Clinical trial NCT05285787
Conditions: End-Stage Renal Disease (ESRD)
Sponsor: Epizon Pharma, Inc.
Start date: 2019-03-01; Completion date: 2021-04-30
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with End Stage Renal Disease (ESRD) are prone to early and accelerated vascular calcification. Both the prevalence and extent of the vascular calcification are predictive for cardiovascular morbidity and all-cause mortality in this population. There is a growing body of evidence suggesting that dialysis patients have a primary, functional deficiency of Vitamin K2 as evidenced by reduced levels of circulating biomarkers including carboxylated forms of Matrix Gla Protein (MGP), Osteocalcin, and Fetuin-A, which are important inhibitors of vascular calcification. Decreased levels of Vitamin K2 are known to lead to microvascular calcification and are associated with dermatological and cardiovascular conditions such as calciphylaxis and peripheral arterial disease (PAD).

The purpose of this Phase 2 study is to examine the safety and pharmacokinetics of EPN-701 (menaquinone-7; MK-7) and to assess the effects on certain circulating biomarkers when MK-7 is orally administered once daily for 14 days.

Detailed description:
Patients with End Stage Renal Disease (ESRD) are prone to early and accelerated vascular calcification. Both the prevalence and extent of the vascular calcification are predictive for cardiovascular morbidity and all-cause mortality in this population. There is a growing body of evidence suggesting that dialysis patients have a primary, functional deficiency of Vitamin K2 as evidenced by reduced levels of circulating biomarkers including carboxylated forms of Matrix Gla Protein (MGP), Osteocalcin, and Fetuin-A, which are important inhibitors of vascular calcification. Decreased levels of Vitamin K2 are known to lead to microvascular calcification and are associated with dermatological and cardiovascular conditions such as calciphylaxis and peripheral arterial disease (PAD). The purpose of this Phase 2 study is to examine the safety and pharmacokinetics of EPN-701 (menaquinone-7; MK-7) and to assess the effects on certain circulating biomarkers when MK-7 is orally administered once daily for 14 days.

Arms: arm 1: Single arm
Interventions: intervention 1: EPN-701 (Oral)
Intervention descriptions: intervention 1: MK-7

Protocol documents:
Prot_SAP_000.pdf: 
EPIZON PHARMA, INC. 
CONFIDENTIAL 
 
 
 
 
 
 
 
EPIZON PHARMA, INC. 
 
 
CLINICAL STUDY PROTOCOL 
 
 
A Phase 1, Prospective Safety Trial of EPN-701 in Subjects with Stable End Stage 
Renal Disease (ESRD) Receiving Outpatient Hemodialysis 
 
 
Protocol Number: EPN-701-001 
IND Number: 129344 
 
Amendment 3, Dated January 16, 2020 
Replaces Protocol Version: Amendment 2, Dated: March 23, 2019 
 
 
 
 
 
Sponsor: Epizon Pharma, Inc. 
445 Park Avenue, Suite 908 
New York, NY 10022 
Telephone: +917.912.9900 
Facsimile: +212.829.5611 
 
 
 
 
CONFIDENTIALITY 
This document contains confidential information belonging to Epizon Pharma, Inc., and is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and the 
reviewing Ethics Committee or Institutional Review Board. Except as otherwise agreed to in writing, by 
accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose 
it to others (except where required by law) or use it for unauthorized purposes. In the event of any actual or 
suspected breach of this obligation, Epizon must be promptly notified. 
 
 
Protocol Number: EPN-701-001, Amendment 3 
1 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
1. 
SPONSOR SIGNATORIES 
 
 
SPONSOR: 
John M. Rudey, Chairman 
Epizon Pharma, Inc. 
445 Park Avenue, Suite 908 
New York, NY 10022, USA 
Telephone: +1.917.912.9900 
Email:Jrudey@epizonpharma.com 
 
 
 
 
Date 
 
 
Chief Operating Officer 
Epizon Pharma, Inc. 
445 Park Avenue, Suite 90B 
New York, NY 10022, USA 
Telephone: +1.50B.487.0830 
E-mail: wgannon@epizonpharma.com 
 
 
 
 
Date 
 
SPONSOR'S 
MEDICAL 
REPRESENTATIVE: 
James A. Tumlin, MD 
Founder and Director of Nephronet Clinical Trials Consortium 
923 Preserve Bluff Drive 
Atlanta, GA 30518, USA 
 
Telephone: +1.770.490.9203 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
Protocol Number. EPN-701·001, Amendment 3 
2 
 
 
 
 
iam E. Gannon Jr., MD 
Email: jamestumllnmdnephronet 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
3 
 
 
 
 
2. 
INVESTIGATOR AGREEMENT 
 
 
TITLE: 
A Phase 1, Prospective Safety Trial of EPN-701 in Subjects 
with Stable End Stage Renal Disease (ESRD) Receiving 
Outpatient Hemodialysis 
PROTOCOL NUMBER: 
EPN-701-001 
VERSION NUMBER: 
6.0 (Amendment 3) 
VERSION DATE: 
January 16, 2020 
IND NUMBER: 
129344 
TEST PRODUCT: 
EPN-701 
SPONSOR: 
Epizon Pharma, Inc. 
I agree to conduct this clinical trial according to the protocol described herein, and to comply with 
its requirements, subject to ethical and safety considerations and guidelines. I also agree to 
conduct this study in compliance with Good Clinical Practice (GCP) standards as defined by the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice, all 
applicable national, state, and local regulations, as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) and any other institutional 
requirements. 
I understand that the information in this protocol is confidential and should not be disclosed to 
others without written authorization from Epizon Pharma, Inc., except to the extent necessary to: 
(1) obtain informed consent from persons to whom the drug may be administered; and (2) inform 
those directly involved in the execution or the scientific/ethical review of the study. 
I understand that failure to comply with the requirements of the protocol may lead to my 
participation as an Investigator for this study to be terminated. 
 
 
 
Principal Investigator’s Name (print) 
Principal Investigator’s Signature 
Date 
 
Please retain the signed original of this form for your study files. Please return a copy of the signed 
form as instructed by your local clinical research associate (CRA). 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
4 
 
 
 
 
3. 
STUDY ADMINISTRATIVE STRUCTURE 
 
RESPONSIBILITY 
NAME & CONTACT DETAILS 
Sponsor Medical Monitor / 
Study Medical Monitor 
Katherine M. Smith, MD 
5205 Indigo Moon Way 
Raleigh, NC 27613 
Telephone: +1.919.264.5626 
E-mail: ksmith@safeharborpv.com 
Independent Medical Monitor 
J. Bruce McClain, MD 
11673 Garnet Road 
Lovettsville, VA 20180 
Mobile: +1.202.236.6975 
E-mail: drjblmcclain@aol.com 
Safety Reporting 
and Pharmacovigilance Analysis 
MedAssessment, Inc. 
14 Calle Vista Del Sol 
San Clemente, CA 92673-6913 
Telephone: +1.949.369.1931 
Website: www.medassessment.com 
Contract Research Organization 
(CRO) 
NephroSynergy, LLC 
575 Professional Drive, Suite 250 
Lawrenceville, GA 30046 
Telephone: +1.423.943.4265 
Fax: +1.888.242.1406 
Email: jwhitson@nephrosynergy.com 
Central Laboratory 
(Safety Laboratory, Biomarker, and 
PK Assessments) 
Biomarker Laboratories 
(PIVKA-II, dp-ucMGP, and T-50; 
Respectively) 
Covance Central Laboratory Services 
8211 SciCor Drive 
Indianapolis, Indiana 46214 
Telephone: +1.317.271.1200 
Fax: +1.317.273.4030 
Website: www.covance.com 
Ventana Medical Systems, Inc 
Pharma Services Laboratory 
1910 East Innovation Park Drive 
Tucson, AZ 85755 
Telephone: +1.520.273.8520 
Email: noah.theiss@roche.com 
University of Liège – Dept. of Chemistry 
Bone & Cartilage Markers Laboratory 
Hospital Avenue B35 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
5 
 
 
 
 
RESPONSIBILITY 
NAME & CONTACT DETAILS 
Route 52, Porte 52 
4000 Liège 
Belgium 
Telephone: +00.324.366.8817 
Email: anne-catherine.bekaert@chuliege.be 
Calciscon AG 
Aarbergstrasse 5 
2560 Nidau 
Switzerland 
Telephone: +41.32.530.8860 
Email: swapna.karthik@calciscon.com 
Study Drug Packaging, Labeling, 
and Distribution 
Sherpa Clinical Packaging dba PCI Pharma Services 
6166 Nancy Ridge Drive 
San Diego, CA 92121 
Telephone: +1.858.223.0841 
Website: SherpaClinical.com 
Institutional Review Board 
Copernicus Group IRB 
5000 CentreGreen Way, Suite 200 
Cary NC 27513 
Telephone: +1.919.465.4310 
Facsimile: +1.919.465.4311 
Email: irb@cgirb.com 
Website: www.wcgclinical.com 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
6 
 
 
 
 
TABLE OF CONTENTS 
1. 
SPONSOR SIGNATORIES ....................................................................................... 2 
2. 
INVESTIGATOR AGREEMENT ................................................................................ 3 
3. 
STUDY ADMINISTRATIVE STRUCTURE ................................................................. 4 
4. 
LIST OF ABBREVIATIONS ..................................................................................... 10 
5. 
PROTOCOL SYNOPSIS ......................................................................................... 13 
6. 
BACKGROUND ...................................................................................................... 25 
6.1 
Background on Vitamin K2 ................................................................................. 25 
6.1.1 
Vitamin K Metabolism and the Impact of Hemodialysis ................................. 25 
6.1.2 
Long-Active Derivatives of Vitamin K2: Therapeutic role for 
Menaquinone-7 ............................................................................................ 29 
6.2 
Background on EPN-701.................................................................................... 30 
6.2.1 
Summary of Nonclinical Studies ................................................................... 30 
6.2.2 
Summary of Clinical Studies of EPN-701 ...................................................... 31 
6.2.3 
Clinical Pharmacokinetics of EPN-701.......................................................... 32 
6.2.4 
Anticipated Risks Associated with EPN-701 ................................................. 32 
6.2.5 
Benefit-Risk Assessment .............................................................................. 33 
6.3 
Rationale for the Study and Study Design .......................................................... 33 
6.3.1 
Rationale for the Study and Study Population ............................................... 33 
6.3.2 
Rationale for the EPN-701 Dose and Schedule ............................................ 33 
6.3.3 
Rationale for Biomarker Assessments .......................................................... 34 
7. 
OBJECTIVES AND ENDPOINTS ............................................................................ 35 
8. 
STUDY DESIGN ...................................................................................................... 38 
8.1 
Description of the Study ..................................................................................... 38 
8.1.1 
Schedule of Assessments ............................................................................ 39 
8.1.2 
Study Committees ........................................................................................ 39 
8.2 
End of Study and Length of Study ...................................................................... 39 
9. 
MATERIALS AND METHODS ................................................................................. 40 
9.1 
Subjects ............................................................................................................. 40 
9.1.1 
Inclusion Criteria........................................................................................... 40 
9.1.2 
Exclusion Criteria ......................................................................................... 40 
9.2 
Method of Treatment Assignment and Blinding .................................................. 41 
9.2.1 
Randomization and Blinding ......................................................................... 41 
9.2.2 
Treatment Assignment ................................................................................. 41 
9.3 
Study Drug: EPN-701 ......................................................................................... 41 
9.3.1 
Description of the Study Drug ....................................................................... 42 
9.3.2 
Study Drug Packaging, Storage, and Handling ............................................. 42 
9.3.3 
Study Drug Labeling ..................................................................................... 42 
9.3.4 
Study Drug Dispensing ................................................................................. 43 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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9.3.5 
Study Drug Dosage, Administration, and Compliance................................... 43 
9.3.6 
Study Drug Accountability............................................................................. 43 
9.3.7 
Post-Trial Access to EPN-701 ...................................................................... 44 
9.4 
Concomitant Therapy ......................................................................................... 44 
9.4.1 
Prohibited Therapy ....................................................................................... 45 
9.4.2 
Prohibited Food ............................................................................................ 45 
9.5 
Study Visits ........................................................................................................ 45 
9.5.1 
Screening Visit (Day -7 to Day -1) ................................................................ 46 
9.5.2 
Visit 1 (Day 1, Baseline), Visit 4 (Day 8), Visit 7 (Day 15, End-of- 
Treatment), and Visit 10 (Day 22) [Mondays] ................................................ 47 
9.5.3 
Visits 2 & 3 (Days 3 & 5), Visits 5 & 6 (Days 10 & 12), Visits 8 & 9 
(Days 17 & 19), and Visits 11 & 12 (Days 24 & 26) [Wednesdays & 
Fridays] ........................................................................................................ 48 
9.5.4 
End-of-Study/Early Termination Visit (Day 29) .............................................. 48 
9.6 
Study Assessments ............................................................................................ 48 
9.6.1 
Informed Consent Forms and Subject Log ................................................... 48 
9.6.2 
Medical History and Demographic Data Collection ....................................... 49 
9.6.3 
Baseline and Concomitant Medications ........................................................ 49 
9.6.4 
Physical Examinations and Measurements................................................... 49 
9.6.5 
Vital Signs Measurements ............................................................................ 49 
9.6.6 
Electrocardiograms ....................................................................................... 49 
9.6.7 
Assessment of Dialysis Adequacy (Kt/V) ...................................................... 50 
9.6.8 
Laboratory, Biomarker, and PK Samples ...................................................... 50 
9.6.9 
Efficacy Evaluations ..................................................................................... 53 
9.7 
Treatment, Subject, Site, and Study Discontinuation .......................................... 54 
9.7.1 
Study Drug Discontinuation .......................................................................... 54 
9.7.2 
Withdrawal of Subjects from the Study ......................................................... 54 
9.7.3 
Study Discontinuation ................................................................................... 55 
9.7.4 
Site Discontinuation ...................................................................................... 55 
10. 
ASSESSMENT OF SAFETY ................................................................................... 55 
10.1 
Definitions .......................................................................................................... 55 
10.2 
Overall Safety Plan ............................................................................................ 57 
10.2.1 Dose Modifications and Interruptions due to Adverse Events ....................... 58 
10.3 
Recording and Assessment of Adverse Events .................................................. 58 
10.3.1 Adverse Event Recording and Reporting Period ........................................... 58 
10.3.2 Adverse Event Recording Guidelines ........................................................... 58 
10.3.3 Assessment of Adverse Events .................................................................... 59 
10.3.4 Adverse Event Follow-up Period................................................................... 61 
10.4 
Immediate Reporting Requirements ................................................................... 62 
10.4.1 Immediately Reportable Events .................................................................... 62 
10.4.2 Reporting Requirements for SAEs and AESIs .............................................. 62 
10.4.3 Reporting Requirements for Pregnancies ..................................................... 63 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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10.5 
Expedited Reporting to Health Authorities, Investigators, AND Institutional 
Review Boards ................................................................................................... 63 
10.6 
Safety Reviews by the Study SRC ..................................................................... 64 
11. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................... 64 
11.1 
General Considerations And Analysis Populations ............................................. 64 
11.2 
Determination of Sample Size ............................................................................ 64 
11.3 
Summaries of Subject Disposition ...................................................................... 65 
11.4 
Demographic and Baseline Characteristics ........................................................ 65 
11.5 
Efficacy Analyses ............................................................................................... 65 
11.6 
Safety Analyses ................................................................................................. 65 
11.6.1 Adverse Events ............................................................................................ 65 
11.6.2 Concomitant Medications ............................................................................. 66 
11.6.3 Safety Laboratory Parameters ...................................................................... 66 
11.6.4 ECG Changes and Abnormalities ................................................................. 66 
11.7 
Pharmacokinetic Analyses ................................................................................. 67 
11.8 
Biomarker Analyses ........................................................................................... 67 
11.9 
Subgroup Analyses ............................................................................................ 67 
11.10 Interim Analysis .................................................................................................. 67 
11.11 Handling of Missing Data ................................................................................... 68 
12. 
DATA COLLECTION AND MANAGEMENT ............................................................ 68 
12.1 
Case Report Forms ............................................................................................ 68 
12.2 
Data Quality Assurance ...................................................................................... 68 
12.3 
Site Monitoring and Audits ................................................................................. 68 
12.3.1 Source Documentation ................................................................................. 69 
12.3.2 Source Data Verification ............................................................................... 69 
12.4 
Retention of Records ......................................................................................... 69 
13. 
ETHICAL CONSIDERATIONS ................................................................................ 70 
13.1 
Regulatory Compliance ...................................................................................... 70 
13.2 
Informed Consent .............................................................................................. 70 
13.3 
Institutional Review Board .................................................................................. 70 
13.4 
Subject Confidentiality ........................................................................................ 71 
14. 
STUDY DOCUMENTATION .................................................................................... 71 
14.1 
Study Documentation ......................................................................................... 71 
14.2 
Protocol Amendments ........................................................................................ 71 
14.3 
Protocol Deviations ............................................................................................ 72 
14.4 
Publication Policy ............................................................................................... 72 
15. 
REFERENCES ........................................................................................................ 73 
16. 
APPENDIX 1 - DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY 
DISEASE (CKD) ..................................................................................................... 78 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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LIST OF TABLES 
 
Table 1 
Schedule of Study Activities ......................................................................... 21 
Table 2 
Study Objectives and Corresponding Endpoints ........................................... 37 
Table 3 
Washout Periods for Prohibited Medications ................................................ 45 
Table 4 
Biomarker Assessments ............................................................................... 52 
Table 5 
Guidance for the Assessment of Adverse Event Causality ........................... 60 
 
 
 
LIST OF FIGURES 
 
Figure 1 – Vitamin K Cycle .................................................................................................. 26 
Figure 2 – The Carboxylation of Protein Residues Serine and Threonine ............................ 28 
Figure 3 – In vivo Plasma Protein Carbonyl Formation ........................................................ 28 
Figure 4 – Vitamin K Structures ........................................................................................... 29 
Figure 5 – Sequence of PK Sampling, Visits 1 – 8 ............................................................... 53 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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4. 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AVF 
arteriovenous fistula 
BGP 
bone Gla protein 
BUN 
blood urea nitrogen 
β-hCG 
beta-human chorionic gonadotropin 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHD 
coronary heart disease 
CI 
confidence interval 
CKD 
chronic kidney disease 
cMGP 
carboxylated Matrix Gla Protein 
CMP 
complete metabolic panel 
Cmax 
maximum plasma concentration 
CPP 
calciprotein particles 
CRA 
clinical research associate 
CRO 
contract research organization 
CUA 
Calcific Uremic Arteriolopathy (calciphylaxis) 
CVA 
cerebrovascular accident 
dba 
DNA 
doing business as 
deoxyribonucleic acid 
dp-cMGP 
desphospho-carboxylated Matrix Gla Protein 
dp-ucMGP 
dephosphorylated and uncarboxylated Matrix Gla Protein 
eCRF 
electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EFSA 
European Food Safety Authority 
EOS 
End-of-Study (visit) 
EOT 
End-of-Treatment (visit) 
ESRD 
end-stage renal disease 
FAO 
Food and Agriculture Organization (of the United Nations) 
FDA 
Food and Drug Administration 
FSI 
first subject in 
GCP 
Good Clinical Practice 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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Abbreviation 
Definition 
GGCX 
gamma glutamate carboxylase 
Gla 
gamma-carboxyglutamic acid 
GLP 
Good Laboratory Practice 
HBeAg 
hepatitis B “e” antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPLC 
high performance liquid chromatography 
hs-CRP 
high-sensitivity C-Reactive Protein 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug application 
INR 
International Normalized Ratio 
IOM 
Institute of Medicine 
IP 
investigational product 
IV 
intravenous(ly) 
KH2 
vitamin K hydroquinone 
Kt/V 
measure of dialysis adequacy; K=dialyzer urea clearance, t=duration 
of the dialysis session, V=volume of urea distribution 
LC/MS/MS 
liquid chromatography tandem mass spectrometry 
LDL 
low-density lipoprotein 
LSLV 
last subject last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGP 
Matrix Gla Protein 
MK-4 
menaquinone-4 
MK-7 
menaquinone-7 
mRNA 
messenger ribonucleic acid 
NADP 
nicotinamide adenine dinucleotide phosphate 
NOAC 
novel oral anticoagulants 
NOAEL 
no-observed-adverse-effect-level 
LSLV 
last subject last visit 
PCR 
polymerase chain reaction 
PIVKA-II 
Protein Induced in Vitamin K Absence/Antagonist-II (also known as 
descarboxyprothrombin or des-gamma-carboxy prothrombin [DCP]) 
PK 
Pharmacokinetic(s) 
PT 
preferred term 
PTT 
partial thromboplastin time 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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Abbreviation 
Definition 
RBC 
red blood cell 
RNA 
ribonucleic acid 
ROS 
reactive oxygen species 
RR 
relative risk 
SAE 
serious adverse event 
SD 
standard deviation 
SMF 
Site Master File 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TG 
triglycerides 
T-50 
Time to Formation of Secondary Calciprotein Particles 
TIA 
transient ischemic attack 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
USA/US 
United States of America 
USP 
United States Pharmacopeia 
VKD 
vitamin K-dependent 
VKOR 
vitamin K oxidoreductase 
VKORC1 
vitamin K epoxide reductase C1 
VKORC1L1 
vitamin K epoxide reductase C1-Like-1 
VKR 
vitamin K reductase 
WBC 
white blood cell 
WHO 
World Health Organization 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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5. 
PROTOCOL SYNOPSIS 
 
Study Title 
A Phase 1, Prospective Safety Trial of EPN-701 in Subjects with 
Stable End Stage Renal Disease (ESRD) Receiving Outpatient 
Hemodialysis 
Study Number 
EPN-701-001 
Clinical Development 
Phase 
Phase 1 
Indication 
End Stage Renal Disease (ESRD) on hemodialysis 
Study Design 
This is a Phase 1, prospective, open label study to evaluate the 
safety, tolerability, and pharmacokinetics (PK) of EPN-701, 
administered once daily for 14 days in subjects with ESRD on a 
stable hemodialysis regimen. 
Study Objectives 
Primary Objectives: 
• 
To determine the safety and tolerability of EPN-701 
(administered for two weeks at a daily dose of 10 mg) in 
subjects with ESRD on stable hemodialysis. 
Secondary Objectives 
• 
To determine, in subjects with ESRD on stable hemodialysis, 
the plasma levels of the following biomarkers after two weeks 
of EPN-701 treatment relative to baseline: uncarboxylated 
MGP; uncarboxylated osteocalcin; Activated Protein C; and 
Protein Induced Vitamin K Absence-II (PIVKA-II). 
Exploratory Objectives: 
• 
To determine the pharmacokinetic profile of EPN-701 in 
subjects with ESRD on stable hemodialysis. 
• 
To determine, in subjects with ESRD on stable hemodialysis, 
the plasma levels of the following biomarkers after two weeks 
of EPN-701 treatment relative to baseline: osteoprotegerin, 
Fetuin A, high-sensitivity C-Reactive Protein (hs-CRP) and 
Time to Formation of Secondary Calciprotein Particles (T-50 
Test), including CPP size. 
Study Population 
A total of 15 eligible subjects with ESRD on a stable maintenance 
dialysis regimen will be enrolled and treated with EPN-701. 
Inclusion Criteria 
Subjects must meet all inclusion criteria to be enrolled in the 
study: 
1.  Male or female ≥18 years of age 


EPIZON PHARMA, INC. 
CONFIDENTIAL 
Protocol Number: EPN-701-001, Amendment 3 
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2. Diagnosed with ESRD and treated with stable maintenance 
hemodialysis at least three times a week for at least three 
months prior to the first dose of study drug. Subjects may 
have missed (less than or equal to) 4 hemodialysis sessions 
within three months prior to enrollment, provided that the 
Principal Investigator deems them suitable for study 
participation. 
3. Clinically stable medical condition, consistent with ESRD, as 
judged by the investigator based on the results of screening 
safety evaluations (physical examination, medical history, 
clinical laboratory tests, vital signs, and 12-lead 
electrocardiogram [ECG]) 
4. Written informed consent 
5. Able and willing to comply with the requirements of the study 
protocol 
6. For females of child-bearing potential: 
o Negative serum pregnancy test; 
o Abstinence (refraining from heterosexual intercourse) or 
use of an acceptable contraception for at least 1 month 
prior to screening, and willingness to continue for at least 
1 month after the last study drug administration. 
A woman is considered to be of childbearing potential if she is 
post-menarche, has not reached a postmenopausal state 
( 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone 
surgical sterilization (removal of ovaries and/or uterus, or 
bilateral tubal ligation). 
Examples of acceptable contraceptive methods include: 
hormonal contraceptives that inhibit ovulation, hormone- 
releasing intrauterine devices, and copper intrauterine 
devices. 


EPIZON PHARMA, INC. 
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Protocol Number: EPN-701-001, Amendment 3 
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Exclusion Criteria 
Subjects meeting any of the following exclusion criteria will be 
excluded from the study: 
1. Chronic kidney disease not requiring hemodialysis 
2. Acute kidney injury treated with hemodialysis 
3. Diagnosis of confirmed calciphylaxis 
4. History of any solid organ transplant 
5. History of malignancy within 2 years of study enrollment, 
except for adequately treated carcinoma in situ of the cervix 
and non-melanoma skin carcinoma 
6. History of any major surgery (defined as a surgical procedure 
involving the cranium, chest, abdomen, or pelvic cavity, or 
other procedure performed under general anesthesia) within 1 
month prior to the first dose of study drug. Subjects with a 
recent (within <1 month) revision and/or placement of 
arteriovenous fistula (AVF) will be allowed to participate. 
7. History of a major cardiovascular event (such as 
cerebrovascular accident [CVA], transient ischemic attack 
[TIA], myocardial infarction, unstable angina) within 1 month 
prior to the first dose of study drug. 
8. Any co-existing disease or condition that may compromise the 
safety of study participants and/or the integrity of the study, 
including, but not limited to: 
o Class C or Class D Cirrhosis of the liver 
o Known intestinal malabsorption 
o Inability to take oral medication 
9. Life-expectancy <3 months 
10. Known history or positive serology for Human 
Immunodeficiency Virus (HIV), positive serologies of E antigen 
or with polymerase chain reaction (PCR) positive titers for 
hepatitis B virus (HBV). Subjects with positive serologies for 
hepatitis C but with negative PCR for active virus will be 
allowed. 
11. Severe infection requiring intravenous (IV) antibiotics within 
two weeks prior to the first dose of study drug. 
12. Warfarin taken within two weeks prior to the first dose of study 
drug. Subcutaneous heparin, enoxaparin and novel oral 
anticoagulants (NOAC; such as apixaban) are permitted. 
13. Treatment with an investigational drug within four weeks prior 
to the first dose of study drug. 


EPIZON PHARMA, INC. 
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Protocol Number: EPN-701-001, Amendment 3 
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14. Pregnancy or lactation 
15. Any other disease or condition which, in the judgment of the 
Investigator, would place a subject at undue risk by being 
enrolled in the trial, or cause inability to comply with the trial. 
Study Assessments & 
Schedule 
A total of 15 consenting subjects meeting the study eligibility 
criteria will be enrolled and treated with EPN-701 10 mg (one 10 
mg capsule to be taken orally once a day, at the same time each 
morning), for 14 days. 
The expected duration of study participation for an individual 
subject is approximately five weeks, including up to one week for 
screening, two weeks of study treatment, and two weeks of post- 
treatment safety follow-up. Subjects will undergo a total of 14 
visits during their study participation: Screening visit (within seven 
days prior to the first dose of study drug), three visits per week 
during the two-week treatment, and two-week safety follow-up 
periods (coinciding with the subject’s hemodialysis schedule), and 
the End-of-Study (EOS)/Early Termination visit. Baseline 
assessments will be completed prior to the first study drug intake 
on Day 1. End-of-Treatment (EOT) assessments will be 
completed after the last dose of study drug on study Day 15 (or 
earlier in case of an early discontinuation of the study treatment). 
The EOS/Early Termination visit will occur two weeks after the 
last dose of study drug (on study Day 29). 
Subjects will be monitored for adverse events (AEs), and 
concomitant medications will be recorded throughout their study 
participation (from screening through the EOS/Early Termination 
Visit). Additional safety assessments will include: physical 
examinations, safety laboratory tests (hematology, including 
complete blood count [CBC]; complete metabolic panel [CMP, 
including electrolytes, renal and liver function tests, and lipid 
profile]; and coagulation panel), vital signs measurements, and 
12-lead ECG. In addition, occurrence of dialyzer clotting will be 
assessed at each dialysis session, and Kt/V (a measure of 
dialysis adequacy) will be calculated at baseline (as the average 
of the last three pre-study Kt/V values obtained as part of the 
subject’s standard of care) and at the end of treatment. 
Blood for PK assessments will be sampled as follows: 
• 
On Day 1 (baseline) and Day 8 (Week 2, on-treatment): pre- 
dialysis (at the time of needle placement, denoted as 0 hours), 
immediately followed by study drug administration, and then at 
1 hour (+/- 5 minutes), 2 hours (+/- 5 minutes), 3 hours (+/- 5 


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Protocol Number: EPN-701-001, Amendment 3 
17 
 
 
 
 
minutes), 4 hours (+/- 30 minutes)/before needle removal, 6 
hours (+/- 30 minutes), 8 hours (+/- 30 minutes), and 24 hours 
(+/- 60 minutes) after study drug administration; 
• 
On Days 3, 5, 10, 12, and 15: pre-dialysis (at the time of 
needle placement, at 0 hours), immediately followed by study 
drug administration, and then at 4 hours (+/- 30 
minutes)/before needle removal; and 
• 
On Day 17 (Week 3, off-treatment) pre-dialysis only (at the 
time of needle placement). 
Pre- and post-dialysis blood samples for biomarker analyses will 
be collected at Baseline, and on select Mondays during the 
two-week treatment, and two-week safety follow-up periods. 
Refer to Table 1, Schedule of Study Activities for further details. 
Investigational Medicinal 
Product (IMP; Test 
Product) identity, dose, 
and mode of 
administration 
EPN-701 (a new formulation containing highly purified 
Menaquinone-7 or MK-7 as the active ingredient) is the test 
product in this study, and will be provided by the study sponsor at 
the following dosage strength: 
• 
10 mg soft-gel capsule for oral administration. 
Each subject will take one 10 mg capsule of EPN-701 per day 
orally over 14 days. 
The study drug is to be taken at the same time each morning. 
Comparator product 
identity, dose, and mode 
of administration 
Not applicable; this is an uncontrolled study. 
Efficacy Endpoints 
Not applicable 
Safety Endpoints 
Primary Safety Endpoint: 
• 
Frequency of treatment-emergent AEs and treatment- 
emergent AEs assessed as related to the study drug (defined 
as possibly, probably, and definitely related events). A 
treatment-emergent AE is defined as any AE with an onset 
between the first dose of the study drug and the last study 
visit, or any AE with an onset prior to first dose that increases 
in severity or frequency after the first dose of study drug. 
Adverse events include both clinical events and laboratory 
abnormalities that are assessed as clinically significant. 
Secondary Safety Endpoints: 
• 
Frequency of serious adverse events (SAEs), AEs leading to 
study drug discontinuation, and AEs of special interest (AESI) 


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Protocol Number: EPN-701-001, Amendment 3 
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• 
Changes from baseline in safety laboratory parameters 
• 
Changes from baseline in vital signs measurements 
• 
Changes from baseline in ECG parameters. 
Biomarker Endpoints 
Secondary Endpoints: 
• 
Plasma levels of the following biomarkers on Day 15 (end-of- 
treatment) and Day 22 compared to baseline: uncarboxylated 
MGP; uncarboxylated osteocalcin; Activated Protein C, and 
PIVKA-II protein. 
Exploratory Endpoints: 
• 
Plasma levels of the following biomarkers on Day 15 (end-of- 
treatment) and Day 22 compared to baseline: osteoprotegerin, 
Fetuin A, hs-CRP. 
• 
Time to Formation of Secondary Calciprotein Particles (T-50 
Test), including CPP size. 
Pharmacokinetic 
Endpoints 
Exploratory Endpoints: 
• 
EPN-701 plasma concentrations (ng/mL) at each measured 
time-point will be determined according to standard 
procedures, using a validated high-performance liquid 
chromatography (HPLC) tandem mass spectrometric 
(LC/MS/MS) method. 
In addition, depending on the observed plasma levels, the 
following PK parameters may be determined for EPN-701: 
• 
Maximum plasma concentration (Cmax) [ng/mL] 
• 
Time to maximum plasma concentration (Tmax) [hr] 
• 
Area under the concentration-time curve (AUC) from time 0 to 
24 hours (AUC0-24 [hr×ng/mL]) 
Interim Safety 
Assessments by the 
Safety Review 
Committee (SRC) 
A SRC will review the safety data accumulated during the study at 
regular intervals. The SRC will be comprised of the Sponsor’s 
Medical Monitor, Independent Medical Monitor, and the Principal 
Investigator. Further details will be provided in the SRC Charter. 
Statistical Methods 
Sample Size Calculation 
No formal sample size calculation was performed. The selected 
sample size of 15 subjects is consistent with preliminary safety 
and PK studies of a similar design and is expected to provide 
sufficient information to identify safety issues, while limiting 
subject exposure. 


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Analysis Populations 
• 
The safety population will include all subjects who received at 
least one dose of study drug. 
• 
The PK population will include all subjects who received at 
least one dose of study drug and have sufficient plasma 
concentrations data for PK analysis. 
General Considerations 
• 
All analyses will be descriptive. Binary and categorical data 
will be summarized by number and percentage of subjects. 
Continuous data will be summarized by means, standard 
deviations (SDs), medians, and ranges (minimum, maximum), 
as appropriate. 
• 
All data will be included in appropriate per-subject listings. 
Efficacy Analyses 
Not applicable. 
Safety Analyses 
• 
Adverse Events: All AEs will be coded using the current 
version of the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be included in per-subject listings. In 
addition, treatment-emergent AEs will be summarized in 
frequency tables, by MedDRA System Organ Class (SOC) 
and by Preferred Term (PT). Adverse events assessed as 
related to the study drug will be summarized in a similar 
manner. A summary of AEs by maximum severity grade will 
also be provided. 
• 
Concomitant Medications: All concomitant medications will be 
coded using the most current version of the World Health 
Organization (WHO) Drug Dictionary and will be included in 
per-subject listings. 
• 
Laboratory parameters will be summarized at each time point 
measured using descriptive statistics, including means, SDs, 
medians, and ranges, as appropriate. Change from baseline 
will be summarized similarly, with 95% confidence intervals 
(CIs) for each change. Shift tables may also be provided, if 
warranted by the data. All safety laboratory data will be 
included in appropriate per-subject listings, along with 
reference ranges, and indication of clinically significant 
departures from the respective reference ranges. 


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• 
ECG parameters: will be included in appropriate per-subject 
listings and summaries. 
Pharmacokinetic Analyses 
EPN-701 plasma concentration data will be measured at specific 
timepoints (see Table 1), tabulated and summarized. Descriptive 
statistics for plasma concentrations and PK parameters will 
include arithmetic means and SDs, geometric means and 
coefficients of variation, medians, and ranges, as appropriate. 
Biomarker Analyses 
Biomarkers will be summarized in a similar manner as described 
for safety laboratory parameters, with summary at each time point 
along with change from baseline. Depending of the distribution of 
the biomarkers, transformations to minimize skew and outliers 
may be performed. 
Interim Analyses 
Not applicable. 
Study Duration 
Overall Study Duration: 
All subjects are expected to be enrolled within approximately 
three months. The end of the study is defined as the last subject 
last visit (LSLV), which is expected approximately six to seven 
months after the enrollment of the first subject. The actual length 
of the study and the time for final analysis will depend on the 
recruitment rate. 
Duration of Study Participation Per Subject: 
The expected duration of the study for an individual subject is 
approximately five weeks, including up to one week for screening, 
two weeks of study treatment, and two weeks of post-treatment 
safety follow-up. Subjects will undergo a total of 14 visits during 
the study participation. 
Participating Centers 
The study will be conducted at one to three dialysis centers in the 
United States. 
The schedule of study activities is provided in Table 1 below. 


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Protocol Number: EPN-701-001, Amendment 3 
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Table 1 
Schedule of Study Activities 
 
WEEK -1 
WEEK 1 
ON-TREATMENT 
WEEK 2 
ON-TREATMENT 
WEEK 3 
POST-TREATMENT 
WEEK 4 
POST-TREATMENT 
EOS/ 
EARLY 
TERMINA 
TION 
VISIT SCHEDULE 
Screening 
1 
BL 
2 
3 
4 
5 
6 
7 
EOT 
8 
9 
10 
11 
12 
Study Day 
-7 to -1 
1 
3 
5 
8 
10 
12 
15 
17 
19 
22 
24 
26 
29 
Day of the week 
Mon 
Wed 
Fri 
Mon 
Wed 
Fri 
Mon 
Wed 
Fri 
Mon 
Wed 
Fri 
Mon 
Informed Consent & HIPAA Authorization 
X 
Demographics [1] 
X 
Medical History [2] 
X 
Disease History [3] 
X 
Physical examination [4] 
X 
(X) 
X 
Weight and height measurements [5] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standard 12-lead ECG [6] 
X 
X 
X 
Vital signs measurements [7] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, CMP, Coagulation panel [8] 
X 
X 
X 
X 
X 
X 
Testing for HIV, Hepatitis B and C [9] 
X 
Serum β-hCG Pregnancy Test [10] 
X 
Eligibility Criteria 
X 
X 
Concomitant Medications [11] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event recording [12] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration [13] 
Once daily, from Day 1 through Day 14 
EPN-701 PK assessments [14] 
X 
X 
X 
X 
X 
X 
X 
X 
Kt/V assessment [15] 
X 
X 
Biomarker assessments 
MGP, Osteocalcin, Activated Protein C, 
PIVKA-II protein, Fetuin A, 
osteoprotegerin, hs-CRP, and Time to 
Formation of Secondary Calciprotein 
X 
X 
X 


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WEEK -1 
WEEK 1 
ON-TREATMENT 
WEEK 2 
ON-TREATMENT 
WEEK 3 
POST-TREATMENT 
WEEK 4 
POST-TREATMENT 
EOS/ 
EARLY 
TERMINA 
TION 
VISIT SCHEDULE 
Screening 
1 
BL 
2 
3 
4 
5 
6 
7 
EOT 
8 
9 
10 
11 
12 
Study Day 
-7 to -1 
1 
3 
5 
8 
10 
12 
15 
17 
19 
22 
24 
26 
29 
Day of the week 
Mon 
Wed 
Fri 
Mon 
Wed 
Fri 
Mon 
Wed 
Fri 
Mon 
Wed 
Fri 
Mon 
Particles (T-50 Test), including CPP size 
[16] 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; ALT=alanine amino transferase; AST=aspartate amino transferase; 
BL=Baseline (visit); BUN=blood urea nitrogen; CMP=Complete Metabolic Panel; CPP=calciprotein particles; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; EOS=End-of-Study (visit); EOT=End-of-Treatment (visit); β-hCG=beta-human chorionic gonadotropin (pregnancy test); 
HDL=high-density lipoprotein; hs-CRP=high sensitivity C-reactive protein; INR=international normalized ratio; K=dialyzer clearance; 
LC/MS/MS=liquid chromatography tandem mass spectrometry; LDL=low-density lipoprotein; MGP=Matrix Gla protein; PK=pharmacokinetic(s); 
PTT=partial thromboplastin time; RBC=red blood cell (count); RNA= ribonucleic acid; SAE=serious adverse event; t=time; T-50 Test=Time to 
Formation of Secondary Calciprotein Particles; V=volume of urea distribution; WBC=white blood cell (count) 
Note: Visit 1 will be the Baseline visit. End-of-Treatment (EOT) assessments will be completed after the last dose of study drug on study Day 
15/Visit 7 (or earlier in case of an early discontinuation of the study treatment). 
[1] Demographic data include age, sex, and self-reported race/ethnicity. 
[2] General medical history includes clinically significant diseases (except those listed under “Disease history”), surgeries, reproductive status, and 
any conditions/symptoms present prior to the first dose of study drug. 
[3] Disease history includes details on the underlying condition, including renal (ESRD) and dialysis history. 
[4] A complete physical examination will be performed at screening and at the EOS visit on Day 29. A symptom-driven (abbreviated) physical 
examination may be performed at the EOT visit (Day 15), if the investigator deems it clinically indicated. 
[5] Subjects will undergo body weight and height measurement at screening/baseline, and body weight measurements (as part of their standard 
care on dialysis days) within 60 minutes pre-dialysis and within 60 minutes post-dialysis on each dialysis day during the 2-week treatment period 
(Visits 1 through 6), at the EOT visit (Day 15), and EOS visit (Day 29). 
[6] Standard 12-lead ECG recordings will be obtained within 60 minutes pre-dialysis at screening/baseline, at EOT (Day 15), and at EOS (Day 29). 
ECG recordings should be performed after the subject has been resting in a supine position for at least 5 minutes, and prior to other procedures 
scheduled at that same time (e.g., blood draws). 


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Protocol Number: EPN-701-001, Amendment 3 
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[7] Vital signs (including blood pressure, heart rate, respiratory rate, and oral body temperature) will be measured at screening, and (as part of 
their standard care on dialysis days) within 30 minutes pre-dialysis and within 30 minutes post-dialysis at each treatment visit (Visits 1 through 6), 
at EOT (Day 15), and EOS (Day 29). 
[8] All blood sampling will occur pre-dialysis (at the time of needle placement). Hematology panel includes: RBC count, hemoglobin, hematocrit, 
and WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells), if clinically indicated. CMP 
includes: glucose, albumin, total protein, electrolytes (sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphate), renal function 
tests (BUN, creatinine), liver function tests (ALT, AST, bilirubin), and lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides). Coagulation panel includes: PTT, INR, and platelet count. 
[9] Serology for: HIV, HBV (hepatitis B “e” antigen [HBeAg] and PCR for the active virus [HBV DNA]); and HCV (HCV antibody and PCR for active 
virus [HCV RNA]) 
 
 
[10] Women of child bearing potential must undergo a serum β-hCG pregnancy test within 7 days prior to the first dose of study drug, and the 
result must be negative for enrollment. 
[11] All medications (including over-the-counter medications) or therapy administered to the subject during the 30 days prior to the first dose of 
study drug will be recorded at screening/baseline. Any changes to concomitant medications will be documented regularly throughout the study. 
[12] All AEs with an onset between the time the informed consent is signed and 14 days after the last dose of study drug (EOS/Early Termination 
visit) are to be recorded on the appropriate Adverse Event CRF pages and in source documents. SAEs, AESIs, and pregnancies occurring during 
or within 30 days after the last dose of EPN-701 will also be reported in an expedited fashion. SAEs and AESI considered to be related to the 
study drug by the investigator, will be reported to the Sponsor even if they occurred after the protocol-specified reporting period (i.e., more than 30 
days after the last dose of EPN-701). Any occurrence of dialyzer clotting (assessed at each dialysis session) is to be recorded as an AE. 
[13] EPN-701 10 mg per day (1 capsule of 10 mg). The study drug will be taken at approximately the same time each morning. On hemodialysis 
days (Days 1, 3, 5, 8, 10, and 12), subjects will take their study drug dose pre-dialysis (immediately after needle placement and biomarker 
sampling, as applicable); on the remaining days during Weeks 1 and 2, subjects will take their study drug dose at home. 
[14] Blood for PK assessments will be sampled as follows: 
• 
On Day 1 (baseline) and Day 8 (Week 2, on-treatment): pre-dialysis (at the time of needle placement, denoted as 0 hours), immediately 
followed by study drug administration, and then at 1 hour (+/- 5 minutes), 2 hours (+/- 5 minutes), 3 hours (+/- 5 minutes), 4 hours (+/- 30 


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Protocol Number: EPN-701-001, Amendment 3 
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minutes)/before needle removal, 6 hours (+/- 30 minutes), 8 hours (+/- 30 minutes), and 24 hours (+/- 60 minutes) after study drug 
administration; 
• 
On Days 3, 5, 10, 12, and 15: pre-dialysis (at the time of needle placement, at 0 hours), immediately followed by study drug administration, 
and then at 4 hours (+/- 30 minutes)/before needle removal; and 
• 
On Day 17 (Week 3, off-treatment): pre-dialysis only (at the time of needle placement). 
Plasma levels of EPN-701 will be determined using a validated high-performance LC/MS/MS method. 
[15] Kt/V (a standard measure of dialysis adequacy) will be calculated at baseline (as the average of the last three pre-study Kt/V values obtained 
as part of the subject’s standard of care), and at EOT (Day 15). In case the Kt/V value obtained at EOT is reduced compared to baseline (pre- 
study measurements), the Investigator will determine (in consultation with the Medical Monitor, as needed) if the event qualifies for reporting as an 
AE. 
[16] Blood sampling will always occur pre-dialysis (at the time of needle placement): on Day 1 (Baseline), Day 15 (EOT), and Day 22 (1 week after 
the last study drug dose), for a total of 3 samples collected. Plasma levels of the following biomarkers will be assessed: uncarboxylated MGP; 
uncarboxylated osteocalcin, Activated Protein C, PIVKA-II protein, Fetuin A, osteoprotegerin, hs-CRP, and Time to Formation of Secondary 
Calciprotein Particles (T-50 Test), including CPP size. Instructions for specimen collection and handling will be included in the laboratory manual 
provided by the Central Laboratory. 


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6. 
BACKGROUND 
 
The current Phase 1 clinical trial is a prospective safety study of EPN-701 in subjects currently 
receiving stable hemodialysis for end-stage renal disease (ESRD). EPN-701 is a new formulation 
containing highly purified MK-7. MK-7 belongs to a family of compounds called menaquinones, 
collectively known as vitamin K2. EPN-701 is being developed for the treatment of calciphylaxis 
(also referred to as Calcific Uremic Arteriolopathy [CUA]), a rare, but potentially fatal complication 
of chronic kidney disease (CKD), predominantly affecting patients with ESRD on dialysis. The 
condition is characterized by calcification of subcutaneous arterioles and infarctions of the 
adjacent subcutis and skin (Janigan 2000; Brandenburg et al. 2016; Brandenburg et al. 2017). 
While the mechanisms for soft tissue calcification are not fully understood; there is a growing body 
of evidence that the uremic condition of both CKD and ESRD patients contributes to a functional 
deficiency of vitamin K. Subject to approval by the FDA, EPN-701 would be the first and only drug 
approved for the orphan indication calciphylaxis (CUA) to address peripheral soft tissue 
calcification and medial calcification of the smooth muscle cells of the vasculature. The following 
section provides an overview of (i) the impact of ESRD and hemodialysis on the vitamin K cycle; 
(ii) long-acting derivatives of vitamin K2; non-clinical and clinical background on EPN-701, and 
rationale for the current study, including key study design elements. 
 
6.1 
BACKGROUND ON VITAMIN K2 
 
6.1.1 
Vitamin K Metabolism and the Impact of Hemodialysis 
 
Vitamin K is an essential enzymatic co-factor that is required for posttranslational modifications 
of vitamin K-dependent (VKD) proteins. Of the numerous VKD proteins, several are clinically 
relevant to ESRD patients. They include the central coagulation factors such as factors II, VII, IX, 
and X, as well as intercellular matrix proteins including matrix gamma-carboxyglutamic acid (Gla) 
protein (MGP) and osteocalcin (also referred to as bone Gla protein [BGP]). It has been proposed 
that vitamin K is reduced to vitamin K hydroquinone (KH2) via two pathways: a warfarin-sensitive 
pathway (by vitamin K epoxide reductase [VKORC1]) and a warfarin-resistant pathway (Tie and 
Stafford, 2016). It is only the reduced form of vitamin K that can function as a co-factor for gamma 
glutamate carboxylase (GGCX) which catalyzes the carboxylation of VKD proteins (Gallieni and 
Fusaro, 2014). Warfarin blocks the generation of vitamin K hydroquinone by acting as an inhibitor 
of the vitamin K recycling (Figure 1). The enzymatic carboxylation of glutamate residues results 
in further oxidation of vitamin KH2 to 2,3-epoxide Vitamin K. The final step of the vitamin K cycle 
requires the enzymatic reduction of vitamin K 2,3-epoxide back to its native structure. This step 
is catalyzed by VKORC1 and is a component of the vitamin K cycle along with warfarin (Figure 1) 
(Gallieni and Fusaro, 2014). 


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Figure 1 – Vitamin K Cycle 
 
Conversion of glutamate (Glu) to g-carboxyglutamate (Gla) residues by g-glutamyl carboxylase (GGCX) (1) is essential 
for the activation of vitamin K-dependent (VKD) proteins. g-Carboxylation transforms undercarboxylated (ucVKD) into 
carboxylated (cVKD) proteins. Vitamin K hydroquinone (KH2) is oxidized to vitamin K epoxide (KO). KO is converted 
to vitamin K quinone by vitamin K epoxide reductase (2). A similar reductase enzymatic reaction (2) converts vitamin 
K quinone back into KH2. Another reductase, NAD(P)H-dependent vitamin K reductase (3), or DT-diaphorase, can also 
catalyze the same conversion into KH2. Warfarin inhibits the reductase activity (2) that is dithiol dependent but not the 
NADPH-dependent reductase (3), whose substrate can be dietary vitamin K. 
Source: Gallieni and Fusaro, 2014 
Recent studies have shown that VKOR has two distinct isoenzymes (VKORC1 and VKORC1- 
Like-1 [VKORC1L1]) that differ in both enzymatic properties and tissue distribution (Tie et al. 
2011). VKORC1 and VKORC1L1 both catalyze the reduction of 2,3-epoxide vitamin K via vitamin 
K quinone to vitamin K hydroquinone. VKORC1 is the key enzyme of the classical vitamin K cycle 
by which VKD proteins are γ-carboxylated by the hepatic GGCX. In contrast, the VKORC1 paralog 
enzyme, VKORC1L1, is mainly responsible for antioxidative function by reduction of vitamin K to 
prevent damage by intracellular reactive oxygen species (ROS) (Caspers et al. 2015). The 
available data also suggest that there is an as-yet-unidentified vitamin K reductase (VKR) 
(different from VKORC1) in the vitamin K-dependent carboxylation that allows warfarin poisoning 
to be overcome (Tie and Stafford, 2016). 
Westhofen et al have shown that compared to VKORC1, VKORC1L1 has a 3-fold lower affinity 
for 2,3-epoxide vitamin K (Westhofen et al. 2011). Subsequent work supported the hypothesis 
that VKORC1L1 is a specialized isoform that protects against oxidant injury through the 
regeneration of vitamin K. When cultured HEK293T cells were incubated with hydrogen peroxide 


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(H2O2), VKORC1L1 expression was increased and evidence of membrane oxidant injury was 
reduced (Westhofen et al. 2011; Tie et al. 2013). Cumulatively, observations reported to date 
suggest that any condition or procedure (i.e. hemodialysis) that blocks re-constitution of vitamin 
K predisposes that tissue to pathologic calcification (Caspers et al. 2015). 
It is widely recognized that despite dietary deficiencies, vitamin K levels among ESRD patients 
may not be reduced. For example, Holder et.al studied 172 stable dialysis patients and found that 
only 6% of patients exhibited a clinically significant deficiency in vitamin K. However, when 
patients were examined for the level of uncarboxylated osteocalcin, 60% of patients had reduced 
levels (Holden et al. 2010). To confirm that this was a general effect of reduced vitamin K activity, 
the authors also measured PIVKA-II; another vitamin K-dependent protein. Indeed, 90% of both 
CKD and ESRD patients were found to have reduced levels of carboxylated prothrombin (Holden 
et al. 2010). In a similar study, Pilkey et al measured the vitamin K1 levels in 142 ESRD patients 
and found that most patients had adequate vitamin K stores but 93% of patients had 
uncarboxylated osteocalcin levels that were greater than 20% of the total osteocalcin levels, 
consistent with a subclinical vitamin K deficiency (Pilkey et al. 2007). It is interesting to note that 
there was no correlation between total vitamin K1 and the levels of circulating of uncarboxylated 
osteocalcin. This unexpected finding is consistent with the hypothesis that in uremic patients, total 
vitamin K levels can be normal while generation of reduced forms are blocked by the oxidative 
properties of uremia (Stockler-Pintoa et al. 2016). 
Evidence in the literature suggests that insufficient availability of menaquinones is associated with 
higher levels of dephosphorylated and uncarboxylated MGP (dp-ucMGP), and there is a 
significant correlation between dp-ucMGP and presence of soft tissue calcification (Schurgers et 
al., 2010; Delanaye et al. 2014). These observations suggest that some aspect of the uremic 
condition or even the process of dialysis neutralizes the carboxylating effects of vitamin K. 
Pioneering work by Himmelfarb et al. and others have confirmed that the simple delivery of 
hemodialysis can lead to the oxidation of numerous tissue proteins (Himmelfarb et al. 2000), such 
as the oxidation of the hydroxyl amino acid side chains to carbonyl groups (see Figure 2). 


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Figure 2 – The Oxidation of Protein Residues Serine and Threonine 
Serine 
O 
Residue 
O 
 
N 
H 
 
 
 
 
Threonine 
Residue 
 
N 
H 
OH 
N 
O 
H 
HN 
Uremia Induced 
HN 
Oxidation 
 
 
O 
OH 
O 
O 
 
 
N 
H 
HN 
HN 
 
In a study of CKD and ESRD patients, using carbonyl side chain oxidation as a measure of global 
oxidant burden, Himmelfarb et al demonstrated that both CKD and ESRD patients exhibit a higher 
percentage (15-fold) of carbonyl proteins compared to normal controls (see Figure 3). The 
percentage of carbonyl proteins was even higher among patients receiving dialysis, 
demonstrating that not only does dialysis not reduce oxidative burden, it appears to contribute to 
it (Himmelfarb et al. 2000). We propose that the oxidative load generated by the delivery of 
hemodialysis leads to oxidation of the functional KH2 to the non-functional native vitamin. The 
oxidation of KH2 by hemodialysis may block its ability to function as a co-factor for GGCX, which 
downstream leads to reduced gamma carboxylation of vitamin K-dependent proteins. 
 
Figure 3 – In vivo Plasma Protein Carbonyl Formation 
 
*P=0.05 vs. normal volunteers (N=10 in each group). Error bars represent standard error of the mean. 
Source: Himmelfarb et al. 2000 


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6.1.2 
Long-Active Derivatives of Vitamin K2: Therapeutic role for 
Menaquinone-7 
 
EPN-701 is a new formulation containing highly purified menaquinone-7 (MK-7) that belongs to 
the vitamin K2 family of compounds. Subject to approval by the FDA, EPN-701 would be the first 
and only drug approved for the orphan indication Calciphylaxis (also referred to as Calcific Uremic 
Arteriolopathy [CUA]), specifically to address peripheral soft tissue calcification and related 
calcification of the medial smooth muscle cells of the vasculature present in most ESRD patients. 
Menaquinones have a common functional naphthoquinone ring system (also shared with 
phylloquinone) and an unsaturated polyisoprenyl side chain. They are designated based on the 
length of the aliphatic side chains attached to the naphthoquinone ring (Booth and Suttie, 1998; 
Shearer and Newman, 2008). Menaquinone nomenclature is based on the number of isoprenoid 
units, and ranges from 1 to 15 (e.g., MK-7 for the vitamer with a side chain consisting of 7 
isoprenoid units) (Marles et al. 2017). The chemical structure of MK-4 and MK-7 compared to 
phylloquinone (vitamin K1) is presented in Figure 4. Although both phylloquinones and 
menaquinones are fat-soluble, their lipophilicity increases substantially at increasing chain length. 
Thus, when compared to MK-4, MK-7 has high lipid solubility, greater tissue concentration and 
longer plasma half-life. While MK-7 and MK-4 are both well absorbed in humans, the plasma 
levels of MK-7 are significantly higher due to its longer half-life of 72 hours. In contrast, MK-4 has 
a half-life of approximately 3 hours (Schurgers and Vermeer, 2002; Schurgers et al. 2007c). 
Dietary sources of menaquinones include chicken, egg yolk, dairy products, cow liver, and 
fermented foods such as cheese, yogurt, sauerkraut, and natto, a traditional Japanese food made 
from soybeans fermented with Bacillus subtilis varnatto (Schurgers et al. 2007c; Marles et al. 
2017). 
 
Figure 4 – Vitamin K Structures 
 
The naphthoquinone ring system shared by phylloquinones (vitamin K1) and menaquinones MK-4 and MK-7 (vitamin 
K2). The designation of MK-4 versus MK-7 is dependent upon the length of the aliphatic side chains attached to the 
naphthoquinone ring. 


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In addition, there are more than 200 dietary supplement products containing MK-7 currently on 
the market in the United States, the majority of which have a manufacturer’s suggested MK-7 
dose of 50 μg/d (NIH DSLD 2016). The Acceptable Daily Intake is 120 μg/day (FDA 2012). 
 
6.2 
BACKGROUND ON EPN-701 
 
EPN-701 is a new formulation containing highly purified MK-7. MK-7 belongs to a family of 
compounds called menaquinones, collectively known as vitamin K2. 
The following sections provide an overview of non-clinical and clinical data on MK-7. For further 
details, refer to the EPN-701 Investigator's Brochure. 
6.2.1 
Summary of Nonclinical Studies 
 
The active ingredient in EPN-701 (MK-7) has been studied extensively in a variety of nonclinical 
animal models. 
In a rat model of cardiovascular calcification, MK-7 supplementation inhibited the development of 
cardiovascular calcification and the inhibition was due to a direct effect on secondary 
mineralization of damaged vascular structures and not to a reduction in vascular damage. MK-7 
supplementation also inhibited the increase in aortic alkaline phosphatase activity and resulted in 
a 10-fold increase in the expression of the MGP messenger ribonucleic acid (mRNA) in the aorta 
(Scheiber et al. 2015). Given that MGP is a potent inhibitor of arterial calcification, EPN-701 
administration could be a beneficial treatment for calciphylaxis patients. 
Published non-clinical toxicology studies of MK-7 include single-dose toxicity studies in mice and 
rats, and two-week, five-week, and two 13-week repeat-dose toxicity studies in rats. 
Administration of single oral doses of MK-7 at 2000 mg/kg (equivalent to a human dose of 9730 
mg) to five female mice was not associated with signs of toxicity during the 14-day observation 
period (Pucaj et al. 2011). There were no signs of toxicity, effects on body weight (growth), or 
gross pathologic findings at necropsy after administration of 0.5, 1,10, 20, 2000 mg/kg/day 
(equivalent to human doses of 5, 10, 97, 194, 19400 mg/day, respectively) to eight rats (four male, 
four female) for 14 days (Ravishankar et al. 2015). In a Good Laboratory Practice (GLP)-compliant 
study with 13-week repeat dosing in rats, the no-observed-adverse-effect-level (NOAEL) was 
determined to be 10 mg/day, the highest dose tested (Pucaj et al. 2011), which is equivalent to a 
dose level of 97 mg/day in a 60-kg human subject. The five-week NOAEL for effects on 
cardiovascular function was also 10 mg/kg/day (97 mg/day in a 60-kg human subject), the only 
dose level tested (Siltari et al. 2014). These studies support the 10 mg/day dose in the EPN-701- 
001 clinical study as safe, given that there is a 10-fold safety margin from the NOAEL human 
equivalent dose. 
Genotoxicity studies have shown that MK-7 has no mutagenic or clastogenic potential 
(Ravishankar et al. 2015). 
Refer to the EPN-701 Investigator’s Brochure for further details on the nonclinical studies. 


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6.2.2 
Summary of Clinical Studies of EPN-701 
 
The current EPN-701-001 study will be the first clinical investigation of EPN-701 in humans. Data 
on the clinical benefits and safety of MK-7 (the active ingredient in EPN-701) are available from 
numerous clinical trials and are briefly summarized below. 
6.2.2.1 
Summary of the Clinical Benefits of MK-7 
 
The active ingredient in EPN-701 (MK-7) has been studied extensively in humans. Published 
reports of clinical trials conducted with MK-7 include studies evaluating dietary menaquinone 
intake, studies evaluating MK-7 as a nutritional supplement and clinical studies evaluating the 
effect of MK-7 on various disease indications. 
High dietary menaquinone intake was associated with several beneficial effects in clinical trials 
involving more than 57,000 women and men, including: (1) Reduced coronary calcification in a 
cohort of 564 post-menopausal women (Beulens et al. 2009); (2) Reduced risk of coronary heart 
disease (CHD) in 16,057 women aged 49-70 years (Gast et al. 2008); (3) Reduced relative risk 
(RR) of CHD mortality, all-cause mortality and severe aortic calcification in 4807 subjects with no 
history of myocardial infarction at baseline (Geleijnse et al. 2004); (4) No increase in the risk of 
stroke (hemorrhagic, ischemic, or overall) in a prospective cohort of 35,476 Dutch men and 
women (average age of 49 years, 74% women) during a follow-up of approximately 12 years 
(Vissers et al. 2013); (5) In addition, results of one study involving 105 women suggested that 
higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture 
risk in Japanese women (Kaneki et al. 2001). 
Long-term use of MK-7 supplements (180 µg/day for 3 years) improved arterial stiffness in 244 
healthy postmenopausal women enrolled in a double-blind, randomized, placebo-controlled trial 
(Knapen et al. 2015). 
In a prospective cohort analysis of 7216 participants at high cardiovascular disease risk, 
individuals who increased their intake of vitamin K1 or K2 during the follow-up period (median, 
4.8 years) had a significantly lower risk of cancer and all-cause mortality, and no increase in 
cardiovascular mortality compared to those who decreased or did not change their intake 
(Juanola-Falgarona et al. 2010). 
6.2.2.2 
Summary of the Clinical Safety of MK-7 
 
The safe use of MK-7 is supported by a body of published literature. Multiple studies have been 
performed in humans with MK-7 at various doses and frequencies, both in healthy volunteers and 
patients with various diseases. Several published clinical trials evaluated the safety of MK-7. 
Cumulatively, the findings from these studies indicate, that treatment with MK-7 at levels of up to 
180 μg/day for 3 years (Knapen et al. 2013; Knapen et al. 2015), or up to 360 μg/day for 12 weeks 
(Theuwissen et al. 2012; Dalmeijer et al. 2012), or of up to 1080 μg three times weekly for 8 weeks 
(Caluwé et al. 2014) in treatment populations of up to 120 subjects was associated with no 
significant adverse effects compared with placebo. Adverse effects specifically attributed to MK- 
7 were limited to gastrointestinal upset associated with the product’s smell (Marles et al. 2017). 


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Similarly, a systematic review and meta-analysis of 13 randomized controlled trials (N=1366) 
evaluating vitamin K1 and K2 supplementation for the prevention of bone fractures, none of the 
included studies reporting any serious adverse events (SAEs) associated with vitamin K 
(Cockayne et al. 2006). 
A comprehensive review of the available evidence supporting the safety of MK-7 as an ingredient 
of dietary supplements was recently published (Marles et al. 2017). A search of the literature by 
the Institute of Medicine (IOM) revealed no evidence of toxicity associated with the natural 
menaquinones. Given the lack of adverse effects in humans or animals consuming high doses of 
vitamin K, the IOM was unable to derive a Tolerable Upper Intake Level (IOM 2001). The World 
Health Organization (WHO) and Food and Agriculture Organization (FAO) of the United Nations 
(WHO/FAO 2004) concluded that oral natural K vitamins seem to be free of toxic side effects, an 
observation based on clinical administration of doses of 10-20 mg/day or more. The European 
Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies conducted a 
safety assessment of vitamin K2 (principally MK-7) added to food for nutritional purposes (EFSA 
2008) and concluded there were no adverse effects of MK-7 on blood coagulation at doses of up 
to 6 μg/kg/day in adults and 1.5 μg/kg/day in children. 
Overall, the conclusions of the reviews by all agencies have been supportive of a favorable benefit 
to risk ratio for vitamin K2 (Marles et al. 2017). 
6.2.3 
Clinical Pharmacokinetics of EPN-701 
 
The current EPN-701-001 study will be the first investigation of the pharmacokinetics (PK) of EPN- 
701 in humans. Published clinical PK data for MK-7 is available in the literature. 
In a study comparing the pharmacokinetic profile and the efficacy of MK-7 and vitamin K1, in 
healthy volunteers, maximum serum concentrations of MK-7 were seen approximately 4 hours 
after intake, followed by a steep decline in serum concentrations and then a second phase at 8- 
96 hours in which MK-7 remained stable for up to 4 days or more. MK-7 was shown to have a 
much longer half-life than vitamin K1 (68 hours vs 1-2 hours). Both MK-7 and vitamin K1 showed 
linear dose-response curves at 4 hours post treatment, from 0 to 500 μg; however, at 24 hours, 
MK-7 at 100 μg gave an upper limit of normal range for total serum vitamin K (1 μg/L), whereas 
there was no effect of vitamin K1 at up to 200 μg. MK-7 accumulated during the first two weeks 
until it reached a plateau level of approximately 6 μg/L (Schurgers et al. 2007c). 
6.2.4 
Anticipated Risks Associated with EPN-701 
 
As detailed in Section 6.2.2.2, several published clinical trials evaluated the safety of MK-7. 
Cumulatively, the findings from these studies indicate, that treatment with MK-7 at individual daily 
doses of up to 1080 μg three times per week (Caluwé et al. 2014) was not associated with 
significant adverse effects compared with placebo. Adverse effects specifically attributed to 
MK-7 were limited to gastrointestinal upset associated with the product’s smell (Marles et al. 2017). 
There is a risk for interaction between EPN-701 and anticoagulant drugs (Marles et al. 2017). 
Additional details are provided in the EPN-701 Investigator’s Brochure. 


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6.2.5 
Benefit-Risk Assessment 
 
Based on the publicly available data demonstrating the clinical benefits and safety of MK-7 
supplementation, EPN-701 is expected to have an acceptable safety profile in subjects with ESRD 
on hemodialysis, despite the higher dose to be evaluated in the current study (10 mg/day) 
compared to the daily doses administered in clinical trials of MK-7 supplementation (up to 1080 
μg three times per week). Nevertheless, appropriate measures will be implemented to evaluate 
and minimize the potential risks related EPN-701 throughout the study. These will include 
continuous adverse event monitoring, and regular clinical and laboratory safety assessments. A 
Safety Review Committee (SRC) will review the safety data accumulated during the study at 
regular intervals. The SRC will be comprised of the Sponsor’s Medical Monitor, Independent 
Medical Monitor, and the Principal Investigator. Further details will be provided in the SRC 
Charter. 
 
6.3 
RATIONALE FOR THE STUDY AND STUDY DESIGN 
 
6.3.1 
Rationale for the Study and Study Population 
 
As detailed in Section 6.1, there is a growing body of evidence suggesting that both CKD and 
ESRD patients have a primary, functional deficiency of vitamin K as evidenced by reduced 
circulating levels of carboxylated forms of MGP and osteocalcin. Due to the loss of these proteins 
and their protective effects against soft tissue and vascular calcification, ESRD patients on 
hemodialysis are at risk of developing calciphylaxis. 
Given the therapeutic potential of MK-7 in patients with ESRD on dialysis, the current clinical 
study is a Phase 1 prospective safety and PK study of EPN-701 in 15 subjects currently receiving 
stable hemodialysis for ESRD. Patients who have developed calciphylaxis will be excluded from 
the current study. 
The primary objective of the EPN-701-001 study is to determine the safety and tolerability of EPN- 
701 (administered for two weeks at a daily dose of 10 mg) in subjects with ESRD on chronic 
stable hemodialysis. 
Once the safety and tolerability of the 10 mg dose is determined in the current Phase 1 study, a 
Phase 2b clinical trial is planned to determine whether EPN-701 can normalize levels of calcium- 
chelating proteins and subsequently accelerate the rate of healing of calciphylaxis lesions. 
6.3.2 
Rationale for the EPN-701 Dose and Schedule 
 
In a GLP-compliant study evaluating 13-week repeat dosing in rats, the NOAEL was determined 
to be 10 mg/kg/day, the highest dose tested (Pucaj et al. 2011), which is equivalent to a dose of 
approximately 97 mg/day in a 60-kg human subject. Additionally, a two-week repeat dose study 
in rats included dosing MK-7 as high as 2000 mg/kg/day and resulted in no signs of toxicity 
(Ravishankar et al. 2015). This equates to a human equivalent dose of approximately 19.4 g/day. 
There is no known published LD-50 level for menaquinone-7. 


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The dose selected for the current clinical study is 10 mg/day, providing a 10-fold safety margin 
over the established NOAEL in rats. Therefore, the available data on MK-7 provide sufficient 
evidence of safety to support the proposed clinical study evaluating EPN-701 in humans. 
In addition, the existing literature (Westenfeld et al. 2012; Caluwe et al. 2014) indicates that 
administration of 1.0 mg of MK-7 resulted in an approximately 50% absolute reduction/conversion 
of uncarboxylated matrix GLA protein to carboxylated matrix GLA protein, which is the only 
functional form of the protein capable of inhibiting the deposition of calcium in soft tissues. 
Therefore, a 10 mg dose of EPN-701 is anticipated to be sufficient to augment the carboxylation 
of MGP-1 to levels that will prevent additional calcification of the skin and soft tissues in patients 
with calciphylaxis. 
6.3.3 
Rationale for Biomarker Assessments 
 
A significant proportion of ESRD patients on hemodialysis have functional, but modifiable, vitamin 
K deficiency (Cranenburg et al. 2012; Elliott et al. 2014), and multiple biomarkers have been 
tested as measures of vitamin K status in these patients (Elliott et al. 2014). PIVKA-II is a measure 
of prothrombin undercarboxylation, with elevated levels corresponding to poorer vitamin K status. 
As a biomarker of vitamin K status, PIVKA-II has the advantage of being independent of kidney 
function and lipid profile (Elliott et al. 2014). 
MGP is a potent calcification inhibitor of the arterial wall and other soft tissues, and its activity 
depends on vitamin K-dependent γ-glutamate carboxylation (Schurgers et al. 2007a; Westenfeld 
et al. 2012; Schurgers et al. 2013; Marles et al. 2017). Uncarboxylated MGP, formed as a result 
of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor 
vitamin K status in hemodialysis patients (Westenfeld et al. 2012). The circulating inactive form 
of MGP (dp-ucMGP) was shown to increase progressively in patients with CKD (Schurgers et al. 
2010) and to be predictive of vitamin K status and correlated with vascular calcification in patients 
on hemodialysis (Delanaye et al. 2014). Plasma dp-ucMGP has therefore been proposed as a 
surrogate marker for vascular calcification in CKD (Schurgers et al. 2010). In addition, lower levels 
of circulating desphospho-carboxylated MGP (dp-cMGP) was proposed as a predictor of mortality 
in dialysis patients (Schlieper et al. 2011). 
Osteocalcin is a non-collagenous bone matrix protein synthesized by mature osteoblasts, and 
involved in bone formation and regulation of bone mineralization (Elliott et al. 2014; Marles et al. 
2017). The proportion of osteocalcin that is uncarboxylated is a sensitive marker of vitamin K 
status in bone, and subclinical vitamin K deficiency is defined by an increase in the proportion of 
uncarboxylated osteocalcin above 20% (Elliott et al. 2014). Supplementation with MK-7 at doses 
of 100–200 mg/d for 4 to 12 weeks was shown to increase the ratio of carboxylated to 
undercarboxylated osteocalcin significantly and in a dose-dependent manner (Inaba et al. 2015). 
Vitamin K-dependent γ-carboxyglutamate proteins are synthesized in the liver, and help maintain 
normal blood coagulation through a balance of both procoagulant factors (II, VII, IX, and X) and 
anticoagulant proteins (C and S) (Schurgers et al. 2007c; Marles et al. 2017). Activated Protein 
C regulates the coagulation process by neutralizing the procoagulant activities of factors V and 
VIII in the presence of the cofactor Protein S (Marlar and Gausman, 2017). Hypercoagulable 


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states, such as protein C and/or protein S deficiencies have been reported in patients with 
calciphylaxis (the ultimate target population for EPN-701), and proposed as factors increasing the 
likelihood of calciphylaxis development (Wilmer and Magro, 2002; Nigwekar et al. 2008). 
In a randomized study evaluating the effect of vitamin K2 supplementation on functional vitamin 
K deficiency in adult hemodialysis patients, patients on hemodialysis (N=53) had 4.5-fold higher 
dp-ucMGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with healthy age- 
matched controls (N=50). PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K2 
supplementation induced a dose- and time-dependent decrease in circulating dp-ucMGP, 
uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dp-ucMGP 
levels were 77% and 93% in the groups receiving 135 μg and 360 μg of menaquinone-7, 
respectively (Westenfeld et al. 2012). The results of this study provide a rationale for the use of 
plasma PIVKA-II, MGP, and osteocalcin as biomarkers in an interventional clinical trial of vitamin 
K supplementation in hemodialysis patients. 
Fetuin A has been characterized as a critical regulator of calcification in humans, and as such is 
of interest to monitor in interventions targeting calcification (Jahnen-Dechent et al., 2011). 
Likewise, osteoprotegerin is also thought to be a regulator of calcification, making it of interest 
here (Price et al., 2001). Finally, the T-50 test has been shown to correlate strongly with the 
propensity of blood to form calcifications, wherein a short T-50 is indicative of blood likely to form 
calcifications, and a lengthening of T50 for patients at risk would be desireable (Pasch et al., 
2017). 
Hs-CRP is widely acknowledged to be indicative of inflammations of various kinds and if elevated, 
can signal inflammatory events prior to clinical symptoms. 
 
7. 
OBJECTIVES AND ENDPOINTS 
 
This study will evaluate the safety and PK of EPN-701 in adult subjects with ESRD on stable 
hemodialysis. 
Primary Objective: 
• 
To determine the safety and tolerability of EPN-701 (administered for two weeks at a daily 
dose of 10 mg) in subjects with ESRD on stable hemodialysis. 
Secondary Objectives: 
• 
To determine, in subjects with ESRD on stable hemodialysis, the plasma levels of the 
following biomarkers after two weeks of EPN-701 treatment relative to baseline: 
o Uncarboxylated MGP 
o Uncarboxylated osteocalcin 
o Activated Protein C 
o PIVKA-II. 


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Exploratory Objectives: 
• 
To determine the PK profile of EPN-701 in subjects with ESRD on stable hemodialysis. 
• 
To determine, in subjects with ESRD on stable hemodialysis, the plasma levels of the 
following biomarkers after two weeks of EPN-701 treatment relative to baseline: 
o Osteoprotegerin 
o Fetuin A 
o High-sensitivity C-Reactive Protein (hs-CRP). 
o Time to Formation of Secondary Calciprotein Particles (T-50 Test); including CPP size. 
Specific objectives and corresponding endpoints for the study are outlined (in Table 2) below. 


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Table 2 Study Objectives and Corresponding Endpoints 
Objectives 
Corresponding Endpoints 
Primary Objectives: 
Safety: 
• 
To determine the safety and 
tolerability of EPN-701 
(administered for two weeks at a 
daily dose of 10 mg) in subjects 
with ESRD on stable hemodialysis. 
Primary Safety Endpoint: 
• 
Frequency of treatment-emergent adverse events 
(AEs) and treatment-emergent AEs assessed as 
related to the study drug (defined as possibly, 
probably, and definitely related events). A 
treatment-emergent AE is defined as any AE with 
an onset between the first dose of the study drug 
and the last study visit, or any AE with an onset 
prior to the first dose that increases in severity or 
frequency after the first dose of study drug. Adverse 
events include both clinical events and laboratory 
abnormalities that are assessed as clinically 
significant. 
Secondary Safety Endpoints: 
• 
Frequency of serious adverse events (SAEs), AEs 
leading to study drug discontinuation, and AEs of 
special interest (AESI). 
• 
Changes from baseline in laboratory parameters 
• 
Changes from baseline in ECG parameters 
Secondary Objectives: 
Biomarkers: 
• 
To determine, in subjects with 
ESRD on stable hemodialysis, the 
plasma levels of the following 
biomarkers after two weeks of 
EPN-701 treatment relative to 
baseline: uncarboxylated MGP; 
uncarboxylated osteocalcin; 
Activated Protein C; and PIVKA-II 
protein. 
Biomarker Endpoints: 
• 
Biomarker ratios on Day 15 (end-of-treatment) and 
Day 22 compared to baseline: 
o 
Ratio of uncarboxylated to total MGP 
o 
Ratio of carboxylated to uncarboxylated 
osteocalcin 
o 
Ratio of carboxylated to uncarboxylated Protein C 
• 
Plasma levels of the following biomarkers on Day 15 
(end-of-treatment) and Day 22 compared to baseline: 
o 
Uncarboxylated MGP 
o 
Uncarboxylated osteocalcin 
o 
Activated Protein C 
o 
PIVKA-II protein 


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Exploratory Objectives: 
Pharmacokinetics: 
• 
To characterize the 
pharmacokinetic (PK) profile of 
EPN-701 in in subjects with ESRD 
on stable hemodialysis. 
Pharmacokinetic Endpoints: 
• 
EPN-701 plasma concentration at each measured 
time-point 
In addition, depending on the observed plasma levels, the 
following PK parameters may be determined: 
• 
Maximum plasma concentration (Cmax) [ng/mL] 
• 
Time to maximum plasma concentration (Tmax) [hr] 
• 
Area under the concentration-time curve (AUC) 
from time 0 to 24 hours (AUC0-24 [hr×ng/mL]). 
Biomarkers: 
• 
To determine, in subjects with 
ESRD on stable hemodialysis, 
the plasma levels of the following 
biomarkers after two weeks of 
EPN-701 treatment relative to 
baseline: osteoprotegerin, Fetuin 
A, high-sensitivity C-reactive 
protein (hs-CRP) and Time to 
Formation of Secondary 
Calciprotein Particles (T-50 Test); 
including CPP size. 
Exploratory Biomarker Endpoints: 
• 
Plasma levels of the following biomarkers on Day 
15 (end-of-treatment) and Day 22 compared to 
baseline: 
o 
Osteoprotegerin 
o 
Fetuin A 
o 
hs-CRP 
o 
T-50 Test 
Efficacy Objectives: 
Not applicable 
Not applicable 
 
8. 
STUDY DESIGN 
 
8.1 
DESCRIPTION OF THE STUDY 
 
This is a Phase 1, prospective, open label study to evaluate the safety, tolerability, and PK of 
EPN-701, administered once daily for 14 days in subjects with ESRD on a stable hemodialysis 
regimen. The study will be conducted at one or two dialysis centers in the United States. 
A total of 15 consenting subjects meeting the study eligibility criteria will be enrolled and treated 
with EPN-701 10 mg (one 10 mg capsule to be taken orally once a day, at the same time each 
morning, for 14 days). 
The expected duration of study participation for an individual subject is approximately five weeks, 
including up to one week for screening, two weeks of study treatment, and two weeks of post- 
treatment safety follow-up. Subjects will undergo a total of 14 visits during their study participation: 
Screening visit (within seven days prior to the first dose of study drug), three visits per week during 
the two-week treatment, and two-week safety follow-up periods (coinciding with the subject’s 
hemodialysis schedule), and the End-of-Study (EOS)/Early Termination visit. Baseline 


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assessments will be completed prior to the first study drug intake on Day 1. End-of-Treatment 
(EOT) assessments will be completed after the last dose of study drug on study Day 15 (or earlier 
in case of an early discontinuation of the study treatment). The EOS/Early Termination visit will 
occur two weeks after the last dose of study drug (on study Day 29). 
Subjects will be monitored for adverse events (AEs), and concomitant medications will be 
recorded throughout their study participation (from screening through the EOS Visit). Additional 
safety assessments will include: physical examinations, safety laboratory tests (hematology, 
including complete blood count [CBC]; complete metabolic panel [CMP, including electrolytes, 
renal and liver function tests, and lipid profile]; and coagulation panel), and 12-lead 
electrocardiogram (ECG). In addition, occurrence of dialyzer clotting will be assessed at each 
dialysis session, and Kt/V (a standard measure of dialysis adequacy) will be calculated at baseline 
(as the average of the last three pre-study Kt/V values obtained as part of the subject’s standard 
of care), and at EOT (Day 15). 
Blood for PK assessments will be sampled pre-dose (pre-dialysis) and post-dose (during and/or 
at the end of dialysis/before needle removal) on Days 1, 3, 5, 8, 10, 12, and 15, and pre-dose 
only on Day 17. 
Pre- and post-dialysis blood samples for biomarker analyses will be collected at Baseline, and on 
select Mondays during the two-week treatment, and two-week safety follow-up periods. 
Refer to Table 1, Schedule of Study Activities for further details. 
8.1.1 
Schedule of Assessments 
 
A complete schedule of assessments is provided in Table 1. A list of assessments to be 
completed at each study visit is provided in Section 9.5. 
8.1.2 
Study Committees 
 
An SRC will review the safety data accumulated during the study at regular intervals. The SRC 
will be comprised of the Sponsor’s Medical Monitor, Independent Medical Monitor, and the 
Principal Investigator. Further details will be provided in the SRC Charter. 
 
 
8.2 
END OF STUDY AND LENGTH OF STUDY 
 
All subjects are expected to be enrolled within approximately three months. 
The end of the study is defined as the last subject last visit (LSLV), which is expected 
approximately six to seven months after the enrollment of the first subject (“first subject in” [FSI]). 
The actual length of the study will depend on the actual recruitment rate. 
In addition, the Sponsor may decide to terminate the study at any time (see Section 9.7.3). 


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9. 
MATERIALS AND METHODS 
 
9.1 
SUBJECTS 
 
A total of 15 eligible subjects with ESRD on a chronic stable dialysis regimen will be enrolled at 
one or two dialysis centers in the United States. 
9.1.1 
Inclusion Criteria 
 
Subjects must meet all inclusion criteria to be enrolled in the study: 
1. Male or female ≥18 years of age 
2. Diagnosed with ESRD and treated with stable maintenance hemodialysis at least three times 
a week for at least three months prior to the first dose of study drug. Subjects may have 
missed (less than or equal to) 4 hemodialysis sessions within three months prior to enrollment, 
provided that the Principal Investigator deems them suitable for study participation. 
3. Clinically stable medical condition, consistent with ESRD, as judged by the investigator based 
on the results of screening safety evaluations (physical examination, medical history, clinical 
laboratory tests, vital signs, and 12-lead ECG). 
4. Written informed consent 
5. Able and willing to comply with the requirements of the study protocol 
6. For females of child-bearing potential: 
o Negative serum pregnancy test; 
o Abstinence (refraining from heterosexual intercourse) or use of an acceptable 
contraception for at least 1 month prior to screening, and willingness to continue for at 
least 1 month after the last study drug administration. 
A woman is considered to be of childbearing potential if she is post-menarche, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus, or bilateral tubal ligation). 
Examples of acceptable contraceptive methods include: hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
9.1.2 
Exclusion Criteria 
 
Subjects meeting any of the following exclusion criteria will be excluded from the study: 
1. Chronic kidney disease not requiring hemodialysis 
2. Acute kidney injury treated with hemodialysis 
3. Diagnosis of confirmed calciphylaxis 
4. History of any solid organ transplant 
5. History of malignancy within 2 years of study enrollment, except for adequately treated 
carcinoma in situ of the cervix and non-melanoma skin carcinoma. 


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6. History of any major surgery (defined as a surgical procedure involving the cranium, chest, 
abdomen, or pelvic cavity, or other procedure performed under general anesthesia) within 1 
month prior to the first dose of study drug. Subjects with a recent (within <1 month) revision 
and/or placement of arteriovenous fistula (AVF) will be allowed to participate. 
7. History of a major cardiovascular event (such as cerebrovascular accident [CVA], transient 
ischemic attack [TIA], myocardial infarction, unstable angina) within 1 month prior to the first 
dose of study drug. 
8. Any co-existing disease or condition that may compromise the safety of study participants 
and/or the integrity of the study, including, but not limited to: 
o Class C or Class D Cirrhosis of the liver 
o Known intestinal malabsorption 
o Inability to take oral medication 
9. Life-expectancy <3 months 
10. Known history or positive serology for Human Immunodeficiency Virus (HIV), positive 
serologies of E antigen or with polymerase chain reaction (PCR) positive titers for hepatitis B 
virus (HBV). Subjects with positive serologies for hepatitis C but with negative PCR for active 
virus will be allowed. 
11. Severe infection requiring intravenous (IV) antibiotics within two weeks prior to the first dose 
of study drug. 
12. Warfarin taken within two weeks prior to the first dose of study drug. Subcutaneous heparin, 
enoxaparin and novel oral anticoagulants (NOAC; such as apixaban) are permitted. 
13. Treatment with an investigational drug within four weeks prior to the first dose of study drug. 
14. Pregnancy or lactation. 
15. Any other disease or condition which, in the judgment of the Investigator, would place a 
subject at undue risk by being enrolled in the trial, or cause inability to comply with the trial. 
 
9.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
 
9.2.1 
Randomization and Blinding 
 
Not applicable; this is a non-randomized, uncontrolled, open label study. 
9.2.2 
Treatment Assignment 
 
After written informed consent has been obtained, all screening procedures and assessments 
have been completed, and eligibility has been established for a subject, the subject will be 
assigned a unique identification number. 
 
9.3 
STUDY DRUG: EPN-701 
 
The term "study drug" or “test product” is used throughout this protocol to refer to EPN-701. 


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There is no comparator and no other medication use is mandated by the protocol. All concomitant 
medications will be recorded in the electronic Case Report Form (eCRF). 
9.3.1 
Description of the Study Drug 
 
EPN-701 is a new formulation containing highly purified MK-7, which belongs to a family of 
compounds called menaquinones, collectively more commonly-known as vitamin K2. 
The drug product is formulated as oral soft-gel capsules. Each capsule contains 10 mg of active 
ingredient. 
Further details are provided in the EPN-701 Investigator’s Brochure. 
9.3.2 
Study Drug Packaging, Storage, and Handling 
 
EPN-701 drug product will be supplied by the Sponsor in bottles with child-resistant caps and 
tamper-evident, induction-sealed liners. Study drug shipment to a study site will be conditional of 
the receipt of required approval documents in accordance with applicable regulatory and ethics 
requirements. Investigators will be provided with sufficient amounts of the study drug to carry out 
this protocol for the agreed number of subjects. 
The EPN-701 drug product will be packaged and labeled by Sherpa Clinical Packaging dba PCI 
Pharma Services (San Diego, CA). The recommended storage condition for the bottled finished 
product soft gels is15–30 °C (59-86 °F) (controlled room temperature). 
The Investigator has overall responsibility for ensuring that study drug is stored in a secure, 
limited-access location. Limited responsibility may be delegated to the research pharmacy or 
member of the study team, but this delegation must be documented. 
The study drug must be stored in accordance with labeled storage conditions. 
9.3.3 
Study Drug Labeling 
 
Each container of study drug will be clearly labeled with study-specific information meeting all 
applicable regulatory requirements. Clinical trial drug supply labels may bear the following 
information: 
• 
Statement indicating that the product is limited by federal law to investigational use 
• 
Name, number, or identifying mark of the study drug and quantity of drug in each unit 
• 
Manufacturing date or expiration date of the study drug or re-test date 
• 
Recommended storage conditions for the study drug 
• 
Study drug lot number 
• 
Protocol code or study identification 
• 
Name of the sponsor. 


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9.3.4 
Study Drug Dispensing 
 
The Investigator has overall responsibility for administering/dispensing the investigational product. 
Where permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the Investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The Investigator or his/her designee (as documented by the Investigator in the applicable study 
delegation of authority form) will administer the study drug only to subjects included in this study 
who have (1) signed the current study-specific informed consent form (ICF); (2) completed all 
screening assessments and requirements; and (3) met all eligibility criteria for initiation of study 
treatment. 
Each subject will be given sufficient study drug to carry for two weeks. The pharmacist/designee 
will enter the unique subject identifier and initials on the investigational product bottle/carton label 
as they are dispensed. At each visit during the treatment period, the study coordinator will verify 
that the subject is taking the study drug as specified in the protocol. 
9.3.5 
Study Drug Dosage, Administration, and Compliance 
 
EPN-701, the test product in this study, will be provided by the study sponsor at the following 
capsule dosage strength: 
• 
10 mg soft-gel capsule for oral administration. 
Each subject will take one 10 mg capsule of EPN-701 per day orally over 14 days. 
The study drug is to be taken at the same time each morning. On hemodialysis days (Days 1, 3, 
5, 8, 10, and 12), subjects will take their study drug dose pre-dialysis (immediately after needle 
placement and biomarker sampling, as applicable); on the remaining days during Weeks 1 and 2, 
subjects will take their study drug dose at home. 
Dose modifications of EPN-701 are not permitted during the study. 
Any incorrect administration or overdose of the study drug should be noted on the eCRF. Adverse 
events associated with an incorrect administration or overdose of the study drug should be 
recorded on the Adverse Event eCRF. 
Subject compliance with the study drug schedule must be assessed at the container/packaging 
level for unused investigational product that is contained within the original packaging, or at the 
individual count level for opened bottles. The pharmacist/designee will record details on the Study 
Drug Accountability Form. 
9.3.6 
Study Drug Accountability 
 
The Investigator or designee will acknowledge receipt of the study drug by documenting shipment 
content and condition. Any damaged shipments will be replaced and must be reported 
immediately to the Sponsor. Accurate records of all investigational product dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section. 


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Each time study drug is dispensed to a subject or returned, the date, time and amount taken will 
be documented on the appropriate Study Drug Accountability Form and on the study drug eCRF. 
The site staff will document the doses taken in clinic on the subject’s drug accountability source 
documentation. Doses taken at home (including date, time, and amount taken) will be 
documented by the subject on the Study Drug Home Intake Form. Subjects will be asked to return 
the completed Study Drug Home Intake Form to the clinic at each scheduled visit so that the study 
coordinator can document all study drug intakes in the subject’s source documents and enter on 
the e-CRF. The final Study Drug Home Intake Form will be collected from the subject after the 
last dose has been taken and will be placed in the subject’s study chart. The CRA will verify the 
study drug eCRF entries against the Study Drug Accountability Form and source documents to 
ensure consistency. 
No investigational product stock or returned inventory from this study may be removed from the 
site where originally shipped without prior knowledge and consent by the Sponsor. If such transfer 
is authorized by the Sponsor, all applicable local, state, and national laws must be adhered to for 
the transfer. 
The Sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
At the end of the study, or as instructed by the Sponsor, all unused stock, and empty/used 
investigational product packaging are to be sent to a designated contractor on behalf of the 
Sponsor. Investigational product being returned to the Sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the Sponsor (or designated Contract Research 
Organization [CRO]). For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken, and the labeled amount is to be 
documented in lieu of counting. All certificates of delivery/drug receipts should be signed by the 
site representative to confirm contents of shipment. Shipment return forms, when used, must be 
signed prior to shipment from the site. Returned investigational product must be packed in a 
tamper-evident manner to ensure product integrity. The Sponsor must authorize the return of any 
investigational product prior to shipment. Shipment of all returned investigational product must 
comply with local, state, and national laws. 
All study drugs received at, dispensed from, returned to, and disposed of by the study site should 
be recorded on the Study Drug Accountability Form. 
9.3.7 
Post-Trial Access to EPN-701 
 
Not applicable. 
 
9.4 
CONCOMITANT THERAPY 
 
Concomitant therapy consists of any medication (e.g., prescription and over-the-counter drugs, 
vaccines, and nutritional supplements) used by a subject in addition to the study drug from the 
screening to the EOS/Early Termination visit. All such medications should be recorded on the 
Concomitant Medications eCRF. 


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9.4.1 
Prohibited Therapy 
 
Patients receiving long-term warfarin (Coumadin) frequently develop asymptomatic excessive 
prolongation of their international normalized ratio (INR) results. The anticoagulant effect of 
warfarin, functioning by its interference with the clotting effect of vitamin K, can be offset with as 
little as 1 mg of vitamin K (Crowther et al. 1998). Therefore, use of vitamin K is contraindicated in 
individuals on warfarin therapy (Vitamin K2 Monograph, 2009). 
Medications that are prohibited while the subject is receiving study drug are listed in Table 3. 
 
Table 3 
Washout Periods for Prohibited Medications 
 
Prohibited Medication 
Minimum Washout Period 
Prior to the First Dose of 
Study Drug 
Any investigational therapy 
4 weeks 
Warfarin* 
2 weeks 
IV antibiotics 
2 weeks 
Prescription and non-prescription medications known to be 
sensitive substrates of CYP3A** or CYP4F2*** 
None 
Herbal and homeopathic remedies 
None 
Abbreviations: IV=intravenous 
* Subcutaneous heparin, enoxaparin and novel oral anticoagulants (NOAC; such as apixaban) are 
permitted. 
** As listed in the FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (2017) 
*** Example: fingolimod 
 
 
The investigator should contact the Medical Monitor if questions arise regarding medications not 
listed above. 
9.4.1.1 
Herbal Therapies 
 
The use of herbal therapies will be prohibited during the study. 
9.4.2 
Prohibited Food 
 
No foods are prohibited during treatment with the study drug. 
 
9.5 
STUDY VISITS 
 
The schedule of assessments to be performed during the study is provided in Table 1. All activities 
must be performed and documented for each subject. 


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The expected duration of study participation for an individual subject is approximately five weeks, 
including up to one week for screening, two weeks of study treatment, and two weeks of post- 
treatment safety follow-up. 
Subjects will undergo a total of 14 visits during their study participation: Screening visit (within 
seven days prior to the first dose of study drug), three visits per week during the two-week 
treatment, and two-week safety follow-up periods (coinciding with the subject’s hemodialysis 
schedule), and the EOS/Early Termination visit. Baseline assessments will be completed prior to 
the first study drug intake on Day 1. The EOS/Early Termination visit will occur two weeks after 
the last dose of study drug (on study Day 29). 
Subjects will be closely monitored for safety and tolerability throughout the study. At each 
treatment visit, assessments should be completed prior to the study drug administration, unless 
otherwise stated. 
At each study visit, subjects will also undergo hemodialysis, as per their standard ESRD 
management; hemodialysis is therefore not listed as a study-related assessment in the following 
sections. 
9.5.1 
Screening Visit (Day -7 to Day -1) 
 
Subjects will undergo the following assessments during screening: 
• 
Obtaining informed consent and Health Insurance Portability and Accountability Act (HIPAA) 
authorization (see Section 9.6.1 for details) 
• 
Review of eligibility (inclusion and exclusion) criteria (see Sections 9.1.1 and 9.1.2 for details) 
• 
Recording of general medical history (including menstrual history for females of childbearing 
potential), disease history, and demographics (see Section 9.6.2 for details) 
• 
Recording of baseline and concomitant medications (see Section 9.6.3 for details) 
• 
Complete physical examination, measurement of height and weight (see Section 9.6.4 for 
details) 
• 
Standard 12-lead ECG within 60 minutes pre-dialysis (see Section 9.6.6 for details) 
• 
Measurement of vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature (pre-dialysis) (see Section 9.6.5 for details) 
• 
Testing for HIV, hepatitis B and C (see Section 9.6.8.1 for details) 
• 
Collection of blood samples for safety laboratory tests pre-dialysis (hematology, CMP, 
coagulation panel, and serum β-hCG pregnancy test (females of childbearing potential only) 
(see Section 9.6.8.1 for details). 


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9.5.2 
Visit 1 (Day 1, Baseline), Visit 4 (Day 8), Visit 7 (Day 15, End-of- 
Treatment), and Visit 10 (Day 22) [Mondays] 
 
Subjects will undergo the following assessments during these visits: 
• 
(At baseline/Visit 1 only:) Review of eligibility (inclusion and exclusion) criteria (see Sections 
9.1.1 and 9.1.2 for details) 
• 
Recording of any changes in concomitant medications (see Section 9.6.3 for details) 
• 
(At Visit 7 only, if clinically indicated:) Symptom-driven physical examination (see Section 
9.6.4 for details) 
• 
(At Visits 1, 4, and 7): Measurement of body weight within 60 minutes pre-dialysis and within 
60 minutes post-dialysis (see Section 9.6.4 for details) 
• 
(At Visit 7 only): Standard 12-lead ECG within 60 minutes pre-dialysis (see Section 9.6.6 for 
details) 
• 
(At Visits 1, 4, and 7): Measurement of vital signs (blood pressure, heart rate, respiratory rate, 
and oral body temperature within 30 minutes pre-dialysis and within 30 minutes post-dialysis 
(see Section 9.6.5 for details) 
• 
Collection of blood samples for safety laboratory tests pre-dialysis (hematology, CMP, 
coagulation panel) (see Section 9.6.8.1 for details) 
• 
(At Visits 1, 7, and 10): Collection of blood samples for biomarker assessments pre-dialysis 
(pre-dose) (see Section 9.6.8.2 for details): 
o MGP, osteocalcin, Protein C, PIVKA-II protein, Fetuin A, osteoprotegerin, hs-CRP, and 
Time to Formation of Secondary Calciprotein Particles (T-50 Test); including CPP size. 
• 
Collection of blood samples for PK assessments pre-dialysis/pre-dose (at the time of needle 
placement) (Visits 1, 4, and 7), during dialysis (Visits 1 and 4) and at the end of dialysis (before 
needle removal) (Visits 1, 4 and 7) (see Section 9.6.8.3 for details) 
• 
(At Visits 1 and 4 only): Study drug administration pre-dialysis (immediately after needle 
placement and the pre-dialysis biomarker sampling) (see Section 9.3.5 for details) 
• 
Recording of changes in baseline complaints under general medical history (events occurring 
before the first dose of study drug [Visit 1 only]; see Section 9.6.2 for details) or AEs (events 
occurring after the first dose of study drug [Visit 1 post-dose and subsequent visits]; see 
Section 10.3 for details). Any occurrence of dialyzer clotting (assessed at each dialysis 
session) is to be recorded as an AE (see Section 10.3.2). 
• 
Kt/V will be calculated at baseline as the average of the last three pre-study Kt/V values 
obtained as part of the subject’s standard of care. At Visit 7, Kt/V will be measured and 
compared with the baseline value. 
Assessments completed after the last dose of study drug on study Day 15/Visit 7 (or earlier in 
case of an early discontinuation of the study treatment) will be considered EOT assessments. 
At the end of Visit 1, subjects will receive a sufficient supply of the study drug for two weeks of 
treatment. 


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9.5.3 
Visits 2 & 3 (Days 3 & 5), Visits 5 & 6 (Days 10 & 12), Visits 8 & 9 
(Days 17 & 19), and Visits 11 & 12 (Days 24 & 26) [Wednesdays & 
Fridays] 
 
Subjects will undergo the following assessments during these visits: 
• 
Recording of any changes in concomitant medications (see Section 9.6.3 for details) 
• 
Recording of AEs (see Section 10.3 for details). Any occurrence of dialyzer clotting (assessed 
at each dialysis session) is to be recorded as an AE (see Section 10.3.2). 
• 
(At Visits 2, 3, 5, and 6): Measurement of body weight within 60 minutes pre-dialysis and 
within 60 minutes post-dialysis (see Section 9.6.4 for details) 
• 
(At Visits 2, 3, 5, and 6): Measurement of vital signs (blood pressure, heart rate, respiratory 
rate, and oral body temperature within 30 minutes pre-dialysis and within 30 minutes post- 
dialysis (see Section 9.6.5 for details) 
• 
(Visits 2, 3, 5, and 6 only:) Study drug administration pre-dialysis (immediately after needle 
placement) (see Section 9.3.5 for details) 
• 
Collection of blood samples for PK assessments pre-dialysis/pre-dose (at the time of needle 
placement) (Visits 2, 3, 5, 6, and 8), and at the end of dialysis (before needle removal) (Visits 
2, 3, 5, and 6) (see Section 9.6.8.3 for details). 
9.5.4 
End-of-Study/Early Termination Visit (Day 29) 
 
Subjects will undergo the following assessments during these visits: 
• 
Recording of any changes in concomitant medications (see Section 9.6.3 for details) 
• 
Recording of AEs (see Section 10.3 for details) 
• 
Complete physical examination (see Section 9.6.4 for details) 
• 
Standard 12-lead ECG within 60 minutes pre-dialysis (see Section 9.6.6 for details) 
• 
Measurement of body weight within 60 minutes pre-dialysis and within 60 minutes post- 
dialysis (see Section 9.6.4 for details) 
• 
Measurement of vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature within 30 minutes pre-dialysis and within 30 minutes post-dialysis (see Section 
9.6.5 for details) 
• 
Collection of blood samples pre-dialysis for safety laboratory tests (hematology, CMP, 
coagulation panel) (see Section 9.6.8.1 for details). 
 
9.6 
STUDY ASSESSMENTS 
 
9.6.1 
Informed Consent Forms and Subject Log 
 
Written informed consent for participation in the study must be obtained from all prospective 
subjects before performing any study-specific screening test or procedure. The investigator will 
maintain a log of all subjects who consented to participating in the study. 


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9.6.2 
Medical History and Demographic Data Collection 
 
Details of the underlying condition (including ESRD and dialysis history), as well as general 
medical history (including clinically significant diseases or conditions, surgeries, and reproductive 
status), will be recorded at screening/baseline. Baseline complaints (symptoms or adverse 
experiences present prior to the first dose of study drug) will also be recorded as medical history. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
9.6.3 
Baseline and Concomitant Medications 
 
All medications (including over-the-counter medications) or therapy administered to the subject 
during the 30 days prior to the first dose of study drug will be recorded at screening/baseline 
(including start date, medication name, dosage, frequency, and route of administration). Any 
contraindicated medications will be stopped or replaced by different medication and the subject 
will be required to observe the protocol-specified wash-out period (refer to Section 9.4.1 for 
details). 
Any changes to concomitant medications will be documented regularly throughout the study. 
9.6.4 
Physical Examinations and Measurements 
 
A complete physical examination (including a review of the main body organs and systems) must 
be conducted at screening and the EOS/Early Termination visit (Day 29). In addition, a symptom- 
driven (abbreviated) physical exam may be performed at the End-of-Treatment (EOT) visit (Day 
15), if the investigator deems it clinically indicated; see Table 1. 
Any treatment-emergent clinically significant physical examination findings should be recorded as 
adverse events on the Adverse Event CRF. 
Subjects will also undergo body weight and height measurement at screening/baseline, and body 
weight measurements (as part of their standard care on dialysis days) within 60 minutes pre- 
dialysis and within 60 minutes post-dialysis on each dialysis day during the 2-week treatment 
period (Visits 1 through 6), at the EOT visit (Day 15), and at the EOS visit (Day 29); see Table 1. 
9.6.5 
Vital Signs Measurements 
 
Vital signs (including blood pressure, heart rate, respiratory rate, and oral body temperature) will 
be measured at screening, and (as part of their standard care on dialysis days) within 30 minutes 
pre-dialysis and within 30 minutes post-dialysis at each treatment visit (Visits 1 through 6), at the 
EOT visit (Day 15), and at the EOS visit (Day 29); see Table 1. Any treatment-emergent clinically 
significant vital signs abnormalities should be recorded as adverse events on the Adverse Event 
CRF. 
9.6.6 
Electrocardiograms 
 
Standard 12-lead ECG recordings will be obtained within 60 minutes pre-dialysis at 
screening/baseline, at the EOT visit (Day 15), and at the EOS visit (Day 29); see Table 1. ECG 


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recordings must be performed after the subject has been resting in a supine position for at least 
5 minutes, and prior to other procedures scheduled at that same time (e.g., blood draws). 
The Principal Investigator must review, interpret sign, and date all ECG tracings. ECG 
abnormalities must be documented on the CRF and assessed for clinical significance. All 
treatment-emergent clinically significant ECG abnormalities must be reported as AEs. 
Paper copies of ECG tracings will be kept as part of the subject's file at the site. 
9.6.7 
Assessment of Dialysis Adequacy (Kt/V) 
 
Kt/V is a standard measure of dialysis adequacy, where K stands for the dialyzer urea clearance, 
t stands for the duration of the dialysis session, and V stands for the volume of urea distribution 
(roughly corresponding to the volume of water contained in the patient's body). 
As part of the safety evaluations, Kt/V will be measured at EOT (Day 15), and compared to the 
baseline value, which will be calculated as the average of the last three pre-study Kt/V values 
obtained as part of the subject’s standard of care. In case the Kt/V value obtained at EOT is 
reduced compared to baseline (pre-study measurements), the Investigator will determine (in 
consultation with the Medical Monitor, as needed) if the event qualifies for reporting as an AE. 
9.6.8 
Laboratory, Biomarker, and PK Samples 
 
The assessments listed in this section will be performed at Covance Central Laboratory Services 
(Covance). Instruction manuals and supply kits will be provided by Covance for all central 
laboratory assessments. 
An overview of the standard safety laboratory, biomarker, and PK sampling requirements is 
provided below. For additional details on laboratory assessments and sample handling, refer to 
the laboratory manual. 
9.6.8.1 
Safety Laboratory Assessments 
 
Samples for the following safety laboratory tests will be sent to the central laboratory for analysis: 
• 
Hematology panel: red blood cell (RBC) count, hemoglobin, hematocrit, and white blood cell 
(WBC) count, with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells), if clinically indicated. 
• 
Complete Metabolic Panel (CMP): 
o Glucose, albumin, total protein; 
o Electrolytes: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphate; 
o Renal function tests: blood urea nitrogen (BUN), creatinine; 
o Liver function tests: (ALT, AST, bilirubin), and 
o Lipid profile: total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density 
lipoprotein (HDL) cholesterol, and triglycerides (TG). 
• 
Coagulation panel includes: partial thromboplastin time (PTT), INR, and platelet count. 


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All blood sampling will occur pre-dialysis (at the time of needle placement). 
In addition, all subjects will undergo the following tests at screening only: 
• 
Serology for: 
o HIV 
o HBV: hepatitis B “e” antigen (HBeAg) and PCR for the active virus (HBV deoxyribonucleic 
acid [DNA]); and 
o HCV: HCV antibody and PCR for active virus (HCV ribonucleic acid [RNA]) 
• 
For women of child bearing potential only: serum beta-human chorionic gonadotropin (β-hCG) 
pregnancy test (the results of the screening pregnancy test must be negative for enrolment). 
The schedule for laboratory assessments is provided in Table 1. All baseline laboratory 
assessments may occur during screening (within 7 days prior to the first dose of the study drug). 
The total volume of blood drawn from each subject for safety laboratory assessment will be 
approximately 57 mL over the course of the study. Instructions for safety laboratory specimen 
collection, handling, and shipping will be included in the laboratory manual provided by the Central 
Laboratory (Covance). 
9.6.8.2 
Biomarker Assessments 
 
Blood samples will be obtained for biomarker evaluation according to the schedule in Table 1 and 
Table 4. Serially collected blood samples will be processed to obtain plasma for the determination 
of the following biomarkers: 
• 
Uncarboxylated MGP; uncarboxylated osteocalcin; Activated Protein C, PIVKA-II protein; 
Fetuin A, osteoprotegerin, hs-CRP, and Time to Formation of Secondary Calciprotein 
Particles (T-50 Test); including CPP size. 
Blood sampling for biomarker analysis will always occur pre-dialysis (at the time of needle 
placement): on Day 1 (Baseline), Day 15 (EOT), and Day 22 (1 week after the last study drug 
dose). 
The total volume of blood drawn from each subject for biomarkers assessment will be 
approximately 48 mL over the course of the study (approximately 16 mL per assessment time- 
point). Instructions for biomarker specimen collection, handling, and shipping will be included in 
the laboratory manual provided by the Central Laboratory (Covance). 


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Table 4 
Biomarker Assessments 
 
Sample 
Type 
Timing 
Biomarkers 
Blood 
Day 1, pre-dialysis* 
(Week 1, Baseline) 
Uncarboxylated MGP; unccarboxylated osteocalcin, 
Activated Protein C, PIVKA-II protein, Fetuin A, 
osteoprotegerin, hs-CRP, and Time to Formation of 
Secondary Calciprotein Particles (T-50 Test); including CPP 
size. 
Blood 
Day 15, pre-dialysis* 
(EOT) 
Uncarboxylated MGP; unccarboxylated osteocalcin, 
Activated Protein C, PIVKA-II protein, Fetuin A, 
osteoprotegerin, hs-CRP, and Time to Formation of 
Secondary Calciprotein Particles (T-50 Test); including CPP 
size. 
Blood 
Day 22, pre-dialysis* 
(1 week after the last 
study drug dose) 
Uncarboxylated MGP; unccarboxylated osteocalcin, 
Activated Protein C, PIVKA-II protein, Fetuin A, 
osteoprotegerin, hs-CRP, and Time to Formation of 
Secondary Calciprotein Particles (T-50 Test); including CPP 
size. 
CPP=calciprotein particles; EOT=end-of-treatment; hs-CRP= high-sensitivity C-Reactive Protein; 
MGP=matrix gamma-carboxyglutamic acid (Gla) protein; PIVKA-II=Protein Induced in Vitamin K 
Absence/Antagonist-II; T-50=Time to Formation of Secondary Calciprotein Particles. 
* Pre-dialysis=at the time of needle placement 
 
9.6.8.3 
Pharmacokinetic Assessments 
 
Blood for PK assessments will be sampled as follows: 
• 
On Visit 1/Day 1 (baseline) and Visit 4/Day 8 (Week 2, on-treatment): pre-dialysis (at the time 
of needle placement; denoted as 0 hours), followed by study drug administration, and then at 
1 hour (+/- 5 minutes), 2 hours (+/- 5 minutes), 3 hours (+/- 5 minutes), 4 hours (+/- 30 
minutes)/before needle removal, 6 hours (+/- 30 minutes), 8 hours (+/- 30 minutes), and 24 
hours (+/- 60 minutes) after study drug administration; 
• 
On Visit 2/Day 3, Visit 3/Day 5, Visit 5/Day 10, Visit 6/Day 12, and Visit 7/Day 15: pre-dialysis 
(at the time of needle placement, at 0 hours), immediately followed by study drug 
administration, and then at 4 hours (+/- 30 minutes)/ before needle removal; and 
• 
On Visit 8/Day 17 (Week 3, off-treatment): pre-dialysis only (at the time of needle placement). 
The timing and sequence of PK blood sample collections relative to the study drug administrations 
and dialysis will be as follows: 
• 
PK samples taken pre-dialysis (pre-dose; at 0 hour): Samples will be collected after needle 
placement and will be immediately followed by the study drug administration. Immediately 
following drug administration, dialysis is to be started. 
• 
PK samples taken during dialysis (post-dose): Samples will be collected at 1 hour (+/- 5 
minutes), 2 hours (+/- 5 minutes) and 3 hours (+/- 5 minutes) after the 0-hour PK time-point. 


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Dialysis 
Needle 
Removal 
Post-Dialysis 
Study 
Drug 
Needle 
Placement 
• 
PK samples taken post-dialysis (post-dose): Samples will be collected when the dialysis is 
completed (before needle removal) or at 4 hours (+/- 30 minutes) after the 0-hour PK time- 
point, whichever occurs first. 
• 
Note: The duration of dialysis sessions is expected to be approximately 4 hours; however, the 
actual duration should not have an impact on the PK sample collection time-points. 
The calendar date and actual clock time will be recorded for each PK blood sample collection and 
the actual elapsed time from dosing will be used for the PK calculations. 
Refer to Figure 5 for further details. 
 
Figure 5 – Sequence of PK Sampling, Visits 1 – 8 
 
 
0-hr PK 
1-hr PK 
2-hr PK 
3-hr PK 
4-hr PK 
6-hr PK 
8-hr PK 
24-hr PK 
Sample 
Sample 
Sample 
Sample 
Sample 
Sample 
Sample 
Sample 
Visits 
Visits 
Visits 
Visits 
Visits 
Visits 
Visits 
Visits 
1 - 8 
1 & 4 
1 & 4 
1 & 4 
1 - 7 
1 & 4 
1 & 4 
1 & 4 
 
 
Plasma samples will be assayed for EPN-701 concentrations (ng/mL) according to standard 
procedures, using a validated high-performance liquid chromatography (HPLC) tandem mass 
spectrometric (LC/MS/MS) method. 
Apart from the plasma concentrations at each time-point, depending on the observed levels, the 
following PK parameters may also be determined: 
• 
Maximum plasma concentration (Cmax) [ng/mL] 
• 
Time to maximum plasma concentration (Tmax) [hr] 
• 
Area under the concentration-time curve (AUC) from time 0 to 24 hours (AUC0-24 [hr×ng/mL]). 
The total volume of blood drawn from each subject for PK assessment will be approximately 108 
mL over the course of the study (approximately 4 mL per assessment time-point). Instructions for 
PK specimen collection, handling, and shipping will be included in the laboratory manual provided 
by the Central Laboratory (Covance). 
9.6.9 
Efficacy Evaluations 
 
Not applicable. 


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9.7 
TREATMENT, SUBJECT, SITE, AND STUDY DISCONTINUATION 
 
9.7.1 
Study Drug Discontinuation 
 
Premature discontinuation of the study drug by the Investigator should be discussed whenever 
possible with the Medical Monitor before the subject stops taking the study drug. 
Potential reasons for permanent discontinuation of the study drug are detailed in Section 9.7.2.1. 
The primary reason for study drug discontinuation should be documented on the appropriate 
eCRF along with the date of stopping the study drug, and the total amount of the study drug taken. 
If the study drug is discontinued, regardless of the reason, the end-of-treatment evaluations are 
to be performed as completely as possible. 
9.7.2 
Withdrawal of Subjects from the Study 
 
A subject may voluntarily withdraw from the study at any time for any reason without prejudice to 
their future medical care by the physician or at the institution. In addition, the Investigator or 
Sponsor may withdraw the subject at any time (e.g., in the interest of subject safety). 
To the extent feasible, all withdrawn subjects should undergo the protocol-specified post- 
treatment follow-up. However, subjects will not be followed for any reason after consent has been 
withdrawn. 
The reason for withdrawal from the study must be determined by the Investigator and recorded in 
the subject’s medical record and on the eCRF. If a subject is withdrawn for more than one reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the eCRF. If an AE is (one of) the reason(s) for discontinuation, then 
“Adverse event” must be recorded as the reason for discontinuation on the eCRF. Any comments 
(spontaneous or elicited) pertinent to the withdrawal or complaints made by the subject must be 
recorded in the source documents. 
9.7.2.1 
Reasons for Study Drug Discontinuation and Withdrawal 
 
Reasons for discontinuation from the study drug and for withdrawal from the study include but are 
not limited to: 
• 
Adverse event 
• 
Any medical condition that may jeopardize the subject’s safety 
• 
Significant worsening in the subject’s underlying condition 
• 
Withdrawal of consent by the subject 
• 
Protocol violation (such as subject non-compliance with the study drug or study procedures, 
use of prohibited medication) 
• 
Subject lost to follow-up 
• 
Pregnancy. 


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For any subject lost to follow-up, at least three documented attempts must be made to contact 
the subject prior to the last protocol-mandated study visit. One of these documented attempts 
must include a written communication sent to the subject’s last known address via courier or mail 
with an acknowledgement of receipt request. 
9.7.2.2 
Replacement of Subjects 
 
Subjects prematurely discontinuing study drug or withdrawing from the study (while on treatment 
or during the 2-week post-treatment safety follow-up) may be replaced if the following criteria are 
met: 
• 
If a subject discontinues study drug or withdraws from the study for any reason on or before 
Day 22. 
• 
If a subject misses a visit(s) due to non-compliance, SAE and/or hospitalization at a critical 
PK and/or biomarker timepoint(s) as it relates to the study endpoint. 
A decision to replace subject(s) will be determined by the Sponsor and communicated to the 
Principal Investigator/Site with rationale and further instruction, as applicable. 
9.7.3 
Study Discontinuation 
 
The Sponsor has the right to terminate this study at any time. The Sponsor will notify the 
investigator(s) in case a decision is made to discontinue the study. 
9.7.4 
Site Discontinuation 
 
The Sponsor has the right to close a site at any time. Reasons for closing a site may include, but 
are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonization (ICH) guideline for Good 
Clinical Practice 
• 
Study activities completed (i.e., all subjects have completed the study and all obligations have 
been fulfilled.). 
 
10. 
ASSESSMENT OF SAFETY 
 
10.1 
DEFINITIONS 
 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 


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medicinal (investigational) product, whether related to the medicinal (investigational) product or 
not (ICH Guidance E2A 1994). 
Treatment-emergent AEs are defined as any AE with an onset between the first dose of the 
study drug and the last study visit, or any AE with an onset prior to first dose that increases in 
severity or frequency after the first dose of study drug. 
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose: 
• 
Results in death 
• 
Is life-threatening [1] 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization [2] 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital abnormality/birth defect 
• 
Is an important medical event [3] 
[1] The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it was more severe. 
[2] Hospitalizations which are the result of elective or previously scheduled surgery for pre-existing 
conditions, where such conditions have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia repair would 
not be classified as an SAE. However, complication(s) resulting from a hospitalization for an elective 
or previously scheduled surgery that meets serious criteria must be reported as SAE(s). 
[3] 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 1 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. 
Note: 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe; see Section 10.3.3.1); the event itself 
may be of relatively minor medical significance (such as severe headache without any further 
findings). Severity and seriousness need to be independently assessed for each adverse 
event recorded on the eCRF. 
Adverse events of special interest (AESI): An adverse event of special interest (serious or non- 
serious) is one of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the trial sponsor to 
other parties (e.g., regulators) might also be warranted. 


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The following events will be considered AESIs in this study: 
• 
Treatment-emergent ALT or AST >3 x upper limit of normal (ULN) in combination with (1) total 
bilirubin >2 x ULN and/or (2) clinical jaundice. 
Clinically significant laboratory, ECG, or vital signs abnormalities: A laboratory test or ECG 
abnormality is deemed clinically significant if it meets one or more of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., study drug interruption or discontinuation, or 
dosage modification) 
• 
Results in a medical intervention (e.g. treatment) or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment. 
Study Drug Misuse is defined as intentional use of the investigational product other than as 
directed or indicated at any dose (Note: this includes a situation where the investigational product 
is not used as directed at the dose prescribed by the protocol). 
Overdose is an intentional or unintentional intake of a dose of the investigational product 
exceeding the pre-specified total daily dose of the product. 
Medication Error is an error made in prescribing, dispensing, administration, and/or use of an 
investigational product. 
 
10.2 
OVERALL SAFETY PLAN 
 
The safety plan for this study is based on clinical experience with MK-7 in published clinical 
studies. The anticipated safety risks for EPN-701 are outlined in Section 6.3.4. Please refer to the 
EPN-701 Investigator's Brochure for a complete summary of clinical safety information. 
Several measures will be taken to ensure the safety of subjects participating in this study. These 
include the pre-specified eligibility criteria (see Section 9.1.1 and Section 9.1.2), designed to 
exclude subjects at higher risk for adverse events, close safety monitoring of subjects during the 
study (see Section 9.5), including assessment of the nature, frequency, and severity of adverse 
events (see Section 10.3). 
General safety assessments will consist of monitoring and recording adverse events, including 
SAEs, AESIs, and AEs leading to study drug discontinuation (with or without withdrawal from the 
study), performing protocol specified physical examinations, ECGs and safety laboratory 
assessments (including hematology, CMP, and coagulation panel), and measuring vital signs; 
see Table 1 for the list and timing of study assessments. During on-treatment study visits, 
applicable clinical and laboratory assessments will be completed and reviewed prior to study drug 
administration. Adverse events (regardless of relationship to study drug) will be recorded in the 
AE CRF for 14 days after the last dose of EPN-701 (until the EOS Visit/Day 29), and will be graded 
by severity, and assessed for causality. Serious adverse events (SAEs), AESIs and pregnancies 
occurring during or within 30 days after the last dose of EPN-701 will be reported in an expedited 


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fashion, as described in Section 10.4. Any case of study drug error, misuse, or overdose will also 
be reported in an expedited fashion (see Section 10.4). 
A SRC will review the safety data accumulated during the study at regular intervals. The SRC will 
be comprised of the Sponsor’s Medical Monitor, Independent Medical Monitor, and the Principal 
Investigator; refer to Section 10.6. 
10.2.1 
Dose Modifications and Interruptions due to Adverse Events 
 
Dose reduction of EPN-701 is not permitted in this study. 
There are currently no known adverse events that would require interruption or discontinuation of 
EPN-701 treatment. However, unanticipated adverse events or other safety findings during the 
trial may warrant interruption or discontinuation of study drug. The acceptable length of 
interruption will depend on agreement between the investigator and the Medical Monitor. 
 
10.3 
RECORDING AND ASSESSMENT OF ADVERSE EVENTS 
 
The investigator is responsible for ensuring that all adverse events are recorded on the Adverse 
Event eCRF and reported to the Sponsor in accordance with instructions provided in this section 
and in Section 10.4 (immediate reporting). 
For each adverse event, the investigator will make an assessment of seriousness (see Section 
10.1 for seriousness criteria), severity (see Section 10.3.3.1), and causality (see Section 10.3.3.2) 
on the Adverse Event eCRF. 
10.3.1 
Adverse Event Recording and Reporting Period 
 
All AEs with an onset between the time the informed consent is signed and 14 days after the last 
dose of study drug (EOS/Early Termination Visit) are to be recorded on the appropriate Adverse 
Event CRF pages and in source documents. 
Serious adverse events (SAEs), AESIs and pregnancies occurring during or within 30 days after 
the last dose of EPN-701 will also be reported in an expedited fashion, as described in Section 
10.4. SAEs and AESI considered to be related to the study drug by the investigator, will be 
reported to the Sponsor even if they occurred after the protocol-specified reporting period (i.e., 
more than 30 days after the last dose of EPN-701). Follow-up of SAEs and AESIs will continue 
until resolution or until they reach a chronic/stable condition. In the unlikely event of a pregnancy 
reported during the study, the event should be followed until pregnancy outcome, i.e. birth or 
termination. 
10.3.2 
Adverse Event Recording Guidelines 
 
Investigators should use correct medical terminology/concepts when recording adverse events 
on the Adverse Event eCRF. Colloquialisms and abbreviations should be avoided. 
Only one adverse event term should be recorded in the event field on the Adverse Event eCRF. 


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The following guidelines should be observed when recording AEs: 
• 
Preexisting medical conditions (present at the screening visit): should be recorded on the 
Medical History eCRF. A preexisting medical condition should be recorded as an AE only if 
the frequency or severity worsens during the study. 
• 
Symptoms of the Disease Under Study: should not be recorded as AEs, as long as they are 
within the normal day-to-day fluctuation or expected progression of the disease. However, 
significant worsening of the symptoms should be recorded as an AE. 
• 
Diagnosis vs Symptoms: Where possible, a diagnosis, rather than a list of symptoms, should 
be recorded. If a diagnosis has not been made, then each symptom should be listed 
individually. In addition to untoward AEs, unexpected benefits outside the investigational 
product indication should also be captured on the AE eCRF. 
• 
Secondary AEs: In general, adverse events that are secondary to other events (e.g., clinical 
sequelae or cascade events) should be identified by their primary cause, except for severe or 
serious secondary events. If it is unclear as to whether the events are associated, each AE 
should be recorded separately on the Adverse Event eCRF. 
• 
Persistent AEs (events that extends continuously between study visits): should only be 
recorded once, with the highest overserved/reported severity on the Adverse Event eCRF. 
• 
Recurring AEs (events that resolves between study visits and subsequently recur): each 
recurrence should be recorded as a separate event on the Adverse Event eCRF. 
• 
Abnormal laboratory values: All clinically significant laboratory test results must be reported 
as AEs. If a clinically significant laboratory abnormality is a sign of a disease or syndrome, 
only the diagnosis should be recorded on the Adverse Event eCRF. 
• 
Abnormal ECG results: All treatment-emergent clinically significant ECG abnormalities must 
be reported as AEs. 
• 
Adverse events associated with an incorrect administration (medication error or misuse) or 
overdose of the study drug should be recorded on the Adverse Event eCRF. Any incorrect 
administration of study drug or study drug overdose should be noted on the Study Drug 
Administration CRF and reported as a protocol deviation. 
• 
Any occurrence of dialyzer clotting (assessed at each dialysis session) is to be recorded as 
an AE, using the term “clotting of extracorporeal circuit" or equivalent. 
10.3.3 
Assessment of Adverse Events 
 
10.3.3.1 
Assessment of Severity 
 
The medical assessment of AE severity is determined by using the following definitions: 
• 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 


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• 
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject. 
• 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
The severity of AEs must be assessed during the course of the event. An event that continues, 
but changes in severity over a period of time should be captured once on the AE eCRF form, with 
the highest severity reported though its duration. Worsening of pre-treatment events after initiation 
of investigational product, must be recorded as new AEs (for example, if a subject experiences 
mild intermittent dyspepsia prior to dosing of the investigational product, but the dyspepsia 
becomes severe and more frequent after first dose of investigational product has been 
administered, a new AE of severe dyspepsia [with the appropriate date of onset] is recorded on 
the AE eCRF). 
10.3.3.2 
Assessment of Causality 
 
The causality assessment for each AE must be completed by the investigator. The investigator 
should use medical judgment, including knowledge of the subject, the circumstances surrounding 
the event, and evaluate any potential alternative causes when deciding whether there is a 
reasonable possibility that the event may have been caused by the investigational product. If there 
is no valid reason for suggesting a relationship, the AE should be classified as ‘not related’. 
Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a possible 
cause-and-effect relationship between the investigational product and the occurrence of the AE, 
the AE should be assessed as ‘related’. The causality assessment must be documented in the 
source document and the CRF. 
 
Table 5 
Guidance for the Assessment of Adverse Event Causality 
 
Term 
Relationship 
Definition 
Definitively 
Related 
Yes 
A clinical event, including laboratory test abnormality that occurs in 
an apparent time sequence to the administration of the investigational 
product, is plausible pharmacologically, and cannot be explained by 
concurrent disease or other drugs or chemicals. Withdrawal of the 
drug (dechallenge) was followed by improvement or resolution of the 
event. Recurrence of symptoms on rechallenge (if performed) has 
occurred. 
Probably 
Related 
Yes 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to the administration of the investigational 
product, unlikely to be attributed to concurrent disease or other drugs 
or chemicals. Withdrawal of the drug (dechallenge) was followed by 
improvement or resolution of the event. Rechallenge information is 
not required to fulfil this definition. 


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Term 
Relationship 
Definition 
Possibly 
Related 
Yes 
A clinical event, including laboratory test abnormality, for which a time 
relationship with the administration of the investigational product may 
exist, but which could also be explained by concurrent disease or 
other drugs or chemicals. Information on drug withdrawal may be 
lacking or unclear. 
Unlikely 
Related 
No 
A clinical event, including laboratory test abnormality, with a doubtful 
temporal relationship to the administration of the investigational 
product, and in which other concomitant drugs, chemicals or the 
subject’s underlying disease provide plausible explanations for the 
event. 
Not Related 
No 
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event. 
The investigator’s assessment of the relationship between the AE and the underlying condition 
(including hemodialysis) will also be recorded. 
10.3.3.3 
Assessment and Documentation of Outcome 
 
During the study period, resolution of AEs (with dates) should be documented on the AE eCRF 
and in the subject’s medical record to facilitate source data verification. 
The outcome of AEs must be recorded during the study on the CRF by selecting one of the 
following options: 
• 
Recovered/Resolved 
• 
Recovered/Resolved with Sequelae 
• 
Ongoing, but reached chronic or stable condition at the last follow-up 
• 
Fatal 
• 
Unknown 
10.3.4 
Adverse Event Follow-up Period 
 
The investigator should follow each AE until the event has resolved to baseline or normal status, 
the event is assessed as stable by the investigator (no further improvement or worsening of the 
event is expected), the subject is lost to follow-up, or the subject withdraws consent. When 
appropriate, medical tests and examinations are performed so that resolution of event(s) can be 
documented. 
Every effort should be made to follow all SAEs until a final outcome can be determined. 
In the unlikely event of a pregnancy reported during the study, the event should be followed until 
pregnancy outcome, i.e. birth or termination. 


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10.4 
IMMEDIATE REPORTING REQUIREMENTS 
 
10.4.1 
Immediately Reportable Events 
 
The investigator must report the following events to the Sponsor immediately (i.e., within 24 hours 
of becoming aware of the event), regardless of their relationship to study drug: 
• 
SAEs 
• 
AESIs 
• 
Pregnancies 
• 
Medication errors, misuses, and overdoses. 
10.4.2 
Reporting Requirements for SAEs and AESIs 
 
10.4.2.1 
Serious Adverse Event Reporting Timeframe 
 
All SAEs and AESIs (regardless of their relationship to the study drug) occurring from the time 
the subject provided informed consent until 30 days after the last dose of study drug must be 
reported to the designated Pharmacovigilance Department within 24 hours of the first awareness 
of the event. Thereafter, any SAE(s) or AESI considered “related” to the study drug must be 
reported to the Pharmacovigilance Department within 24 hours of the first awareness of the event 
regardless of how much time has elapsed since the last dose of the study drug. 
Preferred method: The investigator should report these events either by scanning and emailing 
the completed Serious Adverse Event/Adverse Event of Special Interest Reporting Form to the 
following e-mail address: 
epizonsafety@medassessment.com 
Alternative method: The completed Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form may be faxed to the following designated fax number: 
1-949-369-9242 
Attention: Epizon Safety 
Reports should be accompanied by all relevant supplemental material. Receipt will be 
acknowledged in a timely manner via secure email. 
Electronic data capture (EDC) is the primary source for entering SAE data documented on source 
documents. However, a back-up SAE Form (and Guidelines) for SAE reporting should be used 
for reporting to the Safety group within the SAE Reporting Guidelines in the event EDC is down 
or not accessible. 
The investigator must also report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the information). New 
significant information may include any of the following: 
• 
Change in the event’s outcome (including resolution) 


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• 
Change in the diagnosis 
• 
Development of new signs or symptoms or significant worsening in the condition 
• 
Significant new test results 
• 
Change in causality based on new information 
• 
Other significant information on the clinical course of the event. 
Investigators must also comply with local requirements for reporting SAEs to the Institutional 
Review Board (IRB). 
The onset date of the SAE is the date that symptoms of the event began, and the resolution date 
is the date the symptoms resolve, or the event is considered to have reached a chronic/stable 
condition. 
Any SAE that results in the subject’s death must have fatal checked as an outcome with the date 
of death recorded as the resolution date. For all other events ongoing at time of death that did not 
contribute to the subject’s death, the outcome should be considered not resolved, without a 
resolution date recorded. 
10.4.3 
Reporting Requirements for Pregnancies 
 
All pregnancies detected from the time informed consent is signed until 30 days after the last dose 
of study drug are to be reported. 
Any report of pregnancy for any female study participant or the partner of a male study participant 
must be reported within 24 hours from learning about the event using the Pregnancy Report Form. 
If a pregnancy is detected during the study, the subject will be immediately withdrawn. 
Every effort should be made to gather information regarding the pregnancy outcome and condition 
of the infant. It is the responsibility of the Investigator to obtain this information within 30 calendar 
days after the initial notification and approximately 30 calendar days post-partum (or termination 
of the pregnancy). 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported to the Sponsor immediately (i.e., no more than 24 
hours after learning of the event) using the Clinical Trial Serious Adverse Event Form. An elective 
abortion is not considered an SAE. 
In addition, if the Investigator determines that the pregnancy meets seriousness criteria, it must 
be reported as an SAE. The test date of the first positive serum/urine HCG test or ultrasound 
result will determine the pregnancy onset date. 
 
10.5 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, AND INSTITUTIONAL REVIEW BOARDS 
 
The Sponsor will promptly evaluate all SAEs and AESIs against the existing cumulative 
knowledge about the investigational product to identify and expeditiously communicate possible 


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new safety findings to investigators, Institutional Review Boards (IRBs), and the US Food and 
Drug Administration (FDA), as per the applicable regulations and guidelines. 
Reporting requirements to the FDA and IRB(s) will be based on the investigator's assessment of 
causality and seriousness, and the Sponsor’s assessment of the expectedness of the event. 
Expectedness will be evaluated by comparing the severity of the event (and cumulative event 
frequency observed in the study, as applicable) with the severity and frequency reported in the 
applicable reference document (EPN-701 Investigator’s Brochure). 
 
10.6 
SAFETY REVIEWS BY THE STUDY SRC 
 
A SRC will review the safety data accumulated during the study at regular intervals. The SRC will 
be comprised of the Sponsor’s Medical Monitor, Independent Medical Monitor, and the Principal 
Investigator. Further details will be provided in the SRC Charter. 
 
11. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
 
11.1 
GENERAL CONSIDERATIONS AND ANALYSIS POPULATIONS 
 
This is a Phase 1, prospective, open label study to evaluate the safety, tolerability, and PK of 
EPN-701, administered once daily for 14 days in subjects with ESRD on a stable maintenance 
hemodialysis regimen. The primary objective of the study is to determine the safety and tolerability 
of EPN-701 (administered for two weeks at a daily dose of 10 mg). 
There are no efficacy assessments or endpoints in this study. The primary (safety) endpoint is 
the frequency of treatment-emergent AEs and treatment-emergent AEs assessed as related to 
the study drug. Pharmacokinetic parameters and biomarkers represent secondary and/or 
exploratory endpoints. 
The analysis populations are defined as follows: 
• 
Safety population: all enrolled subjects who received at least one dose of study drug. 
• 
PK population: all enrolled subjects who received at least one dose of study drug and have 
sufficient plasma concentrations data for PK analysis. 
All analyses will be descriptive. Binary and categorical data will be summarized by number and 
percentage of subjects. Continuous data will be summarized by means, standard deviations (SDs), 
medians, and ranges (minimum, maximum), as appropriate. 
All data will be included in appropriate per-subject listings. 
Planned analyses are presented in the following sections. 
11.2 
DETERMINATION OF SAMPLE SIZE 
 
No formal sample size calculation was performed. The selected sample size of 15 subjects is 
consistent with preliminary safety and PK studies of a similar design and is expected to provide 
sufficient information to identify safety issues, while limiting subject exposure. 


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11.3 
SUMMARIES OF SUBJECT DISPOSITION 
 
All enrolled subjects will be accounted for. The number of subjects who enroll, discontinue, or 
complete the study will be listed and summarized. All early treatment discontinuations and 
withdrawals from the study will be summarized by primary reason of discontinuation/withdrawal. 
Time in trial and treatment exposure will also be summarized. 
Protocol deviations and reasons for granting waivers (as applicable) will be categorized and 
provided in by-subject listings. 
 
11.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 
Demographic variables such as age, sex, race/ethnicity, and other relevant baseline 
characteristics will be summarized using means, SDs, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate. 
The baseline value of any variable will be defined as the last available value prior to the first 
administration of the study drug. 
 
11.5 
EFFICACY ANALYSES 
 
Not applicable. 
 
11.6 
SAFETY ANALYSES 
 
Safety analyses will include all enrolled subjects who received at least one dose of the study drug 
(EPN-701). 
Safety will be assessed through summaries of AEs, changes in safety laboratory test results, 
changes in vital signs, ECG parameters, and study drug exposures. 
The primary safety endpoint is the frequency of treatment-emergent AEs (defined as any AE 
with an onset between the first dose of the study drug and the last study visit, or any AE with an 
onset prior to first dose that increases in severity or frequency after the first dose of study drug) 
and treatment-emergent AEs assessed as related to the study drug. Adverse events include 
both clinical events and laboratory abnormalities that are assessed as clinically significant. 
Secondary safety endpoints include: 
• 
Frequency of SAEs, AEs leading to study drug discontinuation, and AESIs 
• 
Changes from baseline in safety laboratory parameters 
• 
Changes from baseline in vital signs measurements 
• 
Changes from baseline in ECG parameters. 
11.6.1 
Adverse Events 
 
All AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be included in per-subject listings. In addition, treatment-emergent AEs 


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(defined as any AE with an onset between the first dose of the study drug and the last study 
visit, or any AE with an onset prior to first dose that increases in severity or frequency after the 
first dose of study drug) will be summarized in frequency tables, by MedDRA System Organ 
Class (SOC) and by Preferred Term (PT), regardless of the investigator-determined relationship 
to study drug. For each subject, if there are multiple occurrences of the same AE, the maximum 
severity reported will be used in the summaries. 
Adverse events assessed as related to the study drug will be summarized in a similar manner. A 
summary of AEs by maximum severity grade will also be provided. 
The following treatment-emergent AEs will also be summarized: 
• 
Adverse events leading to permanent discontinuation of study drug (with or without 
withdrawal from the study) 
• 
Adverse events leading to dose interruption 
• 
Serious adverse events 
• 
AESIs 
• 
Deaths. 
11.6.2 
Concomitant Medications 
 
Concomitant Medications: All concomitant medications will be coded using the most current 
version of the World Health Organization (WHO) Drug Dictionary and will be included in per- 
subject listings. 
11.6.3 
Safety Laboratory Parameters 
 
Laboratory parameters will be summarized at each time point measured using descriptive 
statistics, including means, SDs, medians, and ranges, as appropriate. Change from baseline will 
be summarized similarly, with 95% confidence intervals (CIs) for each change. Shift tables may 
also be provided, if warranted by the data. All safety laboratory data will be included in appropriate 
per-subject listings, along with reference ranges, and indication of clinically significant departures 
from the respective reference ranges. 
Clinically significant laboratory abnormalities will be analyzed as part of the analysis of AEs. 
11.6.4 
ECG Changes and Abnormalities 
 
ECG parameters: will be included in appropriate per-subject listings. In addition, a tabulated 
summary of the following parameters will be provided: 
• 
number (%) of subjects with QT interval and QT interval corrected for heat rate using the 
Fridericia’s formula (QTcF) >500 msec 
• 
changes from baseline of >30 msec and of >60 msec in QT and QTcF values 
• 
number (%) of subjects with clinically significant ECG abnormalities. 
Clinically significant ECG abnormalities will be analyzed as part of the analysis of AEs. 


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11.7 
PHARMACOKINETIC ANALYSES 
 
The PK analyses will include all subjects who received at least one dose of study drug and have 
sufficient plasma concentrations data for PK analysis. 
EPN-701 plasma concentration will be measured at specific timepoints (see Table 1), tabulated 
and summarized by assessment time point. Descriptive statistics for plasma concentrations and 
PK parameters will include arithmetic means and SDs, geometric means and coefficients of 
variation, medians, and ranges, as appropriate. 
In addition, depending on the plasma concentrations observed at the pre-specified time-points, 
the following PK parameters may be summarized using the same descriptive statistics as for 
plasma concentrations: 
• 
Cmax [ng/mL] 
• 
Tmax [hr] 
• 
AUC0-24 [hr×ng/mL]. 
 
11.8 
BIOMARKER ANALYSES 
 
Pre-defined biomarker endpoints include: 
• 
Plasma levels of the following biomarkers on Day 15 (end-of-treatment) and Day 22 compared 
to baseline: 
o Uncarboxylated MGP 
o Uncarboxylated osteocalcin 
o Activated Protein C 
o PIVKA-II protein. 
Exploratory biomarker endpoints include: 
• 
Plasma levels of the following biomarkers on Day 15 (end-of-treatment) and Day 22 compared 
to baseline: osteoprotegerin, Fetuin A, hs-CRP, and Time to Formation of Secondary 
Calciprotein Particles (T-50 Test), including CPP size. 
Biomarkers will be summarized in a similar manner as described for safety laboratory parameters, 
with a descriptive summary provided for each assessment time-point along with changes from 
baseline. Depending of the distribution of the biomarkers, transformations to minimize skew and 
outliers may be performed. 
 
11.9 
SUBGROUP ANALYSES 
 
No subgroup analyses are planned. 
 
11.10 
INTERIM ANALYSIS 
 
No interim analyses are planned. 


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A SRC will review the safety data accumulated during the study at regular intervals, as described 
in Section 10.6. 
 
11.11 
HANDLING OF MISSING DATA 
 
To provide the best overview of this small study population, without introducing a possible 
unknown bias through imputation, all study data will be summarized as observed, with no 
imputation of missing values. 
 
12. 
DATA COLLECTION AND MANAGEMENT 
 
12.1 
CASE REPORT FORMS 
 
Subject data collected during the study will be recorded on eCRFs, which will be completed 
through use of a Sponsor-designated EDC system. Sites will undergo appropriate training and 
will receive a manual with instructions on adequate eCRF completion. 
All eCRFs should be completed by designated, trained site staff, and should be reviewed and 
electronically signed and dated by the investigator. eCRFs will be submitted electronically (via the 
EDC system) to the Sponsor (or designee). 
At the end of the study, the investigator will receive all subject data for his or her site in a readable 
format (e.g., on a compact disc) that must be kept with the study records. 
 
12.2 
DATA QUALITY ASSURANCE 
 
Principles of quality control will be applied to each stage of data handling to ensure that all data 
are reliable and have been entered and processed correctly. Only qualified personnel will be 
allowed to enter data into the clinical database, which will have documented requirements for 
completeness, accuracy (including verification of the data), reliability, and consistent intended 
performance. Any changes to the data will be captured in a readable audit trail. Documentation 
will be kept indicating the individual tasks and the personnel authorized to perform them. The data 
will be checked for completeness, accuracy, and logic; any missing, illegible or illogical data will 
be queried. Responses to data queries will be entered following the same process as for the 
original eCRF. The investigator must review and approve all eCRF entries and responses to data 
queries. 
Accurate and reliable data collection will also be assured by verification of the eCRF entries 
against the original source documentation, the drug dispensing log and study drug supplies by 
the study clinical research associate (CRA, also referred to as study monitor); refer to 
Section 12.3. 
 
12.3 
SITE MONITORING AND AUDITS 
 
The investigator will permit Sponsor representatives, CRAs (study monitors), health authorities; 
and the reviewing IRB to inspect facilities and records relevant to this study, including direct 


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access to source data and documents, study drug and related accountability records, and the 
study-specific Site Master File (SMF). 
Site visits will be conducted by the Sponsor or an authorized representative (CRA) at regular 
intervals throughout the study, for inspection of study data, subjects’ medical records, eCRFs, 
and study drug supplies. 
The Investigator must be available during the monitoring visits, as needed, and cooperate with 
the CRA to ensure that any problems detected during monitoring are promptly resolved. 
12.3.1 
Source Documentation 
 
Source documents include, but are not limited to: clinic charts, dialysis flowsheets, subject files, 
hospital records, laboratory notes, subject-reported events and outcomes, ECG printouts, 
evaluation checklists and schedules, pharmacy dispensing records, data recorded from 
automated instruments, X-rays, microfilm, and records kept at pharmacies and laboratories 
involved in a clinical trial. 
Source documents must not be obliterated or destroyed and must be retained for at least 15 years 
after completion or discontinuation of the study, or until at least 2 years after the last approval of 
a marketing application for the study drug, whichever is longer. 
12.3.2 
Source Data Verification 
 
Study monitors will perform ongoing source data verification to confirm that critical protocol data 
entered in the eCRFs by authorized site personnel are accurate, complete, and verifiable from 
source documents. To facilitate source data verification, the investigator must provide the 
Sponsor and its designees direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits (as applicable), and inspection by the applicable health 
authorities and IRB. 
 
12.4 
RETENTION OF RECORDS 
 
Records and documents pertaining to the conduct of this study (including eCRFs, ICFs, ECG, 
and laboratory test results, source documents, and study-specific SMF) and the distribution of 
study drug (such as study drug inventory and accountability records), must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the study, or until 
at least 2 years after the last approval of a marketing application for the study drug, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor. Written notification 
should be provided to the Sponsor prior to transferring any records to another party or moving 
them to another location. 


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13. 
ETHICAL CONSIDERATIONS 
 
13.1 
REGULATORY COMPLIANCE 
 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice, the principles of the Declaration of Helsinki, and with US FDA regulations and applicable 
local, state, and federal laws. The study will also comply with the requirements of the ICH E2A 
guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
 
13.2 
INFORMED CONSENT 
 
The study will be conducted in accordance with FDA Code of Federal Regulations (CFR) Title 21, 
Part 50, Subpart B-Informed Consent of Human Subjects and the applicable local IRB 
requirements. 
The investigator must obtain written informed consent from each prospective subject or they 
legally authorized representative after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study, and before any study-related procedures, 
assessments, treatments, or protocol-required changes in the subject’s ongoing management can 
be made. The clinical records for each subject should document the informed consent process 
and that written informed consent was obtained prior to participation in the study. 
The consent forms will be revised each time there are changes to study procedures or when new 
information becomes available that may affect the willingness of the subject to participate. The 
final revised IRB-approved consent form(s) must be provided to the Sponsor for health authority 
submission purposes. 
Subjects participating in the study must be re-consented to the most current version of the consent 
form, according to the applicable local law and IRB policy. A copy of each signed consent form 
must be provided to the subject or the subject’s legally authorized representative. All signed and 
dated consent forms must remain in each subject’s study file or in the site file and must be 
available for verification by study monitors at any time. 
Subject authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996 may be included 
in the consent form or a separate HIPAA Authorization Form may be utilized, as per the site 
policies. 
 
13.3 
INSTITUTIONAL REVIEW BOARD 
 
The study will adhere to CFR Title 21, Part 56 (Institutional Review Boards). 
This protocol, the consent form, and any accompanying material provided to the subject (such as 
subject information sheets or descriptions of the study used to obtain informed consent) as well 
as any advertising or compensation given to the subject, will be submitted by the investigator to 
the IRB, and must be reviewed and approved by the IRB before the study is initiated. The 


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investigator should obtain written documentation of the IRB approval, specifying the date on which 
the committee met and granted the approval. 
The investigator must also submit any protocol amendments for IRB approval in accordance with 
local procedures and regulatory requirements. Additional documents submitted to the IRB will 
include (as applicable): written IND safety reports or other safety-related communications from 
the Sponsor, and reports on major protocol deviations. Investigators are responsible for ensuring 
that such reports are reviewed and processed in accordance with FDA requirements and the 
policies and procedures established by their IRB and archived in the site’s study file. 
 
13.4 
SUBJECT CONFIDENTIALITY 
 
All information obtained during the conduct of the study that relates to an individual subject will 
be regarded and handled as confidential. Each subject will be assigned a unique subject 
identification (ID) number at enrollment. Throughout the study, participating subjects will be 
referred to using their study ID number, and initials. Subject names or other personal identifiers 
are not included in data sets or any other documents that are transmitted to the Sponsor or CRO 
designee. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives, and collaborators, 
and the reviewing IRB(s), as appropriate. 
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to subjects unless required by law. 
 
14. 
STUDY DOCUMENTATION 
 
14.1 
STUDY DOCUMENTATION 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented, including, but not limited to, the protocol, protocol amendments, ICFs, 
and documentation of IRB approval. In addition, at the end of the study, the investigator will 
receive the subject data, including an audit trail containing a complete record of all changes to 
data. 
 
14.2 
PROTOCOL AMENDMENTS 
 
Protocol amendments may only be prepared and issued by the Sponsor. All protocol amendments 
will be submitted to the FDA and the IRB in accordance with applicable regulatory and IRB 
requirements, and approval must be obtained before implementation of any changes, except (1) 
changes necessary to eliminate an immediate hazard to subjects or (2) administrative changes 
(e.g., change in contact information). 


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14.3 
PROTOCOL DEVIATIONS 
 
The investigator should document each protocol deviation, along with an explanation. The 
investigator should promptly report any deviations that might have an impact on subject safety 
and/or data integrity to the Sponsor and to the IRB in accordance with the IRB policies and 
procedures. 
The Sponsor will review each protocol deviation and assess whether any require reporting to the 
FDA (e.g. deviations representing a serious breach of Good Clinical Practice guidelines). 
Requests to waive protocol eligibility criteria, will not be approved in this study. After the subject 
is enrolled, any protocol exemption request must be approved by the Sponsor/Medical Monitor 
before it can be implemented. 
 
14.4 
PUBLICATION POLICY 
 
The Sponsor will comply with all requirements for publication of study results. 
The investigator must agree to submit any manuscript or abstract related to the study to the 
Sponsor prior to submission for publication or presentation. Authorship will be determined by 
mutual agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
Any inventions and resulting patents or improvements originating from the use of data from this 
study will become and remain the exclusive and unburdened property of the Sponsor. 


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16. 
APPENDIX 1 - DEFINITION AND CLASSIFICATION OF CHRONIC 
KIDNEY DISEASE (CKD) 
 
Chronic Kidney Disease 
Chronic Kidney Disease (CKD) is defined as abnormalities of kidney structure or function (defined 
as a glomerular filtration rate [GFR] <60 mL/min/1.73 m2), present for ≥3 months, with implications 
for health (KDIGO, 2012). Criteria for CKD include are detailed in the following table. 
Table A. Criteria for Chronic Kidney Disease (either of the following present for ≥3 
months) 
 
Source: The National Kidney Foundation (NKF) Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical 
Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, 2012 
Among patients with CKD, the stage of disease is determined based on the level of kidney function 
(with higher stages representing lower GFR levels), irrespective of diagnosis. The KDOQI 
classification of CKD is presented in Table A, and further elaborated in Table B. 
Table B. GFR Categories in Chronic Kidney Disease 
 
Source: The National Kidney Foundation (NKF) Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical 
Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, 2012 
Note: GFR categories G1 through G5 correspond to previous stratification into Stages 1 through 5. 
Source: NKF KDOQI Guidelines 
 
Kidney failure 
Kidney failure is defined as GFR <15 ml/min/1.73 m2 (GFR category G5). Kidney failure leads to 
the commonly recognized symptoms of uremia. The need for treatment of chronic kidney failure 
with dialysis and/or kidney transplantation arises in 1% of patients with CKD (KDIGO, 2012). 


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End-stage renal disease 
End-stage renal disease (ESRD) includes patients treated by dialysis or transplantation, 
irrespective of the level of GFR (KDOQI, 2002). 
Note: The current KDIGO guidelines on CKD (KDIGO, 2012) do not include a definition of ESRD.