A Randomized, Double Blind, Placebo-Controlled, Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
Phase: PHASE2
Conditions: Acquired Hypogonadotropic Hypogonadism, Obesity
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.  
NCT02651688 
 
Study ID: ZA-205 
 
Title: A Randomized, Double Blind, Placebo-Controlled, Multi-Center Study in Men with 
Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and 
Metabolic Parameters with Diet and Exercise in Conjunction with Treatment with 12.5 mg or   
25 mg Enclomiphene 
 
Protocol Amendment 4 Date: 09 December 2016  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ZA-205 Amendment 1 Protocol Summary of Changes 
Page 1 of 5 
Protocol Title:  
A  Randomized,  Double  Blind,  Placebo-Controlled,  Multi-Center  Study  in  Men  with  Acquired 
Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters with 
Diet and Exercise in Conjunction with Treatment with 12.5 mg or 25 mg Enclomiphene 
Changes From: 
From Original Protocol dated December 14, 2015  To: Protocol Amendment 1 dated February 2, 2016 
Reason for Amendment:  
To add 24-hour T and enclomiphene steady state PK assessments after 12 weeks of treatment 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
PROTOCOL 
SYNOPSIS:  
Study Purpose 
 
 
 
 
Study Design and 
Duration of 
treatment 
 
 
Number of Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statement added: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 1 Protocol Summary of Changes 
Page 2 of 5 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
 
 
 
Statistical Methods 
 
 
 
 
 
 
Statement added: 
 
 
    
 
 
Tables 1 and 2 
 
Updated to include new assessments 
 
 
LIST OF 
ABBREVIATIONS  
 
7. TRIAL 
OBJECTIVES 
 
Statement added: 
 
 
 
 
8. TRIAL DESIGN 
8.1.1 Overview of 
Study Design 
 
 
 
 
8.2.2 Exclusion 
Criteria 
 
 
 
 
 
 
 
20.  Enrolled and 
randomized (if 
applicable) in a 
previous 
enclomiphene study 
 
Statement added: 
 
 
 
. 
 
20. 
Enrolled  and  randomized  (if  applicable) to  enclomiphene  in  a 
previous enclomiphene study 
 
 
 
 
 
 
 
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ZA-205 Amendment 1 Protocol Summary of Changes 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
   
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. STATISTICAL 
METHODS 
 
 
 
 
 
Statement added; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 1 Protocol Summary of Changes 
Page 4 of 5 
 
 
 
 
 
 
 
 
l
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 1 Protocol Summary of Changes 
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SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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ZA-205 Amendment 2Protocol Summary of Changes
Page 1of 1
Protocol Title: 
A Randomized, Double Blind, Placebo-Controlled, Multi-Center Study in Men with Acquired 
Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters with 
Diet and Exercise in Conjunction with Treatment with 12.5 mg or 25 mg Enclomiphene
Changes From:
From Original Protocoldated December 14, 2015
To: Protocol Amendment 2dated July 1, 2016
Reason for Amendment:
To add 24-hour T and enclomiphene steady state PK assessments after 12 
weeks of treatment(selected sites) and new questionnaire
Changes to Protocol:
Significant changes to the protocol are listed below.
SECTION
CHANGED FROM
CHANGED TO
REASON 
FOR 
CHANGE
PROTOCOL 
SYNOPSIS: 
 
 
Number of Subjects
 
 
 
 
Statement added:
Fifteen (15) of these subjects will be offered the opportunity to 
participate in the 24-hour testosterone and enclomiphene T subjects to 
be performed after 12 weeks of treatment.
 
 
 
 
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ZA-205 Amendment 2Protocol Summary of Changes
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SECTION
CHANGED FROM
CHANGED TO
REASON 
FOR 
CHANGE
 
 
 
 
 
 
Addition of 
PK 
assessments
LIST OF 
ABBREVIATIONS
Updated to include PK parameters
 
 
 
 
8. TRIAL DESIGN
8.1.1 Overview of 
Study Design
8.1.7 Subject 
Questionnaires
8.2.2 Exclusion 
Criteria
20.  Enrolled and
randomized (if applicable) 
in a previous 
enclomiphene study
  
 
 
20.Enrolled and randomized (if applicable) to enclomiphene in a 
previous enclomiphene study
 
 
Clarification
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ZA-205 Amendment 2Protocol Summary of Changes
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SECTION
CHANGED FROM
CHANGED TO
REASON 
FOR 
CHANGE
 
 
 
 
 
10.
 
 
 
 
 
13. STATISTICAL 
METHODS
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 2Protocol Summary of Changes
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SECTION
CHANGED FROM
CHANGED TO
REASON 
FOR 
CHANGE

   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 2Protocol Summary of Changes
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SECTION
CHANGED FROM
CHANGED TO
REASON 
FOR 
CHANGE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 3 Protocol Summary of Changes 
Page 1 of 2 
Protocol Title:  
A  Randomized,  Double  Blind,  Placebo-Controlled,  Multi-Center  Study  in  Men  with  Acquired 
Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters with 
Diet and Exercise in Conjunction with Treatment with 12.5 mg or 25 mg Enclomiphene 
Changes From: 
From Protocol Amendment 2 dated July 1, 2016  To: Protocol Amendment 3 dated September 14, 2016 
Reason for Amendment:  
To add fatigue assessment at each visit and subject interviews for PRO development at 36 weeks 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
Protocol Synopsis 
 
Study Purpose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 
 
 
 
 
 
 
 
 
 
 
8. TRIAL DESIGN 
8.1.1 Overview of 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ZA-205 Amendment 3 Protocol Summary of Changes 
Page 2 of 2 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1. TITLE PAGE……………………………..……………………………………………………… 
...... 1 
2. TABLE OF CONTENTS 
.......................................................................................................... 2 
3. PROTOCOL SYNOPSIS.......................................................................................................... 4 
4. PROCEDURES AND LABORATORY TABLES 
................................................................... 7 
5. LIST OF ABBREVIATIONS 
................................................................................................. 10 
6. BACKGROUND INFORMATION ....................................................................................... 11 
6.1 
SAFETY DATA 
............................................................................................................ 11 
6.2 
EFFICACY DATA 
......................................................................................................... 11 
6.3 
ETHICAL CONDUCT OF THE STUDY 
............................................................................ 12 
7. TRIAL OBJECTIVES AND PURPOSE 
................................................................................ 13 
8. TRIAL DESIGN 
..................................................................................................................... 14 
8.1 
STUDY DESIGN 
........................................................................................................... 14 
8.1.1 Overview of Study Design 
................................................................................. 14 
8.1.2 Study Drug Accountability 
................................................................................ 14 
8.1.3 Randomization and Blinding 
............................................................................. 15 
8.1.4 Study Medication 
............................................................................................... 15 
8.1.6 Lean Body Mass Assessment ............................................................................ 15 
8.1.11 Diet and Exercise Programs .............................................................................. 16 
8.2 
SELECTION AND WITHDRAWAL OF SUBJECTS 
........................................................... 16 
8.2.1       
Inclusion Criteria 
................................................................................................ 17 
8.2.2       
Exclusion Criteria 
............................................................................................... 17 
9. STUDY PROCEDURES 
........................................................................................................ 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. STUDY ENDPOINTS 
............................................................................................................ 23 
11. ASSESSMENT OF SAFETY 
................................................................................................. 24 
11.1 ADVERSE EVENTS 
...................................................................................................... 24 
11.1.1 Reporting Adverse Experiences 
........................................................................ 24 
11.1.2 Definitions 
......................................................................................................... 24 
11.1.3 Serious Adverse Events (SAEs) 
........................................................................ 25 
12. CONCOMITANT MEDICATIONS ...................................................................................... 26 
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12.1 PROHIBITED MEDICATIONS 
........................................................................................ 26 
13. STATISTICAL METHODS 
................................................................................................... 27 
13.1 DETERMINATION OF SAMPLE SIZE 
............................................................................. 27 
13.2 STATISTICAL AND ANALYTICAL PLAN 
...................................................................... 27 
13.2.1 Interim Analysis 
................................................................................................ 27 
13.2.2 Demographics and Subject Characteristics ....................................................... 27 
13.2.3 Efficacy Analyses 
.............................................................................................. 27 
 
 
 
 
13.3 GENERAL STATISTICAL I
SSUES 
.................................................................................. 31 
14. ETHICS .................................................................................................................................. 33 
14.1 SUBJECT I
NFORMATION AND CONSENT 
..................................................................... 33 
14.2 I
NSTITUTIONAL REVIEW BOARD 
................................................................................ 33 
14.3 MONITORING CASE REPORT FORMS 
.......................................................................... 33 
14.4 STUDY RECORD RETENTION 
...................................................................................... 33 
14.5 DATA QUALITY ASSURANCE 
..................................................................................... 33 
14.6 CONFIDENTIALITY...................................................................................................... 34 
14.7 PUBLICATIONS ........................................................................................................... 34 
15. INVESTIGATOR
'S STATEMENT........................................................................................ 35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. 
PROTOCOL SYNOPSIS 
Test Drugs: 
Enclomiphene 12.5 and 25 mg capsules, and placebo 
Protocol Number: 
ZA-205  
Study Purpose: 
To compare the  effects  of 12  months of  treatment  with 
enclomiphene 12.5  mg,  25  mg, or  placebo capsules on body 
composition  and metabolic  parameters in overweight men  with 
acquired  hypogonadotropic hypogonadism  (confirmed  morning 
T≤300  ng/dL) following  a 6 month  diet  and 15  month exercise 
program.  Subjects must not have been treated with testosterone 
products in  the  6  months  prior  to  the  study  and  must  not ever 
have used testosterone products for a year or longer.   
 
 
  
 
 
 
 
Study Design and Duration 
of Treatment: 
Protocol ZA-205 is  a  randomized,  double-blind,  placebo-
controlled multi-center study  to compare  changes  in metabolic 
parameters following  treatment  with 12.5  mg  or  25  mg  of 
enclomiphene or placebo in conjunction with a 6-month diet and 
15  month exercise  program, in  overweight  men  with  acquired 
hypogonadotropic  hypogonadism.   Subjects  will  receive  a 15-
month  gym  membership  with  personal  
trainer for  12  months,  a 
Fitbit and  a  6  month commercial  diet program.   The  study 
requires 7 clinic  visits and  is  approximately 15 months  in 
duration.  Subjects will be treated with enclomiphene or placebo 
for 12 months.   
 
  The  study  will  enroll 45 male  subjects, 15 randomized  to 
treatment  with enclomiphene  12.5  mg,  15 randomized  to 
treatment  with 25  mg  enclomiphene,  and  15 randomized  to 
Placebo, in a 1:1:1 ratio.     
Eligible  subjects  must  have  2 consecutive assessments  of 
morning testosterone ≤300 ng/dL.  LH must be >1.4 mIU/mL and 
below 9.4 mIU/mL at Screening.  Waist circumference must be ≥ 
40 inches (101.6 cm).  Efficacy assessments will include weight, 
BMI, waist  circumference, lean  body  mass,  and metabolic 
parameters.   
 
 
 
  
  
  
 
 
   
 
Subject Population 
The  study  will  enroll  overweight males,  aged  18-60,  with 
secondary  hypogonadism and  confirmed  morning  testosterone 
levels ≤300ng/dL, with a waist circumference ≥ 40 inches (101.6 
cm), who must not have been treated with testosterone products 
in  
the  6  months  prior  
to  
the  study  and  must  not ever have  used 
testosterone products for a year or longer. 
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Number of Subjects: 
45 male  subjects, 15 randomized  
to the 12.5  mg  enclomiphene 
group,  15 to  the 25  mg  enclomiphene  group  and  15 in  the 
Placebo group, meeting the inclusion/exclusion criteria. 
Fifteen  
(15)  of  
these  subjects  will  be  offered the  opportunity  
to 
participate  in  the  24-hour  testosterone  and  enclomiphene  T 
subjects to be performed after 12 weeks of treatment. 
Study Duration:  
Total participation in the study is approximately 15 months. 
  
 
 
 
 
 
 
 
 
 
 
     
 
  
  
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
   
Test Drugs: 
Enclomiphene 12.5  and 25 mg, and matching  placebo  capsules 
will be supplied by the sponsor.  
Study Endpoints 
The efficacy endpoints will be: 
• Changes in Lean Body Mass (LBM), assessed using DXA 
• Changes in waist circumference, comparing enclomiphene to 
placebo 
• Changes  from  baseline  in  testosterone,  comparing 
enclomiphene to placebo 
• Values and changes in values from baseline in LH, HbA1c, 
FPG, C-reactive protein, Interleukin-6, tumor necrosis factor 
(TNF-α) receptor 2, and leptin compared to placebo 
• Change  in  strength  assessed  from  maximum chest  and leg 
press weight achieved, using an inclined plane leg press and 
vertical chest press 
• Changes in insulin resistance determined by HOMA-IR and 
Quantose IR™ (Metabolon Inc) compared to placebo 
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• Change in weight and BMI compared to placebo 
• Values  for  dihydrotestosterone  (DHT)  and  estradiol  (E2), 
and the ratios of DHT:testosterone and testosterone:E2 
 
 
 
 
 
 
 
 
  
Statistical Methods: 
Although  this  study  is  considered  hypothesis  generating,  a 
Statistical  Analysis  Plan  (SAP)  will  be  prepared  prior  to  the 
unblinding of the study that documents all planned analyses and 
data  assumptions.  
 Interim  analyses  will  be  conducted  after  all 
subjects have been assessed for 6 and 12 months.   
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.   
Analyses  will  focus  on  descriptive  statistics  for  each  efficacy 
endpoint  with  between  and  within  treatment  comparison 
conducted.    It  is  hypothesized  that  subjects  treated  with 
enclomiphene will have additional improvements in testosterone, 
body composition, weight, waist circumference and assessments 
of metabolic parameters.   
Safety  and tolerability 
 
 
 
will  be summarized  
for 
each  treatment  group  separately.    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.  Where applicable, statistical testing of the safety data 
to compare the treatment groups is anticipated.   
 
 
  
 
 
 
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5. 
LIST OF ABBREVIATIONS 
 
AE   
adverse event 
CRF   
case report form 
DHT    
dihydrotestosterone 
dL 
 
deciliter 
DVT   
deep vein thrombosis 
ECG   
electrocardiogram 
FSH   
follicle-stimulating hormone 
g  
 
grams 
GCP   
Good Clinical Practice 
HbA1c    
hemoglobin A
1c 
hCG    
human chorionic gonadotrophin 
Hct   
hematocrit 
Hgb    
hemoglobin 
HOMA-IR 
Homeostasis Model of Assessment – Insulin Resistance 
ICH    
International Conference on Harmonization    
IND   
investigational new drug 
IRB   
Institutional Review Board 
kg    
kilogram(s) 
LBM   
lean body mass 
LH    
luteinizing hormone 
m  
 
meters 
mg   
milligram(s) 
mL   
milliliter 
ng  
  
nanograms 
PRO    
Patient Reported Outcome 
PSA   
prostate specific antigen 
RBC   
red blood cell 
SAE   
serious adverse event 
SHBG    
sex hormone binding globulin 
T  
  
testosterone 
TE  
  
thromboembolic 
Total T  
total testosterone 
t½     
Apparent elimination half life 
Tmax     
Time of the maximum measured plasma concentration 
λz     
Terminal elimination rate constant 
VTE    
venous thromboembolism 
WBC   
white blood cell 
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Page 11 of 47 
 
6. 
BACKGROUND INFORMATION 
The  sponsor  has  completed  a  
full  Phase  III  development  program  demonstrating  
the  safety 
and efficacy of enclomiphene for the treatment of secondary hypogonadism.  Details of non-
clinical findings are provided in the Investigator Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.3 
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 compare the effects of treatment with enclomiphene 
to placebo, upon anthropometric and metabolic parameters in hypogonadal men undergoing a 
6-month diet and 15 month exercise program.   
Additional  study  objectives  are  to document  the  differences in  testosterone  and  LH and 
changes from  baseline in  symptoms using  a  selection  of  subject  questionnaires in 
enclomiphene-treated  men  compared  to  placebo.  
 
 
 
 
 
 
 
 
 
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8. 
TRIAL DESIGN 
8.1 
Study Design 
8.1.1  Overview of Study Design 
Protocol  ZA-205 is  a  randomized,  double-blind,  placebo-controlled multi-
center  study  to  compare  changes  in weight,  lean  body  mass (using  DXA), 
waist  circumference, glycemic  parameters and scores  using  various  subject 
questionnaires following  treatment  with 12.5  or 25  mg enclomiphene or 
placebo in  overweight  men  with  acquired  hypogonadotropic  hypogonadism 
and waist circumference ≥ 40 inches (101.6 cm).  The study requires 7 clinic 
visits and is approximately 15 months in duration.  Subjects will be provided 
with a 15 month gym membership and personal  
trainer,  and  will  exercise  
for 
30-45  minutes  three  times  a  week.    They  will  also  receive a  6  month 
commercial diet program.  Subjects will be treated for 12 months.  
 
   
The  study  will enroll 45 male  subjects, 15 randomized  to  treatment  with 
enclomiphene  12.5  mg, 15 randomized  to  enclomiphene  25  mg  and  15 
randomized to placebo, in a 1:1:1 ratio.   
Eligible subjects must have 2 consecutive assessments of morning T at Visit 1 
(screening).  
 The  assessments  must  be  2-4  days  apart  and  both  must  be  300 
ng/dL or  less.    Subjects  must  also  have LH >1.4  and  < 9.4  mIU/mL at 
Screening.  
 Waist  circumference  must be ≥  40  
inches (101.6  cm).  
 Subjects 
must not have been treated with testosterone products in the 6 months prior to 
the  study.  
  They must  not  have  used  
testosterone  products  
for  12  months or 
longer at any time in the past.  Subjects will follow a commercial diet plan and 
exercise with a personal trainer at least 3 times a week.  At clinic visits, clinical 
laboratory  assessments  will  be  performed  and  subject  questionnaires  will  be 
administered.  Subjects  will  be  called  every  2  weeks  
to  check  on  compliance 
with  their  exercise  regimen  and  diet,  and  solicit  adverse  events. 
 
 
.   
 
 
 
.   
 
 
 
 
8.1.2 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, 
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the Principal  
Investigator at each site will return all unused study medication 
with dispensing records to the Sponsor for final accountability and disposal.  
8.1.3 Randomization and Blinding 
Subjects  will  be  
randomized,  
in a  double-blinded  manner,  
in  a  1:1:1 ratio to 
enclomiphene 12.5 mg, enclomiphene 25 mg, or placebo.  
8.1.4 Study Medication 
All  study  drugs  will  be  supplied  by  Repros  Therapeutics  
Inc.  
 Enclomiphene 
12.5 mg and 25 mg capsules, or placebo capsules, 
 
by  a  clinical  supplies  contract  vendor  designated  by  Repros 
Therapeutics  Inc.  
  Each  bottle  will  have  a  
label  
indicating  
the identification 
number,  
the  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.  
  Subjects  will  
take  one  capsule  with 
approximately 8 ounces of water.   
Subjects should be instructed not to dose on the mornings of clinic visits. 
Subjects  will  record  study  medication  date  and  time  on  subject  Drug  Diary 
Cards.  
  
8.1.6 Lean Body Mass Assessment
 
Lean  body  mass  will  be  assessed  by  DXA.  
  For  
further  details  
reference  
the 
Study Procedures Manual. 
8.1.8 Waist Circumference Measurement 
Waist circumference should be measured at the level of the navel to the nearest 
0.5 cm.  The tape should be held level.  Subject should take 3 breaths and on 
the last exhale (normal exhale) the measurement should be taken. 
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8.1.11 Diet and Exercise Programs 
These programs are described in more detail in the Study Procedures Manual. 
The  sponsor  
is  providing  a  15  month gym  membership  
that  will  commence 
when  subjects  start  treatment  and  conclude  at  the  3-Month  follow  up  visit.  
Subjects  will  be  assigned  a  personal  trainer for  12  months  and  will  be 
instructed  to  exercise  for  at  least 30-45 minutes  3  times  each  week.   The 
workout  will  be  60%  cardiovascular  training  and  40%  resistance  training. 
Strength  progress  will  be  assessed  
from  changes  
in  
leg  press  and  chest  press 
weights.  Subjects will receive a signed letter from the investigator stating that 
the  subject  has  been  cleared  to  participate  in  an  exercise  program  that  the 
subject can provide to their trainer prior to starting their program.   
Subjects  will  also  
receive  a  6-month commercial diet  program  
that  
they  will 
start when they start treatment, and follow until their 6 month visit.  The diet 
plan provides  about 1500 calories/day  comprised as follows: 25% of  calories 
from  lean  protein,  less  than  30%  of  calories  from  fat,  about  50% 
carbohydrates,  
low  sodium  
(less  
than  2,300  mg/day)  and  25-35  g  
fiber  
/day.  
Subjects will select the plan of their choice from those available and modify it 
to  individual  needs,  if  necessary,  with  the  help  of  a plan dietician.   The 
program includes counseling from a plan counselor. 
After completion of the commercial diet program subjects will be counseled at 
each visit to continue with healthy eating habits.  Subjects will be called every 
2  weeks  
(except  on  days  of  clinic  visits),  
to  check  on  compliance  with  
their 
diet and exercise programs and solicit any adverse events. 
8.2 
Selection and Withdrawal of Subjects 
Subjects  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 considered by the investigator to be associated with 
use of the study drug occur 
• Hematocrit >54% and confirmed upon repeat 
• The subject requests to be withdrawn from the study 
• A need for concomitant medication prohibited by the protocol arises 
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• The Principal Investigator decides that it is in the subject’s best interest 
• The subject is noncompliant with the protocol at Sponsor/Investigator discretion 
8.2.1 Inclusion Criteria 
Subjects must meet the following criteria: 
1. Overweight (BMI 30 to 42 kg/m2 inclusive) males age 18 to 60 inclusive 
2. Waist circumference ≥ 40 inches (101.6 cm) 
3. Previously or concurrently diagnosed as having secondary hypogonadism. 
4. Must have 2 morning testosterone assessments at Visit 1, collected before 
10 AM, 2-4 days apart, and both of which must be ≤ 300ng/dL. 
5. LH >1.4 and < 9.4 mIU/mL (at Visit 1 only) 
6. HbA1c ≤7.5 
7. Stable weight for last 3 months (+/- 10 pounds) 
8. Lives or works within 10 miles of the gym that will be used for the study 
9. Must be fit enough to participate in the fitness program 
10. Ability to complete the study in compliance with the protocol requirements 
11. Ability to understand and provide written informed consent 
8.2.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Any  use  of testosterone  products (injectable,  pelleted,  transdermal  or 
sublingual) in  the  6  months  prior  to  the  study  or any prior  use  of 
testosterone products for 12 months or longer at any time.  
2. Use  of testosterone,  Clomid,  5α-reductase  inhibitors,  hCG,  androgen, 
estrogen, anabolic steroid, DHEA, or herbal hormone products during the 
study 
3. Use of Clomid in the past year 
4. Known hypersensitivity to Clomid 
5. Allergy to soy, peanuts or latex 
6. Chronic  use  of  glucocorticoids  (chronic  use  of  inhaled  or  topical 
glucocorticoids is acceptable)  
7. History of drug abuse or chronic narcotic use including methadone 
8. A  recent  history  of  alcoholism  or  illegal  substance  or  steroid  abuse  (<2 
years) or presence of moderate alcohol use (>21 drinks per week) 
9. Use  of  an  investigational  drug  or  product,  or  participation  in  a  drug  or 
medical  device  research  study  within  30  days  prior  to  receiving  study 
medication 
10. A hematocrit >54% 
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11. Presence or known history of hyperprolactinemia with or without a tumor 
(prolactin >20 ng/mL) 
12. Current  or  history  of  prostate  cancer  or  a  suspicion  of  prostate  disease 
unless ruled out by prostate biopsy, or a PSA>3.6 
13. Current or history of breast cancer 
14. Uncontrolled  hypertension  based  on  the  Investigator’s  assessment  at 
screening  
15. History of bulimia nervosa or binge eating 
16. Subject has (had) a lap band or undergone gastric bypass surgery 
17. Subject has celiac disease or gluten intolerance 
18. Subject has Type I diabetes 
19. Subject  has  any  condition  which  
in  
the  opinion  of  
the  
investigator  would 
interfere with the participant’s ability to provide informed consent, comply 
with  study  
instructions,  possibly  confound  
interpretation  of  study  results, 
or endanger the participant if he took part in the study 
20. Enrolled  and  randomized  (if  applicable) to  enclomiphene  in  a  previous 
enclomiphene study 
 
 
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10. 
STUDY ENDPOINTS 
The efficacy endpoints will be: 
• Changes in Lean Body Mass (LBM), assessed using DXA 
• Changes in waist circumference, comparing enclomiphene to placebo 
• Changes from baseline in testosterone, comparing enclomiphene to placebo 
• Values  and  changes  in  values  from baseline  in  LH, HbA1c,  FPG,  high  sensitivity  C-
reactive protein,  Interleukin-6,  tumor  necrosis  factor  (TNF-α)  receptor  2,  and  leptin 
compared to placebo 
• Change in strength assessed from maximum chest and leg press weight achieved 
• Changes  
in  
insulin resistance  determined  by  HOMA-IR  and  Quantose  
IR™  
(Metabolon 
Inc) compared to placebo 
• Change in weight and BMI compared to placebo 
• Values  for  dihydrotestosterone  (DHT)  and  estradiol  (E2),  and  the  ratios  of 
DHT:testosterone and testosterone:E2 
 
 
 
 
 
 
 
 
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11. 
ASSESSMENT OF SAFETY 
 
   
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 if the investigator considers this 
finding to be an adverse event), 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.   
Venous thromboembolic events (VTE) should also be reported to the sponsor 
as  Serious  Adverse  Events  regardless  of  whether  the  above-defined  SAE 
requirements 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  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.  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. 
Venous Thromboembolic Events 
Venous  
thromboembolic  events  (VTE)  should  be  reported  
to  
the  sponsor  as 
Serious  Adverse  Events  regardless  of  whether  the  above-defined  SAE 
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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  initial  drug  administration.   Unless 
medically  necessary  the  dosage  of  chronic  medications  should  not  be  changed.  Unless 
medically necessary the addition of new medications should be avoided. 
12.1 Prohibited Medications 
Use of any of the following medications during the study is prohibited: 
• Any testosterone products other than the randomized study treatment 
• Aromatase inhibitors (e.g. Anastrazole) 
• Clomid 
• 5α-reductase inhibitors 
• hCG 
• Androgen 
• Estrogen 
• Anabolic steroid 
• DHEA  
• Herbal hormone products 
• Chronic systemic steroid use (short term use is acceptable) 
 
 
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13. 
STATISTICAL METHODS  
13.1 Determination of Sample Size 
As  this  is  a  hypothesis-generating  study sample  size  was  not  determined  based  on 
statistical  assumptions  and  calculations.   
 
 
 
 
 
13.2  Statistical and Analytical Plan 
A Statistical Analysis Plan will be prepared prior to study unblinding which will fully 
describe the analyses planned for this study.  
13.2.1 Interim Analysis 
Interim analyses will be conducted after all subjects have been assessed for 6 
and  12  months.    Although  the  results  will  be  unblinded, per-subject 
randomization will  not  be  disclosed  
to  subjects,  site  personnel  and  sponsor’s 
clinical research staff to maintain the blind at the subject-level for the duration 
of  the  study.    The  study  will  not  be  stopped  for  claims  of  efficacy  at  this 
analysis.  However, the study may be stopped for futility or safety at any time.  
No adjustments for the interim analyses will be conducted.  
13.2.2 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. 
13.2.3  Efficacy Analyses 
The analysis of each efficacy endpoint will be conducted in the intent-to-treat 
(ITT)  population,  defined  as  all  subjects  randomized  to  treatment  with 
enclomiphene  or placebo.    The  ITT  population  will  be  determined  prior  to 
unblinding  the  study  data  and  reasons  for  any  subjects  excluded  will  be 
explained  in  the  clinical  study  report.    Handling  of  missing  data  will  be 
described in the Statistical Analysis Plan (SAP) 
 
 
 
t will be of interest to investigate various prognostic factors, such 
as age and diet compliance, to determine how these affect treatment response.  
Those factors will be noted in the SAP. 
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13.2.3.1  Lean Body Mass 
Lean  Body  Mass (LBM) will  be  determined  by  DXA  at  baseline,  6 
months and end of study.  The change from baseline in lean body mass 
will be investigated with at least two measurements: 
• Percentage change in LBM 
• Change in LBM percentage (%LBM) 
Subjects  are  expected  
to  gain  LBM  and  percentage  LBM. Within  and 
between treatment group t-tests or appropriate non-parametric methods 
will  assess  
treatment  affect.  
  Descriptive  statistics  will  summarize  
the 
results. 
13.2.3.2  Body Strength 
Strength will be assessed over the course of the study by assessments of 
the maximum Leg and Chest Press weight obtained.  These values will 
be  assessed  at  baseline  and  weekly.  The  baseline  assessment  will  be 
determined at the subject’s first gym visit.  Analyses will compare the 
periodic  assessments  to  the  subject’s  baseline.    Within  and  between 
treatment  group  t-tests  or  appropriate  non-parametric  methods  will 
assess  treatment  affect.  Descriptive  statistics  will  summarize  the 
results. 
13.2.3.3 Waist Circumference 
Careful assessments of waist circumference will detect change in body 
composition.  The change in waist circumference over the duration of 
the study will be calculated and summarized using descriptive statistics.  
The  change  from  baseline  will  be  compared  within  and  between 
treatment groups using a t-test or appropriate non-parametric method. 
13.2.3.5  Testosterone 
For  each  
treatment  group,  
the T and  change  
from  baseline  
in T (visit 
value minus baseline value) will be summarized at each treatment visit 
using  descriptive  statistics  (sample  size,  mean,  median,  standard 
deviation,  minimum  and  maximum).  
  The  change  from  baseline  
in T 
will be compared within and between treatment groups using a t-test or 
appropriate non-parametric method. 
13.2.3.6 LH 
For each treatment group, the LH and change from baseline in LH (visit 
value minus baseline value) will be summarized at each treatment visit 
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using  descriptive  statistics  (sample  size,  mean,  median,  standard 
deviation, minimum and maximum).  The change from baseline in LH 
will be compared within and between treatment groups using a t-test or 
appropriate non-parametric method. 
13.2.3.7  Metabolic Parameters 
For  each  treatment  group,  the  HbA1c,  FPG,  Insulin, HOMA-IR  and 
Quantose IR assessment of insulin sensitivity and change from baseline 
will  be  summarized  at  each  
treatment  visit  using  descriptive  statistics 
(sample  size,  mean,  median,  standard  deviation,  minimum  and 
maximum).  
  The  change  from  baseline  will  be  compared within  and 
between  
treatment  groups  using  a  
t-test  or  appropriate  non-parametric 
method. 
13.2.3.8  Change in BMI 
For each treatment group, the weight and change from baseline in BMI 
(visit value minus baseline value) will be summarized at Week 16 using 
descriptive  statistics  (sample  size,  mean,  median,  standard  deviation, 
minimum  and  maximum).  
  The  change  
from  baseline  
in  BMI  will  be 
compared within  and between  treatment  groups  using  a  t-test  or 
appropriate non-parametric method.   
 
 
 
 
 
 
 
 
 
    
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
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13.3  General Statistical Issues 
For the efficacy variables, a last observation forward approach will be used to impute 
missing data in some analyses.  If there are no post-baseline efficacy data then a value 
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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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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  enclomiphene  citrate  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: 
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. 
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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 ZA-205 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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ZA-205 Amendment 4 Protocol Summary of Changes 
Page 1 of 1 
Protocol Title:  
A  Randomized,  Double  Blind,  Placebo-Controlled,  Multi-Center  Study  in  Men  with  Acquired 
Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters with 
Diet and Exercise in Conjunction with Treatment with 12.5 mg or 25 mg Enclomiphene 
Changes From: 
From Protocol Amendment 3 dated September 14, 2016  To: Protocol Amendment 4 dated December 9, 2016 
Reason for Amendment:  
To add depression assessment (PHQ-9) at Visits 6 and 7 
Changes to Protocol:   
Significant changes to the protocol are listed below. 
SECTION 
CHANGED FROM 
CHANGED TO 
REASON 
FOR 
CHANGE 
Table 1 
 
Footnote 6 added to include depression assessment 
New study 
assessment 
8. TRIAL DESIGN 
8.1.7 Subject 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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