Conditions: Benign Prostatic Hyperplasia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
This study will evaluate the safety and effectiveness of different doses of OPK-88004 compared to placebo on serum PSA compared to placebo in men with benign prostatic hyperplasia (BPH).

Detailed description:
Study SAR-202 is a phase 2 multicenter, placebo-controlled, double-blind trial to evaluate the effect of OPK-88004 doses (OPK-88004 15 mg, or OPK-88004 25 mg) on serum PSA compared to placebo in men with BPH. Approximately 115 men with BPH will be enrolled in the study, randomized 1:1:1 across three arms (placebo, OPK-88004 15 mg, or OPK-88004 25 mg). The trial will be conducted at approximately up to 35 sites within the US.

The study duration for individual subjects will be up to 24 weeks and will include three phases:

* a screening period (up to 4 weeks, including 1-week washout if required),
* a treatment period (16 weeks), and
* a follow-up period (4 weeks) Subjects will be randomized and receive their first dose of study drug at visit 2. They will begin the once daily oral dosing regimen and return every 4 weeks to the study site during the 16-week treatment period. Assessments during the study period will include vital signs, laboratory testing, weight, adverse events (AEs), concomitant drugs, and study drug compliance. Efficacy assessments will include serum PSA, LBM and fat mass by DXA scans, uroflowmetry parameters, PVR (by ultrasound), and assessment of symptoms by IPSS.

Arms:
arm 1: Placebo Group arm 2: 15mg, OPK-88004 arm 3: 25,mg OPK-88004

Interventions: intervention 1: Group-1 (15mg, OPK-88004) intervention 2: Group-2 (25 mg,OPK-88004) intervention 3: Placebo
Intervention descriptions: intervention 1: 15mg, OPK-88004 intervention 2: 25 mg,OPK-88004 intervention 3: Placebo

Protocol document:
Prot_000.pdf: 
 
CLINICAL TRIAL PROTOCOL: SAR-202 
Study Title: 
A Randomized, Double-blind, Placebo-controlled Dose-ranging Study 
of OPK-88004 Once-a-day Dosing for 16 Weeks in Men with Signs and 
Symptoms of Benign Prostatic Hyperplasia 
Study Number: 
SAR-202 
Study Phase: 
Phase 2 
Product Name: 
OPK-88004 
IND Number: 
 
Indication: 
Benign Prostatic Hyperplasia (BPH) 
Investigators: 
Multicenter 
Sponsor: 
Transition Therapeutics Ireland Ltd. (a subsidiary of OPKO Health, 
Inc.) 
Sponsor Contact: 
Dr. 
  
 Development 
OPKO Health, Inc. 
4400 Biscayne Blvd  
Miami, FL 33137 
Email: 
 
Phone: 
 
Medical Monitor: 
Dr. 
 
Medpace 
 Medical Department 
5375 Medpace Way 
Cincinnati, OH 45227 
Email: 
 
Phone:
 
 
Version Number 
Date 
1 
27 September 2017 
2 
30 October 2017 
3 
06 February 2018 
4 
22 March 2018 
5 
25 June 2018 
6 (not implemented) 
19 October 2018 
7 
09 November 2018 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for the use of clinical investigators.  It 
is the property of Transition Therapeutics ULC Corp. or its subsidiaries and should not be copied or distributed 
to persons not involved in the clinical investigation of OPK-88004 unless such persons are bound by 
confidentiality agreement with Transition Therapeutics ULC Corp. or its subsidiaries 
PPD
PPD
PPD
PPD
PP
PPD
PPD
PPD
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 2 of 61
 
Confidential 
 
SYNOPSIS 
Sponsor: 
Transition Therapeutics Ireland Ltd. (a subsidiary of OPKO Health, Inc.) 
Name of Finished Product:  
OPK-88004 capsules 
Name of Active Ingredient: 
OPK-88004 (carbamic acid, N-[(2S)-7-cyano-1,2,3,4-tetrahydro-4-(2-pyridinylmethyl) 
cyclopent[b]indol-2-yl]-,1-methylethyl ester) 
Study Title: 
A Randomized, Double-blind, Placebo-controlled Dose-ranging Study of OPK-88004 Once-a-
day Dosing for 16 Weeks in Men with Signs and Symptoms of Benign Prostatic Hyperplasia 
Study Number:  
SAR-202 
Study Phase:  
Phase 2 
Primary Objectives:  
1. To evaluate the effect of 15 mg and 25 mg OPK-88004 daily for 16 weeks on serum PSA 
compared with placebo 
2. To evaluate the safety of 15 mg and 25 mg OPK-88004 daily for 16 weeks compared with 
placebo  
Secondary Objectives: 
1. To assess the effects of OPK-88004 on body composition by DXA, specifically lean body 
mass and fat mass   
2. 
  
Study Design: 
This is a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the effect of 
OPK-88004 doses on serum PSA compared to placebo from baseline to week 16.  
Approximately 115 men with BPH will be enrolled in the study, randomized 1:1:1 across three 
arms (placebo, OPK-88004 15 mg, or OPK-88004 25 mg).  A sample size of 28 completed 
subjects per treatment group will provide 80% power to detect a 30% reduction of PSA from 
baseline for any OPK-88004 dose when compared with placebo.  The trial consists of three 
phases: 1) a 4-week screening period, including 1-week washout if required, followed by 2) a 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 3 of 61
 
Confidential 
 
treatment period of 16 weeks and 3) a 4-week follow-up period.  The trial will be conducted at 
up to approximately 35 sites in the US.  
Study Population:  
Approximately 115 subjects will be randomized to treatment.   
Inclusion criteria.   
Subjects are eligible if they meet the following criteria: 
1. Present with BPH-LUTS based on disease diagnostic criteria at visit 1  
2. Are men aged 45 years or older at visit 1 
 
  
4. Have a PSA >1.5 and <10.0 ng/mL at visit 1.  This PSA blood draw must be performed at 
least 1 week after any DRE 
  
5. Subjects with a PSA ≥4.0 and <10.0 ng/mL must have documentation of a negative 
histologic biopsy of carcinoma of the prostate within 12 months of screening (visit 1).  For 
subjects aged ≤80 years and who have not undergone any invasive urological procedure 
within 6 months, if biopsy has not been performed, then 4Kscore Test value must be 
<7.5% at visit 1 
6. Have laboratory tests within normal limits (with the exception of total serum or free 
testosterone).  If laboratory test results are outside normal limits they are determined to be 
not clinically significant at visit 1 
7. Have not received prior treatment with 5-ARIs (finasteride, dutasteride) within the past one 
year for any indication 
8. Have not received herbal BPH preparations within 1 week of visit 1.  If the subject is 
currently on such treatment, a 1-week washout period will be required 
9. Agree not to use any 5-ARIs, herbal or experimental treatments for BPH at any time 
during the study.  Subjects on daily PDE5i’s, alpha-blockers or anticholinergic medications 
for BPH should remain on a stable dose during the study, unless a change in dose is 
medically warranted.  Occasional-use PDE5i’s for erectile dysfunction (ED) are also 
permitted at a stable dose and frequency, however should not be taken within 72 hours 
prior to a study visit 
10. Agree to use an acceptable method of birth control during the study and for 60 days after 
the last dose of IP, unless the female partner is postmenopausal.  Postmenopausal is 
defined as a female >50 years of age and 12 months of amenorrhea, or surgically 
postmenopausal 
11. Are reliable and willing to make themselves available for the duration of the study, and 
who will comply with the required study and dosing visits and abide by the Clinical 
Research Site policy and procedure and study restrictions 
12. Have given written informed consent 
Exclusion criteria.   
Subjects are not eligible to participate if they meet any of the following criteria at visit 1: 
1. History of any of the following pelvic conditions: 
o radical prostatectomy, pelvic surgery for removal of malignancy, or bowel resection 
o pelvic radiotherapy 
o any pelvic surgical procedure on the urinary tract, including transurethral resection of 
the prostate (TURP), penile implant surgery 
o lower urinary tract malignancy or trauma 
C
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 4 of 61
 
Confidential 
 
o pelvic surgery or any other pelvic procedure less than 6 months prior to visit 1 
2. Lower urinary tract instrumentation (including prostate biopsy) within 6 weeks prior to 
screening PSA blood draw 
3. History of urinary retention or lower urinary tract (bladder) stones within 1 month of visit 
1 
4. Minimally invasive procedures for BPH, such as prostatic stent, high intensity focused 
ultrasound (HIFU), holmium laser enucleation of prostate (HoLEP), interstitial laser 
coagulation (ILC), transurethral electroevaporation of the prostate (TUVP), transurethral 
microwave thermotherapy (TUMT), transurethral needle ablation (TUNA), photoselective 
vaporization (PVP), UroLift, within 6 weeks  
5. Clinical evidence of urinary tract infection or urinary tract inflammation (including 
prostatitis)   
6. Intravesical obstruction (eg, intravesical median lobe of the prostate) 
7. Current neurologic disease or condition associated with neurogenic bladder (eg, 
Parkinson’s disease, multiple sclerosis)  
8. History of significant renal insufficiency, defined as receiving renal dialysis or having an 
estimated creatinine clearance <45 mL/min 
9. Active hepatobiliary disease or serologic evidence of active hepatitis A, B, C, hepatitis E 
or HIV 
10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2X the 
upper limit of normal (ULN) 
11. Glycosylated hemoglobin (HbA1c) >9% 
12. Hematocrit ≥50%  
13. HDL-C <35 mg/dL and LDL-C >130 mg/dL   
14. QTcB interval >450 msec.  For heart rates over 75, the ECG may be repeated after 5 
minutes of resting quietly 
15. Abnormality in ECG (eg, left bundle branch block, complete right bundle branch block, or 
delayed intraventricular conduction with a QRS interval >120 msec) that in the opinion of 
the investigator places the subject at an unacceptable risk for study participation, or subject 
has implanted pacemaker   
16. History of any of the following cardiac/coronary conditions within 90 days:  
o history of myocardial infarction or coronary artery bypass graft  
o percutaneous coronary intervention  
o stroke 
17. Any evidence of heart disease (NYHA ≥Class II, Appendix 4) within 6 months, or 
receiving treatment for congestive heart failure (CHF)  
18. Any supraventricular or ventricular arrhythmia with uncontrolled ventricular response 
(mean heart rate >100 bpm) at rest despite medical therapy 
19. Systolic blood pressure >160 or <90 mm Hg or diastolic blood pressure >100 or <50 mm 
Hg as determined by a sitting measurement (if stress is suspected, retest up to two times 
under basal conditions), or malignant hypertension 
20. Have a history or presence of prostatic carcinoma, as well as any conditions that may be 
exacerbated by androgenic medications such as (but not limited to) epilepsy, seizures, 
convulsions, migraine or polycythemia 
21. History of cancer within the previous 5 years, except for excised superﬁcial lesions (such 
as basal cell carcinoma and squamous cell carcinoma of the skin) 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 5 of 61
 
Confidential 
 
22. History of drug, alcohol, or substance abuse within 6 months 
23. Have an alcohol intake of ≥3 units/day or ≥14 units/week during the study (1 unit = 12 
ounces of beer, 5 ounces of wine, 1.5 ounces of distilled spirits) 
24. Any condition that would interfere with subject’s ability to provide informed consent or 
comply with study instructions, would impair ability to perform the study assessments, or 
would place subject at increased risk, or might confound the interpretation of the study 
results 
25. Current treatment with androgens, antiandrogens, estrogens, or anabolic steroids within the 
prior 1 month.  Any prior or current treatment with LHRH agonists/antagonists 
26. Current treatment with potent CYP3A4 inhibitors such as itraconazole or ritonavir 
27. Have taken prescription or over-the-counter medications to promote weight loss within the 
prior 3 months  
28. Any prior use of OPK-88004  
29. Allergic to any component of OPK-88004 
Test Product, Dose, and Mode of Administration:  
OPK-88004 capsules or matching placebo will be taken orally daily for 16 weeks at 0, 15 or 
25 mg.   
Duration of Treatment:  
Each subject may participate in the study for up to 24 weeks.  OPK-88004 will be 
administered for 16 weeks. 
Efficacy Assessments: 
1. Serum PSA  
Safety Assessments: 
1. AEs 
1. Clinical laboratory measurements (lipids, chemistry, hematology, coagulation, HbA1c, 
fasting glucose and insulin, hormone panel, CRP, and urinalysis) 
2. Physical examinations 
3. Vital signs 
4. ECGs 
5. Semen analysis 
Statistical Methods: 
Approximately 115 subjects will be enrolled in the study, randomized 1:1:1 across three arms 
(placebo, OPK-88004 15 mg, or OPK-88004 25 mg).  The primary efficacy objective is to 
evaluate the ability of OPK-88004 doses to reduce PSA compared to placebo from baseline to 
week 16.  Based on the historical data, the treatment differences of percent reduction of PSA 
from baseline to week 16 endpoint between any OPK-88004 dose and placebo is over 30% 
with common standard deviation <40%.  With a sample size of 28 completed subjects per 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 6 of 61
 
Confidential 
 
treatment group, the power for PSA reduction for any OPK-88004 dose compared to placebo 
is over 80%.   
The primary efficacy endpoint will be analyzed in the mITT Population using a mixed-model 
repeated-measures (MMRM).  Sensitivity analysis of the percent change from baseline of PSA 
to week 16 endpoint will be performed using ANCOVA.  Descriptive summary statistics will 
be provided for all safety variables.  
Efficacy analyses will be repeated on the PP Population to test robustness of the analysis on 
the mITT Population  
Study Duration and Dates: 
The study duration for individual subjects will be up to 24 weeks, and will include a screening 
phase of up to 4 weeks, including 1-week washout if required, a 16-week treatment period and 
a 4-week follow-up period.  The trial is expected to commence recruitment during 4Q 2017.   
 
 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 7 of 61
 
Confidential 
 
TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL: SAR-202 ........................................................................1 
SYNOPSIS ................................................................................................................................2 
TABLE OF CONTENTS ........................................................................................................7 
LIST OF IN-TEXT TABLES .................................................................................................9 
LIST OF IN-TEXT FIGURES ...............................................................................................9 
LIST OF APPENDICES .........................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................10 
1 
INTRODUCTION ..........................................................................................................12 
1.1 
Background ................................................................................................................12 
1.2 
Nonclinical Studies .....................................................................................................13 
1.3 
Previous Human Experience .....................................................................................14 
1.4 
Rationale for the Study ..............................................................................................14 
1.4.1 
Rationale for Dose Selection ...............................................................................15 
2 
STUDY OBJECTIVES ..................................................................................................16 
2.1 
Primary Objectives ....................................................................................................16 
2.2 
Secondary Objectives.................................................................................................16 
 
16 
3 
INVESTIGATIONAL PLAN ........................................................................................17 
3.1 
Overall Study Design and Plan .................................................................................17 
3.2 
Rationale for Study Design and Control Group .....................................................18 
3.3 
Study Duration and Dates .........................................................................................18 
4 
STUDY POPULATION SELECTION .........................................................................19 
4.1 
Study Population ........................................................................................................19 
4.2 
Inclusion Criteria .......................................................................................................19 
4.3 
Exclusion Criteria ......................................................................................................20 
5 
STUDY TREATMENT(S) .............................................................................................23 
5.1 
Randomization ...........................................................................................................23 
5.2 
Description of Treatment(s) ......................................................................................23 
5.2.1 
OPK-88004............................................................................................................23 
5.2.2 
Placebo ..................................................................................................................23 
5.3 
Treatments Administered .........................................................................................23 
5.4 
Selection and Timing of Dose for Each Patient .......................................................24 
5.5 
Method of Assigning Patients to Treatment Groups ..............................................24 
5.6 
Blinding .......................................................................................................................24 
5.7 
Concomitant Therapy ................................................................................................24 
5.8 
Restrictions .................................................................................................................25 
5.9 
Packaging and Labeling ............................................................................................25 
5.10 
Storage and Accountability .......................................................................................25 
5.11 
Materials and Supplies ..............................................................................................26 
6 
STUDY PROCEDURES ................................................................................................27 
6.1 
Medical History and Physical Examination ............................................................27 
6.2 
ECG Collection and Reporting .................................................................................27 
6.3 
Semen Analysis ...........................................................................................................27 
6.4 
Clinical Laboratory Tests..........................................................................................27 
6.4.1 
Laboratory Parameters .......................................................................................27 
CC


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 8 of 61
 
Confidential 
 
6.4.2 
Sample Collection, Storage, and Shipping .........................................................29 
6.5 
Dispensing Study Drug ..............................................................................................29 
6.6 
Treatment Compliance ..............................................................................................29 
 
 
6.8 
Efficacy Assessments .................................................................................................30 
6.8.1 
PSA ........................................................................................................................30 
 
 
 
 
6.8.4 
LBM and Fat Mass ..............................................................................................31 
 
 
6.9 
Appropriateness of Measurements ...........................................................................32 
6.10 
Concomitant Medication Assessments .....................................................................32 
7 
DISCONTINUATION ....................................................................................................33 
7.1 
Discontinuation of Subjects .......................................................................................33 
7.2 
Discontinuation of Study Sites ..................................................................................33 
7.3 
Discontinuation of the Trial ......................................................................................33 
8 
SAFETY EVALUATIONS ............................................................................................34 
8.1 
Adverse Events ...........................................................................................................34 
8.1.1 
Severity..................................................................................................................34 
8.1.2 
Relationship ..........................................................................................................35 
8.2 
AEs of Special Interest (AESI)..................................................................................35 
8.2.1 
Clinical Laboratory Testing for Hematology and Lipids .................................35 
8.2.1.1 
Hematology .....................................................................................................35 
8.2.1.2 
Lipid Changes.................................................................................................36 
8.2.2 
Cardiovascular Events.........................................................................................36 
8.2.3 
ECG .......................................................................................................................36 
8.2.4 
Semen Analysis .....................................................................................................36 
8.2.5 
Testosterone and Steroidal Androgen Events ...................................................36 
8.3 
PSA ..............................................................................................................................36 
8.4 
Serious Adverse Events .............................................................................................36 
8.5 
Reporting Serious Adverse Events ...........................................................................37 
8.5.1 
Initial Report ........................................................................................................37 
8.5.2 
Follow-up Reports ................................................................................................38 
9 
STUDY ACTIVITIES ....................................................................................................39 
9.1 
Screening/Visit 1 (Week -4 to Day 0) including 1 week washout if required .......39 
9.2 
Treatment Period (Week 0 to Week 16) ..................................................................39 
9.2.1 
Visit 2 (Day 1) Procedures ...................................................................................39 
9.2.2 
Visit 3 (Week 4 ±2 Days) Procedures .................................................................40 
9.2.3 
Visit 4 (Week 8 ± 2 Days) Procedures ................................................................40 
9.2.4 
Visit 5 (Week 12 ± 2 Days) Procedures ..............................................................41 
9.3 
End of Treatment -Visit 6 (Week 16 ±2 Days) Procedures ....................................41 
9.4 
End of Treatment – Follow up PK Visits 7 and 8 ...................................................42 
9.5 
Follow-up- Visit 9 (Week 20 ± 2 Days) Procedures ................................................42 
9.6 
Early Termination Visit (ET) Procedures ...............................................................42 
10 QUALITY CONTROL AND ASSURANCE ...............................................................44 
10.1 
Data Quality Assurance .............................................................................................44 
CC
C
C
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 9 of 61
 
Confidential 
 
11 PLANNED STATISTICAL METHODS ......................................................................46 
11.1 
General Considerations .............................................................................................46 
11.2 
Determination of Sample Size ...................................................................................46 
11.3 
Analysis Populations and Randomization ...............................................................47 
11.3.1 
Analysis Populations ............................................................................................47 
11.4 
Demographics and Baseline Characteristics ...........................................................47 
11.5 
Study Drug Exposure, Compliance, and Concomitant Therapies ........................47 
11.6 
Primary Efficacy Analysis .........................................................................................47 
11.7 
Safety Analysis ...........................................................................................................48 
11.8 
Secondary Efficacy Analysis .....................................................................................49 
 
 
 
 
12 ADMINISTRATIVE CONSIDERATIONS .................................................................50 
12.1 
Investigators and Study Administrative Structure .................................................50 
12.2 
Institutional Review Board (IRB) Approval ...........................................................50 
12.3 
Ethical Conduct of the Study ....................................................................................51 
12.4 
Subject Information and Consent ............................................................................51 
12.5 
Subject Confidentiality ..............................................................................................51 
12.6 
Case Report Forms and Study Records ...................................................................52 
12.7 
Safety Monitoring ......................................................................................................52 
12.7.1 
Data Monitoring Committee ...............................................................................53 
12.8 
Protocol Deviations ....................................................................................................53 
12.9 
Retention of Data .......................................................................................................53 
12.10 Publication and Disclosure Policy ............................................................................53 
13 REFERENCE LIST........................................................................................................54 
 
LIST OF IN-TEXT TABLES 
Table 1 
List of Laboratory Tests ................................................................................28 
Table 2 
CROs ...............................................................................................................50 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design for SAR-202.............................................................................17 
LIST OF APPENDICES 
APPENDIX 1. 
SCHEDULE OF EVENTS ......................................................................55 
APPENDIX 2. 
PROHIBITED CONCOMITANT MEDICATIONS ...........................57 
 
 
APPENDIX 4. 
NEW YORK HEART ASSOCIATION CARDIAC DISEASE 
CLASSIFICATION ........................................................................................................60 
APPENDIX 5. 
INVESTIGATOR’S SIGNATURE ........................................................61 
 
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 10 of 61
 
Confidential 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
5-ARIs 
5-alpha reductase inhibitors 
BPH 
benign prostatic hyperplasia 
BOO 
bladder outlet obstruction 
CSR 
clinical study report 
DRE 
digital rectal exam 
DXA 
dual energy X-ray absorptiometry 
ECG 
electrocardiogram 
ET 
early termination (visit) 
GCP 
Good Clinical Practices  
hAR 
human androgen receptor 
HDL-C 
high-density lipoprotein cholesterol 
ICH 
International conference on Harmonisation 
IP 
investigational product 
IPSS 
international prostate symptom score  
LBM 
lean body mass 
LDL-C 
low-density lipoprotein cholesterol 
LHRH 
luteinizing hormone releasing hormone 
LOAEL 
lowest observed adverse effect level 
LOCF 
last observation carried forward 
LUTS 
lower urinary tract symptoms 
mITT 
modified Intent-to-Treat (population) 
NOAEL 
no observed adverse effect level 
P1NP 
N-terminal propeptide of procollagen type 1 
PD 
pharmacodynamics 
PDE5i 
phosphodiesterase 5 inhibitor  
PK 
pharmacokinetic 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 11 of 61
 
Confidential 
 
PP 
Per Protocol (population) 
PSA 
prostate-specific antigen 
QoL 
quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARM 
selective androgen receptor modulator 
TEAE 
treatment-emergent adverse event 
 
 
 
 
 
 
 
 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 12 of 61
 
Confidential 
 
1 INTRODUCTION 
1.1 
Background 
Benign prostatic hyperplasia (BPH), characterized by an increase in the size of the prostate, is a 
complex and progressive disease common in aging men.  An estimated 50% of men have BPH 
by the age of 60 years, and 90% by age 85 [Berry et al 1984; Roehrborn 2005].  Men with BPH 
have increased prevalence of lower urinary tract symptoms (LUTS) which may require treatment 
and potentially surgery.  In addition, a very large proportion of this patient population with 
symptomatic BPH have other symptoms such as sexual dysfunction that have been shown to 
increase with advancing age [Rosen et al 2005].   
Mechanical obstruction by the enlarged prostate, dynamic obstruction caused by the tone of the 
prostatic smooth muscle and the reaction of the bladder are thought to contribute to the 
symptoms of BPH [Roehrborn 2005].  Men with BPH may experience lower urinary tract 
symptoms and serious complications of urethral obstruction [Hollingsworth & Wilt 2014].  
Histologically, BPH is characterized by an increased number of both epithelial and stromal cells 
in the periurethral area of the prostate.  It is understood that androgens, growth factors, 
neurotransmitters and other cell interactions play a role in the development of this condition 
[Cunha et al 2004].  Approved medical therapies for the treatment of the signs and symptoms of 
BPH include three drug classes: (1) selective alpha-blockers such as terazosin, tamsulosin, 
doxazosin, and silodosin (2) 5-α-reductase inhibitors (5-ARIs) finasteride and dutasteride 3) 
phosphodiesterase 5 inhibitor (PDE5i), tadalafil. 
While alpha-blockers and PDE5i’s provide rapid relief in the form of improved urinary flow rate, 
their effects do not reduce the overall risk of BPH-related complications.  It is known that 
androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of 
this signaling decreases prostate volume and BPH related urinary tract symptoms.  5-ARIs 
(finasteride and dutasteride) impact the underlying disease by affecting dihydrotesterone, the 
primary androgen involved in normal and abnormal prostate growth.  Through this inhibition, 
prostate size is decreased, thereby reducing the risk of acute urinary retention and BPH-related 
surgery while providing symptom control [Andriole et al 2004; Smith & Carlson 2009].  
Therefore, actively decreasing the size of the prostate through reduction of androgen signaling 
arguably plays an important role in the reduction of long-term risks associated with BPH 
progression.  Targeting the AR may therefore provide a reasonable therapeutic approach for 
treatment of BPH. 
OPK-88004 acts as an oral, tissue-selective androgen receptor modulator (SARM), with 
antagonist effects on the prostate while providing anabolic effects on body composition.  In vitro 
research studies have demonstrated tissue selectivity of OPK-88004 on the human AR (hAR).  
The proposed mechanisms for the tissue selectivity of SARMs include the role of 5α-reductase, 
tissue-specific expression of co-regulators, differences in the complexes formed by the AR in 
anabolic and androgenic tissues, and the tissue-specific role of intracellular signaling cascades 
[Narayanan et al 2008].   
Nonclinical and clinical data supports the use of OPK-88004 to treat the signs and symptoms of 
BPH in men.  In vitro and animal data support that OPK-88004 serves as a potential antagonist to 
testosterone on the prostate and at similar doses provides anabolic activity on muscle and bone.  


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 13 of 61
 
Confidential 
 
In an orchidectomized rat model treatment with OPK-88004 at 3 to 30 mg/kg/day in the presence 
of testosterone demonstrate that OPK-88004 antagonizes the androgenic effects of testosterone 
on the prostate by decreasing prostate and seminal vesical weights.  Further, in chronic 
toxicology studies OPK-88004 decreased prostate weight in naïve, non-orchidectomized rats and 
dogs.  The loss in weight was more pronounced in dogs relative to rats.  In dogs treated with 
doses from 3 to 300 mg/kg/day, a decrease of 60-80% in prostate weight was associated with 
prostate atrophy at 6 and 12 months.  
  These 
observations were supported in a phase 2 trial, where treatment of elderly men for 12 weeks at 5 
mg daily showed a trend of decrease in PSA levels.  These data suggest that OPK-88004 acts as 
a selective androgenic antagonist on the prostate.  The treatment with OPK-88004 may be 
expected to improve lower urinary tract symptoms associated with BPH and reduce the risk of 
urinary retention by affecting the excessive growth of the prostate.  
In a gonadectomized rodent model, OPK-88004 demonstrated anabolic effects on muscle and 
osteoanabolic properties on bone mass and biomechanical strength.  In a multiple dose trial, 
healthy subjects exposed for 28 days to OPK-88004 demonstrated clinically and statistically 
signiﬁcant increases in LBM and calf area.  This was accompanied by changes in bone 
biochemical biomarkers consistent with a bone anabolic increase.  In a phase 2 trial in men with 
ED, OPK-88004 has shown improvement on body composition parameters including lower 
extremity muscle strength and power, LBM and fat mass after 12 weeks of treatment.  The 
concomitant effect of OPK-88004 on LBM and muscle strength may decrease loss of physical 
function and fatigue common in older men with BPH. 
Human clinical studies show an acceptable safety profile for OPK-88004 in that observed effects 
were considered monitorable and reversible. 
Development of an androgen that can effectively treat the distressing symptoms of BPH and 
improve body composition changes would be an innovative clinically beneficial therapeutic 
option for men with moderate to severe BPH-LUTS and enlarged prostate.  As the US population 
ages both the incidence and prevalence of BPH is increasing and subsequently there is a greater 
need for suitable treatment options [Parsons 2010].   
1.2 
Nonclinical Studies 
OPK-88004 is a potent and selective modulator of the hAR with no significant cross reactivity 
against other nuclear hormone receptors.  In toxicology studies, OPK-88004 was generally well 
tolerated for up to 6 months in rats and for up to 12 months in dogs, with no compound-related 
mortality or adverse clinical signs.  OPK-88004 demonstrated no drug-related effects at doses up 
to 1000 mg/kg in gastrointestinal (GI), renal, pulmonary, and cardiovascular function studies. 
OPK-88004-induced pharmacological effects are consistent with agonist activity on the AR in 
repeat-dose toxicological studies.  Noteworthy effects of OPK-88004 included reversible 
changes in the reproductive cycle and in reproductive tissues of males and females.  Functional 
effects related to these changes in rats included reduced sperm count, decreased fertility, and 
reduced embryo viability.  OPK-88004 was teratogenic in mice.  Overall, treatment-related 
findings were, in general, consistent with effects on androgen-responsive tissues and alterations 
in the hypothalamic-pituitary-gonadal (HPG) axis and reproductive cycling.  Safety 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 14 of 61
 
Confidential 
 
pharmacology studies of up to 6-month duration indicate a high safety margin for the drug.  
OPK-88004 was negative in a battery of genotoxicity tests. 
1.3 
Previous Human Experience 
To date, six clinical trials have been completed with OPK-88004, five phase 1 clinical trials and 
one phase 2 clinical trial.  A total of 353 subjects have been exposed to OPK-88004 of which 
200 subjects have received concurrent doses of OPK-88004 and tadalafil (5 mg and 10 mg 
tablet) once a day.  Across these studies, OPK-88004 was well tolerated with a satisfactory 
safety profile at single doses up to 1000 mg, at multiple doses up to 75 mg for 28 days and at 5 
mg for 12 weeks.  Once-daily treatment of combination of OPK-88004 with 5 mg and 10 mg 
tadalafil for 12 weeks was also well tolerated with a satisfactory safety profile.  
Potential reproductive effects were monitored clinically by sperm evaluation in the phase 2 trial.  
Treatment differences across the treatment groups were not considered to be clinically 
meaningful. 
In clinical studies, OPK-88004 showed improvement on body composition parameters.  In a 
multiple dose study healthy subjects exposed for 28 days to OPK-88004 demonstrated clinically 
and statistically signiﬁcant increases in LBM and calf area.  This was accompanied by changes in 
bone biochemical biomarkers consistent with a bone anabolic increase.  Empirical 
pharmacodynamics models demonstrated a positive exposure-response relationship for LBM and 
N-terminal propeptide of procollagen type 1 (P1NP).  In a phase 2 trial, OPK-88004 showed 
improvement on body composition parameters, lower extremity muscle strength and power, 
LBM, fat mass and bone mineral density and biochemical biomarkers after 12 weeks of 
treatment.  Significant increase in LBM and lower extremity muscle power (measured by the 
stair climb) was observed at the 5 mg dose.   
Results from clinical studies completed to date suggest that OPK-88004 acts as a selective AR 
modulator with antagonist effect on the prostate and agonist effects on some tissues, supporting 
the data generated in animal models.   
1.4 
Rationale for the Study 
OPK-88004 has demonstrated the potential to reduce prostate size that can prevent progression 
of LUTS secondary to BPH and reduce the risk of urinary retention.  Additionally, the 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 15 of 61
 
Confidential 
 
concomitant effect of OPK-88004 on LBM and muscle strength may decrease loss of physical 
function and fatigue common in older men.  Human clinical studies show a favorable safety 
profile for OPK-88004 in that observed effects were considered monitorable and reversible.  
These findings formed the basis for the proposed evaluation of OPK-88004 as a treatment for the 
signs and symptoms associated with BPH.   
In this first trial for this indication, the effects of OPK-88004 on PSA will be assessed in a BPH 
patient population with PSA levels of >1.5 ng/mL and prostate volumes >40 cm3 and <80 cm3 
and signs and symptoms of BPH.  Serum PSA levels and safety parameters will be the primary 
endpoints.  
 
 
  The trial will evaluate the safety of two 
doses of OPK-88004 on this patient population.  
 
 
The trial is double-
blinded to permit assessment of more subjective markers of safety compared to placebo 
treatment.  Information available for the 5-ARI dutasteride suggests that effects on prostate 
volume may be observed within three months of treatment.  The length of treatment in this trial 
(16 weeks) is thus adequate to observe changes in PSA, reflecting changes in prostate volume.  
1.4.1 
Rationale for Dose Selection 
Based on nonclinical and clinical data on effect of OPK-88004 on prostate size, clinical doses 
selected to be administered in this trial are 15 mg or 25 mg daily for 16 weeks.  These doses are 
expected to result in a clinically meaningful reduction in PSA levels and prostate size.  A 
reduction in prostate volume of ≥15% has been reported to be associated with clinically 
significant improvement in clinical scores and maximum urinary flow rate [Gormley GJ 1992].   
Prostate size has not been measured in previous clinical trials with OPK-88004, however PSA 
data obtained from clinical studies support the selected dose levels.  A trend of decrease in PSA 
levels relative to placebo was observed in healthy males exposed to OPK-88004 at doses of 15 
and 25 mg daily for 4 weeks (study GPBC).  In study GPEC, treatment of elderly men with 
OPK-88004 at 5 mg daily showed a trend of decrease in PSA levels in those subjects with 
baseline levels of PSA ≥2.5 ng/mL, indicative of prostate hyperplasia.  There was no effect in 
this study of 1 mg OPK-88004 following 12 weeks treatment.   
Population PK modeling showed that dose levels of 15 and 25 mg will provide sufficiently 
separated exposure profiles.   
For all of the safety pharmacology, general toxicology and reproductive toxicology studies, 
safety margins of at least 4-fold are in place with the exception of developmental toxicity in 
mice, which is 0.6-fold.   
 
 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 16 of 61
 
Confidential 
 
2 STUDY OBJECTIVES 
2.1 
Primary Objectives  
The primary objectives of this study are: 
1. To evaluate the effect of 15 mg and 25 mg OPK-88004 daily for 16 weeks on serum PSA 
compared with placebo 
2. To evaluate the safety of 15 mg and 25 mg OPK-88004 daily for 16 weeks compared with 
placebo  
2.2 
Secondary Objectives  
The secondary objectives of this study are:  
1. To assess the effect of OPK-88004 on body composition by DXA, specifically LBM and fat 
mass 
2. To assess PK of OPK-88004 based on a sparse sampling strategy 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 17 of 61
 
Confidential 
 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
Study SAR-202 is a phase 2 multicenter, placebo-controlled, double-blind trial to evaluate the 
effect of OPK-88004 doses (OPK-88004 15 mg, or OPK-88004 25 mg) on serum PSA compared 
to placebo in men with BPH.  Approximately  115 men with BPH will be enrolled in the study, 
randomized 1:1:1 across three arms (placebo, OPK-88004 15 mg, or OPK-88004 25 mg).  The 
trial will be conducted at approximately up to 35 sites within the US.  
The study duration for individual subjects will be up to 24 weeks and will include three phases:  
 a screening period (up to 4 weeks, including 1-week washout if required),  
 a treatment period (16 weeks), and  
 a follow-up period (4 weeks) 
The design for study SAR-202 is illustrated in Figure 1. 
Figure 1 
Study Design for SAR-202 
 
Study procedures and timing are outlined in the Study Event Schedule (Appendix 1).  Subjects 
will be randomized and receive their first dose of study drug at visit 2.  They will begin the once 
daily oral dosing regimen and return every 4 weeks to the study site during the 16-week 
treatment period.  Assessments during the study period will include vital signs, laboratory 
testing, weight, adverse events (AEs), concomitant drugs, and study drug compliance.  Efficacy 
assessments will include serum PSA, LBM and fat mass by DXA scans, 
 
 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 18 of 61
 
Confidential 
 
3.2 
Rationale for Study Design and Control Group 
The study is designed to evaluate the effect on PSA, safety and PK of OPK-88004 doses for 16 
weeks.  Prostate volume will be assessed indirectly by PSA level.  Results from the MTOPS 
(Medical Therapy of Prostatic Symptoms) and CombAT studies [McVary 2005; Roehrborn et al 
2010] suggest that men with larger prostate volume may experience earlier LUTS improvement 
with 5-ARI therapy, so subjects with prostate volume >40 and <80 cm3 will be investigated in 
this phase 2 trial.  Safety measures including AEs, clinical laboratory measurements (lipids, 
chemistry, hematology, coagulation, HbA1c, fasting glucose and insulin, hormone panel, CRP, 
and urinalysis), physical examinations, vital signs, ECGs and semen analysiswill be obtained.  A 
sparse sampling strategy is employed to assess the PK of OPK-88004 in this patient population. 
The primary efficacy endpoint in this trial is PSA levels, an indirect measure of prostate volume, 
after 16 weeks treatment.  Size is the most sensitive marker for an effect on the prostate, and 
reduction in prostate volume is believed to underlie improvement in urinary flow and associated 
symptoms.  This study has been designed to provide over 80% power to detect a 30% reduction 
of PSA from baseline for any OPK-88004 dose when compared with placebo.  Experience with 
the ARIs finasteride and dutasteride suggest that a reduction in prostate size may be measurable 
within three months after starting treatment, and that the effect increases further and is thereafter 
maintained with continued treatment, therefore assessment after 16 weeks treatment is 
appropriate in this initial study to assess effects on PSA.  
 
 
 
  The 16-week treatment period may also provide data on a variety of secondary and 
other efficacy endpoints, including measures of body composition 
. 
Androgenic effects of OPK-88004 will be assessed by measurements of LBM and fat mass (by 
DXA).  The selected dose levels may have a positive effect on 
 
 measurements of body composition.  
 
 
 
   
3.3 
Study Duration and Dates 
The study duration for individual subjects will be up to 24 weeks, and will include a screening 
phase of up to 4 weeks (including 1-week washout if required), a 16-week treatment period and a 
4-week follow-up period.   
The trial is expected to commence recruitment during 4Q 2017.   
 
 
CCI
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 19 of 61
 
Confidential 
 
4 STUDY POPULATION SELECTION 
4.1 
Study Population 
The trial will be conducted in generally healthy men at least 45 years of age at screening with a 
medical history of BPH, an enlarged prostate (>40 cm3 and <80 cm3 as assessed byTRUS) and 
an increased serum PSA level.   
Eligibility for study enrollment will be based on the results of a screening medical history, 
physical examination, vital signs, and clinical laboratory tests.  Any conditions present at the 
time of the physical examination and any pre-existing conditions will be documented.   
If, in the opinion of the investigator, an ineligible lab test result is due to an error or unexpected 
circumstance then that parameter can be re-tested once.  Subjects who do not initially meet the 
criteria for participation in this study (screen failures) may be rescreened only at the discretion of 
the investigator in consultation with the designated medical monitor.  The interval between re-
screenings should be at least 1 week.  Subjects who rescreen must sign a new consent and 
complete all screening tests under a new subject number to confirm eligibility.   
4.2 
Inclusion Criteria 
Subjects are eligible if they meet the following criteria: 
1. Present with BPH-LUTS based on disease diagnostic criteria at visit 1  
2. Are men aged 45 years or older at visit 1 
 
 
 
 
 
  
4. Have a PSA >1.5 and <10.0 ng/mL at visit 1.  This PSA blood draw must be performed at 
least 1 week after any digital rectal exam (DRE) 
 
 
5. Subjects with a PSA ≥4.0 and <10.0 ng/mL must have documentation of a negative 
histologic biopsy of carcinoma of the prostate within 12 months of screening (visit 1).  For 
subjects aged ≤80 years and who have not undergone any invasive urological procedure 
within 6 months, if biopsy has not been performed, then 
 value must be <7.5% 
at visit 1  
6. Have laboratory tests within normal limits (with the exception of total serum or free 
testosterone).  If laboratory test results are outside normal limits they are determined to be 
not clinically significant at visit 1 
7. Have not received prior treatment with 5-ARIs (finasteride, dutasteride) within the past one 
year for any indication 
8. Have not received herbal BPH preparations within 1 week of visit 1.  If the subject is 
currently on such treatment, a 1-week washout period will be required  
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 20 of 61
 
Confidential 
 
9. Agree not to use 5-ARIs, herbal or experimental treatments for BPH, at any time during the 
study.  Subjects on daily PDE5i’s, alpha-blockers or anticholinergic medications for BPH 
should remain on a stable dose during the study, unless a change in dose is medically 
warranted.  Occasional-use PDE5i’s for ED are permitted at a stable dose and frequency, 
however should not be taken within 72 hours prior to a study visit 
10. Agree to use an acceptable method of birth control during the study and for 60 days after the 
last dose of IP, unless the female partner is postmenopausal.  Postmenopausal is defined as a 
female >50 years of age and 12 months of amenorrhea, or surgically postmenopausal 
11. Are reliable and willing to make themselves available for the duration of the study, and who 
will comply with the required study and dosing visits and abide by the Clinical Research Site 
policy and procedure and study restrictions 
12. Have given written informed consent 
4.3 
Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria at visit 
1: 
1. History of any of the following pelvic conditions: 
o radical prostatectomy, pelvic surgery for removal of malignancy, or bowel resection 
o pelvic radiotherapy 
o any pelvic surgical procedure on the urinary tract, including  transurethral resection of the 
prostate (TURP), penile implant surgery  
o lower urinary tract malignancy or trauma 
o pelvic surgery or any other pelvic procedure less than 6 months prior to visit 1 
2. Lower urinary tract instrumentation (including prostate biopsy) within 6 weeks prior to 
screening PSA blood draw 
3. History of urinary retention or lower urinary tract (bladder) stones within 1 month of visit 1 
4. Minimally invasive procedures for BPH, such as prostatic stent, high intensity focused 
ultrasound (HIFU), holmium laser enucleation of prostate (HoLEP), interstitial laser 
coagulation (ILC), transurethral electroevaporation of the prostate (TUVP), transurethral 
microwave thermotherapy (TUMT), transurethral needle ablation (TUNA), photoselective 
vaporization (PVP), UroLift, within 6 weeks 
5. Clinical evidence of urinary tract infection or urinary tract inflammation (including 
prostatitis)   
6. Intravesical obstruction (eg, intravesical median lobe of the prostate) 
7. Current neurologic disease or condition associated with neurogenic bladder (eg, Parkinson’s 
disease, multiple sclerosis)  


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 21 of 61
 
Confidential 
 
8. History of significant renal insufficiency, defined as receiving renal dialysis or having an 
estimated creatinine clearance <45 mL/min 
9. Active hepatobiliary disease or serologic evidence of active hepatitis A, B, C, hepatitis E or 
HIV 
10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2X the 
upper limit of normal (ULN) 
11. Glycosylated hemoglobin (HbA1c) >9% 
12. Hematocrit ≥50%  
13. HDL-C <35 mg/dL and LDL-C >130 mg/dL   
14. QTcB interval >450 msec.  For heart rates over 75, the ECG may be repeated after 5 minutes 
of resting quietly 
15. Abnormality in ECG (eg, left bundle branch block, complete right bundle branch block, or 
delayed intraventricular conduction with a QRS interval >120 msec) that in the opinion of the 
investigator places the subject at an unacceptable risk for study participation, or subject has 
implanted pacemaker   
16. History of any of the following cardiac/coronary conditions within 90 days:  
o history of myocardial infarction or coronary artery bypass graft  
o percutaneous coronary intervention  
o stroke 
17. Any evidence of heart disease (NYHA ≥Class II, Appendix 4) within 6 months, or are 
receiving treatment for congestive heart failure (CHF) 
18. Any supraventricular or ventricular arrhythmia with uncontrolled ventricular response (mean 
heart rate >100 bpm) at rest despite medical therapy 
19. Systolic blood pressure >160 or <90 mm Hg or diastolic blood pressure >100 or <50 mm Hg 
as determined by a sitting measurement (if stress is suspected, retest up to two times under 
basal conditions), or malignant hypertension 
20. Have a history or presence of prostatic carcinoma, as well as any conditions that may be 
exacerbated by androgenic medications such as (but not limited to) epilepsy, seizures, 
convulsions, migraine or polycythemia 
21. History of cancer within the previous 5 years, except for excised superﬁcial lesions (such as 
basal cell carcinoma and squamous cell carcinoma of the skin) 
22. History of drug, alcohol, or substance abuse within 6 months 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 22 of 61
 
Confidential 
 
23. Have an alcohol intake of ≥3 units/day or ≥14 units/week during the study (1 unit = 12 
ounces of beer, 5 ounces of wine, 1.5 ounces of distilled spirits) 
24. Any condition that would interfere with subject’s ability to provide informed consent or 
comply with study instructions, would impair ability to perform the study assessments, or 
would place subject at increased risk, or might confound the interpretation of the study 
results 
25. Current treatment with androgens, antiandrogens, estrogens, or anabolic steroids within the 
prior 1 month.  Any prior or current treatment with LHRH agonists/antagonists 
26. Current treatment with potent CYP3A4 inhibitors such as itraconazole or ritonavir 
27. Have taken prescription or over-the-counter medications to promote weight loss within the 
prior 3 months  
28. Any prior use of OPK-88004  
Allergic to any component of OPK-88004 
 
 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 23 of 61
 
Confidential 
 
5 STUDY TREATMENT(S) 
5.1 
Randomization 
Subjects who have completed the screening visit and meet all of the inclusion and none of 
exclusion criteria are randomized into the study on day 1.  Randomized treatment assignment 
and randomization numbers are assigned via IWRS/IVRS.  Randomization is stratified by 
prostate volume <60 cm3 or ≥60 cm3 and LUTS severity (total IPSS [Q1-Q7] of <16 or ≥16).  
Following randomization, study drug will be dispensed in a double-blind manner.  The sponsor 
and all clinical site personnel (investigator, pharmacist, etc) are blinded to the treatment group 
for each subject.  Subjects also are blinded to the treatment they receive.   
5.2 
Description of Treatment(s) 
OPK-8804 and matching placebo are provided in HDPE bottles with child-resistant closures 
containing 30 capsules per bottle (see Section 5.9). 
5.2.1 
OPK-88004 
Dosage form: 
capsule for oral administration 
Dose strength: 
15 mg and 25 mg per capsule 
Description: 
size 2 white gelatin capsule 
Nonactive components: 
pregelatinized starch, dimethicone  
Storage conditions: 
room temperature (15 to 30oC, 59 to 86 oF) 
5.2.2 
Placebo 
Dosage form: 
capsule for oral administration 
Dose strength: 
0 mg per capsule 
Description: 
size 2 white gelatin capsule 
Nonactive components: 
pregelatinized starch, dimethicone (capsule contents) 
Storage conditions: 
room temperature (15 to 30oC, 59 to 86 oF) 
5.3 
Treatments Administered 
Study drug should NOT be administered to individuals known to be allergic to any component 
of the drug.  All subjects should be observed for allergic reaction following study drug 
administration.  All allergic reactions will be documented as AEs in the source documents and 
the electronic case report forms (eCRF). 
On day 1 (visit 2), eligible subjects will be randomized 1:1:1 to one of three treatment arms, 
namely 0 mg (placebo), 15 mg or 25 mg OPK-88004.  Subjects will receive one bottle of study 
drug at visits 2, 3, 4 and 5.   


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 24 of 61
 
Confidential 
 
Subjects will be instructed to contact the investigator as soon as possible if he has a complaint or 
problem with the study drug so that the situation can be assessed. 
5.4 
Selection and Timing of Dose for Each Patient 
Subjects will be instructed to take one dose (1 capsule) of study drug with water at 
approximately the same time each morning, except for visits 3 and 5.  The dose may be taken 
with or without food.  At visits 3 and 5, the subject will take the dose of study medication while 
at the site in order to facilitate PK sampling. 
5.5 
Method of Assigning Patients to Treatment Groups 
Enrollment and assignment to investigational product will be accomplished using IWRS/ IVRS 
(an automated web randomization system) in a 1:1:1 ratio.   
5.6 
Blinding 
Capsules used in the study will be identical in appearance to maintain double-blind status.  Study 
drug will be managed using IVRS/IWRS.  Each user will have a unique username and passcode 
to access the system.  In an emergency, when knowledge of the treatment assignment for the 
subject is essential for the clinical management or welfare of the subject, the Investigator may 
unblind the subject.  Prior to unblinding, the investigator should make every effort to contact the 
sponsor or designee before proceeding with the unblinding process if possible.  If a subject’s 
treatment assignment is unblinded without sponsor or designee’s prior knowledge, the sponsor 
must be notified immediately. 
Each site will be provided with a sealed envelope containing a six-digit code that can be entered 
into the IVRS/IWRS to unblind a subject’s treatment assignment.    
To preserve the double-blinding of the study a minimum number of sponsor personnel will have 
access to the randomization scheme and treatment assignments before the study is complete.   
The investigator will be blinded to post-randomization laboratory values for HDL-C, hematocrit, 
hemoglobin, testosterone (total and free), and PSA.  PSA increases from baseline >1.4 ng/mL 
and hematocrit values >54 % will be flagged to investigators. 
5.7 
Concomitant Therapy 
Treatment with medications that are excluded in the entry criteria is not permitted.  None of the 
excluded medications may be taken during the study without the approval of the investigator and 
sponsor.  Since OPK-88004 is metabolized primarily by CYP3A4, inhibition of this enzyme may 
result in increased plasma drug concentrations.  As such, concomitant use of potent inhibitors of 
CYP3A4 is prohibited.  A list of prohibited medication is provided in Appendix 2.   
Doses of other prescription medications for treatment of concurrent medical conditions should 
remain stable during the study whenever possible.   
If the need for additional concomitant medication arises, inclusion or continuation of the patient 
may be at the discretion of the investigator after consultation with the sponsor- designated 
medical monitor.   


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 25 of 61
 
Confidential 
 
Non-steroidal anti-inflammatory medications (including aspirin and acetaminophen), cough 
suppressants, antihistamines, vitamin/mineral supplements, antibiotics, and topical ointments 
may be used on an as-needed basis. 
5.8 
Restrictions 
Meals–Subjects shall fast for at least 8 hours overnight prior to all visits except for visit 5 and 
PK follow up visits.  
Subjects should be instructed to continuing their pre-study diet and activity levels.  
Blood donation – Study participants should be instructed not to donate blood or blood products 
during the study or for 8 weeks following the study. 
Calcium Supplements – Subjects should be instructed not to take calcium supplements on the 
day of the DXA scan. 
Contraception – Male subjects or their female partners of child-bearing potential must use 
acceptable contraception during intercourse throughout the treatment period and for 60 days after 
the last dose of IP. 
Acceptable contraception includes male sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate), oral, injected or implanted hormonal 
methods of contraception, intrauterine device or implant, and barrier methods of contraception 
(condom or occlusive cap, diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository.  The use of barrier contraceptives should always be 
supplemented with the use of a spermicide. 
5.9 
Packaging and Labeling 
OPK-88004 is supplied for the proposed clinical trial as capsules packaged in 30-count white, 
induction sealed high density polyethylene (HDPE) bottles with child-resistant closures, and 
should be stored at room temperature.   
Clinical trial materials will be labeled according to regulatory requirements.  The labels will 
include protocol number, name of sponsor, investigational statement, storage conditions and 
instructions for use.  Bottles will be assigned numbers that are linked to the randomization 
scheme through the IWRS/IVRS. 
Bottles should not be dispensed if the seal of the primary package appears compromised. 
5.10 
Storage and Accountability 
While at the study site, study drug bottles will be stored at controlled room temperature (15 - 
30oC, 59 - 86oF) in the supplied packaging, with access granted to authorized personnel only.   
All sites must ensure that study drug has been kept under required conditions prior to dispensing.  
A temperature log recording the daily storage conditions will be maintained at each site for study 
drug.  In the case of temperature excursions, product should not be dispensed, and the 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 26 of 61
 
Confidential 
 
investigator or designee should contact the clinical monitor as soon as possible to receive further 
instruction. 
Accountability for study drug, from receipt until final reconciliation and return of drug by the 
monitor or other sponsor designee will be the responsibility of the investigator or designee.  The 
investigator or assigned designee(s), will maintain study drug accountability records for study 
drug throughout the course of the study.  Specifically, the investigator or assigned designee will 
confirm that all study drug supplies are received intact and in the correct amounts per the 
shipping forms.  This will be documented by signing and dating the shipping forms and 
providing a copy to the sponsor or designee.  A study drug accountability and dispensing log will 
record the study drug disposition, including dates, quantity of drug received, to whom dispensed 
(participant-by-participant accounting), and accounts of any drug accidentally destroyed.  The 
site's running inventory of study drug supplies will be verified routinely throughout the course of 
the study.  All opened and unopened containers of study drug are to be retained at the site until 
the sponsor or designee has performed a complete verification of the dispensation, following 
which study drug will be returned to the sponsor or designee. 
At the conclusion of the study, a final inventory will be performed by the investigator (or 
designee) and verified by the study monitor.  Any discrepancies identified will be indicated, with 
a specific explanation of each discrepancy.  The investigator (or designee) must return all unused 
medication in accordance with the sponsor’s instructions, and a copy of the clinical supplies 
return documentation will be returned to the sponsor or designee.  Drug accountability records, 
clinical drug supply receipts, and returns must be maintained by the investigator. 
5.11 
Materials and Supplies 
The sponsor or assigned designee will supply vacutainers, blood collection tubes, labels, boxes 
with labels for storage of serum and plasma samples and all necessary shipping 
supplies/containers.  The investigator will supply all phlebotomy and centrifugation equipment 
including biohazard and/or safety supplies.  The investigator will ensure that all biohazard wastes 
are disposed of in accordance with investigator site SOPs and local regulations. 
 
 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 27 of 61
 
Confidential 
 
6 STUDY PROCEDURES 
6.1 
Medical History and Physical Examination 
The physical examination will be performed by a qualified personnel.  A detailed medical 
history, vital signs (include systolic and diastolic blood pressure, heart rate and respiratory rate), 
height, weight and 12-lead ECG will be obtained at visit 1.    
6.2 
ECG Collection and Reporting 
For each patient, 12-lead ECGs will be collected according to the schedule of events (Appendix 
1).  12-lead digital ECGs will be obtained after 10 minutes in supine rest.  Whenever vital signs, 
12-lead ECGs, and blood draws are scheduled for the same nominal time, the assessments should 
occur in the following order: 12-lead ECG, vital signs, and then blood draws.  Skin preparation 
should be thorough and electrodes should be placed according to standard 12-lead ECG 
placement.  
ECGs will be digitally recorded and printed on paper.  The printed paper ECG will be used for 
“real time” bedside ECG assessment by the investigator (or designee) who will be responsible 
for the overall interpretation, determination of the clinical significance, and subject eligibility 
based on the ECG findings.  ECG interpretation categories are: Normal ECG, Abnormal ECG – 
not clinically significant, Abnormal ECG – clinically significant ECG.  The original ECGs will 
be retained in the subject’s records at the site.  All digital ECG records will also be submitted to 
the cardiovascular core lab, which will perform the digital ECG analysis and interpretation in 
this study using standard methodology.  If the central reviewer identifies an abnormality, per the 
study alert criteria, the investigator will be notified who will review the ECG and report any AEs 
as necessary. 
The following variables will be reported: HR, RR, PR, QRS, QT, QTcB, and QTcF intervals. 
The investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason.  
6.3 
Semen Analysis 
A semen analysis (total sperm count, sperm concentration, sample volume and pH, sperm 
motility and morphology) will be performed at baseline (visit 2) and at the end of treatment (visit 
6) or early termination (ET) for subjects willing and able to produce a measurable semen sample.  
Local procedures will be followed.  A follow-up semen analysis at 3 months post-treatment will 
be done in those subjects with a decrease in sperm concentration >50% from baseline. 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
Clinical laboratory tests to be assessed are indicated in Table 1.   
 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 28 of 61
 
Confidential 
 
Table 1 
List of Laboratory Tests 
Hematology: 
Hematocrit (Hct)a 
Hemoglobin (Hgb)a 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count with differential  
 
Urinalysis:  
Glucose 
Urine leukocyte esterase 
Occult blood 
Nitrite 
pH 
Protein 
If an abnormal value is observed on the urine 
dipstick test, the sample may be further analyzed 
with urine microscopy 
 
Serology: 
Hepatitis A (IgM) antibody 
Hepatitis B surface antigen 
Hepatitis C antibody 
Hepatitis E (IgM) antibody 
HIV 
 
Sex hormone panel: 
Sex hormone binding globulin (SHBG) 
Luteinizing hormone (LH) 
Follicle-stimulating hormone (FSH) 
Total serum testosterone and free serum 
testosterone, calculateda 
Estradiol 
Thyroid-stimulating hormone (TSH) 
 
 
Semen Analysis 
pH 
Volume 
Total sperm count 
Sperm concentration 
Motility 
Morphology 
Serum Chemistry: 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Alanine aminotransferase (ALT; SGPT) 
Aspartate aminotransferase (AST; SGOT) 
Blood urea nitrogen (BUN) 
Calcium 
25-hydroxyvitamin D 
Creatinine 
Creatine kinase 
Gamma-glutamyl transferase (GGT) 
Glucose, fasting 
Phosphorus 
Potassium  
Sodium  
Total bilirubin 
Direct bilirubin 
 
Coagulation:  
Prothrombin time (PT) 
Activated partial thromboplastin time (PTT) 
INR 
 
Lipid Panel (fasting): 
Total cholesterol 
Triglycerides 
HDL cholesterola 
Direct LDL cholesterol 
Apolipoprotein A1 
Apolipoprotein A2 
Apolipoprotein A5 
Apolipoprotein B 
Apolipoprotein C3 
Lipoprotein (a) 
 
Miscellaneous 
Hemoglobin A1c (HbA1c) 
C-reactive protein (CRP) 
Prostate-specific antigen (PSA)a 
Insulin, fasting 
Urine drug screen 
 
 
a  The investigator is blinded to post-randomization values  
 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 29 of 61
 
Confidential 
 
6.4.2 
Sample Collection, Storage, and Shipping 
Collection, processing, storage and shipping procedures will be performed in accordance with 
the instructions provided by the central laboratory.  Detailed instructions will be provided 
separately from this protocol in the laboratory manual.  Blood samples will be collected and 
analyzed for clinical laboratory and PK analysis.   
Additional blood draws may be needed for unscheduled visits.  Single redraws for samples 
resulting in values outside eligibility criteria ranges may be performed during screening, and the 
medical monitor may be consulted as necessary.  Missed samples should be drawn whenever 
possible, and laboratory samples not collected should be noted as a protocol deviations and 
reported to the site’s IRB if necessary (see Section 12.8).  The investigator will provide a limited 
access, temperature monitored space for the study drug and a -20°C or -70°C space for 
respective serum and plasma aliquots.   
Investigators must document their review of each laboratory safety report.  Any clinically 
significant abnormal results will be reported as an AE (see Section 8.1).   
Blood samples for PK analyses will be collected from all randomized subjects in accordance 
with the study schedule.  Only samples from subjects assigned to treatment with OPK-88004 will 
be analyzed for drug concentration.  Date and time of each sample and of the last OPK-88004 
dose prior to PK blood draw must be clearly recorded.  Drug concentration information that 
would unblind the study will not be reported to study sites or blinded personnel while the study 
is blinded.   
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last subject visit for the study.   
6.5 
Dispensing Study Drug 
Study drug will be dispensed to the subject at visits 2, 3, 4, and 5 according to instructions 
supplied by the IWRS/IVRS.  Subjects will be requested to return bottles at each visit.   
Sites will maintain records of drug dispensed and returned according to Section 5.10. 
6.6 
Treatment Compliance 
Subjects will return for study treatment visits 3, 4, 5 and 6 or early termination (ET) during 
which the study coordinator or designee will perform drug accountability and dosing compliance 
calculations (number of capsules that should have been taken versus actual number taken as 
evidenced by number of returned capsules).  During the treatment period, compliance 
documented as <80% or >120% should be reported as a protocol deviation. 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 30 of 61
Confidential 
 
6.8 
Efficacy Assessments 
6.8.1 
PSA 
Blood samples for PSA measurements will be taken prior to,  or at least 1 week after, any 
examination (eg, DRE, 
 likely to result in increased values.  Subjects should be requested 
to abstain from sexual activity that involves ejaculation, or participate in vigorous physical 
exercise or activity that stimulates the prostate (eg, bicycle or horseback riding) for 48 hours 
prior to collection of samples for PSA.  When a washout period is required during screening, the 
PSA blood sample will be collected after completion of the washout period.   
As part of the study eligibility review, the 
 may be performed at screening for 
subjects aged ≤80 years with PSA ≥4 ng/mL who have not undergone any invasive urological 
procedure within 6 months and without biopsy during the previous 12 months (see Inclusion 
Criteria, Section 4.2) [Punnen et al 2015]. 
Blood samples for 
will be taken prior to, or at least 1 week after, any procedures 
(eg, DRE, 
 likely to result in increased values.  Subjects should be requested to abstain 
from sexual activity that involves ejaculation, or participate in vigorous physical exercise or 
activity that stimulates the prostate for 48 hours prior to collection of samples for 
  
When a washout period is required during screening, the screening 
 sample should 
be collected after completion of the washout period.  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 31 of 61
Confidential 
 
6.8.4 
LBM and Fat Mass 
LBM and fat mass will be measured by DXA.  DXA scans should be obtained in the morning if 
possible, with the subject fasting at least two hours prior to the scan is recommended.  The 
technologist must confirm that the subject has not undergone and radiologic procedures within 
the last two weeks (14 days) that required the use of contrast agents.  All clothing should be 
removed (including jewelry) with the exception of undergarments, unless there is the potential 
they could cause artifact.  The subject should be positioned supine on the imaging table, lying 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 32 of 61
 
Confidential 
 
straight, within the field of view.  It is important that all repeat DXA scans be performed on the 
same DXA machine as was used on the previous scan.   
A detailed overview of the DXA procedures, as well as training on image acquisition, will be 
provided by the imaging core lab.   
6.9 
Appropriateness of Measurements 
PSA levels are recognized to reflect prostate size, thus changes in PSA may be used to monitor 
effects on prostate volume in this trial.  
 
 
 
 
  
 
 
   
Comprehensive safety parameters are assessed in this trial.   
6.10 
Concomitant Medication Assessments 
Medications ongoing at the time of visit 1 as well as any new medication added during the 
course of the study will be recorded as concomitant medications.   
The study coordinator or designee will record concomitant medication history in the source 
document and eCRF at each visit.   
 
 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 33 of 61
 
Confidential 
 
7 DISCONTINUATION 
7.1 
Discontinuation of Subjects 
The criteria for enrollment must be followed explicitly.  If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject is discontinued from the trial, and the 
sponsor or its designee must be contacted and reported to the site’s IRB as appropriate. 
In addition, subjects will be permanently discontinued from the study drug after consultation 
with the sponsor-designated medical monitor in the following circumstances: 
1. The investigator decides that the subject should be withdrawn.  If this decision is made 
because of a serious adverse event (SAE) or a clinically significant laboratory value, the 
study drug is to be discontinued and appropriate measures are to be taken   
2.  Increase in QTc >60 msec above baseline or absolute QTc >500 msec 
3. Hematocrit >54% (confirmed by repeat testing within 1 week).   
4. When a subject meets one of the following criteria: 
o Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) >8X upper limit of 
normal (ULN). 
o ALT or AST >5X ULN for more than 2 weeks. 
o ALT or AST >3X ULN and (total bilirubin levels >2X ULN or INR >1.5).  
o ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).  
In addition, subjects will be discontinued from the trial in the following circumstances: 
 The sponsor or its designee stops the study or stops the subject’s participation in the trial for 
medical, safety, regulatory or other reasons consistent with applicable laws, regulations and 
good clinical practice (GCP).   
 The subject requests to be withdrawn from the trial.   
7.2 
Discontinuation of Study Sites 
Study site participation may be discontinued if the sponsor, the investigator, or the 
investigational review board (IRB) of the study site judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.   
7.3 
Discontinuation of the Trial 
The trial will be discontinued if the sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations and GCP.   


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 34 of 61
 
Confidential 
 
8 SAFETY EVALUATIONS 
Investigators are responsible for monitoring the safety of subjects who have entered this trial and 
for alerting the sponsor or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.  Laboratory values blinded to the investigator 
(see Section 5.6 and Table 1) will be reviewed by sponsor medical monitor(s) and periodically 
by the DSMB. 
The investigator is responsible for the appropriate medical care of subjects during the study.   
The investigator remains responsible for following through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
patient to discontinue before completing the study.  The subject should be followed until the 
event is resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator.   
In addition to records of observations made at specific times, unexpected signs and symptoms 
and concomitant medications will be recorded in the clinical trial records throughout the study.   
8.1 
Adverse Events 
All AEs, including SAEs occurring after the subject signs the ICF through the subject’s final 
visit will be reported and monitored.  AEs that occur following first administration of study drug 
are treatment emergent AEs (TEAEs).  Any clinically significant (CS) abnormal laboratory 
results, physical examination findings, ECGs, and vital signs will be reported as an AE.   
The investigator is not obliged to follow-up with subjects for AEs or SAEs that begin after study 
completion, however if an SAE is reported to the investigator after a subject has completed the 
study, and it is ‘reasonably related’ to the study drug, then the investigator will report it to the 
sponsor and its IRB.   
Investigators will be instructed to report their assessment of the potential relatedness of each AE 
to protocol procedures or study drug via the eCRF.   
8.1.1 
Severity 
The intensity of the AE will be rated by the investigator as mild, moderate or severe using the 
following criteria:   
 Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
 Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
 Severe: Symptoms causing inability to perform usual social and functional activities   
It should be noted that the clinical severity and seriousness of an AE are not synonymous, eg, a 
severe headache is not classified as serious until it meets the required elements as an SAE.   


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 35 of 61
 
Confidential 
 
The maximum severity attained for each AE reported will be recorded in the eCRFs.   
8.1.2 
Relationship 
The investigator decides whether they interpret the observed AEs as either related to disease, to 
the study medication, study procedure or other concomitant treatment or pathologies. To assess 
the relationship of the AE to the study drug, the following terminologies are defined:  
 Definitely related:  a direct cause and effect relationship between the study treatment and the 
AE is likely.  The AE follows a reasonable temporal sequence from drug administration, 
abates on discontinuation of the drug (dechallenge), and/or is confirmed by reappearance of 
the reaction on repeat exposure (rechallenge) 
 Probably related: the AE follows a reasonable temporal sequence from drug administration, 
abates on discontinuation of the drug (dechallenge), and/or cannot be reasonably explained 
by the known characteristics of the subject’s clinical state 
 Possibly related:  a cause and effect relationship between the study treatment and the AE has 
not been demonstrated at this time and is not probable, but is also not impossible.  The AE 
follows a reasonable temporal sequence from drug administration but could have been 
produced by the subject’s clinical state or by other therapies administered to the subject. 
 Unrelated:  the AE is definitely produced by the subject’s clinical state or by other therapies 
administered to the subject. 
All “related”, “probably related” and “possibly related” AEs and SAEs will be defined as related 
to study drug.   
8.2 
AEs of Special Interest (AESI) 
The following Adverse Events of Special Interest (AESIs) of varying clinical significance will be 
used to determine the tolerability of OPK-88004 doses selected for this clinical trial.  All AESIs 
should be captured and reported via eCRF.  All AESIs  that meet the definition of an SAE 
(Section 8.4) must be reported as an SAE.   
8.2.1 
Clinical Laboratory Testing for Hematology and Lipids 
Clinical laboratory testing will be conducted on all subjects as per Schedule of Events (Appendix 
1).  New abnormal findings or worsening of the baseline conditions detected following treatment 
visits (visit 2 or later visit) will be recorded as AESIs on the appropriate eCRF page.   
8.2.1.1 
Hematology 
Increase in total number of RBC count will be monitored for potential androgen-induced 
erythrocytosis.  Blinded hematocrit values >54% will be flagged to the investigator and may lead 
to subject discontinuation (see Section 7.1). 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 36 of 61
 
Confidential 
 
8.2.1.2 
Lipid Changes 
Fasting lipid panel will be monitored for clinically significant changes in lipids (LDL-C, 
triglycerides, and apolipoprotein A1 etc).  HDL-C values are blinded to the investigator. 
8.2.2 
Cardiovascular Events 
Deaths (CV and non-CV), nonfatal MIs, and nonfatal strokes that occur during the treatment 
period or follow-up period will be reviewed by the sponsor-designated medical monitor.  
Investigative sites will also be asked to report any cases of transient ischemic attack (TIA) or 
hospitalization for unstable angina to the sponsor medical monitor as well to ensure that all true 
stroke and MI events are captured.  Cardiovascular event definitions will be based on the 
Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials and 
the ESC/ACCF/AHA/WHF Expert Consensus Document Third Universal Definition of 
Myocardial Infarction [Thygesen et al 2012].   
8.2.3 
ECG  
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the subject will be assessed by the investigator for symptoms (eg, palpitations, near 
syncope, syncope) and to determine whether the subject can continue in the study.  The 
investigator or qualified designee is responsible for determining if any change in subject 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation.  ECGs will be stored at the investigation site.  Any treatment emergent clinically 
significant ECG finding should be reported as adverse event in the eCRF.   
8.2.4 
Semen Analysis 
Since androgens can impact sperm counts, semen analysis is being performed as baseline and at 
visit 6/ET in subjects willing and able to produce a measurable semen sample.  A follow-up 
semen analyses at 3 months post-treatment will be done in those subjects with a decrease in 
sperm concentration >50% from baseline.   
8.2.5 
Testosterone and Steroidal Androgen Events 
Subjects will be monitored for fluid retention (edema), sleep disturbances, emotional and 
psychological effects such as depression and anger, breast enlargement and breast pain, increased 
acne and increased sex drive (libido).  
8.3 
PSA 
Subjects with PSA increase from baseline >1.4 ng/mL should be re-tested immediately, and if 
confirmed, repeated in 4 weeks.  If this value remains elevated, the subject should be referred to 
a urologist for further evaluation.  The subject may remain on study drug, at the discretion of the 
investigator.   
8.4 
Serious Adverse Events 
An SAE is defined by the investigator or sponsor as any AE occurring at any dose that results in 
any of the following outcomes:  


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 37 of 61
 
Confidential 
 
 death,  
 life-threatening AE,  
 hospitalization or prolongation of existing hospitalization,  
 a persistent or significant disability/incapacity,   
 a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
8.5 
Reporting Serious Adverse Events 
8.5.1 
Initial Report 
All SAEs occurring from the time of signed informed consent until 30 days following the last 
administration of study drug must be reported to Medpace Clinical Safety within 24 hours of the 
knowledge of the occurrence (this refers to any AE that meets any of the aforementioned serious 
criteria).  All SAEs that the investigator considers related to study drug occurring after the 30-
day follow-up period must be reported to the sponsor.   
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study.  When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form.   
If the event meets serious criteria and it is not possible to access the EDC system, send an email 
to Medpace Safety (email address listed below) or call the Medpace SAE hotline (phone number 
listed below), and fax the completed paper SAE form to Medpace (fax number listed below) 
within 24 hours of awareness.  When the EDC system becomes available, the SAE information 
must be entered within 24 hours of the system becoming available.   
Safety Contact Information: 
Medpace SAE Reporting Phone Line: 
Telephone: 
 
Facsimile
 
e-mail: medpace-safetynotification@medpace.com 
The investigator is responsible for informing his or her IRB of any SAEs at that site.   
A subject experiencing one or more SAEs will receive treatment and follow-up evaluations by 
the investigator, or they will be referred to another appropriate physician for treatment and 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 38 of 61
 
Confidential 
 
follow-up.  Withdrawal from the study and all therapeutic measures will be at the discretion of 
the investigator at the site.   
The investigator must continue to follow the subject until resolution or until the condition 
becomes chronic in nature, stabilizes (in the case of persistent impairment) or the subject dies.  
The subject will be followed for a minimum of 30 days after study drug administration and 
subsequently all events will be closed.  Female partner pregnancies will be followed until 6 
weeks following delivery to determine the outcome.   
8.5.2 
Follow-up Reports 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
electronically within the EDC system and submit any supporting documentation (e.g., subject 
discharge summary or autopsy report) to Medpace Clinical Safety using the contacts listed above 
for initial reporting.   
 
 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 39 of 61
 
Confidential 
 
9 STUDY ACTIVITIES 
9.1 
Screening/Visit 1 (Week -4 to Day 0) including 1 week washout if required 
Subjects will sign informed consent prior to any study procedures being performed.  A 1-week 
washout period during screening is permitted for subjects on previous BPH therapy (see 
inclusion criterion 8, Section 4.2).  All lab tests, 
 
 will be conducted after completion of the washout period, if a 
washout is required.   
 A signed ICF will be obtained prior to any study-related activities 
 Review of inclusion/exclusion criteria 
 Medical history and demographics 
 Medication history 
 General physical examination, vital signs, weight and height 
 12-lead ECG (obtain after 10 minutes supine rest) 
 Blood samples (fasting serum chemistry including lipids, hematology and coagulation, 
HbA1c, fasting glucose, fasting insulin; serology, PSA, 
, if applicable)   
 Urinalysis 
 Urine drugs of abuse screen 
 Concomitant medications assessment  
9.2 
Treatment Period (Week 0 to Week 16) 
9.2.1 
Visit 2 (Day 1) Procedures 
 Review of entry criteria 
 AE assessment 
 Concomitant medication review 
 Physical examination including vital signs 
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 40 of 61
 
Confidential 
 
 Blood samples (fasting serum chemistry excluding 25-hydroxyvitamin D, including lipids, 
hematology and coagulation, HbA1c, fasting glucose, fasting insulin, hormone panel, CRP, 
PSA and 
 
 
   
 Urinalysis 
 LBM and fat mass (DXA).  This assessment should be done within 14 days prior to visit 2.  
If necessary, DXA rescan can occur up to 7 days after dosing 
 Semen analysis.  Semen collection can occur any time after screening (visit 1) but must be 
more than 48 hours prior to PSA 
 on visit 2  
 Randomization 
 IP dispensed.  The first dose must occur at the investigational site and be witnessed for 10 
minutes to ensure that an allergic reaction does not occur 
9.2.2 
Visit 3 (Week 4 ±2 Days) Procedures 
The subject will be reminded not to take their daily dose at home on the day of this visit; this will 
be taken at the site and the actual time of dosing noted 
 AE assessment 
 Concomitant medication review 
 Vital signs 
 12-lead ECG (Obtain after 10 minutes supine rest) 
 Blood samples (fasting serum chemistry excluding 25-hydroxyvitamin D and including 
lipids, hematology and coagulation, HbA1c, fasting glucose, fasting insulin, CRP) 
 Urinalysis 
 Drug accountability/treatment compliance 
 IP dispensed, daily dose taken 
 
 
9.2.3 
Visit 4 (Week 8 ± 2 Days) Procedures 
 AE assessment 
 Concomitant medication review 
CCI
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 41 of 61
 
Confidential 
 
 Physical examination 
 Vital signs 
 12-lead ECG (Obtain after 10 minutes supine rest) 
 Blood samples (fasting serum chemistry excluding 25-hydroxyvitamin D and including 
lipids, hematology and coagulation, HbA1c, fasting glucose, fasting insulin, hormone panel, 
PSA) 
 Urinalysis 
 Drug accountability/treatment compliance 
 IP dispensed 
9.2.4 
Visit 5 (Week 12 ± 2 Days) Procedures 
The subject will be reminded not to take their daily dose at home on the day of this visit; this will 
be taken after pre-dose PK blood sampling, and the time of dosing noted. 
 AE assessment 
 Concomitant medication review 
 Vital signs 
 Drug accountability/treatment compliance 
 IP dispensed, dose taken 
9.3 
End of Treatment -Visit 6 (Week 16 ±2 Days) Procedures 
 AE assessment 
 Concomitant medication review 
 Physical examination 
 Vital signs 
 12-lead ECG (obtain after 10 minutes supine rest) 
 Blood samples (fasting serum chemistry including lipids, hematology and coagulation, 
HbA1c, fasting glucose, fasting insulin, hormone panel, PSA, 
 and CRP)  
 Urinalysis 
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 42 of 61
Confidential 
 
 LBM and fat mass (DXA) 
 Semen analysis.  Semen collection should not occur within 48 hours prior to PSA 
 
 and may occur up to 7 days after PSA 
 
  
 Drug accountability/treatment compliance 
9.4 
End of Treatment – Follow up 
 Visits 7 and 8 
Two additional visits for collection of 
 samples will be scheduled 4 and 7 days following 
administration of final dose of study drug. 
9.5 
Follow-up- Visit 9 (Week 20 ± 2 Days) Procedures  
 AE assessment 
 Concomitant medication review 
 Physical exam 
 Vital signs 
 Fasting serum chemistry excluding 25-hydroxyvitamin D, including lipids 
 Hematology and coagulation 
9.6 
Early Termination Visit (ET) Procedures 
When a subject terminates early from the trial, the following assessments will be performed, if 
possible: 
 AE assessment 
 Concomitant medication review 
 Physical examination 
 Vital signs 
 12-lead ECG (obtain after 10 minutes supine rest) 
CCI
CCI
CCI
CCI
CC
CC


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 43 of 61
 
Confidential 
 
 Blood samples (fasting serum chemistry including lipids, hematology and coagulation, 
HbA1c, fasting glucose, fasting insulin, hormone panel, PSA, 
 and CRP)  
 PK sample 
 Urinalysis 
 Semen analysis.  Semen collection should not occur within 48 hours prior to PSA and 
 blood draws and may occur up to 7 days after PSA and 
 blood 
draws  
 Drug accountability 
 
 
CCI
CCI
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 44 of 61
 
Confidential 
 
10 QUALITY CONTROL AND ASSURANCE 
A quality assurance audit may be performed by the sponsor and/or its designee at selected sites 
to verify that the study was conducted in accordance with the protocol, ICH/GCP [International 
Conference on Harmonisation (ICH) and Good Clinical Practice (GCP)], and applicable SOP 
and regulations, to ensure that the safety and welfare of subjects are addressed, and to confirm 
that problems reported by study monitors have been resolved.  Verification of study documents 
and study activities (if applicable) will be conducted to confirm accuracy of recorded data and its 
analysis.  Audit observations and findings will be documented and communicated to appropriate 
study personnel and management.  An inspection may be conducted by regulatory authorities.  
The investigator must allow direct access to study documents during these inspections and 
audits.  
Monitoring visits will be performed to evaluate study conduct, data integrity, protocol, and GCP 
compliance.   
Each investigator is responsible for the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents are to be completed in a neat, legible manner to ensure 
accurate interpretation of data. 
Source documents and laboratory reports will be reviewed to ensure that they are accurate and 
complete. 
10.1 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following: 
 provide instructional material to the study sites, as appropriate 
 provide start-up training to instruct the investigators and study coordinators.  This training 
will give instruction on the protocol, the completion of the CRFs, and study procedures 
 make periodic visits to the study site 
 be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax 
 review and evaluate CRF data and use standard computer edits to detect errors in data 
collection 
 conduct a quality review of the database 
In addition, the sponsor or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  Investigators will maintain study records in 
a secure location on completion of the study and the file archive location will be provided to the 
sponsor or its representatives.  


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 45 of 61
 
Confidential 
 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the subject files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRBs with 
direct access to original source documents. 
 
 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 46 of 61
 
Confidential 
 
11 PLANNED STATISTICAL METHODS 
11.1 
General Considerations 
Any change to the data analysis methods described in the protocol will require a protocol 
amendment only if it changes a principal feature of the protocol.  Any other change to the data 
analysis methods described in the protocol and the justification for making the change will be 
described in the statistical analysis plan (SAP) or clinical study report (CSR).  
 
 
 
.    
The SAP will be finalized before database lock.  The clinical SAP will detail the statistical 
methodology to be used and will outline the statistical programming specifications, tables, and 
listings.  The SAP will describe the variables and populations, anticipated data transformations 
and manipulations, and other details of the analyses not provided in the protocol. 
Data from screen failures will not be presented.  Data from enrolled subjects will be presented in 
data listings by treatment group.  A subject who is randomized but does not receive study drug 
will be included in the data listings but excluded from all data summaries.  
All observed assessments, will be included in the data listings.   
Continuous data will be presented with number of observations (n), mean, and median, standard 
deviation (SD), minimum and maximum.  Frequencies and percentages will be used for 
summarizing discrete (categorical) data.   
Data that are reported as missing will be presented as missing in the data listings and treated as 
missing in all data summaries.  No imputations for missing data will be made unless otherwise 
specified for endpoint derivation.  
No adjustments for multiplicity will be performed due to the exploratory nature of this study.  
All tests of treatment effects will be conducted at a two-sided alpha level of 0.05 and/or two- 
sided 95% confidence interval (CI), unless otherwise stated. 
11.2 
Determination of Sample Size 
Approximately 115 subjects will be enrolled in the study, randomized 1:1:1 across three arms 
(placebo, OPK-88004 15 mg, or OPK-88004 25 mg).  The primary efficacy objective is to 
evaluate the ability of OPK-88004 doses to reduce PSA compared to placebo from baseline to 
week 16.  
 
 
  From historical 
data, the treatment difference of percent reduction of PSA from baseline to week 16 endpoint 
between any OPK-88004 dose and placebo is over 30% with common standard deviation <40%.  
With a sample size of 28 completed subjects per treatment group, the power for the test 
significance of PSA reduction for any OPK-8804 dose compared to placebo  is over 80%.  A 
dropout rate of 10% from randomization to study completion is anticipated   
CCI
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 47 of 61
 
Confidential 
 
The treatment effect, standard deviation, and dropout rate used in the sample size calculation are 
based on historical data. 
11.3 
Analysis Populations and Randomization 
11.3.1 
Analysis Populations 
The Randomized Population will include all subjects who sign the informed consent form and 
are assigned a randomization number.  Baseline and demographic characteristics will be 
summarized for this population. 
The Safety Population will include subjects in the Randomized Population who receive at least 1 
dose of randomized study medication.  All safety analyses will be conducted based on the Safety 
Population. 
The modified Intent-to-Treat (mITT) Population will include all subjects in the Safety Population 
who have a baseline efficacy measurement and have at least 1 post-randomization measurement 
for the appropriate efficacy endpoint.  The mITT Population is the primary analysis population, 
and all efficacy analyses will be performed using the mITT Population. 
The Per-Protocol (PP) Population will include all subjects in the mITT Population who complete 
the 16-week, double-blind treatment period without any significant deviations from the protocol 
procedures.  The PP Population will be used to assess robustness of the primary analysis results.  
A final listing of all subjects to be excluded from the PP Population will be completed prior to 
unblinding the study database. 
11.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group. Categorical 
variables will be summarized by frequencies and percentages.  For categorical variables, 
comparisons between treatment groups will be assessed using a Pearson Chi-Square test.  
Continuous variables will be summarized by means and SDs.  For continuous variables, 
comparisons between the treatment groups will be performed using a one-way Analysis of 
Variance (ANOVA) with treatment as the fixed effect. 
11.5 
Study Drug Exposure, Compliance, and Concomitant Therapies 
Concomitant medication/therapy verbatim terms will be coded using the World Health 
Organization (WHO) Drug Dictionary version March 2017E or higher.  The number and 
percentage of subjects taking concomitant medications will be summarized by Anatomical & 
Therapeutic Chemical classification and preferred term for each treatment group.  Listings of all 
prior and concomitant medications will be provided. 
Total exposure days to study medication will be summarized by treatment group.  Overall 
percent compliance to study medication, calculated as percent of doses taken relative to doses 
scheduled to be taken, will be summarized by treatment group. 
11.6 
Primary Efficacy Analysis 
The primary efficacy endpoint of this study is: 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 48 of 61
 
Confidential 
 
 Percent change from baseline PSA levels (visit 2) to week 16 endpoint. 
This endpoint will be analyzed based on mITT Population.  
Analysis of the percent change from baseline of PSA to week 16 endpoint will be performed 
using a MMRM, implemented using SAS® Proc Mixed.  The factors in the model will be 
treatment, prostate volume stratification group, and IPSS stratification group, visit, and the 
treatment group by visit interactions and baseline PSA as a covariate.  Treatment difference 
between OPK-88004 doses and placebo at week 16 will be estimated from the MMRM model, as 
well as confidence intervals and p-values.  Sensitivity analysis of the percent change from 
baseline of PSA to week 16 endpoint will be performed using ANCOVA modeled with 
treatment, prostate volume stratification group and IPSS stratification group as fixed effects and 
baseline PSA as a covariate.  Additional covariates may be added and will be detailed in the 
SAP.  
The efficacy analysis of the primary efficacy variable will be repeated on the PP Population to 
test the robustness of the analysis on mITT Population.  
Descriptive statistics by treatment for PSA, and percent change from baseline at the 16-week 
endpoint will be presented using all observed data with no imputations and no elimination of 
patients with protocol violations.  The descriptive statistics will be presented by visit.   
11.7 
Safety Analysis 
Descriptive summary statistics will be provided for all safety variables, including AEs, clinical 
laboratory measurements (lipids, chemistry, hematology, coagulation, fasting HbA1c, glucose 
and insulin, hormone panel, CRP, and urinalysis), vital signs, physical examinations,  ECGs, and 
semen analysis. 
Adverse events will be summarized by the MedDRA system organ class and preferred terms, as 
well as by worst severity.  TEAEs will be presented in the CSR, ie, those events occurring 
following administration of study drug.  For each event classification term, the number of 
subjects experiencing a TEAE with that classification term will be tabulated.  The number of 
subjects experiencing treatment-related TEAEs will also be tabulated.  Treatment-related TEAEs 
are defined as TEAEs that are indicated by the investigator on the CRF to be treatment-related.  
If a subject reports the occurrence of a particular event more than once, the most severe of those 
events will be included in the summary tables of TEAEs, and the most severe of the related 
events will be included in the summary tables of treatment-related events.  Discontinuations due 
to TEAEs and SAEs will be listed by subject and summarized by treatment group.  
Analysis comparing the incidence of TEAEs of particular interest and the incidence of treatment-
related TEAEs of particular interest will be performed using Fisher’s exact tests across all groups 
in the study.   
Summary statistics will provided by treatment group for clinical laboratory measurements, vital 
signs, ECGs, and semen analysis at baseline and post-baseline visits, including the change from 
baseline to each visit. 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 49 of 61
 
Confidential 
 
11.8 
Secondary Efficacy Analysis 
Secondary efficacy endpoints include body composition by DXA, specifically lean body mass 
and fat mass.  Both change and percent change from baseline at the week 16 endpoint will be 
summarized and analyzed with ANCOVA modeled with treatment, prostate volume stratification 
group and IPSS stratification group as fixed effects and baseline as a covariate.   
The efficacy analysis of the secondary efficacy variables will be repeated on the PP Population 
to test the robustness of the analysis on the mITT Population. 
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 50 of 61
 
Confidential 
 
12 ADMINISTRATIVE CONSIDERATIONS 
12.1 
Investigators and Study Administrative Structure 
This trial will be performed at up to approximately 35 clinical sites located in the US.   
At screening, the subject will be offered notification of their primary care physician that he is 
participating in a clinical study.  If the subject accepts, a brief letter outlining the study and 
identifying the study drug will be sent once the subject is enrolled. 
Table 2 lists contract organizations involved in the trial conduct. 
Table 2 
CROs  
Organization 
Responsibility 
Medpace  
5375 Medpace Way 
Cincinnati, OH 45227 
CRO for the study 
Sherpa Clinical Package 
6166 Nancy Ridge Dr, 
San Diego, CA 92121, USA 
Drug distribution 
InVentiv Health Clinique 
2500 rue Einstein 
Quebec, QC, Canada 
Bioanalysis of plasma OPK-88004 and 
 analysis 
BioReference Laboratories 
481 Edward H Ross Dr 
Elmwood Park, NJ 07407, USA 
  
 
 
12.2 
Institutional Review Board (IRB) Approval 
The investigator will submit all required documentation and obtain IRB approval to implement 
the study prior to the conduct of any study procedures.  At a minimum, the study protocol, 
protocol amendments, ICF, Investigator’s Brochure, and subject-related information, relevant 
curricula vitae and promotional materials will be submitted. 
The sponsor or designee will approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the ICH guideline on GCP. 
Documentation of IRB approval of the protocol and the ICF must be provided before the study 
may begin at the investigative site(s).  If it is necessary to amend the protocol during the course 
of the study, the investigator must ensure that the IRB reviews and approves the amendment.  No 
amendments will be implemented without the agreement of the investigator and the sponsor as 
well as the IRB, where applicable.   
The investigator will comply with requirements for reporting to the IRB.   
C
CCI


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 51 of 61
 
Confidential 
 
12.3 
Ethical Conduct of the Study 
The study will be conducted in accordance with GCP (ICH GCP) and all applicable laws and 
regulations including the ethical principles of the Declaration of Helsinki (Edinburgh 2000, with 
Note of Clarification, Tokyo 2004) and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
In accordance with applicable country-specific regulations, the sponsor will obtain approval from 
the appropriate regulatory authority(ies) prior to initiating the study in that country. 
12.4 
Subject Information and Consent 
The investigator will obtain a written informed consent form for each subject prior to the 
performance of any study-related procedures.  The investigator is responsible for ensuring that 
the subject fully understands the nature of the study, potential risks and benefits of participating, 
including answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to continue 
participation in the study.   
The investigator will ensure that the ICF is signed and dated by each subject and that 
documentation of consent being obtained will be recorded in the subject’s medical record/source 
documents.   
As used in this protocol, the term “informed consent” includes all consent and assent given by 
subjects.   
12.5 
Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the study investigators, their staff, the 
sponsor and their authorized representatives.  This confidentiality includes clinical information 
relating to participating subjects and their biological sample testing.   
The study protocol, documentation, data, and all other information will be held in strict 
confidence.  No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor.   
Authorized representatives of the sponsor, contract research organizations (if applicable), study 
monitors, employees of government authorities (eg, US FDA or other), and IRB members may 
inspect all study-related documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the subjects in this study.  The investigator and clinical study site will permit access to such 
records.   
No information that would permit the identification of a specific individual will be provided for 
entry into the study database or study report.  Study documentation submitted to the sponsor will 
identify study participants by study code and initials.  The investigator will keep a separate 
confidential enrollment log that matches identifying study codes with the subject names and 
contact information.   


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 52 of 61
 
Confidential 
 
12.6 
Case Report Forms and Study Records 
This study will utilize an electronic data capture system for the management of clinical data.  
Data capture and management will be consistent with applicable ICH/GCP guidelines.   
All data collected during the study for subjects will be recorded in an individual, subject-specific 
electronic case report forms (eCRF) as part of an electronic data capture (EDC) system.  Access 
to the electronic system will be restricted and users will only be able to access the system via 
authorized individual accounts.  The sponsor or designee will provide training to the 
investigative site on the EDC system and eCRFs.  All eCRFs will be completed as soon as data 
are available in the source for each subject.  As electronic data capture will be utilized, 
instructions, training records, and a log will be maintained to identify the designated site 
personnel who can enter data and/or sign off on an eCRF.   
A subject eCRF must be completed for each subject who signs a consent form and undergoes 
randomization.   
To ensure the quality of the clinical data across all subjects and sites, a Clinical Data 
Management review will be performed by the sponsor or designee on subject data entered or 
integrated into the EDC system.  During the review, subject data will be checked for consistency, 
omissions, and any apparent discrepancies.  In addition, the data will be reviewed for adherence 
to the protocol, and ICH/GCP.  Moreover, all data from external sources, eg, central laboratory 
and PD processing/analysis will be reconciled with subject eCRF data.  To resolve any questions 
arising from the Data Management review process, data queries and/or data clarification 
notifications will be generated via the EDC system for completion and resolution.   
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the investigator reviewed the data on the 
eCRF, the data queries, and the data clarifications and agrees with the content.   
12.7 
Safety Monitoring  
A study level safety review will be conducted to monitor and assess safety data collected during 
the study.  Specifically, any signs or trends indicating potential underlying safety issues will be 
identified.  The safety review will be scheduled regularly and reviewed by the sponsor-
designated medical monitor.  More details will be provided in the safety review team (SRT) plan 
including the type of safety data, frequency of review, and unblinding plan if necessary.   
The sponsor will monitor safety within time frames mandated by company procedures.  The 
medical monitor will periodically review: 
 Trends in safety data and laboratory analysis 
 Serious and non-serious adverse events including adverse events of special interest (see 
Section 8.2)  
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding 
the subject or at a group level, the study team will follow the company procedures for unblinding 
and safety reporting, respectively. 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 53 of 61
 
Confidential 
 
12.7.1 
Data Monitoring Committee  
An independent Data and Safety Monitoring Committee (DSMB) consisting of one statistician 
and two clinicians with appropriate expertise will monitor the study at regular intervals, and may 
make recommendations for changes to the conduct of the trial to reflect safety concerns.   
Specific responsibilities and activities of the DSMB will be defined in the charter to be ratified at 
the organizational meeting of the DSMB. 
12.8 
Protocol Deviations 
Protocol deviations are any intentional or unintentional change from an IRB approved protocol 
that was not approved by the IRB prior to initiation of the change. 
The investigator is responsible for ensuring protocol and study compliance by all study staff 
members.  Deviations from protocol will be documented in subjects’ study records. 
The sponsor requires that all major protocol deviations be reported to the IRB.  In addition, the 
investigator is responsible for adhering to his/her IRB’s protocol deviation reporting 
requirements. 
12.9 
Retention of Data 
The investigator/institution will maintain all CRFs and all source documents that support the 
subject data collected, and all study documents as specified in ICH/GCP Section 8, Essential 
Documents for the Conduct of a Clinical Trial and as specified by the applicable regulatory 
requirement.  The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents. 
Essential documents must be retained until at least two years after the last approval of a 
marketing application in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor.  It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the study, 
the responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility.  The sponsor must be notified in writing of the name and address of the 
new custodian.  Under no circumstances shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor. 
12.10 Publication and Disclosure Policy 
Data derived from the study are the exclusive property of the sponsor.  Publication rights are 
outlined in the clinical study agreement. 


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 54 of 61
 
Confidential 
 
13 REFERENCE LIST 
Andriole G, Bruchovsky N, Chung LW et al. Dihydrotestosterone and the prostate: The scientific 
rationale for 5-alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J. Urol 
2004; 172:1399–1403 
Berry SJ, Coffey DS, Walsh PC et al. The development of human benign prostatic hyperplasia 
with age, J Urol 1984; 132:474-9 
Cunha GR, Ricke W, Thomson A et al. Hormonal, cellular, and molecular regulation of normal 
and neoplastic prostatic development. J Steroid Biochem Mol Biol. 2004; 92:221–236 
Gormley GJ, Stoner E, Bruskewitz et al.  Effects of finasteride in men with benign prostatic 
hyperplasia. N Engl J Med 1992; 327:1185-91 
Hollingsworth JM, Wilt TJ.  Lower urinary tract symptoms in men, BMJ. 2014 14;349:g4474 
McVary K. The Medical Therapy of Prostatic Symptoms Trial.  Current Urology Reports 2004; 
Volume 5 (4):249-250 
Narayanan R, Mohler ML, Bohl CE et al. Selective androgen receptor modulators in preclinical 
and clinical development. Nucl Recept Signal 2008; 6:e010. doi: 10.1621/nrs.06010 
Parsons JK.  Benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology 
and risk factors.  Curr Bladder Dysfunction Rep. 2010; 5: 212–218 
Punnen S, Pavan N, Parekh DJ.  Finding the wolf in sheep’s clothing: the 4Kscore is a novel 
blood test that can accurately identify the risk of aggressive prostate cancer.  Rev Urol 2015; 17: 
3-13 
Roehrborn CG.  Benign prostatic hyperplasia: an overview. Rev Urol. 2005;7 Suppl 9:S3-S14 
Roehrborn C, Siami P, Barkin J et al.  The effects of combination therapy with dutasteride and 
tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-Year 
results from the CombAT Study.  Eur Urol 2010; 57:123–131 
Rosen RC, Giuliano F, Carson CC.  Review: Sexual dysfunction and lower urinary tract 
symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).  Eur Urol. 2005; 47:824-
837 
Smith AB, Carson CC.  Finasteride in the treatment of patients with benign prostatic hyperplasia: 
a review.  Ther Clin Risk Manag. 2009; 5: 535–545 
Thygesen et al 201 ESC/ACCF/AHA/WHF Expert Consensus Document. Circulation. 2012; 
126:2021-2033


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 55 of 61
 
Confidential 
 
Appendix 1.  
Schedule of Events 
 
Screening 
Treatment Period 
Follow-up 
ET 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
 
Evaluation 
-4 weeks to 
Day 0 
Day 1 
Week 4  
± 2 days 
Week 8  
± 2 days 
Week 12  
± 2 days 
Week 16  
± 2 days 
4 days 
post final 
dose 
7 days 
post final 
dose 
Week 20  
± 2 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics/medical historya 
X 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
X 
 
X 
 
 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Fasting serum chemistryc 
Xd 
X 
X 
X 
 
X 
 
 
X 
X 
Hematology & coagulation 
Xd 
X 
X 
X 
 
X 
 
 
X 
X 
Fasting HbA1c, glucose, insulin 
Xd 
X 
X 
X 
 
X 
 
 
 
X 
Hormone panele 
 
X 
 
X 
 
X 
 
 
 
X 
CRP 
 
X 
X 
 
 
X 
 
 
 
X 
Urinalysis 
Xd 
X 
X 
X 
 
X 
 
 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
Semen analysis 
 
Xf 
 
 
 
Xg,h 
 
 
 
X 
12-lead ECG 
X 
 
X 
X 
 
X 
 
 
 
X 
PSA 
Xd 
X 
 
X 
 
X 
 
 
 
X 
 
Xi 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LBM and fat mass (DXA) 
 
X 
 
 
 
Xj 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Drug dispensed 
 
X 
X 
X 
X 
 
 
 
 
 
Drug accountability/compliance 
 
 
X 
X 
X 
X 
 
 
 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
 
 
X 
X 
Conmed Assessment 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 blood samplingk 
 
Xk 
Xk 
 
Xk 
Xk 
Xk 
Xk 
 
Xk 
CCI
C
CCI
C
C
C
C
CCI
C
C
C
C
C
C
CCI
CCI
C
C
C
C
C


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 56 of 61
 
Confidential 
 
a. 
Includes medication history 
b. Includes weight; height will be measured only at screening 
c. 
Fasting serum chemistry (sodium, potassium, total bilirubin, direct bilirubin, ALP, ALT, AST, GGT, BUN, CK, creatinine, calcium, 25-hydroxyvitamin D (at visits 1 and 
6/ET only), albumin, phosphorus) includes fasting lipid panel at visits 1, 2, 3, 4,  6, 9/ET (total cholesterol, TG, HDL cholesterol, direct LDL cholesterol, apolipoproteins 
A1, A2, B, C3 and A5, lipoprotein (a)) 
d. When a washout period is required, all lab tests,  
 will be conducted after the washout period 
e. 
Hormone panel includes total testosterone, free testosterone (calculated), SHBG, LH, FSH, estradiol and TSH 
f. 
Semen collection can occur any time after screening (visit 1) but must be more than 48 hours prior to PSA and 
 on visit 2 
g. Additional semen analysis to be conducted 3 months post final dose in those subjects with a decrease in sperm concentration >50% from baseline.  
h. Not required if sample not obtained at visit 2 
i. 
 may be performed at visit 1 in subjects ≤80 years old with PSA ≥4 ng/mL who have not undergone an invasive urological procedure within 6 months and 
without biopsy within 12 months, per inclusion criterion 5. 
j. 
DXA scans can occur within ±7 days 
k. 
 samples: visit 2 : single pre-dose sample (within 1 hour); visit 3, two samples: 1-2 h and 3-5 h post dose; visit 5, single pre-dose (within 1 hour),visit 6: two samples: 
3-5 h and 8-10 h post-dose;  visit 7: single sample 4 days post final dose;  visit 8: single sample  7 days post final dose; ET, single sample 
 
 
 
CCI
CCI
CCI
C


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 57 of 61
 
Confidential 
 
Appendix 2.  
Prohibited Concomitant Medications 
This is a representative listing of medications that are specifically excluded per protocol.  The list 
is to serve as a guideline only and is not inclusive of all generic, over-the-counter, or nutraceutical 
products excluded for this study.  Enquiries should be addressed with the sponsor or designee. 
5-α- Reductase Inhibitors: finasteride (Proscar®, Propecia®), dutasteride (Avodart™) 
Androgens:  
testosterone (Androderm®) Androgel®, Testoderm®, Testim™, 
Depo-Testosterone®), methyltestosterone (Testred®)  
Anabolic Steroids:  
oxymethalone (Anadrol-50®), oxandrolone  (Oxandrin®) 
Antiandrogens:  
bicalutamide (Casodex®), flutamide (Eulexin®), nilutamide 
(Nilandron®) 
Dehydroepiandrosterone (DHEA): Andromon®, Fibrinase®, Tofipan® 
Herbal Supplements:  
red clover, ginkgo biloba, gotu kola, muira puama, tribulus, 
damiana, maitake, licorice root, ginseng, hawthorn, wild yam, 
horny goat weed, Cholest-Natural 
OTC steroid supplements:  Tren, Epi-Tren, Stakabol, Black Mass Tren Stack 
Phytotherapies:  
Saw Palmetto, Prostata, Yohimbine, Pygeum Africanum  
Potent CYP3A4 inhibitors: amiodarone, aprepitant (Emend®), cyclosporine (Gengraf®, 
Neoral®, Sandimmune®), clarithromycin (Biaxin®), conivaptan 
(Vaprisol®), chlorzoxazone (Parafon Forte DSC®), chlortrimazole, 
cimetidine, erythromycin, diltiazem (Cardizem®, Cartia XT®, 
Dilacor XR®, Taztia XT®), fluvoxamine (Luvoz CR®), fluconazole 
(Diflucan®), grapefruit products, indinavir (Crixivan®), imatinib 
(Gleevec®), itraconazole (Sporanox®), ketoconazole, mibefradil, 
nelfinavir (Viracept®), norfloxacin (Noroxin®), nefazodone, 
posaconazole (Noxafil®), ritonavir (Kaletra®, Norvir®), saquinavir 
(Fortovase®), schisandra sphenathera extract, starfruit, 
telithromycin (Ketek®), troleandomycin (Tao®), verapamil 
(Tarka®), voriconazole (Vfend®) 
 
 






OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 60 of 61
 
Confidential 
 
Appendix 4. NEW YORK Heart Association Cardiac Disease Classification 
Functional Capacity 
Class I 
Patients with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause fatigue, palpitation, dyspnea, or anginal pain 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal 
pain 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain 
Class IV 
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort.  Symptoms of heart failure or angina syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort increase. 
[CCNYHA] The Criteria Committee of the New York Heart Association, 1994. Nomenclature 
and criteria for diagnosis of disease of the heart and great vessels. 9th ed. Boston (MA): Little, 
Brown&co. 
  


OPK-88004 
Transition Therapeutics Ireland Ltd.
Protocol SAR-202 V7, 09 November 2018 
Page 61 of 61
 
Confidential 
 
Appendix 5. Investigator’s Signature 
Study Title: 
A Randomized, Double-blind, Placebo-controlled Dose-ranging 
Study of OPK-88004 Once-a-Day Dosing for 16 Weeks in Men with 
Signs and Symptoms of Benign Prostatic Hyperplasia 
Study Number: 
SAR-202 
Version Date: 
x09 November 2018 
I agree: 
 
To assume responsibility for the proper conduct of the study at this site. 
 
To conduct the study in compliance with this protocol, with any future amendments, and with any other written 
study conduct procedures provided and reviewed and approved by Transition Therapeutics Ireland Ltd. or its 
designee(s). 
 
Not to implement any deviations from or changes to the protocol without agreement from the sponsor and prior 
review and the written approval from IRB/IEC/REB, except where necessary to eliminate an immediate hazard 
to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory 
requirements). 
 
That I am thoroughly familiar with the appropriate use of the investigational drug, as described in this protocol, 
and any other information provided by the sponsor including, but not limited to, the following: the current 
Investigator’s Brochure or equivalent document provided by Transition Therapeutics Ireland Ltd. or its 
designee(s). 
 
That I am aware of, and will comply with, GCP and all applicable regulatory requirements, including the 
regulations governing the use of controlled substances. 
 
To ensure that all persons assisting me with the study are adequately informed about the investigational drug 
and of their study-related duties and functions as described in the protocol. 
 
That I have been informed that certain regulatory authorities require the sponsor to obtain and supply details 
about the investigator's ownership interest in the sponsor or the study drug, and more generally about his/her 
financial ties with the sponsor.  Transition Therapeutics Ireland Ltd. will use and disclose the information solely 
for the purpose of complying with regulatory requirements. 
Hence, I: 
 
Agree to supply Transition Therapeutics Ireland Ltd. with any information regarding ownership interest and 
financial ties (including those of my spouse and dependent children), including with OPKO Health, Inc., and 
any of its affiliates. 
 
Agree to update this information if any relevant changes occur during the course of the study and for one year 
following completion of the study. 
 
Agree that Transition Therapeutics Ireland Ltd. may disclose this information about such ownership interests 
and financial ties to regulatory authorities. 
 
 
Signed: 
 
 
Date:  
 
 
Printed Name:   
 


Signature Page for Protocol SAR-202 v8.0
Signature Page for 
Approval
12-Nov-2018 15:39:15 GMT+0000
PPD
CCI

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
DOSE-RANGING STUDY OF OPK-88004 ONCE-A-DAY DOSING FOR 
16 WEEKS IN MEN WITH SIGNS AND SYMPTOMS OF BENIGN 
PROSTATIC HYPERPLASIA 
 
Protocol Number: 
SAR-202 
Phase:  
2 
Investigational Product: 
OPK-88004 
IND Number: 
 
Indication: 
Benign Prostatic Hyperplasia (BPH) 
Sponsor: 
Transition Therapeutics Ireland Ltd. (a subsidiary 
of OPKO Health, Inc.) 
Sponsor Contact: 
Dr. 
  
 Medical Development 
OPKO Health, Inc. 
4400 Biscayne Blvd  
Miami, FL 33137 
Email: 
 
Phone: 305.575.4172 
Protocol: 
V1 / 27-SEP-2017 
V2 / 30-OCT-2017 
V3 / 06-FEB-2018 
V4 / 22-MAR-2018 
V5 / 25-JUN-2018 
V6 / 19-OCT-2018 (not implemented) 
V7 / 09-NOV-2018 
SAP: 
V1.0 / 21-FEB-2019 
V2.0 / 06-MAR-2019 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Transition Therapeutics ULC Corp. or its 
subsidiaries and should not be copied or distributed to persons not involved in the 
clinical investigation of OPK-88004 unless such persons are bound by confidentiality 
agreement with Transition Therapeutics ULC Corp. or its subsidiaries 
PPD
PPD
PPD
CCI




Transition Therapeutics Ireland Ltd.  
Page 3 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
TABLE OF CONTENTS 
1 
SUMMARY OF CHANGES ........................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................... 5 
3 
STUDY OBJECTIVES .................................................................................................................... 5 
3.1 
Primary Objectives ................................................................................................................. 5 
3.2 
Secondary Objectives ............................................................................................................. 5 
 
6 
4 
STUDY OVERVIEW ...................................................................................................................... 6 
4.1 
Study Design .......................................................................................................................... 6 
4.2 
Randomization and Blinding .................................................................................................. 7 
5 
ANALYSIS ENDPOINTS............................................................................................................... 7 
5.1 
Primary Efficacy Endpoint ..................................................................................................... 7 
5.2 
Secondary Efficacy Endpoints ............................................................................................... 8 
 
 8 
5.4 
Safety Endpoints .................................................................................................................... 8 
6 
STATISTICAL METHODOLOGY ................................................................................................ 8 
6.1 
Sample Size Determination .................................................................................................... 8 
6.2 
Baseline, Endpoint, and Other Statistical Considerations ...................................................... 9 
6.3 
Analysis Populations ............................................................................................................ 10 
6.3.1 
Randomized Population .......................................................................................... 10 
6.3.2 
Safety Population .................................................................................................... 10 
6.3.3 
mITT Population ..................................................................................................... 10 
6.3.4 
Per-Protocol Population .......................................................................................... 11 
6.4 
Subject Disposition .............................................................................................................. 11 
6.5 
Demographic and Baseline Characteristics .......................................................................... 11 
6.6 
Medical History .................................................................................................................... 12 
6.7 
Prior and Concomitant Medications ..................................................................................... 12 
6.8 
Study Medication Exposure and Compliance ...................................................................... 12 
6.9 
Efficacy Analysis ................................................................................................................. 13 
6.9.1 
Primary Efficacy Endpoint ...................................................................................... 13 
6.9.2 
Secondary Endpoints ............................................................................................... 14 
 
 14 
 
 14 
 
 14 
 
15 
6.11 Safety Analysis .................................................................................................................... 15 
6.11.1 Adverse Events ........................................................................................................ 15 
6.11.2 Clinical Laboratory Evaluations .............................................................................. 16 
6.11.3 Physical Examination Including Body Weight ....................................................... 16 
C
C
CCI
CCI
CCI
CCI


Transition Therapeutics Ireland Ltd.  
Page 4 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
6.11.4 Vital Signs ............................................................................................................... 16 
6.11.5 12-Lead ECG .......................................................................................................... 17 
6.11.6 Semen Analysis ....................................................................................................... 17 
 
 17 
7 
GENERAL INFORMATION ........................................................................................................ 17 
7.1 
Statistical Software............................................................................................................... 17 
8 
CHANGES FROM THE PROTOCOL PLANNED ANALYSES ................................................ 17 
 
CCI


Transition Therapeutics Ireland Ltd.  
Page 5 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
1 
SUMMARY OF CHANGES 
SAP Version History 
Version Date 
Description of Changes 
1.0 
21-FEB-2019 
Original signed version. 
2.0 
06-MAR-2019 
Prior to database lock, remove analyses which are no longer 
considered to be needed: 
 DXA percent change from baseline 
2 
Introduction 
This Statistical Analysis Plan (SAP) provides a description of the statistical methods and 
procedures to be implemented for the analyses of efficacy and safety data from Transition 
Therapeutics Ireland Ltd. Protocol SAR-202. Any deviations from this analysis plan will be 
substantiated by sound statistical rationale and will be documented in the final clinical study 
report. 
 
3 
Study Objectives 
3.1 
Primary Objectives 
1. To evaluate the effect of 15 mg and 25 mg OPK-88004 daily for 16 weeks on serum 
prostate-specific antigen (PSA) compared with placebo 
2. To evaluate the safety of 15 mg and 25 mg OPK-88004 daily for 16 weeks compared 
with placebo 
3.2 
Secondary Objectives 
1. To assess the effects of OPK-88004 on body composition by dual energy X-ray 
absorptiometry (DXA), specifically lean body mass and fat mass 
2.
   
CCI
CCI
CCI


Transition Therapeutics Ireland Ltd.  
Page 6 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
4 
STUDY OVERVIEW 
4.1 
Study Design 
Study SAR-202 is a phase 2 multicenter, placebo-controlled, double-blind trial to evaluate 
the effect of OPK-88004 doses (OPK-88004 15 mg, or OPK-88004 25 mg) on serum PSA 
compared to placebo in men with BPH.  Subjects will be instructed to take one dose 
(1 capsule) of study drug with water at approximately the same time each morning. 
Approximately 115 men with BPH will be enrolled in the study, randomized 1:1:1 across 
three arms (placebo, OPK-88004 15 mg, or OPK-88004 25 mg).  The trial will be conducted 
at up to approximately 35 sites within the US.   
The study duration for individual subjects will be up to 24 weeks and will include three 
phases: 
 a screening period (up to 4 weeks, including 1-week washout if required),   
 a treatment period (16 weeks), and   
 a follow-up period (4 weeks). 
CCI


Transition Therapeutics Ireland Ltd.  
Page 7 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
Study Design for SAR-202 
 
The schedule of events for the study is provided in Protocol Appendix 1. 
4.2 
Randomization and Blinding 
Subjects who have completed the screening visit and meet all of the inclusion and none of 
exclusion criteria are randomized into the study on day 1.  Randomized treatment assignment 
and randomization numbers are assigned via interactive web response system (IWRS) / 
interactive voice response system (IVRS).  Randomization is stratified by prostate volume 
<60 cm3 or ≥60 cm3 and lower urinary tract symptoms (LUTS) severity (total IPSS 
[Question 1 – Question 7] of <16 or ≥16).  Following randomization, study drug will be 
dispensed in a double-blind manner.  The sponsor and all clinical site personnel (investigator, 
pharmacist, etc.) are blinded to the treatment group for each subject.  Subjects also are 
blinded to the treatment they receive. 
5 
ANALYSIS ENDPOINTS  
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is percent change in PSA from baseline to Week 16. Since the 
primary analysis model will use mixed model repeated measures (MMRM), no imputation 
will be made for the missing Week 16 values. 
If certain events occur that complicate the description and interpretation of the treatment 
effect on PSA (e.g. prostatitis, riding a bike prior to a study visit, or sexual activity), then the 
PSA results affected by those intercurrent events will be excluded from all efficacy 


Transition Therapeutics Ireland Ltd.  
Page 8 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
summaries and analyses. The PSA results to be excluded due to intercurrent events will be 
defined prior to study unblinding. 
5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the observed change from baseline to Week 16/last 
observation carried forward (LOCF) in lean body mass and fat mass by DXA. 
If certain events occur that complicate the description and interpretation of the treatment 
effect on DXA parameters (e.g. going on a weight-loss diet or excessive exercise program), 
then the DXA results affected by those intercurrent events will be excluded from all efficacy 
summaries and analyses. The DXA results to be excluded due to intercurrent events will be 
defined prior to study unblinding. 
5.4 
Safety Endpoints 
Safety assessments include all adverse events (AEs), laboratory measurements (lipids, 
chemistry, hematology, coagulation, fasting HbA1c, glucose, insulin, hormone panel, CRP, 
and urinalysis), vital signs, physical examinations, ECGs, and semen analysis. 
6 
STATISTICAL METHODOLOGY 
6.1 
Sample Size Determination 
Approximately 115 subjects will be enrolled in the study, randomized 1:1:1 across three arms 
(placebo, OPK-88004 15 mg, or OPK-88004 25 mg).  The primary efficacy objective is to 
evaluate the ability of OPK-88004 doses to reduce PSA compared to placebo from baseline 
to week 16.  
 
  
 
  
CCI
CCI




Transition Therapeutics Ireland Ltd.  
Page 10 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
If there is more than one assessment within a visit window, then the analysis visit will be 
assigned by the following priorities:  
1. Use the visit with the matching visit label  
2. Use the visit closest to the target visit day. In the case of ties, use the later assessment.  
For all other efficacy and safety assessments, analysis visits will be assigned according to the 
visit recorded on the electronic case report form (eCRF). For efficacy, assessments must be 
within 10 days of the last dose date in order to be included for analysis. 
6.3 
Analysis Populations 
6.3.1 
Randomized Population 
The Randomized Population includes all subjects who sign the informed consent form and 
are assigned a randomization number.  Baseline and demographic characteristics will be 
summarized for this population. 
6.3.2 
Safety Population 
The Safety Population includes subjects in the Randomized Population who receive at least 1 
dose of randomized study drug.  All safety analyses will be conducted based on the Safety 
Population. In the event of treatment allocation errors, subjects will be analyzed for safety 
according to the treatment group they received. 
6.3.3 
mITT Population 
The modified Intent-to-Treat (mITT) Population includes all subjects in the Safety 
Population who have a baseline efficacy endpoint and at least 1 valid (i.e. within last dose 
date +10 days and without intercurrent events) post-dose efficacy endpoint. The mITT 
Population is the primary analysis population, and all efficacy analyses will be performed 
using the mITT Population. In the event of allocation errors, subjects will be analyzed for 
efficacy according to the treatment to which they were randomized. 
Since each efficacy assessment has a different schedule of events, the number of subjects 
included in other efficacy assessments may be different than the overall mITT Population. 
The analysis of each efficacy endpoint will be performed on all subjects that have a baseline 
efficacy result and at least 1 valid post-dose result for the specified efficacy parameter. 
Exclusion of results due to intercurrent events will be determined prior to study unblinding. 
Subjects may be included in the mITT Population but have certain results excluded due to 
intercurrent events. For example if the subject has baseline and Week 8 PSA but Week 16 
PSA is excluded due to an intercurrent event, the subject will still be included in the mITT 
Population. 


Transition Therapeutics Ireland Ltd.  
Page 11 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
6.3.4 
Per-Protocol Population 
The Per-Protocol (PP) Population will include all subjects in the mITT Population who 
complete the 16-week, double-blind treatment period without any significant deviations from 
the protocol procedures. The PP Population will be used to assess robustness of the primary 
analysis results. A final listing of all subjects to be excluded from the PP Population will be 
completed prior to unblinding the study database. 
The following criteria may be evaluated for major deviations prior to unblinding the study 
database. A final listing of all subjects to be excluded from the PP Population will be 
completed prior to unblinding the study database. 
 No eligibility criterion violations; 
 Did not withdrawal prior to Week 16; 
 Subjects with overall study drug compliance 80 – 120%; 
 Not taking any prohibited medications; and 
 No other substantial protocol deviations, including but not limited to significant 
changes in pre-study diet and activity levels. 
6.4 
Subject Disposition 
Frequencies and percentages of all randomized, discontinued, and completed subjects in the 
study will be presented by treatment group and total. Frequencies and percentages of subjects 
in each analysis population will also be provided. The reasons for discontinuations will be 
summarized by treatment group. Summaries for the total OPK-88004 treatment group (i.e. 15 
mg and 25 mg combined) will be provided as well. 
6.5 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively by treatment 
group and total for the Randomized Population. If they differ from the Randomized 
Population, summaries will also be provided for the mITT Population, PP Population, and 
Safety Population. Summaries for the total OPK-88004 treatment group (i.e. 15 mg and 25 
mg combined) will be provided as well for the mITT Population and the PP Population. 
Demographic and baseline characteristics include, but are not limited to, age at informed 
consent, gender, race, ethnicity, body weight, BMI, baseline PSA, baseline DXA 
assessments, prostate volume stratification group (<60 cm3 or ≥60 cm3), LUTS severity 
stratification group (total IPSS of <16 or ≥16). The baseline is defined in Section 6.2, 
Baseline, Endpoint, and Other Statistical Considerations. 
For categorical variables, comparisons between treatment groups will be assessed using a 
Pearson Chi-Square test.  For continuous variables, comparisons between the treatment 


Transition Therapeutics Ireland Ltd.  
Page 12 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
groups will be performed using a one-way Analysis of Variance (ANOVA) with treatment as 
the fixed effect. 
6.6 
Medical History 
Medical/surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.1. All medical history will be listed. 
6.7 
Prior and Concomitant Medications 
Medication start and stop dates that are recorded on the Prior & Concomitant Medications 
case report form will be used to determine whether the medications are prior or concomitant 
to the study drug. Medications ongoing at the time of first dose of study drug as well as any 
new medication added during the course of the study will be considered concomitant 
medications. Prior medications are defined as those used prior to and stopped before the first 
dose of study drug. All prior and concomitant medication verbatim terms will be coded using 
the World Health Organization Drug Dictionary September 2017 Global B3 version. The 
numbers and percentages of subjects taking concomitant medications in each treatment group 
and in total will be summarized by anatomic therapeutic chemical term and preferred term 
for the Safety Population. All prior and concomitant medications will be listed. 
6.8 
Study Medication Exposure and Compliance 
Subjects’ exposure to randomized study drug will be summarized with descriptive statistics 
for the Safety Population. Days of exposure is defined as:  
date of last dose of study drug – date of first dose + 1 
If the date of last dose of study drug is unavailable, then days of exposure will be defined as 
the early termination (ET) visit date – date of first dose for subjects that discontinue prior to 
Week 16, and the Week 16 visit date – date of first dose for subjects who complete Week 16. 
A contingency table will be provided to display the number and percentage of subjects in 
each treatment group with exposure in the following categories: 1-28 days (>0-4 weeks), 
29-56 days (>4-8 weeks), 57-84 days (>8-12 weeks), 85-112 days (>12-16 weeks), and 
>112 days (>16 weeks). 
Summary statistics will be presented for percent overall compliance to study medication by 
treatment group and total. The count and percentage of subjects will also tabulated by groups 
with overall compliance < 80%, 80% - 120% (inclusive), and > 120%. The percent overall 
compliance to study medication will be calculated as:  
100 × number of capsules / days of exposure 


Transition Therapeutics Ireland Ltd.  
Page 13 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
The number of capsules is the total number of capsules dispensed minus the total number of 
capsules returned as reported on the eCRF. If a bottle is not returned, it will be assumed that 
all capsules from that bottle were used. 
6.9 
Efficacy Analysis 
6.9.1 
Primary Efficacy Endpoint 
The primary efficacy analysis is to evaluate the effect of 15 mg and 25 mg OPK-88004 daily 
for 16 weeks versus placebo on PSA percent change from baseline to Week 16. Analysis of 
the percent change from baseline of PSA to Week 16 will be performed using a MMRM 
based on the mITT Population, implemented using SAS® Proc Mixed.  The factors in the 
model will be treatment, prostate volume stratification group, and IPSS stratification group, 
visit, and the treatment group by visit interactions and baseline PSA as a covariate. Treatment 
difference between OPK-88004 doses and placebo at Week 16 will be estimated from the 
MMRM model, as well as confidence intervals and p-values. This analysis will be based on 
the mITT Population and repeated on the PP Population. Sample SAS code is provided 
below. 
***********************************************************************  
Note:   
  USUBJID = unique subject identifier  
  TREATMENT = 0 (placebo), 1 (OPK-88004 15 mg), 2 (OPK-88004 25 mg) 
  PV: prostate volume stratification <60 or >=60 cm3 
  LUTS: total IPSS <16 or >=16 
  VISIT = visit (Week 8 and Week 16) 
  BASE = baseline PSA  
  PCHG = percent change from baseline to the specified visit  
**********************************************************************;  
proc mixed;   
  class USUBJID PV LUTS TREATMENT BASE VISIT;   
  model PCHG = PV LUTS TREATMENT BASE VISIT TREATMENT*VISIT;   
  Repeated VISIT / TYPE=UN sub=USUBJID;   
  lsmeans VISIT*TREATMENT / cl slice=VISIT;   
run;   
The appropriateness of the statistical model will be evaluated by testing the treatment group 
by baseline PSA interaction at a significance level of 0.10. If the interaction term is 
significant, the nature of the interaction will be investigated 
 
 
The same analysis will be performed for total OPK-88004 (i.e. 15 mg and 25 mg combined) 
versus Placebo. 
Supportive Analysis  
Results for Week 8 from the primary MMRM model above will also be reported. 
CCI


Transition Therapeutics Ireland Ltd.  
Page 14 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
The number and percentage of subjects that have an increase or zero change in PSA (i.e. non-
responder) or a decrease in PSA (i.e. responder) at Weeks 8 and 16 relative to baseline will 
be tabulated. Cochran-Mantel-Haenszel tests will be performed adjusting for the prostate 
volume and IPSS stratification groups. The general association p-value will be provided. 
Then for each OPK-88004 treatment group compared to placebo, the odds ratio, 95% 
confidence interval, and Breslow-Day test for homogeneity of the odds ratio p-value will be 
provided. The analysis will be performed on the mITT Population and repeated for the PP 
Population. The analysis will be performed based on observed data, i.e. only including 
subjects with a result at the specified visit. The same analysis will be performed for total 
OPK-88004 (i.e. 15 mg and 25 mg combined) versus Placebo. 
6.9.2 
Secondary Endpoints 
The observed change from baseline to Week 16/LOCF in lean body mass and fat mass will 
be analyzed using ANCOVA modeled with treatment, prostate volume stratification group 
and IPSS stratification group as fixed effects and baseline result as a covariate. If the Week 
16 measurement is missing, the LOCF algorithm will be applied to impute the missing Week 
16 value for all subjects (Week 16/LOCF). The least-squares means, standard errors, and the 
2-tailed 95% confidence intervals (CIs) for each treatment group and for comparison of each 
OPK-88004 dose to placebo will be presented. The 2-sided p-values testing for significance 
within treatment group change from baseline and comparison between treatment groups will 
be presented. This analysis will be based on the mITT Population and repeated on the PP 
Population. The same analysis will be performed for total OPK-88004 (i.e. 15 mg and 25 mg 
combined) versus Placebo. 
CCI


Transition Therapeutics Ireland Ltd.  
Page 15 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
6.11 
Safety Analysis 
All safety analyses will be conducted on the Safety Population. The evaluation of safety will 
be based primarily on TEAEs, safety laboratory measures, physical exams, vital signs, 
12-lead ECG, and semen analysis. Other safety data will be summarized as appropriate. 
6.11.1 
Adverse Events 
All AEs, including serious AEs (SAEs) occurring after the subject signs the ICF through the 
subject’s final visit will be reported and monitored. Any clinically significant abnormal 
laboratory results, physical examination findings, ECGs, and vital signs will be reported as 
an AE. All AEs will be coded using MedDRA version 20.1. 
TEAEs are defined as events that are newly reported after first dose of study drug or reported 
to worsen in severity or relationship to study drug after first dose of study drug.  
An overview of AEs will be provided by treatment group and in total for the following 
information: 
 All TEAEs, 
 Maximum severity of TEAEs, 
 Study drug-related TEAEs (defined as definitely, probably, or possibly related), 
 Maximum severity of drug-related TEAEs, 
 All serious adverse events (SAEs), 
 All treatment-emergent SAEs, 
 Drug-related SAEs, 
 Death due to AEs, 
 Withdrawals due to AEs, and 
CCI


Transition Therapeutics Ireland Ltd.  
Page 16 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
 Withdrawals due to study drug-related AEs. 
The numbers and percentages of subjects with TEAEs, including number of events, will be 
tabulated for each treatment group and in total by MedDRA system organ class and preferred 
term. Similar summaries will be provided by maximum severity. Drug-related TEAEs will be 
summarized in the same manner.  
Listings of SAEs and AEs leading to study medication discontinuation will be provided. 
AEs of Special Interest 
The number and percent of subjects (including number of events) experiencing AEs of 
special interest (AESIs) (see Protocol Section 8.2) and treatment-emergent AESIs will be 
tabulated for each treatment group and in total by system organ class and preferred term. A 
listing will be provided of all AESIs, which will be identified prior to database lock. Analysis 
will be performed using Fisher’s exact tests across all treatment groups. 
6.11.2 
Clinical Laboratory Evaluations 
Summary statistics will be provided for safety laboratory tests at baseline and all scheduled 
post-baseline visits for chemistry (including glucose and insulin), hematology, lipids, 
coagulation, and urinalysis assessments by treatment group and in total. The change from 
baseline to post-baseline visits will also be presented.  
The number and frequency of subjects with laboratory abnormalities (worst value post first 
dose for each subject) will be summarized by treatment group and in total. Shift tables from 
baseline to worst value post first dose will be presented for ALT and AST (>1xULN to 
≤2xULN, >2xULN to ≤3xULN, >3xULN) and CK (>1xULN to ≤5xULN, >5xULN to 
≤10xULN, >10xULN); where ULN = upper limit of normal. 
6.11.3 
Physical Examination Including Body Weight 
Counts and percentages of the physical examination overall interpretation (normal, abnormal 
clinically significant, abnormal, not clinically significant) will be tabulated at baseline and 
each scheduled post-baseline visit by treatment group and in total.  
Body weight will be summarized at baseline and each scheduled post-baseline visit by 
treatment group and in total. The change from baseline will also be presented.  
6.11.4 
Vital Signs  
Systolic blood pressure, diastolic blood pressure, pulse rate, temperature and respiratory rate 
will be summarized at baseline and each scheduled post-baseline visit by treatment and in 
total. The change from baseline will also be presented.  


Transition Therapeutics Ireland Ltd.  
Page 17 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
 
6.11.5 
12-Lead ECG 
Counts and percentages of the 12-lead ECG overall interpretation as reported on the eCRF 
(normal, abnormal clinically significant, abnormal, not clinically significant) will be 
tabulated at baseline and each scheduled post-baseline visit by treatment group and in total.  
12-Lead ECG parameters (heart rate, PR, RR, QRS, QT, T Wave Amplitude, QTcB, and 
QTcF) will be summarized at baseline and each scheduled post-baseline visit by treatment 
group and in total. The change from baseline will also be presented.  
6.11.6 
Semen Analysis 
Results from semen analysis will be summarized at baseline and Week 16/ET by treatment 
group and in total. The observed change and percent change from baseline will also be 
presented. All results, including the 3-month post-treatment follow-up visit if applicable, will 
be listed. 
7 
GENERAL INFORMATION 
The mock-ups for SAS-generated tables/figures/listings will be prepared in a separate 
document and finalized before database lock for the study. 
7.1 
Statistical Software 
The creation of analysis datasets and all statistical analyses will be done using SAS® version 
9.4. The Medpace standard operating procedures will be followed for the validation of all 
SAS programs and outputs. 
8 
CHANGES FROM THE PROTOCOL PLANNED ANALYSES 
Per Protocol, a sensivity analysis of the percent change from baseline to Week 16 in PSA 
will be performed using an ANCOVA model. This sensitivity analysis has been removed 
since the study will terminate early; only the primary analysis model (MMRM) will be used. 
The Protocol specifies that the observed change and percent change from baseline will be 
summarized and analyzed for lean body mass and fat mass by DXA 
 
. However, only the observed change from baseline 
will be summarized and analyzed. The percent change from baseline is no longer considered 
to be needed. 
CCI
CCI


Transition Therapeutics Ireland Ltd.  
Page 18 of 18 
SAR-202 Statistical Analysis Plan 
V2.0 / 06-MAR-2019 
Per Protocol, AEs that occur following first administration of study drug are TEAEs. 
However, for analysis, TEAEs will be defined as new or worsening AEs (see Section 6.11.1) 
 
CCI