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 Orally in the Treatment of Premenopausal Women With Confirmed Symptomatic Uterine Fibroids
Phase: PHASE2
Conditions: Uterine Fibroids
Sponsor: Repros Therapeutics Inc.

*Any inconsistent numbering or deletion of pages is due to the removal of a full protocol due to its 
summary of changes being supplied.  
NCT02301897 
 
Study ID: ZPU-203 
 
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 Orally in 
the Treatment of Premenopausal Women With Confirmed Symptomatic Uterine Fibroids 
 
Protocol Amendment 5 Date: 20 June 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ZPU-203 Amendment 1 Summary of Changes 
ZPU-203 Protocol Amendment 1 Summary of Changes 
Protocol Title:   
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of  6  and  12  mg  Proellex®  (Telapristone  Acetate)  Administered  Orally  in  the  Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Original Protocol dated January 29, 2014  
To: Protocol Amendment 1 dated November 14, 2014 
Reason for Amendment: 
Study  split  
into  2  protocols, ZPU-203 Am 1 one  
for  2  courses of  
treatment  and  a  separate  Extension 
Study for further treatment 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
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STUDY TITLE 
A  Phase  2/3,  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 Uterine Fibroids 
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  Orally  in  the  Treatment  of 
Premenopausal  Women  with  Confirmed 
Symptomatic Uterine Fibroids 
Change  in  Study 
Design 
PROTOCOL 
SYNOPSIS: Study 
Purpose 
To determine the safety and efficacy of two 
doses of Proellex in premenopausal women 
with  symptomatic  (menorrhagia)  uterine 
fibroids confirmed by ultrasound 
To  determine  
the  safety  and  efficacy  of  
two 
doses of  Proellex  in  premenopausal  women 
with  symptomatic  (menorrhagia)  uterine 
fibroids confirmed by MRI 
Change in study 
design 
PROTOCOL 
SYNOPSIS: Study 
Design and 
Duration 
This study is a phase 2/3 3-arm-study with 2 
18-week  dosing  courses and  an  option  to 
extend treatment for 2 additional courses of 
active  treatment.    The  study  will  be 
conducted in three stages.   
In the first stage, women will receive daily 
single  blind  dosing  with  placebo  prior  to 
enrollment,  until  15  days  after  
the  start  of 
their second menstrual  event. During  this 
This study is a phase 2 3-arm-study with two 
18-week  dosing  courses.  
  The  study  will  be 
conducted in two stages.   
 
 
In  the  first  stage,  women  will undergo a 
baseline assessment  period with no 
treatment,  until  15-20  days  after the  start 
of  their second  or  third menstrual  event. 
Change in Study 
Design 
 
 
Clarification 
 
 
 
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phase  a  pictorial  blood  loss  assessment 
chart  will  be  utilized  as  well  as  sanitary 
products  collected  for  alkaline  hematin 
assay to determine menstrual blood loss. 
 
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  and 
receive  2  18-week  courses  of  treatment  at 
their  randomized  dose  (6mg,  12  mg  or 
placebo),  separated  by  an  off-drug  
interval 
(ODI).  The start of the first 18-week course 
of treatment in this stage should commence 
15-20  days  after  
the  start  of  
their  previous 
menses.  Once dosing for the first course is 
stopped,  subjects  will  be  followed  until 
menses returns.  The start of the second 18 
week  course  of  treatment  will  commence 
15-20  days  after  the  start  of  their  menses 
following withdrawal of drug after the first 
18  week  course has  been  completed.  
During  the  ODI;  subjects  will  continue  to 
record study information in the daily paper 
diary. 
After  completion  of  stage  2  dosing  (2 
courses),  subjects  will  be  
followed  
through 
the  subsequent  6  menses  (recovery  menses 
plus  an  additional  5  menstrual  events.    In 
the event that a subject’s menstrual bleeding 
During  this  phase  a  pictorial  blood  loss 
assessment  chart  will  be  utilized  as  well  as 
sanitary  products  collected  from  their first 
menstrual event, for alkaline hematin assay, 
to  determine  menstrual  blood  loss  and 
confirm eligibility. 
In  the  second  stage,  subjects  will  be 
randomized  into  one  of  3  arms  in  a  1-1-1 
fashion and receive two  18-week  courses  of 
treatment at their randomized dose (6mg, 12 
mg  or  placebo),  separated  by  an  off-drug 
interval (ODI). The start of the first 18-week 
course  of  treatment (Course  1)  should 
commence 15-20 days after the start of their 
previous menses.  Once dosing for Course 1 
is  stopped,  subjects  will  be  followed  until 
menses  
returns.  
  The  start  of  
the  second  18 
week  course  of  treatment (Course  2) will 
commence 15-20 days after the start of their 
menses  following  withdrawal  of  drug  after 
Course  1 has  been  completed.  
  During  the 
ODI, subjects  will  continue  
to  record  study 
information  in  the  daily  paper  diary and 
PBAC charts  as  well  as  collect  sanitary 
products for alkaline hematin assay. 
After completion of stage 2 dosing (Courses 
1  and  2),  subjects  will  be  followed  
through 
the  subsequent  6  menses  (recovery  menses 
plus an additional 5 menstrual events).  In the 
event  that  a  subject’s  menstrual  bleeding 
 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Requirements for 
Alkaline Hematin 
assay added 
 
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returns  to  >80  mL  (assessed  by  PBAC) 
during  
the  6  follow-up  menses,  
the  subject 
will be  offered an additional  2  courses  of 
active  treatment  at  their  randomized  dose.  
Placebo-treated  subjects  will  receive 
treatment  at  12  mg/day.    All  subjects  will 
receive  active  treatment  but  the  treatment 
dose  (6  mg  or  12  mg/day)  will  remain 
double blind.  Throughout the study women 
will record study information in the diary or 
questionnaires  as  outlined  in  the  study 
procedures.  
A  DSMB  will  be  established  before  the 
study starts and will review any liver safety 
events  (LFTs  ≥3  x  ULN  or  bilirubin  ≥2  x 
ULN)  as  well  as  perform an  
interim  safety 
review  after 30 subjects  have  completed  at 
least 8 weeks of treatment. 
returns  to >80  mL  (assessed  by  alkaline 
hematin  assay) at  the  end  of  this  period, 
the subject may be offered the opportunity 
to enroll in an extension study.  Throughout 
the  study  women  will  record  study 
information  in  the  diary, PBAC, and 
questionnaires  as  outlined  in  the  study 
procedures.  
Subjects  will  collect  and  return  used 
sanitary  materials  for  alkaline  hematin 
assay during screening and for the 28 days 
following the end of treatment in Course 1.  
A DSMB will be established before the study 
starts and will review any liver safety events 
(LFTs ≥3 x ULN or bilirubin ≥2 x ULN) as 
well  as  perform  an  interim  safety  review 
after 15 subjects  have  completed  at  least  8 
weeks of treatment. 
 
 
 
 
 
 
 
 
 
 
Change in sample 
size 
PROTOCOL 
SYNOPSIS 
Subject Population 
The  study  will  enroll  healthy  adult,  pre-
menopausal  women  with  confirmed  uterine 
fibroids  via ultrasound and  confirmed 
menorrhagia  (>120  mL  blood  loss  per 
menstrual  cycle  by  historical  PBAC 
assessment, nominal 28 days. 
The  study  will  enroll  healthy  adult,  pre-
menopausal  women  with  confirmed  uterine 
fibroids via MRI and confirmed menorrhagia 
(>120 mL blood loss per menstrual cycle by 
historical  PBAC  assessment,  nominal  28 
days to ensure a MBL of at least 80 mL by 
Alkaline Hematin Assay). 
 
 
Clarification 
PROTOCOL 
SYNOPSIS 
Number of Subjects 
Up to 90 female subjects, 30 per dose arm 
Up to 45 female subjects, 15 per dose arm
 
Change in Sample 
Size 
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PROTOCOL 
SYNOPSIS 
Number of Sites 
Approximately 20 sites 
Approximately 10 sites 
Change in Sample 
Size 
 
 
 
  
  
 
 
  
 
  
 
  
  
 
    
  
 
 
 
 
 
 
 
 
    
  
  
 
 
 
 
 
 
  
  
  
  
  
   
 
  
 
 
 
 
    
 
 
 
   
 
   
  
  
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL 
SYNOPSIS and 
Section 8.1 
Study Endpoints 
The study endpoints will be  
• Change from baseline in total blood loss 
assessed  by  alkaline  hematin  assay  of 
sanitary  products  used  during  
the  study 
comparing  
the  baseline  nominal  28-day 
menstrual  cycle  (including  menstrual 
The primary endpoint will be  
• Percentage  of  subjects  who  become 
amenorrheic after  one  course  of 
treatment 
 
 
 
Change in Primary 
Endpoint 
 
Change in 
secondary 
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event)  
to  a  similar  period  
leading  up  
to 
the last day of dosing at Week 18.  It is 
anticipated  that  subjects  randomized  to 
active treatment will stop menstruating. 
• Percentage  of  subjects  who  become 
amenorrheic.  
• Percentage change from baseline in total 
tumor volume measured by MRI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary endpoints will be: 
• Percentage  of  subjects  who  become 
amenorrheic after 2 courses of treatment 
• Change  from  baseline  in  total  blood 
loss assessed by alkaline hematin assay 
of  sanitary  products  used  during  the 
study  comparing  the  baseline  nominal 
28-day  menstrual  cycle  (including 
menstrual  event)  to  a  similar  period 
leading  up  
to  
the  
last  day  of  dosing  at 
Week 18.  It is anticipated that subjects 
randomized  to  active  treatment  will 
stop menstruating. 
• Percentage  change  
from  baseline  
in  
total 
uterine fibroid volume measured by MRI  
 
 
 
 
 
 
endpoints 
 
 
 
 
 
 
 
 
 
 
Clarification 
PROTOCOL 
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 
Clarification 
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additional  treatment  cycles  which  will  be 
conducted  after  all  subjects  complete 
study treatment and follow-up in Stage 2. 
 
 
 
 
6.0 BACKGROUD 
INFORMATION 
6.6 DSMB 
The board will also conduct a safety review 
of  study  safety  data  (clinical  laboratory 
assessments  and  adverse  events)  after 30 
subjects  have  competed  at  
least  8  weeks  of 
treatment at their randomized dose. 
The  board  will  also  conduct  a  safety  
review 
of  study  safety  data  (clinical  laboratory 
assessments  and  adverse  events)  after 15 
subjects  have  competed  at  least  8  weeks  of 
treatment at their randomized dose. 
Change in sample 
size 
8. TRIAL DESIGN 
8.2.1 Overview of 
study Design 
This study is a phase 2/3 3-arm-study with a 
36 week active dosing period and an option 
to extend treatment for 2 additional courses.  
The study will be conducted in three stages.   
In  
the  
first  stage,  women  will  
receive  daily 
single  blind  dosing  with  placebo  prior  to 
enrollment,  until  15  days  after  the  start  of 
their  second  menstrual  event.    During  this 
phase a pictorial blood loss assessment chart 
will be utilized and sanitary products will be 
collected  for  alkaline  hematin  assay  to 
determine menstrual blood loss.   
 
 
 
 
This study is a phase 2 3-arm-study with a 36 
week active dosing period.  The study will be 
conducted in two stages.   
 
In  the  first  stage,  women  will undergo  a 
baseline  assessment  period,  with  no 
treatment, until 15-20 days after the start of 
their  second or  third menstrual  event.  
During  this  phase  a  pictorial  blood  loss 
assessment  chart  and  daily  diaries  will  be 
utilized.  
 Used  sanitary  products  
from  
the 
first menstrual event will be collected and 
returned to the clinic for alkaline hematin 
assay.    This  assay  will  confirm  subject 
eligibility (MBL must be 80 mL or greater 
by  alkaline  hematin  assay  for  subjects  to 
qualify).  
Change in study 
design 
 
 
Clarification 
 
 
 
 
 
 
Clarification 
 
 
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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(Course 1) 
in this stage of the study should commence 
15-20  days  after  
the  start  of  
their previous 
menses.    Once  active  dosing  is  stopped, 
subjects  will  be  followed  until  menses 
returns.    The  start  of  the  second  18  week 
dosing  period  (Course  2)  will  commence 
15-20  days  after  the  start  of  their  menses 
following  withdrawal  of  drug  after  
the first 
18  weeks  are completed.    During  the  non 
dosing  off-drug  interval;  subjects  will 
continue  
to  
record  study  
information  
in  
the 
daily paper diary. 
 
Subjects  will  be  followed  through  the 
subsequent  recovery  menses  and  for  an 
additional 5 menstrual events.  In the event 
that  a  subject’s  menstrual  bleeding  returns 
to  >80  mL  during  
the 6  
follow-up  menses, 
the  subject will be  offered an  additional  2 
courses of active treatment (6 or 12 mg  
for 
women  randomized to active  treatment in 
the  second  stage  or  12  mg  for  women 
randomized  to  placebo)  and  followed  in  a 
similar  fashion  as  before  (stage  3).  
Throughout  the  study  women  will  record 
study  information  in  the diary  or 
In  the  second  stage,  subjects  will  be 
randomized  into  one  of  3  arms  in  a  1-1-1 
fashion.    The  start  of  the  18  week  dosing 
period  (Course  1)  
in  
this  stage  of  
the  study 
should  commence  15-20  days  after  
the  start 
of  their first menses after  Visit  2.    Once 
active  dosing  is  stopped,  subjects  will  be 
followed  until  menses  returns.  
  The  start  of 
the second 18 week dosing period (Course 2) 
will  commence  15-20  days  after  
the  start  of 
their  menses  following  withdrawal  of  drug 
after  Course  1  has  been  completed.  
  During 
the  non  dosing  off-drug  interval  (ODI), 
subjects  will  continue  to  record  study 
information  in  the  daily  paper  diary  and 
PBAC charts. 
 
Subjects  will  be  followed  through  the 
subsequent recovery menses and for up to an 
additional  5  menstrual  events.  
  In  
the  event 
that a subject’s menstrual bleeding returns to 
≥80  mL (by  PBAC)  at  any  time  after  the 
first  recovery  menses,  during  the 
subsequent  5  
follow-up  menses,  
the  subject 
may be offered the opportunity to enroll in 
an  extension  study.  
 Throughout  the  study 
women  will  record  study  
information  
in  
the 
diary  or  questionnaires  as  outlined  in  the 
study procedures.  
 
 
 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
Change in study 
design 
 
 
 
 
 
 
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questionnaires  as  outlined  in  the  study 
procedures.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instructions for 
Alkaline Hematin 
Assay Added 
 
 
 
 
 
 
 
 
 
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A  DSMB  will  be  established  before  the 
study starts and will review any liver safety 
events  (LFTs  ≥3  x  ULN  or  bilirubin  ≥2  x 
ULN)  as  well  as  perform  an  
interim  safety 
review  after 30 subjects  have  completed  at 
least 8 weeks of treatment. 
 
 
 
 
 
  
  
  
   
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
A DSMB will be established before the study 
starts and will review any liver safety events 
(LFTs ≥3 x ULN or bilirubin ≥2 x ULN) as 
well  as  perform  an  interim  safety  review 
after 15 subjects  have  completed  at  least  8 
weeks of treatment. 
The  primary  efficacy  analysis  will  be 
conducted  when  all  subjects  complete  the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Change in sample 
size 
 
 
 
Clarification 
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first cycle of treatment.  A second analysis 
will  summarize  the  subject’s  second 
treatment  cycle  which  will  be  conducted 
after all subjects complete study treatment 
and follow-up. 
 
8.2.3 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  a 
total  of  36  weeks  (two  18  week  courses 
followed  by  an  ODI  before  the second 
course of dosing is started.  After the second 
treatment  course  is  completed  the  subjects 
will  be  followed  for  6  menstrual  events  to 
determine  durability  of  effect  of  treatment.  
If  subjects  return  to  a PBAC  score  of  >80 
they  may  elect  to  receive  two  additional 
courses of treatment.  As before, dosing will 
commence only after a recovery menses has 
been  experienced.  
  Subjects  randomized  to 
either  
the  6  or  12  mg  dose  will  remain  on 
the  same  dose  unless  
in  
the  opinion  of  
the 
investigator the 6 mg dose was insufficiently 
effective  
(i.e.  
failure  
to  
induce  amenorrhea, 
defined  as  the  last  28  days  of  Course  1 
bleeding intensity no greater than 1).  In that 
case those women would up-titrate to the 12 
mg  dose.    Subjects  randomized  to  placebo 
At  Visit  3,  subjects  will  be  randomized  to 
treatment in Arms 1, 2, or 3.  Subjects will be 
treated with one capsule daily of 6 mg or 12 
mg  of  Proellex,  or  placebo,  which  will  be 
administered for a total of 36 weeks (two 18 
week courses followed by an ODI) before the 
6 cycle follow up is started.  After the second 
treatment  course  is  completed  the  subjects 
will  be  followed  for  6  menstrual  events  to 
determine durability of effect of treatment.  If 
subjects  
return  
to  a MBL  score  of  >80  mL 
at  the  end  of  this  period,  assessed  by 
alkaline  hematin  assay,  they  may  be 
offered  the  opportunity  to  enroll  in  an 
extension study.  Each treatment course will 
be separated by an ODI.  Blinded treatments 
kits  will  be  randomized  and  distributed  by 
the packaging company.  
 
 
 
 
 
 
 
 
 
Change in study 
design 
 
 
 
Change in study 
design 
 
 
 
 
 
 
 
 
 
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treatment  will  receive  treatment  at  12 
mg/day.   Each  treatment  course  will  be 
separated  by  an  ODI.    Blinded  treatments 
kits  will  be  randomized  and  distributed  by 
the packaging company.    
 
 
 
For  the  statistical  analysis  at  the  end  of  the 
first  course  of  
treatment,  only  statistical  staff 
will be unblinded.  All clinical operations staff 
and  staff  at  investigative  sites  will  remain 
blinded until completion of the study. 
 
 
 
Clarification 
8.2.4 Study 
Medication  
Test drug, Proellex, will be supplied in 30 count 
bottles  and  will  be  packaged  by  a  clinical 
supplies  contract  vendor  designated  by  Repros 
Therapeutics  Inc.    The  placebo  will  also  be 
supplied in 30 count bottles  
Test  drug,  Proellex  will  be  supplied  
in 40  count 
bottles  and  will  be  packaged  by  a  clinical 
supplies  contract  vendor  designated  by  Repros 
Therapeutics  Inc.    The placebo  will  also  be 
supplied in 40 count bottles  
Change is Study 
Medication 
packaging quantity  
 
 
 
 
 
  
 
 
    
  
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
    
  
  
  
 
 
 
    
  
  
  
 
 
 
  
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8.3.1 Inclusion 
Criteria 
Subjects must meet the following criteria: 
• Healthy adult females between 18 and 47 
years of age experiencing  menorrhagia 
due to confirmed uterine fibroids. 
 
 
 
 
 
 
Subjects must meet the following criteria: 
• Otherwise healthy adult females between 
18 and 47 years  
• Subject  has  a  history  of  at  least  3 
regular  menstrual  cycles  in  which 
menorrhagia is due to uterine fibroids. 
 
 
 
 
 
 
Change in 
Inclusion Criteria 
 
 
 
 
 
 
 
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• History  of  menstrual  events  occurring  
in 
regular cycles 
 
 
 
  
    
 
 
 
 
 
  
  
  
  
 
  
  
  
 
 
 
 
 
 
• Visit  1  historical PBAC  of  >120  mL  of 
blood loss 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
  
 
 
 
 
• Visit  1  historical  PBAC  of  >120  mL  of 
blood  loss, to ensure  subjects  have  a 
MBL  of  at  least  80  mL  by  Alkaline 
Hematin Assay. 
 
 
 
 
 
 
 
 
Clarification 
 
 
 
 
 
 
 
 
 
Change in Study 
Design 
 
8.3.2 Exclusion 
Criteria 
• Subject  is  pregnant  or  lactating  or  is 
attempting  or  expecting  to  become 
pregnant  during  the 6-7  month study 
period 
 
• Subject  is  pregnant or  lactating  or  is 
attempting  or  expecting  to  become 
pregnant during the entire study period
 
 
Change in 
Exclusion Criteria 
 
 
 
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Has  an  IUD  in  place. Copper  IUDs 
(non-hormone  containing  will  be 
permitted)  
 
 
 
 
 
 
 
 
 
  
 
 
• Has an IUD in place 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Addition of 
Exclusion Criteria 
 
 
 
  
  
  
 
   
 
 
  
  
 
 
 
 
    
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CHANGE 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12DEC2018 Abbreviated CSR ZPU-203
150

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151

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12DEC2018 Abbreviated CSR ZPU-203
152

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12DEC2018 Abbreviated CSR ZPU-203
153

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12DEC2018 Abbreviated CSR ZPU-203
154

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… 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
    
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
12DEC2018 Abbreviated CSR ZPU-203
155

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12DEC2018 Abbreviated CSR ZPU-203
156

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12DEC2018 Abbreviated CSR ZPU-203
157

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12DEC2018 Abbreviated CSR ZPU-203
158

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12DEC2018 Abbreviated CSR ZPU-203
159

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12DEC2018 Abbreviated CSR ZPU-203
160

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12DEC2018 Abbreviated CSR ZPU-203
161

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10 ASSESSMENT 
OF EFFICACY 
 
Entire  section  deleted,  subsequent  sections 
renumbered 
Repeated 
Information 
Deleted 
10.1.1 Reporting 
Adverse 
Experiences 
Any AE (clinical sign, symptom, or disease) 
temporally  associated  with  the  use  of  this 
investigational  drug,  whether  or  not 
considered  related  to  the  investigational 
product,  shall  be  documented  on  
the  CRF.  
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. 
Any AE (clinical sign, symptom, or disease) 
temporally  associated  with  the  use of  this 
investigational  drug,  whether  or  not 
considered  related  to  the  investigational 
product,  shall  be  documented  on  the  CRF 
and eDC.  All SAEs and AEs reported by the 
subject  or  observed  by  the  Principal 
Investigator for up to 30 days after the last 
dose  of  study  medication will  be 
individually listed.  After Visit 20, all SAEs 
and  any  adverse  events  that  the 
Addition of SAE 
Requirements & 
Clarification  
12DEC2018 Abbreviated CSR ZPU-203
162

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investigator  considers  to  be  due  to  the 
study  drug  (e.g.  hepatotoxicity)  and  not 
those  considered  to  be  due  to  withdrawal 
of the drug (e.g. vaginal bleeding), will be 
collected.  The signs and symptoms, time of 
onset (24-hour clock), duration, action taken 
and follow-up procedures will be reported.  
10 ASSESSMENT 
OF SAFETY 
10.1.2 Definitions 
and 10.1.3 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. 
FDA Requirement 
Added 
10.1.3 Serious 
Adverse Events 
(SAEs) 
The  Principal  Investigator  shall  document 
all SAEs  
in  a  subject  receiving  study  drug 
or  during  30  days  following  the  last  dose 
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.   
The Principal Investigator shall document all 
SAEs in a subject receiving study drug until 
completion  of  the  study and  must  be 
reported  to  the  Repros  Therapeutics  Inc. 
Safety  Monitor  within  24  hours  by  Fax  or 
telephone,  even  
if  
the  SAE  does  not  appear 
to be drug-related. 
  
Clarification 
11. 
CONCOMITANT 
MEDICATIONS 
11.1 Prohibited 
Medications 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
12DEC2018 Abbreviated CSR ZPU-203
163

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12. STATISTICAL 
METHODS 
12.1 Determinations 
of Sample Size 
Up to 90 female  
subjects, 30 per dose arm, 
meeting the inclusion/exclusion criteria will 
be  randomized  in  a  1-1-1  fashion.  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
   
Up  
to 45 female  subjects, 15 per  dose  arm, 
meeting  the  inclusion/exclusion  criteria  will 
be  randomized  in  a  1-1-1  fashion.   The 
primary  endpoint  
is  amenorrhea.  
  
 
    
  
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
    
 
 
 
 
 
Change in sample 
size 
Change in Primary 
Endpoint 
12.2.2 Efficacy 
Analyses   
Efficacy  analyses  will  be  conducted  in  the 
Intent-to-Treat  population,  which  will 
A  Statistical  Analysis  Plan  (SAP)  will  be 
prepared prior to unblinding of the study 
Addition of SAP  
12DEC2018 Abbreviated CSR ZPU-203
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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. 
data.  Efficacy analyses will be conducted in 
the Intent-to-Treat  population,  which  will 
consist  of  all  subjects  who  are  randomized 
and who receive study drug. 
12.2.2.1 Primary 
Endpoint: Incidence 
of Amenorrhea 
Primary  Endpoint: Change  in  Alkaline 
Hematin Assay from Baseline to End of last 
28 days of dosing (Week 18) 
The  change  and  percent  change  in  the 
alkaline  hematin  assay  comparing  the 
baseline menstrual cycle (28 days) to the 28 
days leading up to the last day of dosing in 
Course 1 (Week 18)  will be summarized for 
each treatment group.   
The primary  efficacy analysis will compare 
the  pooled  Proellex  dose  to  the  placebo 
group with a t-test.  Pairwise comparisons of 
the  treatment  groups  will  be  made  using  a 
two-sample t-test. Within group paired tests 
will also be used to assess treatment  effect.  
Non-parametric methods will be employeed 
as  appropriate.    If  data  are  missing,  a  last 
observation  carried  forward  procedure  will 
be used, including the baseline, if necessary.   
Change  in  blood  loss  assessed  by  alkaline 
hematin  will  also  be  evaluated  in  each  28 
day period and during the ODI. 
Primary  
Endpoint: 
Incidence  
of 
Amenorrhea 
The  percentage  of  subjects  who  become 
amenorrheic  during  the  28  days  leading 
up  to  the  last  day  of  dosing  at  Week  18 
will  be  compared  by  Chi-Square  test.  
Amenorrhea  after  a  second  course  of 
treatment will be analyzed as a secondary 
endpoint.  Testing will evaluate the pooled 
Proellex  doses  compared  
to  placebo,  each 
Prollex  dose  compared  
to  Placebo  as  well 
as  compare  the  active  dose  groups.    A 
Fisher’s  Exact  test  will  be  utilized  if  the 
cell sizes are small.  
A  subject  is  deemed  amenorrheic  if  they 
have  no  bleeding  intensity  score  greater 
than  1 using  the  Daily  Diary  Card  in 
Appendix  3  (spotting  not  requiring 
hygiene  products)  during  the  28  day 
period. 
Change in Primary 
Endpoint 
12.2.2.2 Secondary 
Endpoints 
Incidence of Amenorrhea 
The  percentage  of  subjects  who  become 
Change  in  Alkaline  Hematin  Assay  from 
Baseline  
to  End  of  Last  28  days  of  Dosing 
(Week 18) 
Change in 
Secondary 
Endpoint 
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amenorrheic  during  
the  28  days  
leading  up 
to the last day of dosing at Week 18 will be 
compared  by  Chi-Square  
test.  
  Testing  will 
evaluate  the  pooled  Proellex  doses 
compared  to  Placebo,  each  Prollex  dose 
compared to Placebo as well as compare the 
active  dose  groups.    A  Fisher’s  Exact  test 
will be utilized if the cell sizes are small.  
A  subject  is  deemed  amenorrheic  if  they 
have no bleeding intensity score greater than 
1  (spotting  not  requiring  hygene  products) 
during the 28 day period.   
 
 
 
 
The  change  and  percent  change  in  the 
alkaline  hematin  assay  comparing  the 
baseline  menstrual  cycle  (28  days)  to  the 
28 days leading up to the last day of dosing 
in  Course  1  (Week  18)    will  be 
summarized for each treatment group.   
The  primary  efficacy  analysis  will 
compare  the  pooled  Proellex  dose  to  the 
placebo  group  with  a  t-test.    Pairwise 
comparisons  of  the  treatment  groups  will 
be made using a two-sample t-test. Within 
group  paired  tests  will  also  be  used  to 
assess  treatment  effect.    Non-parametric 
methods will be employed as appropriate.  
If  data  are  missing,  a  last  observation 
carried  forward  procedure  will  be  used, 
including the baseline, if necessary.   
Change  
in  blood  
loss  assessed  by  alkaline 
hematin  will  also  be  evaluated  
in  each  28 
day period and during the ODI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
12DEC2018 Abbreviated CSR ZPU-203
166

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12DEC2018 Abbreviated CSR ZPU-203
167

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12DEC2018 Abbreviated CSR ZPU-203
168

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12DEC2018 Abbreviated CSR ZPU-203
169

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12DEC2018 Abbreviated CSR ZPU-203
170

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12DEC2018 Abbreviated CSR ZPU-203
171

Page 1 of 10 
ZPU-203 Amendment 2 Summary of Changes 
ZPU-203 Protocol Amendment 2 Summary of Changes 
 
Protocol Title:   
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of  6  and  12  mg  Proellex®  (Telapristone  Acetate)  Administered  Orally  in  the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Amendment 1, dated November 14, 2014  
To: Protocol Amendment 2 dated February 24, 2015 
Reason for Amendment: 
Change procedures, make corrections, add clarifications and change eligibility criteria 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
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PROTOCOL 
SYNOPSIS: Study 
Population  
 
Subjects  with  evidence  of  prior  heavy 
blood  loss  may be  enrolled  at  the 
sponsor’s discretion. 
Change in 
eligibility 
requirements 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
Correction 
 
 
 
 
 
 
12DEC2018 Abbreviated CSR ZPU-203
235

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236

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8. TRIAL DESIGN 
8.2.1 Overview of 
study Design 
In  the  first  stage,  women  will  undergo  a 
baseline  assessment  period,  with  no 
treatment, until 15-20 days after the start of 
their second or third menstrual event.  
 
 
 
 
 
 
 
 
 
 
 
 
  
In  the  first  stage,  women  will  undergo  a 
baseline  assessment  period,  with  no 
treatment, until 15-20 days after the start of 
their second complete menstrual event.  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
   
Change in 
procedures 
 
 
 
 
 
 
 
 
8.3.1 Inclusion 
• Subject  has  a  history  of  at  least  3 • Subject has a history of at least 3 regular Clarification 
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237

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Criteria 
regular  menstrual  cycles  in  which 
menorrhagia is due to uterine fibroids 
 
 
 
 
 
  
  
   
 
 
 
 
• Visit 1 historical PBAC  of >120 mL  of 
blood  loss,  to  ensure  subjects  have  a 
MBL  of  at  least  80  mL  by  Alkaline 
Hematin  Assay  (during  the  baseline 
assessment period).   
menstrual cycles in which menorrhagia is 
due  to  uterine  fibroids (a  past  or 
concurrent diagnosis of uterine fibroids 
is acceptable). 
 
 
 
 
 
 
 
 
 
 
• Visit  1  historical  PBAC  of  >120  mL  of 
blood loss, unless approved by sponsor, 
to ensure subjects have a MBL of at least 
80  mL  by  Alkaline  Hematin Assay 
(during  the  baseline  assessment  period).  
Subjects  with  evidence  of  prior  heavy 
blood  loss  may  be  enrolled  at  the 
sponsor’s discretion. 
 
 
 
 
 
 
New procedure 
8.3.2 Exclusion 
Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12DEC2018 Abbreviated CSR ZPU-203
238

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12DEC2018 Abbreviated CSR ZPU-203
239

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12DEC2018 Abbreviated CSR ZPU-203
240

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12DEC2018 Abbreviated CSR ZPU-203
241

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12. Statistical 
Methods 
12.2 Statistical and 
Analytical Plan 
 
A  Statistical  Analysis  Plan  (SAP)  will  be 
prepared  prior  to  unblinding  the  data.  
The  first  efficacy  analysis  will  be 
conducted when all subjects complete the 
first cycle of treatment.  A second analysis 
will  summarize  the  subject’s  additional 
treatment  cycles  which  will be  conducted 
after  all  subjects  complete  study 
treatment  and  follow-up  in  Stage  2.  In 
this  Phase  2  study  there  will  be  no 
statistical corrections for interim analyses 
or multiple comparisons.   
For  the  statistical  analysis  at  the  end  of 
the  first  course  of  treatment,  only 
statistical  staff  will  be  unblinded.    All 
clinical  operations  staff  and  staff  at 
investigative  sites  will  remain  blinded 
until completion of the study. 
Clarification 
12DEC2018 Abbreviated CSR ZPU-203
242

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12DEC2018 Abbreviated CSR ZPU-203
243

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12DEC2018 Abbreviated CSR ZPU-203
244

Page 1 of 2 
ZPU-203 Amendment 3 Summary of Changes 
ZPU-203 Amendment 3 Protocol Summary of Changes 
 
Protocol Title:   
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of  6  and  12  mg  Proellex®  (Telapristone  Acetate)  Administered  Orally  in  the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Protocol Amendment 2 dated February 24, 2015  
To: Protocol Amendment 3 dated September 4, 
2015 
Reason for Amendment:  
Changes study requirements for endometrial stripe ≥18mm. 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
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REASON 
FOR 
CHANGE 
 
 
 
 
 
 
 
  
  
  
  
  
 
   
 
 
 
 
 
 
 
 
 
    
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
   
  
 
 
  
 
 
  
 
  
 
  
 
 
12DEC2018 Abbreviated CSR ZPU-203
304

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12DEC2018 Abbreviated CSR ZPU-203
305

Page 1 of 2 
ZPU-203 Amendment 4 Summary of Changes 
ZPU-203 Amendment 4 Protocol Summary of Changes 
 
Protocol Title:   
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of  6  and  12  mg  Proellex®  (Telapristone  Acetate)  Administered  Orally  in  the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Protocol Amendment 3 dated September 4, 2015  
To: Protocol Amendment 4 dated April 5, 2016 
Reason for Amendment:  
Addition of Alkaline Hematin Assay at the end of Course 2 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
SECTION 
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CHANGE 
Protocol Synopsis-
Study Design and 
Duration of 
Treatment 
Subjects  will  collect  and  
return  used  sanitary 
materials for  alkaline  hematin  assay  
for  
their 
first menstrual event during screening, for the 
recovery  menses  following  Courses  1 and  2 
and  for  the  2
nd,  4
th and  6
th menstrual  cycles 
after end of treatment in Course 2. 
Subjects  will  collect  and  return  used  sanitary 
materials  for  alkaline  hematin  assay  for  their 
first  menstrual  event  during  screening,  
for  
the 
recovery  menses  following  Course  1, for  the 
28  days leading  up  
to  
the  end  of  
treatment 
in  Course  2,  and  for  the  1
st,  2
nd,  4
th and  6
th 
menstrual  cycles  after  end  of  treatment  in 
Course 2. 
Addition  of 
Alkaline 
Hematin  assay 
at  the  end  of 
Course 2 
8.2.1 Overview of 
Study Design 
 
Statement added: 
Sanitary products will be collected for alkaline 
hematin assay during the following timepoints: 
• From  the  28  days  leading  up  to  end  of 
treatment  
in  Course  2  (Visit  17  to Visit 
18) 
Addition of 
Alkaline 
Hematin assay 
at the end of 
Course 2 
  
 
 
 
  
 
 
 
 
 
 
 
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382

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ZPU-203 Amendment 4 Summary of Changes 
SECTION 
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FOR 
CHANGE 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Charts and footnotes were updated to reflect the changes above. 
12DEC2018 Abbreviated CSR ZPU-203
383

12DEC2018 Abbreviated CSR ZPU-203
384

Repros Therapeutics Inc. 
 
June 20, 2016 
Protocol ZPU-203, Amendment 5 
Page 2 of 57 
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 
8.1.1 
Primary Efficacy Endpoint 
............................................................................................... 21 
8.1.2 
Secondary Endpoints 
........................................................................................................ 21 
 
8.2 
STUDY DESIGN 
.................................................................................................................... 22 
8.2.1 
Overview of Study Design 
................................................................................................ 22 
8.2.2 
Study Drug Accountability 
............................................................................................... 24 
8.2.3 
Randomization and Blinding 
............................................................................................ 24 
8.2.4 
Study Medication 
.............................................................................................................. 24 
 
 
 
  
 
   
 
8.3.1 
Inclusion Criteria 
.............................................................................................................. 26 
8.3.2 
Exclusion Criteria 
............................................................................................................. 27 
10. ASSESSMENT OF SAFETY 
........................................................................................................ 36 
10.1 ADVERSE EVENTS 
............................................................................................................... 36 
10.1.1 
Reporting Adverse Experiences 
............................................................................... 36 
12DEC2018 Abbreviated CSR ZPU-203
385

Repros Therapeutics Inc. 
 
June 20, 2016 
Protocol ZPU-203, Amendment 5 
Page 3 of 57 
10.1.2 
Definitions 
................................................................................................................ 36 
10.1.3 
Serious Adverse Events (SAEs) 
............................................................................... 37 
11. CONCOMITANT MEDICATIONS 
............................................................................................ 39 
11.1 PROHIBITED MEDICATIONS 
................................................................................................. 39 
11.2 OTHER MEDICATIONS TAKEN DURING THE STUDY ........................................................... 39 
12. STATISTICAL METHODS 
......................................................................................................... 40 
12.1 DETERMINATION OF SAMPLE SIZE 
...................................................................................... 40 
12.2 STATISTICAL AND ANALYTICAL PLAN 
............................................................................... 40 
12.3 GENERAL STATISTICAL I
SSUES 
........................................................................................... 43 
13. ETHICS .......................................................................................................................................... 44 
13.1 SUBJECT I
NFORMATION AND CONSENT 
.............................................................................. 44 
13.2 I
NSTITUTIONAL REVIEW BOARD 
......................................................................................... 44 
13.3 MONITORING CASE REPORT FORMS 
................................................................................... 44 
13.4 STUDY RECORD RETENTION 
............................................................................................... 44 
13.5 DATA QUALITY ASSURANCE 
.............................................................................................. 44 
13.6 CONFIDENTIALITY............................................................................................................... 
45 
13.7 PUBLICATIONS .................................................................................................................... 45 
14. INVESTIGATOR'S STATEMENT 
............................................................................................. 46 
 
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3. 
PROTOCOL SYNOPSIS 
 
Test Drugs: 
Proellex® (Telapristone  Acetate):  6  and  12  mg  gelatin  capsules  and 
matching placebo 
Protocol Number: 
ZPU-203  
Study Purpose: 
To  determine  the  safety  and  efficacy  of  two  doses  of  Proellex  in 
premenopausal  women  with symptomatic (menorrhagia)  uterine 
fibroids confirmed by MRI. 
Study Design and 
Duration 
Of Treatment: 
This  study  is  a  phase  2 3-arm-study  with two 18-week  dosing 
courses.  The study will be conducted in two stages.   
In the first stage, women will undergo  a  baseline  assessment  period 
with no  treatment, until 15-20 days  after  the  start  of their second 
complete menstrual  event.  
  During  
this  phase  a  pictorial  blood  
loss 
assessment  chart  will  be  utilized  as  well  as  sanitary  products 
collected from their first menstrual event, for alkaline hematin assay, 
to determine menstrual blood loss and confirm eligibility.   
In the second stage, subjects will be randomized into one of 3 arms in 
a 1-1-1 fashion and receive two 18-week courses of treatment at their 
randomized dose (6mg, 12 mg or placebo), separated by an off-drug 
interval  (ODI).  
 The  start  of  the first 18-week course  of treatment 
(Course  1) should  commence 15-20  days  after  the  start  of  their 
previous menses.  Once dosing for Course 1 is stopped, subjects will 
be  
followed  until  menses  
returns.  
  The  start  of  
the  second  18  week 
course  of  
treatment (Course  2) will  commence  15-20  days after  
the 
start of their menses following withdrawal of drug after Course 1 has 
been completed.  
  During  
the ODI, subjects  will  continue  
to  record 
study information in the daily paper diary and PBAC charts as  well 
as collect sanitary products for alkaline hematin assay. 
After completion of stage 2 dosing (Courses 1 and 2), subjects will be 
followed through the subsequent 6 menses (recovery menses plus an 
additional  5 menstrual  events),  after  which  
(at  Visit  24) the  subject 
may be  offered the  opportunity  
to  enroll  
in  an open-label extension 
study.  
  Subjects  who  fail  
to  achieve  amenorrhea  may  enroll  
in  
the 
extension  study  at  Visit  19.  
  Amenorrhea  
is  defined  as  any  28-day 
period during treatment (not including the ODIs) without a bleeding 
score >1.  Throughout the study women will record study information 
in  the  diary,  PBAC,  and  questionnaires  as  outlined  in  the  study 
procedures.  
Subjects  will  collect  and  return  used  sanitary  materials  for  alkaline 
hematin assay for their first menstrual event during screening, for the 
recovery  menses  
following  Course  1,  
for  
the  28  days  
leading  up  
to 
the  end  of  treatment  in  Course  2,  and  for  the  1
st,  2
nd,  4
th and  6
th 
menstrual cycles after end of treatment in Course 2. 
A DSMB will be established before the study starts and will review 
any liver safety events (LFTs ≥3 x ULN or  bilirubin  ≥2 x  ULN)  as 
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well  as  perform  an  interim  safety  review  after 15 subjects  have 
completed at least 8 weeks of treatment. 
Subject Population: The  study  will  enroll  healthy  adult,  pre-menopausal  women with 
confirmed uterine  fibroids  via MRI and  confirmed  menorrhagia 
(>120 mL  blood  loss  per  menstrual  cycle by  historical  PBAC 
assessment, nominal 28 days to ensure a MBL of at least 80 mL by 
Alkaline Hematin  Assay). Subjects  with  evidence  of  prior  heavy 
blood loss may be enrolled at the sponsor’s discretion. 
Number of Subjects: Up to 45 female subjects, 15 per dose arm 
Number of Sites 
Approximately 10 sites  
Study Duration:  
Total participation in the study is approximately 18 months. 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
 
   
 
  
  
  
 
  
 
 
 
 
 
Study Endpoints 
The primary endpoint will be:  
• Percentage of subjects who become amenorrheic after one course 
of treatment 
Secondary endpoints will be: 
• Percentage  of  subjects  who  become amenorrheic  after  2  courses 
of treatment 
• Change and percentage change in PBAC score over the course of 
the study.  Specifically comparing the baseline menstrual cycle to 
the matching end-of-study period leading up to Week 18 and the 
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end of treatment as well as comparing the baseline PBAC to the 
ODI time periods. 
• Percentage  change  in  UFSQOL Symptom  Severity score (UFS-
SSS) comparing  Week  18  to  Baseline  (three  month  look  back) 
and for the ODI. 
• Percentage change in the individual UFS-SSS sub scores 
• Percentage  change  
from  baseline  
in  
total uterine  
fibroid volume 
measured by MRI  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Statistical Methods: A  Statistical  Analysis  Plan  (SAP)  will  be  developed  prior  to 
unblinding  of  the  data  that  will  outline  all  planned  analyses  and 
analysis  populations.  
 The  first  efficacy  analysis  will  be  conducted 
when  all  subjects  complete  the first cycle  of  treatment.  
  A  second 
analysis  will  summarize  the  subject’s  additional  treatment  cycles 
which  will  be  conducted  after all subjects complete study treatment 
and follow-up in Stage 2. 
Summaries for quantitative variables include the sample size, mean, 
median,  standard  deviation,  minimum,  and  maximum.  
  Summaries 
for categorical variables  
include the number  and  percent of patients 
for each outcome.  All summaries will be prepared for each treatment 
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group.  
Continuous efficacy endpoints, such as the change from baseline in 
the alkaline hematin assay will assess treatment effect using a t-test 
or appropriate non-parametric technique.  Pairwise comparisons 
between treatment groups will also be conducted with the same 
methods.  Other continuous efficacy variables will be treated 
similarly. The percentage of subjects becoming amenorrheic within 
each treatment and dose group will be compared by Chi-square test 
or appropriate non-parametric method. 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
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5. 
LIST OF ABBREVIATIONS 
 
AE    
Adverse event 
Cavg    
Average concentration 
Cmax    
Maximum concentration 
CRF    
Case report form 
DHEA   
Dehydroepiandrosterone 
dL    
Deciliter 
ECG   
Electrocardiogram 
FSH    
Follicle-stimulating hormone 
GCP   
Good Clinical Practice 
GnRH  
  
Gonadotrophin releasing hormone 
g  
  
Grams 
hCG    
Human chorionic gonadotrophin 
ICH    
International Conference on Harmonization    
IGF-1    
Insulin-like growth factor-1 
IRB   
Institutional Review Board 
IND    
Investigational new drug 
IUD    
Intra-uterine device 
kg     
Kilogram(s) 
LD50    
Median lethal dose 
LH    
Luteinizing hormone 
LSC   
Least Significant Change 
m  
  
Meters 
MBL    
Menstrual Blood Loss 
mg    
Milligram(s) 
mL    
Milliliter 
ng    
Nanograms 
OC    
Oral Contraceptive 
ODI   
Off-Drug Interval 
PBAC  
  
Pictorial Blood Loss Assessment Chart 
PCOS    
Polycystic Ovarian Syndrome 
PK    
Pharmacokinetic 
RBC    
Red blood cell 
SAE    
Serious adverse event 
UFSQOL 
Uterine Fibroid Symptom Quality of Life Survey 
UFS-SSS 
Uterine Fibroid Symptom Quality of Life Survey Symptom Severity 
Score (first 8 questions) 
WBC    
White blood cell 
 
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6. 
BACKGROUND INFORMATION 
6.1 
Rationale for Current Study 
Repros believes  telapristone  offers  the  potential  to  provide  significant 
symptomatic  relief  to  women  that  suffer  from  a  variety  of  reproductive 
disorders in which progesterone may be implicated.  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
 
Based on findings from the recently completed ZP-204 low dose study of oral 
Proellex,  doses from  1 mg up  to  12 mg  daily  were  administered for 
10 consecutive  weeks  with  no  observed  elevations  of  
liver  enzymes  or  even 
trends  
towards  
increasing  
liver  enzymes with increasing  dose.  At  
the  same 
time induction of amenorrhea was seen in a consistent fashion starting at a 3 
mg  daily  dose  as  long  as  trough  levels  of  the  drug  were  observed.  The 
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sponsor believes there is a direct correlation of symptomatic relief for uterine 
fibroids and endometriosis with induction of amenorrhea. 
 
 
 
 
 
  Typically  women  are 
dosed for 4 months (120 days) after which time the drug is withdrawn to allow 
for  menses  to  return.   Once  menses  has  occurred  women  may  resume 
treatment  
for  another  dosing  period.  
In  
this  
fashion  
the  drug  can  be  used  
to 
control  the  symptoms  of  endometriosis  and  fibroids  until  the  onset  of 
menopause.    
6.2 
Non-Clinical Data 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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6.3 
Clinical Data/Human Experience 
In addition to the preclinical studies, a Phase I/II study of orally administered 
Proellex in pre-menopausal women with symptomatic leiomyomata had been 
completed.  The objectives of this study were to test the safety, efficacy, and 
pharmacokinetics  of  three  doses  of  Proellex  (12.5  mg,  25  mg,  and  50  mg) 
administered as a once daily dose for 90 days, with study visits at one-month 
intervals.  The safety and effectiveness of Proellex was compared to placebo 
and the active control leuprolide acetate for depot suspension (Lupron Depot).  
At  the  conclusion  of  this  study,  exploratory  analyses  showed  statistically 
significant  efficacy  differences  between  treatment  groups  (overall  and  pair-
wise). 
 
  
  
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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FDA Guidance For Liver Enzyme 
Elevation Characterization as SAE
•1.
LFTs ≥ 8 x ULN
•2.
LFTs ≥ 5 x ULN for 2 consecutive weeks
•3.
LFTs ≥ 3 x ULN + Bilirubin 2 x ULN
•4.
LFTs ≥ 3 x ULN + clinical signs or 
symptoms (nausea; jaundice; etc.)
 
 
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6.5 
Ethical Conduct of the Study 
This  trial  will  be  conducted  in  strict  compliance  with  the  protocol  and  all 
applicable  FDA  regulations  and  GCP  guidelines  to  insure  Good  Clinical 
Practice  standards.   IntegReview,  3001  S.  Lamar  Blvd.,  Suite  210,  Austin, 
Texas  78704,  will  serve  as  an Institutional Review  Board  
(IRB)  
for  clinical 
sites who will accept their review.  
DSMB6.6  
Drug Safety Monitoring Board (DSMB) 
A DSMB will be established prior to the study starting.  The board will review 
the  data  from  any  subject  who  has  elevation  of  LFTs  ≥3  x ULN  and/or a 
bilirubin level ≥2 x ULN.   
 
 
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7. 
TRIAL OBJECTIVES AND PURPOSE 
The primary objective of this study is to determine the safety and efficacy of two oral 
doses of Proellex administered for up to 2 courses of treatment (18 weeks each), each 
separated  by  an  Off-Drug  Interval  (ODI), to  premenopausal  women with 
symptomatic uterine fibroids.   
 
 
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8. 
TRIAL DESIGN 
8.1 
Study Endpoints 
8.1.1  Primary Efficacy Endpoint 
• Percentage  of  subjects  who  become  amenorrheic  after  one  course 
of treatment 
8.1.2 Secondary Endpoints 
• Percentage of subjects who become amenorrheic after 2 courses of 
treatment 
• Change  and percentage  change in PBAC score over the course of 
the study.  Specifically comparing the baseline menstrual cycle to 
the  matching  end-of-study  period  
leading  up  
to  Week  18  and  
the 
end  of  
treatment as  well  as  comparing  
the  baseline  PBAC  
to  
the 
ODI time periods. 
• Percentage  change  in  UFSQOL  Symptom  Severity  score  (UFS-
SSS) comparing Week 18 to Baseline (three month look back) and 
for the ODI. 
• Percentage change in the individual UFS-SSS subscores 
• Percentage  change  from  baseline  in  total uterine  fibroid  volume 
measured by MRI  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.2 
Study Design 
8.2.1  Overview of Study Design 
This  study  is  a phase  2  3-arm-study  with  a  36  week  active  dosing 
period.  The study will be conducted in two stages.   
In  
the  
first  stage,  women  will undergo  a  baseline  assessment  period, 
with  no  treatment,  until  15-20 days  after  the  start  of  their  second 
complete menstrual  event.    During  this  phase  a  pictorial  blood  loss 
assessment  chart  and  daily  diaries will  be  utilized.   Used  sanitary 
products from the first menstrual event will be collected and returned 
to  the  clinic  for  alkaline  hematin  assay.    This  assay  will  confirm 
subject eligibility (MBL must be 80 mL or greater by alkaline hematin 
assay for subjects to qualify). 
In the second stage, subjects will be randomized into one of 3 arms in 
a 1-1-1 fashion.  The start of the 18 week dosing period (Course 1) in 
this stage of the study should commence 15-20 days after the start of 
their first menses after Visit 2.  Once active dosing is stopped, subjects 
will be followed until menses returns.  The start of the second 18 week 
dosing period (Course 2) will commence 15-20 days after the start of 
their  menses  following  withdrawal  of  drug  after Course  1  has  been 
completed.  
  During  
the  non  dosing  off-drug  
interval (ODI), subjects 
will continue to record study information in the daily paper diary and 
PBAC charts. 
After end of dosing in Course 2, subjects will be followed through the 
subsequent recovery menses and for an additional 5 menstrual events, 
after which the subject may be offered the opportunity to enroll in an 
extension study.  Subjects who fail to achieve amenorrhea may enroll 
in the extension study at Visit 19.  Amenorrhea is defined as any 28-
day  period  during  treatment  (not  including  the  ODIs)  without  a 
bleeding  score  >1.    Throughout  the  study  women  will  record  study 
information in the diary,  PBAC  and questionnaires  as outlined in the 
study procedures.  
In  addition  to  the diary  information,  endometrial  thickness  will  be 
recorded  at  screening  and  every  month  thereafter.    Assessment  of 
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trough levels of drug will be determined at every office visit during the 
first and second 18 week dosing periods. 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A  DSMB  will  be  established  before  
the  study  starts  and  will  
review 
any liver safety events (LFTs ≥3 x ULN or bilirubin ≥2 x ULN) . 
The primary efficacy  analysis  will  be  conducted  when  all  subjects 
complete  the first cycle  of  treatment.    A  second  analysis  will 
summarize  the  subject’s second treatment  cycle  which  will  be 
conducted after all subjects complete study treatment and follow-up. 
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8.2.2 Study Drug Accountability 
The  designee  assigned  by  
the  Principal  Investigator  at  each  site  will 
maintain accurate records of receipt of all study drugs, including dates 
of  receipt.    Reasons  for  deviation  from  the  expected  dispensing 
regimen  must  also  be  recorded.    A  Drug  Dispensing  Form  will  be 
provided  for  this  purpose.  To  satisfy  regulatory  requirements 
regarding  drug  accountability  and  destruction, the  Principal 
Investigator  at  each  site  will  return  all  used,  unused, empty, and 
partially used study medication with dispensing records to the Sponsor 
for  final  accountability  and  disposal,  after  accountability  has  been 
verified by the study monitor.  
8.2.3 Randomization and Blinding 
At Visit 3, subjects will be randomized to treatment in Arms 1, 2, or 3.  
Subjects will  be  
treated with one  capsule  daily  of 6 mg  or  12 mg of 
Proellex,  or  placebo,  which will  be  administered  for a  total  of  36 
weeks (two 18 week courses separated by an ODI) before the 6 cycle 
follow  up is  started.  
 After  
the  second treatment  course is  completed 
the  subjects  will  be  followed  for  6 menstrual  events  to  determine 
durability  of  effect  of  
treatment,  after  which they  may be offered  
the 
opportunity to enroll in an open-label extension study.  Subjects who 
fail to achieve amenorrhea may  enroll in the  extension study  at  Visit 
19.  Amenorrhea is defined as any 28-day period during treatment (not 
including  the  ODIs)  without  a  bleeding  score  >1.   Each  treatment 
course will  be  separated  by  an  ODI.  
 Blinded  
treatments  kits  will  be 
randomized and distributed by the packaging company.  
For  
the  statistical  analysis  at the  end  of  
the first course  of  
treatment, 
only statistical staff will be unblinded.  All clinical operations staff and 
staff at investigative sites will remain blinded until completion of the 
study.  
8.2.4 Study Medication 
All  study  drugs  will  be  supplied  by  Repros  Therapeutics  Inc.  Test 
drug,  Proellex  will  be  supplied  in 40 count  bottles  and  will  be 
packaged by a clinical supplies contract vendor designated by Repros 
Therapeutics  Inc.    The  placebo  will also be  supplied  in 40  count 
bottles 
 
ctive  and  matching  placebo  capsules  will  be  bottled  in 
identical  packaging.  
 
 
and 
instructions  to  take  1  capsule  daily  in  the  morning with breakfast.  
Subjects  will  
take  one  capsule  with  approximately  8  ounces  of  water 
and study medication should be taken roughly at the same time every 
day.  
  Subjects  will  
record  study  medication  date  and  
time  on subject 
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drug  diary cards.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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Course  2,  or  is  no  heavier  than 
bleeding was prior to treatment. 
8.3.1 Inclusion Criteria 
Subjects must meet the following criteria: 
• Otherwise healthy adult females between 18 and 47 years 
• Subject has a history of at least 3 regular menstrual cycles in which 
menorrhagia  is  due  to  uterine  fibroids (a  past  or  concurrent 
diagnosis of uterine fibroids is acceptable). 
• Screening ultrasound confirms presence of uterine fibroids 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
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• A Body Mass Index (BMI) between 18 and 45 inclusive 
 
 
• Visit  1 historical PBAC  of  >120 mL of  blood  loss,  unless 
approved by sponsor, to ensure subjects have a MBL of at least 80 
mL  by  Alkaline  Hematin  Assay (during  the  baseline  assessment 
period).  Subjects with evidence of prior heavy blood loss may be 
enrolled at the sponsor’s discretion. 
8.3.2 Exclusion Criteria 
Subjects  meeting  any  of  
the  
following  criteria  will  be  excluded  
from 
the study: 
 
 
 
 
• Subject  is  pregnant  or  lactating  or  is  attempting  or  expecting  to 
become pregnant during the entire study period 
•  Subjects with  abnormally  high  liver  enzymes  or  liver  disease. 
 
 
 
 
 
 
• Received  an investigational  drug  in  the  30  days  prior  to  the 
screening for this study 
 
 
 
 
 
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• Has an IUD in place 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Observation  or  history  of  abnormal  endometrial  biopsy  
including 
the presence of EIN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. 
ASSESSMENT OF SAFETY 
 
 
10.1 Adverse Events 
10.1.1 Reporting Adverse Experiences 
Any  AE  (clinical  sign,  symptom,  or  disease)  temporally  associated 
with  the  use  of  this  investigational  drug,  whether or  not  considered 
related to the investigational product, shall be documented on the CRF 
and eDC.  All SAEs and AEs reported by the subject or observed by 
the Principal Investigator for up to 30 days after the last dose of study 
medication will  be  
individually  
listed.  
  After  Visit 20,  all  SAEs  and 
any  adverse  events  that  the  investigator  considers  to  be  due  to  the 
study drug (e.g. hepatotoxicity) and not those considered to be due to 
withdrawal of the drug (e.g. vaginal bleeding), will be collected.  The 
signs  and  symptoms,  
time  of  onset  (24-hour  clock),  duration,  action 
taken and follow-up procedures will be reported.   
10.1.2 Definitions 
Adverse  Event  – Any  untoward  medical  occurrence  in  a  clinical 
investigation  subject  administered  a  drug  and  does  not  necessarily 
have  a causal  
relationship with this treatment.   An AE  can therefore, 
be  any  unfavorable  and  unintended  sign  (including  an  abnormal 
laboratory  finding),  symptom,  or  disease  temporally  associated  with 
the  use  of  an  investigational  product,  whether  or  not  related  to  the 
investigational product. 
Serious  Adverse  Event  (SAE)  – An  adverse  drug  experience  that 
results  in  any  of  the  following  outcomes:    death,  a  life-threatening 
experience,  requires  or  prolongs  subject  hospitalization,  results  in 
persistent  or  significant  disability/incapacity,  or  is  a  congenital 
anomaly or birth defect.   
Cases  of  liver  transaminases  that  increase  above  3  times  the  upper 
limit  of  normal  must  be  reported  as  SAEs  regardless  of  whether  
the 
above defined SAE criteria are met. 
Unexpected Adverse Event: Any adverse event that is not identified in 
nature, severity, or frequency in the current Investigator’s Brochure. 
Additionally,  the  Principal  Investigator  will  evaluate  all  AEs  as 
follows: 
Action  taken:    whether  or  not  the  AE  caused  the  subject/patient  to 
discontinue the study medication. 
 
 
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Intensity, to be graded as: 
DEGREE DESCRIPTION 
Mild 
Awareness of signs and symptoms; easily tolerated 
Moderate Discomfort sufficient to interfere, but not prevent 
daily activity 
Severe 
Unable to carry out usual activity 
 
Relationship to study medication, to be graded as: 
DEGREE 
DESCRIPTION 
Definitely 
There is evidence of exposure to the study drug, 
for example, reliable history or acceptable 
compliance assessment; the temporal sequence of 
the AE onset relative to the medication is 
reasonable; the AE is most likely to be explained 
by the treatment than by another cause; the AE 
shows a pattern consistent with previous 
knowledge of the treatment. 
Probably 
There is evidence of exposure to the study drug; 
the temporal sequence of the AE onset relative to 
medication administration is reasonable; the AE is 
more likely explained by the treatment than by 
another cause. 
Possibly 
There is evidence of exposure to the study drug; 
the temporal sequence of the AE relative to the 
medication administration is reasonable; the AE 
could have been due to another equally likely 
cause. 
Probably 
not 
There is evidence of exposure to the study drug; 
there is another more likely cause of the AE. 
Definitely 
not 
The subject/patient did not receive the study drug; 
or temporal sequence of the AE onset relative to 
administration of the study drug is not reasonable; 
or there is another obvious cause of the AE. 
10.1.3 Serious Adverse Events (SAEs) 
The  Principal  Investigator  shall  document all SAEs  in  a  subject 
receiving  study  drug until  completion  of  the  study and  must  be 
reported  to  the  Repros  Therapeutics  Inc.  Safety  Monitor  within  24 
hours by Fax or telephone, even if the SAE does not appear to be drug-
related.    This  report  should  include  all  available  information  at  the 
time  of  notification.    This  notification  should  be  followed  with 
submitting a SAE Report Form provided by Repros Therapeutics Inc, 
and notifying the IRB.    
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All  additional  follow-up  reports  must be  reported  to  the  Repros 
Therapeutic Inc. monitor as soon as available. 
Cases  of  liver  transaminases  that  increase  above  3  times  the  upper 
limit  of  normal  must  be  reported  as  SAEs  regardless  of  whether  
the 
above defined SAE criteria are met. 
 
 
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11. 
CONCOMITANT MEDICATIONS 
11.1 Prohibited Medications 
The following medications are prohibited during the study and during the 6-
month follow up after discontinuation of study medication: 
• Testosterone 
• Progestin 
• Androgen 
• Estrogen 
• Anabolic steroids 
• DHEA 
• Other hormonal products 
• Any other treatment for uterine fibroids 
 
 
 
 
 
 
 
 
 
 
11.2 Other Medications Taken During the Study 
Any other prescription or over-the-counter medication taken during the study 
will be recorded in the appropriate section of the CRF.  Subject must be on a 
stable dosage of approved concomitant medications at least 48 hours prior to 
drug administration. 
 
 
 
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12.  STATISTICAL METHODS 
12.1 Determination of Sample Size 
Up  
to 50 female  subjects, 15 per  dose  arm,  meeting  
the  
inclusion/exclusion 
criteria  will  be  randomized  in  a  1-1-1  fashion with  the  expectation  that 
approximately  45  will  be  fully  eligible  for  efficacy  analyses.  
 The  primary 
endpoint is amenorrhea.  
 
   
 
 
 
 
 
12.2  Statistical and Analytical Plan 
A  Statistical  Analysis  Plan  (SAP)  will  be  prepared  prior  to  unblinding  the 
data.  The first efficacy analysis will be conducted when all subjects complete 
the first  cycle of treatment.  A second analysis  will summarize  
the  
subject’s 
additional  treatment  cycles  which  will  be  conducted  after  all  subjects 
complete study treatment and follow-up in Stage 2. In this Phase 2 study there 
will be no statistical corrections for interim analyses or multiple comparisons.   
For  the  statistical  analysis  at  the  end  of  the  first  course  of  treatment,  only 
statistical  staff  will  be  unblinded.  
  All  clinical  operations  staff  and  staff  at 
investigative sites will remain blinded until completion of the study. 
12.2.1 Demographics and Subject Characteristics 
For all subjects included in this study, subject accountability, baseline 
demographic  and  medical  history  data  will  be  summarized  for  each 
treatment  group.    Summaries  for  quantitative  variables  include  the 
sample  size,  mean,  median,  standard  deviation,  minimum,  and 
maximum.  
  Summaries  for  categorical  variables  
include  
the  number 
and percent of patients for each outcome.  No statistical testing will be 
performed to compare these factors between treatment groups. 
12.2.2 Efficacy Analyses 
A Statistical Analysis Plan (SAP) will be prepared prior to unblinding 
of the study data.  Efficacy analyses will be conducted in the Intent-to-
Treat  population,  which  will  consist  of  all  subjects  who  are 
randomized and who receive study drug.   
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12.2.2.1  Primary Endpoint: Incidence of Amenorrhea 
The  percentage  of  subjects  who  become  amenorrheic  during 
the 28 days leading up to the last day of dosing at Week 18 will 
be  compared  by  Chi-Square  
test.  
 Amenorrhea  after  a  second 
course of treatment will  be  analyzed  as  a  
secondary  endpoint.  
Testing  will  evaluate  the  pooled  Proellex  doses  compared  to 
placebo,  each Proellex dose  compared  to  Placebo  as  well  as 
compare the active dose groups.  A Fisher’s Exact test will be 
utilized if the cell sizes are small.  
A  subject  is  deemed  amenorrheic  if  they  have  no  bleeding 
intensity  score  greater  than  1 using  the  Daily  Diary  Card  in 
Appendix  3 (spotting  not  requiring hygiene products)  during 
the 28 day period.   
12.2.2.2  Secondary Endpoints 
Percentage Change in PBAC scores 
The  percentage  change  in  PBAC  scores  over  each  28  day 
period for each menstrual cycle will be recorded and compared 
to  baseline  
to  determine  onset  of  benefit.  Additionally  PBAC 
scores  will  be  used  to  monitor  the  level  of  vaginal  bleeding 
during  the  ODI  and  the  time  to  return  to  baseline  vaginal 
bleeding  to  determine  duration  of  benefit  during  the  five 
menstrual cycle follow-up after dosing Course 2. 
Within  treatment  group  paired  t-tests  will  evaluate  treatment 
effect.  
  Pairwise  comparisons  of  
the  
treatment  groups  will  be 
made using a two-sample t-test as well as compare the pooled 
Proellex doses to placebo.  While the primary assessment will 
be after 18 weeks of treatment, summaries will be prepared for 
each of the other visits.  If data are missing, a last observation 
carried forward procedure will be used, including the baseline, 
if  necessary. Non-parametric  methods  will  be employed as 
appropriate.   
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Percentage change in total and individual symptom severity 
scores for the UFS-SSS 
The UFS-SSS is an 8 question symptom severity score and has 
been validated as a three month look back questionnaire.  The 
survey  will  be  administered  at  the  baseline  of  each  dosing 
course and at the end of each course.  An analysis of UFS-SSS 
scores  will  compare  the  pooled  Proellex  dose  results  to  the 
placebo  group  with  a  t-test.   Pairwise  comparisons  of  the 
treatment  groups  will  be  made  using  a  two-sample  t-test. 
Within group paired tests will also be used to assess treatment 
effect.    Non-parametric  methods  will  be employed as 
appropriate.  The primary assessment will be based on Visit 12 
(after  18  weeks  of  treatment).    If  data  are  missing,  a  last 
observation  carried  
forward  procedure  will  be  used,  
including 
the baseline, if necessary. 
Percentage Change in Uterine Fibroid Volume by MRI 
The  percent  change  from  baseline  in  total uterine  fibroid 
volume will be determined at the end of each 18 week dosing 
course and  after  
the  6  months  of  
recovery  menses  
(Visit  24).  
This  study  will  assess up  
to 3  fibroids present  at  baseline  in 
each subject.  The volume of these 3 fibroids will be summed 
to  determine  the  total  uterine  fibroid  volume  at  each 
assessment.   
An  analysis  of  percentage  change  in uterine  fibroid  volume 
will  compare  
the  pooled  Proellex doses  
to  
the  placebo  group 
with  a  t-test.    Pairwise  comparisons  of  the  treatment  groups 
will  be  made  using  a two-sample  
t-test.  Within  group  paired 
tests  will  also be  used  to  assess  treatment  effect.  Non-
parametric  methods  will  be employed as  appropriate.    The 
primary assessment will  be based on  Visit 12 (after 18 weeks 
of  treatment).    However,  analyses  will  continue  for  each 
volume  assessment.    If  data  are  missing,  a  last  observation 
carried forward procedure will be used, including the baseline, 
if necessary. 
 
 
 
 
 
 
 
  
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12.3  General Statistical Issues 
A  Statistical  Analysis  Plan  (SAP)  will  be  finalized  prior  to  unblinding  the 
study. For the efficacy variables a last observation forward approach will be 
used to impute missing data to generate a complete ITT data.  If there are no 
post-baseline efficacy data then a value of no change will be imputed for the 
missing efficacy measure.  Statistical significance will be declared if the two-
sided  p-value  is  ≤  0.05.  
 
 
 
 
 
 
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13. 
ETHICS 
13.1 Subject Information and Consent 
A properly executed, written informed consent in compliance with Food and 
Drug  Administration  (FDA)  regulations  and  Good  Clinical  Practice  (GCP) 
guidelines  will  be  obtained  
from  each  subject  prior  
to  entering  
the  study  or 
performing  any  unusual  or  non-routine  procedure  
that  
involve  a  risk  
to  
the 
subject.  The Principal Investigator will submit a copy of the informed consent 
document  
to  
the  Institutional  Review  Board  for  review  and  approval  before 
research subjects are enrolled.  The Principal Investigator will provide a copy 
of  the  signed  informed  consent  to  the  subject  and  the  original  will  be 
maintained in the subject
's medical record. 
13.2  Institutional Review Board 
The Principal Investigator will provide the Institutional Review Board with all 
requisite material, including a copy of the informed consent.  The study will 
not be initiated until the IRB provides written approval of the protocol and the 
informed  consent  and  until  approved  documents  have  been  obtained  by  
the 
Principal  Investigator  and  copies  received  by  the  Sponsor.    Appropriate 
reports on the progress of this study by the Principal Investigator will be made 
to  the  Institutional  Review  Board  and  the  Sponsor  in  accordance  with  the 
applicable  government  regulations  and  in  agreement  with  the  policy 
established by the Sponsor. 
13.3  Monitoring Case Report Forms 
Repros  Therapeutics  Inc.  or  their  designee  will  monitor  all  aspects  of the 
study  with  respect  to  current  GCP  and  standard  operating  procedures  for 
compliance  with  applicable  
federal  
regulations.  
  These  
individuals  will  have 
access  to  all  records  necessary  to  ensure  integrity  of  the  data  and  will 
periodically review progress of the study with the Principal Investigator. 
13.4 Study Record Retention 
In  accordance  with  FDA  regulations  and  GCP  guidelines,  all  study-related 
documentation shall be retained by the Principal Investigator for a minimum 
of 2 years after FDA approval of telapristone acetate or clinical development 
has  been  terminated.    At  that  time,  the  Principal  Investigator  will  contact 
Repros  Therapeutics  Inc.  regarding  further  disposition  of  the  study  records 
and comply with instructions. 
13.5  Data Quality Assurance 
All  data  
recorded  during  
the  study  will  be  available  
for  audit  against  source 
data  and  for  compliance  with  GCP  and  specific  protocol  requirements.  
Monitoring of the study progress and conduct will be ongoing.  The Principal 
Investigator will be responsible for the following: 
 
1. Monitoring  study  conduct  to  ensure  that  the  rights  of  subjects  are 
protected; 
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2. Monitoring study conduct to ensure trial compliance with GCP guidelines; 
and 
3. Monitoring accuracy, completion and verification from source documents 
of study data. 
13.6 Confidentiality 
All information provided to the Principal Investigator by Repros Therapeutics 
Inc. or their designees including non-clinical data, protocols, CRFs and verbal 
and written information will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study.  It is recognized that this 
information may be released in confidence to the IRB.  In addition, no reports 
or information about the study or its progress will be provided to anyone not 
involved in the study other than to Repros Therapeutics Inc. or their designees 
or in confidence to the IRB, except if required by law. 
13.7 Publications 
Following  completion  of  the  study,  the  data  from  the  entire  study  or  from 
subsets of the study may be considered for reporting at a scientific meeting or 
for publication in a scientific journal, in which case Repros Therapeutics Inc. 
will  be  responsible  for  these  activities  and  will  work  with  the  Principal 
Investigator  to  determine  how  the  manuscript  is  written  and  edited,  the 
number and order of authors, the publication to which it will be submitted and 
other related issues. 
 
 
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14. 
INVESTIGATOR'S STATEMENT 
I  have  reviewed  the  ZPU-203 protocol  and  Investigator  Brochure  and  agree  to 
conduct  this  study  as  outlined  in  the  protocol  and  in  compliance  with  ICH/GCP 
Guidelines. 
 
 
_________________________________    
______________________ 
Investigator    
  
  
  
 
Date 
 
________________________________ 
Printed name 
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Repros Therapeutics Inc. 
 
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Repros Therapeutics Inc. 
 
 
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Page 1 of 4 
ZPU-203 Amendment 5 Summary of Changes 
ZPU-203 Amendment 5 Protocol Summary of Changes 
 
Protocol Title:   
A Phase 2, Multi-Center, Parallel Design, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy 
of  6  and  12  mg  Proellex®  (Telapristone  Acetate)  Administered  Orally  in  the Treatment  of  Premenopausal 
Women with Confirmed Symptomatic Uterine Fibroids 
Changes From: 
From Protocol Amendment4 dated April 8, 2016  To: Protocol Amendment 5 dated June 20, 2016 
Reason for Amendment:  
Addition of MRI at Visit 24, addition of requirements for enrollment in Extension Study 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
Protocol Synopsis-
Study Design and 
Duration of 
Treatment 
After completion of stage 2 dosing (Courses 1 
and 2), subjects will be  
followed through the 
subsequent  6  menses  (recovery  menses  plus 
an  additional  5  menstrual  events).  In  the 
event  that  a  subject’s  menstrual  bleeding 
returns  to  ≥80mL  (assessed  by  alkaline 
hematin  assay)  at  
the  end  of  
this  period,  
the 
subject  may  be  offered  the  opportunity  to 
enroll in an extension study.     
After completion of stage 2 dosing (Courses 1 
and  2),  subjects  will  be  followed  
through  
the 
subsequent 6 menses (recovery menses plus an 
additional 5 menstrual events), after which (at 
Visit  24) the  subject  may  be  offered  the 
opportunity  to  enroll  in  an open-label 
extension study.  Subjects who fail to achieve 
amenorrhea  may  enroll  in  the  extension 
study at Visit 19.  Amenorrhea is defined as 
any  28-day  period  during  treatment  (not 
including  the  ODIs)  without  a  bleeding 
score >1.   
Change  
in 
study design 
6. BACKGROUND 
INFORMATION 
6.6  DSMB  
The  board will  also  conduct  a  safety  review 
of  study  safety  data  (clinical  laboratory 
assessments  and  adverse  events)  after  15 
subjects  have  competed  at  least  8  weeks  of 
treatment at their randomized dose. 
 
DSMB 
procedures 
standardized 
for all Proellex 
studies 
8.2.1 Overview of 
Study Design 
After end of dosing in Course 2, subjects will After end of dosing in Course 2, subjects  will  
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ZPU-203 Amendment 5 Summary of Changes 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
be followed through the subsequent recovery 
menses  and  for  an  additional  5  menstrual 
events.  In the event that a subject’s menstrual 
bleeding  returns  to  >80  mL  (assessed  by 
alkaline  hematin  assay)  at  the  end  of  this 
period the  subject  may  be  offered  the 
opportunity to enroll in an extension study.   
 
 
A DSMB will be established before the study 
starts  and  will  
review  any  
liver  safety  events 
(LFTs ≥3 x ULN or bilirubin ≥2 x ULN) as 
well as perform an interim safety review after 
15 subjects have competed at least 8 weeks of 
treatment.
 
be  followed  through  the  subsequent  recovery 
menses  and  for  an  additional  5  menstrual 
events, after which the subject may be offered 
the opportunity to enroll in an extension study.  
Subjects  who  fail  to  achieve  amenorrhea 
may enroll in the extension study at Visit 19.  
Amenorrhea is defined as any 28-day period 
during  treatment  (not  including  the  ODIs) 
without a bleeding score >1.   
 
A  DSMB  will  be  established  before  
the  study 
starts  and  will  
review  any  
liver  safety  events 
(LFTs ≥3 x ULN or bilirubin ≥2 x ULN). 
 
 
Requirements 
for roll-over 
into Extension 
Study added 
 
 
 
DSMB 
procedures 
standardized 
for all Proellex 
studies 
8.2.3 Randomization 
and Blinding 
After  the  second  treatment  course  is 
completed the subjects will be followed for 6 
menstrual  events  to  determine  durability  of 
effect  of  treatment.  If  subjects  return  to  a 
MBL  score  of  ≥80  mL  at  the  end  of  this 
period,  assessed  by  alkaline  hematin  assay, 
they may be offered the opportunity to enroll 
in an extension study.     
After the second treatment course is completed 
the  subjects  will  be  followed  for  6  menstrual 
events  to  determine  durability  of  effect  of 
treatment, after which they may be offered the 
opportunity  to  enroll  in  an open-label 
extension study.  Subjects who fail to achieve 
amenorrhea  may  enroll  in  the  extension 
study at Visit 19.  Amenorrhea is defined as 
any  28-day  period  during  treatment  (not 
including  the  ODIs)  without  a  bleeding 
score >1.   
 
 
 
 
Requirements 
for roll-over 
into Extension 
Study added 
 
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ZPU-203 Amendment 5 Summary of Changes 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
12. STATISTICAL 
METHODS 
12.2.2.2 Secondary 
Endpoints 
Percentage Change in Uterine Fibroid 
Volume by MRI 
The  percent  change  from  baseline  in  total 
uterine  
fibroid  volume  will  be  determined  at 
the end of each 18 week dosing course.   
Percentage Change in Uterine Fibroid Volume 
by MRI 
The  percent  change  from  baseline  in  total 
uterine  fibroid  volume  will  be  determined  at 
the  end  of  each  18  week  dosing  course and 
after the 6 months of recovery menses (Visit 
24).   
 
 
 
New 
procedure 
added 
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ZPU-203 Amendment 5 Summary of Changes 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Charts and footnotes were updated to reflect the changes above. 
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