Clinical trial NCT05885763
Conditions: End Stage Renal Disease on Hemodialysis
Keywords: Difelikefalin Pharmacokinetics
Sponsor: Vifor Fresenius Medical Care Renal Pharma
Start date: 2023-06-26; Completion date: 2023-10-09
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1, single-arm, open-label study to evaluate the safety, PK, and tolerability of a repeated (3 times weekly) dose of difelikefalin administered as IV bolus injections to adult Chinese HD subjects. Treatment period is one week and there is a safety follow-up period of 1 week.

Detailed description:
This is a Phase 1, single-arm, open-label study to evaluate the safety, PK, and tolerability of a repeated (3 times weekly) dose of difelikefalin administered as IV bolus injections to adult Chinese HD subjects.

Total study duration for a single subject is up to 5 weeks including a screening period of up to 3 weeks, a treatment period of 1 week, and a safety follow-up period of 1 week.

The duration of PK sampling is 12 days.

The primary objective of the study is to evaluate the PK profile of a repeated (3 times weekly) dose of difelikefalin in Chinese HD subjects over a 1-week treatment period.

Arms: arm 1: None
Interventions: intervention 1: Difelikefalin Injection
Intervention descriptions: intervention 1: Participants receive Difelikefalin three times a week (0,5 micrograms/kg dry body weight). Difelikefalin is administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each dialysis.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
The information contained in this document is proprietary to Vifor Pharma and is not to be copied, disclosed or otherwise 
distributed by an outside authority to any person or persons without the prior written permission of Vifor Pharma. 
 
 
Clinical Study Protocol 
 
Title: 
A Phase 1, Single-arm, Open-label Study to 
Evaluate the Pharmacokinetics and Safety of 
Intravenous Difelikefalin in Adult Chinese 
Subjects on Haemodialysis 
 
 
Clinical Protocol Number: 
KOR-CHINA-101 
 
 
Version Date: 
15 July 2021 
 
 
Version Number: 
1.0 
 
 
Prior Version/Amendments: 
Not applicable 
 
 
Investigational Drug 
Difelikefalin (CR845) 
 
 
Co-ordinating Investigator: 
Professor Li Zuo 
 
 
Sponsor Contact: 
Milica Enoiu, PharmD, PhD 
 
 
Sponsor Address:  
Vifor Fresenius Medical Care 
Renal Pharma Ltd. 
Rechenstrasse 37 
St. Gallen CH-9014 
Switzerland  
 
 




 
 
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SIGNATURE PAGE 
Declaration of Co-ordinating Investigator 
Title: A Phase 1, Single-arm, Open-label Study to Evaluate the Pharmacokinetics and 
Safety of Intravenous Difelikefalin in Adult Chinese Subjects on Haemodialysis 
Clinical Protocol Number: KOR-CHINA-101 
Version/Amendment Number/Date: Version 1.0, 15 July 2021 
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the Declaration of Helsinki, and the International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline for 
Guideline for Good Clinical Practice as amended. 
 
 
 
Signature of Co-ordinating Investigator 
 
Date (day month year) 
Professor Li Zuo 
Director, Department of Nephrology, 
Peking University People's Hospital 
Unit 10C, Ward Building 
11 Xizhimennan Street, Xicheng District 
Beijing, 100044 
China 
Telephone: +86 10 8832 4008 
 
 
 


 
 
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INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
Title: A Phase 1, Single-arm, Open-label Study to Evaluate the Pharmacokinetics and 
Safety of Intravenous Difelikefalin in Adult Chinese Subjects on Haemodialysis 
Clinical Protocol Number: KOR-CHINA-101 
Version/Amendment Number/Date: Version 1.0, 15 July 2021 
I have read the attached protocol as specified on this page and agree to abide by all 
provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Guideline for Good 
Clinical Practice as amended, and applicable local regulations, and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• me (including, if applicable, my spouse (or legal partner) and dependent children) 
• my Sub-investigators 
before the start of the study and to report any changes that affect my financial disclosure 
status for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Vifor Pharma. 
Signature by the Investigator on this Protocol Signature Page documents review, 
agreement, and approval of the requirements contained within this protocol. 
 
 
 
Signature of Principal Investigator 
 
Date (day month year) 
 
 
 
Name, Title, Address, Telephone 
Number of Principal Investigator 
 
 
 


 
 
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SYNOPSIS 
KOR-CHINA-101 
Title: 
A Phase 1, Single-arm, Open-label Study to Evaluate the Pharmacokinetics and 
Safety of Intravenous Difelikefalin in Adult Chinese Subjects on Haemodialysis 
Short Title: 
Pharmacokinetics(PK)  of intravenous (IV) difelikefalin in Chinese subjects on 
haemodialysis (HD) 
Study Product: 
Difelikefalin (CR845) 
Study Population: 
Adult Chinese subjects on HD 
Phase: 
1 
Sponsor: 
Vifor Fresenius Medical Care Renal Pharma Ltd. 
Protocol Number: 
KOR-CHINA-101 
Co-ordinating 
Investigator:  
Professor Li Zuo, Peking University People's Hospital, Beijing, China 
Objectives: 
Primary Objective: 
• 
To evaluate the PK profile of a repeated (3 times weekly) dose of 
difelikefalin in Chinese HD subjects over a 1-week treatment period. 
Secondary Objective: 
• 
To evaluate the safety and tolerability of a repeated (3 times weekly) dose of 
difelikefalin in Chinese HD subjects over a 1-week treatment period. 
Design: 
This is a Phase 1, single-arm, open-label study to evaluate the safety, PK, and 
tolerability of a repeated (3 times weekly) dose of difelikefalin administered as 
IV bolus injections to adult Chinese HD subjects. 
Duration: 
Total study duration for a single subject is up to 5 weeks including a screening 
period of up to 3 weeks, a treatment period of 1 week, and a safety follow-up 
period of 1 week (1 week to 10 days). 
The duration of PK sampling is 12 days (starting from treatment Day 1). 
Treatment: 
Investigational Product: 
Difelikefalin solution (IV formulation) will be provided in 2 R glass vials with 
an extractable volume of 1 ml of difelikefalin at a concentration of 50 µg/ml in 
0.04 M isotonic acetate buffer, pH 4.5. 
Dosage and Administration: 
Eligible subjects will be administered 0.5 µg/kg of difelikefalin as a single IV 
bolus 3 times, within 15 minutes post-dialysis for 1 week. 
Inclusion Criteria: 
Subjects are eligible to be included in the study only if all of the following 
inclusion criteria apply: 
1. Appropriate written informed consent has been provided by subject or 
legally acceptable representative. Written informed consent must be 
provided before any study-specific procedures are performed, including 
screening procedures. 


 
 
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2. Subjects have the ability to understand the requirements of the study, in the 
Investigator’s opinion. 
3. Chinese subjects aged ≥18 to 85 years (inclusive), at the time of consent. 
4. End-stage renal disease (ESRD) subjects who have been on HD for at least 
3 months before enrolment in the study and are currently on HD 3 times per 
week. Subjects with or without associated pruritus may be enrolled.  
5. Subjects with a prescription dry body weight between 40 and 100 kg, 
inclusive. 
6. If female, is not pregnant, or nursing. 
7. If female: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for at least 1 year and is over the age of 
55 years; or 
c. Has a negative serum pregnancy test within 7 days before first dose of 
investigational product, and agrees to use adequate contraceptive 
precautions (e.g., hormonal contraceptives, barrier with spermicide, 
intrauterine device, vasectomised partner, or abstinence) from the time 
of informed consent until 7 days after the last dose of investigational 
product. Note: If the result from serum pregnancy testing at screening is 
indeterminate due to possible human chorionic gonadotropin elevation 
secondary to ESRD unrelated to pregnancy, a serum pregnancy re-test 
may be repeated prior to treatment Day 1 to establish if a negative result 
can be confirmed. 
8. If male, agrees not to donate sperm from the first dose of investigational 
product administration (Day 1) until 7 days after last dosing, and agrees to 
use a condom with spermicide or abstain from heterosexual intercourse 
during the study until 7 days after the last dose of investigational product. 
Note: No restrictions are required for a vasectomised male, provided his 
vasectomy was performed ≥4 months prior to screening. 
Exclusion Criteria: 
1. Known to be non-compliant with HD treatments and deemed unlikely to 
complete the study by the Principal Investigator (i.e., has a history of missed 
HD sessions due to non-adherence in the past 2 months). 
2. Planned or anticipated to receive a kidney transplant during the study. Note: 
Being listed on a kidney transplant list is not an exclusion criterion. 
3. Known or suspected history of alcohol, narcotic, or other drug abuse, or 
dependence within 12 months prior to screening. 
4. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) 
greater than 2.5 × the reference upper limit of normal (ULN), or bilirubin 
(total) greater than 4 × the ULN at screening. 
5. Subjects with severe hepatic impairment (Child-Pugh Class C). 
6. Acute or unstable medical condition(s) such as congestive heart failure 
(New York Heart Association Class IV), which in the opinion of the 
Investigator would pose undue risk to the subject or would impede complete 
collection of the data or its evaluability. 


 
 
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7. Known history of allergic reaction to opiates such as hives. Note: Side 
effects related to the use of opioids such as constipation or nausea would not 
exclude the subjects from the study. 
8. Subject has known hypersensitivity to the study intervention or any 
component of the investigational product formulation. 
9. Subject has received another investigational drug within 30 days prior to the 
start of the screening visit or has planned to participate in another clinical 
trial while enrolled in this study. 
Primary and 
Secondary 
Endpoints: 
Primary Endpoint: 
• 
Evaluate the PK profile of difelikefalin, e.g., Cmax, Tmax, area under the curve 
(AUC)0‑t, AUCinf, AUCextrap(%), t½, clearance, and volume of distribution 
(Vz), when administered after each dialysis session (3 times a week) over a 
1-week treatment period. 
Secondary Endpoint: 
• 
Overall safety and tolerability of difelikefalin as assessed by incidence of 
adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, and 
clinical safety laboratory evaluations over the study period. 
Procedures: 
See Table 1 for full details of protocol required assessments, procedures, and 
applicable visits (and timings of each visit). 
During the screening period, which may occur up to 21 days prior to the 
treatment period, following the signing of the informed consent, subjects are 
assessed for study eligibility. 
Eligible subjects will be admitted to the research unit clinic on Day -1. Dosing 
and PK assessments will begin on Day 1, which will be the first scheduled 
dialysis day of the week for the subject (i.e., either Monday, or Tuesday). 
Subjects must remain overnight in the research unit on the nights of Days -1, 1, 
4, and 5 (i.e., domiciled continuously from Day -1 to middle of Day 2 and from 
Day 4 to middle of Day 6) at minimum and will be dialysed in the research unit 
on Days 1, 3, 5, 8, 10, and 12. Based on logistical considerations, subjects may 
also remain overnight in the research unit on the nights of Days 2 and 3 (i.e., 
domiciled continuously from Day -1 to middle of Day 6). 
The investigational product will be administered as an IV bolus within 
15 minutes after the end of the dialysis session on Days 1, 3, and 5. The 
investigational product will be administered based on 0.5 µg/kg of dry body 
weight. The total dose volume (ml) required from the difelikefalin vial should be 
calculated as follows: 0.01 × prescription dry body weight (kg), rounded to the 
nearest tenth (0.1 ml). The investigational product may be given either during or 
after rinse back of the dialysis circuit. Following the IV push of investigational 
product, the venous line must be flushed with at least 10 ml of normal saline.  
PK samples will be collected on Days 1, 2, 3, 5, 6, 8, 10, and 12. PK samples are 
to be obtained from a venous access different from the site used for difelikefalin 
administration to avoid cross contamination. 
Vitals signs, physical examinations, 12-lead ECG, clinical laboratory tests will 
be monitored periodically, and AEs and concomitant medications will be 
continuously recorded during the study. A final safety follow-up visit will be 
conducted on Day 14 (up to +3 days). 


 
 
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Sample Size: 
This study will enrol 30 subjects.  
The sample size for this Phase 1 study is based on a pragmatic approach. No 
formal sample size calculation has been conducted. 
Study Sites: 
1-4 study sites in China 
Statistical Methods: 
Detailed methodology for summary and statistical analyses of the data collected 
in this trial will be documented in a Statistical Analysis Plan (SAP), which will 
be finalised prior to database lock. Any deviation from the SAP will be noted 
and explained in the clinical study report. All individual data will be listed as 
measured. 
Frequency tables for categorical variables (absolutes and relative frequencies) 
and descriptive statistics for continuous variables (i.e., number of subjects, mean, 
standard deviation (SD), minimum, median, quartiles, and maximum) will be 
calculated. All statistical analyses will be purely descriptive. 
Analysis Populations: 
The following subject populations will be used for presentation and analysis of 
the data: 
• 
The safety analysis set (SAF) consists of all enrolled subjects who have 
received at least 1 dose of investigational product. 
• 
The PK population is defined as all subjects who have received the 
investigational product, did not have major protocol deviations or other 
events that may affect PK, and have sufficient plasma concentration. The 
PK population will be finalised prior to database lock. 
Pharmacokinetics 
All PK analyses will be performed using the PK analysis set. 
Noncompartmental PK analysis will be applied to derive all PK parameters in 
this study. 
Plasma difelikefalin concentrations will be summarised descriptively by nominal 
time at each time point. Individual and mean plasma concentration-time profiles 
and spaghetti plots (individual subject profiles in one plot) will be provided. In 
addition, individual plasma difelikefalin concentrations will be listed by subject.  
All PK parameters (e.g., Cmax, Tmax, AUC0‑t, AUCinf, AUCextrap(%), t½, clearance, 
and Vz) will be summarised descriptively. Descriptive statistics will include N, 
mean (arithmetic and geometric), SD, median, coefficient of variation, 
minimum, quartiles, and maximum.  
Safety 
All safety analyses will be performed using the SAF. 
Incidence of AEs, adverse events of special interest (AESI), and serious adverse 
events (SAEs) will be tabulated by system organ class (SOC) and preferred term 
(PT), using Medical Dictionary for Regulatory Activities (MedDRA) coded 
terms. Incidence of AEs will also be summarised by maximum intensity and 
maximum relationship to the investigational product. Vital signs, biochemistry, 
haematology data, and 12-lead ECG recordings will be descriptively summarised 
by visit as applicable, in addition to change from baseline. 
 


 
 
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Figure 1 
Study Design 
 
 
Screening Period 
Day -21 to Day -2  
Treatment Period
Week 1
Follow-up  Period
1 week
Dialysis
Days 8, 10, 12
End of Study
Day 14 (up to +3 days)
Check-in
Day -1
Day 8
Day 3
Day  5
Dialysis & Dosing
Days 1, 3, 5
Enrolment
Day 1
Day 10
Day 12
Check-in
Day 4


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Table 1 
Schedule of Events and Assessments 
Dialysis Day 
Screening 
Treatment Period 
Follow-Up 
Week 
-3 to -1
Week 1 
Week 2 
End of Study/ 
Early Termination 
Day −21 to 
Day −2(1) Day −1 Day 1 
Pre-dose 
Day 1 
Post-dose Day 2 Day 3 Day 4 Day 5 Day 6 Day 8 Day 10 Day 12 
Day 14 
(+ up to 
3 days) 
M/Tu 
W/Th 
F/Sa 
M/Tu W/Th 
F/Sa 
Informed consent 
X 
Dispense subject identification card 
X 
Eligibility criteria 
X 
X(2) 
Demographics 
X 
Medical/surgical history 
X 
X(2) 
Admission to clinic within 24 hours before dialysis 
X 
X 
Overnight stay in clinic during night of visit(3)
X 
X 
X 
X 
Dialysis(4) 
X 
X 
X 
X 
X 
X 
Investigational product administration (post-dialysis)(5) 
X 
X 
X 
Blood sample(s) for PK (see Table 2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X(2)
X 
Height 
X 
Prescription dry body weight 
X 
X 
12-lead ECG (pre-dialysis)
X(6) 
X(7) 
X(7) 
Pre-dialysis vital signs 
X(6) 
X(7) 
X(7) 
X(7) 
X(7) 
X(6) 
Serum chemistry and haematology (pre-dialysis)(8) 
X(6,9) 
X(7) 
X(7) 
X(7) 
X(7) 
X(6) 


 
 
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Dialysis Day 
Screening 
 
Treatment Period 
Follow-Up 
Week 
-3 to -1 
 
Week 1 
Week 2 
End of Study/ 
Early Termination 
Day −21 to 
Day −2(1) Day −1 Day 1 
Pre-dose 
Day 1 
Post-dose Day 2 Day 3 Day 4 Day 5 Day 6 Day 8 Day 10 Day 12 
Day 14 
(+ up to 
3 days) 
 
 
M/Tu 
 
W/Th 
 
F/Sa 
 
M/Tu W/Th 
F/Sa 
 
Serum pregnancy(9) 
X(10) 
 
 
 
 
 
 
 
 
 
 
 
X(6) 
AEs monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Visit at screening and at end of study/early termination should be on a dialysis day (for assessments to be performed pre-dialysis). 
2 
To be done either on Day −1 or on Day 1. 
3 
Based on logistical considerations, subjects may also remain overnight in the research unit on Days 2 and 3 (i.e., domiciled continuously from Day −1 to middle of Day 6). 
4 
The dialysis prescription should be kept constant throughout the study (See Section 9.7 for details). 
5 
Administration of investigational product takes place after dialysis (see Section 6.2 for details). Investigational product will be administered as an IV bolus into the venous line of the dialysis either during or 
after rinse back of the dialysis circuit, followed by flushing with at least 10 ml of normal saline. The actual dose of investigational product given (in ml) will be recorded in eCRF. 
6 
Obtain within 6 hours prior to starting dialysis, whenever possible. 
7 
Obtain within 2 hours prior to starting dialysis. 
8 
Serum chemistry: albumin, bilirubin (total), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, serum creatinine, blood urea nitrogen, electrolytes (sodium, potassium, 
chloride, calcium, and phosphorus). Haematology: haemoglobin, haematocrit, platelet count, white blood cell count (including differential). 
9 
Performed at central laboratory. 
10 
To be done in women of childbearing potential within 7 days prior to the first dose of investigational product. 
Notes: AEs=Adverse events; ECG=Electrocardiogram; eCRF=Electronic Case Report Form; F=Friday; IV=Intravenous; M=Monday; PK=Pharmacokinetic; S=Saturday; Th=Thursday; Tu=Tuesday; 
W=Wednesday. 
 


 
 
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Table 2 
Pharmacokinetic Samples Schedule 
 
Time After Drug Administration 
Study Day 
Pre-dialysis(1) 
Post-dialysis(2) 
5 min(3) 
15 min(3) 
30 min(3) 
1 h(3) 
2 h(3) 
4 h(3) 
6 h(3) 
8 h(3) 
12 h(3) 
24 h(3) 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
2 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
X 
3 
X 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
6 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
X 
8 
X 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
10 
X 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
12 
X 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
1 Pre-dialysis blood samples will be taken at any time prior to the start of dialysis. 
2 Blood samples will be taken at 5 minutes (±2 minutes) following the end of the dialysis. 
3 Time is relative to the time of injection (i.e., t=0). A ±2-minutes window is allowed for pharmacokinetics blood draws up to 30 minutes (inclusive); a ±5-minutes window is allowed for the 1-hour to 8-hours 
blood draws and ±1 hour for the 12- and 24-hours blood draws.  
Note: 
Pharmacokinetic samples are to be obtained from a venous access different from the site used for difelikefalin administration to avoid cross contamination. 
 


 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..........................................................................................................2 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE .....................................4 
SYNOPSIS ..........................................................................................................................5 
TABLE OF CONTENTS ................................................................................................13 
LIST OF TABLES ...........................................................................................................17 
LIST OF FIGURES .........................................................................................................18 
LIST OF ABBREVIATIONS .........................................................................................19 
1. 
INTRODUCTION AND BACKGROUND ............................................................21 
1.1 
Background of the Disease and Treatment Options ..............................................21 
1.2 
Summary of Nonclinical and Clinical Data ...........................................................22 
1.2.1 
Summary of Nonclinical Data ............................................................................22 
1.2.2 
Summary of Clinical Data ..................................................................................23 
1.2.2.1 
Pharmacokinetics .............................................................................................24 
1.2.2.2 
Safety of IV Difelikefalin ................................................................................24 
1.2.2.3 
Efficacy of IV Difelikefalin .............................................................................25 
2. 
RATIONALE ...........................................................................................................28 
2.1 
Patient Need ...........................................................................................................28 
2.2 
Study Design ..........................................................................................................28 
2.3 
Dose Selection .......................................................................................................29 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................30 
3.1 
Primary Objective ..................................................................................................30 
3.2 
Secondary Objectives.............................................................................................30 
3.3 
Primary Endpoint ...................................................................................................30 
3.4 
Secondary Endpoint ...............................................................................................30 
4. 
INVESTIGATIONAL PLAN .................................................................................31 
4.1 
Overall Study Design .............................................................................................31 
4.2 
Duration of Subject Participation and Study .........................................................31 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................32 
5.1 
Number of Subjects................................................................................................32 
5.2 
Inclusion Criteria ...................................................................................................32 
5.3 
Exclusion Criteria ..................................................................................................33 
5.4 
Withdrawal of Subjects ..........................................................................................33 
5.4.1 
Withdrawal of Subjects from the Study ..............................................................33 
6. 
STUDY TREATMENTS .........................................................................................35 
6.1 
Dosage Forms/Formulation ...................................................................................35 
6.2 
Investigational Product Dosage and Administration .............................................35 


 
 
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6.3 
Package and Labelling ...........................................................................................36 
6.4 
Study Treatment Allocation ...................................................................................36 
6.5 
Site Supply, Storage, Accountability .....................................................................36 
6.5.1 
Site Supply ..........................................................................................................36 
6.5.2 
Storage ................................................................................................................37 
6.5.3 
Accountability .....................................................................................................37 
6.6 
Drug Dose Modification ........................................................................................37 
6.6.1 
Procedures for Overdose .....................................................................................37 
6.7 
Concomitant Treatment .........................................................................................37 
7. 
RISKS/PRECAUTIONS .........................................................................................39 
7.1 
Risks .......................................................................................................................39 
7.2 
Precautions .............................................................................................................39 
7.2.1 
Drug Interactions ................................................................................................39 
7.2.2 
Drug Abuse and Dependency .............................................................................39 
7.2.3 
Hypersensitivity ..................................................................................................40 
7.2.4 
Women of Childbearing Potential ......................................................................40 
7.2.5 
Pregnancy and Lactation .....................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................41 
8.1 
Allowed Adaptations in Case of Extraordinary Events, e.g., COVID-19 .............41 
8.2 
Screening Procedures (Day -21 to Day -2) ............................................................42 
8.3 
Day −1 ....................................................................................................................43 
8.3.1 
Day 1 ...................................................................................................................43 
8.3.2 
Day 2 ...................................................................................................................44 
8.3.3 
Day 3 ...................................................................................................................44 
8.3.4 
Day 4 ...................................................................................................................45 
8.3.5 
Day 5 ...................................................................................................................45 
8.3.6 
Day 6 ...................................................................................................................46 
8.3.7 
Day 8 ...................................................................................................................47 
8.4 
Follow-up Procedures ............................................................................................48 
8.4.1 
Day 10 .................................................................................................................48 
8.4.2 
Day 12 .................................................................................................................48 
8.4.3 
End of Study (or Early Discontinuation) Procedures/Day 14 (+ up to 
3 Days) ................................................................................................................48 
9. 
STUDY ASSESSMENTS ........................................................................................50 
9.1 
Demographics and Medical/Surgical History ........................................................50 
9.2 
Physical Examination, Height, Vital Signs ............................................................50 
9.3 
12-lead ECG...........................................................................................................51 
9.4 
Clinical Laboratory Tests .......................................................................................51 
9.5 
Adverse Events ......................................................................................................52 
9.6 
PK Assessments .....................................................................................................52 
9.7 
Dialysis ..................................................................................................................52 
10. EVALUATION, RECORDING, AND REPORTING OF AES ..........................53 


 
 
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10.1 
Definition of AEs ...................................................................................................53 
10.2 
AE Reporting Period ..............................................................................................53 
10.3 
Eliciting AEs ..........................................................................................................53 
10.4 
Assessing AEs ........................................................................................................53 
10.4.1 
Intensity/Severity ................................................................................................53 
10.4.2 
Causality and Reporting......................................................................................54 
10.4.3 
Outcome Categorisation .....................................................................................55 
10.5 
Recording and Reporting .......................................................................................55 
10.5.1 
Persistent or Recurrent AEs ................................................................................55 
10.5.2 
Diagnosis Versus Signs and Symptoms .............................................................56 
10.5.3 
Pre-existing Medical Conditions ........................................................................56 
10.5.4 
Clinical Laboratory Evaluations .........................................................................56 
10.5.5 
Worsening of the Disease Under Study ..............................................................57 
10.5.6 
Abnormal Vital Signs and Other Abnormalities.................................................57 
10.6 
ADR and Reference Safety Information ................................................................58 
10.6.1 
Adverse Drug Reaction .......................................................................................58 
10.6.2 
Reference Safety Information .............................................................................58 
10.7 
Serious Adverse Event ...........................................................................................58 
10.7.1 
Definition of SAE ...............................................................................................58 
10.7.1.1 
Situations that are Not Considered SAEs ........................................................59 
10.7.2 
SAE Reporting ....................................................................................................60 
10.7.3 
Suspected Unexpected Serious Adverse Reaction..............................................60 
10.7.3.1 
SAE Expedited Reporting ................................................................................60 
10.8 
Special Situations ...................................................................................................61 
10.8.1 
Definition of Special Situations ..........................................................................61 
10.8.2 
Special Situation Recording and Reporting ........................................................61 
10.8.3 
Pregnancy Exposure and Birth Events................................................................62 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events .......................................62 
10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting ...................62 
10.8.4 
Adverse Event of Special Interest .......................................................................63 
10.8.4.1 
Definition of AESI ...........................................................................................63 
10.8.4.2 
AESI Reporting and Recording .......................................................................63 
11. DATA AND SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE PROCEDURES .............................................................................64 
12. STATISTICAL ANALYSIS ...................................................................................65 
12.1 
Statistical Methods .................................................................................................65 
12.2 
Sample Size and Power Calculations .....................................................................65 
12.3 
Randomisation .......................................................................................................65 
12.4 
Analysis Sets ..........................................................................................................65 
12.4.1 
Safety Analysis Set .............................................................................................65 
12.4.2 
PK Set .................................................................................................................65 
12.5 
Background and Demographic Characteristics ......................................................65 
12.6 
Investigational Product ..........................................................................................66 


 
 
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12.7 
Concomitant Therapy.............................................................................................66 
12.8 
Pharmacokinetics ...................................................................................................66 
12.9 
Efficacy Evaluations ..............................................................................................67 
12.10 Safety Evaluations .................................................................................................67 
12.10.1 Adverse Events ...................................................................................................67 
12.10.2 Special Situations ................................................................................................68 
12.10.3 Vital Signs...........................................................................................................68 
12.10.4 12-lead ECG .......................................................................................................69 
12.10.5 Physical Examination .........................................................................................69 
12.10.6 Clinical Laboratory Tests....................................................................................69 
12.11 Other Evaluations...................................................................................................69 
12.11.1 Dialysis Details ...................................................................................................69 
12.12 Handling of Missing Data ......................................................................................69 
13. STUDY ETHICAL CONSIDERATIONS .............................................................70 
13.1 
Ethical Conduct of the Study .................................................................................70 
13.2 
Informed Consent...................................................................................................70 
13.3 
Independent Ethics Committee ..............................................................................70 
13.4 
Insurance ................................................................................................................70 
14. QUALITY CONTROL AND QUALITY ASSURANCE .....................................72 
14.1 
Quality Management: Critical Processes and Data ................................................72 
15. REPORTING AND RECORDING OF DATA .....................................................74 
15.1.1 
Source Documentation ........................................................................................74 
15.1.2 
Records Retention ...............................................................................................74 
15.1.3 
Site Documentation.............................................................................................75 
16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .......................................................................76 
16.1 
Protocol Deviations ................................................................................................76 
16.2 
Protocol Amendments ............................................................................................76 
16.3 
Study Termination .................................................................................................76 
17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ................77 
18. REFERENCES .........................................................................................................78 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Schedule of Events and Assessments ........................................................10 
Table 2 
Pharmacokinetic Samples Schedule ..........................................................12 
Table 3 
Total Dose Volumes per Weight Range ....................................................36 
 


 
 
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LIST OF FIGURES 
Page 
Figure 1 
Study Design ................................................................................................9 
 


 
 
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LIST OF ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CKD 
chronic kidney disease 
CKD-aP 
chronic kidney disease-associated pruritus 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRO 
Contract Research Organisation 
ECG 
electrocardiogram 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
electronic data capture 
ESRD 
end-stage renal disease 
EU 
European Union 
GCP 
Good Clinical Practice 
HD 
haemodialysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IV 
intravenous 
KOR 
kappa opioid receptor 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 


 
 
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PT 
preferred term 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
Vz 
volume of distribution 
WI-NRS 
Worst Itching Intensity Numerical Rating Scale 
 


 
 
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1. INTRODUCTION AND BACKGROUND 
Difelikefalin is a novel, selective kappa opioid receptor (KOR) agonist that is being 
developed as a therapeutic agent for the symptomatic relief of pruritus and pain. 
Chronic kidney disease-associated pruritus (CKD-aP), also known as uraemic pruritus, is a 
distressful medical condition, common in >60% of chronic kidney disease (CKD) patients 
undergoing HD [1]. However, there are currently no approved treatments for CKD-aP in 
the US, Europe, or China. Difelikefalin is a KOR agonist with limited central nervous 
system (CNS) penetration that aims to fill this void by effectively and safely reducing itch 
in HD patients. At the time of this study protocol, difelikefalin has not been approved for 
marketing in any country. 
1.1 
Background of the Disease and Treatment Options 
CKD-aP is characterised by a generalised and persisting itch, which has a negative impact 
on quality of life and is associated with depression, anxiety, sleep disturbance, and 
increased mortality. The incidence of CKD-aP is decreasing given advances in HD 
technology; however, approximately 42%, 21%, 11%, and 8% of HD patients in China, are 
somewhat bothered, moderately bothered, very much bothered, and extremely bothered by 
pruritus [1]. In a single-centre study in China described by Li et al, 2015, the prevalence of 
uraemic pruritus was reported to be 65.2% in continuous ambulatory peritoneal dialysis 
patients [2]. In another single-centre study conducted in China, Wen et al, 2020 reported 
that over 80% of HD patients were bothered by uraemic pruritus (among those bothered, 
36-57% had moderate-to-severe pruritus) [3]. 
The pathophysiology of CKD-aP is not well understood; however, it is multifactorial and 
is attributed to imbalance of opioid receptors, uraemic toxins build-up, immune system 
dysregulation, systemic inflammation, peripheral neuropathy, hyperparathyroidism, etc 
[4,5]. 
Treatment of pruritus in HD patients depends on the severity of itching; treatment varies 
from use of topical therapy (emollients, steroid analgesics, local anaesthetics) in patients 
with mild or localised symptoms, to optimisation of dialysis parameters and systemic 
treatment in patients with more severe or generalised itching [6]. However, many patients 
have an inadequate response to existing treatments (topical or internal). Nalfurafine 
hydrochloride, an oral mixed nonselective mu partial agonist/KOR agonist, is effective in 
treating pruritus and is approved in Japan and South Korea for improvement of pruritus in 
HD patients; however, because of the oral formulation, HD patients have to take a large 
number of tablets, which increases the already high burden of these patients having to take 
many oral drugs. In addition, many HD patients have decreased salivary secretion and 
restricted fluid intake, and thus may have difficulty in taking the oral drug. Furthermore, as 
nalfurafine hydrochloride activates KOR in the CNS and in the gastrointestinal tract, this 
frequently induces adverse drug reactions (ADRs), such as sleep loss and constipation [7]. 


 
 
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This creates the need to develop new treatments that are more convenient for use and cause 
fewer ADRs. 
Opioid receptors are involved in the modulation of pain and itching signals and are 
subdivided into 3 subtypes, classified as mu, kappa, and delta. These receptor subtypes are 
found in the CNS (i.e., brain and spinal cord), on sensory ganglionic neurons and their 
nerve fibres innervating peripheral tissues such as skin, and on certain cell types of the 
immune system. The mu opioid receptor binds to β-endorphin, inhibits pain, and induces 
itching; KOR binds to dynorphin and inhibits pain and itching [8,9]. Morphine, the most 
widely clinically used opiate analgesic, acts primarily via activation of mu opioid receptors 
located in the CNS and peripheral nervous system. As such, it is associated with a wide 
array of side effects such as sedation, respiratory depression, abuse liability, constipation, 
cardiovascular collapse, and death. To avoid these undesirable effects, difelikefalin, a 
small, synthetic peptide KOR agonist, was designed; difelikefalin has a limited entry into 
the CNS, thereby predominantly activating KORs expressed on peripheral neurons and 
immune cells. 
Difelikefalin has greater than 30,000-fold selectivity over human mu and delta opioid 
receptors, and no significant detectable activity at other receptors, ion channels, 
transporters, or enzymes. The selective activity of difelikefalin at KORs avoids the mu 
opioid receptor associated side effects characteristic of most opioid analgesics, such as 
respiratory depression, dependence, and euphoria [10,11].  
Because of its physicochemical properties (i.e., hydrophilic) difelikefalin is expected to be 
safer and more tolerable; difelikefalin does not pass through the blood-brain barrier, which 
limits such undesirable CNS effects as activation of central KORs, i.e., dysphoria and 
psychomimetic effects [10]. In addition, difelikefalin is mostly renally excreted, resulting 
in a long half-life in HD patients (t½ about 24 hours) and clearance by dialysis (see the latest 
difelikefalin Investigator’s Brochure (IB)). 
Furthermore, difelikefalin is expected to enhance the quality of pharmaceutical 
management that includes treatment compliance, treatment instructions, and remaining 
drug check because it is an injectable formulation administered directly from the dialysis 
circuit at the end of each dialysis session without fail under the supervision of a physician. 
There are currently no marketed peptide KOR agonists in the US, the EU, or China. 
1.2 
Summary of Nonclinical and Clinical Data 
1.2.1 
Summary of Nonclinical Data 
Provided here is a summary of the nonclinical data for difelikefalin. For more details, please 
refer to the latest version of difelikefalin IB. 


 
 
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• The physicochemical properties of difelikefalin (hydrophilic, synthetic D-amino acid 
peptide with high polar surface area and charge at physiological pH) minimise passive 
diffusion or active transport through the blood-brain barrier, thus limiting penetration 
into the brain. The limited to no brain exposure is further supported by radiolabelled 
studies and pharmacological studies suggesting that difelikefalin does not readily enter 
the CNS, and preferentially activates KORs located primarily in the peripheral nervous 
system and on immune cells. 
• Nonclinical pharmacological studies indicate that difelikefalin has combined 
antipruritic, analgesic, and anti-inflammatory properties. 
• Difelikefalin is primarily excreted unchanged into the urine and bile with no major 
metabolites identified. Nonclinical data indicate that difelikefalin should not 
significantly affect the clearance and/or metabolism of any co-administered drug(s). 
• Generally, dose-proportional, linear PK in systemic exposure were observed following 
single IV or oral doses, with t½ ranging from 1.1 to 5.5 hours. Similar kinetics were 
observed after repeated administration. 
• No notable safety concerns after IV or oral administration of difelikefalin were 
identified in studies of acute and chronic toxicology (up to 6 months in the rat and 
9 months in the monkey), safety pharmacology, reproductive and development 
toxicology, genotoxicity, and carcinogenicity. 
1.2.2 
Summary of Clinical Data 
This will be the first Phase 1 clinical trial for evaluating PK, safety, and tolerability of 
difelikefalin in Chinese HD subjects. However, PK, safety, and efficacy of IV difelikefalin 
for the treatment of CKD-aP in HD patients have been previously investigated in multiple 
Phase 1, 2, and 3 clinical studies conducted outside of China (including 2 Phase 1 and 2 
Phase 2 clinical studies in Japan). 
Difelikefalin has been evaluated as either IV bolus or 15-minute infusion as single or 
repeated doses ranging from 0.25 to 40 µg/kg. In the clinical development program, IV 
difelikefalin has been administered to 3,478 subjects; 2,488 subjects have received IV 
formulation, and 990 have received oral formulation. A total of 1,592 CKD subjects on HD 
have received IV difelikefalin; of these, 1,096 subjects have received IV difelikefalin for at 
least 12 weeks; and 415 subjects with moderate-to-severe pruritus have received IV 
difelikefalin for at least 48 weeks. 
Considering all the data relevant to the efficacy and safety of IV difelikefalin, the 
benefit/risk profile of difelikefalin in HD patients is considered favourable.  
Provided below is a summary of the clinical data for difelikefalin. For more details, please 
refer to the latest version of difelikefalin IB. 


 
 
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1.2.2.1 
Pharmacokinetics 
In subjects with normal renal function, difelikefalin has linear and dose-proportional PK, 
with t½ of approximately 2-3 hours after single dose IV administration. In subjects with 
CKD on HD, t½ increases at least 10-fold compared with subjects with normal renal 
function. 
Following single dose IV administration of (14C)-difelikefalin to healthy volunteers or HD 
subjects, >99% of circulating plasma radioactivity remained as unchanged difelikefalin. 
In both healthy volunteers and HD subjects, most of the dose excreted into urine and faeces 
was unchanged difelikefalin with minor quantities of putative metabolites, none exceeding 
2.5%. 
In a Japanese clinical pharmacology study in healthy subjects (Study PR-13A9-P1-A), the 
cumulative urinary excretion rate became almost constant by 36 hours after the initial dose 
(i.e., 15 hours after the final dose). The cumulative urinary excretion rate for up to 72 hours 
after the initial dose (i.e., 51 hours after the final dose) ranged from 71.6% to 76.8%, being 
similar across the dose groups (1.0, 3.0, 5.0, 10, 20, and 40 µg/kg). 
In Japanese HD subjects (Study PR-13A9-P1-B), plasma difelikefalin concentrations after 
the first and third IV doses showed a biphasic elimination pattern of a rapid initial phase 
and a slow elimination phase. The t½ of difelikefalin was 34.1 to 39.0 hours after the first 
dose and 40.0 to 49.3 hours after the third dose. The accumulation ratio of Day 5 to Day 1 
calculated using the Cmax, AUC0-48, and trough values indicated a low likelihood of 
accumulation of difelikefalin.  
1.2.2.2 
Safety of IV Difelikefalin 
In general, IV difelikefalin has been well tolerated in both single and repeat-dose clinical 
studies for up to 12 weeks at doses <5 µg/kg in healthy volunteers and subjects with CKD. 
In subjects with normal renal function, IV difelikefalin produces a transient and generally 
dose-related increase in urine output without loss of electrolytes (0 to 12 hours after 
dosing). This aquaretic effect (i.e., free water loss) is a known pharmacological effect of 
KOR agonists and is managed with fluid replacement, as applicable. 
In healthy volunteers exposed to IV difelikefalin, the most common treatment-emergent 
adverse events (TEAEs) (≥5.0% of subjects) with an incidence ≥1.0% greater compared 
with placebo were, in descending frequency, paraesthesia, hypoaesthesia, dizziness, 
sedation, headache, and fatigue. There was an apparent dose-response relationship with 
difelikefalin for the majority of TEAEs, with the highest incidence observed at IV 
difelikefalin doses >5 µg/kg. There was 1 reported SAE of sinus tachycardia in a 
difelikefalin-treated subject and none in placebo-treated subjects. No specific TEAEs 
leading to investigational product discontinuation occurred in >1 subject. 


 
 
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In subjects with CKD on HD exposed to IV difelikefalin, the most common TEAEs (≥5.0% 
of subjects) with an incidence ≥1.0% greater compared with placebo were, in descending 
frequency, diarrhoea, nausea, insomnia, fall, hypotension, abdominal pain, dizziness, 
vomiting, hyperkalaemia, headache, pneumonia, and dyspnoea. The most common SAEs 
(≥1.0% of subjects) among difelikefalin-treated subjects with an incidence ≥1.0% greater 
compared with placebo were, in descending frequency, pneumonia, fluid overload, sepsis, 
hyperkalaemia, respiratory failure, mental status changes, acute myocardial infarction, 
gastrointestinal haemorrhage, syncope, asthenia, and non-cardiac chest pain. Observed 
SAEs were consistent with underlying medical conditions in the subject population. The 
most common TEAEs leading to investigational product discontinuation among 
difelikefalin-treated subjects were cardiac arrest, somnolence, and dizziness. 
In a Japanese Phase 1 clinical study (Study PR-13A9-P2-A, healthy volunteers), blood 
sodium increased was reported in 4/6 subjects in the 5.0 µg/kg group during the 
repeated-dose period. These events were reported only in clinical studies in subjects with 
normal renal function and have not been reported in clinical studies in HD subjects. 
In a Japanese Phase 2 clinical study (Study MR13A9-3, JapicCTI-163265, n=84 subjects 
on HD), common TEAEs (reported in ≥10% of subjects) included blood thyroid stimulating 
hormone decreased, dizziness, blood prolactin increased, nausea, feeling abnormal, and 
somnolence. Study treatment was discontinued or interrupted due to 1 event in 1 subject in 
the 0.25 µg/kg group, 2 events in 2 subjects in the 0.5 µg/kg group, 1 event in 1 subject in 
the 1.0 µg/kg group, and 17 events in 10 subjects in the 1.5 µg/kg group. Dependency was 
assessed as being present in 2 subjects in the placebo group and 1 subject in the 0.5 µg/kg 
difelikefalin group. 
In a Japanese Phase 2 clinical study (Study MR13A9-4, NCT03802617, n=184 subjects on 
HD), common TEAEs (reported in ≥3% of subjects) included somnolence, dizziness, 
palpitations, vomiting, nausea, and blood thyroid stimulating hormone decreased. Study 
treatment was discontinued or interrupted due to 5 events in 4/61 subjects in the 0.5 µg/kg 
group and 6 events in 5/62 subjects in the 1.0 µg/kg group. Dependency was assessed as 
being absent in all evaluable subjects. 
1.2.2.3 
Efficacy of IV Difelikefalin 
The efficacy of IV difelikefalin in reducing itch-related quality of life in subjects with CKD 
on HD has been demonstrated in Phase 2 and Phase 3 clinical studies. 
• In a Phase 2 study CR845-CLIN2101 [12], the efficacy outcomes were similar across 
the 0.5, 1, and 1.5 µg/kg dose groups after each HD (i.e., 3 times a week; 8 weeks of 
treatment); with statistically significant differences favouring difelikefalin over placebo 
most often observed in the 0.5 µg/kg dose group. Together with the more favourable 
safety profile seen in the 0.5 µg/kg group, the 0.5 µg/kg dose group was selected for 
evaluation in Phase 3 studies (12 weeks of treatment). 


 
 
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• In a Japanese Phase 2 clinical study (MR13A9-3), 105 CKD-aP subjects on HD 
received IV difelikefalin (0.25, 0.5, 1.0, or 1.5 µg/kg), or placebo 3 times weekly for 
2 weeks. The primary endpoint of change in visual analogue scale (i.e., change based 
on the larger visual analogue scale value either in the morning or the evening during 
the 7 days, the latter half of the treatment period) suggested a dose-dependent 
improvement by treatment with difelikefalin at doses ≥0.5 µg/kg. 
• In a Japanese Phase 2 clinical study (MR13A9-4), 247 CKD-aP subjects on HD 
received IV difelikefalin (0.25, 0.5, or 1.0 µg/kg, or placebo 3 times weekly for 
8 weeks). The primary variable of change from baseline in the mean Numerical Rating 
Scale score at Week 8 of the treatment period (adjusted mean ± standard error) was 
−2.97±0.29 in the difelikefalin 0.25 µg/kg group, −3.65±0.30 in the 0.5 µg/kg group, 
and −3.64±0.30 in the 1.0 µg/kg group, compared with −2.86±0.29 in the placebo 
group. These results showed significant improvement in the difelikefalin 0.5 and 
1.0 µg/kg groups compared with the placebo group, indicating a dose-response 
relationship showing a constant effect at doses of ≥0.5 µg/kg. 
• In the first Phase 3 double-blind, randomised, placebo-controlled, parallel group US 
study (CR845-CLIN3102) [13] in subjects with CKD on HD with moderate-to-severe 
pruritus, IV bolus administration of difelikefalin 0.5 µg/kg after each HD (i.e., 3 times 
a week) for 12 weeks resulted in a significant effect, with a higher proportion of subjects 
treated with difelikefalin showing ≥3-point (least squares (LS) mean of 51.0% of 
difelikefalin subjects versus 27.6% of placebo subjects, p<0.001) and ≥4-point (LS 
mean of 38.9% of difelikefalin subjects versus 18.0% of placebo subjects, p<0.001) 
reductions in Worst Itching Intensity Numerical Rating Scale (WI-NRS) score at 
Week 12; the reduction in the severity of itch intensity was observed within 1 week of 
treatment. Significant improvements in itch-related quality of life were observed in this 
study. 
• In the second Phase 3 double-blind, randomised, placebo-controlled, parallel group 
global study (CR845-CLIN3103) in subjects with CKD on HD with moderate-to-severe 
pruritus, IV bolus administration of difelikefalin 0.5 µg/kg after each HD (i.e., 3 times 
a week) for 12 weeks resulted in a significant effect, with a higher proportion of subjects 
treated with difelikefalin showing ≥3-point (LS mean of 54.0% of difelikefalin subjects 
versus 42.2% of placebo subjects, p=0.020) and ≥4-point (LS mean of 41.2% of 
difelikefalin subjects versus 28.4% of placebo subjects, p=0.010) reductions in 
WI-NRS score at Week 12; the reduction in the severity of itch intensity was observed 
within 2 weeks of treatment. Improvements in itch-related quality of life were also 
observed in this global study. 


 
 
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• In a Phase 3, 12-week, open-label study (CR845-CLIN3105) in subjects with CKD on 
HD with moderate-to-severe pruritus, difelikefalin 0.5 µg/kg IV resulted in a reduction 
in pruritus, as measured by the percentage of subjects with a ≥3-point (73.7%) and 
≥4-point (59.3%) improvement in WI-NRS score. Improvements in itch-related quality 
of life were also observed. 


 
 
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2. RATIONALE  
2.1 
Patient Need 
The number of patients in China undergoing HD is increasing each year [14]. 
Approximately 42% of HD patients in China, are distressed by moderate or severe pruritus 
[1]. The benefits of the KOR agonist difelikefalin in reducing itch in CKD-aP patients 
undergoing HD has been demonstrated in multiple Phase 2 and Phase 3 clinical studies 
outside of China. Currently, in China, there are no approved KOR agonists for the treatment 
of itch in subjects with CKD on HD. Study KOR-CHINA-101 will be the first clinical trial 
with IV difelikefalin in subjects on HD to be conducted in China.  
Clinical data outside of China have shown the benefits of difelikefalin in patients 
undergoing HD; IV difelikefalin was well tolerated with an acceptable safety profile in 
CKD-aP patients undergoing HD. 
Considering all the data relevant to the efficacy and safety of IV difelikefalin, the 
benefit/risk profile of the product in subjects with CKD-aP is considered favourable. 
2.2 
Study Design 
This study is designed to evaluate the PK, safety, and tolerability of 0.5 µg/kg IV 
difelikefalin in Chinese subjects with ESRD on HD (3 times weekly) with or without 
associated pruritus. A dialysis frequency of 3 times a week (versus twice weekly), is 
prevalent for the dialysis practice in China [14]. 
The eligibility criteria for the present study will provide a cohort of Chinese subjects who 
have ESRD and are undergoing HD (and may have or not CKD-aP). In these subjects, HD 
is often associated with pruritus, and subjects will benefit from an investigational product 
that reduces the intensity of pruritus.  
This study design (e.g., dose, investigational product administration, time points for PK 
sampling) is based on previous clinical trials with difelikefalin in CKD subjects on HD 
conducted by Cara Therapeutics, Inc. previously outside of China (including clinical trials 
conducted in Japan by licensees of Cara Therapeutics, Inc.).  
The PK and safety parameters are standard for the assessment of these aspects of an 
investigational product. Considering the PK profile of difelikefalin—limited membrane 
permeability, metabolically stable, and primarily excreted unchanged in the urine—
difelikefalin PK in Chinese subjects is expected to be similar to the PK data obtained in 
clinical trials outside of China. 
IV administration of difelikefalin will occur at the end of HD by using the return HD line 
or via injection directly into a vein. In order to avoid the contamination of PK samples with 
difelikefalin, PK samples are to be collected from a different venous access than the site 
used for investigational product administration. 


 
 
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2.3 
Dose Selection 
The dose to be evaluated in this study, a single dose of 0.5 µg/kg difelikefalin (administered 
3 times weekly), is based on results of clinical studies conducted outside of China. The 
dose of 0.5 µg/kg IV difelikefalin was shown to be effective and with a favourable safety 
profile in global studies and in clinical studies in Japan. A lower dose (0.25 µg/kg) did not 
show efficacy in a Phase 2 study in Japan (M13A9-4); a higher dose (1 µg/kg) was shown 
to be effective in Western subjects and in Japanese subjects; however, the incidence of AEs 
also increased in a dose-dependent manner.  
The efficacy of 0.5 µg/kg IV difelikefalin in CKD subjects has been confirmed in 2 pivotal, 
Phase 3, randomised 12-week placebo-controlled studies, demonstrating statistically 
significant and clinically relevant reductions in pruritus. The treatment effect started as 
early as 1 week after initiating treatment, and the benefit was maintained for at least 1 year 
in the long-term extensions of these studies. No unexpected safety signals emerged during 
a long-term treatment of up to 52 weeks with 0.5 µg/kg IV difelikefalin, with the nature 
and rate of the reported safety events aligning with published morbidity and mortality data 
of patients with CKD-aP undergoing HD. 


 
 
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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective  
• To evaluate the PK profile of a repeated (3 times weekly) dose of difelikefalin in 
Chinese HD subjects over a 1-week treatment period. 
3.2 
Secondary Objectives 
• To evaluate the safety and tolerability of a repeated (3 times weekly) dose of 
difelikefalin in Chinese HD subjects over a 1-week treatment period. 
3.3 
Primary Endpoint 
• To evaluate the PK profile of difelikefalin, e.g., Cmax, Tmax, AUC0‑t, AUCinf, 
AUCextrap(%), t½, clearance, and Vz, when administered after each dialysis session (3 
times a week) over a 1-week treatment period. 
3.4 
Secondary Endpoint 
• Overall safety and tolerability of difelikefalin as assessed by incidence of AEs, vital 
signs, 12-lead ECG, and clinical safety laboratory evaluations over the study period. 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 1, single-arm, uncontrolled, open-label study to evaluate the PK, safety, and 
tolerability of a repeated (3 times weekly) dose of difelikefalin administered as IV bolus 
injections to adult Chinese HD subjects (Figure 1). 
Subjects eligible for the study will receive a unique subject number. Enrolled subjects who 
terminate their study participation for any reason regardless of whether the investigational 
product was administered or not, will retain their number. The next subject will be given 
the next unique subject number. 
Enrolled subjects will be administered 0.5 µg/kg of difelikefalin as a single IV bolus 
3 times, within 15 minutes post-dialysis for 1 week. The first dose will be administered on 
Day 1. The first HD will be the first scheduled dialysis day of the calendar week for the 
subject (i.e., Monday, or Tuesday). 
The schedule of assessments is provided in Table 1. 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is a maximum of 5 weeks: screening period 
duration is up to 3 weeks; treatment period duration is 1 week; and follow-up period is 
1 week (1 week to 10 days).  
The end of study is defined as the last subject last visit. 


 
 
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5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects 
This study will enrol 30 subjects. The sample size for this Phase 1 study is based on a 
pragmatic approach. No formal sample size calculation has been conducted. 
5.2 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following inclusion criteria 
apply: 
1. Appropriate written informed consent has been provided by subject or legally 
acceptable representative. Written informed consent must be provided before any 
study-specific procedures are performed, including screening procedures. 
2. Subjects have the ability to understand the requirements of the study, in the 
Investigator’s opinion. 
3. Chinese subjects aged ≥18 to 85 years (inclusive), at the time of consent. 
4. End-stage renal disease (ESRD) subjects who have been on HD for at least 3 months 
before enrolment in the study and are currently on HD 3 times per week. Subjects with 
or without associated pruritus may be enrolled.  
5. Subjects with a prescription dry body weight between 40 and 100 kg, inclusive. 
6. If female, is not pregnant, or nursing. 
7. If female: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for at least 1 year and is over the age of 55 years; or 
c. Has a negative serum pregnancy test within 7 days before first dose of 
investigational product, and agrees to use adequate contraceptive precautions (e.g., 
hormonal contraceptives, barrier with spermicide, intrauterine device, vasectomised 
partner, or abstinence) from the time of informed consent until 7 days after the last 
dose of investigational product. Note: If the result from serum pregnancy testing at 
screening is indeterminate due to possible human chorionic gonadotropin elevation 
secondary to ESRD unrelated to pregnancy, a serum pregnancy re-test may be 
repeated prior to treatment Day 1 to establish if a negative result can be confirmed. 


 
 
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8. If male, agrees not to donate sperm from the first dose of investigational product 
administration (Day 1) until 7 days after last dosing, and agrees to use a condom with 
spermicide or abstain from heterosexual intercourse during the study until 7 days after 
the last dose of investigational product. Note: No restrictions are required for a 
vasectomised male, provided his vasectomy was performed ≥4 months prior to 
screening. 
5.3 
Exclusion Criteria 
The following criteria exclude a subject from participating in this trial:  
1. Known to be non-compliant with HD treatments and deemed unlikely to complete the 
study by the Principal Investigator (i.e., has a history of missed HD sessions due to non-
adherence in the past 2 months). 
2. Planned or anticipated to receive a kidney transplant during the study. Note: Being 
listed on a kidney transplant list is not an exclusion criterion. 
3. Known or suspected history of alcohol, narcotic, or other drug abuse, or dependence 
within 12 months prior to screening. 
4. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) greater than 
2.5 × the reference upper limit of normal (ULN), or bilirubin (total) greater than 4 × the 
ULN at screening. 
5. Subjects with severe hepatic impairment (Child-Pugh Class C). 
6. Acute or unstable medical condition(s) such as congestive heart failure (New York 
Heart Association Class IV), which in the opinion of the Investigator would pose undue 
risk to the subject or would impede complete collection of the data or its evaluability. 
7. Known history of allergic reaction to opiates such as hives. Note: Side effects related 
to the use of opioids such as constipation or nausea would not exclude the subjects from 
the study. 
8. Subject has known hypersensitivity to the study intervention or any component of the 
investigational product formulation. 
9. Subject has received another investigational drug within 30 days prior to the start of the 
screening visit or has planned to participate in another clinical trial while enrolled in 
this study. 
5.4 
Withdrawal of Subjects 
5.4.1 
Withdrawal of Subjects from the Study 
Subjects may voluntarily withdraw from study participation at any time without having to 
provide a reason. Subjects may be withdrawn because of the appearance of a new health 


 
 
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condition requiring care or medications prohibited by the protocol, unacceptable AEs, 
refusal to continue treatment, major non-compliance with study procedures, significant 
protocol deviations, or at the Investigator’s discretion if it is in the subject’s best interest. 
If a subject withdraws from the study at any time either at his or her request or at the 
Investigator’s discretion, the reason(s) for withdrawal must be recorded on the relevant 
page of the subject’s eCRF and source documentation. Subjects who withdraw from the 
study prematurely should undergo all end of study assessments, if possible. 
If a subject is withdrawn from the study due to an AE, it is vital to obtain follow-up data. 
In any case, every effort must be made to undertake protocol-specified safety follow-up 
procedures (see Section 10.3). If a subject is discontinued due to an AE, the event should 
be followed by the Investigator through contact with the subject until resolution or 
stabilisation has occurred. All AEs should be followed until resolution, stabilisation, or the 
subject is lost to follow-up and cannot be contacted.  
If a subject refuses to continue study procedures, the reason for refusal should be fully 
documented in the subject’s source document and recorded in the study-specific eCRF. 
Although subjects are not obliged to give a reason for withdrawing consent, the Investigator 
should make every effort to obtain the reason, while fully respecting the subject’s rights. If 
the subject withdraws from the trial without providing a reason, the source documents and 
the eCRF should document the reason for discontinuation as “withdrawal by subject”. 
Subjects who discontinue from the study after administration of the first dose of 
investigational product and before completing the protocol procedures will not be replaced. 


 
 
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6. STUDY TREATMENTS 
6.1 
Dosage Forms/Formulation 
The investigational product used in this study has been manufactured in accordance with 
current Good Manufacturing Practice. 
Investigational product (IV formulation) will be provided in 2 R glass vials with an 
extractable volume of 1 ml of difelikefalin at a concentration of 50 µg/ml in 0.04 M isotonic 
acetate buffer, pH 4.5. Investigational product will be provided by the Sponsor for this 
study. 
Active Ingredient: 
Difelikefalin 
Chemical Name: 
4-amino-1-((R)-6-amino-2-((R)-2-((R)-2-((R)-2-amino-
3-phenylpropanamido)-3-phenylpropanamido)-4-
methylpentanamido)hexanoyl)piperidine-4-carboxylic 
acid 
Abbreviated Peptide Sequence: D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl-γ-
(4-N-piperidinyl)-amino-carboxylic acid, acetate salt 
Strength: 
0.05 mg (free base)/ml 
Excipients: 
0.04 M isotonic acetate buffer, pH 4.5 
Appearance: 
Clear, colourless solution 
Dosage Form: 
Injection 
Manufacturer: 
Siegfried Hameln GmbH 
Storage: 
Do not freeze 
6.2 
Investigational Product Dosage and Administration 
The investigational product will be dispensed by qualified staff members who have 
received training on investigational product handling and administration.  
Individual IV doses of investigational product are based on subject body weight (0.5 µg/kg 
dry body weight) and prepared by withdrawing subject-specific volume of investigational 
product with sterile, single-use 1 ml Plastipak syringe (or equivalent) and sterile single-use 
needles. A single vial cannot be used for multiple subjects. Vials contain an extractable 
volume of 1 ml of investigational product.  
The total dose volume (ml) required from the vial should be calculated as follows: 
0.01 × prescription dry body weight (kg), rounded to the nearest tenth (0.1 ml). The total 
dose volumes per weight range are detailed in Table 3. 


 
 
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Table 3 
Total Dose Volumes per Weight Range 
Weight Range  
(Dry Body Weight in kg) 
Dose  
(ml) 
40 
44 
0.4 
45 
54 
0.5 
55 
64 
0.6 
65 
74 
0.7 
75 
84 
0.8 
85 
94 
0.9 
95 
100 
1.0 
 
If the syringes are prepared using aseptic techniques, subjects must be dosed (IV bolus) 
within 24 hours of syringe preparation with capped syringes stored at 2°C to 8°C until use. 
If the syringes are not prepared using aseptic techniques (i.e., prepared under a sterile hood), 
subjects must be dosed within 60 minutes of syringe preparation. If the syringes are used 
within 60 minutes of preparation, they do not need to be kept refrigerated. No other special 
procedures are required for the safe handling of the solutions.  
Difelikefalin will be administered by IV bolus injection within 15 minutes following the 
end of the dialysis on the scheduled investigational product administration day. 
Difelikefalin may be given either during or after rinse back of the dialysis circuit. 
Difelikefalin administration can be done by injection into the dialysis venous line (e.g., into 
the venous port) or by direct injection into a vein. If the dialysis line is used, following the 
bolus, the venous line must be flushed with at least 10 ml of normal saline. The actual dose 
of difelikefalin administered (in ml) will be recorded in the eCRF. 
Additional details on dose preparation and administration will be provided in the Pharmacy 
Manual.  
6.3 
Package and Labelling 
The investigational product will be packaged and labelled in accordance with local 
regulations for investigational products.  
6.4 
Study Treatment Allocation 
This is an open-label study. All subjects will receive difelikefalin. 
6.5 
Site Supply, Storage, Accountability 
6.5.1 
Site Supply 
Once a site has been approved to receive investigational product, the site will be supplied 
with an initial stock of investigational product used in the study. The need for drug resupply 
will be assessed on a regular basis considering the number of subjects enrolled, and the 
number of subjects in screening at the site. 


 
 
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6.5.2 
Storage 
The investigational product must be stored at 15º to 25ºC. Each site should have a 
thermometer that records minimum and maximum temperatures daily. Maintenance of a 
temperature log is mandatory. The log should be updated by site personnel every workday. 
This log must be available for review by the Monitor during on-site monitoring visits. 
Additional information on storage of the investigational product including prepared dosing 
syringes is provided in the Pharmacy Manual. 
6.5.3 
Accountability 
The Investigator at each site is responsible for investigational product supplies. The 
Investigator will ensure that adequate records of the receipt, preparation, administration 
and return of the investigational product are kept and that the investigational product is 
used only for subjects enrolled in the study. All data regarding the investigational product 
(including kit and batch numbers) must be recorded in the eCRF and on any other relevant 
forms provided. 
Each study site will maintain a drug inventory/dispensing record for all drugs dispensed 
and returned. At the end of the study, 1 copy of the drug inventory/dispensing record should 
be sent to the Sponsor for the central study file. The original will be kept in the site files. 
After completion of the study, or if it is prematurely terminated, all unused materials will 
be returned to the Sponsor. The decision to destroy investigational product at site must first 
be made by the Sponsor. If the investigational product is destroyed at site, the Investigator 
will forward the certificate of destruction to the Sponsor. 
6.6 
Drug Dose Modification 
Dose modifications are not allowed in this study. 
6.6.1 
Procedures for Overdose 
There is no information available on the effect of overdosing with difelikefalin. In an 
attempt to reverse this condition, an opioid antagonist such as naloxone may be considered 
for acute management of IV overdose although the clinical effectiveness of naloxone to 
antagonise the effects of difelikefalin has not been confirmed in humans. In extreme cases, 
dialysis may be considered for the treatment of overdose. 
Any occurrence of an overdose must be communicated to the Medical Monitor and the 
Sponsor (see Section 10.8). 
6.7 
Concomitant Treatment 
Any concomitant treatment (including traditional Chinese medicines) given for any reason 
during the study must be recorded on the eCRF and in the subject’s medical records, 
including dosage, start and stop dates and reason for use. 


 
 
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All prescription and non-prescription medications (e.g., over-the-counter drugs and herbal 
supplements) that subjects report taking during the 30 calendar days prior to the screening 
visit will be recorded in the eCRF as prior medications.  
All drugs and therapies used after the Informed Consent Form (ICF) was signed should be 
recorded in the eCRF as concomitant medications.  
For each medication, documentation should list the trade or generic name, the total daily 
dose including units (or the dose, units, and scheduled and actual frequency of 
administration if the medication is not taken daily), the route of administration, and the 
reason for use.  
Changes, additions, or discontinuations to medications will be assessed and recorded in the 
eCRF during each study visit. All as needed prescriptions should be converted to reflect 
actual dose taken per day. 
Any medication or therapy that is taken by or administered to the subject during the study 
must be recorded in the eCRF.  
COVID-19 vaccination during study participation will be recorded as concomitant 
medications. Based on the mechanism of action of difelikefalin, an interaction with the 
COVID-19 vaccinate or an impact of the vaccination on difelikefalin PK are unlikely. 
Moreover, the administration of investigational product 3 times a week for 1 week as well 
as the short duration of samples collection for PK limit the impact of the COVID-19 
vaccination on the study. 


 
 
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7. RISKS/PRECAUTIONS 
7.1 
Risks 
In clinical studies, IV difelikefalin has been administered to 1,096 CKD subjects on HD for 
at least 12 weeks (3 months); of these subjects, 415 CKD subjects on HD with 
moderate-to-severe pruritus have been exposed to IV difelikefalin for at least 48 weeks 
(12 months). 
The most common (≥5.0% of subjects) adverse effects to difelikefalin reported from 
clinical studies in subjects with CKD on HD with an incidence ≥1.0% greater compared 
with placebo were, in descending frequency, diarrhoea, nausea, insomnia, fall, hypotension, 
abdominal pain, dizziness, vomiting, hyperkalaemia, headache, pneumonia, and dyspnoea. 
Somnolence (including MedDRA PTs of somnolence and sedation) and mental status 
changes (including MedDRA PTs of mental status changes and confusional state) have 
been reported as serious ADRs, with frequencies of 0.12% and 0.17%, respectively, in 
subjects being treated with difelikefalin during clinical developmental (including the 
indication for treating pruritus; N=3,478). 
7.2 
Precautions 
Aquaresis is defined as the increase in urinary water excretion with the sparing of 
electrolytes, which can result in dehydration, hypotension, tachycardia, and increases in 
serum sodium. 
Aquaresis may be observed in subjects with normal renal function. The increases in serum 
sodium in difelikefalin-treated subjects with normal renal function have been generally 
dose-related, transient, and clinically asymptomatic. 
In CKD subjects on HD, the aquaretic effects of difelikefalin do not apply due to 
insufficient functioning of nephrons. 
7.2.1 
Drug Interactions 
The nonclinical data suggest that difelikefalin should possess minimal to no drug-drug 
interaction potential in humans. However, the effects of other drugs on difelikefalin kinetic 
parameters have not been evaluated. 
7.2.2 
Drug Abuse and Dependency 
Difelikefalin has been shown to have a low to no risk to induce drug-seeking behaviour in 
humans. Based on clinical data including dedicated physical dependence studies conducted 
in humans and rodents, it can be concluded that difelikefalin has very low to no physical 
dependence potential. 


 
 
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7.2.3 
Hypersensitivity 
Difelikefalin is contraindicated in subjects with hypersensitivity to KOR agonists or any 
component of difelikefalin formulation. 
7.2.4 
Women of Childbearing Potential 
Women of childbearing potential can only be enrolled in the study if: 
• They are surgically sterile 
• Have been amenorrhoeic for at least 1 year and are over the age of 55 years 
• Have a negative serum pregnancy test within 7 days before first dose of investigational 
product, and agree to use adequate contraceptive precautions (e.g., hormonal 
contraceptives, barrier with spermicide, intrauterine device, vasectomised partner, or 
abstinence) from the time of informed consent until 7 days after dosing 
Note: If the result from serum pregnancy testing at screening is indeterminate due to 
possible human chorionic gonadotropin elevation secondary to ESRD unrelated to 
pregnancy, a serum pregnancy re-test may be repeated prior to treatment Day 1 to 
establish if a negative result can be confirmed. 
7.2.5 
Pregnancy and Lactation 
Safety and efficacy of difelikefalin have not been established in pregnant women. Although 
difelikefalin does not affect embryonic development in animal models, pregnant women 
cannot be enrolled in this study. 
Safety and efficacy of difelikefalin have not been established in nursing mothers. Animal 
data indicate that difelikefalin is secreted into breast milk. Therefore, difelikefalin may only 
be administered after breastfeeding is discontinued and nursing mothers cannot be enrolled 
in this study. 


 
 
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8. STUDY ASSESSMENTS AND PROCEDURES 
For a detailed schedule of assessments and procedures (including all protocol required 
assessments, visits and visit windows) please refer to Table 1. 
8.1 
Allowed Adaptations in Case of Extraordinary Events, e.g., 
COVID-19 
The guidance below is intended for subjects who have been successfully enrolled into the 
study and who are unable to attend in person clinic visits due to COVID-19 restrictions. 
Every reasonable effort should be made to ensure that the subject continues on the study 
per-protocol. Study visits which coincide with dialysis days should be conducted on-site. 
In the event that a subject cannot come to the clinic after baseline visit due to 
self-quarantine, local restrictions, or illness, a visit at another local hospital may be 
considered.  
If the subject misses, or is expected to miss, 2 consecutive clinic visits due to COVID-19, 
the Investigator must contact the Medical Monitor to discuss discontinuation of the subject 
from the study. In either scenario, the subject should return to the clinic for assessment at 
their earliest convenience. If it is determined that the subject must be discontinued, the 
reason for termination should be documented as ‘related to COVID-19’ under Reason for 
Termination: Other in the eCRF. 
Extraordinary events may call for specific measures to maintain subject safety and 
guarantee conduct of clinical investigations according to established general and specific 
guidelines and regulations to meet agreed regulatory, quality, and scientific expectations. 
For this, the following adaptations are considered for specific situations: 
• Site visits are not possible within the defined time window, possibly leading to delayed 
visit: 
− 
On-site monitoring: accept delayed on-site monitoring, conduct remote monitoring. 
− 
On-site auditing: accept delayed on-site auditing, conduct remote auditing. 
− 
AE/SAE/special situation reporting: frequent phone call visits. 
• Site visits are not possible within the defined time window, possibly leading to no visit: 
− 
Vital signs: consultation by local physician, follow-up clinical assessment via phone 
remote visits at subject’s home (e.g., home nursing). 
− 
On-site monitoring: accept delayed on-site monitoring, conduct remote monitoring. 
− 
On-site auditing: accept delayed on-site auditing, conduct remote auditing. 


 
 
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− 
AE/SAE/special situation reporting: frequent phone call visits. 
8.2 
Screening Procedures (Day -21 to Day -2) 
The screening visit is to occur within 21 calendar days prior to the start of treatment; it 
should be on a dialysis day (for assessments to be performed pre-dialysis).  
After the subject has signed the ICF, the following assessments will be performed and 
recorded in the subject’s source documentation/medical record and on the eCRF: 
• Assign subject number and dispense subject identification card 
• Eligibility criteria 
• Demographics 
• Medical/surgical history 
• Physical examination 
• Height and prescription dry body weight 
• 12-lead ECG (pre-dialysis) obtained within 6 hours prior to starting dialysis, whenever 
possible 
• Pre-dialysis vital signs obtained within 6 hours prior to starting dialysis, whenever 
possible 
• Serum chemistry obtained within 6 hours before starting dialysis, whenever possible 
(central laboratory assessment) 
− 
Albumin, bilirubin (total), alkaline phosphatase (AP), ALT, AST, glucose, serum 
creatinine, blood urea nitrogen (BUN) 
− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 
• Haematology obtained within 6 hours before starting dialysis, whenever possible 
(central laboratory assessment) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• Serum pregnancy in women of childbearing potential (central laboratory assessment) 
to be done within 7 days prior to the first administration of investigational product 
• AEs assessment 


 
 
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• Concomitant medications 
8.3 
Day −1 
The following assessments and procedures will be performed 1 day before start of the 
investigational product administration: 
• Confirmation of eligibility criteria 
• Update medical/surgical history, if needed 
• Admission to clinic 24 hours before dialysis 
• Subject stays overnight in clinic during night of visit 
• Physical examination, any time prior to the first dose (may also be done at Day 1) 
• AEs assessment 
• Concomitant medications 
8.3.1 
Day 1 
The following assessments and procedures will be performed: 
• Confirmation of eligibility criteria (if not done at Day −1) 
• Update medical/surgical history (if needed and not done at Day –1) 
• Physical examination (if not done at Day –1) 
• Prescription dry body weight 
Overnight stay in clinic during night of visit (based on logistical considerations, subjects 
may also remain overnight in the research unit on Days 2 and 3) 
• 12-lead ECG to be obtained within 2 hours prior to starting dialysis 
• Assess vital signs within 2 hours prior to starting dialysis 
• Serum chemistry obtained within 2 hours before starting dialysis (local laboratory 
assessment) 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, serum creatinine, BUN 
− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 


 
 
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• Haematology obtained within 2 hours before starting dialysis (local laboratory 
assessment) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• Pre-dialysis blood sample for PK can be taken at any time before starting dialysis 
• Dialysis (first dialysis session of the study, i.e., Monday for subjects on a 
Monday-Wednesday-Friday dialysis schedule or Tuesday for subjects on a 
Tuesday-Thursday-Saturday dialysis schedule) 
• Post-dialysis blood sample for PK will be taken at 5 minutes (±2 minutes) following 
the end of the dialysis. PK samples are to be obtained from a venous access different 
from the site used for difelikefalin administration to avoid cross contamination 
• Within 15 minutes after dialysis, administer investigational product as an IV bolus into 
the venous line of the dialysis either during or after rinse back of the dialysis circuit, 
followed by flushing with at least 10 ml of normal saline 
• Post-dose blood samples for PK as listed in Table 2. PK samples are to be obtained 
from a venous access different from the site used for difelikefalin administration to 
avoid cross contamination 
• AEs assessment 
• Concomitant medications 
8.3.2 
Day 2 
• AEs assessment 
• Concomitant medications 
• Blood samples for PK at 24 hours (±1 hour) post-dose (investigational product 
administered on the previous day −Day 1). PK samples are to be obtained from a venous 
access different from the site used for difelikefalin administration to avoid cross 
contamination. 
8.3.3 
Day 3 
The following procedures and assessments will be performed: 
• Pre-dialysis blood samples for PK (can be taken at any time before starting dialysis). 
PK samples are to be obtained from a venous access different from the site used for 
difelikefalin administration to avoid cross contamination 


 
 
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• Assess vital signs within 2 hours before starting dialysis 
• Serum chemistry obtained within 2 hours before starting dialysis (local laboratory 
assessment) 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, serum creatinine, BUN 
− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 
• Haematology obtained within 2 hours before starting dialysis(local laboratory 
assessment) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• AEs assessment 
• Concomitant medications 
• Dialysis (second dialysis session of the study, i.e., Wednesday for subjects on a 
Monday-Wednesday-Friday dialysis schedule or Thursday for subjects on a 
Tuesday-Thursday-Saturday dialysis schedule) 
• Post-dialysis blood samples will be taken at 5 minutes (±2 minutes) following the end 
of the dialysis. PK samples are to be obtained from a venous access different from the 
site used for difelikefalin administration to avoid cross contamination 
• Within 15 minutes after dialysis, administer investigational product as an IV bolus into 
the venous line of the dialysis either during or after rinse back of the dialysis circuit, 
followed by flushing with at least 10 ml of normal saline 
8.3.4 
Day 4 
The following procedures and assessments will be performed: 
• Admission to clinic 24 hours before dialysis 
• Overnight stay in clinic during night of visit 
• AEs assessment 
• Concomitant medications 
8.3.5 
Day 5 
The following procedures and assessments will be performed: 
• Overnight stay in clinic during night of visit 


 
 
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• AEs assessment 
• Concomitant medications 
• Pre-dialysis blood sample for PK to be taken at any time before starting dialysis. PK 
samples are to be obtained from a venous access different from the site used for 
difelikefalin administration to avoid cross contamination 
• Assess vital signs within 2 hours prior to starting dialysis 
• Serum chemistry obtained within 2 hours before starting dialysis (local laboratory 
assessment). 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, serum creatinine, BUN 
− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 
• Haematology obtained within 2 hours before starting dialysis (local laboratory 
assessment) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• Dialysis (Friday for subjects on a Monday-Wednesday-Friday dialysis schedule or 
Saturday for subjects on a Tuesday-Thursday-Saturday dialysis schedule) 
• Post-dialysis blood samples for PK will be taken at 5 minutes (±2 minutes) following 
the end of the dialysis. PK samples are to be obtained from a venous access different 
from the site used for difelikefalin administration to avoid cross contamination 
• Within 15 minutes after dialysis, administer investigational product as an IV bolus into 
the venous line of the dialysis either during or after rinse back of the dialysis circuit, 
followed by flushing with at least 10 ml of normal saline 
• Post-dose blood samples for PK as listed in Table 2. PK samples are to be obtained 
from a venous access different from the site used for difelikefalin administration to 
avoid cross contamination 
8.3.6 
Day 6 
The following procedures and assessments will be performed: 
• AEs assessment 
• Concomitant medications 


 
 
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• Blood samples for PK at 24 hours (±1 hour) post-dose (investigational product 
administered on the previous day, Day 5). PK samples are to be obtained from a venous 
access different from the site used for difelikefalin administration to avoid cross 
contamination 
8.3.7 
Day 8 
The following procedures and assessments will be performed: 
• AEs assessment 
• Concomitant medications 
• Physical examination 
• 12-lead ECG to be obtained within 2 hours prior to starting dialysis 
• Assess vital signs within 2 hours prior to starting dialysis 
• Serum chemistry obtained within 2 hours before starting dialysis (local laboratory 
assessment) 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, serum creatinine, BUN 
− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 
• Haematology obtained within 2 hours before starting dialysis (local laboratory 
assessment) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• Pre-dialysis blood sample for PK to be taken at any time before starting dialysis. PK 
samples are to be obtained from a venous access different from the site used for 
difelikefalin administration to avoid cross contamination 
• Dialysis (Friday for subjects on a Monday-Wednesday-Friday dialysis schedule or 
Saturday for subjects on a Tuesday-Thursday-Saturday dialysis schedule) 
• Post-dialysis blood samples for PK will be taken at 5 minutes (±2 minutes) following 
the end of the dialysis. PK samples are to be obtained from a venous access different 
from the site used for difelikefalin administration to avoid cross contamination 


 
 
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8.4 
Follow-up Procedures 
8.4.1 
Day 10  
• Pre-dialysis blood sample for PK can be taken at any time before starting dialysis. PK 
samples are to be obtained from a venous access different from the site used for 
difelikefalin administration to avoid cross contamination 
• Dialysis 
• Post-dialysis blood sample for PK will be taken at 5 minutes (±2 minutes) following 
the end of the dialysis. PK samples are to be obtained from a venous access different 
from the site used for difelikefalin administration to avoid cross contamination 
• AEs assessment 
• Concomitant medications 
8.4.2 
Day 12  
• Pre-dialysis blood sample for PK can be taken at any time before starting dialysis. PK 
samples are to be obtained from a venous access different from the site used for 
difelikefalin administration to avoid cross contamination 
• Dialysis 
• Post-dialysis blood sample for PK will be taken at 5 minutes (±2 minutes) following 
the end of the dialysis. PK samples are to be obtained from a venous access different 
from the site used for difelikefalin administration to avoid cross contamination 
• AEs assessment 
• Concomitant medications 
8.4.3 
End of Study (or Early Discontinuation) Procedures/Day 14 (+ up to 
3 Days) 
On completion of the study (i.e., Day 14 plus up to 3 days), or if subject is 
discontinued/withdrawn early, a last study visit should be conducted (on a dialysis day) and 
the following assessments and procedures should be performed: 
• Assess vital signs within 6 hours prior to starting dialysis, whenever possible 
• Serum chemistry obtained within 6 hours before starting dialysis, whenever possible 
(local laboratory assessment) 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, serum creatinine, BUN 


 
 
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− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 
• Serum pregnancy in women of childbearing potential (central laboratory assessment) 
to be done within 6 hours prior to starting dialysis, whenever possible 
• Haematology obtained within 6 hours before starting dialysis, whenever possible (local 
laboratory assessment) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• 
AEs assessment 
• 
Concomitant medications 


 
 
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9. STUDY ASSESSMENTS 
All assessments will be performed as noted in the Schedule of Events (Table 1). 
9.1 
Demographics and Medical/Surgical History 
Subject’s demographics (gender, age, race, and ethnicity) and baseline characteristics 
including prescription dry body weight, and medical history will be taken during the 
screening visit. 
Information to be collected will include the aetiology and clinical presentation of CKD and 
CKD-related events (e.g., pruritus, CKD-mineral and bone disorder, secondary 
hyperparathyroidism), and the date when CKD was first diagnosed, and other clinically 
relevant past and present medical conditions which were diagnosed/occurred prior to 
signing the informed consent and/or for which the subject is currently treated. Any history 
of alcohol, narcotic, or other drug abuse or dependence within 12 months prior to screening 
will be collected. 
All medications and treatments prescribed at the time of informed consent must be 
documented on the appropriate eCRF pages. In addition, treatments prescribed up to at least 
3 months prior to obtaining the informed consent must be documented on the appropriate 
eCRF pages, irrespective if the treatment is still ongoing at the time of screening. All 
changes to or addition of concomitant treatments as of informed consent must be recorded 
(including changes in dose, change in formulation, starting or stopping medications) in the 
eCRF. If the indication for changing a subject’s concomitant treatment constitutes a new 
medical condition or a worsening of an existing clinical condition which is considered by 
the Investigator as being clinically relevant, the indication must be documented as an AE 
(see Section 10). 
Also, the date of the last HD will be recorded in the eCRF. 
9.2 
Physical Examination, Height, Vital Signs 
Physical examination will include general appearance, cardiovascular, respiratory, 
abdominal, musculoskeletal, neurological, lymph nodes, and skin. Any findings before first 
administration of investigational product should be reported in the medical history. 
Clinically significant findings after first administration of study drug should be reported as 
AEs. 
Height without shoes will be recorded in centimetres. 
Vital signs will include body temperature (°C), respiratory rate, radial pulse rate, systolic 
and diastolic blood pressures. Sitting recordings are to be made after the subject has been 
sitting for at least 5 minutes with their feet squarely on the floor and arms relaxed, bent at 
the elbow.  
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9.3 
12-lead ECG 
Standard 12-lead ECGs will be measured after the subject has been resting for minimum of 
5 minutes. 
All 12-lead ECG recordings (including heart rate, QT, QTcF, QTcB, RR interval, P-wave, 
QRS complex duration, and PR interval) will be performed and interpreted at study sites 
by Investigators. ECGs will be planned to coincide with first dialysis of the week. If this is 
not possible, ECGs should be planned for the same session of the week.  
At screening, the Investigator must document clinically relevant ECG findings on the 
appropriate baseline eCRF pages. Any new clinically relevant ECG finding, or 
aggravation/worsening of an already existing finding as assessed by the Investigator, must 
be reported as an AE (see Section 10). 
9.4 
Clinical Laboratory Tests 
The following clinical laboratory tests are to be performed as indicated in the Schedule of 
Events (Table 1). 
• Serum chemistry (central laboratory assessment at screening, local laboratory 
assessments at subsequent visits) 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, serum creatinine, BUN 
− 
Electrolytes (sodium, potassium, chloride, calcium, and phosphorus) 
• Haematology obtained (central laboratory assessment at screening, local laboratory 
assessments at subsequent visits) 
− 
Haemoglobin, haematocrit, platelet count, white blood cell count (including 
differential) 
• Other:  
− 
Serum pregnancy test in women of childbearing potential (central laboratory 
assessment) 
Details on the processing and shipment of specimens are provided in the Laboratory 
Manual. In the event of an unexplained clinically noteworthy abnormal laboratory test 
value, the test should be repeated immediately and followed up until it has returned to the 
normal range and/or an adequate explanation of the abnormality is found. 
Details on the clinical laboratories used in this clinical trial, such as address, accreditation 
certificates, are available in the Trial Master File. 


 
 
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9.5 
Adverse Events 
See Section 10. 
9.6 
PK Assessments 
PK samples will be obtained from a venous access different from the site of difelikefalin 
administration to avoid cross contamination. Samples will be obtained at timepoints as 
noted in Table 1 and Table 2, within the allowed time windows. The exact time of PK 
samples collection must be recorded. 
Details of the procedures to be followed for sample collection, storage, and shipment will 
be documented in a separate Laboratory Manual. 
These samples will not be used to assess biomarkers or genetic markers. 
9.7 
Dialysis 
The HD prescription should be kept constant throughout the study. If the dialysis 
prescription must be changed or if there is an access problem that precludes achieving the 
prescribed blood flows, please contact the Medical Monitor. Record procedural data (start 
and stop times, net ultrafiltration, access changes). 


 
 
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10. EVALUATION, RECORDING, AND REPORTING OF AES 
10.1 Definition of AEs 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the 
investigational product. 
10.2 AE Reporting Period 
The AE reporting period begins at the time the ICF is signed by the subject. The AE 
reporting period ends at the last study visit (end of study/early termination). For SAE 
reporting period, see Section 10.7.2. 
10.3 Eliciting AEs 
If the subject reports an AE, it is the Investigator’s responsibility to acquire sufficient 
information in order to assess causality. This may require additional laboratory testing, 
physical examinations, telephone contacts, etc.  
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, 
such as “How are you feeling?” It is also important to question the subject in a non-leading 
way about changes in their health or concomitant medication usage since their last visit. 
This information should be collected prior to completion of assessments at all study visits. 
In addition, any symptoms/conditions reported during assessments and deemed to be 
clinically significant by the Investigator will be assessed as AEs. 
10.4 Assessing AEs 
10.4.1 Intensity/Severity 
The medical assessment of intensity will be determined by using the following definitions: 
Mild: 
The AE is easily tolerated and does not interfere with usual activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to function.  
Severe: 
The AE is incapacitating, and the subject is unable to work or complete 
usual activity. 
Every change in intensity of a particular AE experienced by the subject during the course 
of the event is recorded.  
It is important to note the distinctions between severe AEs and SAEs. Severity is a 
classification of intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); however, the event itself may be of relatively minor medical significance (such 


 
 
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as severe headache). An SAE, however, is an AE that meets any of the regulatory specified 
criteria required for designation as seriousness described in Section 10.7.1, i.e., a headache 
may be severe (interferes significantly with subject's usual function but would not be 
classified as serious unless it met 1 of the criteria for SAEs).  
10.4.2 Causality and Reporting 
An Investigator who is qualified in medicine must make the determination of relationship 
to investigational product for each AE and SAE. The Investigator should decide whether, 
in her/his medical judgement, there is a reasonable possibility that the event may have been 
caused by the investigational product.  
If there is no valid reason for suggesting a relationship, then the AE/SAE should be 
classified as unrelated or unlikely related and an alternative suspected aetiology should be 
provided if available (i.e., concomitant medications, intercurrent illness/events). Otherwise, 
if there is any valid reason, even if undetermined or untested, for suspecting a 
cause-and-effect relationship between the investigational product and the occurrence of the 
AE/SAE, then the AE/SAE should be considered certainly, probably/likely, or possibly 
related.  
The following additional guidance may be helpful: 
Term 
Relationship 
Definition 
Certain 
Yes 
• 
Event or laboratory test abnormality, with plausible time relationship to 
drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e., an 
objective and specific medical disorder or a recognised pharmacological 
phenomenon) 
• 
Rechallenge satisfactory, if necessary. 
Probable/ 
Likely 
Yes 
• 
Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required. 
Possible 
Yes 
• 
Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear. 
Unlikely 
No 
• 
Event or laboratory test abnormality with a time to drug intake that makes a 
relationship improbable (but not impossible). Disease or other drugs 
provide plausible explanation. 
Unrelated 
No 
• 
Event or laboratory test abnormality which is clearly related to 
circumstances not connected with the drug intake. 
 
If the causal relationship between an AE/SAE and the investigational product is determined 
to be “certainly, probably/likely, or possibly related”, the event will be considered to be 


 
 
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related to the investigational product for the purposes of expedited regulatory reporting. In 
circumstances where the causal relationship has not been provided, the event will be 
considered as related and qualify for expedited regulatory reporting. 
10.4.3 Outcome Categorisation 
Outcome may be classified as: 
recovered/resolved (i.e., without 
sequelae); 
recovered/resolved with sequelae; recovering/resolving; not recovered/not resolved; fatal; 
or unknown (if follow-up is not possible).  
If the outcome of an SAE is reported as recovered/resolved with sequelae, the Investigator 
should specify the kind of sequelae on the SAE form. If the outcome of an SAE is reported 
as unknown, the Investigator should specify (on the SAE form) the rationale why unknown 
was selected. 
“Fatal” should be recorded as an outcome when the AE results in death. If more than 1 AE 
is possibly related to the subject's death, the outcome of death should be indicated for the 
AE that, in the opinion of the Investigator, is the most plausible cause of death. All other 
ongoing AE/SAEs will be recorded as not recovered/not resolved at the time of death.  
In case of a fatal outcome, the Investigator should provide a working diagnosis (event 
which caused outcome, e.g., death due to fatal myocardial infarction) instead of reporting 
only death; and an autopsy report should be provided where possible. If the cause of death 
later becomes available (e.g., after autopsy), this working diagnosis should be replaced by 
the established cause of death. 
Although “fatal” is usually an outcome of an event, events such as sudden death or 
unexplained death should be reported as SAEs. 
10.5 Recording and Reporting 
10.5.1 Persistent or Recurrent AEs 
AEs that extend continuously, without resolution, between trial assessments should only be 
recorded once in the eCRF.  
The initial severity of the event should be recorded, and the severity should be updated to 
reflect the most extreme severity any time the event worsens.  
AEs that resolve and subsequently recur should have each recurrence recorded separately 
in the eCRF. 
All AEs persisting at the time of study completion will be followed by the Investigator 
through contact with the subject until resolution or stabilisation, or the subject is lost to 
follow-up and cannot be contacted. The outcome must be documented in the subject’s 
source documents. 


 
 
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10.5.2 Diagnosis Versus Signs and Symptoms 
Where possible, the Investigator should report a diagnosis rather than individual signs and 
symptoms or abnormal laboratory values. However, if a constellation of signs and/or 
symptoms cannot be medically characterised as a single diagnosis or syndrome at the time 
of reporting, each individual event should be recorded in the eCRF. If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified and replaced by 1 AE report based on the single diagnosis, with a starting date 
that corresponds to the starting date of the first symptom of the eventual diagnosis. 
The Investigator should use standard medical terminology/concepts; avoid colloquialisms 
and abbreviations. Only 1 AE term should be recorded in each event field in the eCRF. 
10.5.3 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the medical history eCRF. A pre-existing medical 
condition should be recorded as an AE only if the frequency, severity, or character of the 
condition worsens during the study. When recording such events on the AE eCRF, it is 
important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
10.5.4 Clinical Laboratory Evaluations 
Not every out-of-range laboratory result qualifies as an AE. A laboratory investigation 
result must be reported as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) 
or a change in concomitant therapy 
• Presents shift of a parameter from a normal value to a pathological value, or results in 
a deterioration of common terminology criteria grade, or a further worsening of an 
already pathological value 
• Is clinically significant in the Investigator’s judgement 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgement should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either 
while continuing treatment or after the end of treatment with the investigational product, 


 
 
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and the range of variation of the respective parameter within its reference range, must be 
taken into consideration. 
If, at the end of the treatment phase, there are pathological laboratory values which were 
not present at baseline, further clinical or laboratory investigations should be performed 
until the values return to within reference range or until a plausible explanation 
(e.g., concomitant disease) is found for the pathological laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. If the Investigator considers such an AE as serious (e.g., medically 
significant event fulfilling criteria per Section 10.7.1), it must be reported as an SAE. 
If a laboratory abnormality meeting the above criteria is a sign of a disease or syndrome 
only the diagnosis should be recorded in the eCRF.  
If a laboratory abnormality meeting the above criteria is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in the eCRF, along with a descriptor indicating if 
the test result is above or below the normal range (e.g., “elevated potassium,” as opposed 
to “abnormal potassium”).  
If the laboratory abnormality can be characterised by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE, for example, hypercalcaemia or 
hypoglycaemia. Observations of the same laboratory abnormality from visit to visit should 
not be repeatedly recorded in the eCRF unless the aetiology changes. The initial severity 
of the event should be recorded, and the severity or seriousness should be updated any time 
the event worsens. 
All pathological laboratory findings/values diagnosed throughout the treatment period 
should be reviewed by the Investigator to provide a final clinical assessment in view of the 
dynamic of laboratory changes/abnormalities. 
10.5.5 Worsening of the Disease Under Study 
Symptoms and signs of the disease under study should not be considered AEs as long as 
they are not regarded as worsening of the clinical features of the disease under study. If a 
sign or symptom of the disease has unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study, the symptoms and signs should be recorded 
as AEs, and clearly marked as worsening of the signs or symptoms in the eCRF. 
10.5.6 Abnormal Vital Signs and Other Abnormalities 
Not every abnormal vital sign, ECG, or other safety assessment qualifies as an AE. A result 
must be reported as an AE if it meets any of the following criteria:  
• Accompanied by clinical symptoms or lead to a diagnosis (in such case the symptom 
or diagnosis will be recorded as an AE) 


 
 
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• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• Results in a medical intervention, a change in concomitant therapy, or subject referral 
for further testing outside the protocol 
• Clinically significant abnormality in the Investigator’s judgement 
It is the Investigator’s responsibility to review all vital signs, ECG, and other safety 
findings. Medical and scientific judgement should be exercised in deciding whether an 
isolated abnormality should be classified as an AE. 
If a clinically significant abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded in the eCRF. 
Observations of the same clinically significant abnormality from visit to visit should not be 
repeatedly recorded in the eCRF unless the aetiology changes. The initial severity of the 
event should be recorded, and the severity or seriousness should be updated any time the 
event worsens. 
10.6 ADR and Reference Safety Information  
10.6.1 Adverse Drug Reaction 
An ADR is a response to a medical product (any dose administered). A causal relationship 
between an investigational product and an AE is at least a reasonable possibility. This 
means that there are facts (evidence) or arguments to suggest a causal relationship. 
All AEs judged as having a reasonable causal relationship to an investigational product will 
be designated as ADRs.  
10.6.2 Reference Safety Information 
The Reference Safety Information presents the basis for expectedness assessment of an 
adverse reaction for expedited reporting and annual safety reporting, as well as surveillance 
of subject’s safety in a clinical trial by regulatory (and ethic) bodies. 
In the context of this study, the Reference Safety Information is integrated in the latest 
version of difelikefalin IB. 
10.7 Serious Adverse Event 
10.7.1 Definition of SAE 
An SAE is defined as any untoward medical occurrence that either: 
• Results in death 


 
 
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• Is life-threatening (the term life-threatening in the definition of serious refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe) 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation (unless 
elective surgery (a planned, non-emergency medical procedure)) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (i.e., medically significant) 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. These events should also be considered as serious. 
Any worsening of a pre-existing medical condition or any new medical condition that meets 
the above SAE criteria should be considered as an SAE. 
Any suspected transmission of any infectious agent via a medicinal product should be 
considered as an important medical event (i.e., medically significant) and therefore 
documented as an SAE. 
The Investigator is encouraged to discuss with the Sponsor (or its delegate, e.g., Contract 
Research Organisation (CRO)) any AEs for which the issue of seriousness is unclear or 
questionable. 
10.7.1.1 
Situations that are Not Considered SAEs 
The following situations are not considered as SAEs:  
• Visits to the emergency room or hospital department that do not result in a hospital 
admission lasting more than 24 hours 
• Elective or pre-planned surgery for a pre-existing condition that has not worsened 
• Routine health assessments requiring admission not associated with any deterioration 
in condition 
• Social admission (lack of housing, family circumstances, etc.) 
• A planned overnight stay for logistical reasons only prior to investigational product 
administration does not fulfil the criteria of an SAE unless there is also a medical reason 
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10.7.2 SAE Reporting 
The SAE reporting period begins at the time the ICF is signed by the subject. The SAE 
reporting period ends 30 days following the last study visit or until 30 days after last 
investigational product administration, whichever is longer. After last study visit, SAEs 
that comes to the attention of the Investigator must be reported to the CRO/Sponsor and 
will be documented in the safety database of the Sponsor only and not in eCRF. 
A death occurring during the study, or which comes to the attention of the Investigator 
within 30 days after the last study visit or until 30 days after the last investigational product 
administration, whichever is longer, whether considered treatment-related or not, must be 
reported to the Sponsor (or its delegate, e.g., CRO). 
Any SAE considered to have a causal relationship (i.e., related) to the investigational 
product and discovered by the Investigator at any time after the study should be reported. 
A rationale for the assessment of a causal relationship must be provided by the Investigator. 
Any safety information that is obtained after database lock of the clinical database will be 
documented in the safety database and implications for handling the data in the clinical 
database assessed on an individual case basis.  
The occurrence of an SAE must be immediately reported to the Sponsor (or its delegate, 
e.g., CRO) within 24 hours of awareness using the study-specific Sponsor SAE form/via 
SAE CRF/eCRF in the electronic data capture (EDC), or as defined in the study monitoring 
plan. This includes all SAEs (independent of relationship to study treatment). 
The onset date of the SAE is defined as the date the signs and symptoms/diagnosis became 
serious (i.e., met at least 1 of the criteria for seriousness; see Section 10.7.1). If the condition 
started as a non-serious event and then became serious, 1 AE and 1 SAE will be recorded. 
The resolution date of the SAE is defined as when the symptoms resolve, or the event is 
considered chronic (e.g., sequelae) or stable, and/or if the seriousness criteria are no longer 
applicable.  
10.7.3 Suspected Unexpected Serious Adverse Reaction 
The definition of a suspected unexpected serious adverse reaction is any ADR (see 
Section 10.6.1) that is both serious (see Section 10.7.1) and unexpected (per the Reference 
Safety Information; see Section 10.6.2) that, based on the opinion of the Investigator or 
Sponsor, is felt to have a reasonable possibility or suspected causal relationship to an 
investigational product.  
10.7.3.1 
SAE Expedited Reporting 
The Sponsor will notify all Investigators of all SAEs requiring expedited reporting to 
Regulatory Authorities.  


 
 
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The Investigator is responsible for notifying the Independent Ethics Committee (IEC) in 
accordance with local regulations of all SAEs that occur. The Investigator must review and 
file the safety report with the IB. 
10.8 Special Situations 
10.8.1 Definition of Special Situations 
The following are defined as special situations: 
• Use of an investigational product during pregnancy or breastfeeding 
• Use of an investigational product in a paediatric population  
• Medication error: any unintentional error in the prescribing, dispensing or 
administration of an investigational product during the study 
• Medication misuse: an intentional and inappropriate use of an investigational product 
not in accordance with the protocol dose, route of administration, and/or the 
indication(s) 
• Medication overdose: the administration of a quantity of investigational product given 
per administration, which is above the protocol maximum permitted dose  
• Drug interaction involving investigational product 
• Unexpected therapeutic or clinical benefit from investigational product use  
Suspected AEs associated with medication errors of the investigational product or use 
outside that foreseen in the protocol (e.g., overdose,) are also considered as ADRs. Any 
special situation occurring with/without ADR/AE shall be recorded in the study-specific 
documentation. 
10.8.2 Special Situation Recording and Reporting 
All special situations have to be documented in the subject’s eCRF and source documents. 
The Investigator should also complete and submit the Sponsor paper Special Situation form 
immediately (i.e., within 24 hours of awareness) to the Sponsor, following the same 
procedure as for SAEs (Section 10.7.2). 
If any special situation leads to an SAE (see Section 10.8.1), then the event must be 
immediately reported to the Sponsor (or its delegate, e.g., CRO) within 24 hours of 
awareness using the study-specific Sponsor SAE form/via SAE CRF/eCRF in EDC. 


 
 
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10.8.3 Pregnancy Exposure and Birth Events 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events 
When a female subject becomes pregnant during the study and study treatment has been 
administered to the subject, the outcome of the pregnancy needs to be monitored and the 
safety of the mother and unborn child need to be safeguarded (as per-protocol, pregnancy 
is an exclusion criteria). Therefore, the outcome of all such pregnancies (including normal 
births) must be followed up and documented, even if the subject was withdrawn from the 
study or the study has been completed. 
Women of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, should have a negative serum pregnancy test within 7 days before first dose of 
investigational product is administered and at the end of study treatment (Day 8). 
Investigational product should not be initiated by the Investigator until a report of a negative 
pregnancy test has been obtained. As per inclusion criteria, women of childbearing 
potential must agree to use adequate contraceptive precautions (e.g., hormonal 
contraceptives, barrier with spermicide, intrauterine device, vasectomised partner, or 
abstinence) from the time of informed consent until 7 days after dosing. Please also refer 
to the eligibility criteria (Section 5). 
Per inclusion criteria, male subjects will agree not to donate sperm from investigational 
product administration until 7 days after the dosing and will agree to use a condom with 
spermicide or abstain from heterosexual intercourse during the study until 7 days after 
investigational product administration. 
A female subject must immediately inform the Investigator if she becomes pregnant during 
the study and be instructed to stop taking investigational product. The Investigator should 
counsel the subject and discuss the risks of continuing with the pregnancy and the possible 
effects on the foetus.  
The Investigator/Sponsor is responsible for monitoring the subject and pregnancy outcome. 
Every effort should be made to gather information regarding the pregnancy outcome until 
90 days postpartum (or otherwise as appropriate). It will be the responsibility of the 
Sponsor, together with the appropriate support of the Investigator, to obtain this 
information.  
10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting 
Any report of pregnancy recorded for any female subject or for a female partner of a male 
subject should be reported to the Sponsor (or its delegate, e.g., CRO) within the same 
timelines as an SAE, i.e., immediately (within 24 hours of awareness). The outcome of all 
such pregnancies (including normal births) must be followed up and documented, even if 
the subject was discontinued from the study. Complications of pregnancy such as abortion 
(spontaneous or induced), premature birth (before 37 weeks gestational age) or congenital 
abnormality are considered SAEs and should be reported using the study-specific Sponsor 
SAE form.  


 
 
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All pregnancies occurring in a female subject or the female partner of a male subject within 
90 days after discontinuation of the investigational product should be reported within the 
same timelines as a SAE to the Sponsor (or its delegate, e.g., CRO). 
10.8.4 Adverse Event of Special Interest 
10.8.4.1 
Definition of AESI 
An AESI is a medical occurrence specific to the product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor is appropriate. 
Such an event, depending on the nature and the outcome, may be serious (see 
Section 10.7.1) or non-serious.  
Based upon results of the studies in the HD population, the following categories (MedDRA 
PT) were identified as AESIs for the HD population: 
• Gait disturbance (gait disturbance) 
• Falls (fall) 
• Dizziness (dizziness) 
• Somnolence (somnolence) 
• Seizures (seizure) 
• Syncope (syncope) 
• Mental status changes (mental status changes) 
• Mood changes (mood altered) 
• Unusual feeling/sensation (feeling abnormal) 
• Tachycardia (sinus tachycardia, tachycardia, and tachyarrhythmia) 
• Palpitations (palpitations) 
10.8.4.2 
AESI Reporting and Recording 
AEs classified as AESIs will be noted in the AE section of the subject's eCRF and source 
documentation. Any AESI satisfying any of the criteria for seriousness should be reported 
using the study-specific Sponsor SAE form/via SAE CRF/eCRF in EDC. The Investigator 
should notify the Sponsor immediately (i.e., within 24 hours of awareness), following the 
same procedure as for SAEs (Section 10.7.2). 


 
 
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11. DATA AND SAFETY MONITORING BOARD/DATA 
MONITORING COMMITTEE PROCEDURES 
An independent Data and Safety Monitoring Board/Data Monitoring Committee will not 
be used in this open-label study, whose primary objective is to evaluate the PK profile of a 
single dose (3 times weekly) of difelikefalin in Chinese subjects undergoing HD.  


 
 
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12. STATISTICAL ANALYSIS 
12.1 Statistical Methods 
All statistical analyses will be performed using SAS Version 9.4 or later (SAS Institute Inc. 
SAS/STAT, Cary, NC, US) and with WinNonlin® Version 8.3 or higher (Pharsight 
Corporation, Mountain View, CA, US). Detailed methodology for summary and statistical 
analyses of the data collected in this trial will be documented in a SAP, which will be 
finalised prior to study completion. A general description of the planned methods is 
provided below. Any deviation from the SAP will be noted and explained in the final study 
report. 
Frequency tables for categorical variables (absolutes and relative frequencies) and 
descriptive statistics for continuous variables (i.e., number of subjects, mean, SD, 
minimum, median, quartiles, and maximum) will be calculated. All statistical analyses will 
be purely descriptive.  
12.2 Sample Size and Power Calculations 
This study will enrol 30 subjects. The sample size for this Phase 1 study is based on a 
pragmatic approach. No formal sample size calculation has been conducted. 
12.3 Randomisation 
This is an open-label study, and no randomisation will be applied. Enrolment is defined as 
the time of signed informed consent. 
12.4 Analysis Sets 
12.4.1 Safety Analysis Set 
The SAF consists of all enrolled subjects who have received at least 1 dose of 
investigational product.  
12.4.2 PK Set 
The PK population is defined as all subjects who have received the investigational product, 
did not have major protocol deviations or other events that may affect PK, and have 
sufficient plasma concentration. The PK population will be finalised prior to database lock. 
12.5 Background and Demographic Characteristics 
The number of subjects enrolled, treated, completed, or discontinued from the study, along 
with the reason for discontinuation, will be summarised. 
In addition, the number of subjects in each analysis set will be tabulated. 
Subject demographics and baseline characteristics will be summarised using descriptive 
statistics on the SAF; no formal statistical analysis tests will be performed. 


 
 
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For quantitative variables the mean, SD, median, minimum and maximum will be 
calculated. For qualitative variables, frequencies and associated percentages will be 
tabulated. 
Medical history data will be coded using MedDRA and summarised by MedDRA SOC and 
PT. The data will also be listed, including the verbatim Investigator description of the 
relevant medical condition, the coded terms (SOC, PT), start date, end date, and whether 
or not the condition is ongoing. 
12.6 Investigational Product 
The investigational product will be administered as a single dose of 0.5 µg/kg, 3 times a 
week over a period of one week. The total amount of investigational product given will be 
calculated for each subject and will be compared to the amount expected to be given for 
each subject. Treatment compliance will be calculated for each subject and summarised 
overall. 
In addition, the number and percentage of subjects who were administered 1, 2, or 3 doses 
will be summarised with the actual dose received at each administration, i.e., on Day 1, 3, 
and 5.  
Results will be summarised on the SAF by means of descriptive statistics (n, mean, SD, 
median, minimum, quartiles and maximum) for quantitative variables and by means of 
frequencies and associated percentages for qualitative variables. 
12.7 Concomitant Therapy 
Medications will be coded using the World Health Organization Drug Dictionary. Counts 
and percentages of subject use for each concomitant medication will be tabulated by 
appropriate World Health Organization Drug Dictionary classifications on the SAF. Prior 
medications will be presented in a listing only using the SAF. Traditional Chinese 
medicines should also be recorded. 
A prior medication is defined as any medication taken any time with an end date before the 
date of the first administration of investigational product.  
A concomitant medication is defined as any medication/therapy used on or after the date of 
the first administration of investigational product or with a missing end date. If missing, 
the medication will be assumed to be ongoing and considered as concomitant. 
12.8 Pharmacokinetics 
All PK analyses will be performed using the PK analysis set.  
Noncompartmental PK analysis will be applied to derive all PK parameters in this study. 


 
 
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Plasma difelikefalin concentrations will be summarised descriptively by nominal time at 
each time point. Individual and mean plasma concentration-time profiles and spaghetti 
plots (individual subject profiles in one plot) will be provided. In addition, individual 
plasma difelikefalin concentrations will be listed by subjects.  
All PK parameters (e.g., Cmax, Tmax, AUC0‑t, AUCinf, AUCExtrap(%), t½, clearance, and Vz) 
will be summarised descriptively. Descriptive statistics will include N, mean (arithmetic 
and geometric), SD, median, coefficient of variation, minimum, quartiles, and maximum. 
12.9 Efficacy Evaluations 
Not applicable. 
12.10 Safety Evaluations 
All safety analyses will be performed on the SAF. Incidence of AEs, AESIs, and SAEs will 
be tabulated by SOC and PT, using MedDRA coded terms. Incidence of AEs will also be 
summarised by maximum intensity and maximum relationship to the investigational 
product. Vital signs, biochemistry, haematology data, and 12-lead ECG recordings will be 
descriptively summarised by visit as applicable, in addition to change from baseline. 
Details are listed as below. 
12.10.1 Adverse Events 
All AEs and pre-treatment AEs will be coded using MedDRA to MedDRA SOC and PT 
for standardisation and summary purposes. 
All reported AEs will be included in summary tables and in by-subject AE listings.  
An AE is defined as any AE that has an onset on or after the first investigational product 
administration, or any pre-existing condition that has worsened on or after the first 
administration of investigational product.  
A pre-treatment AE is defined as any AE that has an onset before the first investigational 
product administration. 
The number and percentage of subjects experiencing AEs, as well as the number of events 
will be summarised. A subject will be counted only once in the incidence count for a 
MedDRA SOC or PT, although a subject may have multiple occurrences (start and stop) of 
an event associated with a specific MedDRA SOC or PT.  
In addition, the incidence and percentage of subjects experiencing treatment-emergent 
SAEs and AEs leading to investigational product discontinuation will be presented by the 
appropriate MedDRA SOC and PT.  
AEs will also be summarised by severity and by relationship to investigational product. If 
the severity and/or relationship to the investigational product of an AE is missing, a 
worst-case scenario will be assumed (i.e., the AE will be categorised as “severe” and/or 


 
 
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“related” to the investigational product). If a subject reports the same AE multiple times 
the event with the worst severity and the strongest relationship to investigational product 
will be tabulated.  
An overall summary table will be provided, presenting the number and percentage of 
subjects as well as the number of events for AEs, SAEs, treatment-emergent deaths, 
treatment-related AEs, treatment-related SAEs, severe AEs, AEs leading to investigational 
product discontinuation and AESIs.  
In addition, the following summary tables will be presented and will include the number 
and percentage of subjects as well as the number of events for: 
• AEs by SOC and PT 
• SAEs by SOC and PT 
• 
AEs by SOC, PT, and maximum severity  
• 
Related AEs by SOC and PT 
• 
AEs leading to investigational product discontinuation by SOC and PT 
• 
AESIs by PT 
• 
Related AESIs by PT 
All AEs will be listed in chronological order, including information such as subject 
identifier, age, sex, a flag indicating whether the event was treatment-emergent, and all 
related event status information (start and stop dates, whether the event was ongoing, study 
day of onset, severity, seriousness, relationship to investigational product, action taken with 
investigational product, and outcome). Separate listings will be generated for SAEs, deaths, 
AEs leading to investigational product discontinuation, and pre-treatment AEs. 
Pre-treatment AEs will not be included in any summary tables.  
12.10.2 Special Situations 
All special situations will be coded using MedDRA (when applicable). 
All reported special situations will be included in a by-subject listing.  
12.10.3 Vital Signs 
Summary statistics for absolute vital sign value and the changes from baseline will be 
presented for each visit. 


 
 
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12.10.4 12-lead ECG 
Baseline and change from baseline in ECG parameters will be summarised at each 
post-baseline time point. 
All 12-lead ECG data will be listed in a by-subject listing. 
12.10.5 Physical Examination 
Not applicable as physical examination findings will be recorded through medical history 
or AEs if clinically relevant. 
12.10.6 Clinical Laboratory Tests 
Summary statistics for absolute value and the changes from baseline will be presented for 
each visit and for each laboratory variable. In addition, each reading will be classified as 
below, within, or above normal range, based on ranges supplied by the laboratory used. 
Shift tables from baseline to each post-baseline time point measurements will also be 
presented. 
12.11 Other Evaluations 
12.11.1 Dialysis Details 
Dialysis details will be listed only using the SAF. 
12.12 Handling of Missing Data 
Procedures for managing missing data, imputation for missing or partially missing data will 
be provided in the SAP. 
Definitions of baseline will be specified in the SAP and will include rules for identification 
of baseline values when assessments are missing at the scheduled baseline visit. 


 
 
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13. STUDY ETHICAL CONSIDERATIONS 
13.1 Ethical Conduct of the Study 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki [15], and the ICH guidelines for Good Clinical Practice (GCP) [16] 
as amended. The Sponsor will ensure that the study complies with all local, federal, or 
country regulatory requirements.  
The Investigator must ensure the anonymity of all subjects participating in the study. Each 
subject will be assigned a unique subject number, and this should be used on all forms 
associated with the subject’s documents or samples that will be supplied to the Sponsor or 
any party completing testing on behalf of the Sponsor (e.g., blood for central laboratory 
assessments).  
All anonymous data remains the property of the Sponsor. 
13.2 Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, regulatory and 
legal requirements of China, and ICH guidelines; and must have been approved by the IEC 
prior to use. The Investigator or an authorised associate must explain orally and in writing 
the nature of the study and the treatment in such a manner that the subject is aware of 
potential benefits and risks. Subjects must also be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. Subjects must 
be provided sufficient time to consider participation, including discussion with family 
members prior to signing the ICF. Documentation of the discussion and the date of 
informed consent must be recorded in the source documentation. Subjects must give 
informed consent in writing. If applicable, consent from female partners (who become 
pregnant during the study) of male subjects will also be acquired. 
13.3 Independent Ethics Committee 
The protocol, any protocol amendments and consent form for the proposed clinical study 
and any other documents required by the local IEC must be submitted by the Investigator 
for review and approval to the IEC. The Investigator must also ensure that the IEC reviews 
the progress of the study on a regular basis and, if necessary, renews its approval of the 
study on an annual basis. A copy of the approval letter must be forwarded to the Sponsor 
before the study is implemented. 
Approval by the Human Genetics Resources Administration of China will be obtained prior 
to study initiating for the different study sites. 
13.4 Insurance 
The Sponsor confirms that it carries liability insurance which protects non-employee 
physicians or Investigators against claims for which they may become liable as a result of 
damages caused by Sponsor products used in clinical studies. Insurance coverage is not 


 
 
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extended to damages that the Investigators or third parties may suffer by reason of acts of 
commission or omission on the part of such Investigators and that are not in accordance 
with accepted common medical practices (lege artis procedures). The Sponsor will 
reimburse the subject for all study-related injuries provided that the injury does not arise 
from the subject’s misuse of the investigational product or failure to follow the 
Investigator’s instructions. 


 
 
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14. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator must ensure that all trial related site source data, study-related documents 
and reports will be available, and that the provision of direct access for monitoring and 
auditing by the Sponsor or its designees will be permitted. In addition, the Investigator must 
ensure that all trial related site source data, study-related documents and reports will be 
made available for Sponsor audit and inspection by the appropriate Regulatory Authority 
and review by the IEC. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Monitor (source document verification), 
and the maintenance of a drug dispensing log by the Investigator. The data collected will 
be entered (double-data entry or EDC) into the study database. A comprehensive validation 
check program will verify the data and queries will be generated for resolution by the 
Investigator. Throughout the study, the Sponsor or its designates may review data as 
deemed necessary. 
The following steps will be taken to ensure that the trial is conducted by the investigational 
site in compliance with the study protocol, GCP, and other applicable regulatory 
requirements: 
• Investigator meeting and/or 
• Investigator site initiation 
• Routine site monitoring 
• Documented protocol and GCP training 
• eCRF and query review against source documents 
• Collection of local laboratory normal ranges 
14.1 Quality Management: Critical Processes and Data 
The following processes and data have been identified during the risk management 
activities for this trial as critical to ensure human subject protection and the reliability of 
trial results. 
The Sponsor and its designees will ensure a close oversight of the site's activities related to 
the trial. Throughout the study, the clinical study team will work to ensure that the trial is 
operationally feasible and focuses on study activities essential to human subject protection 
and the reliability of trial results, including (but not limited to): 
• Study protocol design and implementation 
• Tools and procedures supporting data collection and processing 


 
 
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• Tools and procedures safeguarding the rights and protection of human subjects 
• Activities essential to trial decision-making and compliance  


 
 
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15. REPORTING AND RECORDING OF DATA 
All required study data must be entered in the eCRF created for the study. Training on the 
system will be provided to all sites, including instructions on how to address missing data, 
corrections, query procedures, and electronic signatures. Only individuals who are 
identified on the authorised signature page may enter/correct data in the eCRF. For those 
subjects who withdraw before completion of the study, all available efficacy and safety 
data must be entered in the eCRF. Incomplete or inconsistent data on the eCRF will result 
in data queries addressed to the Investigator for resolution. 
15.1.1 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which case 
reports for each subject are based. They are to be separate and distinct from eCRFs. These 
records should include detailed notes on: 
• The medical history 
• The basic identifying information, such as demographics, that link the subject’s source 
documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject 
• The subject’s exposure to study treatment 
• All AEs and pregnancies 
• All special situations as defined in Section 10.8.1 
• The subject’s exposure to any concomitant therapy (including date and quantity 
dispensed) 
• All relevant observations and data on the condition of the subject throughout the study 
• The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study). The date of informed consent must be 
recorded in the source documentation 
All data for the study must be available in source documentation. 
15.1.2 Records Retention 
The Investigator must arrange for the retention of all study documentation (such as eCRF 
files or printed forms, research files, and master files) for the duration specified in their 
respective site contract or as specified by the applicable Regulatory Authority, whichever 
is longer. The Sponsor will inform the Investigator in writing when files can be destroyed. 


 
 
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Archived data may be held on DVD, USB, or through a secure file transfer protocol site, 
or electronic record, provided that a back-up copy exists and that a hard copy can be 
generated if required. 
The Investigator must inform the Sponsor immediately if any documents are lost, to be 
transferred to a different facility, or to be transferred to a different owner. 
15.1.3 Site Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
 


 
 
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16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
16.1 Protocol Deviations  
The Investigator will not deviate from the protocol without prior written approval from the 
Sponsor, except in medical emergencies. In the event of a medical emergency, the 
Investigator must notify the Sponsor Medical Expert as soon as possible. Any other change 
to the protocol must be implemented as an amendment to the protocol (see Section 16.2). 
The criteria describing protocol deviation(s) and how they will be handled will be 
documented in the SAP. 
16.2 Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of the Sponsor. Each applicable 
Regulatory Authority/IEC will review and approve amendments prior to their 
implementation. Regulatory Authority/IEC approval need not be obtained prior to removal 
of an immediate hazard to subjects. 
16.3 Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a site at any time. 
Reasons for termination may include (but are not limited to) unsatisfactory subject 
enrolment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, the Sponsor and the Investigator will assure that adequate 
consideration is given to the protection of the subject’s interests. Both parties will arrange 
the procedures on an individual basis after review and consultation and in accordance with 
the study contract. 


 
 
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17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The Sponsor is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles [17]. The 
Clinical Trial Agreement describes the Sponsor’s publication terms.  
Where possible, authorship will be agreed at the beginning of the study. The authors will 
form a publication committee and this committee will propose and develop appropriate 
scientific manuscripts or abstracts from the study data. Investigators may not present or 
publish partial or complete study results individually. Any manuscript or abstract proposed 
by the Investigators must be reviewed and approved in writing by Vifor Fresenius Medical 
Care Renal Pharma Ltd. before submission for publication. Names of all Investigators 
participating in the study will be included in the publication. 
The publication committee for a study will comprise of authors selected in adherence with 
the International Committee of Medical Journal Editors criteria for authorship [18]. That 
is, all authors must meet each of the following 4 criteria: 
1. Substantial contribution to the conception and design of the work; or the acquisition, 
analysis, or interpretation of data for the work; and 
2. Drafting the work or revising it critically for important intellectual content; and 
3. Final approved of the version to be published; and 
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.  
In addition, certain Sponsor employees involved in the design and conception of the 
protocol, study management, and data analysis and interpretation are qualified authors and 
will be included in the publication committee e.g., the lead physician, statistician, and study 
project manager, or their equivalents. 


 
 
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18. REFERENCES 
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3. 
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4. 
Swarma S, Aziz K, Zubair T, Qadir N, Khan M. Pruritus associated with chronic 
kidney disease: a comprehensive literature review. Cureus. 2019;11(7):e5256. 
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Verduzco HA and Shirazian S. CKD-associated pruritus: new insights into 
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Weisshaar E, Szepietowski JC, Dalgard F, Garcovich S, Gieler U, Giménez-Arnau 
A, et al. European S2k guideline on chronic pruritus. Acta Derm Venereol. 
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Drug Interview Form for REMITCH® Capsules 2.5 µg, OD Tablets 2.5 µg. Toray 
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delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ 
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Yaksh T, Wallace M. Opioids, analgesia, and pain management. In: Brunton LL, 
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14. 
Zhao X, Niu Q, Gan L, Hou FF, Liang X, Ni Z, et al. Baseline data report of the 
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World Medical Association Declaration of Helsinki. Ethical principles for medical 
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ICH Harmonised Guideline. ICH E6(R2): Integrated addendum to ICH E6(R1) 
guideline for good clinical practice. 2016 Nov 9. 
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PhRMA. Principles on conduct of clinical trials. Communication of clinical trial 
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