Clinical trial NCT04510090
Conditions: Pruritus Cholestasis Kidney Failure
Sponsor: Escient Pharmaceuticals, Inc
Start date: 2020-09-07; Completion date: 2021-07-08
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This first in human, Phase 1/1b trial will evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of EP547 in healthy subjects and subjects with cholestatic or uremic pruritus.

Detailed description:
This study consists of both single and multiple ascending doses in healthy subjects and in subjects with cholestatic or uremic pruritus.

Up to 48 healthy subjects will receive a single dose of EP547 or placebo. There will be a screening period of up to 28 days prior to the first dose, and a follow up visit 7 days after dosing is completed.

24 healthy subjects will receive multiple doses of EP547 or placebo for 7 days. There will be a screening period of up to 28 days prior to the first dose, and a follow up visit 7 days and then 14 days after dosing is completed.

6 subjects with cholestatic disease will receive a single dose of EP547. There will be a screening period of up to 28 days prior to the first dose, and a follow up visit 7 days after dosing is completed.

Up to 16 subjects with cholestatic pruritus will receive multiple doses of EP547 or placebo for 7 days. There will be a screening period of up to 28 days prior to the first dose, and a follow up visit 7 days and then 14 days after dosing is completed.

6 subjects with uremic disease will receive a single dose of EP547. There will be a screening period of up to 28 days prior to the first dose, and a follow up visit 7 days after dosing is completed.

Up to 16 subjects with uremic pruritus will receive multiple doses of EP547 or placebo for 7 days. There will be a screening period of up to 28 days prior to the first dose, and a follow up visit 7 days and then 14 days after dosing is completed.

12 healthy subjects will receive two doses of EP547 under fasted or fed condition.

Arms: arm 1: Single doses of EP547 arm 2: Multiple doses of EP547 arm 3: Single doses of placebo arm 4: Multiple doses of placebo
Interventions: intervention 1: EP547 intervention 2: Placebo
Intervention descriptions: intervention 1: EP547 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 




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Investigator’s Agreement 
I have read the protocol for EP-547-101 and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
Date 








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SAD-HS will be 25 mg, which is 23-fold lower than the human equivalent dose (HED) of the no- 
observed-adverse-effect level (NOAEL) in monkeys, the most sensitive and relevant species. 
Following confirmation by the Safety Review Team that escalation should proceed, each subsequent 
dose level tested in SAD-HS will be increased by no more than 3-fold from the preceding dose level. 
Dose levels to be tested will not exceed 1,100 mg. 
All dose levels in SAD-HS will be dosed according to a sentinel dosing design to ensure optimal 
safety. This means that initially, 2 subjects in each dose level will be allocated to receive EP547 or 
placebo. If the safety and tolerability results of the first 24 hours following dosing for the initial 
subjects are acceptable to the Safety Review Team, the other 6 subjects will be randomized in a 
5:1 ratio (EP547:placebo) to receive EP547 or placebo. 
The following treatments for SAD-HS are planned to be administered. However, fewer dose levels 
may be evaluated if the data from those groups can fully meet the objectives of the study. 
Group 1: single PO dose of 25 mg EP547 (n = 6) or matching placebo (n = 2) 
Group 2: single PO dose of EP547 that is no more than 3-fold greater than the dose in Group 1 (n = 6) 
or matching placebo (n = 2) 
Group 3: single PO dose of EP547 that is no more than 3-fold greater than the dose in Group 2 (n = 6) 
or matching placebo (n = 2) 
Group 4: single PO dose of EP547 that is no more than 3-fold greater than the dose in Group 3 (n = 6) 
or matching placebo (n = 2) 
Group 5: single PO dose of EP547 that is no more than 3-fold greater than the dose in Group 4 
 
 (n = 6) or matching placebo (n = 2) 
If an additional dose level requires evaluation after conducting Group 5, Group 6 may be enrolled to 
evaluate a single PO dose of EP547 that is no more than 3-fold higher than the highest dose evaluated 
in the previous dose levels and less than or equal to 1,100 mg (n = 6) or matching placebo (n = 2). 
MAD-HS can begin after 3 dose levels of SAD-HS have been fully evaluated by the Safety Review 
Team. Subjects who participated in SAD-HS may not participate in MAD-HS. All dose levels in 
MAD-HS must fall within the range of doses tested in SAD-HS that were confirmed to be well 
tolerated. 
The initial dose level for MAD-HS will be no higher than the second dose tested in SAD-HS with 
predicted PK concentrations no higher than those observed in SAD-HS. Following confirmation by the 
Safety Review Team that escalation should proceed, each subsequent dose level tested in MAD-HS 
will be increased by no more than 3-fold from the preceding dose level. MAD-HS is anticipated to 
consist of 3 dose levels. Each level will include 8 subjects who will be randomized to receive EP547 or 
placebo as a daily PO dose over 7 days in a 3:1 ratio (EP547:placebo); there will be no sentinel dosing. 
The following treatments for MAD-HS are planned to be administered. However, fewer dose levels 
may be evaluated if the data from those groups can fully meet the objectives of the study. 
Group 1: daily PO dose of EP547 that is no higher than the second dose tested in SAD-HS with 
predicted PK concentrations no higher than those observed in SAD-HS (n = 6) or matching 
placebo (n = 2) over 7 days 
Group 2: daily PO dose of EP547 that is no more than 3-fold greater than the dose in Group 1 (n = 6) 
or matching placebo (n = 2) over 7 days 


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Group 3: daily PO dose of EP547 that is no more than 3-fold greater than the dose in Group 2 (n = 6) 
or matching placebo (n = 2) over 7 days 
Subjects with Cholestatic Pruritus 
SD-CP may be conducted when the results from all dose levels of SAD-HS have been fully evaluated 
by the Safety Review Team. SD-CP is not placebo-controlled (ie, all subjects will receive EP547) and 
will be conducted in an unblinded manner. The dose level for SD-CP will be no higher than the third 
dose tested in SAD-HS. SD-CP will consist of 1 dose level. The dose level will include 6 subjects who 
will receive EP547 as a single PO dose. 
MAD-CP can begin when the results from SD-CP have been fully evaluated by the Safety Review 
Team. Based on data obtained from SD-CP, the EP547 dose to be evaluated in MAD-CP must have 
predicted steady-state PK concentrations lower than that of the highest tolerated dose in MAD-HS. 
MAD-CP is anticipated to consist of 1 dose level. If an additional dose level requires evaluation after 
conducting the first dose level, a second dose level may be enrolled to evaluate a daily PO dose of 
EP547 that is no more than 3-fold greater than the dose in the previous group. Each dose level will 
include a minimum of 8 subjects who will be randomized to receive EP547 or placebo as a daily PO 
dose over 7 days in a 3:1 ratio (EP547:placebo); there will be no sentinel dosing. If additional subjects 
are available to participate in any MAD-CP dose level, up to 4 more subjects (for a total of 12) may be 
enrolled. 
Subjects with Uremic Pruritus 
SD-UP may be conducted when the results from all dose levels of SAD-HS have been fully evaluated 
by the Safety Review Team. SD-UP is not placebo-controlled (ie, all subjects will receive EP547) and 
will be conducted in an unblinded manner. The dose level for SD-UP will be no higher than the third 
dose tested in SAD-HS. SD-UP will consist of 1 dose level. The dose level will include 6 subjects who 
will receive EP547 as a single PO dose the day after a hemodialysis session. 
MAD-UP can begin when the results from SD-UP have been fully evaluated by the Safety Review 
Team. Based on data obtained from SD-UP, the EP547 dose to be evaluated in MAD-UP must have 
predicted steady-state PK concentrations lower than that of the highest tolerated dose in MAD-HS. 
MAD-UP is anticipated to consist of 1 dose level. If an additional dose level requires evaluation after 
conducting the first dose level, a second dose level may be enrolled to evaluate a daily PO dose of 
EP547 that is no more than 3-fold greater than the dose in the previous group. Each dose level will 
include a minimum of 8 subjects who will be randomized to receive EP547 or placebo as a daily PO 
dose over 7 days in a 3:1 ratio (EP547:placebo) with hemodialysis occurring 4 to 6 hours after dosing 
on Days 1, 4, and 6; there will be no sentinel dosing. If additional subjects are available to participate 
in any MAD-UP dose level, up to 4 more subjects (for a total of 12) may be enrolled. 
Study Schedule 
Although the number of dose levels to be evaluated in each single dose segment may differ, the overall 
study design amongst them is similar. The same is true for the multiple dose segments. 
Subjects should fast for at least 8 hours before study days that require a blood sample for assessment of 
clinical chemistry, multiple blood samples for PK, 
 as described in 
the Fasting Requirements section. 






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Abstinence is considered a highly effective method of birth control if the subject refrains 
from heterosexual intercourse from the time of informed consent until 30 days after the last 
dose of study drug. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the subject. 
3. If male and is not surgically sterile for at least 3 months, must be willing to not donate sperm and 
must agree to use a barrier method of contraception (eg, condom) during intercourse and at least 
1 other acceptable contraceptive measure (eg, hormonal contraceptives, intrauterine device, female 
surgical sterilization, male vasectomy, or abstinence) from Screening through 90 days after the last 
dose of study drug 
4. Body mass index ≥19 to ≤35 kg/m2 
5. Medically healthy with no clinically significant medical history, physical examination, vital sign, 
standard 12-lead ECG, chemistry, hematology, urinalysis, or coagulation results at Screening as 
deemed by the Investigator 
6. Must be able to communicate well with the Investigator, understand and comply with the 
requirements of the study (including required confinement periods), and understand and provide 
written consent 
Subjects with Cholestatic Pruritus 
To be eligible for study participation, all subjects with cholestatic pruritus must meet all the following 
inclusion criteria: 
1. Age 18 to 80 years, inclusive 
2. Has a cholestatic disorder as a result of one of the following conditions: 
a. Diagnosis of primary biliary cholangitis (PBC) that is consistent with American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2019) and European 
Association for the Study of the Liver (EASL) Practice Guidelines (EASL 2017), defined 
as having ≥2 of the following 3 diagnostic factors: 
i. History of elevated alkaline phosphatase (ALP) levels for at least 6 months 
ii. Positive antimitochondrial antibody (AMA) titer or if AMA is negative or low titer 
(≤1:80), PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or 
antibodies against the major M2 components (pyruvate dehydrogenase complex 
E2 component and 2-oxo-glutaric acid dehydrogenase complex) 
iii. Liver biopsy consistent with PBC (collected at any time before Screening) 
b. Diagnosis of primary sclerosing cholangitis (PSC) based on cholangiography at any point 
in time (EASL 2009, Chapman 2010) 
c. Confirmed diagnosis of chronic hepatitis B or C virus (HBV or HCV) 
3. If female, must be willing to not donate eggs from the time of informed consent until 30 days after 
the last dose of study drug and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year and is over the age of 55 years; or 
c. Has a negative serum pregnancy test at Screening and agrees to use a barrier method (eg, 
condom) during intercourse and at least 1 other acceptable contraceptive measure (eg, 
hormonal contraceptives, intrauterine device, vasectomized partner, or abstinence) from 
the time of informed consent until 30 days after the last dose of study drug 
Abstinence is considered a highly effective method of birth control if the subject refrains 
from heterosexual intercourse from the time of informed consent until 30 days after the last 
dose of study drug. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the subject. 






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Subjects with Cholestatic Pruritus 
All subjects with cholestatic pruritus meeting any of the following criteria will be excluded from this 
study: 
1. Has a concomitant disease or a history of any medical condition that, in the opinion of the 
Investigator, could pose undue risk to the subject, impede completion of the study procedures, or 
would compromise the validity of the study measurements, including, but not limited to: 
a. Presence of decompensated cirrhosis within 12 months before Screening 
b. Presence of cirrhosis at Screening with Child-Pugh score >6, ascites or hepatic 
encephalopathy within 12 months of Screening, albumin of ≤2.8 g/dL (≤28 g/L), total 
bilirubin ≥3 mg/dL (≥51.3 µmol/L), or international normalized ratio (INR) ≥1.8 
c. Presence of drug-induced cholestasis 
2. Recent, current, or planned use of any new medications or adjustments to current medications 
within 14 days of Screening until the end of the study 
3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5× upper limit of normal 
(ULN) at Screening 
4. Screening platelet count <100,000/µL 
5. Screening total bilirubin ≥3 mg/dL (≥51.3 µmol/L) (total bilirubin ≥3 mg/dL [≥51.3 µmol/L] is 
acceptable if bilirubin is fractionated and direct bilirubin <50%) 
6. Positive result for HIV at Screening 
7. History of malignancy of any organ system (other than localized squamous cell or basal cell 
carcinoma of the skin that have been excised or resolved), treated or untreated, within the past 
5 years 
8. Positive drug, alcohol, or cotinine screen results at Screening or Day -1 
9. Significant history of abuse of drugs, solvents, or alcohol (>3 servings or units/day on average; 
1 unit = 12 ounces [350 mL] of 5% alcohol beer, 5 ounces [150 mL] of 12% wine, or 1.5 ounces 
[45 mL] of 80 proof distilled spirits) in the past 2 years before Screening 
10. Unable or unwilling to abstain from alcohol for 48 hours before Screening and from 48 hours 
before Day -1 until the end of the study 
11. Participation in any clinical study with an investigational or approved drug/device within 30 days 
before Screening or is planning to participate in another clinical study while enrolled in this study 
(previous participation in SD-CP is allowed) 
12. Allergy to any component of study drug 
13. Previously participated in another dose level group in MAD-CP 
14. Donated or lost >200 mL of blood within 60 days before Day -1, donated plasma within 7 days 
before Day -1, or plans to donate blood or plasma during the study 
15. Female who is pregnant, nursing, or intends to become pregnant during the study 
16. Is directly affiliated with the study at the study site or is an immediate family member (spouse, 
parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the 
study at the study site 
17. Is employed by Escient Pharmaceuticals, Inc. (that is an employee, temporary contract worker, or 
designee responsible for the conduct of the study) or is an immediate family member of an 
employee of Escient Pharmaceuticals, Inc. 
18. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
19. Scheduled to receive a liver transplant during the study (placement on a transplant waiting list is 
not exclusionary) 


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20. Is receiving ongoing ultraviolet B (UVB) treatment or anticipates receiving such treatment during 
the study 
21. For subjects participating in MAD-CP, pruritus is secondary to biliary obstruction 
22. History or presence of hepatocellular carcinoma, hepatic abscess, or acute portal vein thrombosis 
Subjects with Uremic Pruritus 
All subjects with uremic pruritus meeting any of the following criteria will be excluded from this 
study: 
1. Has a concomitant disease or a history of any medical condition that, in the opinion of the 
Investigator, could pose undue risk to the subject, impede completion of the study procedures, or 
would compromise the validity of the study measurements, including, but not limited to: 
a. Significant systolic or diastolic heart failure (eg, New York Heart Association Class IV 
congestive heart failure 
2. Recent, current, or planned use of any new medications or adjustments to current medications 
within 14 days of Screening until the end of the study unless modification to the hemodialysis 
regimen is needed or for subject safety 
3. Positive result for HIV or presence of actively replicating viral hepatitis due to HBV or HCV 
infection at Screening 
4. History of malignancy of any organ system (other than localized squamous cell or basal cell 
carcinoma of the skin that have been excised or resolved), treated or untreated, within the past 
5 years 
5. Positive alcohol screen result at Screening or Day -1 or known use of drugs or tobacco at 
Screening 
6. Significant history of abuse of drugs, solvents, or alcohol (>3 servings or units/day on average; 
1 unit = 12 ounces [350 mL] of 5% alcohol beer, 5 ounces [150 mL] of 12% wine, or 1.5 ounces 
[45 mL] of 80 proof distilled spirits) in the past 2 years before Screening 
7. Unable or unwilling to abstain from alcohol for 48 hours before Screening and from 48 hours 
before Day -1 until the end of the study 
8. Participation in any clinical study with an investigational or approved drug/device within 30 days 
before Screening or is planning to participate in another clinical study while enrolled in this study 
(previous participation in SD-UP is allowed) 
9. Allergy to any component of study drug 
10. Previously participated in another dose level group in MAD-UP 
11. Female who is pregnant, nursing, or intends to become pregnant during the study 
12. Is directly affiliated with the study at the study site or is an immediate family member (spouse, 
parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the 
study at the study site 
13. Is employed by Escient Pharmaceuticals, Inc. (that is an employee, temporary contract worker, or 
designee responsible for the conduct of the study) or is an immediate family member of an 
employee of Escient Pharmaceuticals, Inc. 
14. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
15. Scheduled to receive a kidney transplant during the study (placement on a transplant waiting list is 
not exclusionary) 
16. Is receiving ongoing UVB treatment or anticipates receiving such treatment during the study 
17. Known noncompliance with hemodialysis treatment that, in the opinion of the Investigator, would 
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Safety Assessments 
Safety evaluations, including AEs, concomitant medications, medical history, vital signs, body weight, 
physical examinations, standard 12-lead ECGs, and laboratory evaluations of safety will be performed 
as indicated in the Schedule of Assessments (Appendix A for the single dose segments and 
Appendix B for the multiple dose segments). 
Although SAD-HS and all of the MAD segments will be conducted in a blinded manner (ie, subjects, 
Investigator, study-site personnel, and CRO staff not involved in PK sample analysis or regulatory 
reporting will be blinded to treatment), the Sponsor, including the Sponsor Medical Monitor, will be 
unblinded to treatment assignment to assess safety on an ongoing basis. The SD-CP and SD-UP 
segments are not placebo-controlled (ie, all subjects will receive EP547) and will be conducted in an 
unblinded manner. 
Adverse Event Collection 
AEs will be documented from the signing of the Informed Consent Form (ICF) until the end of study 
participation. 
Discontinuation of Study Drug Due to an Adverse Event 
Subjects may be withdrawn from the study due to an AE at any time based on the clinical judgment of 
the Investigator in consideration with the subject’s wishes. Subjects who terminate the treatment period 
early should complete the early study termination evaluations as soon as possible after the last dose of 
study drug, ideally within 2 days after the last dose. If termination occurs during the treatment period, 
the subject will have a follow-up visit approximately 1 week (±1 day) after the last dose of study drug. 
If termination of the treatment period occurs while participating in a MAD segment, the subject will 
also have a follow-up visit approximately 2 weeks (±2 days) after the last dose of study drug. After the 
final study visit, further standard of care treatment will be determined by the subject and treating 
physician. Subjects who discontinue before completing the treatment period or are non-evaluable may 
be replaced in order to meet evaluable subject requirements. 
Safety Criteria for Determining if a Dose Level is Well Tolerated 
The nature of any AEs, including the number and severity of AEs, and the suspected relationship of the 
AEs to study drug, will be used to determine if a dose level for a given segment is considered generally 
well tolerated in the population in which it is being evaluated. 
Safety Criteria for Stopping Dose Escalation 
Dose escalation (or MAD dosing) for any segment will cease if 50% of EP547-treated subjects in the 
same dose level experience a treatment-related AE of severe intensity. Other signs of limited 
tolerability will also be considered, such as clustering of AEs within a System Organ Class that are 
largely moderate to severe in intensity. Additionally, all clinically significant abnormalities in 
chemistry, hematology, urinalysis, standard 12-lead ECG, physical examination, and vital sign results 
will be evaluated by the Safety Review Team before any dose escalation. 
Safety Criteria for Stopping Dosing 
Study drug dosing will be held for all subjects if any of the following criteria are met: 
• 
A subject receiving EP547 experiences a serious adverse reaction (ie, a serious AE [SAE] 
considered at least possibly related to the study drug) 
• 
At least 2 subjects receiving EP547 in the same dosing group experience a severe non-serious 
adverse reaction (ie, a severe, non-serious AE considered at least possibly related to the study drug) 


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Study drug dosing will only restart when all appropriate evaluations are performed to ensure subject 
safety and only if the Safety Review Team agrees that it is appropriate to restart. External expert 
opinion may be sought to assist in evaluating the risk to subjects and determining if study drug dosing 
should be continued. 
Pharmacokinetic Criteria for Selecting, Adjusting, or Stopping Doses 
PK concentrations and/or PK parameters from each dose level in each population will be evaluated by 
the Safety Review Team before selection of doses in the subsequent segment. Any anticipated 
accumulation will be considered for PK predictions of doses in the MAD segments. There are no pre- 
defined PK criteria to adjust or stop dosing. 
Pharmacokinetic Assessments 
Blood, urine, and skin samples for PK will be utilized to analyze EP547 concentrations; the metabolite 
profile may also be analyzed from these samples. 
Blood Sampling for Pharmacokinetics 
Blood sampling for PK of EP547 will be collected as follows: 
• 
SAD-HS, SD-CP, and SD-UP: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hours 
postdose on Day 1; 18, 24, and 36 hours postdose on Day 2; 48 hours postdose on Day 3; and at 
follow-up on Day 8. 
• 
MAD-HS: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 18 hours postdose relative to 
the dose of study drug on Day 1; predose on Day 2 through Day 6; predose and at 0.25, 0.5, 1, 1.5, 
2, 2.5, 3, 4, 6, 9, 12, and 24 hours postdose relative to the last dose of study drug on Day 7; and at 
follow-up on Day 14 and Day 21. 
• 
MAD-CP: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 18 hours postdose relative to 
the dose of study drug on Day 1; predose on Day 2; predose on Day 4; predose and at 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hours postdose relative to the last dose of study drug on Day 7; and 
at follow-up on Day 14 and Day 21. 
• 
MAD-UP: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 18 hours postdose relative to 
the dose of study drug on Days 1, 2, and 6; predose on Day 4; predose and at 0.25, 0.5, 1, 1.5, 2, 
2.5, 3, 4, 6, 9, 12, and 24 hours postdose relative to the last dose of study drug on Day 7; and at 
follow-up on Day 14 and Day 21. 
The MAD dosing and PK blood sampling schedule is summarized in Appendix C. The assessment 
window for blood sample collection timepoints for the single and multiple dose segments is also 
included in Appendix C. 
Urine Collection for Pharmacokinetics (SAD-HS Only) 
Urine sampling for PK of EP547 will be collected at predose (-6 to 0 hours) and from >0 to 6, >6 to 12, 
and >12 to 18 hours postdose on Day 1; >18 to 24, >24 to 30, and >30 to 36 hours postdose on Day 2; 
and >36 to 42 and >42 to 48 hours postdose on Day 3. 
Skin Biopsy for Pharmacokinetics (Last Dose Level for MAD-HS and All Dose Levels for MAD-CP and 
MAD-UP Only) 
Given that EP547 is hypothesized to be an inverse agonist (inhibitor) of mas-related G protein-coupled 
receptor X4 (MRGPRX4) in the skin to reduce itch, three 3-mm biopsies of the skin from the back will 
be performed under local anesthesia on Day 1 at 2 hours postdose with an assessment window of 
+30 minutes. One biopsy will be used for PK to evaluate drug concentrations at the site of action and 








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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................ 1 
2. 
SYNOPSIS .................................................................................................................... 5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ................ 23 
TABLE OF CONTENTS ............................................................................................................... 23 
LIST OF FIGURES ........................................................................................................................ 27 
LIST OF TABLES ......................................................................................................................... 28 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 29 
5. 
INTRODUCTION ...................................................................................................... 32 
5.1. 
Cholestatic and Uremic Pruritus ................................................................................. 32 
5.2. 
Mas-Related G Protein-Coupled Receptor X4 ............................................................ 33 
5.3. 
EP547 .......................................................................................................................... 33 
5.4. 
EP547 Dose Rationale ................................................................................................. 34 
6. 
TRIAL OBJECTIVES AND PURPOSE .................................................................... 35 
6.1. 
Primary Objective ....................................................................................................... 35 
6.2. 
Secondary Objectives .................................................................................................. 35 
6.3. 
Exploratory Objectives................................................................................................ 35 
7. 
INVESTIGATIONAL PLAN ..................................................................................... 36 
7.1. 
Overall Study Design .................................................................................................. 36 
7.1.1. 
Healthy Subjects ......................................................................................................... 37 
7.1.2. 
Subjects with Cholestatic Pruritus ............................................................................... 38 
7.1.3. 
Subjects with Uremic Pruritus .................................................................................... 38 
7.1.4. 
Study Schedule ............................................................................................................ 39 
7.1.4.1. 
Single Dose Segments ................................................................................................. 39 
7.1.4.2. 
Multiple Dose Segments ............................................................................................. 40 
7.2. 
Number of Subjects ..................................................................................................... 40 
7.3. 
Dose Adjustment Criteria ............................................................................................ 41 
7.3.1. 
Safety Criteria for Determining if a Dose Level is Well Tolerated ............................ 41 
7.3.2. 
Discontinuation of Study Drug Due to an Adverse Event ........................................... 41 


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7.3.3. 
Safety Criteria for Stopping Dose Escalation ............................................................. 41 
7.3.4. 
Safety Criteria for Stopping Dosing ............................................................................ 41 
7.3.5. 
Pharmacokinetic Criteria for Selecting, Adjusting, or Stopping Doses ...................... 42 
7.4. 
Criteria for Study Termination ..................................................................................... 42 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 43 
8.1. 
Subject Inclusion Criteria ............................................................................................ 43 
8.1.1. 
Healthy Subjects ......................................................................................................... 43 
8.1.2. 
Subjects with Cholestatic Pruritus ............................................................................... 44 
8.1.3. 
Subjects with Uremic Pruritus .................................................................................... 45 
8.2. 
Subject Exclusion Criteria .......................................................................................... 46 
8.2.1. 
Healthy Subjects ......................................................................................................... 46 
8.2.2. 
Subjects with Cholestatic Pruritus ............................................................................... 47 
8.2.3. 
Subjects with Uremic Pruritus .................................................................................... 48 
8.3. 
Study Restrictions ....................................................................................................... 50 
8.4. 
Subject Withdrawal Criteria ........................................................................................ 50 
9. 
TREATMENT OF SUBJECTS .................................................................................. 52 
9.1. 
Treatment Assignment ................................................................................................ 52 
9.2. 
Treatment Compliance ................................................................................................ 52 
9.3. 
Randomization and Blinding ...................................................................................... 52 
9.3.1. 
Randomization ............................................................................................................ 52 
9.3.2. 
Blinding ....................................................................................................................... 52 
9.3.2.1. 
Emergency Unblinding ............................................................................................... 52 
9.3.2.2. 
Unblinding for Regulatory Reporting ......................................................................... 53 
9.4. 
Study Visits ................................................................................................................. 53 
9.4.1. 
SAD Segments ............................................................................................................ 53 
9.4.1.1. 
Screening Period .......................................................................................................... 53 
9.4.1.2. 
Treatment Period ......................................................................................................... 55 
9.4.1.3. 
Safety Follow-Up Visit (Visit 3 [Day 8]) .................................................................... 57 
9.4.1.4. 
Early Study Termination Visit .................................................................................... 57 
9.4.2. 
MAD Segments ........................................................................................................... 58 
9.4.2.1. 
Screening Period .......................................................................................................... 58 
9.4.2.2. 
Treatment Period ......................................................................................................... 60 
9.4.2.3. 
Safety Follow-Up Period ............................................................................................. 65 


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9.4.2.4. 
Early Study Termination Visit .................................................................................... 67 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT .............................................. 68 
10.1. 
Study Drugs ................................................................................................................ 68 
10.2. 
Study Drug Packaging and Labeling ........................................................................... 68 
10.3. 
Study Drug Storage ..................................................................................................... 68 
10.4. 
Study Drug Administration ......................................................................................... 68 
10.5. 
Additional Dosing Instructions for Subjects with Uremic Pruritus............................. 68 
10.6. 
Study Drug Dispensing and Accountability ................................................................ 68 
10.7. 
Study Drug Handling and Disposal ............................................................................. 69 
10.8. 
Product Quality Complaints ........................................................................................ 69 
11. 
SAFETY ASSESSMENTS ......................................................................................... 70 
11.1. 
Adverse Events ............................................................................................................ 70 
11.1.1. 
Definition of an Adverse Event .................................................................................. 70 
11.1.2. 
Determining Severity of Adverse Events .................................................................... 70 
11.1.3. 
Determining Causality of Adverse Events .................................................................. 71 
11.1.4. 
Recording Adverse Events .......................................................................................... 71 
11.1.4.1. 
Special Instructions for Recording Adverse Events in the eCRF ............................... 71 
11.2. 
Serious Adverse Events .............................................................................................. 72 
11.2.1. 
Definition of a Serious Adverse Event ........................................................................ 72 
11.2.2. 
Reporting Serious Adverse Events ............................................................................. 73 
11.2.3. 
Pregnancy .................................................................................................................... 73 
11.3. 
Concomitant Medications ........................................................................................... 74 
11.4. 
Medical History ........................................................................................................... 74 
11.5. 
Vital Signs ................................................................................................................... 74 
11.6. 
Body Weight ............................................................................................................... 74 
11.7. 
Physical Examinations ................................................................................................. 75 
11.8. 
Standard 12-Lead Electrocardiograms .......................................................................... 75 
11.9. 
Laboratory Evaluations of Safety ............................................................................... 75 
11.10. 
Other Laboratory Evaluations ..................................................................................... 76 
11.11. 
Subject Safety Guidelines ........................................................................................... 76 
11.11.1. 
Potential Side Effects .................................................................................................. 76 
11.11.2. 
Overdose ..................................................................................................................... 76 
12. 
PHARMACOKINETICS ASSESSMENT ................................................................... 77 




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16. 
QUALITY CONTROL AND DATA MANAGEMENT ............................................ 85 
16.1. 
Data Quality Assurance ............................................................................................... 85 
16.2. 
Data Management ....................................................................................................... 85 
16.3. 
Monitoring .................................................................................................................. 85 
16.4. 
Confidentiality and Auditing ...................................................................................... 85 
16.5. 
Case Report Forms ...................................................................................................... 86 
16.6. 
Source Documents ....................................................................................................... 86 
16.7. 
Records Retention ........................................................................................................ 86 
16.8. 
Informed Consent ........................................................................................................ 86 
16.9. 
Institutional Review Board/Independent Ethics Committee ....................................... 87 
17. 
STUDY MANAGEMENT .......................................................................................... 88 
17.1. 
Protocol Deviations ...................................................................................................... 88 
17.2. 
Publications ................................................................................................................. 88 
17.3. 
Change in Study Site Staff .......................................................................................... 88 
18. 
LIST OF REFERENCES ............................................................................................ 89 
APPENDIX A. SCHEDULE OF ASSESSMENTS FOR THE SINGLE DOSE 
SEGMENTS ............................................................................................................... 91 
APPENDIX B. SCHEDULE OF ASSESSMENTS FOR THE MULTIPLE DOSE 
SEGMENTS ............................................................................................................... 94 
APPENDIX C. DOSING AND PK BLOOD SAMPLING SCHEDULE FOR THE 
MAD SEGMENTS ..................................................................................................... 99 
 
 
 
 
 
 
APPENDIX I. SUMMARY OF CHANGES BY AMENDMENT ........................................... 107 
LIST OF FIGURES 
Figure 1: 
EP-547-101 Study Design ...........................................................................................36 
Figure 2: 
Study Schedule for the Single Dose Segments ...........................................................39 
Figure 3: 
Study Schedule for the Multiple-Dose Segments .......................................................40 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ................................................................................... 4 
Table 2: 
Abbreviations and Specialist Terms ........................................................................... 29 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
Ae 
amount of drug excreted in urine 
AE 
adverse event 
AASLD 
American Association for the Study of Liver Diseases 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemistry 
%AUCextra 
Percentage of estimated part for the calculation of AUC∞ 
AUCt 
area under the concentration-time curve calculated to the 
last observable concentration at time t 
AUCτ 
area under the plasma concentration time curve over a 
dosing interval τ 
AUC∞ 
area under the concentration-time curve from time 0 to 
infinity 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CKD 
chronic kidney disease 
CL/F 
apparent clearance 
CLr 
renal clearance 
Cmax 
maximum (peak) plasma concentration 
CP 
cholestatic pruritus 
CPK 
creatine phosphokinase 
CRO 
Contract Research Organization 
Ctrough 
trough plasma concentration 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
eCRF 
electronic case report form 


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Abbreviation or Specialist Term 
Explanation 
ESRD 
end-stage renal disease 
FDA 
Food and Drug Administration 
Fe 
urinary recovery rate 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyltransferase 
HED 
human equivalent dose 
HEENT 
head, eyes, ears, nose, throat 
HEK 
human embryonic kidney 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL-c 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HS 
healthy subject 
GCP 
Good Clinical Practice 
IC100 
maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgE 
immunoglobulin E 
INR 
international normalized ratio 
IP-1 
inositol phosphate-1 
IRB 
Institutional Review Board 
kel 
terminal elimination rate constant 
LDH 
lactate dehydrogenase 
LDL-c 
low-density lipoprotein cholesterol 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MRGPR 
mas-related G protein-coupled receptor 
MRSD 
maximum recommended starting dose 
NCA 
noncompartmental analysis 
NOAEL 
no-observed-adverse-effect-level 


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Abbreviation or Specialist Term 
Explanation 
OTC 
over-the-counter 
PBC 
primary biliary cholangitis 
PD 
pharmacodynamics 
 
 
PK 
pharmacokinetics 
PO 
oral 
PQC 
product quality complaint 
PSC 
primary sclerosing cholangitis 
PT 
prothrombin time 
QC 
quality control 
QTc 
corrected QT 
Rss 
exposure ratio 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAER 
Serious Adverse Event Report 
SAP 
Statistical Analysis Plan 
SD 
single dose 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to achieve maximum (peak) plasma concentration 
ULN 
upper limit of normal 
UP 
uremic pruritus 
US 
United States 
UVB 
ultraviolet B 
Vz/F 
apparent volume of distribution at terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 


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5. 
INTRODUCTION 
5.1. 
Cholestatic and Uremic Pruritus 
Patients with cholestatic liver disease, such as primary biliary cholangitis (PBC) and primary 
sclerosing cholangitis (PSC), often suffer from chronic itch or pruritus that is experienced by up 
to 70% to 80% of these patients over the course of their disease (Mittal 2016). 
Uremic pruritus is common in patients with kidney failure, with prevalence rates ranging from 
20% to 90% in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) 
receiving hemodialysis. The broad range is likely due to varying characteristics of the studied 
populations, the era when studies were performed, and the diagnostic instruments used to define 
itch (Shirazian 2017). A recent meta-analysis of 42 studies comprising 11,800 patients estimates 
that the overall prevalence of CKD-associated pruritus among adult hemodialysis patients is 55% 
(Hu 2018). 
Patients with cholestatic or uremic pruritus have difficulty coping with the intense itching and 
develop associated stress. Pruritus also has a negative effect on patients’ quality of life, sleep, 
emotional state, and social relations (Bassari 2015, Ibrahim 2016), and contributes to the 
development of skin and soft tissue lesions and/or infections (Ozen 2018). 
The pathophysiology of cholestatic and uremic pruritus is not fully understood and the itch- 
causing pruritogen(s) and their cognate receptor(s) have remained largely elusive. Cholestatic 
itch is often nonresponsive to standard pharmacological treatments, including antihistamines, and 
instead requires physically removing the causative obstruction (such as gallstones), draining the 
bile, or transplanting the liver to alleviate itch (Bergasa 2014). Because these procedures are 
often curative, the responsible pruritogens are hypothesized to originate from the liver and bile. 
Numerous candidate pruritogens are present in bile and up-regulated in cholestatic patients, 
including opioids, lysophosphatidic acid, bilirubin, and bile acids. Therapies targeting these 
mechanisms, such as opioid antagonists, rifampicin, and bile acid-binding resins like 
cholestyramine, are frontline therapy for cholestatic itch (Bassari 2015, Mittal 2016), however, 
patients are poorly managed with these therapies (Bassari 2015, Mittal 2016). 
Uremic pruritus is typically resistant to treatment and difficult to manage. Other than a kidney 
transplant, which is curative, there remains considerable uncertainty about effective treatments 
and optimal solutions remain poorly defined (Simonsen 2017). The initial therapy for 
hemodialysis patients with uremic pruritus may consist of dialysis modification, correction of 
phosphorus and calcium levels, hyperparathyroid treatment (if applicable), and topical treatments 
(Rayner 2017). Patients with continued symptoms despite initial therapy may be treated with an 
oral antihistamine and, if that is ineffective, gabapentin, selective serotonin reuptake inhibitors, 
or leukotriene receptor antagonists (Mettang 2016). For patients who are refractory to previous 
lines of therapy, ultraviolet B (UVB) phototherapy is a therapeutic option (Mettang 2016). UVB 
irradiation is effective in the treatment of uremic pruritus, however, symptoms may resume after 
stopping therapy. 
Although a variety of interventions have been explored, the need for improved treatment of 
cholestatic and uremic pruritus remains high. Therefore, development of additional safe and 
effective therapeutic options for these conditions is essential. 












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MAD-HS can begin after 3 dose levels of SAD-HS have been fully evaluated by the Safety 
Review Team. Subjects who participated in SAD-HS may not participate in MAD-HS. All dose 
levels in MAD-HS must fall within the range of doses tested in SAD-HS that were confirmed to 
be well tolerated (Section 7.3.1). 
The initial dose level for MAD-HS will be no higher than the second dose tested in SAD-HS 
with predicted PK concentrations no higher than those observed in SAD-HS. Following 
confirmation by the Safety Review Team that escalation should proceed, each subsequent dose 
level tested in MAD-HS will be increased by no more than 3-fold from the preceding dose level. 
MAD-HS is anticipated to consist of 3 dose levels. Each level will include 8 subjects who will be 
randomized to receive EP547 or placebo as a daily PO dose over 7 days in a 3:1 ratio 
(EP547:placebo); there will be no sentinel dosing. 
The following treatments for MAD-HS are planned to be administered. However, fewer dose 
levels may be evaluated if the data from those groups can fully meet the objectives of the study. 
Group 1: daily PO dose of EP547 that is no higher than the second dose tested in SAD-HS with 
predicted PK concentrations no higher than those observed in SAD-HS (n = 6) or 
matching placebo (n = 2) over 7 days 
Group 2: daily PO dose of EP547 that is no more than 3-fold greater than the dose in Group 1 
(n = 6) or matching placebo (n = 2) over 7 days 
Group 3: daily PO dose of EP547 that is no more than 3-fold greater than the dose in Group 2 
(n = 6) or matching placebo (n = 2) over 7 days 
 
7.1.2. 
Subjects with Cholestatic Pruritus 
SD-CP may be conducted when the results from all dose levels of SAD-HS have been fully 
evaluated by the Safety Review Team. SD-CP is not placebo-controlled (ie, all subjects will 
receive EP547) and will be conducted in an unblinded manner. The dose level for SD-CP will be 
no higher than the third dose tested in SAD-HS. SD-CP will consist of 1 dose level. The dose 
level will include 6 subjects who will receive EP547 as a single PO dose. 
MAD-CP can begin when the results from SD-CP have been fully evaluated by the Safety 
Review Team. Based on data obtained from SD-CP, the EP547 dose to be evaluated in MAD-CP 
must have predicted steady-state PK concentrations lower than that of the highest tolerated dose 
in MAD-HS. MAD-CP is anticipated to consist of 1 dose level. If an additional dose level 
requires evaluation after conducting the first dose level, a second dose level may be enrolled to 
evaluate a daily PO dose of EP547 that is no more than 3-fold greater than the dose in the 
previous group. Each dose level will include a minimum of 8 subjects who will be randomized to 
receive EP547 or placebo as a daily PO dose over 7 days in a 3:1 ratio (EP547:placebo); there 
will be no sentinel dosing. If additional subjects are available to participate in any MAD-CP dose 
level, up to 4 more subjects (for a total of 12) may be enrolled. 
7.1.3. 
Subjects with Uremic Pruritus 
SD-UP may be conducted when the results from all dose levels of SAD-HS have been fully 
evaluated by the Safety Review Team. SD-UP is not placebo-controlled (ie, all subjects will 
receive EP547) and will be conducted in an unblinded manner. The dose level for SD-UP will be 
no higher than the third dose tested in SAD-HS. SD-UP will consist of 1 dose level. The dose 






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7.3. 
Dose Adjustment Criteria 
Dosages of study drug should be maintained constant for each subject in a MAD segment. 
However, study drug dosing could be placed on hold as a result of safety findings. Safety criteria 
for determining if a dose level is well tolerated, discontinuing study drug due to an AE, stopping 
dose escalation, stopping dosing for all subjects, and PK criteria for selecting, adjusting, or 
stopping doses is described in Sections 7.3.1 through 7.3.5. 
7.3.1. 
Safety Criteria for Determining if a Dose Level is Well Tolerated 
The nature of any AEs, including the number and severity of AEs, and the suspected relationship 
of the AEs to study drug, will be used to determine if a dose level for a given segment is 
considered generally well tolerated in the population in which it is being evaluated. 
 
7.3.2. 
Discontinuation of Study Drug Due to an Adverse Event 
Subjects may be withdrawn from the study due to an AE at any time based on the clinical 
judgment of the Investigator in consideration with the subject’s wishes. Subjects who terminate 
the treatment period early should complete the early study termination evaluations as soon as 
possible after the last dose of study drug, ideally within 2 days after the last dose. If termination 
occurs during the treatment period, the subject will have a follow-up visit approximately 1 week 
(±1 day) after the last dose of study drug. If termination of the treatment period occurs while 
participating in a MAD segment, the subject will also have a follow-up visit approximately 
2 weeks (±2 days) after the last dose of study drug. After the final study visit, further standard of 
care treatment will be determined by the subject and treating physician. Subjects who 
discontinue before completing the treatment period or are non-evaluable may be replaced in 
order to meet evaluable subject requirements. 
 
7.3.3. 
Safety Criteria for Stopping Dose Escalation 
Dose escalation (or MAD dosing) for any segment will cease if 50% of EP547-treated subjects in 
the same dose level experience a treatment-related AE of severe intensity. Other signs of limited 
tolerability will also be considered, such as clustering of AEs within a System Organ Class that 
are largely moderate to severe in intensity. Additionally, all clinically significant abnormalities in 
chemistry, hematology, urinalysis, standard 12-lead ECG, physical examination, and vital sign 
results will be evaluated by the Safety Review Team before any dose escalation. 
 
7.3.4. 
Safety Criteria for Stopping Dosing 
Study drug dosing will be held for all subjects if any of the following criteria are met: 
• A subject receiving EP547 experiences a serious adverse reaction (ie, a serious AE 
[SAE] considered at least possibly related to the study drug) 
• At least 2 subjects receiving EP547 in the same dosing group experience a severe 
non-serious adverse reaction (ie, a severe, non-serious AE considered at least possibly 
related to the study drug) 
Study drug dosing will only restart when all appropriate evaluations are performed to ensure 
subject safety and only if the Safety Review Team agrees that it is appropriate to restart. External 


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expert opinion may be sought to assist in evaluating the risk to subjects and determining if study 
drug dosing should be continued. 
 
7.3.5. 
Pharmacokinetic Criteria for Selecting, Adjusting, or Stopping Doses 
PK concentrations and/or PK parameters from each dose level in each population will be 
evaluated by the Safety Review Team before selection of doses in the subsequent segment. Any 
anticipated accumulation will be considered for PK predictions of doses in the MAD segments. 
There are no pre-defined PK criteria to adjust or stop dosing. 
 
7.4. 
Criteria for Study Termination 
The Sponsor may terminate the study at a study site at any time (eg, Good Clinical Practice 
[GCP] noncompliance or poorly performing sites, as determined by the number of subjects 
enrolled or the quality of the study data). If instructed by the Sponsor or designee, the 
Investigator must implement the termination in a timeframe to ensure subject safety and 
well-being. 
The Investigator and/or Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason for doing so. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects who have an exclusionary result during the screening period (between Visit 1 and 
Visit 2) may have that assessment repeated once at the discretion of the Investigator within the 
screening window and be enrolled if a repeat assessment is within the indicated range as 
specified below for participating in the study. 
 
8.1. 
Subject Inclusion Criteria 
8.1.1. 
Healthy Subjects 
To be eligible for study participation, all healthy subjects must meet all the following inclusion 
criteria: 
1. Age 18 to 60 years, inclusive 
2. If female, must be willing to not donate eggs from the time of informed consent until 
30 days after the last dose of study drug and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year and is over the age of 55 years; or 
c. Has a negative serum pregnancy test at Screening and agrees to use a barrier method 
(eg, condom) during intercourse and at least 1 other acceptable contraceptive measure 
(eg, hormonal contraceptives, intrauterine device, vasectomized partner, or 
abstinence) from the time of informed consent until 30 days after the last dose of 
study drug 
Abstinence is considered a highly effective method of birth control if the subject 
refrains from heterosexual intercourse from the time of informed consent until 
30 days after the last dose of study drug. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject. 
3. If male and is not surgically sterile for at least 3 months, must be willing to not donate 
sperm and must agree to use a barrier method of contraception (eg, condom) during 
intercourse and at least 1 other acceptable contraceptive measure (eg, hormonal 
contraceptives, intrauterine device, female surgical sterilization, male vasectomy, or 
abstinence) from Screening through 90 days after the last dose of study drug 
4. Body mass index ≥19 to ≤35 kg/m2 
5. Medically healthy with no clinically significant medical history, physical examination, 
vital sign, standard 12-lead ECG, chemistry, hematology, urinalysis, or coagulation 
results at Screening as deemed by the Investigator 
6. Must be able to communicate well with the Investigator, understand and comply with the 
requirements of the study (including required confinement periods), and understand and 
provide written consent 


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8.1.2. 
Subjects with Cholestatic Pruritus 
To be eligible for study participation, all subjects with cholestatic pruritus must meet all the 
following inclusion criteria: 
1. Age 18 to 80 years, inclusive 
2. Has a cholestatic disorder as a result of one of the following conditions: 
a. Diagnosis of PBC that is consistent with American Association for the Study of Liver 
Diseases (AASLD) (Lindor 2019) and European Association for the Study of the 
Liver (EASL) Practice Guidelines (EASL 2017), defined as having ≥2 of the 
following 3 diagnostic factors: 
i. History of elevated alkaline phosphatase (ALP) levels for at least 6 months 
ii. Positive antimitochondrial antibody (AMA) titer or if AMA is negative or low 
titer (≤1:80), PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or 
antibodies against the major M2 components (pyruvate dehydrogenase 
complex E2 component and 2-oxo-glutaric acid dehydrogenase complex) 
iii. Liver biopsy consistent with PBC (collected at any time before Screening) 
b. Diagnosis of PSC based on cholangiography at any point in time (EASL 2009, 
Chapman 2010) 
c. Confirmed diagnosis of chronic hepatitis B or C virus (HBV or HCV) 
3. If female, must be willing to not donate eggs from the time of informed consent until 
30 days after the last dose of study drug and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year and is over the age of 55 years; or 
c. Has a negative serum pregnancy test at Screening and agrees to use a barrier method 
(eg, condom) during intercourse and at least 1 other acceptable contraceptive measure 
(eg, hormonal contraceptives, intrauterine device, vasectomized partner, or 
abstinence) from the time of informed consent until 30 days after the last dose of 
study drug 
Abstinence is considered a highly effective method of birth control if the subject 
refrains from heterosexual intercourse from the time of informed consent until 
30 days after the last dose of study drug. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject. 
4. If male and is not surgically sterile for at least 3 months, must be willing to not donate 
sperm and must agree to use a barrier method of contraception (eg, condom) during 
intercourse and at least 1 other acceptable contraceptive measure (eg, hormonal 
contraceptives, intrauterine device, female surgical sterilization, male vasectomy, or 
abstinence) from Screening through 90 days after the last dose of study drug 
5. No clinically relevant medical history, physical examination, vital sign, standard 
12-lead ECG, chemistry, hematology, urinalysis, or coagulation results at Screening 
beyond what is expected for subjects with a cholestatic disorder that would place the 
subject at undue risk as deemed by the Investigator 






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12. Donated or lost >200 mL of blood within 60 days before Day -1, donated plasma within 
7 days before Day -1, or plans to donate blood or plasma during the study 
13. Female who is pregnant, nursing, or intends to become pregnant during the study 
14. Is directly affiliated with the study at the study site or is an immediate family member 
(spouse, parent, child, or sibling; biological or legally adopted) of personnel directly 
affiliated with the study at the study site 
15. Is employed by Escient Pharmaceuticals, Inc. (that is an employee, temporary contract 
worker, or designee responsible for the conduct of the study) or is an immediate family 
member of an employee of Escient Pharmaceuticals, Inc. 
16. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
 
8.2.2. 
Subjects with Cholestatic Pruritus 
All subjects with cholestatic pruritus meeting any of the following criteria will be excluded from 
this study: 
1. Has a concomitant disease or a history of any medical condition that, in the opinion of the 
Investigator, could pose undue risk to the subject, impede completion of the study 
procedures, or would compromise the validity of the study measurements, including, but 
not limited to: 
a. Presence of decompensated cirrhosis within 12 months before Screening 
b. Presence of cirrhosis at Screening with Child-Pugh score >6, ascites or hepatic 
encephalopathy within 12 months of Screening, albumin of ≤2.8 g/dL (≤28 g/L), total 
bilirubin ≥3 mg/dL (≥51.3 µmol/L), or international normalized ratio (INR) ≥1.8 
c. Presence of drug-induced cholestasis 
2. Recent, current, or planned use of any new medications or adjustments to current 
medications within 14 days of Screening until the end of the study 
3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5× upper limit of 
normal (ULN) at Screening 
4. Screening platelet count <100,000/µL 
5. Screening total bilirubin ≥3 mg/dL (≥51.3 µmol/L) (total bilirubin ≥3 mg/dL 
[≥51.3 µmol/L] is acceptable if bilirubin is fractionated and direct bilirubin <50%) 
6. Positive result for HIV at Screening 
7. History of malignancy of any organ system (other than localized squamous cell or basal 
cell carcinoma of the skin that have been excised or resolved), treated or untreated, within 
the past 5 years 
8. Positive drug, alcohol, or cotinine screen results at Screening or Day -1 
9. Significant history of abuse of drugs, solvents, or alcohol (>3 servings or units/day on 
average; 1 unit = 12 ounces [350 mL] of 5% alcohol beer, 5 ounces [150 mL] of 12% 
wine, or 1.5 ounces [45 mL] of 80 proof distilled spirits) in the past 2 years before 
Screening 


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10. Unable or unwilling to abstain from alcohol for 48 hours before Screening and from 
48 hours before Day -1 until the end of the study 
11. Participation in any clinical study with an investigational or approved drug/device within 
30 days before Screening or is planning to participate in another clinical study while 
enrolled in this study (previous participation in SD-CP is allowed) 
12. Allergy to any component of study drug 
13. Previously participated in another dose level group in MAD-CP 
14. Donated or lost >200 mL of blood within 60 days before Day -1, donated plasma within 
7 days before Day -1, or plans to donate blood or plasma during the study 
15. Female who is pregnant, nursing, or intends to become pregnant during the study 
16. Is directly affiliated with the study at the study site or is an immediate family member 
(spouse, parent, child, or sibling; biological or legally adopted) of personnel directly 
affiliated with the study at the study site 
17. Is employed by Escient Pharmaceuticals, Inc. (that is an employee, temporary contract 
worker, or designee responsible for the conduct of the study) or is an immediate family 
member of an employee of Escient Pharmaceuticals, Inc. 
18. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
19. Scheduled to receive a liver transplant during the study (placement on a transplant 
waiting list is not exclusionary) 
20. Is receiving ongoing UVB treatment or anticipates receiving such treatment during the 
study 
21. For subjects participating in MAD-CP, pruritus is secondary to biliary obstruction 
22. History or presence of hepatocellular carcinoma, hepatic abscess, or acute portal vein 
thrombosis 
 
8.2.3. 
Subjects with Uremic Pruritus 
All subjects with uremic pruritus meeting any of the following criteria will be excluded from this 
study: 
1. Has a concomitant disease or a history of any medical condition that, in the opinion of the 
Investigator, could pose undue risk to the subject, impede completion of the study 
procedures, or would compromise the validity of the study measurements, including, but 
not limited to: 
a. Significant systolic or diastolic heart failure (eg, New York Heart Association 
Class IV congestive heart failure) 
2. Recent, current, or planned use of any new medications or adjustments to current 
medications within 14 days of Screening until the end of the study unless modification to 
the hemodialysis regimen is needed or for subject safety 
3. Positive result for HIV or presence of actively replicating viral hepatitis due to HBV or 
HCV infection at Screening 


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4. History of malignancy of any organ system (other than localized squamous cell or basal 
cell carcinoma of the skin that have been excised or resolved), treated or untreated, within 
the past 5 years 
5. Positive alcohol screen result at Screening or Day -1 or known use of drugs or tobacco at 
Screening 
6. Significant history of abuse of drugs, solvents, or alcohol (>3 servings or units/day on 
average; 1 unit = 12 ounces [350 mL] of 5% alcohol beer, 5 ounces [150 mL] of 12% 
wine, or 1.5 ounces [45 mL] of 80 proof distilled spirits) in the past 2 years before 
Screening 
7. Unable or unwilling to abstain from alcohol for 48 hours before Screening and from 
48 hours before Day -1 until the end of the study 
8. Participation in any clinical study with an investigational or approved drug/device within 
30 days before Screening or is planning to participate in another clinical study while 
enrolled in this study (previous participation in SD-UP is allowed) 
9. Allergy to any component of study drug 
10. Previously participated in another dose level group in MAD-UP 
11. Female who is pregnant, nursing, or intends to become pregnant during the study 
12. Is directly affiliated with the study at the study site or is an immediate family member 
(spouse, parent, child, or sibling; biological or legally adopted) of personnel directly 
affiliated with the study at the study site 
13. Is employed by Escient Pharmaceuticals, Inc. (that is an employee, temporary contract 
worker, or designee responsible for the conduct of the study) or is an immediate family 
member of an employee of Escient Pharmaceuticals, Inc. 
14. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
15. Scheduled to receive a kidney transplant during the study (placement on a transplant 
waiting list is not exclusionary) 
16. Is receiving ongoing UVB treatment or anticipates receiving such treatment during the 
study 
17. Known noncompliance with hemodialysis treatment that, in the opinion of the 
Investigator, would impede completion or validity of the study 
18. For subjects participating in MAD-UP, pruritus is attributed mainly to any disease 
unrelated to kidney disease, is only present during the hemodialysis sessions, or is 
attributed to a skin disorder that occurs in this population with associated itch (eg, 
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8.3. 
Study Restrictions 
Unless stated otherwise, subjects must adhere to the following restrictions from Screening until 
the end of the study unless subject safety is compromised: 
• Abstain from alcohol during the 48 hours before Screening and from 48 hours before 
Day -1 until the end of the study. 
• Abstain from eating food containing poppy seeds for 48 hours before Screening and 
from 48 hours before Day -1 until the end of the study. 
• Avoid strenuous exercise from the 72 hours before Screening until the end of the 
study. 
• Do not take any new prescribed medication, over-the-counter (OTC) medication, 
vitamin preparations or other food supplements, health supplements, or herbal 
remedies during the study (unless done so in consultation with the Medical Monitor). 
− An exception is made for acetaminophen (up to 1 gram per 24-hour period) as 
permitted by the Investigator for the treatment of headache or any other pain. 
Other medication to treat AEs may only be prescribed if deemed necessary by the 
Investigator. 
• Maintain current dose and regimen of all prescribed medication, OTC medication, 
vitamin preparations or other food supplements, health supplements, and herbal 
remedies during the study (unless changed in consultation with the Medical Monitor). 
• For subjects with cholestatic or uremic pruritus, do not undergo UVB treatment 
• Do not use any drugs of abuse. 
• Do not use any investigational drugs/devices. 
• Do not donate blood or plasma. 
8.4. 
Subject Withdrawal Criteria 
Subjects will be free to withdraw consent and discontinue participation from the study at any 
time and without prejudice to further care per standard clinical practice. A subject’s participation 
in the study may also be discontinued at any time at the discretion of the Investigator or Sponsor. 
Individual subjects may be excluded from the study if a medical records review indicates 
protocol deviations, or if other factors suggest that the subject will not be a suitable study 
subject. 
If a subject is withdrawn from the study, the reason will be recorded on the electronic case report 
form (eCRF) page and the Sponsor will be notified promptly. 
Subjects who terminate the treatment period early should complete the early study termination 
evaluations as soon as possible after the last dose of study drug, ideally within 2 days after the 
last dose. If termination occurs during the treatment period, the subject will have a follow-up 
visit approximately 1 week (±1 day) after the last dose of study drug. If termination of the 
treatment period occurs while participating in a MAD segment, the subject will also have a 
follow-up visit approximately 2 weeks (±2 days) after the last dose of study drug. After the final 


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study visit, further standard of care treatment will be determined by the subject and treating 
physician. Subjects who discontinue before completing the treatment period or are non-evaluable 
may be replaced in order to meet evaluable subject requirements. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Treatment Assignment 
Treatment assignments for healthy subjects, subjects with cholestatic pruritus, and subjects with 
uremic pruritus are described in Sections 7.1.1, 7.1.2, and 7.1.3, respectively. 
The Sponsor will allocate sequential randomization codes and kit numbers for each dose level 
from the randomization code and kit assignment list. Sites will request the allocated 
randomization and kit numbers from the Sponsor in advance of dosing by contacting 
. 
 
9.2. 
Treatment Compliance 
To ensure treatment compliance, the Investigator or authorized designee will administer all doses 
of study drug. Compliance will be further confirmed by bioanalytical assessment of EP547 in 
plasma. 
The exact times of study drug administration and the number of capsules administered will be 
recorded in the eCRF. 
 
9.3. 
Randomization and Blinding 
9.3.1. 
Randomization 
Subjects will be assigned a subject number after signing the Informed Consent Form (ICF). 
Subjects who meet all eligibility criteria will be randomized and assigned a randomization 
number just before dosing. Subjects in SAD-HS, MAD-HS, MAD-CP, and MAD-UP will be 
assigned to EP547 or placebo in a 3:1 ratio (EP547:placebo), with a block size of 4 for the MAD 
segments. The randomization code for each dose level will be generated by the CRO and 
managed by the Sponsor. Subjects in SD-CP and SD-UP will only receive EP547 and do not 
require randomization. 
Subjects who withdraw for any reason without completing all screening evaluations successfully 
will be considered “screening failures”. 
 
9.3.2. 
Blinding 
Although SAD-HS and all of the MAD segments will be conducted in a blinded manner (ie, 
subjects, Investigator, study-site personnel, and CRO staff not involved in PK sample analysis or 
regulatory reporting will be blinded to treatment), the Sponsor, including the Sponsor Medical 
Monitor, will be unblinded to treatment assignment to assess safety on an ongoing basis. 
Communication between the blinded Investigator and unblinded Sponsor will be managed to 
ensure treatment assignment is not revealed. The SD-CP and SD-UP segments are not placebo- 
controlled (ie, all subjects will receive EP547) and will be conducted in an unblinded manner. 
9.3.2.1. 
Emergency Unblinding 
Blinding codes should only be broken in emergency situations for reasons of subject safety and 
when knowledge of the treatment assignment will impact the clinical management of the subject. 




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enrolled in the study. Any questions regarding eligibility may be discussed with the Medical 
Monitor. 
The following assessments may be conducted over more than 1 day but must be completed 
between Day -28 and Day -2: 
• Completion of informed consent before performance of any study procedures or 
assessments 
• Medical history 
• Height 
• Complete physical examination 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− HIV, HBV, and HCV serology 
− Drug and cotinine screens (SAD-HS and SD-CP only) 
− Alcohol screen 
− Serum pregnancy test (females only) 
− Follicle-stimulating hormone (FSH) (females only) 
− Chemistry and hematology 
− Urinalysis (SAD-HS and SD-CP only) 
− Coagulation 
• Assessment of baseline concomitant medications, including: 
− All medications taken within 14 days before Screening 
− Medications taken to treat a cholestatic disorder or ESRD within 12 weeks before 
Screening (SD-CP and SD-UP only) 
− Medications known to impact pruritus within 4 weeks before Screening (SD-CP 
and SD-UP only) 
• Assessment of AEs 
• Eligibility check 
Screening results will be reviewed by the Investigator to determine the subject’s eligibility. 
Subjects who are confirmed to be eligible will be asked to return to the site for Visit 2 (Day -1) 
to enroll in the study. 


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9.4.1.1.2. Visit 2 (Day -1) - Admission 
Subjects who meet all eligibility requirements will be admitted for mandatory confinement at the 
clinic during Visit 2 (Day -1) and will undergo the following assessments: 
• 
 
 
 
• Abbreviated physical examination 
• Laboratory assessments: 
− Drug and cotinine screens (SAD-HS and SD-CP only) 
− Alcohol screen 
− Urine pregnancy test (SAD-HS and SD-CP females only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Hemodialysis (SD-UP only) 
• Eligibility check 
Visit 2 (Day -1) results will be reviewed by the Investigator to confirm the subject’s eligibility. 
Subjects who are confirmed to be eligible will continue to remain confined to the clinic until 
completion of Visit 2 (Day 3). 
 
9.4.1.2. 
Treatment Period 
 
9.4.1.2.1. Visit 2 (Day 1) - Predose 
For subjects in SD-UP, Day 1 must be the day after a hemodialysis session. Subjects will 
continue to be confined at the clinic during Visit 2 (Day 1) and will undergo the following 
assessments before administration of study drug: 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis (SAD-HS and SD-CP only) 
− 
 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment 


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• Continuous digital 12-lead ECG recording for Holter monitoring beginning 
approximately 1 hour before study drug administration (SAD-HS only) 
• Urine collection for PK assessment from -6 to 0 hours predose (SAD-HS only) 
• Allocation to EP547 or placebo in a 3:1 ratio (SAD-HS only) 
Upon completion of the assessments listed above, study drug is to be administered orally as 
intact capsules (swallowed whole, not chewed or crushed), and taken with water. All dose levels 
in SAD-HS will be dosed according to a sentinel dosing design (Section 7.1.1). All subjects in 
SD-CP and SD-UP will receive EP547. 
 
9.4.1.2.2. Visit 2 (Day 1) - Postdose 
Subjects will continue to be confined at the clinic during Visit 2 (Day 1) and will undergo the 
following assessments after administration of study drug: 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Urine collection for PK assessment from >0 to 6, >6 to 12, and >12 to 18 hours 
postdose (SAD-HS only) 
• Blood sample draw for PK assessment at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 
12 hours postdose 
• Continue 24-hour continuous digital 12-lead ECG recording for Holter monitoring 
(SAD-HS only) 
• Vital signs at 1, 2, 4, 9, and 12 hours postdose 
• Standard 12-lead ECG at 3 hours postdose 
9.4.1.2.3. Visit 2 (Day 2) 
Subjects will continue to be confined at the clinic during Visit 2 (Day 2) and will undergo the 
following assessments: 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis (SAD-HS and SD-CP only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment at 18, 24, and 36 hours postdose 
• End 24-hour continuous digital 12-lead ECG recording for Holter monitoring 
(SAD-HS only) 
• Urine collection for PK assessment from >18 to 24, >24 to 30, and >30 to 36 hours 
postdose (SAD-HS only) 


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• Vital signs at 24 hours postdose 
9.4.1.2.4. Visit 2 (Day 3) - Discharge 
Subjects will continue to be confined at the clinic during Visit 2 (Day 3) until completion of the 
following assessments: 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis (SAD-HS and SD-CP only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Vital signs at 48 hours postdose 
• Standard 12-lead ECG at 48 hours postdose 
• Urine collection for PK assessment from >36 to 42 and >42 to 48 hours postdose 
(SAD-HS only) 
• Blood sample draw for PK assessment at 48 hours postdose 
Subjects may be discharged from the clinic after completion of all assessments listed above. 
 
9.4.1.3. 
Safety Follow-Up Visit (Visit 3 [Day 8]) 
Subjects are to arrive at the clinic after an overnight fast (at least 8 hours) and will undergo the 
following assessments during the ±1-day visit window for Visit 3 (Day 8): 
• Complete physical examination 
• Vital signs 
• Body weight 
• Laboratory assessments: 
− Serum pregnancy test (females only) 
− Chemistry and hematology 
− Urinalysis (SAD-HS and SD-CP only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment 
9.4.1.4. 
Early Study Termination Visit 
Subjects who discontinue from the study early should have the Early Study Termination Visit 
conducted as soon as possible after the dose of study drug, ideally within 2 days after the dose of 


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study drug. Subjects are to arrive at the clinic after an overnight fast (at least 8 hours) and will 
undergo the following assessments during the Early Study Termination Visit: 
• Complete physical examination 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− Serum pregnancy test (females only) 
− Chemistry and hematology 
− Urinalysis (SAD-HS and SD-CP only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 
9.4.2. 
MAD Segments 
 
9.4.2.1. 
Screening Period 
 
9.4.2.1.1. Visit 1 (Day -28 to Day -4) 
During the screening period, subjects are to arrive at the clinic after an overnight fast (at least 
8 hours) and will undergo assessments at the site to determine their study eligibility. Subjects 
will be screened and should meet all inclusion criteria and none of the exclusion criteria to be 
enrolled in the study. Any questions regarding eligibility may be discussed with the Medical 
Monitor. 
The following assessments may be conducted over more than 1 day but must be completed 
between Day -28 and Day -4, unless specified otherwise: 
• Completion of informed consent before performance of any study procedures or 
assessments 
• Medical history 
• Height 
• Complete physical examination 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− HIV, HBV, and HCV serology 
− Drug and cotinine screens (MAD-HS and MAD-CP only) 
















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approval of the Sponsor. Subjects will undergo the following assessments after an overnight fast 
(at least 8 hours) during the ±1-day visit window for Visit 3 (Day 14): 
• 
 
 
 
 
 
• Abbreviated physical examination 
• Vital signs 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis (MAD-HS and MAD-CP only) 
− 
 
− Serum pregnancy test (females only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment 
9.4.2.3.2. Visit 4 (Day 21) 
Subjects are to return to the site to complete scheduled assessments for Visit 4 (Day 21). 
However, a nurse visit to their home may be permitted on a case-by-case basis with prior 
approval of the Sponsor. Subjects will undergo the following assessments after an overnight fast 
(at least 8 hours) during the ±2-day visit window for Visit 4 (Day 21): 
• 
 
 
 
 
 
• Complete physical examination 
• Vital signs 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis (MAD-HS and MAD-CP only) 
− 
 
− Serum pregnancy test (females only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 


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• Blood sample draw for PK assessment 
9.4.2.4. 
Early Study Termination Visit 
Subjects who discontinue from the study early should have the Early Study Termination Visit 
conducted as soon as possible after the last dose of study drug, ideally within 2 days after the last 
dose of study drug. Subjects are to arrive at the clinic after an overnight fast (at least 8 hours) and 
will undergo the following assessments during the Early Study Termination Visit: 
• 
 
 
 
 
 
• Complete physical examination 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− Serum pregnancy test (females only) 
− Chemistry and hematology 
− Urinalysis (MAD-HS and MAD-CP only) 
• Assessment of concomitant medication usage 
• Assessment of AEs 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drugs 
EP547 lockable capsules will be prepared by the central vendor to contain the desired amount of 
drug substance to meet the needs of the given dose level. Each lockable placebo capsule will 
contain placebo such as microcrystalline cellulose and will be manufactured in a way to ensure 
the study blind. Each dose may be made up of multiple capsules of the same or different capsule 
strengths. 
10.2. 
Study Drug Packaging and Labeling 
Just-in-time manufacturing will be used to supply the study drug, EP547 or placebo capsules, at 
the specified dose level selected for each segment. Each study drug kit will be labeled with a 
unique kit number and will be supplied to study sites in a blinded manner. Study drug shipments 
will be sent to sites with code break envelope(s) containing the treatment assignment(s) that can 
be utilized by the site for emergency unblinding. 
10.3. 
Study Drug Storage 
The study drug capsules may be stored at controlled room temperature, 20°C to 25°C 
(68°F to 77°F), with excursions to 10°C (50°F). 
 
10.4. 
Study Drug Administration 
Study drug is to be administered orally as intact capsules (swallowed whole, not chewed or 
crushed), and taken with water. During the MAD segments, doses are to be administered daily at 
approximately the same time of day over 7 days. There are no fasting or fed requirements for 
study drug administration (only for study procedures as described in Section 9.4). Subjects who 
routinely take a bile acid sequestrant (eg, cholestyramine, colestipol, or colesevelam) will be 
instructed to hold their morning dose until 2 hours after study drug administration. If their bile 
acid sequestrant baseline dosing regimen does not allow for a 2-hour hold, dosing of these 
medications must be held for a minimum of 1 hour after study drug administration. Alternatively, 
the bile acid sequestrant may be taken at least 4 hours prior to study drug administration. 
10.5. 
Additional Dosing Instructions for Subjects with Uremic Pruritus 
For subjects in SD-UP, Day 1 (study drug administration) must be the day after a hemodialysis 
session. 
For subjects in MAD-UP, study drug will be administered 4 to 6 hours before the hemodialysis 
session on Days 1, 4, and 6 and at approximately the same time of day on Days 2, 3, 5, and 7 
(days without a hemodialysis session). 
 
10.6. 
Study Drug Dispensing and Accountability 
All study drug is to be administered at the study site. The site staff will be responsible for 
documenting and maintaining study drug dispensation and accountability records. 


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10.7. 
Study Drug Handling and Disposal 
Study drug will be sent to the study site under appropriate storage conditions. Upon receipt of 
study drug, study staff are to open the shipment, and verify that the amount and identity of the 
contents match that stated in the enclosed shipping form. The Sponsor (or designee) is to be 
notified immediately about any irregularities, discrepancies, or damage. 
All study drug will be provided for use only in this study and is not to be used for any other 
purpose. The study staff will maintain a full record of study drug accountability as described in 
Section 10.6. 
Upon completion of the study, used and unused study drug and study drug containers are to be 
returned to the Sponsor (or designee) or, if prior Sponsor approval is obtained, disposed of in 
accordance with applicable site procedures. Study staff must maintain documentation of any 
missing or unreturned study drug. The final disposition of all study drug received at the site is to 
be documented. 
10.8. 
Product Quality Complaints 
A product quality complaint (PQC) is defined as any suspicion of a product defect or deficiency 
related to manufacturing, labeling, or packaging (ie, any dissatisfaction relative to the identity, 
quality, durability, reliability, safety, effectiveness, or performance of a product, including its 
labeling or package integrity). A PQC may have an impact on the safety and efficacy of the 
product. Timely, accurate, and complete reporting and analysis of PQC information from studies 
are crucial for the protection of subjects. 
All initial PQCs must be reported to the Sponsor or CRO by study-site personnel within 24 hours 
after being made aware of the potential defect. Whenever possible, the associated product should 
be maintained in accordance with the label instructions pending further guidance from the 
Sponsor. 


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11. 
SAFETY ASSESSMENTS 
Safety evaluations, including AEs, concomitant medications, medical history, vital signs, body 
weight, physical examinations, standard 12-lead ECGs, and laboratory evaluations of safety will 
be performed as indicated in the Schedule of Assessments (Appendix A for the single dose 
segments and Appendix B for the multiple dose segments). 
Although SAD-HS and all of the MAD segments will be conducted in a blinded manner (ie, 
subjects, Investigator, study-site personnel, and CRO staff not involved in PK sample analysis or 
regulatory reporting will be blinded to treatment), the Sponsor, including the Sponsor Medical 
Monitor, will be unblinded to treatment assignment to assess safety on an ongoing basis. The 
SD-CP and SD-UP segments are not placebo-controlled (ie, all subjects will receive EP547) and 
will be conducted in an unblinded manner. 
 
11.1. 
Adverse Events 
11.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable or unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product. 
Medical conditions present at baseline that worsen in severity or frequency after exposure to 
study drug are considered treatment-emergent AEs (TEAEs). Planned hospital admissions or 
surgical procedures for an illness or a disease that existed before administration of study drug, 
and for which the condition has not worsened since starting study drug, are not to be considered 
TEAEs/treatment-emergent SAEs. Events with emergency room visits that are less than 24 hours 
will also not be considered SAEs unless they meet one of the criteria listed in Section 11.2.1. 
Clinically significant abnormal laboratory tests, 12-lead ECG assessments, or vital sign results 
may, in the opinion of the Investigator, constitute an AE. However, whenever possible, the 
underlying diagnosis should be listed in lieu of associated abnormal results. Abnormalities 
deemed not clinically significant by the Investigator should not be reported as AEs. 
 
11.1.2. 
Determining Severity of Adverse Events 
The Investigator will assess the severity of an AE using the 3-point scale below: 
• Mild - Awareness of a sign or symptom that is easily tolerated 
• Moderate - Discomfort enough to cause interference with usual activity 
• Severe - Incapacitating or causes inability to work or undertake usual activity 


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11.1.3. 
Determining Causality of Adverse Events 
Causality refers to the relationship of the event to the study drug (EP547 or placebo). The 
Investigator will assess the causality of the event according to the following criteria: 
• Not related - A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
• Related - A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug, which 
may or may not reasonably have been produced by a number of other factors including 
underlying disease, complications, concomitant drugs, or concurrent treatments; and/or 
that could not be reasonably explained by other factors such as underlying disease, 
complications, concomitant drugs, or concurrent treatments; and/or disappears or 
decreases on cessation or reduction in study drug dose; and/or reappears or worsens when 
the study drug is administered. 
 
11.1.4. 
Recording Adverse Events 
All AEs must be recorded in the source documents and in the eCRFs provided by the Sponsor 
from the signing of the ICF until the end of study participation. AEs will be assessed for 
likelihood of causal relationship to the study drug (EP547 or placebo) and severity. 
The new onset of signs, symptoms, or other findings that occur before signing of the ICF will be 
captured as medical history (Section 11.4). 
 
11.1.4.1. Special Instructions for Recording Adverse Events in the eCRF 
Diagnosis versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF rather than 
the individual signs and symptoms (eg, record only hepatitis rather than elevated transaminases, 
bilirubin, and jaundice). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an SAE or AE on the eCRF. If a diagnosis is subsequently 
established, it should be reported as follow-up and should replace the individual signs and/or 
symptoms as the event term on the eCRF, unless the signs/symptoms are clinically significant. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, clinical sequelae or a cascade of events) 
should be identified by their primary cause. For example, if severe vomiting is known to result in 
dehydration, it is sufficient to record only vomiting as an SAE or AE on the eCRF. However, 
medically significant AEs occurring secondary to an initiating event that are separated in time 
should be recorded as independent events on the eCRF. For example, if severe vomiting leads to 
acute renal failure, both events should be recorded on the eCRF. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
timepoints. Such events should only be recorded once on the eCRF. If a persistent AE becomes 
more severe or lessens in severity, it should be recorded as a new AE on the eCRF. 


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A recurrent AE is one that occurs and resolves between subject evaluation timepoints, and 
subsequently recurs. Each reoccurrence of an AE should be recorded on the eCRF. 
Abnormal Laboratory Values or Vital Signs 
Protocol defined laboratory values and vital signs will be reported as AEs if the abnormal 
laboratory or vital sign result: 
• Requires an adjustment in the study drug(s) or discontinuation of treatment; 
• Requires additional testing, excluding repeat testing of the lab in question, or surgical 
intervention; 
• Is associated with accompanying signs/symptoms that are not considered part of a 
pre-existing diagnosis or syndrome; or 
• Is considered clinically significant by the Investigator 
If an abnormal laboratory value or vital sign is the result of an evaluation of clinical signs, 
symptoms, or suspected diagnosis during the conduct of the study, the signs/symptoms or 
diagnosis should be reported as an AE (or if appropriate, an SAE) only if clinically significant, 
and the associated laboratory value or vital sign should be considered additional information that 
must be collected on the relevant eCRF. 
11.2. 
Serious Adverse Events 
11.2.1. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence, that at any dose: 
• Results in death; 
• Is life-threatening, ie, the subject is, in the opinion of the Investigator, at immediate risk 
of death from the event as it occurred, (it does not include an event that, had it occurred 
in a more severe form, might have caused death); 
• Requires hospital admission or prolongs hospitalization. Planned hospital admissions or 
surgical procedures for an illness or a disease that existed before administration of study 
drug, and for which the condition has not worsened since starting study drug, are not to 
be considered SAEs. Emergency room visits that are less than 24 hours will also not be 
considered SAEs; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is a medically significant event that, based on appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
Note: A distinction should be drawn between SAEs and severe AEs. Severity is a measure of the 
intensity of an AE, while the criteria for seriousness are indications of adverse subject outcomes 
for regulatory reporting purposes. A severe AE is not necessarily considered an SAE. For 
example, a headache that persists for several hours may be considered a severe AE but not an 


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SAE. Conversely, a wound infection that may be considered minor could be an SAE if it 
prolonged hospitalization. 
 
11.2.2. 
Reporting Serious Adverse Events 
The Investigator and the Sponsor will monitor safety for this study. A Serious Adverse Event 
Report (SAER) Form is to be completed for each SAE occurring after signing of the ICF until 
30 days after the last dose of study drug, regardless of causality. The SAER Form must be 
submitted to the Sponsor or designee within 24 hours of the Investigator’s first awareness of the 
event. Follow-up information to all SAEs should be submitted to the Sponsor, or designee, in the 
same timeframe as initial reports. 
All SAE reports must be reported within 24 hours of the Investigator's knowledge of the 
event to 
. Any supporting documentation (eg, medical records) sent to 
Novotech with the SAER Form must have subject identifying information (eg, subject names, 
subject addresses, and medical records number) redacted by the site. 
All SAEs will be followed until resolution or medical stabilization (in cases where resolution 
would not be expected). 
In accordance with applicable regulations and local laws, the Sponsor or designee will report all 
serious and unexpected AEs assessed as related to study drug by the Investigator and/or Sponsor, 
to the regulatory authorities within the required timeframe. The Investigator will be responsible 
for reporting this safety information to their IRBs/IECs. 
If the Investigator becomes aware of an SAE any time after study completion and determines it is 
related to the study drug, the SAE must be reported to the Sponsor within 24 hours of the 
Investigator's knowledge of the SAE. 
 
11.2.3. 
Pregnancy 
Pregnancy in and of itself is not an AE, although pregnancies occurring in subjects or partners of 
male subjects are considered immediately reportable events. If a pregnancy occurs in a subject, 
study drug must be discontinued immediately. The pregnancy must be reported to Novotech via 
email at 
 within 24 hours of the Investigator’s knowledge of the 
pregnancy using the Pregnancy Reporting Form. 
The Investigator will follow the pregnant woman until completion of the pregnancy, and must 
notify the Sponsor, or designee, of the outcome within 24 hours of the Investigator’s knowledge 
of the pregnancy outcome. The Investigator will provide this information on the Pregnancy 
Reporting Form. This notification includes pregnancies resulting in live, “normal” births. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE (ie, spontaneous abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, 
or congenital anomaly), the Investigator should follow the procedures for reporting SAEs 
(ie, report the event to Novotech via email at 
 within 24 hours of the 
Investigator’s knowledge of the event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
causality) should be reported as SAEs to the Sponsor. In addition, any infant death or congenital 


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anomaly occurring after study completion that the Investigator suspects is related to the in utero 
exposure to the study drug should also be reported to the Sponsor. 
 
11.3. 
Concomitant Medications 
The addition of concomitant medications is not permitted during the study, except for 
acetaminophen (up to 1 gram per 24-hour period) as permitted by the Investigator for the 
treatment of headache or any other pain. Other medication to treat AEs may only be prescribed if 
deemed necessary by the Investigator. For subjects with cholestatic or uremic pruritus, dosages 
of any concomitant therapies are to remain stable for the duration of this study unless 
adjustments are needed for subject safety. 
Any change in regimen for any concomitant medication other than acetaminophen must be 
reported to the Sponsor in a timely manner and done in consultation with the Medical Monitor if 
subject safety is not immediately compromised. 
All medications taken within 14 days before Screening and details of concomitant medications 
from Screening through the end of study participation should be recorded in the subject’s source 
documents and in the eCRF. In addition, medications taken to treat a cholestatic disorder or 
ESRD within 12 weeks before Screening or medications known to impact pruritus within 
4 weeks before Screening should also be recorded. 
 
11.4. 
Medical History 
The Investigator will collect and review the subject’s medical history to evaluate the subject’s 
eligibility for study participation. The new onset of signs, symptoms, or other findings that occur 
from before signing of the ICF will be captured as medical history. 
 
11.5. 
Vital Signs 
Vital signs, including supine systolic and diastolic blood pressure, pulse rate, oxygen saturation, 
body temperature, and respiratory rate, will be measured after at least 5 minutes of rest. 
For the single dose segments, vital signs will be measured at Screening; predose and at 1, 2, 4, 9, 
and 12 hours postdose on Day 1; 24 hours postdose on Day 2; 48 hours postdose on Day 3; on 
Day 8; and Early Study Termination, if applicable. The time margin for vital signs is 15 minutes 
for 1 and 2 hours postdose and 15 minutes for 4, 9, and 12 hours postdose. 
For the multiple dose segments, vital signs will be measured at Screening; predose and at 1, 2, 4, 
9, and 12 hours postdose on Day 1; predose on Days 2 to 7; 24 hours after the last dose on 
Day 8; on Days 14 and 21; and at Early Study Termination, if applicable. The time margin for 
vital signs is 15 minutes for 1 and 2 hours postdose and 20 minutes for 4, 9, and 12 hours 
postdose. 
 
11.6. 
Body Weight 
Body weight should be measured with no shoes on and using a calibrated scale throughout the 
study. 


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11.7. 
Physical Examinations 
Complete physical examinations will include but are not limited to an assessment of general 
appearance, skin, HEENT (head, eyes, ears, nose, throat), musculoskeletal, thyroid/endocrine, 
cardiovascular, chest/lung, neurologic, abdomen, and extremities/general body systems, 
including standard Child-Pugh scoring assessments to determine whether ascites or hepatic 
encephalopathy are present. Abbreviated physical examinations will include HEENT, 
cardiovascular, chest/lung, abdomen, and extremities. 
 
11.8. 
Standard 12-Lead Electrocardiograms 
12-lead ECGs are to be performed with subjects in a supine position after at least 5 minutes of 
rest. For the single dose segments, the standard 12-lead ECG is to be performed during 
Screening; predose and at 3 hours postdose on Day 1; 48 hours postdose on Day 3; and Early 
Study Termination, if applicable. For the multiple dose segments, the standard 12-lead ECG is to 
be performed at Screening; predose and at 3 hours postdose on Day 1; predose on Day 3; 
24 hours after the last dose on Day 8; and Early Study Termination, if applicable. The time 
margin for 12-lead ECGs is 20 minutes for 3 hours postdose. 
11.9. 
Laboratory Evaluations of Safety 
Samples for the following laboratory tests will be collected after an overnight fast (at least 
8 hours): 
• Chemistry: sodium, albumin, ALP, bicarbonate, calcium, bile acids, corrected calcium, 
chloride, total and direct bilirubin, AST, ALT, BUN, urea, creatinine, magnesium, 
phosphorus, potassium, creatine phosphokinase (CPK), total cholesterol, triglycerides, 
high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol 
(LDL-c), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), and total 
protein 
• Hematology: hemoglobin, hematocrit, white blood cell (WBC) count (total and 
differential), red blood cell count, platelet count, and platelet volume 
• Urinalysis (dipstick) (SAD-HS, SD-CP, MAD-HS, and MAD-CP only): leukocyte 
esterase, nitrites, pH, protein, specific gravity, glucose, occult blood, ketones, bilirubin, 
urobilinogen, and albumin; microscopic analysis is to be performed only if protein, 
leukocyte esterase, blood or nitrite is positive 
• Coagulation: activated partial thromboplastin time (aPTT), INR, and prothrombin time 
(PT) 
• Pregnancy testing: urine testing on Day -1 for all female SAD-HS, SD-CP, MAD-HS, 
and MAD-CP subjects and serum testing for all female subjects for all other instances 
The urine pregnancy test for female subjects will be conducted locally; all other planned 
laboratory evaluations of safety will be conducted at a central laboratory. See the laboratory 
manual for additional details. 


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11.10. 
Other Laboratory Evaluations 
Samples for the following laboratory tests will be collected after an overnight fast (at least 
8 hours): 
• Serology: HIV, HBV, HCV 
• Non-childbearing confirmation: FSH (females only) 
• Drug screen (SAD-HS, SD-CP, MAD-HS, and MAD-CP only): Cannabinoids, cocaine, 
opiates, amphetamines, barbiturates, and benzodiazepines 
• Cotinine screen (SAD-HS, SD-CP, MAD-HS, and MAD-CP only) 
• Alcohol screen 
The drug and cotinine screens on Day -1 and the alcohol screen at Screening and Day -1 will be 
conducted locally; all other planned laboratory evaluations will be conducted at a central 
laboratory. See the laboratory manual for additional details. 
 
11.11. 
Subject Safety Guidelines 
11.11.1. 
Potential Side Effects 
Results from nonclinical studies of EP547 demonstrate a nonclinical profile suitable for 
advancement into human clinical studies. Refer to the Investigator’s Brochure for additional 
EP547 information regarding nonclinical study results. 
 
11.11.2. 
Overdose 
No specific information is available on the treatment of overdose of EP547. Additionally, there is 
no specific antidote to EP547. In a case of overdose, appropriate supportive measures should be 
employed. 


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12. 
PHARMACOKINETICS ASSESSMENT 
Blood, urine, and skin samples for PK will be utilized to analyze EP547 concentrations; the 
metabolite profile may also be analyzed from these samples. 
 
12.1. 
Blood Sampling for Pharmacokinetics 
Blood sampling for PK of EP547 will be collected as follows: 
• SAD-HS, SD-CP, and SD-UP: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 
12 hours postdose on Day 1; 18, 24, and 36 hours postdose on Day 2; 48 hours 
postdose on Day 3; and at follow-up on Day 8. 
• MAD-HS: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 18 hours 
postdose relative to the dose of study drug on Day 1; predose on Day 2 through 
Day 6; predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hours postdose 
relative to the last dose of study drug on Day 7; and at follow-up on Day 14 and 
Day 21. 
• MAD-CP: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 18 hours 
postdose relative to the dose of study drug on Day 1; predose on Day 2; predose on 
Day 4; predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hours postdose 
relative to the last dose of study drug on Day 7; and at follow-up on Day 14 and 
Day 21. 
• MAD-UP: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 18 hours 
postdose relative to the dose of study drug on Days 1, 2, and 6; predose on Day 4; 
predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, and 24 hours postdose relative to 
the last dose of study drug on Day 7; and at follow-up on Day 14 and Day 21. 
The MAD dosing and PK blood sampling schedule is summarized in Appendix C. The 
assessment window for blood sample collection timepoints for the single and multiple dose 
segments is also included in Appendix C. 
 
12.2. 
Urine Collection for Pharmacokinetics (SAD-HS Only) 
Urine sampling for PK of EP547 will be collected at predose (-6 to 0 hours) and from >0 to 6, 
>6 to 12, and >12 to 18 hours postdose on Day 1; >18 to 24, >24 to 30, and >30 to 36 hours 
postdose on Day 2; and >36 to 42 and >42 to 48 hours postdose on Day 3. 
 
12.3. 
Skin Biopsy for Pharmacokinetics (Last Dose Level for MAD-HS 
and All Dose Levels for MAD-CP and MAD-UP Only) 
Given that EP547 is hypothesized to be an inverse agonist (inhibitor) of MRGPRX4 in the skin 
to reduce itch, three 3-mm biopsies of the skin from the back will be performed under local 
anesthesia on Day 1 at 2 hours postdose with an assessment window of +30 minutes. One biopsy 
will be used for PK to evaluate drug concentrations at the site of action and the other 2 biopsies 
will be used for PD assessment as described in Section 14.5 to further elucidate the mechanism 
of action of EP547. 


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13. 
CARDIODYNAMIC ASSESSMENT 
13.1. 
Holter Monitoring for 12-Lead ECG Acquisition and Subsequent 
Cardiodynamic Analysis (SAD-HS Only) 
Clinical evaluation of QT/QTc interval prolongation risk and proarrhythmic potential will be 
conducted for EP547, which is recommended by the US FDA for all new non-antiarrhythmic 
drugs having systemic bioavailability (FDA 2005a). Continuous digital 12-lead ECGs will be 
recorded from approximately 1 hour predose on Day 1 to 24 hours postdose on Day 2 under 
constant supervision for subjects in SAD-HS only. Subjects will rest quietly in the supine 
position for at least 10 minutes before each extraction timepoint and for 5 minutes during each 
extraction with the understanding that a full undisturbed supine period may not be possible given 
other assessments at competing timepoints. Twelve-lead ECG extraction timepoints will be 
at -30, -20, and -10 minutes predose on Day 1; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hours 
postdose on Day 1; and at 18 and 24 hours postdose on Day 2. Twelve-lead ECGs will be 
extracted from the continuous recording from a 5-minute window preceding the ECG timepoints 
and scheduled to end 1 to 2 minutes before the scheduled PK draw to conduct early QT 
assessment based on concentration-QT analysis. Subjects are to continue fasting through 4 hours 
postdose as food can impact the results. 








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15. 
STATISTICS 
A formal Statistical Analysis Plan (SAP) will be prepared and finalized before database lock. 
Additional statistical analysis details will be included in the SAP. 
 
15.1. 
Populations for Analysis 
The following analysis populations will be considered: 
• Enrolled Population: This population will comprise all subjects who sign the ICF to 
participate in the study, complete the screening visit procedures, and meet all eligibility 
criteria for enrollment. 
• Safety Population: This population will comprise all subjects who receive at least 1 dose 
of study drug. 
• PK Population: This population will comprise all subjects who receive at least 1 dose of 
EP547 and provide adequate blood samples for bioanalysis. 
• PD Population: This population will comprise all subjects belonging to the Safety 
Population without major protocol deviations. 
 
15.2. 
Outcome Measures 
15.2.1. 
Primary Safety Outcome Measures 
Primary safety outcome measures include: 
• AEs 
• Clinical laboratory assessments 
• Vital signs and body weight 
• Standard 12-lead ECGs 
• Physical examinations 
15.2.2. 
Secondary Pharmacokinetic and Cardiodynamic Outcome Measures 
Secondary PK and cardiodynamic outcome measures include: 
• Plasma EP547 and metabolites (as applicable) concentrations 
• Plasma PK parameters estimated using noncompartmental analysis (NCA), as 
appropriate 2: 
− SAD segments: Cmax, tmax, kel, t1/2, AUC∞, AUCt, %AUCextra, CL/F, and Vz/F 
− MAD segments: Cmax, Ctrough, tmax, kel, t1/2, AUCτ (as appropriate), AUCt, CL/F, 
Vz/F, and Rss 
 
 
 
 
2 The PK parameters definitions are in Section 4. 






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16. 
QUALITY CONTROL AND DATA MANAGEMENT 
16.1. 
Data Quality Assurance 
The following measures will be implemented to ensure accuracy, consistency, completeness, and 
reliability of data: 
• Investigator discussions 
• Site initiation training 
• Early site visits following enrollment 
• Routine site management 
• Ongoing site communication and training 
• Periodic site monitoring 
• Review of the eCRF against source data for all subjects 
• Data management quality control (QC) checks 
• Statistical QC checks 
16.2. 
Data Management 
Based on the final eCRF, a database will be designed and built to meet US FDA: 21 Code of 
Federal Regulations (CFR) 11 requirements. A Data Management Plan will be written specifying 
the procedures that will be used for data cleaning, medical coding, SAE reconciliation, QC, 
laboratory data, and data cleaning that will occur for the study. A Data Validation Plan will be 
written and edit checks will be programmed and validated. 
16.3. 
Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
International Conference on Harmonisation (ICH) Guideline for GCP, and applicable regional 
regulations and guidelines. 
A monitor (or monitors) will review and verify protocol compliance with a focus on AE/SAE 
reporting, eCRF data, source documentation, ICFs, and any other study-related documentation, 
including review of site pharmacy procedures, drug accountability documentation, and drug 
storage facilities and records. 
Monitoring will be on an ongoing basis. Before database lock, 100% eCRF data verification will 
be performed against the source documents. The Investigator will agree to the monitor(s) making 
periodic site visits during the study. The monitor(s) and the study staff will agree upon the timing 
of these visits. 
 
16.4. 
Confidentiality and Auditing 
The Investigator, the Sponsor, and the Sponsor’s representatives will preserve the confidentiality 
of all subjects participating in this study, in accordance with ICH GCP, local regulations, and 
institutional requirements. Only initials, date of birth, and study subject number will be used to 


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identify subjects on the eCRFs and other study-related documents submitted to the Sponsor (or 
designee). Documents that are not submitted to the Sponsor (eg, ICFs) should be kept in strict 
confidence by the investigative staff. 
In compliance with ICH GCP, it is required that the Investigator and institution permit 
authorized representatives of the Sponsor, the IRB/IEC, the US FDA, and other appropriate 
regulatory authority or health authority inspectors direct access to all study-related sites, source 
data, documents, and reports for verification of study records and data. Direct access is the 
permission to examine, analyze, verify, and reproduce any records and reports that are important 
to the evaluation of a clinical study. The Investigator is obligated to inform and obtain consent 
from the subject to permit these representatives to have access to their study-related records for 
this verification. Any party (eg, domestic and foreign regulatory authorities, Sponsors, and 
auditors) with direct access should take all reasonable precautions within the constraints of the 
applicable regulatory requirement(s) to maintain the confidentiality of subjects. 
 
16.5. 
Case Report Forms 
eCRFs will be used for this study. Site personnel will receive training on eCRF completion. Each 
eCRF is to be reviewed and approved by the Investigator. 
During periodic monitoring visits, the Investigator will make the eCRFs available to the study 
monitor so that he or she may verify the data entries with the source documentation. 
 
16.6. 
Source Documents 
The Investigator will prepare and maintain adequate and accurate source documents (eg, medical 
records, 12-lead ECG results, and raw data collection forms) to record all observations and other 
pertinent data for each subject enrolled into the study. The data recorded on the eCRFs will be 
derived from these source documents. The Investigator will ensure that data on the eCRFs and 
completed queries are accurate, consistent with source documentation, and submitted to the 
Sponsor in a timely manner. The Investigator will also ensure that all data on required study logs 
are accurate and kept up to date. 
16.7. 
Records Retention 
The Investigator must maintain essential study documents (protocol and amendments, completed 
eCRFs, source documentation, signed ICFs, relevant correspondence and approvals, and all other 
supporting documentation) until notified by the Sponsor. Subject identification codes (subject 
names and corresponding study numbers) will be retained for this same period and stored 
separately. Custody of the records may be transferred to another responsible party, acceptable to 
the Sponsor, which agrees to abide by the retention policies. Written notice of transfer must be 
submitted to the Sponsor. The Investigator must contact the Sponsor before disposing of any 
study records. 
Records retention will follow the data protection requirements in each country. 
 
16.8. 
Informed Consent 
Written informed consent will be obtained from each subject before any study-related procedures 
are performed. The Investigator has an ethical and legal responsibility to ensure each subject 


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being considered for inclusion in the study is given a full explanation of the study. The 
Investigator, or his/her designee, shall inform each subject, in writing, of all aspects pertaining to 
participation in the study, including (but not limited to) aims, methods, anticipated benefits, and 
potential risks. Subjects will have the opportunity to inquire about details of the study and to 
decide whether to participate. Subjects should understand that they are free to refuse to 
participate in, or to withdraw from, the study at any time without prejudice or loss of medical 
care to which they are otherwise entitled. Each subject must personally sign and date a 
study-specific ICF to be a subject in the study. The ICF must be countersigned by the site 
Investigator (or designee) who conducted the informed consent discussion. This will be 
documented on a written ICF. Each ICF will include the elements required by US 21 CFR 50 and 
ICH E6, Section 4.8. The Investigator agrees to obtain approval from the Sponsor of any written 
informed consent for use in the study before submission to the IRB/IEC. 
Each subject who provides written informed consent for the study (by signing and dating the 
ICF), will be given a copy of the signed ICF. The original will be kept in the subject’s medical 
record or study chart as permitted by the institution. The Investigator will inform subjects of new 
information that may be relevant to the subjects’ willingness to continue participation in the 
study according to local ethics requirements. 
It is important to obtain complete follow-up for all subjects. Every attempt should be made to 
undertake all protocol-specified assessments and complete the eCRFs except for those subjects 
who specifically withdraw consent for release of such information. 
Subjects will be provided a separate consent form before providing blood samples for genetic 
analysis and must be willing and able to provide consent as described above. 
 
16.9. 
Institutional Review Board/Independent Ethics Committee 
The Investigator will not begin the study until the protocol and ICF have been approved by the 
appropriate independent IRB/IEC. Any amendments to the protocol must also be approved in 
writing by the Sponsor and IRB/IEC, before implementation by the Investigator, except where 
necessary to eliminate an immediate hazard to subjects. 
All IRB/IEC correspondence, including progress reports, will be retained on file at the site. 


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17. 
STUDY MANAGEMENT 
17.1. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any major way without proper 
notification to the Sponsor (or designee). Only the Sponsor may revise the protocol. Any change 
in study conduct considered necessary by the Investigator will be made only after consultation 
with the Sponsor, who will then issue a formal protocol revision to implement the change and 
obtain regulatory approval. The only exception is when the Investigator considers a subject’s 
safety to be compromised if immediate action is not taken. 
In the event of an important deviation from the protocol, the Investigator or designee must 
contact the Sponsor or representative at the earliest possible time. This will allow an early joint 
decision regarding the subject’s continuation in the study. 
Examples of important deviations include: 
• Subject did not give appropriate informed consent 
• Inclusion or exclusion criteria not satisfied 
• Non-permitted concomitant medications that may meaningfully impact efficacy or safety 
outcomes 
• Meaningful dosing error 
• Randomization error 
The Investigator and Sponsor will both document this decision. The IRB/IEC will be informed of 
all important protocol deviations by the Investigator in accordance with established procedures. 
 
17.2. 
Publications 
No publication of the results shall take place without the Sponsor’s written consent. All 
publication or presentation rights for the findings of the clinical investigation under this protocol 
shall be governed by the appropriate terms of the clinical research agreement between the 
Investigator, the investigational site, and the Sponsor. 
 
17.3. 
Change in Study Site Staff 
In the event that the Principal Investigator at a site is unable to continue the study, another 
suitable person will be designated as the Investigator, and documentation testifying to this will 
be submitted to Sponsor or its designee within 10 days, who must approve the change along with 
the IRB/IEC before the study can be continued at that investigative site. 






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APPENDIX A. SCHEDULE OF ASSESSMENTS FOR THE SINGLE DOSE SEGMENTS 
 
Visit 
Screeninga 
Treatment Period 
Safety 
Follow-Up 
Early 
Study 
Termb 
Notes 
Visit 1 
Visit 2 
Visit 3 
Study Day (Visit Window) 
-28 to -2 -1 1 (pre- 
dose) 
1 (post- 
dose) 
2 
3 
8 (±1) 
Mandatory Confinement 
X 
X 
X 
X 
X 
Admission 
X 
Discharge 
X 
General Assessments 
Informed consent 
X 
Medical history 
X 
Height 
X 
Measured using a stadiometer with no shoes. 
FSH (females only) 
X 
HIV, HBV, HCV serology 
X 
Drug and cotinine screens (SAD-HS 
and SD-CP only) 
X 
X 
Day -1 will be conducted locally. 
Alcohol screen 
X 
X 
Will be conducted locally. 
Eligibility check 
X 
X 
Randomization 
X 
All dose levels in SAD-HS will be dosed according to a 
sentinel dosing design (Section 7.1.1). All subjects in 
SD-CP and SD-UP will receive EP547. 
Study drug administration 
X 
Administered orally as intact capsules with water. For 
SD-UP, Day 1 (study drug administration) must be the day 
after a hemodialysis session. 
Hemodialysis (SD-UP only) 
X 
Refer to note above. 
Safety Assessments 
Pregnancy testing 
X 
X 
X 
X 
Urine pregnancy test on Day -1 for all female SAD-HS and 
SD-CP subjects and serum pregnancy test for all female 
subjects for Screening, Day 8, and Early Study Term, if 
applicable. 


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Visit 
Screeninga 
Treatment Period 
Safety 
Follow-Up 
Early 
Study 
Termb 
Notes 
Visit 1 
Visit 2 
Visit 3 
Study Day (Visit Window) 
-28 to -2 -1 1 (pre- 
dose) 
1 (post- 
dose) 
2 
3 
8 (±1) 
Physical examination 
C 
A 
C 
C 
Will be either complete (C) or abbreviated (A) 
(Section 11.7). 
Standard 12-lead ECG 
X 
X 
X 
X 
X 
To be performed in a supine position after ≥5 min of rest 
during Screening; predose and at 3 h postdose on Day 1; 
48 h postdose on Day 3; and Early Study Term, if 
applicable. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Includes supine systolic and diastolic blood pressure, pulse 
rate, oxygen saturation, body temperature, and respiratory 
rate, measured after ≥5 min of rest at Screening; predose 
and at 1, 2, 4, 9, and 12 h postdose on Day 1; 24 h postdose 
on Day 2; 48 h postdose on Day 3; on Day 8; and Early 
Study Term, if applicable. 
Body weight 
X 
X 
X 
X 
Should be measured with no shoes on and using a calibrated 
scale throughout the study. 
Chemistry and hematology 
X 
X 
X 
X 
X 
X 
Drawn after an overnight fast (≥8 h) and predose as 
applicable. Refer to Section 11.9 for chemistry, 
hematology, and urinalysis (dipstick) assessments. 
Urinalysis (SAD-HS and SD-CP 
only) 
X 
X 
X 
X 
X 
X 
Refer to Section 11.9 for chemistry, hematology, and 
urinalysis (dipstick) assessments. 
Coagulation 
X 
Refer to Section 11.9 for coagulation assessments. 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Record all of the following: 
• Medications taken within 14 days before Screening (all 
subjects) 
• Medications taken to treat a cholestatic disorder or 
ESRD within 12 weeks before Screening (SD-CP and 
SD-UP only) 
• Medications known to impact pruritus within 4 weeks 
before Screening (SD-CP and SD-UP only) 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
To be documented from the signing of the Informed 
Consent Form until the end of study participation. 




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APPENDIX B. SCHEDULE OF ASSESSMENTS FOR THE MULTIPLE DOSE SEGMENTS 
 
Visit 
Screeninga 
Treatment Period 
Safety Follow- 
Upb 
Early 
Study 
Termc 
Notes 
Visit 1 
Visit 2 
Visit 3 Visit 4 
Study Day 
(Visit Window) 
-28 
to -4 
-1 
1 
(pre- 
dose 
1 (post- 
dose) 
2 3 4 5 6 7 8 
14 
(±1) 
21 
(±2) 
MAD-HS 
Mandatory 
Confinement 
X 
X 
X 
X X X X X X X 
Admission 
X 
Discharge 
X 
MAD-CP 
Mandatory 
Confinement 
X 
X 
X 
X 
X X 
For Days 3-6, subjects may choose to remain confined, 
return to the site each morning, or have a nurse visit their 
home to the complete scheduled assessments. 
Admission 
X 
X 
Discharge 
X 
X 
MAD-UP 
Mandatory 
Confinement 
X 
X 
X 
X 
X X X 
For Days 3-5, subjects may choose to remain confined, 
return to the site each morning, or have a nurse visit their 
home to the complete scheduled assessments. 
Admission 
X 
X 
Discharge 
X 
X 
General Assessments 
Informed consent 
X 
Medical history 
X 
Height 
X 
Measured using a stadiometer with no shoes. 
FSH (females 
only) 
X 
HIV, HBV, HCV 
serology 
X 
Drug and cotinine 
screens (MAD-HS 
and MAD-CP 
only) 
X 
X 
Day -1 will be conducted locally. 


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Visit 
Screeninga 
Treatment Period 
Safety Follow- 
Upb 
Early 
Study 
Termc 
Notes 
Visit 1 
Visit 2 
Visit 3 Visit 4 
Study Day 
(Visit Window) 
-28 
to -4 
-1 
1 
(pre- 
dose 
1 (post- 
dose) 
2 3 4 5 6 7 8 
14 
(±1) 
21 
(±2) 
Alcohol screen 
X 
X 
Will be conducted locally. 
Eligibility check 
X 
X 
Randomization 
X 
Subjects in each dosing group will be randomized in a 
3:1 ratio (EP547:placebo). 
Study drug 
administration 
X 
X X X X X X 
Administer study drug QD for 7 days as intact capsules 
with water. For MAD-UP, administer study drug 4 to 6 h 
before the hemodialysis session on Days 1, 4, and 6 and at 
approximately the same time of day on Days 2, 3, 5, and 7 
(days without a hemodialysis session). 
Hemodialysis 
(MAD-UP only) 
X 
X 
X 
Refer to note above. 
Safety Assessments 
Pregnancy testing 
X 
X 
X 
X 
X 
Urine pregnancy test on Day -1 for all female MAD-HS 
and MAD-CP subjects and serum pregnancy test for all 
female subjects for Screening, Days 14 and 21, and Early 
Study Term, if applicable. 
Physical 
examination 
C 
A 
A 
C 
C 
Will be either complete (C) or abbreviated (A) 
(Section 11.7). 
Standard 12-lead 
ECG 
X 
X 
X 
X 
X 
X 
To be performed in a supine position after ≥5 min of rest 
during Screening; predose and at 3 h postdose on Day 1; 
predose on Day 3; 24 h after the last dose on Day 8; and 
Early Study Term, if applicable. 
Vital signs 
X 
X 
X 
X X X X X X X 
X 
X 
X 
Includes supine systolic and diastolic blood pressure, pulse 
rate, oxygen saturation, body temperature, and respiratory 
rate, measured after ≥5 min of rest at Screening; predose 
and at 1, 2, 4, 9, and 12 h postdose on Day 1; predose on 
Days 2-7; 24 h after the last dose on Day 8; on Days 14 and 
21; and at Early Study Term, if applicable. 












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Section 
Original Version 
Amendment 1.0 
Reason for Change 
Synopsis (Inclusion Criteria) 
8.1.2 (Subjects with Cholestatic 
Pruritus) 
• 9. If currently taking medications 
to treat the cholestatic disorder or 
any pruritus associated with it, 
must be on a stable dose for 
>12 weeks before Screening and 
plans to maintain the regimen 
throughout the study 
9. If currently taking medications to 
treat the cholestatic disorder, must 
be on a stable dose for >12 weeks 
before Screening and plans to 
maintain the regimen throughout 
the study 
10. If currently taking medications 
known to impact pruritus, must 
be on a stable dose for >4 weeks 
before Screening and plans to 
maintain the regimen throughout 
the study 
The revised duration will allow more 
subjects with a cholestatic disorder 
taking medications for pruritus to 
participate without confounding 
baseline efficacy measurements or 
impacting subject safety. 
Synopsis (Inclusion Criteria) 
8.1.3 (Subjects with Uremic 
Pruritus) 
2. Has end-stage renal disease 
(ESRD) and is receiving 
hemodialysis 3× per week of at 
least 4 hours in duration for 
≥3 months before Screening; 
hemodialysis must be adequate (ie, 
≥2 urea reduction ratio 
measurements ≥65% on different 
hemodialysis days during the 
month before Screening) 
2. Has end-stage renal disease 
(ESRD) and is receiving 
hemodialysis 3× per week of at 
least 4 hours in duration for 
≥3 months before Screening; 
hemodialysis must be adequate 
(ie, ≥2 urea reduction ratio 
measurements ≥65% on different 
hemodialysis days from the month 
before Screening to Day -1) 
The window for collecting urea 
reduction ratio measurements for 
determining eligibility for subjects 
with ESRD was increased to be 
consistent with standard of care. 
Synopsis (Inclusion Criteria) 
8.1.3 (Subjects with Uremic 
Pruritus) 
9. If currently taking medications to 
treat any pruritus associated with 
ESRD, must be on a stable dose for 
>12 weeks before Screening and 
plans to maintain the regimen 
throughout the study 
9. If currently taking medications 
known to impact pruritus, must be 
on a stable dose for >4 weeks 
before Screening and plans to 
maintain the regimen throughout 
the study 
The revised duration will allow more 
subjects with ESRD taking 
medications for pruritus to participate 
without confounding efficacy baseline 
measurements or impacting safety. 
Synopsis (Exclusion Criteria) 
8.2.3 (Subjects with Uremic 
Pruritus) 
5. Positive drug, alcohol, or cotinine 
screen results at Screening or 
Day -1 
5. Positive alcohol screen result at 
Screening or Day -1 or known use 
of drugs or tobacco at Screening 
Known use of drugs or tobacco use at 
Screening was added since the drug 
and cotinine assessments for subjects 
with ESRD were removed. 
Synopsis (Study Drug Storage) 
10.3 (Study Drug Storage) 
The study drug capsules may be stored 
at controlled room temperature, 
20°C to 25°C (68°F to 77°F). 
The study drug capsules may be stored 
at controlled room temperature, 
20°C to 25°C (68°F to 77°F), with 
excursions to 10°C (50°F). 
Study drug storage conditions were 
revised to incorporate findings from a 
recently completed drug stability 
study. 


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Section 
Original Version 
Amendment 1.0 
Reason for Change 
Synopsis (Study Drug 
Administration) 
10.4 (Study Drug Administration) 
New text 
Subjects who routinely take a bile 
acid sequestrant (eg, 
cholestyramine, colestipol, or 
colesevelam) will be instructed to 
hold their morning dose until 
2 hours after study drug 
administration. If their bile acid 
sequestrant baseline dosing regimen 
does not allow for a 2-hour hold, 
dosing of these medications must be 
held for a minimum of 1 hour after 
study drug administration. 
Alternatively, the bile acid 
sequestrant may be taken at least 
4 hours prior to study drug 
administration. 
Bile acid sequestrants bind bile acids 
and disrupt their enterohepatic 
circulation by preventing their 
reabsorption from the gut. If EP547 
undergoes significant enterohepatic 
circulation, bile acid sequestrants will 
also bind EP547 and disrupt its 
absorption into the bloodstream. 
Synopsis (Fasting Requirements) 
9.4 (Study Visits) 
Appendix A (Schedule of 
Assessments for the Single Dose 
Segments [Footnotes]) 
Appendix B (Schedule of 
Assessments for the Multiple Dose 
Segments [Footnotes]) 
Appendix C (Dosing and PK Blood 
Sampling Schedule for the MAD 
Segments [Footnotes]) 
New text 
If a subject with ESRD has a daily 
fluid restriction, study drug may be 
administered with a smaller volume 
of water at the Investigator’s 
discretion. 
Relaxing the water volume 
requirement will allow subjects with 
ESRD who have a daily fluid 
restriction the opportunity to 
participate in the study. 


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Section 
Original Version 
Amendment 1.0 
Reason for Change 
Synopsis (Safety Criteria for 
Stopping Dosing) 
7.3.4 (Safety Criteria for Stopping 
Dosing) 
Study drug dosing will be held for all 
subjects if any of the following criteria 
are met: 
• At least 1 subject receiving EP547 
experiences a serious AE (SAE) 
that results in drug related death or 
is a drug related event that is 
immediately life threatening 
• At least 2 subjects receiving EP547 
experience a drug related SAE in 
the same System Organ Class 
Study drug dosing will be held for all 
subjects if any of the following criteria 
are met: 
• A subject receiving EP547 
experiences a serious adverse 
reaction (ie, a serious AE [SAE] 
considered at least possibly 
related to the study drug) 
• At least 2 subjects receiving EP547 
in the same dosing group 
experience a severe non-serious 
adverse reaction (ie, a severe, 
non-serious AE considered at 
least possibly related to the study 
drug) 
The safety criteria for stopping dosing 
were clarified to be more consistent 
with Section 8.2.9 (Stopping Rules) of 
the following European Medicines 
Agency Publication: Guideline on 
strategies to identify and mitigate risks 
for first-in-human and early clinical 
trials with investigational medicinal 
products. 
Synopsis (Blood Sampling for 
Pharmacokinetics) 
12.1 (Blood Sampling for 
Pharmacokinetics) 
New text 
The assessment window for blood 
sample collection timepoints for the 
single and multiple dose segments is 
also included in Appendix C. 
Text was added to reflect the addition 
of blood sample collection timepoints 
for the single dose segments to 
Appendix C. 
Synopsis (Skin Biopsy for 
Pharmacokinetics [Last Dose Level 
for MAD-HS and All Dose Levels 
for MAD-CP and MAD-UP Only]) 
12.3 (Skin Biopsy for 
Pharmacokinetics [Last Dose Level 
for MAD-HS and All Dose Levels 
for MAD-CP and MAD-UP Only]) 
Given that EP547 is hypothesized to 
be an inverse agonist (inhibitor) of 
mas-related G protein-coupled 
receptor X4 (MRGPRX4) in the skin 
to reduce itch, three 3-mm biopsies of 
the skin from the back will be 
performed under local anesthesia on 
Day 1 at 2 hours postdose. 
Given that EP547 is hypothesized to 
be an inverse agonist (inhibitor) of 
mas-related G protein-coupled 
receptor X4 (MRGPRX4) in the skin 
to reduce itch, three 3-mm biopsies of 
the skin from the back will be 
performed under local anesthesia on 
Day 1 at 2 hours postdose with an 
assessment window of +30 minutes. 
An assessment window for biopsy 
collection was included for clarity. 






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Section 
Original Version 
Amendment 1.0 
Reason for Change 
9.3.1 (Randomization) 
Subjects who meet all eligibility 
criteria will be assigned a subject 
number just before dosing. 
Subjects will be assigned a subject 
number after signing the Informed 
Consent Form (ICF). Subjects who 
meet all eligibility criteria will be 
randomized and assigned a 
randomization number just before 
dosing. 
The text was revised to clarify when 
subject and randomization numbers 
will be assigned. 
9.4.1.1.1 (Visit 1 [Day -28 to 
Day -2]) 
• Assessment of baseline 
concomitant medications, 
including: 
− 
All medications taken within 
14 days before Screening 
− 
Medications taken to treat a 
cholestatic disorder or ESRD 
or any pruritus associated with 
these conditions within 
12 weeks before Screening 
(SD-CP and SD-UP only) 
• Assessment of baseline 
concomitant medications, 
including: 
− 
All medications taken within 
14 days before Screening 
− 
Medications taken to treat a 
cholestatic disorder or ESRD 
within 12 weeks before 
Screening (SD-CP and 
SD-UP only) 
− 
 Medications known to 
impact pruritus within 
4 weeks before Screening 
(SD-CP and SD-UP only) 
The revised duration will allow more 
subjects with a cholestatic disorder or 
ESRD taking medications for pruritus 
to participate without confounding 
baseline efficacy measurements or 
impacting safety. 
9.4.1.2.1 (Visit 2 [Day 1] – 
Predose) 
• Continuous digital 12-lead ECG 
recording for Holter monitoring 
beginning 1 hour before study drug 
administration (SAD-HS only) 
• Continuous digital 12-lead ECG 
recording for Holter monitoring 
beginning approximately 1 hour 
before study drug administration 
(SAD-HS only) 
The start of predose recordings of the 
continuous digital 12-lead ECGs was 
revised from 1 hour predose to 
approximately 1 hour predose to allow 
for greater flexibility. 




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Section 
Original Version 
Amendment 1.0 
Reason for Change 
9.4.2.2.9 (Visit 2 [Day 8] – 
Discharge) 
New assessment 
• Body weight 
Body weight was added to the final 
day of the treatment period to allow 
for assessment of safety. 
11.3 (Concomitant Medications) 
In addition, medications taken to treat 
a cholestatic disorder or ESRD or any 
pruritus associated with these 
conditions within 12 weeks before 
Screening should also be recorded. 
In addition, medications taken to treat 
a cholestatic disorder or ESRD within 
12 weeks before Screening or 
medications known to impact 
pruritus within 4 weeks before 
Screening should also be recorded. 
The revised duration will allow more 
subjects with a cholestatic disorder or 
ESRD taking medications for pruritus 
to participate without confounding 
baseline efficacy measurements or 
impact safety. 
11.6 (Body Weight) 
Appendix A (Schedule of 
Assessments for the Single Dose 
Segments [Body Weight Row]) 
Appendix B (Schedule of 
Assessments for the Multiple Dose 
Segments [Body Weight Row]) 
Body weight should be measured with 
no shoes on and using the same scale 
throughout the study. 
Body weight should be measured with 
no shoes on and using a calibrated 
scale throughout the study. 
The ability to use more than one 
calibrated scale during the study was 
added to provide more flexibility. 
11.9 (Laboratory Evaluations of 
Safety) 
• Urinalysis (dipstick): leukocyte 
esterase, nitrites, pH, protein, 
specific gravity, glucose, occult 
blood, ketones, bilirubin, and 
urobilinogen; microscopic analysis 
is to be performed only if protein, 
leukocyte esterase, blood or nitrite 
is positive 
• Urinalysis (dipstick) (SAD-HS, 
SD-CP, MAD-HS, and MAD-CP 
only): leukocyte esterase, nitrites, 
pH, protein, specific gravity, 
glucose, occult blood, ketones, 
bilirubin, urobilinogen, and 
albumin; microscopic analysis is 
to be performed only if protein, 
leukocyte esterase, blood or nitrite 
is positive 
Albumin was added to the list of 
urinalysis analytes for completeness. 
11.9 (Laboratory Evaluations of 
Safety) 
11.10 (Other Laboratory 
Evaluations) 
New text 
See the laboratory manual for 
additional details. 
Reference to the laboratory manual 
was added to direct sites to details not 
provided in the protocol. 












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Investigator’s Agreement 
I have read this protocol addendum for EP-547-101 and agree to conduct the study as outlined. I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol addendum. 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
Date 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................ 1 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES.................. 4 
TABLE OF CONTENTS ............................................................................................... 4 
LIST OF FIGURES ...................................................................................................... 5 
LIST OF TABLES ........................................................................................................ 5 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................... 6 
4. 
PURPOSE ..................................................................................................................... 7 
5. 
BACKGROUND AND RATIONALE ......................................................................... 7 
6. 
OBJECTIVE ................................................................................................................. 7 
7. 
INVESTIGATIONAL PLAN ....................................................................................... 7 
7.1. 
Substudy Design ........................................................................................................... 7 
7.2. 
Study Schedule .............................................................................................................. 8 
7.3. 
Number of Subjects ....................................................................................................... 9 
8. 
STUDY POPULATION ................................................................................................. 9 
9. 
RANDOMIZATION AND BLINDING ....................................................................... 9 
9.1.1. 
Randomization .............................................................................................................. 9 
9.1.2. 
Blinding ....................................................................................................................... 10 
9.2. 
Study Visits ................................................................................................................. 10 
9.2.1. 
Screening Period ......................................................................................................... 10 
9.2.1.1. 
Visit 1 (Day -28 to Day -2) ......................................................................................... 10 
9.2.1.2. 
Visit 2 (Day -1) and Visit 4 (Day -1) - Admission ..................................................... 11 
9.2.2. 
Treatment Period ......................................................................................................... 11 
9.2.2.1. 
Visit 2 (Day 1) and Visit 4 (Day 1) - Predose ............................................................. 11 
9.2.2.2. 
Visit 2 (Day 1) and Visit 4 (Day 1) - Postdose ........................................................... 12 
9.2.2.3. 
Visit 2 (Day 2) and Visit 4 (Day 2) ............................................................................. 12 
9.2.2.4. 
Visit 2 (Day 3) and Visit 4 (Day 3) - Discharge ......................................................... 13 
9.2.2.5. 
Visit 3 (Day 8) and Visit 5 (Day 8) ............................................................................. 13 
9.2.3. 
Safety Follow-Up Visit (Visit 5 [Day 8]) ................................................................... 13 
9.2.4. 
Early Study Termination Visit ..................................................................................... 13 


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10. 
PHARMACOKINETICS ASSESSMENT ................................................................... 14 
11. 
STATISTICS .............................................................................................................. 14 
12. 
REFERENCES............................................................................................................ 15 
APPENDIX A. SCHEDULE OF ASSESSMENTS FOR THE FOOD EFFECT 
SUBSTUDY ............................................................................................................... 16 
LIST OF FIGURES 
Figure 1: 
Study Schedule.............................................................................................................. 9 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ............................................................................. 6 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AUC∞ 
area under the concentration-time curve from time 0 to 
infinity 
AUCt 
area under the concentration-time curve calculated to the 
last observable concentration at time t 
CI 
confidence interval 
Cmax 
maximum (peak) plasma concentration 
CP 
cholestatic pruritus 
FDA 
Food and Drug Administration 
FE 
food effect 
FSH 
follicle-stimulating hormone 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HS 
healthy subject 
ICF 
Informed Consent Form 
MAD 
multiple ascending dose 
PK 
pharmacokinetic(s) 
PO 
oral 
SAD 
single ascending dose 
SD 
single dose 
t1/2 
terminal half-life 
tmax 
time to achieve maximum (peak) plasma concentration 
UP 
uremic pruritus 


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4. 
PURPOSE 
This addendum is a pilot evaluation of the effect of food on the pharmacokinetics (PK) of a 
single dose of EP547 in healthy subjects at a single site. 
 
5. 
BACKGROUND AND RATIONALE 
Protocol EP-547-101 is a first-in-human, Phase 1, randomized, single and multiple ascending 
dose (SAD and MAD) study with EP547 in healthy subjects and subjects with cholestatic or 
uremic pruritus. Each population includes a SAD or single dose (SD) segment followed by a 
MAD segment for a total of 6 segments (SAD-HS and MAD-HS in healthy subjects [HS]; 
SD-CP and MAD-CP in subjects with cholestatic pruritus [CP]; and SD-UP and MAD-UP in 
subjects with uremic pruritus [UP]). 
To date, clinical conduct for SAD-HS and MAD-HS is complete; evaluations in subjects with 
cholestatic or uremic pruritus are ongoing. EP547 has been tested in 48 healthy subjects with 
18 treated in the multiple dose regimen. Dosing levels evaluated in healthy subjects included 
25 mg to 675 mg single doses and 25, 75, and 225 mg multiple dose regimens. All doses tested 
to date were well tolerated with no safety signals identified. 
For this addendum, a food effect segment in healthy subjects (FE-HS) at a single site will be 
evaluated. Data from this substudy will provide data to inform appropriate dosing instructions for 
future studies. 
 
6. 
OBJECTIVE 
The objective of this substudy is: 
• To assess the single-dose PK of EP547 following oral administration under fed and 
fasted conditions in healthy subjects 
 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Substudy Design 
Twelve healthy subjects will participate in this 2-period, unblinded, randomized, crossover food 
effect substudy to evaluate the PK of a single dose of EP547 administered orally (PO) in a fasted 
or fed condition. Subjects who participated in SAD-HS or MAD-HS may not participate in 
FE-HS. Subjects will be randomized in a 1:1 ratio to either Sequence 1 (Fasted for FE Period 1, 
Fed for FE Period 2) or Sequence 2 (Fed for FE Period 1, Fasted for FE Period 2). The dose level 
to be tested in FE-HS will be 75 mg, which was selected based on safety and tolerability data and 
EP547 PK characteristics from SAD-HS and MAD-HS, and from data generated by nonclinical 
studies. 
Doses between the 2 FE Periods must be separated by a minimum of 10 days to allow for 
washout of study drug. Study drug for each FE Period will be administered with approximately 
240 mL of water; additional water will not be allowed from 1 hour predose to 1 hour postdose. 


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Fasted Regimen: 
EP547 will be administered after an overnight fast for a minimum of 8 hours. Subjects will 
remain fasted until after the 4-hour PK blood sample is collected. 
Fed Regimen: 
Subjects will fast overnight for a minimum of 8 hours. Approximately 30 minutes before 
administration of study drug, subjects will be provided a high fat/high calorie breakfast and will 
be instructed to consume the entire meal in 30 minutes or less. Subjects must consume at least 
90% of their meal to be eligible for dosing. The start and stop time and percentage of the 
breakfast consumed will be recorded. Per guidance from the Food and Drug Administration 
(FDA), the high fat/high calorie meal should derive approximately 150, 250, and 500 to 600 
calories from protein, carbohydrate, and fat, respectively (FDA 2002). No other food or drink 
(other than water as specified above) will be permitted until after the 4-hour PK blood sample is 
collected. 
Both Regimens: 
Each meal and/or snack served at the clinic will be standardized, similar in caloric content and 
composition (except for the high-fat/high calorie breakfast served as part of the fed regimen), 
and consumed at approximately the same time in each FE Period during confinement. 
7.2. 
Study Schedule 
Subjects should fast for at least 8 hours before study days that require a blood sample for 
assessment of clinical chemistry or multiple blood samples for PK as described in Section 9.4 of 
Protocol EP-547-101, Amendment 2.0. 
Screening: 
Visit 1 (Screening) is to occur between Day -28 and Day -2. 
FE Periods: 
For each FE Period, there is 1 mandatory confinement period in the 
clinic, beginning from Day -1 (admission) to Day 3 until after the 
48-hour postdose assessments are completed (discharge). Subjects 
are to return to the clinic on Day 8 to complete additional 
assessments. 
Treatment Period: 
The Treatment Period includes a portion of both FE periods and is to 
begin on Day 1 of Visit 2 and end on Day 3 of Visit 4. 
Safety Follow-Up: 
Visit 5 (Day 8) is also the Safety Follow-Up Visit and is to occur 
7 days after the last administration of study drug. If termination 
occurs during the Treatment Period, the subject will have a Safety 
Follow-Up Visit approximately 7 days (±1 day) after the last dose of 
study drug and is to undergo the procedures for Visit 5 (Day 8). 




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Subjects who withdraw for any reason without completing all screening evaluations successfully 
will be considered “screening failures”. 
9.1.2. 
Blinding 
The FE-HS segment is open-labeled and will be conducted in an unblinded manner. 
 
9.2. 
Study Visits 
Study procedures are listed for each visit in the following sections and summarized in the 
Schedule of Assessments (Appendix A). Further details regarding the listed safety, PK, and 
pharmacodynamic assessments are located in Sections 11, 12, and 14, of Protocol EP-547-101, 
Amendment 2.0, respectively. 
 
9.2.1. 
Screening Period 
 
9.2.1.1. 
Visit 1 (Day -28 to Day -2) 
During the Screening Period, subjects are to arrive at the clinic after an overnight fast (at least 
8 hours) and will undergo assessments at the site to determine their study eligibility. Subjects 
will be screened and should meet all inclusion criteria and none of the exclusion criteria to be 
enrolled in the study. Any questions regarding eligibility may be discussed with the Medical 
Monitor. 
The following assessments may be conducted over more than 1 day but must be completed 
between Day -28 and Day -2: 
• Completion of informed consent before performance of any study procedures or 
assessments 
• Medical history 
• Height 
• Complete physical examination 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C 
virus (HCV) serology 
− Drug and cotinine screens 
− Alcohol screen 
− Serum pregnancy test (females only) 
− Follicle-stimulating hormone (FSH) (females only) 
− Chemistry and hematology 


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− Urinalysis 
− Coagulation 
• Assessment of baseline concomitant medications, including all medications taken 
within 14 days before Screening 
• Assessment of adverse events (AEs) 
• Eligibility check 
Screening results will be reviewed by the Investigator to determine the subject’s eligibility. 
Subjects who are confirmed to be eligible will be asked to return to the site for Visit 2 (Day -1) 
to enroll in the study. 
9.2.1.2. 
Visit 2 (Day -1) and Visit 4 (Day -1) - Admission 
Subjects will be admitted for mandatory confinement at the clinic during Day -1 of each FE 
Period and will undergo the following assessments: 
• Abbreviated physical examination 
• Laboratory assessments: 
− Drug and cotinine screens 
− Alcohol screen 
− Urine pregnancy test 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Eligibility check (Visit 2 only) 
Visit 2 (Day -1) results will be reviewed by the Investigator to confirm the subject’s eligibility. 
For both FE Periods, eligible subjects will continue to remain confined to the clinic until 
completion of Day 3 assessments of the respective period. 
9.2.2. 
Treatment Period 
 
9.2.2.1. 
Visit 2 (Day 1) and Visit 4 (Day 1) - Predose 
Subjects will continue to be confined at the clinic during Day 1 of each FE Period and will 
undergo the following assessments before administration of study drug: 
• Vital signs 
• Standard 12-lead ECG 
• Body weight (Visit 2 only) 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis 


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− 
 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment 
• Randomization to Sequence 1 or Sequence 2 in a 1:1 ratio 
• Remain fasted or consume a high fat/high calorie breakfast approximately 30 minutes 
predose as determined by randomized treatment sequence. 
Upon completion of the assessments listed above, study drug is to be administered orally as 
intact capsules (swallowed whole, not chewed or crushed), and taken with water. 
 
9.2.2.2. 
Visit 2 (Day 1) and Visit 4 (Day 1) - Postdose 
Subjects will continue to be confined at the clinic during Day 1 of each FE Period and will 
undergo the following assessments after administration of study drug: 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 
12 hours postdose 
• Vital signs at 1, 2, 4, 9, and 12 hours postdose 
• Standard 12-lead ECG at 3 hours postdose 
9.2.2.3. 
Visit 2 (Day 2) and Visit 4 (Day 2) 
Subjects will continue to be confined at the clinic during Day 2 of each FE Period and will 
undergo the following assessments: 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis 
− 
 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment at 18, 24, and 36 hours postdose 
• Vital signs at 24 hours postdose 


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9.2.2.4. 
Visit 2 (Day 3) and Visit 4 (Day 3) - Discharge 
Subjects will continue to be confined at the clinic during Day 3 of each FE Period until 
completion of the following assessments: 
• Laboratory assessments: 
− Chemistry and hematology 
− Urinalysis 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Vital signs at 48 hours postdose 
• Standard 12-lead ECG at 48 hours postdose 
• Blood sample draw for PK assessment at 48 hours postdose 
Subjects may be discharged from the clinic after completion of all assessments listed above. 
 
9.2.2.5. 
Visit 3 (Day 8) and Visit 5 (Day 8) 
Subjects are to arrive at the clinic after an overnight fast (at least 8 hours) and will undergo 
assessments on Day 8 of each FE Period: 
• Complete physical examination (Visit 5 only) 
• Vital signs 
• Body weight (Visit 5 only) 
• Laboratory assessments: 
− Serum pregnancy test (females only) 
− Chemistry and hematology 
− Urinalysis 
• Assessment of concomitant medication usage 
• Assessment of AEs 
• Blood sample draw for PK assessment 
9.2.3. 
Safety Follow-Up Visit (Visit 5 [Day 8]) 
In addition to being the last visit in FE Period 2, Visit 5 [Day 8] is also the Safety Follow-Up 
Visit. If termination occurs during the Treatment Period, the subject will have a Safety 
Follow-Up Visit approximately 7 days (±1 day) after the last dose of study drug and is to 
undergo the procedures for Visit 5 (Day 8) as described in Section 9.2.2.5. 
 
9.2.4. 
Early Study Termination Visit 
Subjects who discontinue from the study early should have the Early Study Termination Visit 
conducted as soon as possible after the dose of study drug, ideally within 2 days after the dose of 


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study drug. Subjects are to arrive at the clinic after an overnight fast (at least 8 hours) and will 
undergo the following assessments during the Early Study Termination Visit: 
• Complete physical examination 
• Vital signs 
• Standard 12-lead ECG 
• Body weight 
• Laboratory assessments: 
− Serum pregnancy test (females only) 
− Chemistry and hematology 
− Urinalysis 
• Assessment of concomitant medication usage 
• Assessment of AEs 
 
10. 
PHARMACOKINETICS ASSESSMENT 
Blood sampling for PK of EP547 will be collected as follows for each FE Period: 
• FE-HS: predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, and 12 hours postdose on 
Day 1; 18, 24, and 36 hours postdose on Day 2; 48 hours postdose on Day 3; and on 
Day 8. 
The assessment window for blood sample collection timepoints for the FE-HS segment is the 
same as the single dose segments and the first dose in the multiple dose segments, which is 
included in Appendix C of Protocol EP-547-101, Amendment 2.0. 
 
11. 
STATISTICS 
The effect of food on the PK of EP547 (area under the concentration-time curve from time 0 to 
infinity, area under the concentration-time curve calculated to the last observable concentration 
at time t, maximum [peak] plasma concentration, terminal half-life, and time to achieve 
maximum [peak] plasma concentration [AUC∞, AUC0-t, Cmax, t1/2, and tmax]) will be examined. An 
analysis of variance model will be fitted separately to each of the log transformed PK parameters 
with period and treatment (fed or fasted) as fixed effects and subject as a random effect. Point 
estimates for the differences in means (EP547 fed – EP547 fasted) and corresponding 90% 
confidence intervals (CIs) will be constructed from the least-squares means, using the residual 
variance. These will then be back-transformed to provide point estimates and corresponding 90% 
CIs for the ratio of geometric means fed:fasted. 
The sample size of 12 subjects was selected as the minimum needed to adequately estimate the 
effect of food on the PK of EP547. 


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12. 
REFERENCES 
 
FDA. Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. FDA 
Maryland; 2002. p. 1-9. 


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APPENDIX A.  SCHEDULE OF ASSESSMENTS FOR THE FOOD EFFECT SUBSTUDY 
 
Visit 
Screening 
Visit 1a 
FE Period 1 / FE Period 2b 
Early 
Study 
Termc 
Notes 
Visit 2 / Visit 4 
Visit 3 / 
Visit 5d 
Study Day (Visit Window) 
-28 to -2 
-1 1 (pre- 
dose) 
1 (post- 
dose) 
2 
3 
8 
Mandatory Confinement 
X 
X 
X 
X 
X 
Admission 
X 
Discharge 
X 
General Assessments 
Informed consent 
X 
Medical history 
X 
Height 
X 
Measured using a stadiometer with no shoes. 
FSH (females only) 
X 
HIV, HBV, HCV serology 
X 
Drug and cotinine screens 
X 
X 
Day -1 will be conducted locally. 
Alcohol screen 
X 
X 
Will be conducted locally. 
Eligibility check 
X 
Xe 
Randomization 
Xe 
Subjects will be randomized in a 1:1 ratio to either 
Sequence 1 (Fasted for FE Period 1 followed by Fed for 
FE Period 2) or Sequence 2 (Fed for FE Period 1 
followed by Fasted for FE Period 2). 
Study drug administration 
X 
Administered orally as intact capsules with water. 
Fed regimen 
X 
To be assessed during Visit 2 or Visit 4 as determined by 
treatment sequence. High fat/high calorie breakfast will 
be provided approximately 30 min prior to dosing. 
Fasted regimen 
X 
To be assessed during Visit 2 or Visit 4 as determined by 
treatment sequence. Subjects will remain fasted until after 
the 4-hour PK blood sample is collected. 


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Visit 
Screening 
Visit 1a 
FE Period 1 / FE Period 2b 
Early 
Study 
Termc 
Notes 
Visit 2 / Visit 4 
Visit 3 / 
Visit 5d 
Study Day (Visit Window) 
-28 to -2 
-1 1 (pre- 
dose) 
1 (post- 
dose) 
2 
3 
8 
Safety Assessments 
Pregnancy testing 
X 
X 
X 
X 
For all female subjects. Urine pregnancy test on Day -1 
and serum pregnancy test for all other indicated visits. 
Physical examination 
C 
A 
Cf 
C 
Will be either complete (C) or abbreviated (A) 
(Section 11.7 of Protocol EP-547-101, Amendment 2.0). 
Standard 12-lead ECG 
X 
X 
X 
X 
X 
To be performed in a supine position after ≥5 min of rest 
during Screening; predose and at 3 h postdose on Day 1; 
48 h postdose on Day 3; and Early Study Term, if 
applicable. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Includes supine systolic and diastolic blood pressure, 
pulse rate, oxygen saturation, body temperature, and 
respiratory rate, measured after ≥5 min of rest at 
Screening; predose and at 1, 2, 4, 9, and 12 h postdose on 
Day 1; 24 h postdose on Day 2; 48 h postdose on Day 3; 
on Day 8; and Early Study Term, if applicable. 
Body weight 
X 
Xe 
Xf 
X 
Should be measured with no shoes on and using a 
calibrated scale throughout the study. 
Chemistry and hematology 
X 
X 
X 
X 
X 
X 
Drawn after an overnight fast (≥8 h) and predose as 
applicable. Refer to Section 11.9 of Protocol EP-547-101, 
Amendment 2.0, for chemistry and hematology 
assessments. 
Urinalysis 
X 
X 
X 
X 
X 
X 
Refer to Section 11.9 of Protocol EP-547-101, 
Amendment 2.0, for urinalysis (dipstick) assessments. 
Coagulation 
X 
Refer to Section 11.9 of Protocol EP-547-101, 
Amendment 2.0, for coagulation assessments. 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Record all medications taken within 14 days before 
Screening (all subjects) 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
To be documented from the signing of the Informed 
Consent Form until the end of study participation. 



SAP_001.pdf: 
Protocol Number: EP-547-101 
 
2021-06-03 
Document status: Final Version 2.0 
 
Novotech - Strictly Confidential 
Page 1 of 66 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Randomized, Single and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of EP547 in Healthy Subjects and Subjects 
with Cholestatic or Uremic Pruritus 
 
PROTOCOL NO.: 
EP-547-101 
 
PRODUCT CODE: EP547 
 
PREPARED FOR: 
Escient Pharmaceuticals, Inc. 
 
10578 Science Center Drive, Suite 250, 
 
San Diego, CA 92121 
 
 
USA 
 
PREPARED BY: 
Novotech (Australia) Pty Ltd 
 
Level 3, 235 Pyrmont Street 
 
Pyrmont, NSW, 2009  
 
Australia  
 
DATE OF ISSUE: 
2021-06-03 
 
 
VERSION/STATUS: 
Final Version 2.0 
 
 
VERSION HISTORY: Draft Version 1.1 (2021-05-17) 
                                           Draft Version 1.2 (2021-05-26) 
                                           Final Version 2.0 (2021-06-03) 
 
 
AUTHOR: 
 
 
The information in this document is confidential and proprietary to Novotech Pty Ltd and its 
clients. The information may only be used by the entities to which it was disclosed for the purpose 
it was disclosed. To the maximum extent permissible by law, the information must not be 
disclosed to any third parties without the prior written consent of Novotech. 


Protocol Number: EP-547-101 
 
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Document status: Final Version 2.0 
 
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Page 2 of 66 
SAP APPROVAL 
 
By my signature, I confirm that this SAP has been reviewed by Escient Pharmaceuticals, Inc. and has 
been approved for use on the EP-547-101 study: 
 
Name 
Title / Company 
Signature 
Date 
 
 
Vice President,  
Head of Clinical Development,  
Escient Pharmaceuticals 
 
 
   
 
 
Senior Director,  
Biometrics and Data Analytics  
Escient Pharmaceuticals, Inc. 
 
 
Principal Biostatistician / Novotech 
 
 
Principal Pharmacometrician/ 
Novotech 
 
 
 
 
 
 


Protocol Number: EP-547-101 
 
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Document status: Final Version 2.0 
 
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Page 3 of 66 
Table of contents 
 
1. 
INTRODUCTION 
7 
2. 
PROJECT OVERVIEW 
8 
2.2 
Objectives 
9 
2.3 
Endpoints 
10 
2.4 
Sample Size 
11 
2.5 
Randomization 
11 
3. 
STATISTICAL CONSIDERATIONS 
13 
3.1 
General Considerations 
13 
3.2 
Key Definitions 
14 
3.3 
Inferential Analyses 
16 
3.4 
Multiple Comparisons and Multiplicity Adjustments. 
17 
3.5 
Handling of Missing Data 
17 
3.6 
Coding of Events and Medications 
17 
3.7 
Treatment Groups/Treatment Sequence 
18 
4. 
ANALYSIS POPULATIONS 
21 
4.1 
Population Descriptions 
21 
5. 
PARTICIPANT DISPOSITION AND ANALYSIS POPULATIONS 
22 
6. 
PROTOCOL DEVIATIONS 
23 
7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
24 
7.1 
Demographics and Baseline Characteristics 
24 
7.2 
Medical history 
24 
7.3 
Disease History 
25 
7.4 
Hemodialysis History 
25 
7.5 
Itch History 
25 
7.6 
Drug Screening and other Screening laboratory 
26 
7.7 
Inclusion/Exclusion Criteria Exceptions and Eligibility Criteria 
26 
8. 
TREATMENT EXPOSURE 
27 
9. 
PRIOR AND CONCOMITANT MEDICATIONS 
28 
10. 
PHARMACOKINETICS 
29 
10.1 
Plasma PK Analysis 
29 
10.2 
Urine PK Analysis (SAD-HS only) 
34 
10.3 
Skin PK Analysis 
35 
10.4 
Pharmacokinetic Noncompartmental Analysis (NCA) 
36 
 
 
 
 
 
 
 
 
 


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12. 
EFFICACY 
42 
13. 
SAFETY 
43 
13.1 
Adverse Events 
43 
13.2 
Safety Laboratory Assessments 
43 
13.3 
Vital Signs 
45 
13.4 
12-Lead Electrocardiogram (ECG) 
46 
13.5 
Physical Examinations 
46 
13.6 
Hemodialysis 
46 
14. 
IMMUNOGENICITY 
48 
15. 
CHANGES TO THE PLANNED ANALYSIS 
49 
16. 
INTERIM AND FINAL ANALYSIS 
50 
16.1 
Interim Analysis 
50 
16.2 
Final Analysis (End of Study) 
50 
17. 
SOFTWARE 
51 
18. 
TABLES 
52 
19. 
LISTINGS 
61 
20. 
FIGURES 
65 
21. 
REFERENCES 
66 




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Page 6 of 66 
Abbreviation 
Description 
 
 
PK 
Pharmacokinetic 
PT 
Preferred Term 
RBC 
Red blood cells (erythrocytes) 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 
SD-CP 
Single Dose - Cholestatic Pruritus 
SD-UP 
Single Dose - Uremic Pruritus 
S.I. 
International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
TEAE 
Treatment Emergent Adverse Event 
t1/2 
Apparent Plasma Terminal Elimination Half Life 
Tmax 
Time to maximum concentration 
 
 
UP 
Uremic Pruritus 
 
 
WBC 
White blood cells (leukocytes) 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 
 
 


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1. 
INTRODUCTION 
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of data 
collected from the EP-547-101 study (Protocol Original dated 17 June 2020). 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), regulatory 
submissions, or future manuscripts. Also, post hoc exploratory analyses not necessarily identified in this 
SAP may be performed to further examine study data. Any post hoc, or unplanned, exploratory analyses 
performed will be clearly identified as such in the final CSR. 
This amendment to SAP is done to incorporate the changes made to the study as per the various revisions 
of protocol:  
• 
Protocol Amendment 1.0 dated 14 December 2020 
• 
Protocol Amendment 2.0 dated 19 February 2021 
• 
Protocol Addendum 1.0 to Amendment 2.0 dated 19 March 2021 
 
 


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2. 
PROJECT OVERVIEW 
2.1.1 
Study Design 
This study is a first-in-human, Phase 1, randomized, single and multiple ascending dose (SAD and MAD) 
study with EP547 in healthy subjects and subjects with cholestatic or uremic pruritus. As shown in Figure 
1, each population will include a SAD or single dose (SD) segment followed by a MAD segment for a 
total of 6 segments (single ascending dose – healthy subject [SAD-HS] and multiple ascending dose – 
healthy subject [MAD-HS] in healthy subjects [HS]; single dose – cholestatic pruritus [SD-CP] and 
multiple ascending dose - cholestatic pruritus [MAD-CP] in subjects with cholestatic pruritus [CP]; and 
single dose - uremic pruritus [SD-UP] and multiple ascending dose - uremic pruritus [MAD-UP] in 
subjects with uremic pruritus [UP]. Each segment will evaluate at least 1 dose level. Pruritus is not a 
mandatory requirement for participation in SD-CP or SD-UP. 
Although SAD-HS and all of the MAD segments will be conducted in a blinded manner (ie, subjects, 
Investigator, study-site personnel, and Contract Research Organization [CRO] staff not involved in PK 
sample analysis or regulatory reporting will be blinded to treatment), the Sponsor, including the Sponsor 
Medical Monitor, will be unblinded to treatment assignment to assess safety on an ongoing basis.  
SAD-HS will evaluate at least 5 dose levels of EP547, establish the highest well-tolerated dose in healthy 
subjects, and guide MAD dosing in the same population. Evaluation of the first of 3 dose levels for 
MAD-HS may commence after 3 dose levels from SAD-HS have been fully evaluated by the Safety 
Review Team. When the results of all dose levels from the SAD-HS segment have been fully evaluated 
by the Safety Review Team, evaluation of a single dose level for SD-CP and SD-UP may commence. 
SD-CP and SD-UP will confirm predicted PK concentrations and guide MAD dosing in their respective 
populations. SD-CP and SD-UP may be conducted in parallel. Evaluation of at least 1 dose level for 
MAD-CP and MAD-UP may commence when the dose level from the SD segment specific to their 
population has been fully evaluated by the Safety Review Team. Subjects from the SD-CP and SD-UP 
segments may screen to determine eligibility for participation in the MAD segment specific to their 
population. 
Figure 1: 
EP-547-101 Study Designs 
 
2.1.2 
Food effect (FE) Sub study 
Twelve healthy subjects will participate in this 2-period, unblinded, randomized, crossover food effect 
sub study to evaluate the PK of a single dose of EP547 administered orally (PO) in a fasted or fed 
condition. Subjects who participated in SAD-HS or MAD-HS may not participate in FE-HS. Subjects 
will be randomized in a 1:1 ratio to either Sequence 1 (Fasted for FE Period 1, Fed for FE Period 2) or 
Sequence 2 (Fed for FE Period 1, Fasted for FE Period 2). The dose level to be tested in FE-HS will be 
75 mg, which was selected based on safety and tolerability data and EP547 PK characteristics from 
SAD-HS and MAD-HS, and from data generated by nonclinical studies. 






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• 
 
• 
 
• 
 
• 
 
• 
Plasma PK parameter estimated using noncompartmental analysis (NCA) for the FE segment, as 
appropriate: 
o 
Cmax, tmax, Kel, t1/2, AUC∞, AUCt, %AUCextra, CL/F, and Vz/F 
2.4 
Sample Size 
No formal sample size calculation has been made. The sample size has been selected to provide adequate 
information on safety, tolerability, PK, and PD following single and multiple doses of EP547. 
80 to 132 subjects are expected to participate in the study, including 64 to 72 healthy subjects, 8 to 30 
CP subjects, and 8 to 30 UP subjects: 
• 
5 to 6 groups of 8 subjects each in SAD-HS 
• 
3 groups of 8 subjects each in MAD-HS 
• 
1 group of 6 subjects each in SD-CP and SD-UP (non-randomised) 
• 
1 to 2 groups of 8 to 12 subjects each in MAD-CP and MAD-UP; up to 6 subjects each from the 
SD-CP and SD-UP segments will participate in the MAD segment specific to their population if 
they meet the requirement for pruritus (will be rescreened and allocated a new participant ID 
following washout) 
For FE sub study a sample size of 12 subjects was selected to estimate the effect of food on the PK of 
EP547. 
2.5 
Randomization 
SAD-HS and all of the MAD segments will be conducted in a blinded manner (i.e., subjects, Investigator, 
study-site personnel, and Contract Research Organization staff not involved in PK sample analysis or 
regulatory reporting will be blinded to treatment). The Sponsor, including the Sponsor Medical Monitor, 
will be unblinded to treatment assignment to assess safety on an ongoing basis.  
SD-UP and SD-CP will be open label, with all subjects assigned active treatment (EP547) and do not 
require randomization. 
FE sub study will be open label and randomized. 
Furnished below are the details of randomisation in each segment.  
• 
SAD-HS:  
o Up to 5 dose levels (with the flexibility to evaluate a sixth level)  
o 8 participants per group, randomized EP547: Placebo 3:1  
o Sentinel dosing - sentinels randomised EP547: Placebo 1:1  
o Non-sentinel dosing randomised EP547: Placebo 5:1  
• 
MAD-HS:  
o Up to 3 dose levels  
o 8 participants per group, randomized to receive EP547 or placebo for 7 days in a 3:1 
ratio  
o No sentinel dosing  
• 
SD-CP/UP:  


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o Initiated after all dose levels of SAD-HS have been fully evaluated by the Safety 
Review Team  
o No randomization, unblinded, 1 dose level each (SD-CP and SD-UP), 6 participants per 
group 
• 
MAD-CP:  
o 1 dose level (with potential 2nd cohort if required)  
o 8 participants, randomized to receive EP547 or placebo for 7 days in a 3:1 ratio  
o Potential to enroll up to 4 more subjects (for a total of 12)  
o No sentinel dosing  
• 
MAD-UP:  
o 1 dose level (with potential 2nd cohort if required)  
o 8 participants, randomized to receive EP547 or placebo for 7 days in a 3:1 ratio  
o Potential to enroll up to 4 more subjects (for a total of 12)  
o No sentinel dosing  
• 
FE:  
o Single dose of EP547 administered orally (PO) in a fasted or fed condition 
o 12 participants, randomized to one of the two sequence in 1:1 ratio  
[Sequence 1 (Fasted for FE Period 1, Fed for FE Period 2) or Sequence 2 (Fed for FE 
Period 1, Fasted for FE Period 2)] 
 


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3. 
STATISTICAL CONSIDERATIONS 
Data will be handled and processed per the sponsor’s representative (Novotech) Standard Operating 
Procedures (SOPs), which are written based on the principles of good clinical practice (GCP).  
Each study segment (SAD-HS, MAD-HS, SD-CP/UP, MAD-CP/UP, FE) will be presented separately 
for tables. Listing will include all data separated by segment and dose level (if applicable).  For FE 
segment separate listing will be provided. Novotech will not be responsible to generate any figures for 
the study. 
3.1 
General Considerations 
All data collected on the electronic case report form (eCRF) will be presented in the data listings and 
will be listed and sorted by treatment group, participant number and visit, where applicable. All 
descriptive summaries will be presented by treatment group and nominal visit/time point (where 
applicable).  
Unless otherwise stated, the following methods will be applied: 
• 
Continuous variables: Descriptive statistics will include the number of non-missing values (n), 
arithmetic mean, standard deviation (SD), median, minimum and maximum values.  
The minimum and maximum values will be displayed to the same decimal precision as the source 
data, the arithmetic mean, SD and median values will be displayed to one more decimal than the 
source data for the specific variable. 
The appropriate precision for derived variables will be determined based on the precision of the 
data on which the derivations are based, and statistics will be presented in accordance with the 
above mentioned rules. 
• 
PK data: The actual blood sampling dates and times relative to dosing time will be listed by 
treatment group, participant and nominal sampling time, with time deviation calculated, for all 
participants with available plasma concentration data, including participants excluded from the 
PK population. Individual (for each participant) and mean plasma and skin EP547 and metabolites 
(as applicable) concentrations over time will be displayed graphically in linear and semi-
logarithmic plots of concentrations versus time. The actual collection time will be used for 
individual plasma and skin EP547 and metabolites (as applicable) concentration curves and the 
nominal time will be used for the plots of mean concentration curves. 
For plasma and skin PK concentration data, the number of non-missing values, number of below 
limit of quantification (BLQ) values, arithmetic mean, standard deviation, median, minimum, 
maximum, coefficient of variation (CV%), geometric mean, geometric standard deviation (SD) 
and geometric coefficient of variation (geo CV%) values will be presented. For the calculation of 
summary statistics, unrounded data will be used and reported to three significant figures with the 
exception of n, n BLQ, and CV% which will be presented to the nearest integer and one decimal 
place, respectively. 
For PK parameter data, the number of non-missing values, arithmetic mean, standard deviation, 
geometric mean, geometric SD, geometric CV, median, minimum and maximum values will be 
presented. Individual PK parameters will be presented to three significant figures with the 
exception of Tmax which will be presented to two decimal places. 
• 
Categorical variables: Descriptive statistics will include counts and percentages per category. The 
denominator in all percentage calculations will be the number of participants in the relevant 
analysis population with non-missing data, unless specifically stated otherwise. Percentages will 
be displayed to one decimal place. Proportions will be displayed to 3 decimal places. 
• 
Repeat/unscheduled assessments: Only values collected at scheduled study visits/time points will 
be presented in summary tables. If a repeat assessment was performed, the result from the original 
assessment will be presented as the result at the specific visit/time point. All collected data will be 
included in the data listings. 




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For events occurring on or after Day 1, study day will be calculated as: 
Study Day = (Date of Event - Date of First Study Drug Administration) + 1 
Study days will only be calculated for events with complete dates and will be undefined for 
events that are ‘Ongoing’ at the end of the study. 
Relative days compared to an alternative reference point will be calculated similarly, but the 
alternative starting reference start date will be used instead of the date of the first study drug 
dosing. 
• 
Period Study Day: For FE segment, the Period Study Day of an event is defined as the relative 
day of the event relative to the previous study drug administration date.   
Period Study Day = (Date of Event – Date of Previous Study Drug Administration) + 1 
If an event occurs prior to the first administration of study drug, period study day will be 
calculated as: 
Study Day = (Date of Event - Date of First Study Drug Administration) 
• 
Actual Time from First Dose (hours) = (Date/Time of PK Sample collection) – (Date/Time of 
First Dose on Day 1) 
• 
For FE segment the actual time from first dose (hours) will be derived based on the dosing day in 
each period.  
ie; Actual Time from First Dose (hours) = (Date/Time of PK Sample collection) – (Date/Time of 
First Dose on Day 1 in each period) 
• 
Actual Time Deviation (hours) = (Actual PK Sample Collection Time Post Dose) – (Scheduled 
PK Sample Collection Time Post Dose).  
• 
Prior Medications: Prior medications are defined as any medication where the use was stopped 
prior to the first administration of the study medication. 
• 
Concomitant Medications: Concomitant medications are defined as any medication (other than 
the study drug) that was used at least once after the first administration of the study drug. 
Medications that were stopped on the same date as the first study drug administration will be 
included as concomitant medications. If a clear determination cannot be made (partial medication 
end dates) the medication will be classified as concomitant. 
• 
For FE segment concomitant medication will be defined as follows: 
• 
All medications stopped post study drug administration in Period 1 but prior to study 
drug administration in Period 2 will be attributed to Period 1 treatment only.  
• 
All medications started prior to study drug administration in Period 1 and stopped after 
study drug administration in Period 2 will be attributed to both treatments. 
• 
All medications started post to study drug administration in Period 2 will be attributed to 
Period 2 treatment only. 
• 
Treatment Emergent Adverse Events (TEAEs) are defined as adverse events that occurred 
following the first administration of study medication. 
• 
For FE segment treatment emergent adverse events will be defined as follows: 
• 
TEAEs that start on or after the study drug administration of Period 2 will be attributed 
to Period 2 treatment only.  
• 
TEAEs that start on or after the study drug administration of Period 1 but prior to study 
drug administration of Period 2 will be attributed to Period 1 treatment only.  
Any change in severity will be seen as a new event and will be allocated to the treatment in the 
same way. 


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If only the event start year (and month) is present, the event will be allocated to all treatment with 
the same start year (and month), unless the event end date clearly indicates that an event did not 
occur within certain periods. 
If complete dates are missing (start and end dates), the event will automatically be classified as an 
event for all treatment (Period). 
3.3 
Inferential Analyses 
Descriptive statistics will be used to summarize the safety and PK data. No formal hypothesis testing is 
planned. To further explore on the plasma PK data, dose proportionality will be assessed for SAD-HS 
and MAD-HS segments. 
• 
Dose Proportionality 
o SAD-HS 
Dose proportionality will be assessed for Cmax, AUCt and AUC0-inf  using the power model.  
An assessment of dose proportionality will not be based strictly on statistical rules criteria 
but rather, several factors will be considered when assessing dose proportionality, such as 
results derived from a Power Model (e.g., the slope estimate, and the width of the 90% 
confidence intervals [CIs]), graphical evaluation, and descriptive statistics by dose level.  
Details are as follows: 
 
Power Model: The power model will be used to estimate the slope parameter and the 
90% CIs for the slope. The general form of the power model is described as: 
ln (PK Parameter) = β0 + β1 ln(Dose) + ε 
This approach is usually referred to as a power model because after exponentiation: 
PK Parameter = α Dose β1 
where α only depends on β0 and ε and represents the y-intercept of the line and β1 
represents the slope of the line. 
Linear relationships between the log-transformed PK parameter and the log of the dose 
will be tested to obtain an estimate of the slope parameter (β1) and 90% confidence 
interval (CI) for the slope. Dose proportionality can generally be concluded if the 90% 
CI around the slope estimate (i.e., β1) includes the value of 1. 
o MAD-HS 
o Similar model as explained above will be used to assess dose proportionality for the 
parameters Cmax, AUCt , AUC0-inf  and AUCτ calculated on Day 1 and Day 7 separately.  
 
Food Effect Analysis 
o FE Segment 
The effect of food will be assessed for AUC∞, AUC0-t , Cmax using mixed effect model.   
A mixed effect model will be fitted separately to each of the log transformed PK parameters with period 
and treatment (fed or fasted) as fixed effects and subject as a random effect. Model assumptions will be 
checked and appropriate adjustments may be applied to the data. Point estimates for the differences in 
means (EP547 fed – EP547 fasted) and corresponding 90% confidence intervals (CIs) will be constructed 
from the least-squares means, using the residual variance. These will then be back-transformed to 
provide point estimates and corresponding 90% CIs for the ratio of geometric means fed:fasted. Intra-
subject coefficient from the model will also be presented. 
The effect of food on Tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test to 
compute the point estimate and 90% CI for the median difference (EP547 fed – EP547 fasted). This 
endpoint will not be log transformed for analysis. 


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3.4 
Multiple Comparisons and Multiplicity Adjustments. 
Not applicable for this study. 
3.5 
Handling of Missing Data 
For the classification of Treatment emergent adverse event (TEAE) and Concomitant medication, the 
following will be applied in the following order: 
a. 
If all dates/times (start and stop) missing, the event/medication will automatically be classified as 
a TEAE/Concomitant medication. 
b. 
For adverse events (AEs) with a missing start date/time, if the event end date/time is prior to first 
study drug administration, the event will not be classified as a TEAE. 
c. 
If only the AE start year/ medication end year is present and is the same or is after the first study 
drug administration year unit, the event/medication will be classified as a TEAE/Concomitant 
medication. 
d. 
If the AE start month and year/medication end month and year are present and are the same or 
after the first study drug administration month and year units, the event/medication will be 
classified as a TEAE/Concomitant medication. 
For the PK analysis the following will be applied: 
a. 
For the concentration descriptive summaries, concentrations may be excluded if sampling time 
deviation is considered large to affect the profile at the discretion of the pharmacokineticist.  
b. 
Concentrations (plasma and skin) that are below limit of quantification (BLQ which is 10 ng/mL 
undiluted) prior to the first quantifiable value will be set equal to zero. Post dose BLQ 
concentrations will be set to missing. 
c. 
Where there are no results (NR), these will be set to missing. 
d. 
If more than 75% of values per nominal timepoint and treatment group are BLQ, then all 
descriptive statistics, except for nBLQ, will be denoted as not calculable (NC). 
e. 
For the calculation and graphical representation (semi-log and log-log plots) of geometric 
descriptive statistics, 0 values will be set to missing. 
f. 
For the purpose of calculating the non-compartmental PK parameters, plasma concentrations that 
are BLQ prior to the first quantifiable value will be set equal to zero. BLQ values after measurable 
concentrations will be set to missing.  
g. 
For the calculation of summary statistics of PK parameters, all NR and NC values in a data series 
will be set to missing. 
Conversion of categorical values 
In some instances, continuous variables are expressed as a range (i.e. < 10). In such cases, values may 
be converted to the range boundary (upper or lower limit as applicable). As an example, a value of <10 
may be converted to 10. Such substitutions will be clearly documented in the footnotes of relevant 
outputs.  
3.6 
Coding of Events and Medications 
Medical history and AE verbatim terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), version 23.0. Terms will be coded to the full MedDRA hierarchy, but the system 
organ class (SOC) and preferred terms (PT) will be of primary interest for the analysis. 
Prior and concomitant medications will be coded using the World Health Organization Drug Dictionary, 
version March 2020. Medications will be mapped to the full WHO-DD Anatomical Therapeutic 
Chemical (ATC) class hierarchy, but PTs will be of primary interest in this analysis. 


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3.7 
Treatment Groups/Treatment Sequence 
3.7.1 
Baseline Characteristic, Demography, Safety and PD outputs 
For listings, all segment data will be presented together in one listing as per segment and dose level 
(available) with the following treatment group labels: 
Group 1: SAD HS/ EP547 25 mg 
Group 2: SAD HS/ EP547 75 mg 
Group 3: SAD HS/ EP547 225 mg 
Group 4: SAD HS/ EP547 450 mg 
Group 5: SAD HS/ EP547 TBD mg 
Group 6: MAD HS/ EP547 25 mg QD 
Group 7: MAD HS/ EP547 75 mg QD 
Group 8: MAD HS/ EP547 TBD mg QD 
Group 9: SD CP/ EP547 TBD mg 
Group 10: SD UP/ EP547 TBD mg 
Group 11: MAD CP/ EP547 TBD mg QD 
Group 12: MAD CP/ EP547 TBD mg QD (optional) 
Group 13: MAD UP/ EP547 TBD mg QD 
Group 14: MAD UP/ EP547 TBD mg QD (optional) 
 
For summary, separate tables will be provided for each segment (SAD-HS, MAD-HS, SD-CP/SD-UP, 
MAD-CP/MAD-UP) with the following treatment group labels: 
SAD-HS: 
EP547 25 mg (N = x) 
EP547 75 mg (N = x) 
EP547 225 mg (N = x) 
EP547 450 mg (N = x) 
EP547 TBD mg (N = x) 
Overall EP547 (N = xx) 
Overall Placebo (N = xx) 
 
MAD-HS: 
EP547 25 mg QD (N = x) 
EP547 75 mg QD (N = x) 
EP547 TBD mg QD (N = x) 
Overall EP547 (N = xx) 
Overall Placebo (N = xx) 
 
SD-CP/SD-UP: 


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CP EP547 TBD mg (N = x) 
UP EP547 TBD mg (N = x) 
 
MAD-CP/MAD-UP: 
CP EP547 TBD mg QD (N = x) 
CP EP547 TBD mg QD (N = x) (optional) 
UP EP547 TBD mg QD (N = x) 
UP EP547 TBD mg QD (N = x) (optional) 
CP Overall EP547 (N = x) (optional) 
UP Overall EP547 (N = x) (optional) 
CP Overall Placebo (N = x)  
UP Overall Placebo (N = x)  
Placebo and active treatment groups will be pooled for all descriptive analysis for healthy subject 
segments. For MAD/CP and MAD/UP segments, placebo and active treatment groups will be pooled 
only if there are multiple dose levels.  Continuous and Categorical analysis will be conducted as 
described in section 3.1. 
3.7.2 
PK outputs 
The same treatment group labels as mentioned in section 3.7.1 will be used for all by-participant listings. 
For summary separate tables will be provided for each segment (SAD-HS, MAD-HS, SD-CP/SD-UP, 
MAD-CP/MAD-UP) with the following treatment group labels: 
SAD-HS: 
EP547 25 mg (N = x) 
EP547 75 mg (N = x) 
EP547 225 mg (N = x) 
EP547 450 mg (N = x) 
EP547 TBD mg (N = x) 
 
MAD-HS: 
EP547 25 mg QD (N = x) 
EP547 TBD mg QD (N = x) 
EP547 TBD mg QD (N = x) 
 
SD-CP/SD-UP: 
CP EP547 TBD mg (N = x) 
UP EP547 TBD mg (N = x) 
 
MAD-CP/MAD-UP: 
CP EP547 TBD mg QD (N = x) 
CP EP547 TBD mg QD (N = x) (optional) 


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UP EP547 TBD mg QD (N = x) 
UP EP547 TBD mg QD (N = x) (optional) 
Continuous analysis will be conducted as described in section 3.1. 
3.7.3 
Food Effect Segment 
Separate tables and listings will be presented for FE segment.  
 
All baseline, demographic,
 tables will be presented by Sequence.  
 
• 
Sequence 1 (N = x) 
• 
Sequence 2 (N = x) 
• 
Overall (N = x) 
Where sequence 1 (Fasted for FE Period 1 followed by Fed for FE Period 2)  
            sequence 2 (Fed for FE Period 1 followed by Fasted for FE Period 2). 
 
All safety, analysis population, and PK tables will be presented by treatment. 
• 
   EP547 75 mg Fed (N = x) 
• 
   EP547 75 mg Fasted (N = x) 
• 
   Overall (N = x) [Only for AE, CM and analysis population table] 
 
         
 
 


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4. 
ANALYSIS POPULATIONS  
In this study 4 analysis sets are defined: Enrolled, Safety, Pharmacokinetic (PK), and Pharmacodynamic 
(PD) population. 
Furthermore, any additional exploratory analysis not identified in the SAP will be included in the final 
CSR as exploratory post hoc analyses, including analyses for additional study populations or subgroups 
of interest. 
4.1 
Population Descriptions 
4.1.1 
Enrolled Population  
This population will comprise all subjects who sign the informed consent form (ICF) to participate in 
the study, complete the screening visit procedures, and meet all eligibility criteria for enrollment.  
All listings will be presented by the Enrolled Population. 
4.1.2 
Safety Population 
This population will comprise all subjects who receive at least 1 dose of study drug, whether prematurely 
withdrawn from the study or not and will be based on actual treatment received. 
For FE segment, Safety Population will include all randomized subjects who receive any amount of 
study drug (EP547 75 mg Fasted or EP547 75 mg Fed) and will be based on the actual treatment received, 
if this differs from what the subject was randomized to.  
All safety analyses will be based on the Safety Population. 
4.1.3 
Pharmacokinetic (PK) Population 
Plasma PK population: 
Non FE segments: This population will comprise all subjects who receive at least one dose of study drug 
(EP547) and have any measurable plasma concentrations of EP547 and had no important protocol 
deviations affecting the pharmacokinetics of EP547 and for whom a sufficient number of samples are 
available to determine at least one PK parameter among Cmax, Tmax and AUC0-t. Subjects will be assessed 
on a subject-by-subject basis for inclusion in the PK Population and will be determined by the study and 
sponsor pharmacokineticist. The PK Population determination will be made before unblinding post 
database lock.  
The PK analyses for EP547 and its metabolites (as applicable) will be conducted based on the PK 
Population for plasma concentration data. 
For FE segment: This population will include all randomized subjects who receive at least one dose of 
study drug (EP547 75 mg Fasted or EP547 75 mg Fed) who had no important protocol deviations 
affecting the PK variables of EP547 and for whom a sufficient number of samples are available to 
determine at least 1 PK parameter among AUC0-t, Cmax or Tmax. All PK analysis will be based on this 
population.  Subjects will be assessed on a subject-by-subject basis for inclusion in the PK Population 
and will be determined by the study and sponsor pharmacokineticist. 
Urine PK population: 
This population will comprise all subjects who receive at least one dose of study drug (EP547) and have 
any measurable urine concentrations of EP547 and had no important protocol deviations.  The urine PK 
population determination will be made on subject-by-subject basis by the study and sponsor 
pharmacokineticist before unblinding post database lock.  
The PK analyses for urine concentrations and parameters will be conducted based on the urine PK 
Population. 
Skin PK population: 


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This population will comprise all subjects who receive at least one dose of study drug (EP547) and have 
any measurable skin concentrations of EP547 and had no important protocol deviations. The summary 
skin concentrations data of EP547 and its metabolites (as applicable) will be based on the PK population 
for skin concentration data. 
The PK analyses for skin concentrations will be conducted based on the PK Population for skin 
concentration data. 
4.1.4 
Pharmacodynamic (PD) Population 
This population will comprise all subjects belonging to the Safety Population without major protocol 
deviations. 
The PD analyses will be conducted based on the PD Population. 
5. 
PARTICIPANT DISPOSITION AND ANALYSIS POPULATIONS 
Participant disposition and analysis population analyses will be based on the Safety and Enrolled 
population respectively. Participant disposition and analysis populations will be summarized 
descriptively as described in section 3.1 (categorical descriptive analysis). The screen failure including 
reason for screen failure will be presented in the by-participant data listings and will be summarized 
descriptively as described in section 3.1 (categorical descriptive analysis).  
5.1.1 
Participant Disposition 
Participant disposition will include the number of participants who completed the study treatment as 
planned and completed the post-treatment follow-up, participants withdrawn from the study treatment 
and from post-treatment follow-up, as well as the primary reason for treatment termination and post-
treatment follow-up termination. Participant disposition will be summarized descriptively. 
5.1.2 
Analysis Populations 
The number of participants included in each study populations will be summarized descriptively. 
In addition, the inclusion of each participant into/from each of the defined analysis populations will be 
presented in the by-participant data listings. 
 
 
 


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6. 
PROTOCOL DEVIATIONS 
Protocol deviations will be presented for each participant in the by-participant data listings and the 
classification and important protocol deviation will be summarized descriptively as described in section 
3.1 (categorical descriptive analysis) under the Safety Population. 
Prior to database lock, all protocol deviations will be tracked in the Novotech Clinical Trial Management 
System (CTMS).  All important deviations are documented on an Important Protocol Deviation (IPD) 
form and are reviewed and approved by Novotech medical monitor and sponsor. 
Protocol deviations and important protocol deviations will be categorized as noted in the protocol 
deviation management plan version 1.0 dated 2020-08-25. 
 


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7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
Demographic and baseline information analysis will be based on the Safety Population. If there is a 
difference from the Safety Population, demographic and baseline information analysis will be repeated 
for the PK and PD population.   
 Demographic and baseline information will be summarized descriptively as described in section 3.1. 
7.1 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics parameters will be analyzed: 
Continuous descriptive analysis: 
• 
Age (years) 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body Mass Index (BMI) (kg/m2) = weight (kg) / [height (m)]2 
• 
Estimated Glomerular Filtration Rate (eGFR)  (only for UP segments) 
• 
Child-Pugh Score (only for CP segments) 
Categorical descriptive analysis: 
• 
Sex 
• 
Race  
• 
Ethnicity 
• 
eGFR (only for UP segments): G1 (≥90), G2 (60 to 89), G3a (45 to 59), G3b (30 to 44), G4 (15 
to 29), and G5 (<15) 
• 
Child-Pugh Score (only for CP segments): Class A (5 to 6 points), Class B (7 to 9 points), Class 
C (10 to 15 points) 
Baseline eGFR will be derived using the CKD-EPI equation (Levey 2009) 
eGFR=141 x min (SCr/κ,1)α  x max(SCr /κ,1)-1 209 x 0.993Age x 1.018 [if female] x1.159 [if Black] 
where 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
SCr (standardized serum creatinine) = mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
7.2 
Medical history 
Medical history will be coded using MedDRA® and will be presented in the by-participant data listings. 
Summary tables will include the number of participants (%) experiencing an event and the number of 
events. Participants will be counted only once for each SOC and PT level (categorical descriptive 
analysis).  


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7.3 
Disease History 
Disease history will be presented for SD-CP, SD-UP, MAD-CP and MAD-UP participants in the by-
participant data listings. Summary tables will include the number of participants (%) experiencing each 
disease including liver disease, end stage renal disease, pruritus, suicidal indentaions and so on 
(categorical descriptive analysis).  
7.4 
Hemodialysis History 
Hemodialysis history will be presented for SD-UP and MAD-UP participants in the by-participant data 
listings.  
The following parameters will be summarized: 
Continuous descriptive analysis: 
• 
Years required for chronic hemodialysis 
• 
Years using current hemodialysis procedure 
• 
Times a week that the patient undergoes hemodialysis 
• 
Hemodialysis undergone per week 
• 
Hours taken for hemodialysis procedure 
• 
The dialysate - Sodium/Na (meq/L) 
• 
The dialysate - Potassium/K (meq/L) 
• 
The dialysate - Calcium/Ca (meq/L) 
• 
The dialysate - Magnesium/Mg (meq/L) 
• 
The dialysate - Bicarbonate/HC03 (meq/L) 
• 
The dialysate - Chloride/Cl (meq/L) 
• 
The dialysate - Acetate (meq/L) 
• 
The dialysate - Glucose (mg/dL) 
• 
Dry weight 
• 
Dialysis adequacy measurement (Kt/V and/or URR) 
Categorical descriptive analysis: 
• 
Residual renal function 
• 
Type of hemodialysis 
• 
Procedure membrane 
• 
Type of heparin 
7.5 
Itch History 
Itch history will be presented for MAD-CP and MAD-UP participants only in the by-participant data 
listings.  
The following parameters will be summarized: 
Categorical descriptive analysis: 
• 
Number of patients having significant or consistent itch prior to liver/kidney disease diagnosis 
• 
Time when itch is worse 
• 
Does itching interfere patient’s sleep 


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• 
Areas of body which are itchy 
• 
Any secondary lesions to scratching ? 
• 
Is itch more prominent in different seasons ? 
• 
Seasons in which itch are worse 
• 
Circumstance that aggravate itching 
• 
Has UV light been used for itching 
7.6 
Drug Screening and other Screening laboratory 
Drug Screening and other Screening laboratory including Hepatitis B Surface Antigen (HBsAg), 
Hepatitis C Antibody (HCVAb), Human Immunodeficiency Virus (HIV-1/HIV-2), urine drug test,  
Cotinine test, alcohol test, coagulation (including INR, APTT, PT), pregnancy test, and follicle-
stimulating hormone (FSH) results will be presented in the by-participant data listings and will be 
summarized descriptively as described in section 3.1 (categorical descriptive analysis and continuous 
descriptive analysis) under the Safety Population. 
7.7 
Inclusion/Exclusion Criteria Exceptions and Eligibility Criteria 
The subject eligibility responses as well as the violation of specific inclusion/exclusion criteria will be 
summarized descriptively and also presented in the by-subject data listings. 
 


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8. 
TREATMENT EXPOSURE  
All study drug administration information (study drug administered (Yes/No), reason not administered, 
number of capsules taken, and date and time of administration will be presented in the by-participant 
data listings under the Safety Population. 
Treatment exposure in duration and the number of capsules will be summarized descriptively as 
described in section 3.1 under the Safety population. 
• 
The Treatment Exposure (duration in days) is defined as: 
Date of Last Study Drug Administration - Date of First Study Drug Administration + 1. 
 
 
 


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9. 
PRIOR AND CONCOMITANT MEDICATIONS 
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) class Level 
2 and PT as noted in section 3.1 (categorical descriptive analysis). Participant who used the same 
medication on multiple occasions will only be counted once in the specific category (PT). PTs will be 
sorted alphabetically. In addition to the summaries by the coded terms, the number of participants who 
used at least one concomitant medication during the study will be presented under the Safety Population. 
Prior medications and Concomitant medications will be presented in the by-participant data listings 
under the Enrolled Population. 




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AUC0-inf 
Area under the drug concentration-time curve, from time zero to infinity (∞) using 
the following formula 
 
Where, C't is the observed concentration at the time t (last time point with a 
measurable plasma concentration above the quantification limit) at which 
quantification was still possible, the calculation of λz or kel is given below. 
 
AUC%extrap 
The percentage of the AUC that has been extrapolated beyond the last observed 
data point, using the following formula 
 
λz or kel 
The apparent terminal elimination rate constant, will be estimated from a 
regression of ln(C) versus time over the terminal log-linear drug disposition 
portion of the concentration-time profiles. 
 
t½ 
Apparent terminal half-life, using the following formula 
CL/F 
 
Apparent total plasma clearance, using the following formula 
 
Where D = Administered dose; AUC0-∞ = AUC0-inf 
 
Vz/F  
 
Apparent terminal volume of distribution, using the following formula 
 
 
Corrected M/P 
ratio for Cmax 
Corrected metabolite to parent ratio for Cmax is calculated using the following 
formulae 
 
(Cmax metabolite/Cmax parent) *(Molecular Weight of parent drug/Molecular Weight of 
metabolite) 
Corrected M/P 
ratio for AUC0-t 
Corrected metabolite to parent ratio for AUC0-t is calculated using the following 
formulae 
 
(AUC0-t metabolite/ AUC0-t parent) *(Molecular Weight of parent drug/Molecular 
Weight of metabolite) 
 
 
 




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(Cmax metabolite/Cmax parent) *(Molecular Weight of parent drug/Molecular Weight of 
metabolite) 
Corrected M/P 
ratio for AUC0-t 
Corrected metabolite to parent ratio for AUC0-t is calculated using the following 
formula 
(AUC0-t metabolite/ AUC0-t parent) *(Molecular Weight of parent drug/Molecular Weight 
of metabolite) 
 
 
 








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10.4 
Pharmacokinetic Noncompartmental Analysis (NCA) 
10.4.1 General Plasma NCA Pharmacokinetic Settings  
The general settings in Phoenix WinNonlin® for generation of plasma PK parameters are as listed below. 
• 
NCA Model Type 
Plasma (200-202)  
• 
Weighting 
Uniform  
• 
AUC Calculation Method: 
Linear Up/Log Down 
• 
Dose Options Type 
Extravascular 
• 
Slopes Setting Fit Method: 
Best Fit  
• 
Rsq_Adjusted Criteria for ‘λz’ 
0.8 
• 
AUC% extrapolation Criteria 
20 
 
10.4.2 General Urine NCA Pharmacokinetic Settings  
The general settings in Phoenix WinNonlin® for generation of urine PK parameters are as listed below. 
• 
NCA Model Type: 
Urine (210-212)  
• 
Weighting: 
Uniform  
• 
AUC Calculation Method (if applicable): Linear Up/Log Down 
 
10.4.3 Inferential Analyses 
For SAD-HS and MAD-HS, the following endpoints will be analyzed as described in section 3.3: 
• 
Dose proportionality: 
o 
Ctrough  (Only Day 7 value to be used to assess DP for MAD ) 
o 
Cmax 
o 
AUC0-t  
o 
AUC0-inf 
o 
AUC0-τ (as appropriate, MAD only) 
Dose proportionality will be assessed graphically (Cmax, AUC0-t and AUC0-inf  versus dose) on log scale 
for both axes. PK parameters derived from Day 1 (SAD & MAD) and Day 7 (MAD) will be subjected 
to dose proportionality assessment for entire dose range studied for EP-547-101. From each model, the 
slope of the regression line β will be presented along with the 90% CI of the slope.  The regression line 
formulae along with correlation coefficient (r2) will be presented in the plot.  
Sample SAS Code for dose-proportionality analysis using power model. Programmers will need to 
modify as appropriate to the study:  
proc mixed;  
     by PKParameter;  
      model lnPKParameter = lnDose / cl alpha=0.1 solution ddfm=kr;  
run; 
 
For FE-HS, the following endpoints will be analyzed as described in section 3.3: 


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• 
Food Effect analysis: 
o 
Cmax 
o 
AUC0-t  
o 
AUC0-inf 
o 
Tmax 
 
 
 










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12. 
EFFICACY 
No efficacy analysis is planned for this study. 
 
 


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13. 
SAFETY  
Safety endpoints will be analyzed using the Safety Population. Safety endpoints will be summarized 
descriptively as described in section 3.1. 
13.1 
Adverse Events 
AEs will be coded using MedDRA. All AE summaries will be restricted to TEAEs only. Summary tables 
will include the number of participants (%) experiencing an event and the number of events. Participants 
will be counted only once for each SOC and PT level (categorical descriptive analysis). 
The TEAE summaries will include: 
• 
Overall summary of TEAEs. 
• 
TEAE summary by SOC and PT. 
• 
TEAE summary of serious events by SOC and PT. 
• 
Drug Related TEAEs summary by SOC and PT. 
• 
TEAE summary by SOC, PT and Maximum Severity. 
• 
TEAE summary of events leading to study treatment withdrawal by SOC and PT. 
All AEs will be listed and will include verbatim term, PT, SOC, serious adverse event (SAE), TEAE, 
severity, outcome, actions taken with study treatment, relationship with study treatment and 
discontinuation from the study. Separate listings will be created for SAEs, Drug-related AE, AEs leading 
to discontinuation of study drug, and AEs resulting in death. These listings will be presented by treatment 
group (grouping provided in section 3.7) sorted by subject ID and AE start date. 
13.2 
Safety Laboratory Assessments 
Blood and urine samples will be collected at the time points specified in the Schedule of Events (refer to 
the Protocol) to conduct hematology/coagulation, chemistry and urinalysis (including microscopic 
examinations) analyses. 
The following tests will be performed within each of the specified test panels: 
Hematology: 
• 
Basophils 
• 
Eosinophils 
• 
Hematocrit 
• 
Hemoglobin 
• 
Lymphocytes 
• 
Monocytes 
• 
MPV 
• 
Neutrophils 
• 
Platelets 
• 
Red blood cells (erythrocytes) (RBC) 
• 
White blood cells (leukocytes) (WBC) (total and differential) 
Chemistry: 
• 
Albumin 
• 
Alkaline Phosphatase (ALP) 


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• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Bicarbonate 
• 
Bile acids 
• 
Blood Urea Nitrogen (BUN) 
• 
Corrected Calcium 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Creatine phosphokinase (CPK) 
• 
Direct Bilirubin 
• 
Gamma-glutamyltransferase (GGT) 
• 
High-Density Lipoprotein cholesterol (HDL-c) 
• 
Lactate Dehydrogenase (LDH) 
• 
Low-Density Lipoprotein cholesterol (LDL-c) 
• 
Magnesium 
• 
Phosphate 
• 
Potassium 
• 
Sodium 
• 
Triglycerides 
• 
Total Bilirubin 
• 
Total Cholesterol 
• 
Total Protein 
• 
Urea 
Urinalysis (Dipstick) & Microscopic Urinalysis: 
• 
Bilirubin 
• 
Blood 
• 
Color 
• 
Glucose  
• 
Ketones 
• 
Leukocytes 
• 
Nitrite 
• 
pH 
• 
Protein 
• 
Specific Gravity 
• 
Urobilinogen 


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• 
Microscopic Examinations (listing only) 
All laboratory data collected at scheduled and unscheduled visits will be included in the listings, but only 
results collected as scheduled visits will be included in the summary tables. 
Results for individual parameters may be reported in different units depending on the analyzing 
laboratory. If required, the results (and the corresponding normal range cut-off values) for individual 
parameters may be converted to International System of Units (S.I.) to summarize the data.  Parameters 
will be presented in both units (S.I and conventional units) in the listing. 
For all the parameters where a unit value has been reported, the parameter names that will be used in the 
outputs will comprise of the test name and the unit of measure, for example, ‘Albumin (g/L)’. For the 
urinalysis parameters, the parameter name will be the reported test name only. Parameters will be sorted 
alphabetically within tables and listings. 
For all parameters where a normal range limit value was reported, the normal range will be derived based 
on the available lower and upper limit values and any reported mathematical symbols. If both a lower 
and upper limit value is available, the normal range will be presented as ‘(Lower, Upper)’. 
The reported results for each parameter with a defined normal range will be classified (‘Low’, ‘Normal’, 
‘High’) in relation to the defined normal range limits. If a result is equal to the normal range cut-off 
value, the result will be considered ‘Normal’. 
The hematology, chemistry and urinalysis results tables will present summary statistics for each 
laboratory parameter within the specific test panel. For each parameter, summaries will be presented for 
the baseline and each scheduled post-baseline visit. In addition, summaries will be presented for the 
change from baseline values at each scheduled post-baseline visit (continuous descriptive analysis). 
The decimal precision to which the summaries for each parameter will be based on the maximum number 
of decimals to which the reported result or the normal range limits are presented to in the raw data. The 
results and normal ranges will be displayed to the same decimal precision in the listings. 
The hematology and chemistry result with values out of normal range will present counts and percentages 
for the reported results at baseline and each post-baseline visit/time point. Result categories will be 
ordered as ‘Low’, ‘Normal’ and ‘High’ (categorical descriptive analysis). 
Additionally, counts (%) of number participants with normal and abnormal CS/NCS at each scheduled 
time point will also be presented along with shift tables that will represent the changes in normal 
categories across post-baseline time points (categorical descriptive analysis).  
13.3 
Vital Signs 
The following vital signs measurements will be taken at the time points specified in the Schedule of 
Events (refer to the Protocol): 
• 
Pulse Rate (beats/min) 
• 
Systolic blood pressure (SBP) (mmHg) 
• 
Diastolic blood pressure (DBP) (mmHg) 
• 
Respiratory rate (breaths/min) 
• 
Temperature (ºC) 
• 
Oxygen Saturation (%) 
• 
Body Weight (kg) 
All vital signs data collected at scheduled and unscheduled visits will be included in the listings, but only 
results collected as scheduled visits will be included in the summary tables. 
The parameter names that will be used in the outputs will comprise of the test name and the unit of 
measure, for example, ‘Systolic Blood Pressure (mmHg)’. Parameters will be sorted in the order that the 
measurements were collected in on the Vital Signs eCRF page within the tables and listings. 


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Vital signs measurements will present summary statistics for the results at the baseline and each 
scheduled post-baseline visit for each of the parameters. In addition, summaries will be presented for the 
change from baseline values at each scheduled post-baseline visit (continuous descriptive analysis). 
The decimal precision to which the summaries for each parameter will presented will be based on the 
maximum number of decimals to which the results were reported on the eCRF. 
13.4 
12-Lead Electrocardiogram (ECG) 
The following ECG measurements will be taken at the time points specified in the Schedule of Events 
(refer to the Protocol): 
• 
Ventricular Rate (beats/min) 
• 
PR Interval (msec) 
• 
QT Interval (msec) 
• 
QTcF Interval (msec) 
• 
QRS Duration (msec) 
• 
Overall Clinical Interpretation Finding 
All ECG data collected at scheduled and unscheduled visits will be included in the listings, but only 
results collected as scheduled visits will be included in the summary tables. 
The parameter names that will be used in the outputs will comprise of the test name and the unit of 
measure, for example, ‘Ventricular Rate (beats/min)’. Parameters will be sorted in the order that the 
measurements were collected in on the ECG eCRF page within the tables and listings. 
ECG measurements will present summary statistics for the results at the baseline and each scheduled 
post-baseline visit for each of the parameters. In addition, summaries will be presented for the change 
from baseline values at each scheduled post-baseline visit (continuous descriptive analysis). 
The decimal precision for each parameter will be based on the maximum number of decimals to which 
the results were reported on the eCRF. 
The summary of overall ECG interpretation findings table will present counts and percentages along 
with shift tables that will represent the changes in normal and abnormal NCS/CS categories across post-
baseline time points (categorical descriptive analysis).  
13.5 
Physical Examinations 
By-participant data listings will be created for all physical examination parameters and all time points. 
13.6 
Hemodialysis 
Hemodialysis will be presented for SD-UP and MAD-UP participants in the by-participant data listings.  
The following hemodialysis measurements will be taken at the time points specified in the Schedule of 
Events (refer to the Protocol) and will be summarized descriptively as described in section 3.1 
(categorical descriptive analysis and continuous descriptive analysis) under the Safety Population. 
Continuous descriptive analysis: 
• 
The dialysate - Sodium/Na (meq/L) 
• 
The dialysate - Potassium/K (meq/L) 
• 
The dialysate - Calcium/Ca (meq/L) 
• 
The dialysate - Magnesium/Mg (meq/L) 
• 
The dialysate - Bicarbonate/HC03 (meq/L) 
• 
The dialysate - Chloride/Cl (meq/L) 


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• 
The dialysate - Acetate (meq/L) 
• 
The dialysate - Glucose (mg/dL) 
• 
Ultrafiltration volume (kg) 
• 
Dialysis adequacy measurement (Kt/V and/or URR) 
Categorical descriptive analysis: 
• 
Type of hemodialysis 
• 
Procedure membrane 
• 
Type of heparin 
 
 
 
 


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14. 
IMMUNOGENICITY 
No immunogenicity analysis is planned for this study. 
 
 


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15. 
CHANGES TO THE PLANNED ANALYSIS 
Not applicable. 


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16. 
INTERIM AND FINAL ANALYSIS 
16.1 
Interim Analysis 
An interim analysis may be performed at Sponsor’s discretion for internal decision making and use the 
data towards Investigational New Drug (IND). Additional data analyses may also be performed during 
the study in the event that the Sponsor and Investigators determine that there is a need for further 
evaluation of the data.  
An unblinded interim analysis is planned once all SAD-HS and MAD-HS subjects have completed the 
study. For these subjects, safety and tolerability together with PK and PD data will be examined as a 
preliminary evaluation of safety and tolerability, PK and PD. The interim analysis will only be conducted 
on SAD-HS and MAD-HS subjects and the results derived out of this interim analysis will only be used 
for internal purposes and may not result in any change to the study protocol. The data for SAD-HS and 
MAD-HS will be frozen prior to the interim analysis thereby having it unblinded to Sponsor as well as 
Novotech.  
16.2 
Final Analysis (End of Study) 
The final analysis will be conducted after all participants have completed the study, the clinical database 
has been locked, the analysis populations have been approved and the study has been unblinded. 
The final analysis will be based on the SAP and include data from all segments. Any deviations from the 
planned analysis will be documented in the CSR. 
 
 


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17. 
SOFTWARE 
• 
SAS® Version 9.2 or higher (SAS Institute, Cary, North Carolina, USA). 
• 
Phoenix WinNonlin® (Certara, USA) Version 8.1 or higher.


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18. 
TABLES 
Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.1 
Demographics and Other Baseline Characteristics 
 
 
 
14.1.1a 
Analysis Population – SAD-HS 
Enrolled 
× 
× 
14.1.1b 
Analysis Population – MAD-HS 
Enrolled 
× 
× 
14.1.1c 
Analysis Population – SD-CP/SD-UP 
Enrolled 
 
× 
14.1.1d 
Analysis Population – MAD-CP/MAD-UP 
Enrolled 
 
× 
14.1.1e 
Analysis Population – FE-HS 
Enrolled 
 
 
14.1.2a 
Inclusion/Exclusion Criteria – SAD-HS 
All Subjects 
× 
× 
14.1.2b 
Inclusion/Exclusion Criteria – MAD-HS 
All Subjects 
× 
× 
14.1.2c 
Inclusion/Exclusion Criteria – SD-CP/SD-UP 
All Subjects 
 
× 
14.1.2d 
Inclusion/Exclusion Criteria – MAD-CP/MAD-UP 
All Subjects 
 
× 
14.1.2e 
Inclusion/Exclusion Criteria – FE-HS 
All Subjects 
 
 
14.1.3a 
Subject Disposition – SAD-HS 
Safety 
× 
× 
14.1.3b 
Subject Disposition – MAD-HS 
Safety 
× 
× 
14.1.3c 
Subject Disposition – SD-CP/SD-UP 
Safety 
 
× 
14.1.3d 
Subject Disposition – MAD-CP/MAD-UP 
Safety 
 
× 
14.1.3e 
Subject Disposition – FE-HS 
Safety 
 
 
14.1.4 
Screen Failures  
All Subjects 
× 
× 
14.1.5a 
Protocol Deviations – SAD-HS 
Safety 
× 
× 
14.1.5b 
Protocol Deviations – MAD-HS 
Safety 
× 
× 
14.1.5c 
Protocol Deviations – SD-CP/SD-UP 
Safety 
 
× 
14.1.5d 
Protocol Deviations – MAD-CP/MAD-UP 
Safety 
 
× 
14.1.5e 
Protocol Deviations – FE-HS 
Safety 
 
 
14.1.6.1a 
Demographics and Baseline Characteristics – SAD-HS 
Safety 
× 
× 
14.1.6.1b 
Demographics and Baseline Characteristics – MAD-HS 
Safety 
× 
× 
14.1.6.1c 
Demographics and Baseline Characteristics – SD-CP/SD-UP 
Safety 
 
× 
14.1.6.1d 
Demographics and Baseline Characteristics – MAD-CP/MAD-UP 
Safety 
 
× 
14.1.6.1e 
Demographics and Baseline Characteristics – FE-HS 
Safety 
 
 
14.1.6.2a 
Demographics and Baseline Characteristics – SAD-HS 
PK 
× 
× 
14.1.6.2b 
Demographics and Baseline Characteristics – MAD-HS 
PK 
× 
× 
14.1.6.2c 
Demographics and Baseline Characteristics – SD-CP/SD-UP 
PK 
 
× 


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Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.1.6.2d 
Demographics and Baseline Characteristics – MAD-CP/MAD-UP 
PK 
 
× 
14.1.6.2e 
Demographics and Baseline Characteristics – FE-HS 
PK 
 
 
14.1.6.3a 
Demographics and Baseline Characteristics – SAD-HS 
PD 
× 
× 
14.1.6.3b 
Demographics and Baseline Characteristics – MAD-HS 
PD 
× 
× 
14.1.6.3c 
Demographics and Baseline Characteristics – SD-CP/SD-UP 
PD 
 
× 
14.1.6.3d 
Demographics and Baseline Characteristics – MAD-CP/MAD-
UP 
PD 
 
× 
14.1.6.3e 
Demographics and Baseline Characteristics – FE-HS 
PD 
 
 
14.1.7a 
Medical History – SAD-HS 
Safety 
× 
× 
14.1.7b 
Medical History – MAD-HS 
Safety 
× 
× 
14.1.7c 
Medical History – SD-CP/SD-UP 
Safety 
 
× 
14.1.7d 
Medical History – MAD-CP/MAD-UP 
Safety 
 
× 
14.1.7e 
Medical History – FE-HS 
Safety 
 
 
14.1.8c 
Disease History – SD-CP/SD-UP 
Safety 
 
× 
14.1.8d 
Disease History – MAD-CP/MAD-UP 
Safety 
 
× 
14.1.9c 
Hemodialysis History – SD-UP 
Safety 
 
× 
14.1.9d 
Hemodialysis History – MAD-UP 
Safety 
 
× 
14.1.10d 
Itch History – MAD-CP/MAD-UP 
Safety 
 
× 
14.1.11a 
Drug Screening and Other Screening Laboratory Results – 
SAD-HS 
Safety 
× 
× 
14.1.11b 
Drug Screening and Other Screening Laboratory Results - 
MAD-HS 
Safety 
× 
× 
14.1.11c 
Drug Screening and Other Screening Laboratory Results - SD-
CP/SD-UP 
Safety 
 
× 
14.1.11d 
Drug Screening and Other Screening Laboratory Results - 
MAD-CP/MAD-UP 
Safety 
 
× 
14.1.11e 
Drug Screening and Other Screening Laboratory Results – FE-
HS 
Safety 
 
 
14.1.12a 
Study Drug Administration – SAD-HS 
Safety 
× 
× 
14.1.12b 
Study Drug Administration – MAD-HS 
Safety 
× 
× 
14.1.12c 
Study Drug Administration – SD-CP/SD-UP 
Safety 
 
× 
14.1.12d 
Study Drug Administration – MAD-CP/MAD-UP 
Safety 
 
× 


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Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.1.12e 
Study Drug Administration – FE-HS 
Safety 
 
 
 
 
 
 
 
14.2 
Efficacy/PK/PD 
 
 
 
14.2.1a 
Plasma EP547 & EP3583 Concentrations by Treatment and 
Time – SAD-HS 
PK 
× 
× 
14.2.1b 
Plasma EP547 & EP3583 Concentrations by Treatment and 
Time – MAD-HS 
PK 
× 
× 
 
 
 
 
 
14.2.1c 
Plasma EP547 & EP3583 Concentrations by Treatment and 
Time – SD-CP/SD-UP 
PK 
 
× 
14.2.1d 
Plasma EP547 & EP3583 Concentrations by Treatment and 
Time – MAD-CP/MAD-UP 
PK 
 
× 
14.2.1e 
Plasma EP547 Concentrations by Treatment and Time – FE-HS 
PK 
 
 
14.2.2a 
Plasma EP547 & EP3583 Pharmacokinetic Parameters by 
Treatment – SAD-HS 
PK 
× 
× 
14.2.2b 
Plasma EP547 & EP3583 Pharmacokinetic Parameters by 
Treatment – MAD-HS 
PK 
× 
× 
14.2.2c 
Plasma EP547 & EP3583 Pharmacokinetic Parameters by 
Treatment – SD-CP/SD-UP 
PK 
 
× 
14.2.2d 
Plasma EP547 & EP3583 Pharmacokinetic Parameters by 
Treatment – MAD-CP/MAD-UP 
PK 
 
× 
14.2.2e 
Plasma EP547 Pharmacokinetic Parameters by Treatment – FE-
HS 
PK 
 
 
14.2.3.1a 
Urine EP547 and EP3583 Concentrations by Treatment and 
Time – SAD-HS 
Urine PK 
× 
× 
14.2.3.2a 
Urine EP547 and EP3538 Pharmacokinetic Parameters by 
Treatment – SAD-HS 
Urine PK 
× 
× 
14.2.4a 
Plasma EP547 Dose Proportionality – SAD-HS 
PK 
× 
× 
14.2.4b 
Plasma EP547 Dose Proportionality – MAD-HS 
PK 
× 
× 
14.2.4e 
Analysis of Food Effect – FE-HS 
PK 
 
 
14.2.5b 
Skin EP547 & EP3583 Concentration by Treatment and Time – 
MAD-HS 
Skin PK 
× 
× 




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Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.3.1e 
Concomitant Medications by ATC Classification – FE-HS 
Safety 
 
 
 
 
 
 
 
14.3.3 
Adverse Events 
 
 
 
14.3.3.1a 
Summary of Treatment Emergent Adverse Events – SAD-HS 
Safety 
× 
× 
14.3.3.1b 
Summary of Treatment Emergent Adverse Events – MAD-HS 
Safety 
× 
× 
14.3.3.1c 
Summary of Treatment Emergent Adverse Events – SD-CP/SD-
UP 
Safety 
 
× 
14.3.3.1d 
Summary of Treatment Emergent Adverse Events – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.3.1e 
Summary of Treatment Emergent Adverse Events – FE-HS 
Safety 
 
 
14.3.3.2a 
Incidence of Treatment-Emergent Adverse Events by SOC and 
PT – SAD-HS 
Safety 
× 
× 
14.3.3.2b 
Incidence of Treatment-Emergent Adverse Events by SOC and 
PT – MAD-HS 
Safety 
× 
× 
14.3.3.2c 
Incidence of Treatment-Emergent Adverse Events by SOC and 
PT – SD-CP/SD-UP 
Safety 
 
× 
14.3.3.2d 
Incidence of Treatment-Emergent Adverse Events by SOC and 
PT – MAD-CP/MAD-UP 
Safety 
 
× 
14.3.3.2e 
Incidence of Treatment-Emergent Adverse Events by SOC and 
PT – FE-HS 
Safety 
 
 
14.3.3.3a 
Incidence of Treatment-Emergent Adverse Events by SOC, PT 
and Maximum Severity – SAD-HS 
Safety 
× 
× 
14.3.3.3b 
Incidence of Treatment-Emergent Adverse Events by SOC, PT 
and Maximum Severity – MAD-HS 
Safety 
× 
× 
14.3.3.3c 
Incidence of Treatment-Emergent Adverse Events by SOC, PT 
and Maximum Severity – SD-CP/SD-UP 
Safety 
 
× 
14.3.3.3d 
Incidence of Treatment-Emergent Adverse Events by SOC, PT 
and Maximum Severity – MAD-CP/MAD-UP 
Safety 
 
× 
14.3.3.3e 
Incidence of Treatment-Emergent Adverse Events by SOC, PT 
and Maximum Severity – FE-HS 
Safety 
 
 
14.3.3.4a 
Incidence of Serious Treatment-Emergent Adverse Events by 
SOC and PT – SAD-HS 
Safety 
× 
× 


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Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.3.3.4b 
Incidence of Serious Treatment-Emergent Adverse Events by 
SOC and PT – MAD-HS 
Safety 
× 
× 
14.3.3.4c 
Incidence of Serious Treatment-Emergent Adverse Events by 
SOC and PT – SD-CP/SD-UP 
Safety 
 
× 
14.3.3.4d 
Incidence of Serious Treatment-Emergent Adverse Events by 
SOC and PT – MAD-CP/MAD-UP 
Safety 
 
× 
14.3.3.4e 
Incidence of Serious Treatment-Emergent Adverse Events by 
SOC and PT – FE-HS 
Safety 
 
 
14.3.3.5a 
Incidence of Drug-Related Treatment-Emergent Adverse Events 
by SOC and PT – SAD-HS 
Safety 
× 
× 
14.3.3.5b 
Incidence of Drug-Related Treatment-Emergent Adverse Events 
by SOC and PT – MAD-HS 
Safety 
× 
× 
14.3.3.5c 
Incidence of Drug-Related Treatment-Emergent Adverse Events 
by SOC and PT – SD-CP/SD-UP 
Safety 
 
× 
14.3.3.5d 
Incidence of Drug-Related Treatment-Emergent Adverse Events 
by SOC and PT – MAD-CP/MAD-UP 
Safety 
 
× 
14.3.3.5e 
Incidence of Drug-Related Treatment-Emergent Adverse Events 
by SOC and PT – FE-HS 
Safety 
 
 
14.3.3.6a 
Incidence of Treatment-Emergent Adverse Events Leading to 
Study Treatment Withdrawal by SOC and PT – SAD-HS 
Safety 
× 
× 
14.3.3.6b 
Incidence of Treatment-Emergent Adverse Events Leading to 
Study Treatment Withdrawal by SOC and PT – MAD-HS 
Safety 
× 
× 
14.3.3.6c 
Incidence of Treatment-Emergent Adverse Events Leading to 
Study Treatment Withdrawal by SOC and PT – SD-CP/SD-UP 
Safety 
 
× 
14.3.3.6d 
Incidence of Treatment-Emergent Adverse Events Leading to 
Study Treatment Withdrawal by SOC and PT – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.3.6e 
Incidence of Treatment-Emergent Adverse Events Leading to 
Study Treatment Withdrawal by SOC and PT – FE-HS 
Safety 
 
 
 
 
 
 
× 
14.3.4 
Laboratory Parameters 
 
 
 
14.3.4.1.1a 
Hematology Results - Change of Hematology Values – SAD-HS 
Safety 
× 
× 


Protocol Number: EP-547-101 
2021-06-03 
Document status: Final Version 2.0 
Novotech - Strictly Confidential 
Page 58 of 66 
Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.3.4.1.1b 
Hematology Results - Change of Hematology Values – MAD-
HS 
Safety 
× 
× 
14.3.4.1.1c 
Hematology Results - Change of Hematology Values – SD-
CP/SD-UP 
Safety 
 
× 
14.3.4.1.1d 
Hematology Results - Change of Hematology Values – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.1.1e 
Hematology Results - Change of Hematology Values – FE-HS 
Safety 
 
 
14.3.4.1.2a 
Hematology Results - Out of Normal Range Values – SAD-HS 
Safety 
× 
× 
14.3.4.1.2b 
Hematology Results - Out of Normal Range Values – MAD-HS 
Safety 
× 
× 
14.3.4.1.2c 
Hematology Results - Out of Normal Range Values – SD-
CP/SD-UP 
Safety 
 
× 
14.3.4.1.2d 
Hematology Results - Out of Normal Range Values – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.1.2e 
Hematology Results - Out of Normal Range Values – FE-HS 
Safety 
 
 
14.3.4.1.3a 
Hematology Results - Normal/Abnormal Shift Table – SAD-HS 
Safety 
× 
× 
14.3.4.1.3b 
Hematology Results - Normal/Abnormal Shift Table – MAD-
HS 
Safety 
× 
× 
14.3.4.1.3c 
Hematology Results - Normal/Abnormal Shift Table – SD-
CP/SD-UP 
Safety 
 
× 
14.3.4.1.3d 
Hematology Results - Normal/Abnormal Shift Table – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.1.3e 
Hematology Results - Normal/Abnormal Shift Table – FE-HS 
Safety 
 
 
14.3.4.2.1a 
Chemistry Results - Change of Chemistry Values – SAD-HS 
Safety 
× 
× 
14.3.4.2.1b 
Chemistry Results - Change of Chemistry Values – MAD-HS 
Safety 
× 
× 
14.3.4.2.1c 
Chemistry Results - Change of Chemistry Values – SD-CP/SD-
UP 
Safety 
 
× 
14.3.4.2.1d 
Chemistry Results - Change of Chemistry Values – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.2.1e 
Chemistry Results - Change of Chemistry Values – FE-HS 
Safety 
 
 
14.3.4.2.2a 
Chemistry Results - Out of Normal Range Values – SAD-HS 
Safety 
× 
× 
14.3.4.2.2b 
Chemistry Results - Out of Normal Range Values – MAD-HS 
Safety 
× 
× 


Protocol Number: EP-547-101 
2021-06-03 
Document status: Final Version 2.0 
Novotech - Strictly Confidential 
Page 59 of 66 
Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
14.3.4.2.2c 
Chemistry Results - Out of Normal Range Values – SD-CP/SD-
UP 
Safety 
 
× 
14.3.4.2.2d 
Chemistry Results - Out of Normal Range Values – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.2.2e 
Chemistry Results - Out of Normal Range Values – FE-HS 
Safety 
 
 
14.3.4.2.3a 
Chemistry Results - Normal/Abnormal Shift Table – SAD-HS 
Safety 
× 
× 
14.3.4.2.3b 
Chemistry Results - Normal/Abnormal Shift Table – MAD-HS 
Safety 
× 
× 
14.3.4.2.3c 
Chemistry Results - Normal/Abnormal Shift Table – SD-
CP/SD-UP 
Safety 
 
× 
14.3.4.2.3d 
Chemistry Results - Normal/Abnormal Shift Table – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.2.3e 
Chemistry Results - Normal/Abnormal Shift Table – FE-HS 
Safety 
 
 
14.3.4.3.1a 
Urinalysis Results - Change of Urinalysis Values – SAD-HS 
Safety 
× 
× 
14.3.4.3.1b 
Urinalysis Results - Change of Urinalysis Values – MAD-HS 
Safety 
× 
× 
14.3.4.3.1c 
Urinalysis Results - Change of Urinalysis Values – SD-CP/SD-
UP 
Safety 
 
× 
14.3.4.3.1d 
Urinalysis Results - Change of Urinalysis Values – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.3.1e 
Urinalysis Results - Change of Urinalysis Values – FE-HS 
Safety 
 
 
14.3.4.3.2a 
Urinalysis Results - Out of Normal Range Values – SAD-HS 
Safety 
× 
× 
14.3.4.3.2b 
Urinalysis Results - Out of Normal Range Values – MAD-HS 
Safety 
× 
× 
14.3.4.3.2c 
Urinalysis Results - Out of Normal Range Values – SD-CP/SD-
UP 
Safety 
 
× 
14.3.4.3.2d 
Urinalysis Results - Out of Normal Range Values – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.4.3.2e 
Urinalysis Results - Out of Normal Range Values – FE-HS 
Safety 
 
 
14.3.4.3.3a 
Urinalysis Results - Normal/Abnormal Shift Table – SAD-HS 
Safety 
× 
× 
14.3.4.3.3b 
Urinalysis Results - Normal/Abnormal Shift Table – MAD-HS 
Safety 
× 
× 
14.3.4.3.3c 
Urinalysis Results - Normal/Abnormal Shift Table – SD-
CP/SD-UP 
Safety 
 
× 
14.3.4.3.3d 
Urinalysis Results - Normal/Abnormal Shift Table – MAD-
CP/MAD-UP 
Safety 
 
× 


Protocol Number: EP-547-101 
2021-06-03 
Document status: Final Version 2.0 
Novotech - Strictly Confidential 
Page 60 of 66 
Table 
Number 
Table Title 
Population 
 
Interim 
 
Final 
 
 
 
 
 
 
 
 
 
 
14.3.4.3.3e 
Urinalysis Results - Normal/Abnormal Shift Table – FE-HS 
Safety 
 
 
 
 
 
 
 
14.3.5 
Other Safety 
 
 
 
14.3.5.1a 
Vital Signs - Values and Change from Baseline – SAD-HS 
Safety 
× 
× 
14.3.5.1b 
Vital Signs - Values and Change from Baseline – MAD-HS 
Safety 
× 
× 
14.3.5.1c 
Vital Signs - Values and Change from Baseline – SD-CP/SD-
UP 
Safety 
 
× 
14.3.5.1d 
Vital Signs - Values and Change from Baseline – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.5.1e 
Vital Signs - Values and Change from Baseline – FE-HS 
Safety 
 
 
14.3.5.2a 
12-Lead ECG Results - Change of 12-Lead ECG Values – SAD-
HS 
Safety 
× 
× 
14.3.5.2b 
12-Lead ECG Results - Change of 12-Lead ECG Values – 
MAD-HS 
Safety 
× 
× 
14.3.5.2c 
12-Lead ECG Results - Change of 12-Lead ECG Values – SD-
CP/SD-UP 
Safety 
 
× 
14.3.5.2d 
12-Lead ECG Results - Change of 12-Lead ECG Values – 
MAD-CP/MAD-UP 
Safety 
 
× 
14.3.5.2e 
12-Lead ECG Results - Change of 12-Lead ECG Values – FE-
HS 
Safety 
 
 
14.3.5.3a 
12-Lead ECG Results - Normal/Abnormal Shift Table – SAD-
HS 
Safety 
× 
× 
14.3.5.3b 
12-Lead ECG Results - Normal/Abnormal Shift Table – MAD-
HS 
Safety 
× 
× 
14.3.5.3c 
12-Lead ECG Results - Normal/Abnormal Shift Table – SD-
CP/SD-UP 
Safety 
 
× 
14.3.5.3d 
12-Lead ECG Results - Normal/Abnormal Shift Table – MAD-
CP/MAD-UP 
Safety 
 
× 
14.3.5.3e 
12-Lead ECG Results - Normal/Abnormal Shift Table – FE-HS 
Safety 
 
 
14.3.5.4c 
Hemodialysis – SD-UP 
Safety 
 
× 
14.3.5.4d 
Hemodialysis – MAD-UP 
Safety 
 
× 










Protocol Number: EP-547-101 
2021-06-03 
Document status: Final Version 2.0 
Novotech - Strictly Confidential 
Page 65 of 66 
20. 
FIGURES 
Novotech is not responsible to generate Figures for this study.  


Protocol Number: EP-547-101 
 
2021-06-03 
Document status: Final Version 2.0 
 
Novotech - Strictly Confidential 
Page 66 of 66 
21. 
REFERENCES 
Protocol Original dated 17 June 2020 
Protocol Amendment 1.0 dated 14 December 2020 
Protocol Amendment 2.0 dated 19 February 2021 
Clinical Study Protocol Addendum 1.0 to Amendment 2.0 Version dated 19 March 2021 
Annotated CRF version dated 15 April 2021