Clinical trial NCT01728454
Conditions: Endometriosis
Sponsor: Repros Therapeutics Inc.
Start date: 2013-05-02; Completion date: 2017-03-15
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to determine the safety and efficacy of two oral doses of telapristone acetate administered to premenopausal women with pelvic pain associated with endometriosis confirmed within the last seven years and using prescription analgesics for symptomatic pain.

Detailed description:
This study is a phase 2, 3-arm-study with an 18-week active dosing period and an option for participants to receive 2 additional 16-week cycles of active treatment at their randomized dose \[6 mg or 12 mg/day\]. Placebo participants who elect additional treatment will receive treatment at 12 mg/day. The treatment dose will remain double-blind. The study will be conducted in 3 stages. The first stage is a no treatment baseline assessment period. This stage will last as long as it takes to record at least one full menstrual cycle (ovulation until ovulation).

For stage 2, following the run-in stage, at Visit 3, 60 participants will be randomized into one of 3 arms in a 1-1-1 fashion. The start of dosing should commence as soon as possible after ovulation following the end of the previous menstrual event.

For stage 3, participants who are eligible to receive additional cycles of treatment and who elect to continue treatment will be scheduled within a week before the second expected menses (+/- 2 days), following the off-drug interval. Participants will receive 2 cycles of treatment separated by an off-drug interval (ODI), after which they will be followed until menses has returned.

Arms: arm 1: Following the Stage 1 no treatment baseline assessment period, placebo matching capsules, orally, once daily for 18 weeks in Stage 2. Eligible participants had the option to receive 2 additional 16-week cycles of active treatment at 12 milligrams (mg)/day separated by an off-drug interval (ODI) in Stage 3. arm 2: Following the Stage 1 no treatment baseline assessment period, telapristone acetate (Proellex®) 6 mg capsules, orally once daily for 18 weeks in Stage 2. Eligible participants had the option to receive 2 additional 16-week cycles of active treatment at 6 mg/day separated by an ODI in Stage 3. arm 3: Following the Stage 1 no treatment baseline assessment period, telapristone acetate (Proellex®) 12 mg capsules, orally once daily for 18 weeks. Eligible participants had the option to receive 2 additional 16-week cycles of active treatment at 12 mg/day separated by an ODI in Stage 3.
Interventions: intervention 1: Placebo intervention 2: Telapristone acetate
Intervention descriptions: intervention 1: Placebo matching capsules, orally, once daily for 18 weeks. intervention 2: Telapristone acetate capsules, orally once daily for 18 weeks.

Protocol documents:
Prot_001.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.  
NCT01728454 
 
Study ID: ZPE-202 
 
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 9 Date: 02 March 2016 


         
 
 
 
Protocol Number: ZPE-202 
 
 
A Phase 2, Multi-Center, Three-Arm, Parallel Design, Randomized, 
Double-Blind Study to Evaluate the Safety and Efficacy of 6 and 12 mg 
Proellex® (Telapristone Acetate) Administered Orally in the Treatment of 
Premenopausal Women with Confirmed Endometriosis 
 
Original Protocol:  July 18, 2012 
 
SPONSOR: 
 
Repros Therapeutics Inc.®  
2408 Timberloch Place, B-7 
The Woodlands, TX 77380 
 
 
IND 76,631 
 
 
 
 
 
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 / 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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Protocol ZPE-202 
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2. 
TABLE OF CONTENTS 
1. COVER PAGE 
........................................................................................................................ 1 
2. TABLE OF CONTENTS ....................................................................................................... 2 
3. PROTOCOL SYNOPSIS 
....................................................................................................... 4 
4. PROCEDURES AND LABORATORY TABLES 
............................................................... 7 
5. LIST OF ABBREVIATIONS .............................................................................................. 11 
6. BACKGROUND INFORMATION .................................................................................... 12 
6.1 
RATIONALE FOR CURRENT STUDY ............................................................................ 12 
6.2 
NON-C
LINICAL DATA ................................................................................................ 13 
6.3 
CLINICAL DATA/H
UMAN EXPERIENCE 
...................................................................... 14 
6.4 
SAFETY DATA 
............................................................................................................ 15 
6.5 
ETHICAL CONDUCT OF THE STUDY 
............................................................................ 17 
6.6 
DRUG SAFETY MONITORING BOARD (DSMB) 
.......................................................... 17 
7. TRIAL OBJECTIVES AND PURPOSE 
............................................................................ 18 
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 
SELECTION AND WITHDRAWAL OF SUBJECTS 
........................................................... 20 
8.3.1 Inclusion Criteria 
.......................................................................................... 20 
8.3.2 Exclusion Criteria 
......................................................................................... 21 
9. STUDY PROCEDURES ...................................................................................................... 23 
 
3 
 
 
 
 
 
 
 
4 
 
5 
 
5 
10. ASSESSMENT OF EFFICACY 
.......................................................................................... 26 
10.1 PRIMARY ENDPOINT................................................................................................... 26 
10.2 SECONDARY ENDPOINTS 
............................................................................................ 26 
 
6 
11. ASSESSMENT OF SAFETY 
............................................................................................... 27 
11.1 ADVERSE EVENTS 
...................................................................................................... 27 
11.1.1 Reporting Adverse Experiences 
.................................................................... 27 
11.1.2 Definitions .................................................................................................... 27 
11.1.3 Serious Adverse Events (SAEs).................................................................... 28 
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12. CONCOMITANT MEDICATIONS 
................................................................................... 29 
13. STATISTICAL METHODS 
................................................................................................ 30 
13.1 DETERMINATION OF SAMPLE SIZE 
............................................................................. 30 
13.2 STATISTICAL AND ANALYTICAL PLAN 
...................................................................... 30 
13.3 GENERAL STATISTICAL I
SSUES 
.................................................................................. 32 
14. ETHICS ................................................................................................................................. 34 
14.1 SUBJECT I
NFORMATION AND CONSENT 
..................................................................... 34 
14.2 I
NSTITUTIONAL REVIEW BOARD 
................................................................................ 34 
14.3 MONITORING CASE REPORT FORMS 
.......................................................................... 34 
14.4 STUDY RECORD RETENTION 
...................................................................................... 34 
14.5 DATA QUALITY ASSURANCE 
..................................................................................... 34 
14.6 CONFIDENTIALITY...................................................................................................... 35 
14.7 PUBLICATIONS ........................................................................................................... 35 
15. INVESTIGATOR'S STATEMENT 
.................................................................................... 36 
: 
37 
: 
39 
 
 
 
 
 
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3. 
PROTOCOL SYNOPSIS 
 
Test Drugs: 
Proellex® (Telapristone  Acetate):  6  and  12  mg  gelatin  capsules  and 
matching placebo 
Protocol Number: 
ZPE-202  
Study Purpose: 
To  determine  the  safety  and  efficacy  of  two  doses  of  Proellex  in 
premenopausal  women  with  pelvic  pain  
in confirmed endometriosis 
patients. 
Study Design and 
Duration 
Of Treatment: 
This study is a phase 2, 3-arm-study with an 18  week active dosing 
period.  The study will be conducted in two stages.  In the first stage, 
women  will  receive daily  single  blind  dosing  with placebo, for at 
least one  full  menstrual cycle.  
  Endometriosis  pain,  dysmenorrhea, 
non-menstrual pelvic pain and dyspareunia (BBSS) as well as use of 
pain  medications  and  vaginal  bleeding  intensity  will  be  recorded 
using  an  electronic  diary.    Following  the  placebo  run-in  phase, 
subjects  will  be  randomized  
into  one  of 3 arms  in  a  1-1-1  fashion 
weighted by a combined BBSS and analgesic score.  The start of the 
18  week dosing  period  
in  
the  double-blind  phase  should  commence 
as  soon  after  ovulation as  possible, after  which  subjects  will  be 
followed  until  menses  has  returned.    During  the  follow-up  period 
subjects  will  continue  
to  record  study  
information  
in  
the  electronic 
diary.  The final follow-up visit should be scheduled after blood flow 
has stopped.  
 
n 
 
 
Subject Population: The  study  will  enroll  healthy  adult,  non-obese  pre-menopausal 
women with surgically confirmed endometriosis. 
Number of Subjects: Up to 60 female subjects, 20 per dose arm 
Number of Sites 
Approximately 10 sites in the US 
Study Duration:  
Total participation in the study is approximately 6-7 months. 
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Protocol ZPE-202 
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r 
 
 
 
 
 
 
 
 
 
Study Endpoints 
• The  primary  efficacy  endpoint  will  be  percent  change  in  daily 
average  combined  BBSS  patient  reported  scores  comparing  the 
baseline menstrual cycle to a similar period leading up to the last 
day of dosing (Week 18) 
• The secondary endpoints will be  
 Change  
in daily  average use  of  analgesics  
from  
the  baseline 
menstrual cycle to the matching end-of- study period 
 Change  in  BBSS  score  incorporating  the  two physician 
reported scores 
 Change  in  the  individual BBSS scores  of  the  three  patient 
reported outcomes  
 Change in number of days and intensity of menstrual or non-
menstrual vaginal bleeding. 
• 
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 
s 
 
ts 
 
of 
 
 
 
 
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.  All summaries will be prepared for each treatment 
group.  
Summaries  will  be  prepared  for  each  treatment  group  of  subject 
accountability, baseline demographic, and medical history data.  
The  primary  efficacy  variable  
is  
the  change  
in  
the subject reported 
outcomes  of  the  BBSS  from  the  baseline  period  to a comparable 
period  leading  up  to  the  end  of  dosing.    An  overall  comparison 
among the 3 treatment groups will be performed. 
The secondary efficacy variables will be treated similarly.  
 
 
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al  
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s.   
 
 
 
  
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Repros Therapeutics Inc. 
 
  
  
  
 
July 18, 2012 
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Repros Therapeutics Inc. 
 
  
  
 
July 18, 2012 
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5. 
LIST OF ABBREVIATIONS 
 
AE    
Adverse event 
PBAC  
 
Pictorial Bleeding Assessment Chart 
BBSS    
Biberoglu Behrman symptom severity scale 
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 
m  
  
Meters 
mg    
Milligram(s) 
mL    
Milliliter 
ng    
Nanograms 
PCOS    
Polycystic Ovarian Syndrome 
PK    
Pharmacokinetic 
PRL    
Prolactin 
PSA    
Prostate specific antigen 
RBC    
Red blood cell 
SAE    
Serious adverse event 
SHBG   
Sex hormone binding globulin 
TT    
Total testosterone 
UFSQOL 
Uterine Fibroid Symptoms Quality of Life Questionnaire 
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.  Most notably the sponsor 
has seen significant clinically relevant impact on the symptoms of both uterine 
fibroids and endometriosis. 
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sponsor believes there is a direct correlation of symptomatic relief for uterine 
a. 
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of 
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-
1. 
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at 
 
 
 
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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y 
f 
 
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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.  
  The  Institutional  Review  Board  (IRB)  for  this  study  is 
IntegReview, 3001 S. Lamar Blvd., Suite 210, Austin, Texas 78704.  
6.6  
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of 
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7. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to determine the safety and efficacy of two oral 
doses  of  Proellex  administered  for  18  weeks to  premenopausal  women with 
confirmed endometriosis.   
8. 
TRIAL DESIGN 
8.1 
Study Endpoints 
The Primary endpoint will be: 
• Percent  change  
in  daily  average  combined  BBSS  patient  
reported  scores 
comparing the baseline  menstrual cycle to  a similar period leading up to 
the last day of dosing (Week 18) 
The Secondary endpoints will be: 
• Change in daily average use of analgesics from the baseline menstrual 
cycle to the matching end-of- study period 
• Change in BBSS score incorporating the two physician reported scores 
• Change in the individual BBSS scores of the three patient reported 
outcomes 
• Change in number of days and intensity of menstrual or vaginal bleeding  
8.2 
Study Design 
8.2.1  Overview of Study Design 
This  study  
is  a  phase 2, 3-arm-study with  an  18  week active  dosing 
period.  
  The  study  will  be  conducted  
in  2  stages.  
  In  
the  first  stage, 
women will receive a daily single-blind placebo.  This stage will last 
as long as it takes to record at least one full menstrual cycle (ovulation 
until ovulation).  Daily patient reported scores for the three elements of 
endometriosis  pain,  dysmenorrhea,  non-menstrual  pelvic  pain  and 
dyspareunia  will  be  recorded  using  an  electronic  diary  with  prompts 
replicating a modified Biberoglu and Behrman symptom severity score 
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(BBSS). 
  
 
 
Following the run-in phase, 60 subjects will be randomized 
into one of 3 arms in a 1-1-1 fashion weighted by a combined BBSS 
and analgesic score.  
ng 
cs 
1 
of 
 The start  of  dosing  
in 
the  double-blind  phase  should  commence as  soon  as  possible  after 
ovulation following the end of the previous menstrual event.  Once the 
18 week active dosing period is completed, subjects will be followed 
until menses has returned (usually within 35 days or less).  The follow-
up visit should be scheduled after blood flow has stopped.  During the 
follow-up period subjects will continue to record study information in 
the electronic diary.  
 
 
 
 
 
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  or  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 
All subjects will receive placebo from Visit 1 until Visit 3.  At Visit 3,  
subjects will be randomized to treatment in Arms 1, 2, or 3 and will be 
treated with one  capsule  daily  of 6 mg  or  12 mg of  Proellex,  or 
placebo, which will be administered for 18 weeks.  Blinded treatments 
kits will be randomized and distributed by the packaging company.    
8.2.4 Study Medication 
All  study  drugs  will  be  supplied  by  Repros  Therapeutics  Inc.  Test 
drug,  Proellex, 
s  and  will  be 
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packaged by a clinical supplies contract vendor designated by Repros 
Therapeutics  Inc.    The  placebo 
 
and  will  be  packaged  by the  same clinical  supplies  contract 
vendor.    Active  and  matching  placebo  capsules  will  be  bottled  in 
identical  packaging.  Each  bottle  will  have  a  label  containing  bottle 
number,  number  of  capsules,  expiration  date,  clinical  use  only  and 
instructions to take 1 capsule daily in the morning approximately  one 
hour  before  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 electronic drug diary cards.  
 
 
 
8.3 
Selection and Withdrawal of Subjects 
Subjects for the study will be selected during screening based on the inclusion 
and exclusion criteria and clinical assessments listed below.  Subjects will be 
discontinued from the study prematurely if: 
• Unacceptable  adverse  events occur considered  by  the  investigator  to  be 
associated with use of the study drug  
• The subject requests to be withdrawn from the study 
• LFT elevation >3 times upper limit of normal 
• ALT > upper limit of normal for 3 successive weeks 
• A need arises for concomitant medication prohibited by the protocol  
• The Principal Investigator decides that it is in the subject’s best interest 
• The subject is noncompliant with the protocol 
• Any  subject  who develops  an  endometrial  thickness  ≥  20  mm  and 
experiences heavy bleeding for 7 days or more will be discontinued from 
the  study.  
  Appropriate  follow  up  
treatment  will  be  provided  as  deemed 
necessary by the investigator. 
8.3.1 Inclusion Criteria 
Subjects must meet the following criteria: 
• Healthy  adult  females  between  18  and  47  years  of  age  with 
surgically confirmed diagnosis of endometriosis (within-10 years).  
A laparoscopic diagnosis is acceptable. 
• Normal  or  abnormal  but  non-clinically  significant  transvaginal 
ultrasound 
• History of menstrual events occurring in regular cycles 
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• Agreement not to attempt to become pregnant during the trial 
• Agreement to limit alcohol consumption to no more than 2 drinks 
per week and to avoid alcohol consumption within 48 hours before 
each visit 
• Ability  to  complete  a  daily electronic subject  diary  and  study 
procedures in compliance with the protocol 
• Agrees to use a double-barrier contraceptive over the course of the 
study   
• Has a negative pregnancy test at the Screening and Baseline visits, 
and subsequent study visits 
• A Body Mass Index (BMI) between 18 and 39 inclusive 
• 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
 
 
 
• Women with abnormally high liver enzymes or liver disease. (ALT 
or AST  exceeding  1.5x  ULN AND total  bilirubin  exceeding 
1.5xULN at screening and confirmed on repeat). 
• Received  an  investigational  drug  in  the  30  days  prior  to  the 
screening for this study 
• Women with a history of PCOS 
• Concurrent use of any testosterone, progestin, androgen, estrogen, 
anabolic steroids, DHEA or hormonal products for at least 2 weeks 
prior to screening and during the study. 
• Use of oral contraceptives in the preceding 30 days.  Use of Depo-
Provera® in the precedin
. 
• 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 after the period of duration of the Lupron dose). 
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• Has an IUD in place 
• Presence of intramural fibroids that impact the endometrial stripe, 
submucosal fibroids (any size), or endometrial polyps.  Subserosal 
and  
intramural  fibroids  with  no  
impact  on  
the  endometrial  stripe 
are acceptable. 
• Present history or condition that causes non-endometriosis related 
dyspareunia (e.g. vulvar vestibulitis). 
• Past  or  present  history  of thrombophlebitis or  thromboembolic 
disorders. 
• Known  or  suspected  carcinoma  of  the  breast  or  reproductive 
organs. 
• History of abnormal ECG that, in the opinion of the investigator, is 
clinically significant and will prevent the subject from completing 
the study, including a QTc of greater than 450 ms. 
• Cervical  dysplasia  classified  as  Atypical  Squamous  Cells  of 
Undetermined  Significance  (ASCUS)  associated  with  high-risk 
human  papilloma  virus  (HPV)  or  Low/High  Grade  Squamous 
Intraepithelial Lesion (LGSIL or HGSIL). 
• History of abnormal endometrial biopsy including the presence of 
EIN. 
• Recent history (within past 6 months) of alcoholism or drug abuse. 
• Known active infection with HIV, Hepatitis A, B or C. 
• Previous  history  of  auto-immune disease  and/or  positive 
antinuclear antigen (ANA). 
• Endometrial stripe ≥18 mm in thickness at Visit 1. 
• Women currently taking cimetidine or spironolactone. 
• 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 EFFICACY 
10.1 Primary Endpoint 
The Primary endpoint will be: 
• The  percent  change  in  daily  average  combined  BBSS  patient  reported 
scores comparing the baseline menstrual cycle to a similar period leading 
up to the last day of dosing (Week 18) 
10.2 Secondary Endpoints 
The Secondary endpoints will be: 
• Change in daily average use of analgesics from the baseline menstrual 
cycle to the matching end-of- study period 
• Change in BBSS score incorporating the two physician reported scores 
• Change in the individual BBSS scores of the three patient reported 
outcomes  
• Change in number of days and intensity of menstrual or vaginal bleeding. 
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, 
 
11.1 Adverse Events 
11.1.1 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.  
All  AEs  reported  by  the  subject  or  observed  by  the  Principal 
Investigator will be individually listed.  The signs and symptoms, time 
of  onset  (24-hour  clock),  duration,  action  taken  and  follow-up 
procedures will be reported. 
11.1.2 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.   
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. 
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 
 
 
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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. 
11.1.3  Serious Adverse Events (SAEs) 
The  Principal  Investigator  shall  document all SAEs  in  a  subject 
receiving  study  drug
  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.  
All  additional  follow-up  reports  must  be  reported  to  the  Repros 
Therapeutic Inc monitor as soon as available. 
 
 
 
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12. 
CONCOMITANT MEDICATIONS 
Any  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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13. 
STATISTICAL METHODS  
13.1 Determination of Sample Size 
The sample size determination was not based on statistical considerations.  Up 
to  60  female  subjects, 20  per  dose  arm,  meeting  the  inclusion/exclusion 
criteria will be randomized in a 1-1-1 fashion weighted by a combined BBSS 
and analgesic score.  
f 
he 
r 
c 
 
  
Adequate  data  are  not  available  for  estimating  
the  sample  size  necessary  
to 
detect  statistical  differences  between  treatment  groups  with  reasonable 
statistical power.  The planned number of patients (20 per dose arm) should 
provide sufficient data to assist with the design  of  
future  
studies.  While the 
sample size was not based on statistical considerations, hypothesis testing will 
be performed for exploratory purposes. 
13.2 Statistical and Analytical Plan 
13.2.1 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. 
13.2.2 Efficacy Analyses 
Efficacy  analyses  will  be  conducted  in  the modified  Intent-to-Treat 
population, which will consist of all subjects who are randomized, who 
receive study drug, and who have some post-baseline efficacy data. 
13.2.2.1 BBSS Patient Reported Scores 
The  primary  efficacy  variable  is  percent  change  in  daily 
average combined BBSS patient-reported scores comparing the 
baseline  menstrual  cycle  
to  a  similar  period  
leading  up  
to  
the 
last day of dosing (Week 18).   An  overall comparison among 
the  3  treatment  groups  will  be  performed  using  a  one-way 
Analysis  of  Variance.    For  each  treatment  group  the  mean 
change  from  baseline  will  be  assessed  for  statistical 
significance  using  a  paired  t-test.    While  the  primary 
assessment  will  be  based  on  Visit 12 (after 18  weeks  of 
treatment)  summaries  will  also  be  prepared  for  each  of  the 
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interim  visits. 
 
 
 
13.2.2.2 Analgesic Usage 
The change  
in  daily  average  use  of  analgesics comparing  
the 
baseline  menstrual  cycle  
to  a  similar  period  
leading  up  
to  
the 
last  day  of  dosing  (Week  18) will  be  summarized  for  each 
treatment group.  An overall comparison among the 3 treatment 
groups  will  be  performed  using  a  one-way  Analysis  of 
Variance.    For  each  treatment  group  the  mean  change  from 
baseline  will  be  assessed  for  statistical  significance  using a 
paired  
t-test.  
  While  
the  primary  assessment  will  be  based  on 
Visit 12 (after 18 weeks of treatment) summaries will also be 
prepared  
for  each  of  
the  
interim  visits.  If  data  are  missing,  a 
last  observation  carried  forward  procedure  will  be  used, 
including the baseline, if necessary. 
13.2.2.3 BBSS Patient and Physician Reported Scores 
The BBSS  score incorporating  the  two  physician-reported 
scores  will  be  analyzed  to  compare  the  baseline  menstrual 
cycle  
to  a  similar  period  
leading  up  
to  
the  
last  day  of  dosing 
(Week  18).    An  overall  comparison  among  the  3  treatment 
groups  will  be  performed  using  a  one-way  Analysis  of 
Variance.    For  each  treatment  group  the  mean  change  from 
baseline  will  be  assessed  for  statistical  significance  using a 
paired  
t-test.  
 While  
the  primary  assessment  will  be  based  on 
Visit 12 (after 18 weeks of treatment) summaries will also be 
prepared  
for  each  of  
the  
interim  visits. 
 
, 
13.2.2.4 Patient Reported Outcomes 
Each of the three patient reported outcomes will be analyzed to 
compare  the  baseline menstrual  cycle  to  a  similar  period 
leading  up  
to  
the  
last  day  of  dosing  (Week  18).  
  An  overall 
comparison  among  
the  3  
treatment  groups  will  be  performed 
on  each  patient  reported  outcome  score using  a  one-way 
Analysis  of  Variance.    For  each  treatment  group  the  mean 
change  from  baseline  will  be  assessed  for  statistical 
significance  using  a  paired  t-test.    While  the  primary 
assessment  will  be  based  on  Visit 12 (after 18  weeks  of 
treatment)  summaries  will  also  be  prepared  for  each  of  the 
interim  visits.  If  data  are  missing,  a  last  observation  carried 
forward  procedure  will  be  used,  including  the  baseline,  if 
necessary. 
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13.2.2.5  Menstrual or Non-menstrual Vaginal Bleeding 
The  number  of  days  and  intensity  of  menstrual  and  non-
menstrual vaginal bleeding will be summarized from the diary 
data.  
  The  
total  number  of  days  and  average  
intensity  will  be 
summarized  from  the  days  preceding  each  visit.    An  overall 
comparison  among  
the  3  
treatment  groups  will  be  performed 
on both the total number of days and average intensity using a 
one-way  Analysis  of  Variance.  
  For  each  
treatment  group  
the 
mean  change  from  baseline  will  be  assessed  for  statistical 
significance  using  a  paired  t-test.    While  the  primary 
assessment  will  be  based  on  Visit 12 (after 18  weeks  of 
treatment)  summaries  will  also  be  prepared  for  each  of  the 
interim  visits.  If  data  are  missing,  a  last  observation  carried 
forward  procedure will  be  used,  including  the  baseline,  if 
necessary. 
s 
as 
ho 
a. 
m 
al 
nd 
al 
dy 
p 
y.    
he 
ge 
d 
e 
d 
r 
al 
al 
p.   
f 
y 
 
  
13.3  General Statistical Issues 
 
 
  Statistical 
significance  will  be  declared  if  the  two-sided  p-value  
is  ≤  0.05.  
  Since  the 
study  was  not  powered  for  efficacy  assessments  based  on  statistical 
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hypotheses,  the  p-values  reported  at  the  conclusion  of  the  study  are  being 
reported  
to  quantify  
the  difference  
in  
the  
treatment  effect  between  
treatment 
groups.   
r 
 
 
 
 
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14. 
ETHICS 
14.1 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. 
14.2  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. 
14.3  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. 
14.4 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. 
14.5  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: 
 
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1.  Monitoring  study  conduct  to  ensure  that  the  rights  of  subjects  are 
protected; 
2. Monitoring study conduct to ensure trial compliance with GCP guidelines; 
and 
3. Monitoring accuracy, completion and verification from source documents 
of study data. 
14.6 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. 
14.7 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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15. 
INVESTIGATOR'S STATEMENT 
I  have  reviewed  the  ZPE-202 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. 
 
  
  
  
  
  
 
July 18, 2012 
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Repros Therapeutics Inc. 
 
  
  
  
  
  
 
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ZPE-202 Amendment 3 Summary of Changes 
Page 1 of 13 
 
ZPE-202 Protocol Summary of Changes 
Protocol Title: 
A  Phase  2,  Multi-Center,  Three-Arm,  Parallel  Design,  Randomized,  Double-Blind  Study  
to  Evaluate  
the  Safety  and 
Efficacy  of  6  and  12  mg  Proellex® (Telapristone  Acetate)  Administered  Orally  
in  
the  Treatment of  Premenopausal 
Women with Confirmed Symptomatic Endometriosis 
Changes From:  
Protocol Amendment 2 dated October 24, 2012    To: Protocol Amendment 3 dated April 23, 2013 
Reason for Amendment: Change in required meds to prescription analgesics and addition of pain scores as inclusion and change in pain 
score as an endpoint 
Changes to Protocol: 
Significant  changes  to  the  protocol  are  listed  below. All  references  to  narcotic  analgesics  were  changed  to 
prescription analgesics. Alcohol breath tests were removed. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
COVER PAGE AND 
HEADERS 
Amendment 2: October 24, 2012 
Amendment 3:  April 23, 2013 
 
Administrative 
3. PROTOCOL 
SYNOPSIS:  
    Study Purpose 
To determine the safety and efficacy of 
two doses of Proellex in 
premenopausal women with pelvic pain 
in endometriosis confirmed within the 
last five years and using narcotics for 
symptomatic pain. 
To determine the safety and efficacy of 
two doses of Proellex in premenopausal 
women with pelvic pain in endometriosis 
confirmed within the last seven years and 
using prescription analgesics for 
symptomatic pain. 
Administrative 
PROTOCOL SYNOPSIS 
Study Design and 
Duration of Treatment: 
 
 
 
This study is a phase 2, 3-arm-study 
with an 18 week active dosing period.  
The study will be conducted in two 
stages.  In the first stage, women will 
receive daily single blind dosing with 
placebo, for at least one full menstrual 
cycle. Endometriosis pain, 
dysmenorrhea, non-menstrual pelvic 
pain and dyspareunia (BBSS) as well 
as use of pain medications, vaginal 
bleeding intensity and alcohol use will 
This study is a phase 2, 3-arm-study with 
an 18 week active dosing period.  The 
study will be conducted in two stages.  In 
the first stage, women will receive daily 
single blind dosing with placebo prior to 
enrollment, until their second ovulation 
event.  Endometriosis pain, 
dysmenorrhea, non-menstrual pelvic pain 
and dyspareunia (BBSS) as well as use of 
pain medications, vaginal bleeding 
intensity and alcohol use will be recorded 
 
 
 
 
Clarification 
 
 
 
 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 2 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
be recorded using an electronic diary.  
Following the placebo run-in phase, 
subjects will be randomized into one of 
3 arms in a 1-1-1 fashion.  The start of 
the 18 week dosing period in the 
double-blind phase should commence 
as soon after ovulation as possible, 
after which subjects will be followed 
until menses has returned.  During the 
follow-up period subjects will continue 
to record study information in the 
electronic diary.  The final follow-up 
visit should be scheduled after blood 
flow has stopped.  
 
using an electronic diary and Visual 
Analog Scale (VAS) pain assessment 
will be utilized.  Following the placebo 
run-in phase, subjects will be randomized 
into one of 3 arms in a 1-1-1 fashion.  The 
start of the 18 week dosing period in the 
double-blind phase should commence as 
soon after ovulation as possible, after 
which subjects will be followed until 
menses has returned.  After completing a 
minimum of 28 days of treatment in 
this stage of the study, subjects may 
discontinue the study and still be 
eligible to qualify for the open-label 
extension study.   
Subjects will be treated for 18 weeks, 
after which subjects will be followed 
until menses has returned.  During the 
follow-up period subjects will continue to 
record study information in the electronic 
diary.  The final follow-up visit will be 
scheduled after blood flow has stopped.  
New assessment 
 
 
 
 
 
 
 
 
Clarification 
 
 
 
 
 
 
Clarification 
PROTOCOL SYNOPSIS 
Study Population: 
The study will enroll healthy adult, 
non-obese pre-menopausal women 
with surgically confirmed 
endometriosis using narcotic analgesics 
for their endometriosis pain. 
The study will enroll healthy adult, non-
obese pre-menopausal women with 
surgically confirmed endometriosis using 
prescription analgesics for their 
endometriosis pain. 
All references to narcotic 
analgesics changed to 
prescription analgesics 
PROTOCOL SYNOPSIS 
Number of Sites: 
Approximately 10 sites in the US 
Approximately 10-20 sites  
Clarification 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 3 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
S 
s: 
an 
ed 
to 
A 
. 
 
 
 
de 
,  
e 
ll 
al 
S 
e 
d. 
 
 
 
 
 
w 
nt 
PROTOCOL SYNOPSIS 
Study Endpoints:  
 
The primary efficacy endpoint will be 
percent change from baseline in use of 
narcotic analgesics comparing the 
baseline nominal 28-day menstrual 
cycle (including menstrual event) to a 
similar period leading up to the last day 
of dosing (Week 18).  It is anticipated 
that subjects randomized to active 
treatment will stop menstruating. 
The secondary endpoints will be:  
• Change  in  daily  average  use  and 
percent  change  of non-narcotic 
prescription  analgesics  from  the 
baseline  menstrual  cycle  to  the 
matching  end-of- study  period 
calculated  based  on  days  with 
reported values 
• Change  in  daily  average  use  of 
narcotic prescription analgesics from 
the  baseline  menstrual  cycle  to  the 
matching  end-of- study  period 
The study endpoints will be:  
• Percent change from baseline in use of 
prescription analgesics  comparing  
the 
baseline  nominal  28-day  menstrual 
cycle  (including  menstrual  event)  to  a 
similar period leading up to the last day 
of  dosing  
(Week  18).  
  
It  
is  anticipated 
that  subjects  randomized  to  active 
treatment will stop menstruating 
• Change  in  daily  average  use  and 
percent  change  of  prescription 
analgesics  
from  
the  baseline  menstrual 
cycle  to  the  matching  end-of- study 
period  calculated  based  on  days  with 
reported values 
• Change  from  baseline  in  pain 
assessed using a Visual Analog Scale 
(VAS)  
Administrative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
New assessment 
 
 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 4 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
calculated  based  on  days  with 
reported values 
 
 
 
PROTOCOL SYNOPSIS 
Statistical Methods:  
 
 
 
 
 
 
The primary efficacy variable will be 
percent change from baseline in use of 
narcotic analgesics comparing the 
baseline nominal 28-day menstrual 
cycle (including menstrual event) to a 
similar period leading up to the last day 
of dosing (Week 18).  An overall 
comparison among the 3 treatment 
groups will be performed using an 
Analysis of Covariance, including the 
baseline narcotic analgesic usage and 
treatment in the model.  Pairwise 
comparisons between treatment groups 
will be made using a two-sample t-test. 
 
The secondary efficacy variables will 
be treated similarly. 
 
m 
es 
n 
he 
 
A Statistical Analysis Plan (SAP) will 
be developed prior to unblinding of the 
data that will outline all planned 
analyses and analysis populations. 
 
Continuous efficacy endpoints, such as 
the percentage change from baseline in 
the use of prescription analgesics, will 
assess treatment effect using an 
Analysis of Covariance, including the 
baseline prescription analgesic usage 
and treatment in the model.  Pairwise 
comparisons between treatment groups 
will be made using a two-sample t-test. 
 
 
 
 
 
 
Other continuous efficacy variables will 
be treated similarly.  
 
 
 
 
 
Clarification 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 5 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
  
: 
 
 
 
 
 
 
  
 
 
5. List of Abbreviations 
 
VAS-Visual Analog Scale 
 
7. TRIAL OBJECTIVES 
AND PURPOSE 
The primary objective of this study is 
to determine the safety and efficacy of 
two oral doses of Proellex administered 
for 18 weeks to premenopausal women 
with pelvic pain in endometriosis 
confirmed within the last five years and 
using narcotics for symptomatic pain. 
The primary objective of this study is to 
determine the safety and efficacy of two 
oral doses of Proellex administered for 18 
weeks to premenopausal women with 
pelvic pain in endometriosis confirmed 
within the last seven years and using 
prescription analgesics for symptomatic 
pain. 
Administrative 
8. TRIAL DESIGN 
8.1  Study Endpoints 
 
8.1 Study Endpoints 
The Primary endpoint will be: 
• Percent change from baseline in use 
of narcotic analgesics comparing 
the baseline nominal 28-day 
menstrual cycle (including 
menstrual event) to a similar period 
leading up to the last day of dosing 
(Week 18) 
The Secondary endpoints will be: 
• Change in daily average use of non-
narcotic prescription analgesics 
from the baseline menstrual cycle 
to the matching end-of- study 
period 
8.1 Study Endpoints 
• Percent change from baseline in use of 
prescription analgesics comparing the 
baseline nominal 28-day menstrual 
cycle (including menstrual event) to a 
similar period leading up to the last day 
of dosing (Week 18) 
• Change in daily average use of 
prescription analgesics from the 
baseline menstrual cycle to the 
matching end-of- study period 
• Change in daily average use of over the 
counter analgesics from the baseline 
menstrual cycle to the matching end-of- 
study period calculated based on days 
 
Administrative 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 6 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
• Change in daily average use and 
percent change of narcotic 
prescription analgesics from the 
baseline menstrual cycle to the 
matching end-of- study period 
calculated based on days with 
reported values 
• Change in daily average use of over 
the counter analgesics from the 
baseline menstrual cycle to the 
matching end-of- study period 
calculated based on days with 
reported values 
with reported values 
• Change from baseline in pain 
assessed using a Visual Analog Scale 
(VAS) 
 
 
 
 
 
New assessment 
 
 
Assessment added as 
endpoint 
 
8.2   Study Design 
     8.2.1 Overview of 
Study Design 
Data must be entered within 24 hours 
of a given timepoint.  
Data must be entered daily. 
 
Subjects who complete at least 28 days 
after visit 3 and wish to exit the study 
due to lack of efficacy will be eligible to 
enter an open-label extension study. 
Subjects who discontinue the study 
prior to this date will not be eligible for 
enrollment in the extension study. 
Administrative 
 
Clarification 
8.3.1 Inclusion Criteria 
• Healthy adult females between 18 
and 47 years of age using an 
average of at least 6 and no more 
than-36 doses of narcotic analgesics 
in a 28-day period for their 
endometriosis related pain 
 
• Endometriosis  diagnosis  must  have 
been  surgically  confirmed  within 5 
• Healthy adult females between 18 
and 47 years of age using 
prescription analgesics for 
endometriosis pain and with a 
BBSS score ≥7 at screening 
(assessed over the previous 28 days, 
see Appendix 2). 
• Endometriosis  diagnosis  must  have 
been  surgically  confirmed  within 7 
 
 
 
New assessment (pain score) 
 
 
 
 
Change in eligibility criterion 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 7 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
years.  
  A  
laparoscopic  diagnosis  
is 
acceptable. 
years.    A  laparoscopic  diagnosis  is 
acceptable. 
8.3.2 Exclusion Criteria 
• Abnormal DEXA scan (baseline T 
score < -1.0STD or Z score       ≤ -
1.50SRD) or diagnosis of osteopenia 
• Has an IUD in place 
 
 
• History of abnormal ECG that, … 
• Has an IUD in place. Copper IUDs 
(non-hormone containing will be 
permitted) 
• Known history of abnormal ECG that 
… 
Change in Exclusion criterion 
 
 
Clarification 
 
 
Clarification 
g 
it 
 
o 
ll 
an 
on 
y; 
f 
ol 
n, 
c 
 a 
e 
n 
y 
e 
od 
ne 
y, 
g, 
h 
 
o 
de 
an 
n 
nt 
e 
e 
he 
a 
on 
e 
 a 
es 
P 
r 
ll 
y 
be 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 8 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
s.   
 
 
 
at 
en 
s-
 
 
g, 
d 
l 
s.   
s 
to 
nd 
as 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
e 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 9 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
 
 
 
 
  
   
 
 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
y 
t 
er 
ed 
l 
a 
r, 
. 
 
e 
ns 
d.  
l 
g 
 
al 
 a 
r, 
. 
 
e 
ic 
A 
e 
e 
ld 
ce 
e 
 
 
 
 
 
 
 
 
t 
 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 10 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
 
e 
  
 
10. ASSESSMENT OF 
EFFICACY 
    10.1 Study Endpoints 
ASSESSMENT OF EFFICACY 
10.1  Primary Endpoint 
The Primary endpoint will be: 
The percent change from baseline in 
use of narcotic analgesics comparing 
the baseline nominal 28-day menstrual 
cycle (including menstrual event) to a 
similar period leading up to the last day 
of dosing (Week 18) 
10.2  Secondary Endpoints 
The Secondary endpoints will be: 
• Change in daily average use and 
percent change of non-narcotic 
prescription analgesics from the 
baseline menstrual cycle to the 
matching end-of- study period 
• Change in daily average use of 
narcotic prescription analgesics from 
the baseline menstrual cycle to the 
matching end-of- study period 
calculated based on days with 
reported values 
 
 
 
 
ASSESSMENT OF EFFICACY 
10.1 Study Endpoints 
• The percent change from baseline in 
use of prescription analgesics 
comparing the baseline nominal 28-day 
menstrual cycle (including menstrual 
event) to a similar period leading up to 
the last day of dosing (Week 18) 
• Change in daily average use and 
percent change of prescription 
analgesics from the baseline menstrual 
cycle to the matching end-of- study 
period 
• Change from baseline in pain 
assessed using a Visual Analog Scale 
(VAS) 
 
 
 
 
 
 
 
 
 
 
Administrative 
 
 
 
 
 
 
 
 
 
 
 
 
 
New assessment (pain score) 
 
 
 
 
 
 
 
 
 
 
 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 11 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
     
, 
 
  
 
 
12. Concomitant 
Medications 
 
 12.1 Prescription 
Analgesics Permitted 
During the Study 
12.1 Analgesics Permitted During 
the Study 
Subjects should not take any analgesics 
during the study unless necessary for 
pain.  In the event that a subject needs 
to use narcotic analgesics for 
endometriosis-related pain, one of the 
following regimens should be 
prescribed: 
 
 
 
 
 
Any deviation from this list requires 
pre-approval by Repros. 
All narcotic and non-narcotic 
medication will be recorded in the 
appropriate section of the CRF. 
12.1 Prescription Analgesics 
Permitted During the Study 
Subjects should not take any analgesics 
during the study unless necessary for pain.  
In the event that a subject needs to use 
prescription analgesics for 
endometriosis-related pain, one of the 
following regimens should be prescribed: 
• Ponstel (mefenamic acid) (500 mg 
initial dose, then 250 mg every 6 
hours) 
• Ibuprofen/Hydrocodone: 1-2 tabs 
every 6-8 hrs prn 
 
Any deviation from this list requires pre-
approval by Repros. 
All narcotic, non-narcotic and over–the-
counter medication will be recorded in 
the appropriate section of the CRF. 
 
 
 
 
 
Change in study design 
 
 
 
Allowed medications added 
 
 
 
 
 
 
Administrative 
13.   STATISTICAL 
METHODS  
 
All references to narcotics changed to 
prescription 
 
13.2.2.1 Prescription 
Analgesic Usage 
 
Reference to primary endpoint removed 
Reference to narcotic changed to 
prescription 
 
13.2.2.2 Non-Narcotic 
Prescription Analgesic 
Usage Removed 
 
Section removed 
 
13.2.2.6 
VAS 
Assessment of Pain 
 
The percentage change from baseline 
VAS pain score will be analyzed within 
New assessment added 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 12 of 13 
 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
 
treatment group and between 
treatment groups.    An overall 
comparison among the 3 treatment 
groups will be performed using a one-
way Analysis of Variance.  Pairwise 
comparisons of the treatment groups 
will be made using t-test or non-
parametric test as appropriate.  While 
the primary assessment will be based 
on scores at Visit 12 (after 18 weeks of 
treatment), summaries will also be 
prepared for each of the interim visits. 
If data are missing, a last observation 
carried forward procedure will be used, 
including the baseline, if necessary. 
:     T
s-
f 
s 
 
n 
e. 
 
: 
Y 
R 
G) 
 
 
d 
y 
 
 
d 
d 
A 
G 
S 
 
d 
 
N 
A 
 
m 
is 
 
 
d 


 
 
ZPE-202 Amendment 3 Summary of Changes 
Page 13 of 13 
 
SECTION 
CHANGED FROM 
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Page 1 of 2 
Summary of Changes for Protocol Amendment 4: June 12, 2013 
ZPE-202 Protocol Summary of Changes 
Protocol Title:  
A Phase 2, Multi-Center, Three-Arm, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety 
and  Efficacy  of  6  and  12  mg  Proellex
® (Telapristone  Acetate)  Administered  Orally  in  the  Treatment  of 
Premenopausal Women with Confirmed Symptomatic Endometriosis 
Changes From:   
Protocol Amendment 3 dated April 23, 2013   
 To:  Protocol Amendment 4 dated June 12, 2013 
Reason for Amendment:  
To  clarify:  pelvic  exam  
is  
required  
for  
investigator  BBSS  assessment,  DEXA  
requirements,  
inclusion 
criteria for analgesic use, LFTs on Visits 1, 6 and 12.  
Changes to Protocol:    
Significant changes to the protocol are listed below. 
SECTIONS CHANGED 
CHANGES MADE 
REASON FOR CHANGE 
8.  TRIAL  OBJECTIVES  AND 
PURPOSE  
8.3.1 INCLUSION CRITERIA 
 
 
 
 
 
12 CONCOMITANT MEDICATIONS  
12.1 PRESCRIPTION ANALGESICS 
PERMITTED DURING THE STUDY 
Healthy  adult  females  between  18  and  47 
years of age using prescribed prescription 
analgesics  (see  section  12.1)  for 
endometriosis pain and with a BBSS score 
≥7 at screening (assessed over the previous 
28  days,  see  Appendix  2).   Note:  it  is 
required  that  subjects  have  been 
prescribed  analgesics,  but  not  
that  
they 
have actually taken them, provided they 
score ≥7  on  the  screening  BBSS 
assessment. 
 
Any  deviation  from  this  list  requires  pre-
approval  by  Repros. Note:  Over-the-
counter  medications  (e.g.  ibuprofen, 
naproxen) do not qualify as prescription 
medications for entrance into the study, 
even  if  a  prescription  has  been  written 
for the specific medication.
Inclusion Clarification  
 
 
 
 
 
 
 
 
 
 
Inclusion Clarification  
S  
 
e 
).   
 
n 
 
 


Page 2 of 2 
Summary of Changes for Protocol Amendment 4: June 12, 2013 
SECTIONS CHANGED 
CHANGES MADE 
REASON FOR CHANGE 
2 
 
T 
T  
 
d 
d. 
 
d 
 
n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G 
S 
e 
2. 
y 
d 
e 
 
 
 
n 
 


Page 1 of 7 
ZPE-202 Amendment 6, January 7, 2014 
ZPE-202 Protocol Summary of Changes 
Protocol Title: 
A  Phase  2,  Multi-Center,  Three-Arm,  Parallel  Design,  Randomized,  Double-Blind  Study  
to  Evaluate  
the  Safety  and 
Efficacy  of  6  and  12  mg  Proellex® (Telapristone  Acetate)  Administered  Orally  
in  
the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Endometriosis 
Changes From:  
Protocol Amendment 4 dated June 12, 2013  
 To: Protocol Amendment 6 dated January 7, 2014 
Reason for Amendment:  Addition of up to 2 additional (optional) cycles of treatment 
Changes to Protocol: 
Significant changes to the protocol are listed below.  
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
SYNOPSIS: Study Purpose: 
To determine the safety and efficacy of two doses 
of Proellex in premenopausal women with pelvic 
pain in endometriosis confirmed within the last 
seven years and using prescription analgesics for 
symptomatic pain. 
To determine the safety and efficacy of two doses of 
Proellex in premenopausal women with pelvic pain 
associated with endometriosis confirmed within the last 
seven years and using prescription analgesics for 
symptomatic pain. 
Administrative change 
SYNOPSIS: Study  Design 
and Duration Of Treatment 
This study is a phase 2, 3-arm-study with an 18 
week active dosing period.  The study will be 
conducted in two stages. 
This study is a phase 2, 3-arm-study with an 18 week active 
dosing period and an option to extend treatment for 2 
additional cycles (US sites only).  The study will be 
conducted in three stages. 
Additional stage added 
 
Following the placebo run-in phase, subjects will 
be  randomized  into  one  of  3  arms  in  a  1-1-1 
fashion.  
  The  start  of  
the  18  week  dosing  period 
in  the  double-blind  phase  should  commence  as 
soon  after  ovulation  as  possible,  after  which 
subjects  will be  followed  until  menses  has 
returned.  
 
 
 
 
   
Subjects will be treated for 18 weeks, after which 
subjects will be followed until menses has 
returned.  During the follow-up period subjects 
will continue to record study information in the 
electronic diary.  The final follow-up visit will be 
scheduled after blood flow has stopped. 
In  the  second  stage, following  the  placebo  run-in  phase, 
subjects  will  be  
randomized  
into  one  of  3  arms  
in  a  1-1-1 
fashion.  The start of the 18 week dosing period for the first 
cycle of treatment should commence as soon after ovulation 
as  possible,  after which  subjects  will  be  followed  until 
menses  returns.   Subjects  who  do  not  wish  to  receive 
additional  cycles  of  treatment  after  stage  2  will  have 
their  last  visit  scheduled  after  blood  flow  has  stopped.  
During  this  off-drug  
interval;  subjects  will  continue  to 
record study information in the electronic diary. 
After completing a minimum of 28 days of treatment in this 
stage  of  
the  study,  subjects  may  discontinue  
the  study  and 
still  be  eligible  
to  qualify  for  up  
to  2  additional  
treatment 
cycles (stage 3, US sites only).    
In the third stage, subjects (US only) who are eligible to 
receive additional cycles of treatment and who elect to 
continue treatment will be scheduled within a week before 
 


Page 2 of 7 
ZPE-202 Amendment 6, January 7, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
the next expected menses (+/- 2 days), following the off-
drug interval.  Subjects will receive 2 cycles of additional 
treatment separated by an off-drug interval (ODI), after 
which they will be followed until menses has returned.  
During the follow-up period subjects will continue to record 
study information in the electronic diary.  The final follow-
up visit will be scheduled after blood flow has stopped. 
SYNOPSIS: Study Duration 
Total participation in the study is approximately 
6-7 months. 
Total participation in the study is approximately 18 months. Extended due to additional 
cycles 
es 
s. 
 
l 
d.  
it 
2. 
 
 
 
 
 
n 
s, 
), 
 
 
 
s. 
 
e 
ug 
S 
of 
ed 
y.    ll 
nt 
d. 
 
r  s y  a
s  
l  i
e  
S  p n 
al 
l 
 
 
 
 
 
 
 
 
SYNOPSIS 
Section 8.1 and  
Section 10.1 Study Endpoints 
 Percent  change  from  baseline  in  use  of 
prescription  analgesics  comparing  the 
baseline  nominal  28-day  menstrual  cycle 
(including  menstrual  event)  to  a  similar 
period  leading  up  to  the  last  day  of  dosing 
(Week  18).   It  is  anticipated  that  subjects 
randomized to  active  treatment  will  stop 
menstruating 
 Change  in  daily  average  use  and  percent 
change  of  prescription  analgesics  from  the 
baseline menstrual cycle to the matching end-
• The percent change from baseline in use of prescription 
analgesics  comparing  the  baseline  nominal  28-day 
menstrual cycle (including menstrual event) to a similar 
period leading up to Week 18, the last day of dosing of 
the first cycle of treatment 
 
 
• Change  in daily  average  use  and  percent  change  of 
prescription  analgesics  from  the  baseline  menstrual 
cycle to the  matching period leading up to Week 18, 
the last day of dosing of the first cycle of treatment 
Administrative 
 
 
 
 
 
 
 
 
Clarification 
 
 


Page 3 of 7 
ZPE-202 Amendment 6, January 7, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
of- study  period  calculated  based  on  days 
with reported values 
 Change  in  daily  average  use  and  percent 
change  over  
the  counter  analgesics  from  
the 
baseline menstrual cycle to the matching end-
of- study period 
 Change  and  percent  change  in  BBSS  score 
incorporating  the  two  physician  reported 
scores 
• Change in daily average use and percent change of over 
the  counter  analgesics  from  the  baseline  menstrual 
cycle  
to  
the  matching  period leading  up  
to  Week  18, 
the last day of dosing of the first cycle of treatment, 
calculated based on days with reported values. 
• Change  and  percent  change  in  BBSS  score 
incorporating  the  two  physician  reported  scores by 
study visit and treatment cycle. 
 
 
Clarification 
 
 
 
 
Clarification 
Study Endpoints (cont) 
 Change and percent change in the  
individual 
BBSS  scores  of  the  three  patient  reported 
outcomes  (dysmenorrhea,  dyspareunia  and 
non-menstrual pelvic pain) 
 Change  from  baseline  in  pain  assessed 
using a Visual Analog Scale (VAS) 
 
 
• 
e: 
 
ts 
 
ds 
 
f 
 
 
 
• Change  and  percent  change  in  the  individual  BBSS 
scores  of  the  three  patient  reported  outcomes 
(dysmenorrhea,  dyspareunia  and  non-menstrual  pelvic 
pain) by study visit and treatment cycle. 
• Change  from  baseline  
in  pain  assessed  using  a  Visual 
Analog  Scale  (VAS) by  study  visit  and  treatment 
cycle. 
 
 
 
 
 
 
 
 
 
  
Clarification 
 
 
 
 
Clarification 
 
 
 
 
 
 
 
 
 
 
SYNOPSIS:  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. 
 
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 
and follow-up. 
Amended to account for 
additional on drug cycles 
5. LIST OF 
ABBREVIATIONS 
 
 
ODI Off drug interval added 
Administrative 


Page 4 of 7 
ZPE-202 Amendment 6, January 7, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
7. TRIAL OBJECTIVES AND 
PURPOSE 
The  primary  objective  of  this  study  is  to 
determine  the  safety  and  efficacy  of  two  oral 
doses  of  Proellex  administered for  18  weeks to 
premenopausal  women  with  pelvic  pain in 
endometriosis confirmed  within  the  last  seven 
years  and  using  prescription  analgesics  for 
symptomatic pain. 
The  primary  objective  of  this  study  is  to  determine  the 
safety  and  efficacy  of  two  oral  doses  of  Proellex 
administered to  premenopausal  women  with  pelvic  pain 
associated  with  endometriosis  confirmed  within  the  last 
seven  years  and  using  prescription  analgesics  for 
symptomatic  pain.  Proellex  will  be  administered  
for  up 
to 3 cycles (18 or 16 weeks in duration), each separated 
by an Off-Drug Interval (ODI). 
Administrative 
 
 
 
 
 
Additional  on  drug  cycles 
added 
8. 
TRIAL DESIGN 
8.1 Study Endpoints 
 
See study endpoint changes in synopsis 
 
 
 
 
 
8.2 Study Design 
8.2.1  Overview of Study 
Design 
This study is a phase 2, 3-arm-study with an 
18 week active dosing period. 
 
 
 
 
The study will be conducted in 2 stages. 
 
Following  the  run-in  stage,  at  Visit  3,  90 
subjects  will  be  randomized  into  one  of  3 
arms in a 1-1-1 fashion. 
 
 
Once  the  18  week  active dosing  period  is 
completed,  subjects  will  be  followed  until 
menses  has returned (usually  within 35 days 
or  less).    The  follow-up  visit  should  be 
scheduled  after  blood  flow  has  stopped.  
During  the  follow-up  period  subjects  will 
continue  to  record  study  information  in  the 
electronic diary. 
This study is a phase 2, 3-arm-study with an 18 week active 
dosing period and  an  option  
for  
subjects  
(US  
sites  only) 
to  receive  2  additional 16-week cycles  of  active 
treatment  at their  randomized  dose  (6  mg  or  12 
mg/day).    Placebo  subjects  who  elect  additional 
treatment  will  receive  treatment  at  12  mg/day.    The 
treatment dose will remain double-blind.  The study will 
be conducted in 3 stages. 
 
For  stage  2, following  the  run-in stage,  at  Visit  3,  90 
subjects  will  be  
randomized  
into  one  of  3  arms  
in  a  1-1-1 
fashion. 
 
Once  the  18  week  active  dosing  period  is  completed, 
subjects will be followed until menses has returned (usually 
within  35  days  or  
less).  
 At  US  sites  only, subjects  may 
elect to receive up to 2 additional cycles of treatment at 
their  randomized  dose  (6  mg  or  12  mg/day),  placebo-
treated subjects will receive treatment at 12 mg/day.  In 
stage 3 all subjects will receive active treatment but the 
treatment  dose  will  remain  double-blind.  
  For  subjects 
who  do  not  choose  additional  treatment  cycles,  their 
final follow-up  visit  should  be  scheduled  after  blood  
flow 
has  stopped.    During  the  follow-up  period  subjects  will 
continue to record study information in the electronic diary. 
 
Additional on drug cycles 
added 
 
 
 
 
 
 
 
 
Administrative 
 
 
 
Additional  on  drug  cycles 
added 


Page 5 of 7 
ZPE-202 Amendment 6, January 7, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
8.2.1  Overview  of  Study 
Design (Cont) 
 
 
 
 
 
 
 
 
 
 
 
 
 
In  addition  
to  
the  diary  
information,  endometrial 
thickness will be recorded at screening and every 
month thereafter.  Assessment of trough levels of 
drug  will  be  determined  at  every  office  visit 
during the 18 week dosing period. 
Subjects who complete at least 28 days after visit 
3  and  wish  to exit  the  study due  to  lack  of 
efficacy  will  be  eligible  to enter  an open-label 
extension  study.  Subjects  who  discontinue  the 
study  prior  to  this  date  will  not  be  eligible  for 
enrollment in the extension study. 
For  stage  3,  subjects  who  are  eligible  to  receive 
additional cycles of treatment and who elect to continue 
treatment  will  be  scheduled  within  a  week  before  the 
next expected menses (+/- 2 days), following the off-drug 
interval.  
  Only  subjects  at  US  sites  will  be  eligible  for 
additional courses of treatment.  Subjects will receive 2 
cycles  of  treatment  separated  by  an  off-drug  interval 
(ODI),  after  which  they  will  be  followed  until  menses 
has returned.  During the follow-up period subjects will 
continue  to  record  study  information  in  the  electronic 
diary.  
  The  
final  
follow-up  visit  will  be  scheduled  after 
blood flow has stopped. 
 
In addition to the diary information, endometrial thickness 
will  be  recorded  at  screening  and  every  month  
thereafter.  
Assessment  of  
trough  
levels  of  drug  will  be  determined  at 
every office visit during the first 18 week dosing period. 
 
Subjects  who  complete  at  least  28  days  after  visit  3  and 
wish to discontinue treatment due to lack of efficacy will 
be  eligible  to start active treatment  (stage  3). Subjects 
who  discontinue  the  study  prior  to  this  date  will  not  be 
eligible for additional treatment. 
Additional on drug cycles 
added 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification 
 
 
 
 
 
Clarification 
8.2.3 Randomization  and 
Blinding 
All subjects  will  receive  placebo  from  Visit  1 
until  Visit  3.    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  18 weeks.    Blinded 
treatments kits will be randomized and distributed 
by the packaging company. 
All subjects will receive placebo from Visit 1 until Visit 3.  
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  18  weeks.   Subjects  who  elect  to 
receive  additional  treatment  cycles  will  be  treated  at 
their  previously  randomized  dose  level.    Subjects 
randomized to placebo treatment will receive treatment 
at  12  mg/day.    Each  18-week  treatment  cycle  will  be 
separated  by  an  ODI.   Blinded  treatments  kits  will  be 
randomized and distributed by the packaging company. 
Additional on drug cycles 
added 
S 
y 
o 
f 
to 
 
r 
o 
n 
n 


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ZPE-202 Amendment 6, January 7, 2014 
SECTION 
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y 
he 
y.   
o 
be 
e. 
).  
be 
S 
s. 
2 
t 
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n 
3 
it 
 
 
7 
 
 
 
 
12.2 
Prohibited 
Medications 
 
The  following  medications  are  prohibited  during  the 
study: 
• Testosterone 
• Progestin 
• Androgen 
• Estrogen 
• Anabolic steroids 
• DHEA 
• Other hormonal products 
New section added 
13.2 
Statistical  
and 
Analytical Plan 
 
 
 
13.2.2 Efficacy Analyses 
 
 
 
 
 
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. 
An  analysis  will  be  conducted  once  Stage  2,  the first 
cycle of treatment, has been completed.  A later analysis 
will  focus  on  the  data  collected  from  the active 
treatment stage of the study, Stage 3. 
 
Efficacy  analyses of  the cycle  of  treatment will be 
conducted  in  the  Intent-to-Treat  population,  which  will 
consist of all subjects who are randomized and who receive 
study drug. 
Amended to account for 
additional treatment cycles 
 
 
 
Clarification 
13.2.2.1 Prescription 
Analgesic Usage  
and 
13.2.2.2 Over the  Counter 
Analgesic Usage 
The  percent  change  in  daily  average  use  of 
prescription  analgesics  comparing  the  baseline 
menstrual cycle (28 days) to the 28 days leading 
up to the last day of dosing (Week 18), and  will 
be summarized for each treatment group. 
The change  and percent  change  in  daily  average  use  of 
prescription  analgesics  comparing  the  baseline  menstrual 
cycle (28 days) to the 28 days leading up to the last day of 
dosing in Cycle 1 (Week 18) will be summarized for each 
treatment group. 
 
Changes  in  prescription  analgesic  use  during  the active 
treatment stage  of  the  study (Stage  3) will  also  be 
summarized. 
Clarification 
 
 
 
 
 
Additional  on  drug  cycles 
added 
13.2.2.3 BBSS  Patient  and 
Physician Reported Scores 
AND  
The BBSS score incorporating the two physician-
reported  scores  will  be  analyzed  
to  compare  
the 
baseline  menstrual  cycle  to  a  similar  period 
The  percent  change  from  baseline  in  each  of  the  daily 
average  combined  BBSS  patient-reported  scores 
(dysmenorrhea, dyspareunia and non-menstrual pelvic pain) 
Clarification 
 
 


Page 7 of 7 
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13.2.2.4 
BBSS  
Patient 
Reported Scores 
leading up to the last day of dosing (Week 18). 
will be analyzed to compare the baseline menstrual cycle to 
a  similar  period  leading  up  to  the  last  day  of  dosing in 
Cycle 1 (Week 18). 
The  BBSS  patient  and  physician  scores  during  the 
active treatment stage of the study (Stage 3) will also be 
summarized. 
 
 
 
Additional  on  drug  cycles 
added 
13.2.2.5 Menstrual  or  Non-
menstrual Vaginal Bleeding 
 
 
Additional  on  drug  cycles 
added 
13.2.2.6 VAS  Assessment  of 
Pain 
 
The  VAS  pain  scores  collected  during  the active 
treatment  stage of  the  study (Stage  3) will  also  be 
summarized. 
Additional  on  drug  cycles 
added 
13.3 
General  Statistical 
Issues 
 
A  Statistical  Analysis  Plan  (SAP)  will  be  developed 
prior to the analyses of the first cycle of treatment.  Two 
analyses will be conducted.  The first analysis will occur 
when  all  subjects  have  completed  the first  cycle  of 
treatment (Week 18) and the second with be conducted 
once  all  subjects  have  completed  the  active  treatment 
stage of the study (Stage 3).  
Amended to account for 
additional on drug cycles 
e  1:  S
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s 
 
 
 
 
l 
or 
es 
 


Page 1 of 11 
ZPE-202 Amendment 7, March 12, 2014 
ZPE-202 Protocol Summary of Changes 
Protocol Title: 
A  Phase  2,  Multi-Center,  Three-Arm,  Parallel  Design,  Randomized,  Double-Blind  Study  
to  Evaluate  
the  Safety  and 
Efficacy  of  6  and  12  mg  Proellex® (Telapristone  Acetate)  Administered  Orally  
in  
the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Endometriosis 
Changes From:  
Protocol Amendment 6 dated January 7, 2014   
 To: Protocol Amendment 7 dated March 12, 2014 
Reason for Amendment:  Addition of up to 2 additional (optional) cycles of treatment 
Changes to Protocol: 
Significant changes to the protocol are listed below.  
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
SYNOPSIS: Study  Design 
and Duration Of Treatment 
Endometriosis pain, dysmenorrhea, non-
menstrual pelvic pain and dyspareunia (BBSS) as 
well as use of pain medications, vaginal bleeding 
intensity and alcohol use will be recorded using 
an electronic diary and Visual Analog Scale 
(VAS) pain assessment will be utilized. 
Endometriosis pain, dysmenorrhea, non-menstrual pelvic 
pain and dyspareunia (BBSS) as well as use of pain 
medications, vaginal bleeding intensity and alcohol use will 
be recorded using a daily electronic or paper diary. Daily 
subject ratings of dysmennorhea and non-menstrual 
pelvic pain will be captured using an 11-point numerical 
rating scale (NRS) and Visual Analog Scale (VAS) pain 
assessment will be utilized. 
Addition of paper diary 
for some/all sites 
 
Addition of NRS to study 
assessments 
SYNOPSIS: Number of 
Subjects 
Up to 90 female subjects, 30 per dose arm 
Up to 60 female subjects, 20 per dose arm. 
Change in sample size 
es 
g 
t 
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d.    
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s.  
o 
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or 
ol 
 
 
  
 
  
a 
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d.  
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s.  
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f 
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y 
ts  
 
 
 
 
y 
es 
n 
 
 
 
 
 
 
 


Page 2 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
 
 
 
, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SYNOPSIS 
Section 8.1 and  
Section 10.1 Study Endpoints 
• The  percent  change  from  baseline  
in  use  of 
prescription  analgesics  comparing  the 
baseline  nominal  28-day  menstrual  cycle 
(including  menstrual  event)  to  a  similar 
period leading up to Week 18, the last day of 
dosing of the first cycle of treatment 
• Change  in  daily  average  use  and  percent 
change  of  prescription  analgesics  from  the 
baseline  menstrual  cycle  to  the  matching 
period leading up to Week 18, the last day of 
dosing of the first cycle of treatment 
• Change  in daily  average  use  and  percent 
change  of  over  the  counter  analgesics  from 
the baseline  menstrual cycle to the  matching 
period leading up to Week 18, the last day of 
dosing  of  the  first  cycle  of  treatment, 
calculated  based  on  days  with  reported 
values. 
• Change  and  percent  change  in  BBSS  score 
incorporating  the  two  physician  reported 
scores by study visit and treatment cycle. 
• Change and percent change in the individual 
BBSS scores of the three patient reported 
outcomes (dysmenorrhea, dyspareunia and 
non-menstrual pelvic pain) by study visit and 
treatment cycle. 
• Change from baseline in pain assessed using 
a Visual Analog Scale (VAS) by study visit 
and treatment cycle. 
Primary Endpoint 
• Change and percent change in the individual BBSS 
scores of the three patient reported outcomes 
(dysmenorrhea, dyspareunia and non-menstrual pelvic 
pain) by study visit and treatment cycle. 
Secondary Endpoints 
• Change  in  daily  average  use  and  percent  change  of 
prescription  analgesics  from  the  baseline  menstrual 
cycle to the matching period leading up to Week 18, the 
last day of dosing of the first cycle of treatment. 
• Change in daily average use and percent change of over 
the counter analgesics from the baseline menstrual cycle 
to  
the  matching  period  
leading  up  
to  Week  18,  
the  
last 
day of  dosing  of  
the  
first  cycle  of  
treatment,  calculated 
based on days with reported values.  
• Change  in  daily  average  use  and  percent  change  of 
overall  analgesic  use,  prescription  and  over  the 
counter,  from  the  baseline  menstrual  cycle  to  the 
matching period leading up to Week 18, the last day 
of  dosing  of  the  first  cycle  of  treatment,  calculated 
based on days with reported values. 
• Change and percent change in BBSS score incorporating 
the  two  physician  reported  scores  by  study  visit  and 
treatment cycle. 
• Change  from  baseline  in  pain  assessed  using  a  Visual 
Analog Scale (VAS) by study visit and treatment cycle. 
• Change from baseline in daily average dysmenorrhea 
and  non-menstrual  pelvic  pain  using  an  11-point 
 
Endpoints  re-ordered  to 
reflect  possible  Phase  3 
study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
New endpoint added 
 
 
 
 
 
 
 
 
 
 
 
New endpoint added 
 


Page 3 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
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REASON FOR CHANGE 
numerical  rating  scale  (NRS)  by  study  visit  and 
treatment cycle.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
5. LIST OF 
ABBREVIATIONS 
 
Added: 
NRS  Numerical Rating Scale 
New study procedure 
8. 
TRIAL DESIGN 
8.2.1  Overview  of  Study 
design 
e 
a, 
l 
h 
d 
ta 
s 
d 
 
 
 
  
For stage 2, following the run-in stage, at Visit 3, 
690  subjects  will  be  randomized  into  one  of  3 
arms in a 1-1-1 fashion.   
 
Assessment  of  trough  levels  of  drug  will  be 
determined at every office visit during the first 18 
week dosing period. 
r 
or 
a, 
a 
er 
he  
r,  
ic  
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d  
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ms 
n 
 
l 
 
 
For stage 2, following the run-in stage, at Visit 3, 60 subjects 
will be randomized into one of 3 arms in a 1-1-1 fashion.   
 
Assessment  of  
trough  
levels  of  drug  will  be  determined  at 
every on-drug office visit. 
 
 
 
 
 
 
 
 
 
 
 
Change in sample size 
 
 
 
Clarification 
 


Page 4 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
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REASON FOR CHANGE 
8.2 Study Design 
8.2.3 Randomization and 
Blinding 
Subjects  randomized  to  placebo  treatment  will 
receive  treatment  at  12  mg/day.    Each  18-week 
treatment  cycle  will  be  separated  by  an  ODI.  
Blinded  treatments  kits  will  be  randomized  and 
distributed by the packaging company.   
Subjects  randomized  to  placebo treatment  will  receive 
treatment at 12 mg/day.  In stage 3 all subjects will receive 
active  treatment  but  the  treatment  dose  will  remain 
double-blind.   Each  18-week  treatment  cycle  will  be 
separated  by  an  ODI.    Blinded  treatments  kits  will  be 
randomized and distributed by the packaging company.   
For  the  statistical  analysis  at  Week  18,  only  statistical 
staff will be unblinded once the acute portion of the study 
database is locked.  All clinical operations staff and staff 
at investigative sites will remain blinded until completion 
of the study.   
 
Clarification 
 
 
 
 
 
Clarification 
8.2.4 Study Medication 
 
Statement added: 
Subjects will not be provided with analgesic medications 
by Repros Therapeutics Inc. 
 
Clarification 
8.3 
Selection  
and 
Withdrawal of Subjects 
• Any  subject  who  develops  an  endometrial 
thickness  ≥ 20 mm and experiences  heavy 
bleeding  for  7  days  or  more  will  be 
discontinued  from  the  study    Appropriate 
follow  up  treatment  will  be  provided  as 
deemed necessary by the investigator. 
• Any subject who develops an endometrial thickness ≥ 18 
mm  or  experiences suspicious  or  unusually heavy 
bleeding  for  7  days or more  will  be  discontinued  
from 
the  study and  undergo  endometrial  biopsy.  
  Women 
with such findings will not be eligible for extension of 
treatment.   Appropriate  follow  up  treatment  will  be 
provided as deemed necessary by the investigator. 
New study requirement 
8.3.2 Exclusion Criteria 
• Has  an  IUD  in  place.  Copper  IUDs  (non-
hormone containing) will be permitted 
• Has  an  IUD  in  place.  Copper  IUDs  (non-hormone 
containing)  will  be  permitted provided  subjects  agree 
to  keep  them  
in  place  for  the  duration  of  the  study 
(unless a medical need to remove it arises) 
New study requirement 
S 
1 
c 
d 
s 
nd 
e. 
r 
d 
of 
c 
d 
of 
 
 
    
y 
d 
n 
 
 


Page 5 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR CHANGE 
 
   
   
 
 
  
 
 
2 
 
 
e 
 
n 
e 
nt 
l 
d.    
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ill 
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be 
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e 
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Page 6 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
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, 
 
 
r 
 
e 
 
 
 
 
 
 
 
 
 
 
   
 
 
s 
 
  
e 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
5 
6 
7 
 
 
 
 
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e 
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Page 7 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
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REASON FOR CHANGE 
k 
3 
3 
). 
 
 
 
 
 
 
…. 
 
c 
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Page 8 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
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REASON FOR CHANGE 
1  
T  
F 
Y 
of 
e  
s,  
al  
s, 
 
s, 
s, 
 
e 
11.1.2 Definitions 
Serious Adverse Event (SAE) 
11.1.3 Serious Adverse Events 
(SAEs) 
 
Statement added: 
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. 
 
New safety requirement 
12  
CONCOMITANT 
MEDICATIONS 
12.1  Prescription  Analgesics 
Permitted During the Study 
• Acetaminophen/Hydrocodone: 1-2  tabs  every 
4-6 hours prn 
• Ibuprofen/Hydrocodone:  1-2  tabs  every  6-8 
hrs prn 
All  narcotic,  non-narcotic  and  over–the-counter 
medication  will  be  recorded  in  the  appropriate 
section of the CRF.  
• Acetaminophen/Hydrocodone: 5-10 mg/325 -750 mg, 1-2 
tabs every 4-6 hours prn 
• Ibuprofen/Hydrocodone: 7.5/200  mg,  1-2  
tabs  every  6-8 
hrs prn 
All  narcotic,  non-narcotic  and  over–the-counter  medication 
for  endometriosis-related  pain  will  be  captured  in  the 
subjects’ daily diary. 
All  narcotic,  non-narcotic  and over–the-counter 
medications  for  non-endometriosis-related  pain will  be 
recorded in the appropriate section of the CRF.  
Analgesic  medications  will  not  be  provided  by  Repros 
Therapeutics Inc. 
Clarification 
 
 
 
 
 
Clarification 
 
 
 
Clarification 
 
 
Clarification 
12.2 Prohibited Medications 
 
Statement added: 
• CYP3A4 inhibitors, e.g. atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin. 
New safety requirement 
added 
13.  
STATISTICAL 
METHODS 
13.1  Determination  of  Sample 
Size 
Up  to 90 female  subjects,  230  per  dose  arm, 
meeting  the  inclusion/exclusion  criteria  will  be 
randomized  in  a  1-1-1  fashion.   Although  the 
primary  analysis  for  each  endpoint  
in  this  study 
will  be  an  Analysis  of  Covariance, the  sample 
size was powered based on the two-sample t-tests 
that  will  be  used  
to  make  pairwise  comparisons 
between  
treatment  groups.  
  I
at 
a 
f 
l 
n 
 
Up to 60 female subjects, 20 per dose arm, meeting the 
inclusion/exclusion criteria will be randomized in a 1-1-1 
fashion.  The sample size was powered based on the two-
sample t-test that will be used to make pairwise comparisons 
between treatment groups. 
 
 
    
Change in sample size 
and justification 
 
 
 
 
 


Page 9 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
CHANGED FROM 
CHANGED TO 
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29 
to 
se 
n 
l.  
 
d 
%.   
 
 
 
 
  
e 
ed 
a 
r 
 
a sample of 18 subjects per group would provide 
80% power to detect a statistically significant difference 
between the treatment groups.   
13.2  Statistical  and  Analytical 
Plan 
 
New statement added: 
A  statistical  analysis  will  be  conducted  once  all  subjects 
have  completed  the  placebo-controlled  portion  of  the 
study, Stages 1 and 2.  A Statistical Analysis Plan will be 
developed  that  outlines  in  detail  all  planned  analyses.  
This  document  will  be  completed  prior  to  unblinding 
study  data  for  the  placebo-controlled  portion  of  the 
study.   
A  separate  analysis  and  reporting  will  occur  once  all 
subjects have completed all study treatment.  A separate 
Statistical  Analysis  Plan  will  describe  these  analyses.  
This  summary  will  
focus  on  
the  results  noted  
in  Stage  3 
of the study. 
 
Clarification 
13.2.2 Efficacy Analyses 
13.2.2.3  Overall  Analgesic 
Use 
 
The change and percent change in daily average use of all 
analgesics (prescription and over the counter) comparing 
the  baseline  menstrual  cycle  (28  days)  to  the  28  days 
leading up to the last day of dosing in Cycle 1 (Week 18) 
will be summarized for each treatment group.  For each 
subject, the total number of pills or tablets of analgesics 
taken  during  each  28  day  menstrual  cycle  will  be 
calculated,  and  the  daily  average  use  of  prescription 
analgesics  will  be  determined  by  dividing  the  total 
number of pills/tablets of analgesics taken during the 28 
day  nominal  period  by  28.    The  percent  change  from 
baseline  in  the  analgesic  usage  will  be  determined  by 
subtracting  the  baseline  analgesic  usage  from  the 
New endpoint added 


Page 10 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
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analgesic usage during the last nominal 28 day menstrual 
cycle,  dividing  by  the  baseline  analgesic  usage,  and 
multiplying by 100%. 
An  overall  comparison  among  the  3  treatment  groups 
will  be  performed  using  a  one-way  Analysis  of 
Covariance,  including  the  baseline  analgesic  usage  and 
treatment  group  
in  
the  model.  
  Pairwise  comparisons  of 
the treatment groups will be made using a two-sample t-
test.  While the primary assessment will be based on Visit 
12  
(after  18  weeks  of  
treatment)  summaries  will  also  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. 
Changes  in  analgesic  use  during  the  active  treatment 
stage of the study (Stage 3) will also be summarized. 
13.2.2.1 Prescription 
Analgesic Usage  
and 
13.2.2.2 Over  the  Counter 
Analgesic Usage 
The  percent  change  in  daily  average  use  of 
prescription  analgesics  comparing  the  baseline 
menstrual cycle (28 days) to the 28 days leading 
up to the last day of dosing (Week 18), and  will 
be summarized for each treatment group. 
The change  and percent  change  in  daily  average  use  of 
prescription  analgesics  comparing  the  baseline  menstrual 
cycle (28 days) to the 28 days leading up to the last day of 
dosing in  Cycle  1 (Week  18)  will  be summarized  for  each 
treatment group. 
 
Changes  in  prescription  analgesic  use  during  the active 
treatment stage  of  the  study (Stage  3) will  also  be 
summarized. 
Clarification 
 
 
 
 
 
Clarification 
13.2.2.8  Assessment  of  Pain 
Using the NRS 
 
New statement added: 
The  average  daily  assessment  will  be  calculated 
separately for dysmenorrhea and pelvic pain within each 
key  28-day  baseline  and  treatment  periods.    The 
percentage change from baseline NRS pain score will be 
analyzed within treatment group and between treatment 
groups.    An overall comparison among the 3 treatment 
groups  will  be  performed  using  a  one-way  Analysis  of 
Variance.  Pairwise comparisons of the treatment groups 
will  be  made  using  t-test  or  non-parametric  test  as 
appropriate.  While the primary assessment will be based 
on scores during the 28-day period prior to Visit 12 (after 
18 weeks of treatment), summaries will also be prepared 
for each of the other visits.   
 
New endpoint added 


Page 11 of 11 
ZPE-202 Amendment 7, March 12, 2014 
SECTION 
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The  average  daily  assessment  of  dysmenorrhea  and 
pelvic  pain  scores  collected  during the  active  treatment 
stage of the study (Stage 3) will also be summarized. 
2 
 
d 
d  to  
c
t 
n  
d e 
on 
3 
 
d 
y 
es 
6 
 
d 
e 
7 
 
 
 
 


Page 1 of 5 
ZPE-202 Amendment 8US, March 31, 2015 
ZPE-202 Protocol Summary of Changes 
Protocol Title: 
A  Phase  2,  Multi-Center,  Three-Arm,  Parallel  Design,  Randomized,  Double-Blind  Study  
to  Evaluate  
the  Safety  and 
Efficacy  of  6  and  12  mg  Proellex® (Telapristone  Acetate)  Administered  Orally  
in  
the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Endometriosis 
Changes From:  
Protocol Amendment 7 dated March 12, 2014   
 To: Protocol Amendment 8US dated March 31, 2015 
Reason for Amendment:  Run in period changed from placebo to no treatment 
Changes to Protocol: 
Significant changes to the protocol are listed below.  
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR 
CHANGE 
Throughout document 
References to “US sites only” have been removed as the protocol is now only for US sites 
References to an electronic diary have been deleted as the study is now using only paper diaries 
 
 
SYNOPSIS: Study  Design 
and Duration Of Treatment 
In the first stage, women will receive daily single 
blind dosing with placebo prior to enrollment, 
until their second ovulation event. 
 
In the second stage, following the placebo run-in 
phase 
 
In the third stage, subjects (US only) who are 
eligible to receive additional cycles of treatment 
and who elect to continue treatment will be 
scheduled within a week before the second 
expected menses (+/- 2 days), following the off-
drug interval).  Subjects will receive 2 cycles of 
additional treatment separated by an off-drug 
interval (ODI), after which they will be followed 
until menses has returned.  
In the first stage, women will undergo a baseline 
assessment period with no treatment, 
until their second 
ovulation event. 
 
In the second stage, following the baseline assessment 
period, 
 
In the third stage, subjects who are eligible to receive 
additional cycles of treatment and who elect to continue 
treatment will be scheduled to start dosing in their next 
course 21 days  (+/- 2 days) after the start of bleeding, 
following the first menses after end of their first course of 
treatment (off-drug interval).  Subjects will receive 2 
courses of additional treatment separated by an off-drug 
interval (ODI), after which they will be followed until 
menses has returned.   
Change in study design 
 
 
 
Change in study design 
 
 
Change in study design 
 
 
 
 
 
 
 
 
 
Establishment of DSMB 
for all Proellex studies 


Page 2 of 5 
ZPE-202 Amendment 8US, March 31, 2015 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR 
CHANGE 
 
 
 
 
 
 
 
 
Change in study design 
 
 
Clarification 
 
 
 
 
6. BACKGROUND 
INFORMATION 
6.6 DSMB 
 
 
 
 
 
 
 
 
 
 
 
8. 
TRIAL DESIGN 
8.2.1  Overview of  Study 
design 
The  study  will  be  conducted  
in  3  stages.  
  
In  
the 
first  stage,  women  will receive  a  daily  single 
blind placebo 
 
The daily number of doses 
 
For stage 2, following the run in stage 
 
Once  the  18  week  active  dosing  period  is 
completed, subjects will be followed until menses 
has returned (usually within 35 days or less).   
 
For  subjects  who  do  not  choose  additional 
treatment cycles, their final follow-up visit should 
be scheduled after blood flow has stopped. 
 
For  stage  3,  subjects  who  are  eligible  
to  receive 
additional  cycles  of  treatment  and  who  elect  to 
continue  treatment  will  be  scheduled  within  a 
week  before  the  second  expected  menses  (+/- 2 
days),  following  the  off-drug  interval. Only 
subjects at US sites will be eligible for additional 
The  study  will  be  conducted  
in  3  stages.  
  
In  
the  
first  stage, 
women will undergo a baseline assessment period with no 
treatment.  
 
The daily number of doses and dosages 
 
For stage 2, following the baseline assessment period, 
 
Once  the  18  week  active  dosing  period  is  completed, 
subjects will be followed until menses has returned (usually 
within 21 days or less).   
 
For subjects who do not choose additional treatment cycles, 
this will be their final follow-up visit  
 
 
For stage 3, subjects who are eligible to receive additional 
cycles of treatment and who elect to continue treatment will 
be scheduled at 21 ± 2 days after start of bleeding in their 
first menses after Visit 12 (recovery menses).  
 
 
Change in study design 
 
 
 
Clarification 
 
 
 
Correction 
 
 
 
Clarification 
 
 
 
 
Correction 
 
 
 
 


Page 3 of 5 
ZPE-202 Amendment 8US, March 31, 2015 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR 
CHANGE 
courses of treatment. 
it 
st 
he 
at 
er 
he 
ts 
ut 
 
 
f 
nt 
or 
e 
of 
of 
g 
s). 
 
 
Correction 
 
8.2 Study Design 
8.2.3 Randomization and 
Blinding 
All  subjects  will  receive placebo treatment  from 
Visit 1 until Visit 3 
All subjects will receive no treatment from Visit 1 until Visit 
3 
Change in study design 
8.3  Selection  and  Withdrawal 
of Subjects 
 
 
• The decision to withdraw from the study because of an 
adverse  event,  including  pain  from  endometriosis  or 
from another condition, is decided by the subject and 
the investigator or her personal physician.   The event, 
and  any  treatment  should  be  recorded  in  the  study 
records. 
Clarification 
8.3.2 Exclusion Criteria 
• Has  an  IUD  in  place.   Copper  IUDs  (non 
hormone  containing)  will  be  permitted 
provided subjects agree to keep them in place 
for the duration of the study (unless a medical 
need arises to remove it). 
• Has an IUD in place.   
• Previous  use  of  
telapristone  acetate  or  participation  
in  a 
Repros clinical study 
Additional safety criterion 
 
Clarification 
 
 
 
e 
 
 
 
 
 
r 
y 
 
 
 
 
 
 
 
 
 
 
 


Page 4 of 5 
ZPE-202 Amendment 8US, March 31, 2015 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR 
CHANGE 
 
 
e  
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
r 
 
y 
 
 
 
 
 
   
 
l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 


Page 5 of 5 
ZPE-202 Amendment 8US, March 31, 2015 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON FOR 
CHANGE 
7 
8 
k 
s) 
y 
es at 
of 
t.  
n 
8 
 a 
t 
). 
he 
17 
n 
2 
c 
ut 
d. 
r 
t 
t. 
n 
3 
d 
 
r 
 
 
12  
CONCOMITANT 
MEDICATIONS 
12.1  Prescription  Analgesics 
Permitted During the Study 
 
12.1.1 
Treatment of Endometriosis-Related Pain 
 
12.1.2 
Treatment of Non-Endometriosis–Related Pain 
If  the  subject  experiences  pain  (not  related  to 
endometriosis),  she  should  be  treated  as 
medically appropriate.  The choice of drug will 
depend  on  the  medical  condition.    Dosage 
forms and route of administration should be as 
per product specifications.  
Formatting changed for 
clarity 
 
 
 
Clarification 
12.2 Prohibited Medications 
 
• St. John’s Wort 
• Spironolactone 
• Cimetidine 
Additional prohibited 
medications added 
13.  
STATISTICAL 
METHODS 
13.2 SAP 
A  statistical  analysis  will  be  conducted  once  all 
subjects  have completed  the  placebo-controlled 
portion of the study, Stages 1 and 2 
A  statistical  analysis  will  be  conducted  once  all  subjects 
have completed the placebo-controlled portion of the study, 
Stage 2 
Change in study design 
X 
4.  
A 
G 
2 
e 
ne 
n 
y 
n 
X 
6 
L  
Y 
W 
s 
X 
7 
L  
 
d 
 


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Repros Therapeutics Inc. 
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
Page 2 of 66 
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 
...................................................................... 16 
6.4 
SAFETY DATA 
............................................................................................................ 17 
6.5 
ETHICAL CONDUCT OF THE STUDY 
............................................................................ 19 
6.6 
DRUG SAFETY MONITORING BOARD (DSMB) 
.......................................................... 19 
7. TRIAL OBJECTIVES AND PURPOSE 
............................................................................ 20 
8. TRIAL DESIGN ................................................................................................................... 21 
8.1 
STUDY ENDPOINTS 
..................................................................................................... 21 
8.2 
STUDY DESIGN 
........................................................................................................... 22 
8.2.1 
Overview of Study Design 
....................................................................................... 22 
8.2.2 
Study Drug Accountability 
...................................................................................... 23 
8.2.3 
Randomization and Blinding 
................................................................................... 23 
8.2.4 
Study Medication 
..................................................................................................... 24 
8.3 
SELECTION AND WITHDRAWAL OF SUBJECTS 
........................................................... 24 
8.3.1 
Inclusion Criteria 
..................................................................................................... 25 
8.3.2 
Exclusion Criteria 
.................................................................................................... 26 
9. STUDY PROCEDURES ...................................................................................................... 28 
1 
8 
2 
9 
3 
9 
4 
29 
5 
E 
E 
E TO 
K F 
30 
6 
D F 
E F 
30 
7 
T F 
30 
8 
1 
9 
1 
0 
2 
1 
D F 
2 
2 
T F 
3 
3 
3 
4 
4 
5 
4 
6 
D F 
4 
7 
35 
 
5 
10. ASSESSMENT OF EFFICACY 
.......................................................................................... 37 
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March 31, 2015 
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Page 3 of 66 
10.1 STUDY ENDPOINTS 
..................................................................................................... 37 
 
7 
11. ASSESSMENT OF SAFETY 
............................................................................................... 38 
11.1 ADVERSE EVENTS 
...................................................................................................... 38 
11.1.1 
Reporting Adverse Experiences 
...................................................................... 38 
11.1.2 
Definitions 
....................................................................................................... 38 
11.1.3 
Serious Adverse Events (SAEs) 
...................................................................... 39 
12. CONCOMITANT MEDICATIONS 
................................................................................... 41 
12.1 PRESCRIPTION ANALGESICS PERMITTED DURING THE STUDY 
.................................. 41 
12.2 PROHIBITED MEDICATIONS 
........................................................................................ 41 
12.3 OTHER MEDICATIONS TAKEN DURING THE STUDY .................................................. 42 
13. STATISTICAL METHODS 
................................................................................................ 43 
13.1 DETERMINATION OF SAMPLE SIZE 
............................................................................. 43 
13.2 STATISTICAL AND ANALYTICAL PLAN 
...................................................................... 43 
13.3 GENERAL STATISTICAL I
SSUES 
.................................................................................. 48 
14. ETHICS ................................................................................................................................. 49 
14.1 SUBJECT I
NFORMATION AND CONSENT 
..................................................................... 49 
14.2 I
NSTITUTIONAL REVIEW BOARD 
................................................................................ 49 
14.3 MONITORING CASE REPORT FORMS 
.......................................................................... 49 
14.4 STUDY RECORD RETENTION 
...................................................................................... 49 
14.5 DATA QUALITY ASSURANCE 
..................................................................................... 49 
14.6 CONFIDENTIALITY...................................................................................................... 50 
14.7 PUBLICATIONS ........................................................................................................... 50 
15. INVESTIGATOR'S STATEMENT 
.................................................................................... 51 
 
2 
 
3 
 
5 
 
7 
 
3 
 
4 
 
5 
 
 
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March 31, 2015 
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Page 4 of 66 
3. 
PROTOCOL SYNOPSIS 
 
Test Drugs: 
Proellex® (Telapristone  Acetate):  6  and  12  mg  gelatin  capsules  and 
matching placebo 
Protocol Number: 
ZPE-202  
Study Purpose: 
To  determine  the  safety  and  efficacy  of  two  doses  of  Proellex  in 
premenopausal  women  with pelvic  pain associated  with 
endometriosis confirmed  within  the  last seven years  and  using 
prescription analgesics for symptomatic pain. 
Study  Design  and 
Duration 
Of Treatment: 
This study is a phase 2, 3-arm-study with an 18  week active dosing 
period and an option to extend treatment for 2 additional cycles.  The 
study will be conducted in three stages.   
In the first stage, women will undergo  a  baseline  assessment  period 
with no treatment until their second ovulation event.  Endometriosis 
pain,  dysmenorrhea,  non-menstrual  pelvic  pain  and  dyspareunia 
(BBSS) as well as use of pain medications, vaginal bleeding intensity 
and  alcohol  use will  be  recorded  using  a daily diary.  Daily  subject 
ratings  of dysmenorrhea and  non-menstrual  pelvic pain  will  be 
captured using an 11-point numerical rating scale (NRS) and Visual 
Analog Scale (VAS) pain assessment will be utilized.   
In  the  second  stage,  following  the baseline  assessment  period, 
subjects  will  be  randomized  
into  one  of 3 arms  
in  a  1-1-1  fashion.  
The start of the 18 week dosing period for the first cycle of treatment 
should  commence  as  soon  after  ovulation  as  possible,  after  which 
subjects will be followed until menses returns.  Subjects who do not 
wish to receive additional cycles of treatment after stage 2 will have 
their  
last  visit  scheduled  after  blood  
flow  has  stopped.  
  During  
this 
off-drug  
interval;  subjects  will  continue  
to  
record  study  
information 
in the daily diaries. 
After completing a minimum of 28 days of treatment in this stage of 
the study, subjects may discontinue the study and still be eligible to 
qualify for up to 2 additional treatment cycles.     
In  the  third  stage,  subjects who  are  eligible to  receive  additional 
cycles  of  treatment  and  who  elect  to  continue  treatment will  be 
scheduled to  start  dosing  
in  
their  next  course 21  days (+/- 2  days) 
after the start of bleeding, following the first menses after end of their 
first  course  of  
treatment  
(off-drug  
interval).  Subjects will receive 2 
courses of additional treatment  separated  by  an  off-drug  interval 
(ODI),  after  which  
they  will  be  
followed  until  menses  has  
returned.  
During  
the  follow-up  period  subjects  will  continue  
to  record  study 
information  in  the daily diary.    The  final  follow-up  visit  will  be 
scheduled after blood flow has stopped.  
w 
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March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
Page 5 of 66 
 
 
 
 
 
Subject Population: 
The  study  will  enroll  healthy  adult,  non-obese  pre-menopausal 
women  with surgically confirmed  endometriosis  using  prescription 
analgesics for their endometriosis pain. 
Number of Subjects: Up to 60 female subjects, 20 per dose arm (US and Argentina) 
Number of Sites 
Approximately 10-20 sites  
Study Duration:  
Total participation in the study is approximately 18 months. 
s:  
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.   
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ill 
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d. 
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al 
l 
 
 
 
 
 
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March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
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Study Endpoints 
The study endpoints will be: 
Primary Endpoint 
• Change and percent change in the individual BBSS scores of the 
three patient reported outcomes (dysmenorrhea, dyspareunia and 
non-menstrual pelvic pain) by study visit and treatment cycle. 
Secondary Endpoints 
• Change  
in daily average  use  and percent  change  of  prescription 
analgesics from  the  baseline  menstrual  cycle  to the  matching 
period leading up to Week 18, the last day of dosing of the first 
cycle of treatment. 
• Change  in  daily  average  use  and  percent  change  of  over  the 
counter  analgesics  from  the  baseline  menstrual  cycle  to  the 
matching period leading up to Week 18, the last day of dosing of 
the  first  cycle  of  treatment,  calculated  based  on  days  with 
reported values.  
• Change  in  daily  average  use  and  percent  change  of  overall 
analgesic use, prescription and over the counter, from the baseline 
menstrual  cycle  
to  
the  matching  period  
leading  up  
to  Week  18, 
the last day of dosing of the first cycle of treatment, calculated based 
on days with reported values. 
• Change and percent change in BBSS score incorporating the two 
physician reported scores by study visit and treatment cycle. 
• Change  from  baseline  in  pain  assessed  using  a  Visual  Analog 
Scale (VAS) by study visit and treatment cycle. 
• Change  from  baseline  in daily average dysmenorrhea  and  non-
menstrual  pelvic  pain  using  an  11-point  numerical  rating  scale 
(NRS) by study visit and treatment cycle. 
e: 
• 
s 
• 
s 
• 
of 
e 
• 
e 
• 
g 
• 
s 
• 
y 
• 
g 
h 
I  
 
 
Statistical Methods: A  Statistical  Analysis  Plan  (SAP)  will  be  developed  prior  to 
unblinding  of  the  data  that  will  outline  all  planned  analyses  and 
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Repros Therapeutics Inc. 
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
Page 7 of 66 
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 
and follow-up. 
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.  
Summaries  will  be  prepared  for  each  treatment  group  of  subject 
accountability, baseline demographic, and medical history data.  
Continuous  efficacy  endpoints,  such  as  
the  percentage  change  
from 
baseline  
in  
the  use  of  prescription  analgesics, will  assess  
treatment 
effect  using an  Analysis  of  Covariance,  including  the  baseline 
prescription analgesic  usage  and  treatment  in  the  model.  
 Pairwise 
comparisons  between  treatment  groups  will  be  made  using  a  two-
sample  t-test.   Other  continuous efficacy  variables  will  be  treated 
similarly.  
s 
of 
al  
s,  
s,  
ne 
g 
s.    
he 
ne 
m 
 
   
 
 
 
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Repros Therapeutics Inc. 
 
  
  
  
  
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
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Repros Therapeutics Inc. 
 
  
  
  
  
  
 
March 31, 2015 
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Repros Therapeutics Inc. 
 
March 31, 2015 
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Repros Therapeutics Inc. 
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
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Repros Therapeutics Inc. 
 
  
  
  
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
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Repros Therapeutics Inc. 
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
5. 
LIST OF ABBREVIATIONS 
 
AE    
Adverse event 
BBSS    
Biberoglu Behrman symptom severity scale 
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 
m  
  
Meters 
mg    
Milligram(s) 
mL    
Milliliter 
ng    
Nanograms 
NRS   
Numerical Rating Scale 
ODI   
Off-Drug Interval 
PCOS    
Polycystic Ovarian Syndrome 
PK    
Pharmacokinetic 
RBC    
Red blood cell 
SAE    
Serious adverse event 
VAS   
Visual Analog Scale 
WBC    
White blood cell 
 
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Repros Therapeutics Inc. 
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
Page 14 of 66 
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.  Most notably the sponsor 
has seen significant clinically relevant impact on the symptoms of both uterine 
fibroids and endometriosis. 
of 
so 
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n 
r.  
ed 
ee 
d 
d 
o.  
is 
s.  
y 
as 
s. 
f 
s 
as 
s 
nt 
d.   
s 
e.  
y 
ug 
t.  
ut 
n 
of 
e 
. 
al 
or 
en 
3 
 
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Repros Therapeutics Inc. 
 
March 31, 2015 
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s 
n 
 
 
 
 
  
2 
a 
n 
i-
s.  
d 
er 
es 
t 
g.  
of 
e 
s. 
d 
of 
al 
s.  
 4 
. 
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is 
e 
c 
he 
ys 
a 
d 
ge 
th 
s.  
-
of 
 a 
of 
 
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Repros Therapeutics Inc. 
 
March 31, 2015 
Protocol ZPE-202, Amendment 8US 
 
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f 
3 
e 
d 
n 
d 
g) 
th 
o 
  
 
Overall,  
findings  were  
favorable  
to  
the  Proellex  
treatments,  
in  particular  
the 
.  
y.   
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hr.  
ll 
e 
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s 
p.  
p 
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s.  
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as 
y. 
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se 
 
e 
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se 
er 
to 
d 
 
 
4  
a 
ly 
ed 
hs 
ct 
o 
n 
at 
e 
s 
or 
: 
 
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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March 31, 2015 
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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.  
  The  Institutional  Review  Board  (IRB)  for  this  study  is 
IntegReview, 3001 S. Lamar Blvd., Suite 210, Austin, Texas 78704.  
  
 
 
 
 
 
 
 
 
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7. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to determine the safety and efficacy of two oral 
doses of Proellex administered to premenopausal women with pelvic pain associated 
with endometriosis  confirmed  within  the  last seven years  and  using prescription 
analgesics for symptomatic pain.  Proellex will be administered for up to 3 cycles (18 
or 16 weeks in duration), each separated by an Off-Drug Interval (ODI).  
 
 
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Page 21 of 66 
8. 
TRIAL DESIGN 
8.1 
Study Endpoints 
Primary Endpoint 
• Change and  percent  change in  the  individual BBSS scores  of  the  three 
patient reported outcomes (dysmenorrhea, dyspareunia and non-menstrual 
pelvic pain) by study visit and treatment cycle 
Secondary Endpoints 
• Change in daily average use and percent change of prescription analgesics 
from the  baseline  menstrual  cycle  to  the  matching period  
leading  up  
to 
Week 18, the last day of dosing of the first cycle of treatment. 
• Change  in  daily  average  use  and  percent  change  of  over  the  counter 
analgesics  from  the  baseline  menstrual  cycle  to  the  matching  period 
leading up to Week 18, the last day of dosing of the first cycle of treatment, 
calculated based on days with reported values.  
• Change in daily average use and percent change of overall analgesic use, 
prescription and over the counter,  from the baseline menstrual cycle to the 
matching period leading up to Week 18, the last day of dosing of the first 
cycle of treatment, calculated based on days with reported values. 
• Change and  percent  change in  BBSS  score  incorporating  the  two 
physician-reported scores by study visit and treatment cycle. 
• Change and  percent  change in  the  individual BBSS scores  of  the  three 
patient reported outcomes (dysmenorrhea, dyspareunia and non-menstrual 
pelvic pain) by study visit and treatment cycle. 
• Change from baseline in pain assessed using a Visual Analog Scale (VAS) 
by study visit and treatment cycle. 
• Change  
from  baseline  
in  daily  average dysmenorrhea  and  non-menstrual 
pelvic pain using an 11-point numerical rating scale (NRS) by study visit 
and treatment cycle. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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a 
 
 
8.2 
Study Design 
8.2.1  Overview of Study Design 
This  study  
is  a  phase 2, 3-arm-study  with  an  18  week active  dosing 
period and  an  option  for  subjects to  receive  2  additional 16-week 
cycles  of  active  treatment  at  their  randomized  dose  (6  mg  or  12 
mg/day).  Placebo subjects who elect additional treatment will receive 
treatment at 12 mg/day.  The treatment dose will remain double-blind.  
The study will be conducted in 3 stages.  In the first stage, women will 
undergo  a  baseline  assessment  period with  no  
treatment.  
 This  stage 
will last as long as it takes to record at least one full menstrual cycle 
(ovulation until ovulation).  
Subjects  will  be  provided  with  a daily  diary  with  which  to  record 
patient  reported  scores  for  
the  
three  elements  of endometriosis  pain: 
dysmenorrhea,  non-menstrual  pelvic  pain  and  dyspareunia  (BBSS).  
of 
cs 
n 
n-
 
   
For  stage  2,  following  
the baseline  assessment  period, at  Visit  3, 60 
subjects will be randomized into one of 3 arms in a 1-1-1 fashion.  The 
start  of  dosing  should  commence  as  soon  as  possible  after  ovulation 
following the end of the previous menstrual event.    
Once the 18 week active dosing period is completed, subjects will be 
followed  until  menses  has  returned  (usually  within 21 days  or  
less).  
Subjects may elect to receive up to 2 additional cycles of treatment at 
their  
randomized  dose  
(6  mg  or  12  mg/day),  placebo-treated  subjects 
will receive treatment at 12 mg/day.  In stage 3 all subjects will receive 
active treatment but the treatment dose will remain double-blind.  For 
subjects  who  do  not  choose  additional  
treatment  cycles,  
this  will  be 
their  
final  
follow-up  visit.  
  During  
the  
follow-up  period  subjects  will 
continue to record study information in the daily diary.   
For  stage  3,  subjects  who  are  eligible  
to  
receive  additional  cycles  of 
treatment and who elect to continue treatment will be scheduled at 21 
±  2 days  after  start  of  bleeding in  their  first  menses  after  Visit  12 
(recovery  menses).  Subjects  will  receive  2  cycles  of  treatment 
separated  by  an  off-drug  interval  (ODI),  after  which  they  will  be 
followed  until  menses  has  returned.    During  the  follow-up  period 
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subjects  will  continue  
to  
record  study  
information  
in  
the daily  diary.  
The  final  follow-up  visit  will  be  scheduled  after  blood  flow  has 
stopped. 
 
 
 
e 
e 
 2 
nd 
 
e 
 
Subjects who  complete at  least  28  days  after Visit  3  and  wish  to 
discontinue  
treatment due  
to  
lack  of  efficacy will be  eligible  
to start 
active treatment (stage 3).  Subjects who discontinue the study prior to 
this date will not be eligible for additional treatment. 
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,  or 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 
All  subjects will  
receive  no  
treatment  
from Visit  1  until  Visit 3.  
 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 18  weeks.  
Subjects  who  elect  to  receive  additional  treatment  cycles  will  be 
treated  at  their  previously  randomized  dose  level.    Subjects 
randomized to placebo treatment will receive treatment at 12 mg/day.  
In  stage  3  all  subjects  will  
receive  active  
treatment  but  
the  
treatment 
dose will remain double-blind.  Each treatment cycle will be separated 
by an ODI.  Blinded treatments kits will be randomized and distributed 
by the packaging company.   
For  the  statistical  analysis  at  Week  18,  only  statistical  staff  will  be 
unblinded once the acute portion of the study database is locked.  All 
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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 
  and  will  be 
packaged by a clinical supplies contract vendor designated by Repros 
Therapeutics  Inc.    The  placebo 
 
  and  will  be  packaged  by  the  same  clinical  supplies  contract 
vendor.    Active  and  matching  placebo  capsules  will  be  bottled  in 
identical  packaging.  Each  bottle  will  have  a  
label  containing  bottle 
number,  number  of  capsules,  expiration  date, a  statement  “Caution: 
New Drug – Limited by Federal Law (US) to Investigational use” and 
instructions  
to  
take  1  capsule  daily  
in  
the  morning  before  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.  
  
 
 
 
Subjects  will  not  be  provided  with  analgesic  medications  by  Repros 
Therapeutics Inc. 
8.3 
Selection and Withdrawal of Subjects 
Subjects for the study will be selected during screening based on the inclusion 
and exclusion criteria and clinical assessments listed below.  Subjects will be 
discontinued from the study prematurely if: 
• Unacceptable  adverse  events occur considered  by  the  investigator  to  be 
associated with use of the study drug  
• The subject requests to be withdrawn from the study 
• 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  and/or 
eosinophilia (>5%) 
• A need arises for concomitant medication prohibited by the protocol  
• The Principal Investigator decides that it is in the subject’s best interest 
• The subject is noncompliant with the protocol 
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• Any  subject  who develops  an  endometrial  thickness  ≥  18 mm or 
experiences suspicious  or  unusually  heavy bleeding  for  7  days  or  more 
will  be  discontinued  from  the  study and  undergo  endometrial  biopsy.  
Women with such findings will not be eligible for extension of treatment.  
Appropriate follow up treatment will be provided as deemed necessary by 
the investigator. 
• The  decision  to  withdraw from  the  study  because  of  an  adverse  event, 
including  pain  
from  endometriosis  or  
from  another  condition,  
is  decided 
by the subject and the investigator or her personal physician.   The event, 
and any treatment should be recorded in the study records. 
 
8.3.1 Inclusion Criteria 
Subjects must meet the following criteria: 
• Healthy adult females between 18 and 47  years of age (inclusive) 
prescribed prescription  analgesics (see section  12.1) for 
endometriosis  pain  and  with  a  BBSS  score  ≥7 at  screening 
(assessed over the previous 28 days
 
e 
 
• Endometriosis  diagnosis must  have  been  surgically  confirmed 
within 7 years.  A laparoscopic diagnosis is acceptable. 
• Subjects must have a history of at least 3 regular menstrual cycles 
in which symptoms of endometriosis occurred immediately prior to 
screening 
• Normal  or  abnormal  but  non-clinically  significant  transvaginal 
ultrasound 
• History of menstrual events occurring in regular cycles 
• Agreement not to attempt to become pregnant during the trial 
• Agreement to limit alcohol consumption to no more than 2 drinks 
per week and to avoid alcohol consumption within 48 hours before 
each visit 
• Ability  
to  complete  a  daily subject  diary  and  study  procedures  
in 
compliance with the protocol 
• Women  of  child-bearing  potential  must  be  willing  
to  use  double-
barrier  contraception  during  the  study  and  for  30  days  after 
discontinuation  of  study  medication.    Acceptable  double-barrier 
methods  are:  male  condom  with  spermicide;  male  condom  with 
diaphragm; diaphragm containing spermicide plus additional intra-
vaginal spermicide 
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• Has a negative pregnancy test at the Screening and Baseline visits, 
and subsequent study visits 
• A Body Mass Index (BMI) between 18 and 39 inclusive 
• 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 participation in the study 
•  Subjects with  abnormally  high  liver  enzymes  or  liver  disease. 
(ALT  or AST  exceeding 2 x  ULN AND total bilirubin exceeding 
1.5xULN at screening and confirmed on repeat). 
• 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 
prior to screening and during the study. 
• 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 after the period of duration of the Lupron dose). 
• Has an IUD in place. 
• Presence of intramural fibroids that impact the endometrial stripe, 
submucosal fibroids (any size), or endometrial polyps.  Subserosal 
and  
intramural  fibroids  with  no  
impact  on  
the  endometrial  stripe 
are acceptable. 
• Presence of endometrioma(s) 
• Present history or condition that causes non-endometriosis related 
dyspareunia (e.g. vulvar vestibulitis). 
• Past  or  present  history  of  thrombophlebitis  or  thromboembolic 
disorders. 
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• Known  or  suspected  carcinoma  of  the  breast  or  reproductive 
organs. 
• Known  history  of  abnormal  ECG  that,  in  the  opinion  of  the 
investigator,  is  clinically  significant  and  will  prevent  the  subject 
from  completing  
the  study,  
including  a  QTc  of  greater  
than  450 
ms. 
• Cervical  dysplasia  classified  as  Atypical  Squamous  Cells  of 
Undetermined  Significance  (ASCUS)  associated  with  high-risk 
human  papilloma  virus  (HPV)  or  Low/High  Grade  Squamous 
Intraepithelial Lesion (LGSIL or HGSIL). 
• History of abnormal endometrial biopsy including the presence of 
EIN. 
• Recent history (within past 6 months) of alcoholism or drug abuse. 
• Known active infection with HIV, Hepatitis A, B or C. 
• Previous  history  of  auto-immune disease  and/or  positive 
antinuclear antigen (ANA). 
• Endometrial stripe ≥18 mm in thickness at Visit 1. 
• Subject is currently taking cimetidine or spironolactone. 
• Previous  use  of telapristone  acetate or  participation  in  a  Repros 
clinical study 
• 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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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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Page 30 of 66 
27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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March 31, 2015 
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Page 35 of 66 
27AUG2018 Abbreviated CSR ZPE-202
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Page 36 of 66 
 
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10. 
ASSESSMENT OF EFFICACY 
10.1 Study Endpoints 
Primary Endpoint 
• Change  and  percent  change  in  the  individual  BBSS  scores  of  the  three 
patient reported outcomes (dysmenorrhea, dyspareunia and non-menstrual 
pelvic pain) by study visit and treatment cycle. 
Secondary Endpoints 
• Change in daily average use and percent change of prescription analgesics 
from the  baseline  menstrual  cycle  
to the  matching period  
leading  up  
to 
Week 18, the last day of dosing of the first cycle of treatment. 
• Change  in  daily  average  use  and  percent  change of  over  the  counter 
analgesics  from  the  baseline  menstrual  cycle  to  the  matching period 
leading up to Week 18, the last day of dosing of the first cycle of treatment, 
calculated based on days with reported values.  
• Change in daily average use and percent change of overall analgesic use, 
prescription and over the counter, from the baseline menstrual cycle to the 
matching period leading up to Week 18, the last day of dosing of the first 
cycle of treatment, calculated based on days with reported values.  
• Change and  percent  change in  BBSS  score  incorporating  the  two 
physician-reported scores by study visit and treatment cycle. 
• Change from baseline in pain assessed using a Visual Analog Scale (VAS) 
by study visit and treatment cycle. 
• Change  
from  baseline  
in  daily  average dysmenorrhea  and  non-menstrual 
pelvic pain using an 11-point numerical rating scale (NRS) by study visit 
and treatment cycle. 
2 
ts 
e: 
• 
ts 
• 
s 
• 
e 
• 
e 
• 
g 
• 
s  
• 
y 
• 
 a 
DI 
 
 
 
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, 
  
11.1 Adverse Events 
11.1.1 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.  
All  AEs  reported  by  the  subject  or  observed  by  the  Principal 
Investigator will be individually listed.  The signs and symptoms, time 
of  onset  (24-hour  clock),  duration,  action  taken  and  follow-up 
procedures will be reported. 
11.1.2 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. 
11.1.3  Serious Adverse Events (SAEs) 
The  Principal  Investigator  shall  document all SAEs  in  a  subject 
receiving  study  drug
  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.  
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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12. 
CONCOMITANT MEDICATIONS 
12.1 Prescription Analgesics Permitted During the Study 
12.1.1  Treatment of Endometriosis-Related Pain 
Subjects should not take any analgesics during the study unless necessary for 
pain.    In  the  event  that  a  subject  needs  to  use prescription analgesics  for 
endometriosis-related  pain,  one  of  the  following  regimens  should  be 
prescribed: 
• Hydrocodone/Acetominophen: 5-10  mg/325  
-750  mg, 1-2  
tabs  every  4-6 
hours prn 
• Acetaminophen with Codeine:  1  tab  300/30  mg  to  300/60  mg  every  4 
hours prn 
• Oxycodone: 5-15 mg every 4-6 hours prn OR 10 mg (continuous release) 
every 12 hours prn 
• Tramadol: 50-100 mg every 4-6 hours prn up to 400 mg/day 
• Ponstel  (mefenamic  acid)  (500  mg  initial  dose,  then  250  mg  every  6 
hours) 
• Hydrocodone/Ibuprofen: 7.5/200 mg, 1-2 tabs every 6-8 hrs prn 
Any deviation from this list requires pre-approval by Repros. Note: Over-the-
counter medications (e.g. ibuprofen, naproxen) do not qualify as prescription 
medications for entrance into the study, even if a prescription has been written 
for the specific medication. 
12.1.2 Treatment of Non-Endometriosis–Related Pain 
If  
the  subject  experiences  pain  
(not related  
to endometriosis),  she  should  be 
treated  as  medically  appropriate.    The  choice  of  drug  will  depend  on  the 
medical condition.  Dosage forms and route of administration should be as per 
product specifications.   
 
All  narcotic,  non-narcotic and  over–the-counter medication for 
endometriosis-related pain will be captured in the subjects’ daily diary. 
All  narcotic,  non-narcotic  and  over–the-counter  medications for  non-
endometriosis-related pain will be recorded in the appropriate section of 
the CRF.  
Analgesic medications will not be provided by Repros Therapeutics Inc.  
 
12.2 Prohibited Medications 
The following medications are prohibited during the study: 
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• Testosterone 
• Progestin 
• Androgen 
• Estrogen 
• Anabolic steroids 
• DHEA 
• Other hormonal products 
• CYP3A4  inhibitors,  e.g.  atazanavir,  clarithromycin,  indinavir, 
itraconazole,  ketoconazole,  nefazodone,  nelfinavir,  ritonavir,  saquinavir, 
telithromycin. 
• St. John’s Wort 
• Spironolactone 
• Cimetidine 
 
12.3 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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13. 
STATISTICAL METHODS  
13.1 Determination of Sample Size 
Up  
to 60  
female  subjects, 20  per  dose  arm,  meeting  
the  
inclusion/exclusion 
criteria will be randomized in a 1-1-1 fashion.  The sample size was powered 
based on the two-sample t-test that will be used to make pairwise comparisons 
between  treatment  groups.   
 a 
-
y 
is 
 
    
 
 
a sample of 18 
subjects  per  group  would provide 80%  power  to  detect  a  statistically 
significant difference between the treatment groups.     
13.2  Statistical and Analytical Plan 
A statistical analysis will be conducted once all subjects have completed the 
placebo-controlled portion of the study, Stage 2.  A Statistical Analysis Plan 
will be developed that outlines in detail all planned analyses.  This document 
will  be  completed  prior  
to  unblinding  study  data  for  
the  placebo-controlled 
portion of the study.   
A separate analysis and reporting will occur once all subjects have completed 
all  study  
treatment.  
  A separate Statistical  Analysis  Plan  will  describe  
these 
analyses.   This  summary  will  focus  on  the  results  noted  in  Stage  3  of  the 
study. 
13.2.1 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. 
13.2.2 Efficacy Analyses 
An  analysis  will  be  conducted  once  Stage 2,  the first  cycle  of 
treatment, has been completed.  A later analysis will focus on the data 
collected from the active treatment stage of the study, Stage 3. 
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Efficacy  analyses of  
the first  cycle  of  
treatment will  be conducted  
in 
the  
Intent-to-Treat  population,  which  will  consist  of  all  subjects  who 
are  randomized and who  receive  study  drug.  
 Subjects  with  missing 
post-baseline  data  will  have  a  value  of  “no  change”  imputed  for 
analysis. 
13.2.2.1 Prescription Analgesic Usage 
The change  and percent change  in  daily  average  use  of 
prescription analgesics comparing the baseline menstrual cycle 
(28 days) to the 28 days leading up to the last day of dosing in 
Cycle  1 (Week  18) will  be summarized  for  each  treatment 
group.  For each subject, the total number of pills or tablets of 
prescription analgesics during each 28 day menstrual cycle will 
be  calculated,  and  the  daily  average  use  of prescription 
analgesics will be determined by dividing the total number of 
pills/tablets of prescription analgesics taken during the 28 day 
nominal period by 28.  The percent change from baseline in the 
prescription analgesic usage will be determined by subtracting 
the baseline prescription analgesic usage from the prescription 
analgesic usage during the last nominal 28 day menstrual cycle, 
dividing  by  the  baseline prescription analgesic  usage,  and 
multiplying by 100%. 
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed using a one-way Analysis of Covariance, including 
the  baseline prescription analgesic usage  and  
treatment  group 
in  
the  model.  
  Pairwise  comparisons  of  
the  
treatment  groups 
will  be  made  using a two-sample  t-test.    While  the  primary 
assessment  will be  based  on  Visit  12  (after  18  weeks  of 
treatment)  summaries  will  also  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. 
Changes  in  prescription  analgesic  use  during  the active 
treatment stage of the study (Stage 3) will also be summarized. 
13.2.2.2  Over the Counter Analgesic Usage 
The change in daily average use of over the counter analgesics 
comparing  the  baseline  menstrual  cycle  to  a  similar  period 
leading up to the last day of dosing in Cycle 1 (Week 18) will 
be summarized for each treatment group.  For each subject, the 
total  number  of  doses  of  over  the  counter  analgesics  during 
each menstrual cycle will be calculated, and the  daily average 
use  of  over  the  counter  analgesics  will  be  determined  by 
dividing  the  total  number  of  doses  of  over  the  counter 
analgesics  by  the  number  of  days  in  the  menstrual  cycle 
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(number of doses per day).  The percent change from baseline 
in the over the  counter  analgesic usage will  be determined by 
subtracting the baseline over the counter analgesic usage from 
the  over  the  counter  analgesic  usage  during  each  menstrual 
cycle,  dividing  by  the  baseline  over  the  counter  analgesic 
usage, and multiplying by 100%. 
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed using a one-way Analysis of Covariance, including 
the  baseline over  the  counter analgesic  usage  and  treatment 
group  in  the  model.   Pairwise  comparisons  of  the  treatment 
groups  will  be  made  using a two-sample  t-test.   While  the 
primary assessment will be based on  Visit 12 (after 18 weeks 
of  
treatment)  summaries  will  also  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. 
Changes  in  over  the  counter  analgesic  use  during  the active 
treatment stage of the study (Stage 3) will also be summarized. 
13.2.2.3 Overall Analgesic Use 
The  change and  percent  change  in  daily  average  use  of  all 
analgesics  (prescription  and  over  the  counter)  comparing  the 
baseline menstrual cycle (28 days) to the 28 days leading up to 
the  last  day  of  dosing in  Cycle  1 (Week  18) will  be 
summarized  for  each  treatment  group.  
  For  each  subject,  
the 
total number of pills or tablets of analgesics taken during each 
28  day  menstrual cycle  will  be  calculated,  and  the  daily 
average  use  of  prescription  analgesics  will  be  determined  by 
dividing  the  total  number  of  pills/tablets  of analgesics  taken 
during the 28 day nominal period by 28.  
 The percent change 
from  baseline  in  the  analgesic  usage  will  be  determined  by 
subtracting  the  baseline  analgesic  usage  from  the  analgesic 
usage during the last nominal 28 day menstrual cycle, dividing 
by the baseline analgesic usage, and multiplying by 100%. 
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed using a one-way Analysis of Covariance, including 
the baseline analgesic usage and treatment group in the model.  
Pairwise  comparisons  of  the  treatment  groups  will  be  made 
using a two-sample t-test.  While the primary assessment will 
be based on Visit 12 (after 18 weeks of treatment) summaries 
will  also  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. 
Changes  
in  analgesic  use  during  
the  active  
treatment  stage  of 
the study (Stage 3) will also be summarized. 
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13.2.2.4 BBSS Physician Reported Scores 
The BBSS  score  incorporating  the  two  physician-reported 
scores  will  be  analyzed  to  compare  the  baseline  menstrual 
cycle to a similar period leading up to the last day of dosing in 
Cycle  1 (Week  18).    An  overall  comparison  among  the  3 
treatment groups will be performed using a one-way  Analysis 
of Covariance, including baseline BBSS score and treatment in 
the model.  Pairwise comparisons of the treatment groups will 
be made using  a t-test.  While the primary assessment will be 
based on Visit 12 (after 18 weeks of treatment) summaries will 
also  be  prepared  for  each  of  the other visits. 
 
The  BBSS  patient  and  physician  scores  during  the active 
treatment stage of the study (Stage 3) will also be summarized. 
13.2.2.5 BBSS Patient Reported Scores 
The percent change from baseline in each of the daily average 
combined  BBSS  patient-reported  scores (dysmenorrhea, 
dyspareunia and non-menstrual pelvic pain) will be analyzed to 
compare the  baseline  menstrual  cycle  to  a  similar  period 
leading up to the last day of dosing in Cycle 1 (Week 18).  An 
overall  comparison  among  the  3  treatment  groups  will  be 
performed using a one-way  Analysis of Covariance, including 
baseline  BBSS  score  and  treatment  in  the  model.   Pairwise 
comparisons of the treatment groups will be made using a two-
sample t-test.  While the primary assessment will be based on 
Visit 12 (after 18 weeks of treatment) summaries will also be 
prepared for each of the other visits. 
 
 
 
The  BBSS  patient  scores  during  
the active  
treatment stage  of 
the study (stage 3) will also be summarized 
13.2.2.6  Menstrual or Non-menstrual Vaginal Bleeding 
The  number  of  days  and  intensity  of  menstrual  and  non-
menstrual vaginal bleeding will be summarized from the diary 
data.  
  The  
total  number  of  days  and  average intensity  will  be 
summarized  from  the  days  preceding  each  visit.    An  overall 
comparison  among  
the  3  
treatment  groups  will  be  performed 
on both the total number of days and average intensity using a 
one-way  Analysis  of Covariance,  
including  
the  baseline  score 
(number  of  days  or  average  intensity)  and  treatment  in  the 
model.  
 Pairwise  comparisons  of  
the  
treatment  groups  will  be 
made using a two-sample t-test.  While the primary assessment 
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will  be  based  on  Visit 12 (after 18  weeks of  treatment) 
summaries will also be prepared for each of the other visits and 
visit  post-recovery  menses.   If  data  are  missing,  a  last 
observation  carried  
forward  procedure  will  be  used,  
including 
the baseline, if necessary. 
The  number  of  days  and  intensity  of  menstrual  and  non-
menstrual  vaginal  bleeding  will  also  be  summarized  from 
active treatment (Stage 3) diary data collected. 
13.2.2.7 VAS Assessment of Pain 
The percentage  change  
from  baseline  VAS  pain  score  will  be 
analyzed within treatment group and between treatment groups.    
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed  using  a  one-way  Analysis  of Variance.   Pairwise 
comparisons of the treatment groups will be made using t-test 
or  non-parametric  test  as  appropriate.   While  the  primary 
assessment will be based on scores at Visit 12 (after 18 weeks 
of treatment), summaries will also 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. 
The  VAS  pain  scores  collected  during  the  active  treatment 
stage of the study (Stage 3) will also be summarized. 
13.2.2.8 Assessment of Pain Using the NRS 
The average daily assessment will be calculated separately for 
dysmenorrhea and pelvic pain within each key 28-day baseline 
and  treatment  period.  The percentage  change  from  baseline 
NRS pain  score  will  be  analyzed  within  
treatment  group  and 
between treatment groups.  An overall comparison among the 3 
treatment groups will be performed using a one-way  Analysis 
of Variance.    Pairwise  comparisons  of  the  treatment  groups 
will be made using t-test or non-parametric test as appropriate.  
While  
the  primary  assessment  will  be  based  on scores  during 
the  28-day  period  prior  to Visit 12 (after 18  weeks  of 
treatment), summaries  will  also  be  prepared  for  each  of  the 
other visits.   
The average daily assessment of dysmenorrhea and pelvic pain 
scores  collected  during  
the  active  
treatment stage of the study 
(Stage 3) will also be summarized. 
 
 
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a. 
m 
al 
nd 
al 
y 
p 
y.    
he 
ge 
d 
e 
d 
r 
al 
al 
  
 
  
13.3  General Statistical Issues 
A  Statistical  Analysis  Plan  
(SAP)  will  be  developed  prior  
to  
the  analyses  of 
the first  cycle  of  treatment.    Two  analyses  will  be  conducted.    The  first 
analysis  will  occur  when  all  subjects  have  completed  the  first  cycle  of 
treatment (Week 18) and the second with be conducted once all subjects have 
completed the active treatment stage of the study (Stage 3).   
 
 
  Statistical 
significance  will  be declared  if  the  two-sided  p-value  
is  ≤  0.05.  
  Since  the 
study  was  not  powered  for  efficacy  assessments  based  on  statistical 
hypotheses,  the  p-values  reported  at  the  conclusion  of  the  study  are  being 
reported  
to  quantify  
the  difference  
in  
the  
treatment  effect  between  
treatment 
groups.   
r 
 
 
 
 
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14. 
ETHICS 
14.1 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. 
14.2  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. 
14.3  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. 
14.4 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. 
14.5  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: 
 
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1.  Monitoring  study  conduct  to  ensure  that  the  rights  of  subjects  are 
protected; 
2. Monitoring study conduct to ensure trial compliance with GCP guidelines; 
and 
3. Monitoring accuracy, completion and verification from source documents 
of study data. 
14.6 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. 
14.7 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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15. 
INVESTIGATOR'S STATEMENT 
I  have  reviewed  the  ZPE-202 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. 
 
March 31, 2015 
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Repros Therapeutics Inc. 
 
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Repros Therapeutics Inc. 
 
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Repros Therapeutics Inc. 
 
March 31, 2015 
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Repros Therapeutics Inc. 
 
March 31, 2015 
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Repros Therapeutics Inc. 
 
March 31, 2015 
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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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Repros Therapeutics Inc. 
 
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Repros Therapeutics Inc. 
 
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Repros Therapeutics Inc. 
 
March 31, 2015 
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Page 66 of 66 
 
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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 
................................................................... 16 
6.4 
SAFETY DATA ........................................................................................................... 17 
6.5 
ETHICAL CONDUCT OF THE STUDY 
......................................................................... 19 
6.6 
DRUG SAFETY MONITORING BOARD (DSMB) 
....................................................... 19 
7. TRIAL OBJECTIVES AND PURPOSE 
............................................................................ 20 
8. TRIAL DESIGN ................................................................................................................... 21 
8.1 
STUDY ENDPOINTS 
.................................................................................................... 21 
8.2 
STUDY DESIGN 
.......................................................................................................... 22 
8.2.1 
Overview of Study Design 
..................................................................................... 22 
8.2.2 
Study Drug Accountability 
................................................................................... 23 
8.2.3 
Randomization and Blinding 
................................................................................ 23 
8.2.4 
Study Medication 
................................................................................................... 24 
8.2.5 
Endometrial Biopsies 
............................................................................................. 24 
8.3 
SELECTION AND WITHDRAWAL OF SUBJECTS 
....................................................... 24 
8.3.1 
Inclusion Criteria 
................................................................................................... 25 
8.3.2 
Exclusion Criteria 
.................................................................................................. 26 
9. STUDY PROCEDURES ...................................................................................................... 29 
1 
9 
2 
0 
3 
0 
4 
30 
5 
E 
E 
E O 
K F 
31 
6 
D F 
E F 
31 
7 
T F 
32 
8 
2 
9 
3 
0 
3 
1 
D F 
4 
2 
T F 
4 
3 
4 
4 
5 
5 
5 
6 
D F 
6 
7 
36 
 
7 
10. ASSESSMENT OF EFFICACY 
.......................................................................................... 38 
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10.1 STUDY ENDPOINTS 
.................................................................................................... 38 
 
8 
11. ASSESSMENT OF SAFETY 
............................................................................................... 39 
11.1 ADVERSE EVENTS 
..................................................................................................... 39 
11.1.1 
Reporting Adverse Experiences 
................................................................... 39 
11.1.2 
Definitions 
...................................................................................................... 39 
11.1.3 
Serious Adverse Events (SAEs) ................................................................... 40 
12. CONCOMITANT MEDICATIONS 
................................................................................... 42 
12.1 PRESCRIPTION ANALGESICS PERMITTED DURING THE STUDY 
............................ 42 
12.1.1 
Treatment of Endometriosis-Related Pain 
................................................. 42 
12.1.2 
Treatment of Non-Endometriosis–Related Pain 
........................................ 42 
12.2 PROHIBITED MEDICATIONS 
..................................................................................... 42 
12.3 OTHER MEDICATIONS TAKEN DURING THE STUDY .............................................. 43 
13. STATISTICAL METHODS 
................................................................................................ 44 
13.1 DETERMINATION OF SAMPLE SIZE ......................................................................... 44 
13.2 STATISTICAL AND ANALYTICAL PLAN 
.................................................................... 44 
13.2.2.8 Assessment of Pain Using the NRS 
................................................................. 48 
13.3 GENERAL STATISTICAL ISSUES 
............................................................................... 49 
14. ETHICS ................................................................................................................................. 50 
14.1 SUBJECT INFORMATION AND CONSENT 
.................................................................. 50 
14.2 INSTITUTIONAL REVIEW BOARD 
............................................................................. 50 
14.3 MONITORING CASE REPORT FORMS 
...................................................................... 50 
14.4 STUDY RECORD RETENTION ................................................................................... 50 
14.5 DATA QUALITY ASSURANCE 
.................................................................................... 50 
14.6 CONFIDENTIALITY 
.................................................................................................... 51 
14.7 PUBLICATIONS 
.......................................................................................................... 51 
15. INVESTIGATOR'S STATEMENT 
.................................................................................... 52 
: 
53 
: 
R 
54 
. 
56 
: 
58 
: 
G 
64 
 
5 
5 
 
 
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3. 
PROTOCOL SYNOPSIS 
 
Test Drugs: 
Proellex® (Telapristone  Acetate):  6  and  12  mg  gelatin  capsules  and 
matching placebo 
Protocol Number: 
ZPE-202  
Study Purpose: 
To  determine  the  safety  and  efficacy  of  two  doses  of  Proellex  in 
premenopausal  women  with pelvic  pain associated  with 
endometriosis confirmed  within  the  last seven years  and  using 
prescription medications for symptomatic pain. 
Study  Design  and 
Duration 
Of Treatment: 
This study is a phase 2, 3-arm-study with an 18  week active dosing 
period and an option to extend treatment for 2 additional cycles.  The 
study will be conducted in three stages.   
In the first stage, women will undergo  a  baseline  assessment  period 
with no treatment until their second ovulation event.  Endometriosis 
pain,  dysmenorrhea,  non-menstrual  pelvic  pain  and  dyspareunia 
(BBSS) as well as use of pain medications, vaginal bleeding intensity 
and  alcohol  use will  be  recorded  using  a daily diary.  Daily  subject 
ratings  of dysmenorrhea and  non-menstrual  pelvic pain  will  be 
captured using an 11-point numerical rating scale (NRS) and Visual 
Analog Scale (VAS) pain assessment will be utilized.   
In  the  second  stage,  following  the baseline  assessment  period, 
subjects  will  be  randomized  
into  one  of 3 arms  
in  a  1-1-1  fashion.  
The start of the 18 week dosing period for the first cycle of treatment 
should  commence  as  soon  after ovulation  as  possible,  after  which 
subjects will be followed until menses returns.  Subjects who do not 
wish to receive additional cycles of treatment after stage 2 will have 
their  
last  visit  scheduled  after  blood  
flow  has  stopped.  
  During  
this 
off-drug  
interval;  subjects  will  continue  
to  
record  study  
information 
in the daily diaries. 
After completing a minimum of 28 days of treatment in this stage of 
the study, subjects may discontinue the study and still be eligible to 
qualify for up to 2 additional treatment cycles.     
In  the  third  stage,  subjects who  are  eligible to  receive  additional 
cycles  of  treatment  and  who  elect  to  continue  treatment will  be 
scheduled to  start  dosing  
in  
their  next  course 21  days (+/- 2  days) 
after the start of bleeding, following the first menses after end of their 
first course of treatment (off-drug  
interval).  Subjects will receive 2 
courses of additional treatment  separated  by  an  off-drug  interval 
(ODI),  after  which  
they  will  be  
followed  until  menses  has  
returned.  
During  
the  follow-up  period  subjects  will  continue  
to  record  study 
information  in  the daily diary.    The  final  follow-up  visit  will  be 
scheduled after blood flow has stopped.  
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Subject Population: 
The  study  will  enroll  healthy  adult,  non-obese  pre-menopausal 
women  with surgically confirmed  endometriosis prescribed  and/or 
using prescription medication for their endometriosis pain. 
Number of Subjects: Up to 60 female subjects, 20 per dose arm (US and Argentina) 
Number of Sites 
Approximately 10-20 sites  
Study Duration:  
Total participation in the study is approximately 18 months. 
  
 
 
 
 
 
 
 
 
 
 
 
, 
 
 
 
 
o 
l 
 
 
s 
 
 
 
 
 
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Study Endpoints 
The study endpoints will be: 
Primary Endpoint 
• Change and percent change in the individual BBSS scores of the 
three patient reported outcomes (dysmenorrhea, dyspareunia and 
non-menstrual pelvic pain) by study visit and treatment cycle. 
Secondary Endpoints 
• Change  
in daily average  use  and percent  change  of  prescription 
medications from  the  baseline  menstrual  cycle  to the  matching 
period leading up to Week 18, the last day of dosing of the first 
cycle of treatment. 
• Change  in  daily  average  use  and  percent  change  of  over  the 
counter medications  from  the  baseline  menstrual  cycle  to  the 
matching period leading up to Week 18, the last day of dosing of 
the  first  cycle  of  treatment,  calculated  based  on  days  with 
reported values.  
• Change  in  daily  average  use  and  percent  change  of  overall 
medication  use,  prescription  and  over  the  counter, from  the 
baseline  menstrual  cycle  to  the  matching  period  leading  up  to 
Week  18,  the  last  day  of  dosing of  the  first  cycle  of  treatment, 
calculated based on days with reported values. 
• Change and percent change in BBSS score incorporating the two 
physician reported scores by study visit and treatment cycle. 
• Change  from  baseline  in  pain  assessed  using  a  Visual  Analog 
Scale (VAS) by study visit and treatment cycle. 
• Change  from  baseline  in daily average dysmenorrhea  and  non-
menstrual  pelvic  pain  using  an  11-point  numerical  rating  scale 
(NRS) by study visit and treatment cycle. 
 
 
 
 
 
 
f 
 
 
 
 
 
 
 
 
 
 
Statistical Methods: A  Statistical  Analysis  Plan  (SAP)  will  be  developed  prior  to 
unblinding  of  the  data  that  will  outline  all  planned  analyses  and 
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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 
and follow-up. 
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.  
Summaries  will  be  prepared  for  each  treatment  group  of  subject 
accountability, baseline demographic, and medical history data.  
Continuous  efficacy  endpoints,  such  as  
the  percentage  change  
from 
baseline in the use of prescription medications, will assess treatment 
effect  using an  Analysis  of  Covariance,  including  the  baseline 
prescription medication usage and treatment in the model.  Pairwise 
comparisons  between  treatment  groups  will  be  made  using  a  two-
sample  t-test.   Other  continuous efficacy  variables  will  be  treated 
similarly.  
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m 
 
  
 
 
 
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27AUG2018 Abbreviated CSR ZPE-202
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5. 
LIST OF ABBREVIATIONS 
 
AE    
Adverse event 
BBSS    
Biberoglu Behrman symptom severity scale 
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 
m  
  
Meters 
mg    
Milligram(s) 
mL    
Milliliter 
ng    
Nanograms 
NRS   
Numerical Rating Scale 
ODI   
Off-Drug Interval 
PCOS    
Polycystic Ovarian Syndrome 
PK    
Pharmacokinetic 
RBC    
Red blood cell 
SAE    
Serious adverse event 
VAS   
Visual Analog Scale 
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.  Most notably the sponsor 
has seen significant clinically relevant impact on the symptoms of both uterine 
fibroids and endometriosis. 
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3 
 
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 a 
of 
 
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se 
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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.  
  The  Institutional  Review  Board  (IRB)  for  this  study  is 
IntegReview, 3001 S. Lamar Blvd., Suite 210, Austin, Texas 78704.  
  
 
 
 
 
 
 
 
 
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7. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to determine the safety and efficacy of two oral 
doses of Proellex administered to premenopausal women with pelvic pain associated 
with endometriosis  confirmed  within  the  last seven years  and  using prescription 
medications for endometriosis pain.  Proellex will be administered for up to 3 cycles 
(18 or 16 weeks in duration), each separated by an Off-Drug Interval (ODI).  
 
 
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8. 
TRIAL DESIGN 
8.1 
Study Endpoints 
Primary Endpoint 
• Change and  percent  change in  the  individual BBSS scores  of  the  three 
patient reported outcomes (dysmenorrhea, dyspareunia and non-menstrual 
pelvic pain) by study visit and treatment cycle 
Secondary Endpoints 
• Change in daily average use and percent change of prescription analgesics 
from the  baseline  menstrual  cycle  to  the  matching period  
leading  up  
to 
Week 18, the last day of dosing of the first cycle of treatment. 
• Change  in  daily  average  use  and  percent  change  of  over  the  counter 
analgesics  from  the  baseline  menstrual  cycle  to  the  matching  period 
leading up to Week 18, the last day of dosing of the first cycle of treatment, 
calculated based on days with reported values.  
• Change in daily average use and percent change of overall medication use, 
prescription and over the counter,  from the baseline menstrual cycle to the 
matching period leading up to Week 18, the last day of dosing of the first 
cycle of treatment, calculated based on days with reported values. 
• Change and  percent  change in  BBSS  score  incorporating  the  two 
physician-reported scores by study visit and treatment cycle. 
• Change and  percent  change in  the  individual BBSS scores  of  the  three 
patient reported outcomes (dysmenorrhea, dyspareunia and non-menstrual 
pelvic pain) by study visit and treatment cycle. 
• Change from baseline in pain assessed using a Visual Analog Scale (VAS) 
by study visit and treatment cycle. 
• Change  
from  baseline  
in  daily  average dysmenorrhea  and  non-menstrual 
pelvic pain using an 11-point numerical rating scale (NRS) by study visit 
and treatment cycle. 
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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  an  18  week active  dosing 
period and  an  option  for  subjects to  receive  2  additional 16-week 
cycles  of  active  treatment  at  their  randomized  dose  (6  mg  or  12 
mg/day).  Placebo subjects who elect additional treatment will receive 
treatment at 12 mg/day.  The treatment dose will remain double-blind.  
The study will be conducted in 3 stages.  In the first stage, women will 
undergo  a  baseline  assessment  period  with  no  
treatment.  
 This  stage 
will last as long as it takes to record at least one full menstrual cycle 
(ovulation until ovulation).  
Subjects  will  be  provided  with  a  daily  diary  with  which  to  record 
patient  reported  scores  for  
the  
three  elements  of endometriosis  pain: 
dysmenorrhea,  non-menstrual  pelvic  pain  and  dyspareunia  (BBSS).  
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For  stage  2,  following  
the baseline  assessment  period, at  Visit  3, 60 
subjects will be randomized into one of 3 arms in a 1-1-1 fashion.  The 
start  of  dosing  should  commence as  soon  as  possible  after ovulation 
following the end of the previous menstrual event.    
Once the 18 week active dosing period is completed, subjects will be 
followed  until  menses  has  returned  (usually  within 21 days  or  
less).  
Subjects may elect to receive up to 2 additional cycles of treatment at 
their  
randomized  dose  
(6  mg  or  12  mg/day),  placebo-treated  subjects 
will receive treatment at 12 mg/day.  In stage 3 all subjects will receive 
active treatment but the treatment dose will remain double-blind.  For 
subjects  who  do  not  choose  additional  
treatment  cycles,  
this  will  be 
their  
final  
follow-up  visit.  
  During  
the  
follow-up  period  subjects  will 
continue to record study information in the daily diary.   
For  stage  3,  subjects  who  are  eligible  
to  
receive  additional  cycles  of 
treatment and who elect to continue treatment will be scheduled at 21 
±  2 days  after  start  of  bleeding  in  their  first  menses  after  Visit  12 
(recovery  menses).  Subjects  will  receive  2  cycles  of  treatment 
separated  by  an  off-drug  interval  (ODI),  after  which  they  will  be 
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followed  until  menses  has  returned.    During  the  follow-up  period 
subjects  will  continue  
to  
record  study  
information  
in  
the daily  diary.  
The  final  follow-up  visit  will  be  scheduled  after  blood  flow  has 
stopped. 
 
 
 
e 
e 
 2 
nd 
 
e 
 
Subjects who  complete at  least  28  days  after Visit  3  and  wish  to 
discontinue  
treatment due  
to  
lack  of  efficacy will be  eligible  
to start 
active treatment (stage 3).  Subjects who discontinue the study prior to 
this date will not be eligible for additional treatment. 
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,  or 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 
All  subjects will  
receive no  
treatment  
from Visit  1  until  Visit 3.  
 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 18  weeks.  
Subjects  who  elect  to  receive  additional  treatment  cycles  will  be 
treated  at  their  previously  randomized  dose  level.    Subjects 
randomized to placebo treatment will receive treatment at 12 mg/day.  
In  stage  3  all  subjects  will  
receive  active  
treatment  but  
the  
treatment 
dose will remain double-blind.  Each treatment cycle will be separated 
by an ODI.  Blinded treatments kits will be randomized and distributed 
by the packaging company.   
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For  the  statistical  analysis  at  Week  18,  only  statistical  staff  will  be 
unblinded once the acute portion of the study database is locked.  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 
  and  will  be 
packaged by a clinical supplies contract vendor designated by Repros 
Therapeutics  Inc.    The  placebo  will also be 
 
  and  will  be  packaged  by  the  same  clinical supplies  contract 
vendor.    Active  and  matching  placebo  capsules  will  be  bottled  in 
identical  packaging.  Each  bottle  will  have  a  
label  containing  bottle 
number,  number  of  capsules,  expiration  date, a  statement  “Caution: 
New Drug – Limited by Federal Law (US) to Investigational use” and 
instructions  
to  
take  1  capsule  daily  
in  
the  morning  before  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.  
  
 
 
Subjects will not be provided with medication medications by Repros 
Therapeutics Inc. 
8.2.5 
 
 
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d 
 
l 
. 
8.3 
Selection and Withdrawal of Subjects 
Subjects for the study will be selected during screening based on the inclusion 
and exclusion criteria and clinical assessments listed below.  Subjects will be 
discontinued from the study prematurely if: 
• Unacceptable  adverse  events occur considered  by  the  investigator  to  be 
associated with use of the study drug  
• The subject requests to be withdrawn from the study 
• Any of the following occur: 
 ALT or AST >8xULN 
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 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  and/or 
eosinophilia (>5%) 
• A need arises for concomitant medication prohibited by the protocol  
• The Principal Investigator decides that it is in the subject’s best interest 
• The subject is noncompliant with the protocol 
• Any subject who develops an endometrial thickness ≥ 18 mm will undergo 
endometrial  biopsy.  The  endometrial  biopsy  will  be  forwarded  to  a 
member of the Expert Panel for expedited review. If the biopsy shows EIN 
or  hyperplasia  (per  Expert  Panel  review),  subject  will  be  discontinued 
from  
the  study.  If  EIN  or  hyperplasia  
is  diagnosed  
the  sponsor  will  be 
notified and subject discontinued from the study.   Appropriate follow up 
treatment will be provided as deemed necessary by the investigator. 
• Any  subject  who  experiences  heavy  bleeding  
(bleeding  
intensity  of  4  or 
more per the Daily Diary Card in Appendix 3) for 7 consecutive days or 
more  will  be  discontinued  
from  
the  study.  
  This  does  not  apply  
if  heavy 
bleeding  occurs  
in  
the  first  
recovery  menses  after  withdrawal  of  drug  at 
the end of treatment, or is no heavier than bleeding was prior to treatment. 
• Any  subject  who develops  an  endometrial  thickness  ≥  18 mm and 
excessive  bleeding  
that  
requires dilatation  and curettage or  hysterectomy 
will  be  discontinued  from  the  study and  undergo  endometrial  biopsy.  
Women with such findings will not be eligible for extension of treatment.  
Appropriate follow up treatment will be provided as deemed necessary by 
the investigator. 
• Subjects  with  a  biopsy that shows  clear  evidence  of neoplasia,  as 
determined by the expert panel, will be discontinued and be ineligible for 
extension of treatment. 
• The  decision  to  withdraw from  the  study  because  of  an  adverse  event, 
including  pain  
from  endometriosis  or  
from  another  condition,  
is  decided 
by the subject and the investigator or her personal physician.   The event, 
and any treatment should be recorded in the study records. 
 
8.3.1 Inclusion Criteria 
Subjects must meet the following criteria: 
• Healthy adult females between 18 and 47  years of age (inclusive) 
prescribed prescription medication or taking a prescription strength 
dose  of  over-the-counter  medication for endometriosis  pain,  and 
with a BBSS score ≥7 at screening (assessed over the previous 28 
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days,
n 
 
e 
t 
 
• Endometriosis  diagnosis must  have  been  surgically  confirmed 
within 7 years.  A laparoscopic diagnosis is acceptable. 
• Subjects must have a history of at least 3 regular menstrual cycles 
in which symptoms of endometriosis occurred immediately prior to 
screening 
• Normal  or  abnormal  but  non-clinically  significant  transvaginal 
ultrasound 
• History of menstrual events occurring in regular cycles 
• Agreement not to attempt to become pregnant during the trial 
• Agreement  to use  alcohol  in  moderation and  to  avoid  alcohol 
consumption within 48 hours before each visit 
• Ability  
to  complete  a  daily  subject  diary  and  study  procedures  
in 
compliance with the protocol 
• Women  of  child-bearing  potential  must  be  willing  
to  use  double-
barrier  contraception  during  the  study  and  for  30  days  after 
discontinuation  of  study  medication.    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 the Screening and Baseline visits, 
and subsequent study visits 
• A Body Mass Index (BMI) between 18 and 39 inclusive 
• 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 participation in the study 
•  Subjects with  abnormally  high  liver  enzymes  or  liver disease. 
(ALT  or AST  exceeding 2 x  ULN AND total bilirubin exceeding 
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1.5xULN at screening and confirmed on repeat). 
• 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 
prior to screening and during the study. 
• 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 after the period of duration of the Lupron dose). 
• Has an IUD in place. 
• Presence of intramural fibroids that impact the endometrial stripe, 
submucosal fibroids (any size), or endometrial polyps.  Subserosal 
and  
intramural  fibroids  with  no  
impact  on  
the  endometrial  stripe 
are acceptable. 
• Presence of endometrioma(s) 
• Present history or condition that causes non-endometriosis related 
dyspareunia (e.g. vulvar vestibulitis). 
• Past  or  present  history  of  thrombophlebitis  or  thromboembolic 
disorders. 
• Known  or  suspected  carcinoma  of  the  breast  or  reproductive 
organs. 
• Known  history  of  abnormal  ECG  that,  in  the  opinion  of  the 
investigator,  is  clinically  significant  and  will  prevent  the  subject 
from  completing  
the  study,  
including  a  QTc  of  greater  
than  450 
ms. 
• Cervical  dysplasia  classified  as  Atypical  Squamous  Cells  of 
Undetermined  Significance  (ASCUS)  associated  with  high-risk 
human  papilloma  virus  (HPV)  or  Low/High  Grade  Squamous 
Intraepithelial Lesion (LGSIL or HGSIL). 
• History of abnormal endometrial biopsy including the presence of 
EIN. 
• Recent history (within past 6 months) of alcoholism or drug abuse. 
• Known active infection with HIV, Hepatitis A, B or C. 
• Previous  history  of  auto-immune disease  and/or  positive 
antinuclear antigen (ANA). 
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• Endometrial stripe ≥18 mm in thickness at Visit 1. 
• Subject is currently taking cimetidine or spironolactone. 
• Previous  use  of telapristone  acetate or participation  in  a  Repros 
clinical study 
• 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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27AUG2018 Abbreviated CSR ZPE-202
559


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27AUG2018 Abbreviated CSR ZPE-202
560


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27AUG2018 Abbreviated CSR ZPE-202
561


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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
565


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27AUG2018 Abbreviated CSR ZPE-202
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27AUG2018 Abbreviated CSR ZPE-202
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10. 
ASSESSMENT OF EFFICACY 
10.1 Study Endpoints 
Primary Endpoint 
• Change  and  percent  change  in  the  individual  BBSS  scores  of  the  three 
patient reported outcomes (dysmenorrhea, dyspareunia and non-menstrual 
pelvic pain) by study visit and treatment cycle. 
Secondary Endpoints 
• Change  in  daily  average  use  and percent  change of prescription 
medications from the  baseline  menstrual  cycle  to the  matching  period 
leading  up  to Week  18, the  last  day  of  dosing of  the  first  cycle  of 
treatment. 
• Change  in  daily  average  use  and  percent  change of  over  the  counter 
medications  from  the  baseline  menstrual  cycle  to  the  matching period 
leading up to Week 18, the last day of dosing of the first cycle of treatment, 
calculated based on days with reported values.  
• Change in daily average use and percent change of overall medication use, 
prescription and over the counter, from the baseline menstrual cycle to the 
matching period leading up to Week 18, the last day of dosing of the first 
cycle of treatment, calculated based on days with reported values.  
• Change and  percent  change in  BBSS  score  incorporating  the  two 
physician-reported scores by study visit and treatment cycle. 
• Change from baseline in endometrial pain assessed using a Visual Analog 
Scale (VAS) by study visit and treatment cycle. 
• Change  
from  baseline  
in  daily  average dysmenorrhea  and  non-menstrual 
pelvic pain using an 11-point numerical rating scale (NRS) by study visit 
and treatment cycle. 
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, 
 
11.1 Adverse Events 
11.1.1 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.  
All  AEs  reported  by  the  subject  or  observed  by  the  Principal 
Investigator will be individually listed.  The signs and symptoms, time 
of  onset  (24-hour  clock),  duration,  action  taken  and  follow-up 
procedures will be reported. 
11.1.2 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. 
11.1.3  Serious Adverse Events (SAEs) 
The Principal Investigator shall document all SAEs in all subjects after 
signing informed consen
 and 
they 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.  
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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12. 
CONCOMITANT MEDICATIONS 
12.1 Prescription Analgesics Permitted During the Study 
12.1.1  Treatment of Endometriosis-Related Pain 
Subjects should not take any analgesics during the study unless necessary for 
pain.    In  the  event  that  a  subject  needs  to  use prescription analgesics  for 
endometriosis-related  pain,  one  of  the  following  regimens  should  be 
prescribed: 
• Hydrocodone/Acetominophen: 5-10  mg/325  
-750  mg, 1-2  
tabs  every  4-6 
hours prn 
• Ibuprofen 400 mg, 600 mg or 800 mg every 6 hours prn 
• Acetaminophen with Codeine:  1  tab  300/30  mg  to  300/60  mg  every  4 
hours prn 
• Oxycodone: 5-15 mg every 4-6 hours prn OR 10 mg (continuous release) 
every 12 hours prn 
• Tramadol: 50-100 mg every 4-6 hours prn up to 400 mg/day 
• Ponstel  (mefenamic  acid)  (500  mg  initial  dose,  then  250  mg  every  6 
hours) 
• Hydrocodone/Ibuprofen: 7.5/200 mg, 1-2 tabs every 6-8 hrs prn 
Any deviation from this list requires pre-approval by Repros. Note: Over-the-
counter medications (e.g. ibuprofen, naproxen) do not qualify as prescription 
medications for entrance into the study, even if a prescription has been written 
for the specific medication. 
12.1.2 Treatment of Non-Endometriosis–Related Pain 
If  
the  subject  experiences  pain  
(not related  
to endometriosis),  she  should  be 
treated  as  medically  appropriate.    The  choice  of  drug  will  depend  on  the 
medical condition.  Dosage forms and route of administration should be as per 
product specifications.   
All  narcotic,  non-narcotic and  over–the-counter medication for 
endometriosis-related pain will be captured in the subjects’ daily diary. 
All  narcotic,  non-narcotic  and  over–the-counter  medications for  non-
endometriosis-related pain will be recorded in the appropriate section of 
the CRF.  
Analgesic medications will not be provided by Repros Therapeutics Inc.  
 
12.2 Prohibited Medications 
The following medications are prohibited during the study: 
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• Testosterone 
• Progestin 
• Androgen 
• Estrogen 
• Anabolic steroids 
• DHEA 
• Other hormonal products 
• CYP3A4  inhibitors,  e.g.  atazanavir,  clarithromycin,  indinavir, 
itraconazole,  ketoconazole,  nefazodone,  nelfinavir,  ritonavir,  saquinavir, 
telithromycin, omeprazole. 
• St. John’s Wort 
• Spironolactone 
• Cimetidine 
 
12.3 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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13. 
STATISTICAL METHODS  
13.1 Determination of Sample Size 
Up  
to 60  
female  subjects, 20  per  dose  arm,  meeting  
the  
inclusion/exclusion 
criteria will be randomized in a 1-1-1 fashion.  The sample size was powered 
based on the two-sample t-test that will be used to make pairwise comparisons 
between  treatment  groups.   
 a 
-
y 
is 
e 
a.     
S 
d 
 
a sample of 18 
subjects  per  group  would provide 80%  power  to  detect  a  statistically 
significant difference between the treatment groups.     
13.2  Statistical and Analytical Plan 
A statistical analysis will be conducted once all subjects have completed the 
placebo-controlled portion of the study, Stage 2.  A Statistical Analysis Plan 
will be developed that outlines in detail all planned analyses.  This document 
will  be  completed  prior  
to  unblinding  study  data  for  
the  placebo-controlled 
portion of the study.   
A separate analysis and reporting will occur once all subjects have completed 
all  study  
treatment.  
  A separate Statistical  Analysis  Plan  will  describe  
these 
analyses.   This  summary  will  focus  on  the  results  noted  in  Stage  3  of  the 
study. 
13.2.1 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. 
13.2.2 Efficacy Analyses 
An  analysis  will  be  conducted  once  Stage  2,  the first  cycle  of 
treatment, has been completed.  A later analysis will focus on the data 
collected from the active treatment stage of the study, Stage 3. 
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Efficacy  analyses of  
the first  cycle  of  
treatment will  be conducted  
in 
the  
Intent-to-Treat  population,  which  will  consist  of  all  subjects  who 
are  randomized and who  receive  study  drug.  
 Subjects  with  missing 
post-baseline  data  will  have  a  value  of  “no  change”  imputed  for 
analysis. 
13.2.2.1 Prescription Analgesic Usage 
The change  and percent change  in  daily  average  use  of 
prescription analgesics comparing the baseline menstrual cycle 
(28 days) to the 28 days leading up to the last day of dosing in 
Cycle  1 (Week  18) will  be summarized  for  each  treatment 
group.  For each subject, the total number of pills or tablets of 
prescription analgesics during each 28 day menstrual cycle will 
be  calculated,  and  the  daily  average  use  of prescription 
analgesics will be determined by dividing the total number of 
pills/tablets of prescription analgesics taken during the 28 day 
nominal period by 28.  The percent change from baseline in the 
prescription analgesic usage will be determined by subtracting 
the baseline prescription analgesic usage from the prescription 
analgesic usage during the last nominal 28 day menstrual cycle, 
dividing  by  the  baseline prescription analgesic  usage,  and 
multiplying by 100%. 
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed using a one-way Analysis of Covariance, including 
the  baseline prescription analgesic usage  and  
treatment  group 
in  
the  model.  
  Pairwise  comparisons  of  
the  
treatment  groups 
will  be  made  using a two-sample  t-test.    While  the  primary 
assessment  will be  based  on  Visit  12  (after  18  weeks  of 
treatment)  summaries  will  also  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. 
Changes  in  prescription  analgesic  use  during  the active 
treatment stage of the study (Stage 3) will also be summarized. 
13.2.2.2  Over the Counter Analgesic Usage 
The change in daily average use of over the counter analgesics 
comparing  the  baseline  menstrual  cycle  to  a  similar  period 
leading up to the last day of dosing in Cycle 1 (Week 18) will 
be summarized for each treatment group.  For each subject, the 
total  number  of  doses  of  over  the  counter  analgesics  during 
each menstrual cycle will be calculated, and the  daily average 
use  of  over  the  counter  analgesics  will  be  determined  by 
dividing  the  total  number  of  doses  of  over  the  counter 
analgesics  by  the  number  of  days  in  the  menstrual  cycle 
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(number of doses per day).  The percent change from baseline 
in the over the  counter  analgesic usage will  be determined by 
subtracting the baseline over the counter analgesic usage from 
the  over the  counter  analgesic  usage  during  each  menstrual 
cycle,  dividing  by  the  baseline  over  the  counter  analgesic 
usage, and multiplying by 100%. 
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed using a one-way Analysis of Covariance, including 
the  baseline over  the  counter analgesic  usage  and  treatment 
group  in  the  model.   Pairwise  comparisons  of  the  treatment 
groups  will  be  made  using a two-sample  t-test.   While  the 
primary assessment will be based on  Visit 12 (after 18 weeks 
of  
treatment) summaries  will  also  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. 
Changes  in  over  the  counter  analgesic  use  during  the active 
treatment stage of the study (Stage 3) will also be summarized. 
13.2.2.3 Overall Analgesic Use 
The change  and  percent  change  in  daily  average  use  of  all 
analgesics  (prescription  and  over  the  counter)  comparing  the 
baseline menstrual cycle (28 days) to the 28 days leading up to 
the  last  day  of  dosing in  Cycle  1 (Week  18) will  be 
summarized  for  each  treatment  group.  
  For  each  subject,  the 
total number of pills or tablets of analgesics taken during each 
28  day  menstrual cycle  will  be  calculated,  and  the  daily 
average  use  of  prescription  analgesics  will  be  determined  by 
dividing  the  total  number  of  pills/tablets  of  analgesics  taken 
during the 28 day nominal period by 28.  
 The percent change 
from  baseline  in  the  analgesic  usage  will  be  determined  by 
subtracting  the  baseline  analgesic  usage  from  the  analgesic 
usage during the last nominal 28 day menstrual cycle, dividing 
by the baseline analgesic usage, and multiplying by 100%. 
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed using a one-way  Analysis of Covariance, including 
the baseline analgesic usage and treatment group in the model.  
Pairwise  comparisons  of  the  treatment  groups  will  be  made 
using a two-sample t-test.  While the primary assessment will 
be based on Visit 12 (after 18 weeks of treatment) summaries 
will  also  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. 
Changes  
in  analgesic  use  during  
the  active  
treatment  stage  of 
the study (Stage 3) will also be summarized. 
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13.2.2.4 BBSS Physician Reported Scores 
The BBSS  score  incorporating  the  two  physician-reported 
scores  will  be  analyzed  to  compare  the  baseline  menstrual 
cycle to a similar period leading up to the last day of dosing in 
Cycle  1 (Week  18).    An  overall  comparison  among  the  3 
treatment groups will be performed using a one-way  Analysis 
of Covariance, including baseline BBSS score and treatment in 
the model.  Pairwise comparisons of the treatment groups will 
be made using a t-test.  While the primary assessment will be 
based on Visit 12 (after 18 weeks of treatment) summaries will 
also  be  prepared  for  each  of  the other visits. 
 
The  BBSS  patient  and  physician  scores  during  the active 
treatment stage of the study (Stage 3) will also be summarized. 
13.2.2.5 BBSS Patient Reported Scores 
The percent change from baseline in each of the daily average 
combined BBSS  patient-reported  scores (dysmenorrhea, 
dyspareunia and non-menstrual pelvic pain) will be analyzed to 
compare the  baseline  menstrual  cycle  to  a  similar  period 
leading up to the last day of dosing in Cycle 1 (Week 18).  An 
overall  comparison  among  the 3  treatment  groups  will  be 
performed using a one-way  Analysis of Covariance, including 
baseline  BBSS  score  and  treatment  in  the  model.   Pairwise 
comparisons of the treatment groups will be made using a two-
sample t-test.  While the primary assessment will be based on 
Visit 12 (after 18 weeks of treatment) summaries will also be 
prepared for each of the other visits. 
 
 
 
The  BBSS  patient  scores  during  
the active  
treatment stage  of 
the study (stage 3) will also be summarized 
13.2.2.6  Menstrual or Non-menstrual Vaginal Bleeding 
The  number  of  days  and  intensity  of  menstrual  and  non-
menstrual vaginal bleeding will be summarized from the diary 
data.  
  The  
total  number  of  days  and  average  
intensity  will  be 
summarized  from  the  days  preceding  each  visit.    An  overall 
comparison  among  
the  3  
treatment  groups  will  be  performed 
on both the total number of days and average intensity using a 
one-way  Analysis  of Covariance,  
including  
the  baseline  score 
(number  of  days  or  average  intensity)  and  treatment  in  the 
model.  
 Pairwise  comparisons  of  
the  
treatment  groups  will  be 
made using a two-sample t-test.  While the primary assessment 
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will  be  based  on  Visit 12 (after 18  weeks of  treatment) 
summaries will also be prepared for each of the other visits and 
visit  post-recovery  menses.   If  data  are  missing,  a  last 
observation  carried  
forward  procedure  will  be  used,  
including 
the baseline, if necessary. 
The  number  of  days  and  intensity  of  menstrual  and  non-
menstrual  vaginal  bleeding  will  also  be  summarized  from 
active treatment (Stage 3) diary data collected. 
13.2.2.7 VAS Assessment of Pain 
The percentage  change  
from  baseline  VAS  pain  score  will  be 
analyzed within treatment group and between treatment groups.    
An  overall  comparison  among  
the  3  
treatment  groups  will  be 
performed  using  a  one-way  Analysis  of Variance.   Pairwise 
comparisons of the treatment groups will be made using t-test 
or  non-parametric  test  as  appropriate.   While  the  primary 
assessment will be based on scores at Visit 12 (after 18 weeks 
of treatment), summaries will also 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. 
The  VAS  pain  scores  collected  during  the  active  treatment 
stage of the study (Stage 3) will also be summarized. 
13.2.2.8 Assessment of Pain Using the NRS 
The average daily assessment will be calculated separately for 
dysmenorrhea and pelvic pain within each key 28-day baseline 
and  treatment  period.  The percentage  change  from  baseline 
NRS pain  score  will  be  analyzed  within  
treatment  group  and 
between treatment groups.  An overall comparison among the 3 
treatment groups will be performed using a one-way  Analysis 
of Variance.    Pairwise  comparisons  of  the  treatment  groups 
will be made using t-test or non-parametric test as appropriate.  
While  
the  primary  assessment  will  be  based  on scores  during 
the  28-day  period  prior  to Visit 12 (after 18  weeks  of 
treatment), summaries  will  also  be  prepared  for  each  of  the 
other visits.   
The average daily assessment of dysmenorrhea and pelvic pain 
scores  collected  during  
the  active  
treatment stage of the study 
(Stage 3) will also be summarized. 
 
 
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a. 
m 
al 
nd 
al 
dy 
p 
y.    
he 
ge 
d 
e 
d 
er 
al 
al 
  
 
  
13.3  General Statistical Issues 
A  Statistical  Analysis  Plan  
(SAP)  will  be  developed  prior  
to  
the  analyses  of 
the first  cycle of  treatment.    Two  analyses  will  be  conducted.    The  first 
analysis  will  occur  when  all  subjects  have  completed  the  first  cycle  of 
treatment (Week 18) and the second with be conducted once all subjects have 
completed the active treatment stage of the study (Stage 3).   
 
 
  Statistical 
significance  will  be  declared  if  the  two-sided  p-value  
is  ≤  0.05.  
  Since  the 
study  was  not  powered  for  efficacy  assessments  based  on  statistical 
hypotheses,  the  p-values  reported  at  the  conclusion  of  the  study  are  being 
reported  
to  quantify  
the  difference  
in  
the  
treatment  effect  between  
treatment 
groups.   
r 
 
 
 
 
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14. 
ETHICS 
14.1 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. 
14.2  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. 
14.3  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. 
14.4 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. 
14.5  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: 
 
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1. Monitoring  study  conduct  to  ensure  that  the  rights  of  subjects  are 
protected; 
2. Monitoring study conduct to ensure trial compliance with GCP guidelines; 
and 
3. Monitoring accuracy, completion and verification from source documents 
of study data. 
14.6 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. 
14.7 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. 
 
 
27AUG2018 Abbreviated CSR ZPE-202
581


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
 
Page 52 of 65 
 
15. 
INVESTIGATOR'S STATEMENT 
I  have  reviewed  the  ZPE-202 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 
27AUG2018 Abbreviated CSR ZPE-202
582


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
 
Page 53 of 65 
27AUG2018 Abbreviated CSR ZPE-202
583


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
 
Page 54 of 65 
27AUG2018 Abbreviated CSR ZPE-202
584


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
 
Page 55 of 65 
27AUG2018 Abbreviated CSR ZPE-202
585


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US  
Page 56 of 65 
 
27AUG2018 Abbreviated CSR ZPE-202
586


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US  
Page 57 of 65 
27AUG2018 Abbreviated CSR ZPE-202
587


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 58 of 65 
 
27AUG2018 Abbreviated CSR ZPE-202
588


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 59 of 65 
 
27AUG2018 Abbreviated CSR ZPE-202
589


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 60 of 65 
27AUG2018 Abbreviated CSR ZPE-202
590


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 61 of 65 
 
27AUG2018 Abbreviated CSR ZPE-202
591


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 62 of 65 
27AUG2018 Abbreviated CSR ZPE-202
592


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 63 of 65 
 
27AUG2018 Abbreviated CSR ZPE-202
593


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
  
Page 64 of 65 
27AUG2018 Abbreviated CSR ZPE-202
594


Repros Therapeutics Inc. 
 
March 2, 2016 
Protocol ZPE-202, Amendment 9US 
Page 65 of 65 
27AUG2018 Abbreviated CSR ZPE-202
595

SAP_000.pdf: 
 
NCT01728454 
 
Study ID: ZPE-202 
 
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 Date: 30 August 2016