primary efficacy analysis will be conducted when all subjects 
complete the first cycle of treatment.  A second analysis will 
summarize the subject’s second treatment cycle which will be 
conducted after all subjects complete study treatment and follow-up. 
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 
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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 
At Visit 3, subjects will be randomized to treatment in Arms 1, 2, or 3.  
Subjects will be treated with one capsule daily of 6 mg or 12 mg of 
Proellex, or placebo, which will be administered for a total of 36 
weeks (two 18 week courses separated by an ODI) before the 6 cycle 
follow up is started.  After the second treatment course is completed 
the subjects will be followed for 6 menstrual events to determine 
durability of effect of treatment, after which they may be offered the 
opportunity to enroll in an open-label extension study.  Subjects who 
fail to achieve amenorrhea may enroll in the extension study at Visit 
19.  Amenorrhea is defined as any 28-day period during treatment (not 
including the ODIs) without a bleeding score >1.  Each treatment 
course will be separated by an ODI.  Blinded treatments kits will be 
randomized and distributed by the packaging company.  
For the statistical analysis at the end of the first course of treatment, 
only statistical staff will be unblinded.  All clinical operations staff and 
staff at investigative sites will remain blinded until completion of the 
study.  
8.2.4 Study Medication 
All study drugs will be supplied by Repros Therapeutics Inc. Test 
drug, Proellex, will be supplied as placebo, 6, and 12 mg vaginal 
capsules, in blister packs of 10 capsules, by a clinical supplies contract 
vendor designated by Repros Therapeutics Inc.  
 
 
instructions to 
administer 1 capsule vaginally each day at the same time using the 
applicator provided.  Subjects should be instructed to refrain from 
vaginal intercourse or putting anything in the vagina for 48 hours prior 
to clinic visits 2, 3, 12, and 18.  Study medication should be taken at 
the same time of day every day, and clinic visits should be scheduled 
according to each subject’s administration schedule.  
 
 
 
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8.2.5 
 
 
 
 
 
 
 
 
 
8.2.6 
 
 
 
  
 
 
  
 
 
 
 
 
8.3 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3.1 Inclusion Criteria 
Subjects must meet the following criteria: 
• Otherwise healthy adult females between 18 and 47 years 
• Subject has a history of at least 3 regular menstrual cycles in which 
menorrhagia is due to uterine fibroids (a past or concurrent 
diagnosis of uterine fibroids is acceptable). 
• Screening ultrasound confirms presence of uterine fibroids 
• Agreement not to attempt to become pregnant during the trial 
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• Agreement to use only sanitary pads provided throughout the 
course of the study, tampon use is prohibited  
• Ability to complete a daily subject diary and study procedures in 
compliance with the protocol 
• Has a negative pregnancy test at the Screening and Baseline visits 
• A Body Mass Index (BMI) between 18 and 45 inclusive 
• 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 is a post-menopausal woman, defined as either; six (6) 
months or more (immediately prior to screening visit) without a 
menstrual period, or prior hysterectomy and/or oophorectomy. 
• Subject is pregnant or lactating or is attempting or expecting to 
become pregnant during the entire study period 
• Received an investigational drug in the 30 days prior to the 
screening for this study 
• Subject has a history of PCOS 
• Concurrent use of any testosterone, progestin, androgen, estrogen, 
anabolic steroids, DHEA or hormonal products for at least 2 weeks 
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prior to screening and during the study, including the 
 
 
• Use of oral contraceptives in the30 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 
• History or current diagnosis of malignancy other than curatively 
treated basal cell carcinoma 
• Recent history (within past 6 months) of alcoholism or drug abuse 
• Clinically significant abnormal findings on screening 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.  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.  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. 
Not Related 
There is evidence of exposure to the study drug; 
there is another more likely 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.    
All additional follow-up reports must be reported to the Repros 
Therapeutic Inc. monitor as soon as available. 
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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 and during the 6-
month follow up after discontinuation of study medication: 
• 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 
Up to 50 female subjects, 15 per dose arm, meeting the inclusion/exclusion 
criteria will be randomized in a 1-1-1 fashion with the expectation that 
approximately 45 will be fully eligible for efficacy analyses.  The primary 
endpoint is amenorrhea.  
 
   
 
 
 
 
 
12.2 
Statistical and Analytical Plan 
A Statistical Analysis Plan (SAP) will be prepared prior to unblinding the 
data.  The first efficacy analysis will be conducted when all subjects complete 
the first cycle of treatment.  A second analysis will summarize the subject’s 
additional treatment cycles which will be conducted after all subjects 
complete study treatment and follow-up in Stage 2. In this Phase 2 study there 
will be no statistical corrections for interim analyses or multiple comparisons.   
For the statistical analysis at the end of the first course of treatment, only 
statistical staff will be unblinded.  All clinical operations staff and staff at 
investigative sites will remain blinded until completion of the study. 
 
12.2.1 Demographics and Subject Characteristics 
For all subjects included in this study, subject accountability, baseline 
demographic and medical history data will be summarized for each 
treatment group.  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.  No statistical testing will be 
performed to compare these factors between treatment groups. 
12.2.2 Efficacy Analyses 
A Statistical Analysis Plan (SAP) will be prepared prior to unblinding 
of the study data.  Efficacy analyses will be conducted in the Intent-to-
Treat population, which will consist of all subjects who are 
randomized and who receive study drug.   
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12.2.2.1  Primary Endpoint: Incidence of Amenorrhea 
The  percentage  of  subjects  who  become  amenorrheic  during 
the 28 days leading up to the last day of dosing at Week 18 will 
be  compared  by  Chi-Square  
test.  
 Amenorrhea  after  a  second 
course of treatment will  be  analyzed as a secondary endpoint.  
Testing  will  evaluate  the  pooled  Proellex  doses  compared  to 
placebo,  each Proellex dose  compared  to  Placebo  as  well  as 
compare the active dose groups.  A Fisher’s Exact test will be 
utilized if the cell sizes are small.  
A  subject  is  deemed  amenorrheic  if  they  have  no  bleeding 
intensity  score  greater  than  1 using  the  Daily  Diary  Card  in 
Appendix 3 (spotting  not  requiring hygiene products)  during 
the 28 day period.   
12.2.2.2  Secondary Endpoints 
Percentage Change in PBAC scores 
The  percentage  change  in  PBAC  scores  over  each  28  day 
period for each menstrual cycle 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  and the  time  to  return  to  baseline  vaginal 
bleeding  to  determine  duration  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 as compare the pooled 
Proellex doses to placebo.  While the primary assessment will 
be after 18 weeks of treatment, 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.   
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Percentage change in total and individual symptom severity 
scores for the UFS-SSS 
The UFS-SSS is an 8 question symptom severity score and has 
been validated as a three month look back questionnaire.  The 
survey  will  be  administered  at  the  baseline  of  each  dosing 
course and at the end of each course.  An analysis of UFS-SSS 
scores  will  compare  the  pooled  Proellex dose  results  to  the 
placebo  group  with  a  t-test.   Pairwise  comparisons  of  the 
treatment  groups  will  be  made  using  a  two-sample  t-test. 
Within group paired tests will also be used to assess treatment 
effect.    Non-parametric  methods  will  be employed as 
appropriate.  The primary assessment will be based on Visit 12 
(after  18  weeks  of  treatment).    If  data  are  missing,  a  last 
observation  carried  
forward  procedure  will  be  used,  
including 
the baseline, if necessary. 
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 and  after  
the  6  months  of  
recovery  menses  
(Visit  24).  
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.   
An  analysis  of  percentage  change  in uterine  fibroid  volume 
will  compare  
the  pooled  Proellex doses  
to  
the placebo  group 
with  a  t-test.    Pairwise  comparisons  of  the  treatment  groups 
will  be  made  using  a two-sample  
t-test.  Within  group  paired 
tests  will  also  be  used  to  assess  treatment  effect.  Non-
parametric  methods  will  be employed as  appropriate.    The 
primary assessment will  be based on  Visit 12 (after 18 weeks 
of  treatment).    However,  analyses  will  continue  for  each 
volume  assessment.    If  data  are  missing,  a  last  observation 
carried forward procedure will be used, including the baseline, 
if necessary. 
 
 
 
 
 
 
 
  
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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 
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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Protocol ZPV-201, Amendment 4 
 
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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 ZPV-201 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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Repros Therapeutics Inc. 
 
 
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Repros Therapeutics Inc. 
 
 
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Repros Therapeutics Inc. 
 
 
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Repros Therapeutics Inc. 
 
 
 
 
 
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Page 1 of 3 
ZPV-201 Amendment 4 Summary of Changes 
ZPV-201 Amendment 4 Protocol Summary of Changes 
 
Protocol Title:  
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of 6 and 12 mg Proellex® (Telapristone Acetate) Administered Vaginally in the Treatment of Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Protocol Amendment 3 dated April 8, 2016 
To: Protocol Amendment 4 dated June 20, 2016 
Reason for Amendment: 
Addition of MRI at Visit 24, addition of requirements for enrollment in Extension Study 
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 
After completion of stage 2 dosing (Courses 1 
and 2), subjects will be followed through the 
subsequent 6 menses (recovery menses plus 
an additional 5 menstrual events).  In the 
event that a subject’s menstrual bleeding 
returns to ≥80mL (assessed by alkaline 
hematin assay) at the end of this period, the 
subject may be offered the opportunity to 
enroll in an extension study.     
After completion of stage 2 dosing (Courses 1 
and 2), subjects will be followed through the 
subsequent 6 menses (recovery menses plus an 
additional 5 menstrual events), after which (at 
Visit 24) the subject may be offered the 
opportunity to enroll in an open-label 
extension study.  Subjects who fail to achieve 
amenorrhea may enroll in the extension 
study at Visit 19.  Amenorrhea is defined as 
any 28-day period during treatment (not 
including the ODIs) without a bleeding 
score >1.   
Change 
in 
study design 
8.2.1 Overview of 
Study Design 
After end of dosing in Course 2, subjects will 
be followed through the subsequent recovery 
menses and for an additional 5 menstrual 
events.  In the event that a subject’s menstrual 
bleeding returns to >80 mL (assessed by 
alkaline hematin assay) at the end of this 
period the subject may be offered the 
After end of dosing in Course 2, subjects will 
be followed through the subsequent recovery 
menses and for an additional 5 menstrual 
events, after which the subject may be offered 
the opportunity to enroll in an extension study.  
Subjects who fail to achieve amenorrhea 
may enroll in the extension study at Visit 19.  
 
 
Requirements 
for roll-over 
into Extension 
Study added 
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Page 2 of 3 
ZPV-201 Amendment 4 Summary of Changes 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
opportunity to enroll in an extension study.   
Amenorrhea is defined as any 28-day period 
during treatment (not including the ODIs) 
without a bleeding score >1.   
 
8.2.3 Randomization 
and Blinding 
After 
the 
second 
treatment 
course 
is 
completed the subjects will be followed for 6 
menstrual events to determine durability of 
effect of treatment.  If subjects return to a 
MBL score of ≥80 mL at the end of this 
period, assessed by alkaline hematin assay, 
they may be offered the opportunity to enroll 
in an extension study.     
After the second treatment course is completed 
the subjects will be followed for 6 menstrual 
events to determine durability of effect of 
treatment, after which they may be offered the 
opportunity to enroll in an open-label 
extension study.  Subjects who fail to achieve 
amenorrhea may enroll in the extension 
study at Visit 19.  Amenorrhea is defined as 
any 28-day period during treatment (not 
including the ODIs) without a bleeding 
score >1.   
 
 
 
 
Requirements 
for roll-over 
into Extension 
Study added 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
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Page 3 of 3 
ZPV-201 Amendment 4 Summary of Changes 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
Study changed 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
12. STATISTICAL 
METHODS 
12.2.2.2 Secondary 
Endpoints 
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.   
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 and 
after the 6 months of recovery menses (Visit 
24).   
 
 
 
New 
procedure 
added 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Charts and footnotes were updated to reflect the changes above. 
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SAP_001.pdf: 
NCT02323646 
 
Study ID: ZPV-201 
 
Title: A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate 
the Safety and Efficacy of 6 and 12 mg Proellex® (Telapristone Acetate) Administered 
Vaginally in the Treatment of Premenopausal Women with Confirmed Symptomatic Uterine 
Fibroids 
 
Statistical Analysis Plan Amendment 1 Date: 06 April 2016