A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3, Clinical Study of Difelikefalin in Haemodialysis Chinese Adult Subjects With Moderate-to-Severe Pruritus
Phase: PHASE3
Conditions: Uremic Pruritus
Sponsor: Vifor Fresenius Medical Care Renal Pharma

 
 
 
Clinical Study Protocol 
 
Title: 
A Randomised, Double-Blind, 
Placebo-Controlled, Multicentre, Phase 3, 
Clinical Study of Difelikefalin in 
Haemodialysis Chinese Adult Subjects with 
Moderate-to-Severe Pruritus 
 
 
Clinical Protocol Number: 
KOR-CHINA-301 
 
 
Version Date: 
29 March 2022 
 
 
Version Number: 
2.0 
 
 
Prior Version/Amendments: 
Version 1.0, 16 July 2021 
 
 
Investigational Drug 
Difelikefalin (CR845) 
 
 
Co-ordinating Investigator: 
Professor Li Zuo 
 
 
Sponsor Contact: 
 
 
 
Sponsor Address:  
Vifor Fresenius Medical Care 
Renal Pharma Ltd. 
Rechenstrasse 37 
St. Gallen CH-9014 
Switzerland  
 
 
PPD

 
 
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SIGNATURE PAGE 
Declaration of Sponsor 
Title: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3, Clinical 
Study of Difelikefalin in Haemodialysis Chinese Adult Subjects with Moderate-to-Severe 
Pruritus 
Clinical Protocol Number: KOR-CHINA-301 
Version/Amendment Number/Date: Version 2.0, 29 March 2022 
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 Pharmaceuticals for Human Use Guideline for Good Clinical 
Practice as amended. 
  
Sponsor Medical Expert 
 
 Nephrology and 
Orphan-Nephrology 
Vifor Pharma Management Ltd. 
Flughofstrasse 61 
8152 Glattbrugg 
Switzerland 
 
 
 Date (day month year) 
 
S
		

PPD
PPD
PPD
PPD

 
 
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SIGNATURE PAGE 
Declaration of Co-ordinating Investigator 
Title: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3, Clinical 
Study of Difelikefalin in Haemodialysis Chinese Adult Subjects with Moderate-to-Severe 
Pruritus 
Clinical Protocol Number: KOR-CHINA-301 
Version/Amendment Number/Date: Version 2.0, 29 March 2022 
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 Pharmaceuticals for Human Use 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 
 
11 Xizhimennan Street, Xicheng District 
Beijing, 100044 
China 
 
 
 
 
PPD
PPD

 
 
KOR-CHINA-301, Version 2.0 
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INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
Title: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3, Clinical 
Study of Difelikefalin in Haemodialysis Chinese Adult Subjects with Moderate-to-Severe 
Pruritus 
Clinical Protocol Number: KOR-CHINA-301 
Version/Amendment Number/Date: Version 2.0, 29 March 2022 
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, and Email of Principal 
Investigator 
 
 

 
 
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SYNOPSIS 
KOR-CHINA-301 
Title: 
A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3, 
Clinical Study of Difelikefalin in Haemodialysis Chinese Subjects with 
Moderate-to-Severe Pruritus 
Short Title: 
Phase 3 Study of Difelikefalin in Haemodialysis (HD) Chinese Subjects with 
Moderate-to-Severe Pruritus 
Study Product(s): 
Difelikefalin (CR845) 
Study Population: 
HD Chinese subjects with moderate-to-severe pruritus 
Phase: 
3 
Sponsor: 
Vifor Fresenius Medical Care Renal Pharma Ltd. 
Protocol Number: 
KOR-CHINA-301 
Co-ordinating 
Investigator:  
Professor Li Zuo, Peking University People's Hospital, Beijing, China 
Objectives: 
Primary Objective: 
• 
To evaluate the efficacy of difelikefalin 0.5 µg/kg compared to placebo in 
reducing the intensity of itch in HD Chinese subjects with 
moderate-to-severe pruritus. 
Secondary Objectives: 
• 
To evaluate the efficacy of difelikefalin 0.5 µg/kg compared to placebo in 
improving the itch-related quality of life (QoL) in HD Chinese subjects with 
moderate-to-severe pruritus. 
• 
To evaluate the safety of difelikefalin 0.5 µg/kg in HD Chinese subjects 
with moderate-to-severe pruritus. 
Design: 
This multicentre study consists of a double-blind, randomised, 
placebo-controlled, parallel group period, and an optional open-label extension 
period. 
Duration: 
Total study duration for a single subject is 31 to 32 weeks with a 4-week 
screening period (including a 7-day run-in period during the week prior to 
randomisation), a 12-week double-blind period, a 14-week open-label extension 
period (starting within 1 week after the end of the double-blind period), and a 
1-week follow-up period (1 week to 10 days). For subjects not participating in 
the open-label extension period, the total study duration is 17 weeks. 
Treatment: 
Investigational Products 
1. Test drug 
Difelikefalin solution (intravenous (IV) formulation) will be supplied 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. 

 
 
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2. Comparator 
A matching placebo (0.04 M isotonic acetate buffer, pH 4.5) will be supplied in 
2 R glass vials with an extractable volume of 1 ml.  
Dosage and Administration 
1. Screening period 
A 4-week period before entry into the double-blind period is defined as the 
screening period, during which subjects will receive no investigational product. 
Subjects will continuously use any conditionally permitted concomitant 
medications (e.g., anti-itch drugs) used at the start of the screening period. 
2. Double-blind period 
In addition to the use of conditionally permitted concomitant medications (e.g., 
anti-itch drugs) used at the start of the screening period, the investigational 
product will be injected into the venous line of the dialysis circuit at the end of 
each dialysis session for 12 weeks (3 times weekly, 36 times in total). The total 
dose of the investigational product will be determined based on the subject’s 
prescription dry body weight (i.e., the target post-dialysis weight, as determined 
by the patient’s nephrologist or dialysis unit) at the start day of the double-blind 
treatment period.  
The total dose volume (ml) required from the investigational product vial should 
be calculated as follows: 0.01 × prescription dry body weight (kg), rounded to 
the nearest tenth (0.1 ml). 
If any dialysis circuit trouble precludes injection through the dialysis circuit, the 
investigational product will be administered directly intravenously. If in 
exceptional cases an extra fourth dialysis session is required within the week, the 
investigational product will be administered (up to 4 times weekly); if only the 
extracorporeal ultrafiltration method is used at this fourth dialysis session, the 
investigational product will not be administered. 
3. Open-label extension period 
In addition to the use of conditionally permitted concomitant medications (e.g., 
anti-itch drugs) used at the start of the screening period, difelikefalin will be 
injected into the venous line of the dialysis circuit at the end of each dialysis 
session for 14 weeks (3 times weekly; 42 times in total). Investigational 
treatment in the extension period will be started at Week 13 and will be given 
until Week 26 inclusive. The participation in the open-label extension period is 
optional.  
4. Follow-up period 
The follow-up period is defined as 1 week (1 week to 10 days) after last 
administration of difelikefalin (end of extension period or early discontinuation). 
Concomitant Treatments 
Subjects may continuously use any conditionally permitted concomitant 
medication used to treat symptoms of chronic renal failure or other comorbidities 
at the start of the screening period without changing its dosage and 
administration regimen whenever possible until the end of the follow-up period. 
The dosage and administration of any concomitant medication may be changed 
for safety reasons including adverse events (AEs). Any centrally acting 

 
 
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concomitant drug should be used with caution due to possible central AEs that 
might confound the safety profile of difelikefalin. 
5. Prohibited concomitant treatments 
Between the start of the screening period and the end of the follow-up period, 
use of the following drugs will be prohibited: 
• 
Other kappa opioid receptor (KOR) agonists, e.g., nalfurafine hydrochloride 
• 
Opioid antagonists: naloxone hydrochloride, eptazocine hydrobromide, 
naldemedine tosylate, etc., or mixed agonists-antagonists (e.g., 
buprenorphine and nalbuphine) 
• 
Investigational products other than difelikefalin 
6. Conditionally permitted concomitant treatments 
Between the start of the screening period and the end of the follow-up period, 
subjects may use the drugs listed below that have been used before the screening 
period without changing their dosage and administration. However, treatment 
with these drugs should not be initiated during the same time window defined 
above. 
a) Drugs indicated for the treatment of itching (prescription/non-prescription) 
except prohibited concomitant medications 
b) Drugs to treat itching including traditional Chinese medications 
(prescription/non-prescription) except prohibited concomitant medications 
c) Moisturising drugs (prescription/non-prescription) 
d) Steroids 
Note: Local steroids, such as inhalants, nasal drops, ear drops, eye drops, 
and eye ointments, are allowed. 
e) Capsaicin (topical) 
f) 
Opioids 
g) Pregabalin, gabapentin  
h) Antidepressants, anxiolytics  
i) 
Drugs formulated with any of the drugs listed above 
Topical use of any prescription/non-prescription drugs listed in a) to e) above 
that are used to treat itching caused by chronic renal failure or any complication 
of chronic renal failure will not be restricted (concomitant medications for local 
itching caused by insect stings, chilblains, contact dermatitis, etc. will not be 
restricted).  
The use of any combination products that contain ingredients indicated for 
itching but are not indicated itself for itching will not be restricted. 
7. Prohibited concomitant therapies 
Between the start of the screening period and the end of the follow-up period, 
phototherapy to treat itching will be prohibited. 

 
 
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HD Conditions 
Between the start of the screening period and the end of the follow-up period, the 
frequency of dialysis per week and the HD method may not be changed. Any 
temporary change in dialysis frequency or HD method associated with travel or 
admission to other hospitals with no changes in treatment strategies is 
acceptable. The HD conditions (duration of dialysis and dialyser) should not be 
changed whenever possible. 
Inclusion Criteria: 
Double-blind Period 
The double-blind period of this study will enrol HD subjects with pruritus who 
meet all the inclusion criteria and none of the exclusion criteria listed below. 
1. Subject (or legally accepted representative) has provided written informed 
consent. Written informed consent must be provided before any study-
specific procedures are performed including screening procedures. 
2. Chinese subjects aged ≥18 to 85 years (inclusive) at the time of consent. 
3. Able to communicate clearly with the Investigator and staff, able to 
understand the study procedures, and able and willing to comply with the 
study requirements, including providing written responses to questionnaires. 
4. Subjects with chronic kidney disease (CKD) on HD 3 times weekly for 
≥12 weeks prior to the informed consent procedure (including the date of 
informed consent) who can continue HD without changing its frequency or 
method.  
Note 1: Any temporary change in dialysis frequency or method associated 
with travel or admission to other hospitals with no changes in treatment 
strategies is acceptable, from the date of informed consent until the end of 
the follow-up period. Subjects routinely on 4 dialyses a week will not be 
eligible. 
Note 2: Subjects receiving in-home HD may participate as long as they have 
switched to in-centre HD at least 2 weeks prior to screening and plan to 
remain on in-centre HD for the duration of the study. 
Note 3: Subjects receiving alternate dialysis modalities such as nocturnal 
dialysis will not be eligible. 
5. If female, is not pregnant, or nursing.  
6. 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 

 
 
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c. Has a negative serum pregnancy test within 7 days before first dose of 
investigational product and agrees to use acceptable contraceptive 
measures (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 end-stage renal disease (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. If male, agrees not to donate sperm after the first dose of investigational 
product administration until 7 days after the last dose of investigational 
product, 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. 
8. Subjects whose Numerical Rating Scale (NRS) score (Appendix 1) in the 
7-days run-in period (7 days including the score recorded on the start day of 
treatment) meets both of the below: 
a. NRS scores have been recorded for at least 4 days through a 7-day 
run-in period. 
b. The mean value of the recorded scores is ≥5.0 (moderate-to-severe 
pruritus). 
9. Subjects with a prescription dry body weight between 40 and 100 kg, 
inclusive. 
10. Over the last 3 months prior to screening, has had at least 1 of the following: 
a. At least 2 single-pool Kt/V measurements ≥1.2 on different dialysis days 
b. At least 2 urea reduction ratio measurements ≥65% on different dialysis 
days 
c. 1 single-pool Kt/V measurement ≥1.2 and 1 urea reduction ratio 
measurement ≥65% on different dialysis days 
Open-label Extension Period 
Subjects meeting all of the following inclusion criteria at the end of Week 12 of 
the double-blind period will enter the extension period. Subjects not meeting 
these inclusion criteria will be withdrawn from the study and undergo the 
follow-up assessments. 
11. Subjects not withdrawn during the double-blind period. 
12. Subjects receiving at least 30 doses of the planned 36 doses of 
investigational product during the double-blind period. 
13. Has a prescription dry body weight ≥40 kg. 
14. Continues to meet inclusion criteria 1 through 7. 

 
 
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15. Subjects do not have any safety or other reasons, which in the opinion of the 
Investigator, should exclude them from entering the open-label extension 
period. 
Exclusion Criteria: 
1. Known noncompliance with dialysis treatment that in the opinion of the 
Investigator would impede completion or validity of the study. 
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. Subjects with itching caused by conditions other than chronic renal failure 
or complications of chronic renal failure, which could affect the efficacy 
evaluation in the opinion of the Investigator (e.g., atopic dermatitis, chronic 
urticaria). Note: Subjects whose pruritus is attributed to ESRD 
complications, such as hyperparathyroidism, hyperphosphataemia, anaemia, 
or the dialysis procedure, or prescription may be enrolled. 
4. Has localised itch restricted to the palms of the hands. 
5. Has pruritus only during the dialysis session (by subject report). 
6. Subjects with severe hepatic impairment (Child-Pugh Class C) or concurrent 
hepatic cirrhosis. 
7. Subject is receiving ongoing ultraviolet B treatment and anticipates 
receiving such treatment during the study. 
8. Subjects who previously were enrolled in any clinical study of difelikefalin 
and received at least 1 dose of difelikefalin. 
9. Significant systolic or diastolic heart failure (e.g., New York Heart 
Association Class IV congestive heart failure) (Appendix 2). 
10. Subjects with concurrent malignancy except excised basal cell or squamous 
cell carcinoma of the skin, or carcinoma in situ that has been excised or 
resected completely. 
11. Known or suspected history of alcohol, narcotic, or other drug abuse, or 
substance dependence within 12 months prior to screening. 
12. Severe mental illness or cognitive impairment (e.g., dementia) or other 
concurrent mental disorder that, in the opinion of the Investigator, would 
compromise the validity of study measurements.  
13. Any other relevant acute or chronic medical or neuropsychiatric condition 
within 3 months prior to screening (e.g., diagnosis of encephalopathy, coma, 
delirium). 
14. New or change of treatment received for itch including antihistamines and 
corticosteroids (oral, IV, or topical) within 14 days prior to screening. 
15. New or change of prescription for opioids, gabapentin, or pregabalin within 
14 days prior to screening. 
16. Subject is receiving prohibited medication (e.g., nalfurafine hydrochloride, 
opioid antagonists) 

 
 
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17. Subjects who received treatment with any investigational product or study 
device in a clinical study (including clinical studies of medical devices or 
cellular and tissue-based products) within 30 days prior to the informed 
consent procedure, or who are planning to participate in another clinical 
study before the end of the follow-up period of this study. 
Primary and 
Secondary 
Endpoints: 
Efficacy Endpoints 
Primary Endpoint 
• 
Change from baseline in the weekly mean of the daily 24-hour Worst 
Itching Intensity NRS (WI-NRS) score at Week 4 of the double-blind 
period.* 
*The degree of the most intense itching within a day will be assessed using NRS 
scores. 
Secondary Endpoints 
• 
Proportion of subjects achieving ≥3-point improvement from baseline with 
respect to the weekly mean of the daily 24-hour WI-NRS at Week 4 of the 
double-blind period. 
• 
Proportion of subjects achieving ≥3-point improvement from baseline with 
respect to the weekly mean of the daily 24-hour WI-NRS at Week 8 of the 
double-blind period. 
• 
Proportion of subjects achieving ≥3-point improvement from baseline with 
respect to the weekly mean of the daily 24-hour WI-NRS at Week 12 of the 
double-blind period. 
• 
Proportion of subjects achieving ≥4-point improvement from baseline with 
respect to the weekly mean of the daily 24-hour WI-NRS at Week 4 of the 
double-blind period. 
• 
Proportion of subjects achieving ≥4-point improvement from baseline with 
respect to the weekly mean of the daily 24-hour WI-NRS at Week 8 of the 
double-blind period. 
• 
Proportion of subjects achieving ≥4-point improvement from baseline with 
respect to the weekly mean of the daily 24-hour WI-NRS at Week 12 of the 
double-blind period. 
• 
Change from baseline in itch-related QoL at the end of Week 12 of the 
double-blind period, as assessed by the 5-D itch scale total score. 
• 
Change from baseline in itch-related QoL at the end of Week 12 of the 
double-blind period, as assessed by the Skindex-10 scale total score. 
• 
Change from baseline in the weekly mean of the 24-hour WI-NRS score at 
each week of the double-blind period. 
• 
Change from baseline in itch-related QoL at each time point of the 
double-blind period and open-label extension phase, as assessed by the 5-D 
itch scale total score. 
• 
Change from baseline in itch-related QoL at each time point of the double-
blind period and open-label extension phase, as assessed by the Skindex-10 
scale total score. 

 
 
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• 
Patient Global Impression of Change. 
Safety Endpoints 
• 
Overall safety and tolerability of difelikefalin as assessed by incidence of 
AEs, 12-lead electrocardiogram (ECG), vital signs, and clinical safety 
laboratory evaluations over the study period. 
Procedures: 
Double-Blind Period 
The double-blind phase of the study will consist of a screening visit, a 7-day 
run-in period, and a 12-week double-blind period. Informed consent will be 
obtained prior to performing any study-specific procedures.  
See Table 1 for full details of protocol required assessments, procedures, and 
applicable visits (and timings of each visit) during the double-blind period. 
The screening visit will occur within 7 to 28 days prior to randomisation to 
assess eligibility. The site has also the option to conduct the screening visit 
within the run-in period at the discretion of the Investigator. 
Eligible subjects will complete a 7-day run-in period during the week prior to 
randomisation to confirm eligibility, preferably starting on the first dialysis 
session of that week (i.e., Monday for subjects on a Monday-Wednesday-Friday 
dialysis schedule or Tuesday for subjects on a Tuesday-Thursday-Saturday 
dialysis schedule). The purpose of the run-in period is to confirm that each 
subject has moderate-to-severe pruritus (i.e., weekly average WI-NRS ≥5), as 
measured by the subject-daily reported 24-hour WI-NRS, and to establish a 
baseline itch intensity. Subjects must not be informed that they need to report a 
weekly average worst itch score ≥5 to be enrolled in the study. During the first 
visit of the run-in period, subjects will be trained on completion of the 24-hour 
WI-NRS and will start the reporting of their WI-NRS daily score. For 
consistency, subjects will be requested to complete the NRS worksheets (either 
at home or in the dialysis unit, as required) each day at a similar time of day 
around the normal start time of their dialysis. 
Subjects will be trained on other itch-related patient reported outcome (PRO) 
worksheets during the run-in period or on Day 1 of the double-blind period at the 
latest. 
If subjects continue to meet all inclusion and no exclusion criteria at the end of 
the 7-day run-in period, they will be randomised on Day 1 into the double-blind 
period in a 1:1 ratio to receive either difelikefalin or placebo. Subjects will be 
stratified according to their use or non-use of concomitant medications to treat 
their itch during the week prior to randomisation (run-in period) as well as the 
presence or absence of specific medical conditions. These specific medical 
conditions include: 
• 
History of fall or fracture (related to fall) 
• 
Confusional state or mental status change or altered mental status or 
disorientation  
• 
Gait disturbance or movement disorder  

 
 
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Day 1 of the double-blind period will be defined as the day of administration of 
the first dose of investigational product and will occur preferably on the first 
dialysis session of the first treatment week (i.e., Monday for subjects on a 
Monday-Wednesday-Friday dialysis schedule, or Tuesday for subjects on a 
Tuesday-Thursday-Saturday dialysis schedule). Subjects will be administered 
investigational product after the end of each dialysis session during the 12-week 
double-blind period. Each subject is to receive investigational product 3 times 
weekly for a total of 36 doses. 
Prescription dry body weight will be recorded during screening and on Day 1 of 
the double-blind period. 
During the double-blind period, subjects will continue to report their daily 
WI-NRS score over the previous 24 hours. In addition, during selected study 
visits (Day 1 and first day of Weeks 5, 9 and 13, i.e., Days 29, 57 and 85), they 
will complete other PRO measures (Skindex-10 scale and 5-D itch scale). The 
subjects will complete the Patient Global Impression of Change at the end of the 
double-blind phase (Day 85). Subjects will be instructed to record PRO 
measurements, including WI-NRS scores, at a similar time of day, whether in the 
dialysis unit (on dialysis days) or at home (on non-dialysis days).  
Blood samples for clinical laboratory tests will be collected at the screening visit 
and on Days 1 and 85; in addition, blood samples for analysis of serum 
potassium will be collected every 2 weeks (on dialysis days). 12-lead ECG will 
be monitored at the screening visit and on Day 85. Vital signs will be monitored 
periodically, and AEs, and concomitant medications will be continuously 
recorded during the double-blind phase. 
A structured safety evaluation will be performed once during the run-in period 
and weekly (preferably on Wednesday/Thursday) during the double-blind 
period. The structured safety evaluation is performed by study staff using a list 
of specific signs/symptoms (e.g., mental status change, gait disturbance).  
Open-label Extension Period 
Subjects who received at least 30 doses of investigational product (difelikefalin 
or placebo) during the 12-week double-blind period and continue to meet other 
eligibility criteria will be eligible to receive open-label difelikefalin for an 
additional 14 weeks.  
See Table 2 for full details of protocol required assessments, procedures, and 
applicable visits (and timings of each visit) during the open-label period. 
Each subject will receive difelikefalin at a dose of 0.5 µg/kg after the end of each 
dialysis session, 3 times per week for up to 14 weeks, regardless of whether they 
had been previously administered placebo or difelikefalin. Prescription dry body 
weight will be recorded at the start of the open-label extension phase; if there is a 
±10% or more change from the prescription dry body weight recorded at 
screening, then the difelikefalin dose will be adjusted according to the newly 
recorded dry body weight.  

 
 
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The first visit and first dosing for the open-label extension phase of the study 
will occur immediately on the day of the last visit of the double-blind period or 
up to 1 week following the double-blind period. Day 1 of the open-label 
extension period will be defined as the day of administration of the first dose of 
difelikefalin in the open-label extension period and will occur preferably on the 
first dialysis session of the first treatment week (i.e., Monday for subjects on a 
Monday-Wednesday-Friday dialysis schedule, or Tuesday for subjects on a 
Tuesday-Thursday-Saturday dialysis schedule). 
The last dose of open-label difelikefalin will be administered at the last dialysis 
visit on Week 14, or early termination. 
Subjects will complete the Skindex-10 scale and 5-D itch scale at Week 4, 
Week 8, Week 12 and at the end-of-treatment visit, which corresponds to the 
first dialysis visit following the last dose of difelikefalin given in the open-label 
extension (i.e., first dialysis on Week 15).  
Blood samples for clinical laboratory tests will be collected at the end of 
treatment or early termination visit; in addition, blood samples for analysis of 
serum potassium will be collected every 2 weeks (on dialysis days), i.e., at 
Week 2, Week 4, Week 6, Week 8, Week 10 and Week 12 of the open-label 
extension. Vital signs will be monitored on Day 1, at Week 4, Week 8, Week 12 
and at the end of treatment or early termination visit. AEs and concomitant 
medications will be continuously recorded throughout the open-label treatment 
period. 
12-lead ECGs will be monitored at the open-label end of treatment or early 
termination visit. 
Follow-up Period 
A final safety follow-up visit will be conducted in 7 to 10 days: 
• 
After the end-of-treatment visit of the double-blind period for subjects not 
participating in the open-label extension phase 
• 
After the end-of-treatment visit of the open-label extension period for 
subjects participating in the open-label extension phase 
• 
Or after the early termination visit during either the double-blind period or 
the open-label extension phase 
Sample Size: 
Double-blind Period 
Based on the results observed at the end of Week 4 in a Japanese Phase 2 clinical 
study (MR13A9-4) and in the pooled data of 2 Phase 2 clinical studies 
(CLIN3102 and CLIN3103), a mean difference of −0.9 with a common standard 
deviation (SD) of 2.1 is assumed between difelikefalin and the placebo group 
regarding the primary endpoint. Assuming a 2-sided significance level of 5% 
and a statistical power of 90%, 116 subjects per group will be required to detect 
a difference of -0.9, with a common SD of 2.1, between the difelikefalin and the 
placebo group using a 2-sample t-test. In addition, assuming, a 10% drop out 
rate, 258 subjects in total need to be enrolled in the double-blind study period, 
i.e., 129 subjects per group. Please refer to Section 12.2 of the protocol for 
further details. 

 
 
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Open-label Extension Period 
All subjects who completed the double-blind period may continue into the 
14-week open-label extension period if they meet the eligibility criteria. 
Study Sites: 
30-40 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.  
An interim analysis may be conducted. Details will be defined in the SAP. 
Analysis Populations 
The following subject populations will be used for presentation and analysis of 
the data: 
• 
The double-blind safety analysis set (DB-SAF) is defined as all randomised 
subjects who receive at least 1 dose of investigational product during the 
double-blind period. Subjects in the DB-SAF will be analysed according to 
the actual treatment received. The DB-SAF will be used to analyse exposure 
data as well as all safety endpoints collected during the double-blind period. 
• 
The full analysis set (FAS) is defined as all subjects who satisfy the 
following criteria: 
− Randomised to treatment 
− Received at least 1 dose of investigational product 
− Had a non-missing baseline assessment for the weekly mean of the daily 
24-hour WI-NRS score  
− Had at least 1 post-baseline assessment for the weekly mean of the daily 
24-hour WI-NRS score. 
Subjects in the FAS will be analysed according to their randomised treatment, 
regardless of the actual treatment received. The FAS will be used to analyse all 
efficacy endpoints collected during the double-blind period. 
• 
The per-protocol set (PPS) consists of all subjects who, in addition to the 
FAS criteria, do not have any major protocol deviations that will be defined 
and reviewed during the blinded data review meeting prior to unblinding the 
data. Subjects in the PPS will be analysed according to their randomised 
treatment, regardless of the actual treatment received. The PPS will be used 
to analyse efficacy endpoints collected during the double-blind period. 
• 
The open-label safety analysis set (OL-SAF) consists of all subjects who 
receive at least 1 dose of investigational product in the open-label extension 
period. Subjects in the OL-SAF will be analysed according to the actual 
treatment sequence received during the double-blind and open-label periods. 
The OL-SAF will be used to analyse exposure data to difelikefalin, efficacy 
as well as all safety endpoints collected during the open-label extension 
period. 

 
 
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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 and 
presented by treatment groups.  
Demographic and baseline disease characteristics will be summarised 
descriptively by treatment groups. 
Subject exposure and compliance will be calculated and summarised 
descriptively by treatment groups. 
Primary Efficacy Endpoint Analyses (Double-blind Period) 
The primary efficacy endpoint is defined as the change from baseline in the 
weekly mean of the daily 24-hour WI-NRS score at Week 4 (Days 23 to 29) of 
the double-blind period. The FAS will be used as the primary population for the 
analysis of the primary efficacy endpoint as well as for its sensitivity analysis. 
The PPS will be used as a secondary population. 
The weekly mean of the 24-hour WI-NRS score will be defined as the sum of the 
daily WI-NRS score reported during a specific week during the double-blind 
period (e.g., Days 2 to 8, Days 9 to 15, Days 16 to 22, Days 23 to 29) divided by 
the number of days with non-missing scores for that week. If the daily WI-NRS 
is missing for >3 days during a specific week, the corresponding weekly mean 
WI-NRS will be set to missing. The baseline score will be defined as the average 
of the daily 24-hour WI-NRS scores collected over the run-in period, including 
pre-randomisation assessments collected on Day 1. 
The change from baseline in the weekly mean of the daily 24-hour WI-NRS 
score at Week 4 (Days 23 to 29) of the double-blind period will be analysed 
using a mixed-effect model for repeated measures (MMRM). Missing scores will 
not be imputed. Assuming that the data are missing at random (MAR), the 
estimates of the treatment differences calculated from the MMRM described 
below are unbiased. The model will contain treatment, week, and treatment-by-
week interaction as fixed effects; baseline NRS score, use of prior anti-itch 
medication and presence of specific medical conditions as covariates.  
Repeated measures will include values collected at the end of Weeks 1, 2, 3, 
and 4. 
An unstructured covariance matrix will be used to model the within-subject 
errors. Should the model fail to converge, a compound symmetric covariance 
matrix will be used instead.  
The Kenward-Roger2 approximation will be used to estimate the denominator 
degrees of freedom.  
Standard descriptive statistics will be reported on the values and changes from 
baseline at Week 4 of the double-blind period along with the adjusted mean 
change at Week 4 for each group and its 2-sided 95% confidence interval (CI). 
The adjusted mean treatment difference in the change between difelikefalin and 
placebo groups will be estimated at Week 4 of the double-blind period as the 
simple contrast in the treatment effect. Its 2-sided 95% CI as well as its p-value 
will be presented. 

 
 
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Testing of the primary efficacy endpoint will be 2-sided and conducted at the 5% 
error level. The null hypothesis in this study is that there is no treatment 
difference in the primary efficacy analysis of the primary endpoint, i.e., the 
change from baseline in the weekly mean of the daily 24-hour WI-NRS score at 
Week 4 of the double-blind period. The alternative hypothesis is that subjects 
randomised to difelikefalin experience significantly less itching compared to 
subjects randomised to placebo. 
In the primary efficacy analysis, missing NRS data will not be imputed. 
Sensitivity analyses of the primary efficacy endpoint using multiple imputed 
data will be conducted to evaluate the robustness of study results under different 
assumptions and imputation algorithms, as detailed in Section 12.8.1 of the 
protocol. 
Secondary Efficacy Endpoints Analyses 
Secondary and other efficacy endpoints will be analysed using the FAS, as the 
primary population, and PPS, as a secondary population. 
Significance level is set at an alpha of 0.05 (2-sided) and no adjustment will be 
made for testing multiple secondary outcomes. Some significant findings are 
expected to occur by chance so undue consideration will not be given to any 
particular significant difference. Moreover, interpretation of the results will be 
based on patterns of differences and in conjunction with the results of the 
primary analyses. Secondary efficacy endpoints will be analysed as per 
Section 12.8.2 of the protocol. 
Safety Analyses 
Safety data will be summarised descriptively for each study period. No 
inferential statistics are planned. Analyses of safety data will include summaries 
of AEs including adverse events of special interest (AESIs), serious adverse 
events (SAEs) and AEs resulting in study drug discontinuation. AEs 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, and haematology data, and 
12-lead ECG data will be descriptively summarised by visit as applicable, in 
addition to change from baseline for each study period.  
 

 
 
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Figure 1 
Study Design 
 
Notes: Conditionally permitted concomitant medications (anti-itch drugs) are allowed throughout the study. 
 
EoT=End of treatment; ET=Early termination; IP=Investigational product. 

 
 
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Table 1 
Schedule of Events and Assessments for the Double-blind Period 
Study Procedures 
Screening Period 
Double-blind Period(2) 
Double-blind 
End of 
Treatment(3)/ 
Early 
Termination 
Follow-Up Period 
(ONLY for Subjects 
not Participating in 
Open-label 
Extension Phase) 
Screening 
Visit(1) 
Run-in 
Period(1) 
Visit Days 
Day -28 to 
Day -7 
Day -7 to 
Day -1 
Week 1 
Weeks 2 to 12 
Week 13 
Follow-up 
Day 1 to 10 after 
EoT 
 
 
 
M/Tu W/Th F/Sa M/Tu W/Th F/Sa 
 
 
-28 to -7 
-7 to -1 
1 
3 
5 
 
 
 
85 
85 to 95 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Dispense subject identification card 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X(4) 
 
 
 
 
  
 
 
Medical history/prior medications (including antipruritic 
medications)/demographics 
X 
X(4) 
X(4) 
 
 
 
 
 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Safety and efficacy evaluations 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
Prescription dry body weight  
X 
 
X 
 
 
 
 
 
 
 
Pre-dialysis 12-lead ECG(5) 
X(5) 
 
 
 
 
 
 
 
X(5) 
 
Pre-dialysis vital signs 
X 
 
X(6) 
 
 
X(6) 
 
 
X(6) 
X(7) 
Haematology, serum chemistry (pre-dialysis)(8) 
X 
 
X 
 
 
 
 
 
X 
 
Separate serum potassium 
 
 
 
 
 
X(9) 
 
 
 
 
Serum pregnancy (females of childbearing potential only) 
X(10) 
 
 
 
 
 
 
 
X 
 
Subject training on PRO worksheets  
 
X(11,12) 
X(12) 
 
 
 
 
 
X 
 
Worst Itching Intensity NRS (daily)(13) 
 
X 
Record on an ongoing basis 
X 
X(14) 

 
 
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Study Procedures 
Screening Period 
Double-blind Period(2) 
Double-blind 
End of 
Treatment(3)/ 
Early 
Termination 
Follow-Up Period 
(ONLY for Subjects 
not Participating in 
Open-label 
Extension Phase) 
Screening 
Visit(1) 
Run-in 
Period(1) 
Visit Days 
Day -28 to 
Day -7 
Day -7 to 
Day -1 
Week 1 
Weeks 2 to 12 
Week 13 
Follow-up 
Day 1 to 10 after 
EoT 
 
 
 
M/Tu W/Th F/Sa M/Tu W/Th F/Sa 
 
 
-28 to -7 
-7 to -1 
1 
3 
5 
 
 
 
85 
85 to 95 
5-D itch scale, Skindex-10 scale(15) 
 
 
X 
 
 
X(15) 
 
 
X(15) 
 
Patient Global Impression of Change 
 
 
 
 
 
 
 
 
X 
 
IV administration of investigational product 
 
 
Record on an ongoing basis 
 
 
Adverse event monitoring 
X 
X 
Record on an ongoing basis 
X 
X 
Concomitant medications (including antipruritic 
medications)(16) 
 
 
X 
Record on an ongoing basis 
X 
X 
Structured safety evaluation(17) 
 
X 
 
X 
 
 
X 
 
 
X 
1 
Sites have the option to conduct the screening visit during the run-in period at the discretion of the Investigator. 
2 
Each visit during the double-blind period will coincide with the subject’s normal dialysis treatments. 
3 
The end-of-treatment visit in the double-blind phase will be the first dialysis visit following the last dose of investigational product (i.e., first dialysis on Week 13 (Day 85)), which also corresponds to Day 1 
of the first day of the open-label extension. For subjects not participating in the open-label extension, Day 85 corresponds to Day 1 of the follow-up period. 
4 
Medical history will be updated on Day 1 with any changes since the screening visit, and inclusion/exclusion criteria will be confirmed prior to randomisation. Antipruritic medication will be updated at each 
dialysis visit during the run-in period. 
5 
12-lead ECG must be performed prior to the start of dialysis at screening, Day 85 (double-blind period end of treatment), or at early termination visit. 
6 
Pre-dialysis vital signs, including body temperature, heart rate, and blood pressure, will be recorded on Days 1, 15, 29, 43, 57, 71 and 85 (double-blind period end of treatment), or at early termination visit 
only when the subject is in a sitting or semi-recumbent position. Heart rate will be measured at each dialysis; if heart rate is clinically significant at visits outside the pre-specified visits per Schedule of 
Events, the heart rate will be recorded in the eCRF. 
7 
Pre-dialysis vital signs, including body temperature, heart rate, and blood pressure, will be recorded at the follow-up visit (at 7 to 10 days after EoT/ET visit). Heart rate will be measured at each dialysis visit 
during the follow-up period; if heart rate is clinically significant at visits outside the follow-up visit, the heart rate will be recorded in the eCRF. 
8 
Blood samples for clinical laboratory evaluation will be taken at screening, and on Days 1 and 85 (double-blind period end of treatment), or at early termination visit only and will be assessed at central 
laboratory. Haematology will include basophil %, basophil (absolute), eosinophil %, eosinophil (absolute), haematocrit, haemoglobin, lymphocyte %, lymphocyte (absolute), MCH, MCHC, MCV, monocyte 
%, monocyte (absolute), neutrophil %, neutrophil (absolute), platelet, RDW, red blood cells, white blood cells. Serum chemistry will include albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, 
bilirubin (total), BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, sodium. 
9 
Serum potassium will be assessed separately at Weeks 3, 5, 7, 9 and 11 (Days 15, 29, 43, 57 and 71) (central laboratory assessment). 
10 
Within 7 days prior to first dose of investigational product (central laboratory assessment). 
11 
Training on Worst Itching Intensity NRS will be conducted on the first day of the run-in period (Day -7). 

 
 
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12 
Training on Skindex-10 scale and 5-D itch scale may be performed at any time during the week prior to randomisation or on Day 1 of the double-blind period. 
13 
Subjects will be requested to complete their Worst Itching Intensity NRS worksheets each day at a similar time (either at home on non-dialysis days around the normal start time of their dialysis or in the 
dialysis unit). On dialysis days, the worksheets will be completed prior to or during dialysis, but must be completed prior to dosing. 
14 
During the follow-up period, Worst Itching Intensity NRS worksheets will be completed on dialysis days only. 
15 
5-D itch scale and Skindex-10 scale will be completed on Day 1 and the first visit of Week 5 (Day 29), Week 9 (Day 57) and Week 13 (Day 85). 5-D itch scale will preferably be completed first. If the first 
visit of the week is missed, the subject may complete the worksheets at their next visit for the same week. The worksheets will be completed prior to or during dialysis (preferably within 1 hour of the 
dialysis) but must be completed prior to dosing. 
16 
Concomitant medications including antipruritic medication will be updated at each dialysis visit during the double-blind period, and until the end of the follow-up period. 
17 
A list of specific signs/symptoms will be verified with the subject by qualified site staff, preferably to be completed on Wednesday/Thursday each week during the run-in period, the double-blind period, and 
the discontinuation period. Not to be completed on Monday/Tuesday (see Section 10.8.4.1 for a list of the AESIs). 
Notes: AESI=Adverse event of special interest; ALT=Alanine aminotransferase; AST=Aspartate aminotransferase; BUN=Blood urea nitrogen; ECG=Electrocardiogram; eCRF=Electronic Case Report Form; 
EoT=End of treatment; F=Friday; IV=Intravenous; M=Monday; MCH=Mean corpuscular haemoglobin; MCHC=Mean corpuscular haemoglobin concentration; MCV=Mean corpuscular volume; 
NRS=Numerical Rating Scale; PRO=Patient reported outcome; RDW=Red blood cell distribution width; S=Saturday; SGOT=Serum glutamic-oxaloacetic transaminase; SGPT=Serum glutamic-pyruvic 
transaminase, Th=Thursday; Tu=Tuesday; W=Wednesday. 
 

 
 
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Table 2 
Schedule of Events and Assessments for the Open-label Extension Period 
Study Procedures 
 
 
Open-label 
Treatment 
Period(1) 
 
 
EoT/ 
Early 
Termination 
Follow-Up 
Day 1(2) Week 2(1) Week 4(1) Week 6(1) Week 8(1) Week 10(1) Week 12(1) 
First 
Dialysis of 
Week 15(3) 
7 to 10 Days 
After EoT/ 
Early 
Termination(4) 
Inclusion/exclusion criteria 
X(5) 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Prescription dry body weight(6) 
X 
 
 
 
 
 
X 
 
 
Pre-dialysis 12-lead electrocardiogram(7) 
 
 
 
 
 
 
 
X 
 
Pre-dialysis vital signs(8) 
X 
 
X 
 
X 
 
X 
X 
X 
Haematology, serum chemistry (pre-dialysis) 
 
 
 
 
 
 
 
X 
 
Serum potassium (pre-dialysis) 
 
X 
X 
X 
X 
X 
X 
 
 
Serum pregnancy test for women of childbearing 
potential only 
 
 
 
 
 
 
 
X 
 
5-D itch scale, Skindex-10 scale(9) 
 
 
X 
 
X 
 
X 
X 
 
IV administration of investigational product  
After each dialysis, up to Week 14 included 
 
Adverse event monitoring 
Record on an ongoing basis(10) 
Concomitant medications (including antipruritic 
medications) 
Record on an ongoing basis(10) 
1 
Each visit during the open-label treatment period will coincide with the subject’s normal dialysis treatments. The study visit may occur on any chosen dialysis day of a scheduled week if all assessments are 
completed during that visit. 
2 
Day 1 of the open-label treatment period corresponds to the day of the last visit of the double-blind period or up to 1 week following the double-blind period. 
3 
The end-of-treatment visit will be the first dialysis visit following the last dose of investigational product (i.e., first dialysis on Week 15). 
4 
The follow-up visit will coincide with a dialysis day. 
5 
Prior to dosing on Day 1 of the open-label treatment period, the inclusion/exclusion criteria will be confirmed.  
6 
The prescription dry body weight will be captured from the dialysis prescription and will be recorded on Day 1 and at Week 12. If there is a >10% change in prescription dry body weight compared to the 
last value, then the difelikefalin dose will be adjusted.  
7 
Electrocardiogram must be performed prior to the start of dialysis. 

 
 
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8 
Vital signs, including body temperature, heart rate, and blood pressure, will be obtained at the specified visits while the subject is in a sitting or semi-recumbent position prior to the start of dialysis. Heart 
rate will be measured at each dialysis; if the heart rate is clinically significant at visits outside the pre-specified visits per Schedule of Events, the heart rate will be recorded in the eCRF. 
9 
To be completed before or during dialysis (preferably within 1 hour of the dialysis but before dosing). 5-D itch scale will preferably be completed first. 
10 
Adverse events and concomitant medications will be recorded starting on Day 1 of the open-label treatment period. 
Notes: eCRF=Electronic Case Report Form; EoT=End of treatment; IV=Intravenous. 

 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..........................................................................................................2 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE .....................................4 
SYNOPSIS ..........................................................................................................................5 
TABLE OF CONTENTS ................................................................................................24 
LIST OF TABLES ...........................................................................................................29 
LIST OF FIGURES .........................................................................................................30 
LIST OF APPENDICES .................................................................................................31 
LIST OF ABBREVIATIONS .........................................................................................32 
1. 
INTRODUCTION AND BACKGROUND ............................................................34 
1.1 
Background of the Disease and Treatment Options ..............................................34 
1.2 
Summary of Nonclinical and Clinical Data ...........................................................35 
1.2.1 
Summary of Nonclinical Data ............................................................................35 
1.2.2 
Summary of Clinical Data ..................................................................................36 
1.2.2.1 
Pharmacokinetics .............................................................................................36 
1.2.2.2 
Safety of IV Difelikefalin ................................................................................37 
1.2.2.3 
Efficacy of IV Difelikefalin .............................................................................38 
2. 
RATIONALE ...........................................................................................................40 
2.1 
Patient Need ...........................................................................................................40 
2.2 
Study Design ..........................................................................................................40 
2.3 
Dose Selection .......................................................................................................41 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................42 
3.1 
Primary Objective ..................................................................................................42 
3.2 
Secondary Objectives.............................................................................................42 
3.3 
Primary Efficacy Endpoint ....................................................................................42 
3.4 
Secondary Efficacy Endpoints ...............................................................................42 
3.5 
Safety Endpoints ....................................................................................................43 
4. 
INVESTIGATIONAL PLAN .................................................................................44 
4.1 
Overall Study Design .............................................................................................44 
4.2 
Duration of Subject Participation and Study .........................................................45 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................46 
5.1 
Number of Subjects................................................................................................46 
5.1.1 
Double-blind Period ............................................................................................46 
5.1.2 
Open-label Extension Period ..............................................................................46 
5.2 
Inclusion Criteria ...................................................................................................46 
5.3 
Exclusion Criteria ..................................................................................................48 
5.4 
Withdrawal of Subjects ..........................................................................................49 

 
 
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5.4.1 
Withdrawal of Subjects from the Study ..............................................................49 
5.5 
Rescreening of Subjects .........................................................................................50 
6. 
STUDY TREATMENTS .........................................................................................51 
6.1 
Treatment Blinding ................................................................................................51 
6.1.1 
Treatment Unblinding .........................................................................................51 
6.2 
Dosage Forms/Formulation ...................................................................................52 
6.2.1 
Difelikefalin (IV Formulation) ...........................................................................52 
6.2.2 
Placebo ................................................................................................................52 
6.3 
Investigational Product Dosage and Administration .............................................53 
6.4 
Package and Labelling ...........................................................................................54 
6.5 
Study Treatment Allocation ...................................................................................54 
6.6 
Site Supply, Storage, Accountability .....................................................................54 
6.6.1 
Site Supply ..........................................................................................................54 
6.6.2 
Storage ................................................................................................................54 
6.6.3 
Accountability .....................................................................................................54 
6.7 
Drug Dose Modification ........................................................................................55 
6.7.1 
Procedures for Overdose .....................................................................................55 
6.8 
Prohibited Therapy and Concomitant Treatment ...................................................55 
6.8.1 
Concomitant Treatments .....................................................................................56 
6.8.1.1 
Prohibited Concomitant Treatments ................................................................56 
6.8.1.2 
Conditionally Permitted Concomitant Treatments ..........................................56 
6.8.1.3 
Prohibited Concomitant Therapy .....................................................................57 
6.8.2 
HD Conditions ....................................................................................................57 
7. 
RISKS/PRECAUTIONS .........................................................................................58 
7.1 
Risks .......................................................................................................................58 
7.2 
Precautions .............................................................................................................58 
7.2.1 
Drug Interactions ................................................................................................59 
7.2.2 
Drug Abuse and Dependency .............................................................................59 
7.2.3 
Women of Childbearing Potential ......................................................................59 
7.2.4 
Pregnancy and Lactation .....................................................................................59 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................60 
8.1 
Allowed Adaptations in Case of Extraordinary Events, e.g., COVID-19 .............60 
8.2 
Screening Visit (Day -28 to Day -7) ......................................................................61 
8.3 
Run-in Period (Day -7 to Day -1) ..........................................................................62 
8.4 
Double-blind Period ...............................................................................................62 
8.4.1 
Week 1/Day 1 .....................................................................................................63 
8.4.2 
Week 1/Day 3 .....................................................................................................64 
8.4.3 
Week 1/Day 5 .....................................................................................................64 
8.4.4 
Week 2 to Week 12 .............................................................................................65 
8.5 
Double-blind Period End of Treatment/Early Termination/Day 85 ......................65 
8.6 
Follow-up Period (ONLY for Subjects not Participating in the Open-label 
Extension Phase)/Day 85 to Day 95 ......................................................................67 

 
 
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8.7 
Open-label Extension Period .................................................................................67 
8.7.1 
Day 1/Open-label Extension ...............................................................................67 
8.7.2 
Week 2/Open-label Extension ............................................................................68 
8.7.3 
Week 4/Open-label Extension ............................................................................68 
8.7.4 
Week 6/Open-label Extension ............................................................................69 
8.7.5 
Week 8/Open-label Extension ............................................................................69 
8.7.6 
Week 10/Open-label Extension ..........................................................................69 
8.7.7 
Week 12/Open-label Extension ..........................................................................70 
8.7.8 
First Dialysis of Week 15/Open-label Extension End of Treatment/Early 
Termination .........................................................................................................70 
8.7.9 
Follow-up for Subjects Participating in the Open-label Period ..........................71 
9. 
STUDY ASSESSMENTS ........................................................................................72 
9.1 
Demographics and Medical/Surgical History ........................................................72 
9.2 
Physical Examination and Vital Signs ...................................................................72 
9.3 
12-lead ECG...........................................................................................................72 
9.4 
Clinical Laboratory Tests .......................................................................................73 
9.5 
Adverse Events ......................................................................................................73 
9.6 
Prior, Concomitant, and Prohibited Medications ...................................................74 
9.7 
PRO Measures .......................................................................................................74 
9.7.1 
WI-NRS ..............................................................................................................75 
9.7.2 
Skindex-10 Scale ................................................................................................75 
9.7.3 
5-D Itch Scale .....................................................................................................75 
9.7.4 
Patient Global Impression of Change .................................................................75 
10. EVALUATION, RECORDING, AND REPORTING OF AES ..........................76 
10.1 
Definition of AEs ...................................................................................................76 
10.2 
AE Reporting Period ..............................................................................................76 
10.3 
Eliciting AEs ..........................................................................................................76 
10.4 
Assessing AEs ........................................................................................................76 
10.4.1 
Intensity/Severity ................................................................................................76 
10.4.2 
Causality and Reporting......................................................................................77 
10.4.3 
Outcome Categorisation .....................................................................................78 
10.5 
Recording and Reporting .......................................................................................78 
10.5.1 
Persistent or Recurrent AEs ................................................................................78 
10.5.2 
Diagnosis Versus Signs and Symptoms .............................................................79 
10.5.3 
Pre-existing Medical Conditions ........................................................................79 
10.5.4 
Clinical Laboratory Evaluations .........................................................................79 
10.5.5 
Worsening of the Disease Under Study ..............................................................80 
10.5.6 
Abnormal Vital Signs and Other Abnormalities.................................................80 
10.6 
ADR and Reference Safety Information ................................................................81 
10.6.1 
Adverse Drug Reaction .......................................................................................81 
10.6.2 
Reference Safety Information .............................................................................81 
10.7 
Serious Adverse Event ...........................................................................................81 
10.7.1 
Definition of SAE ...............................................................................................81 

 
 
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10.7.1.1 
Situations that are Not Considered SAEs ........................................................82 
10.7.2 
SAE Reporting ....................................................................................................83 
10.7.3 
Suspected Unexpected Serious Adverse Reaction..............................................83 
10.7.3.1 
SAE Expedited Reporting ................................................................................83 
10.8 
Special Situations ...................................................................................................84 
10.8.1 
Definition of Special Situations ..........................................................................84 
10.8.2 
Special Situation Recording and Reporting ........................................................84 
10.8.3 
Pregnancy Exposure and Birth Events................................................................84 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events .......................................84 
10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting ...................85 
10.8.4 
Adverse Events of Special Interest .....................................................................86 
10.8.4.1 
Definition of AESIs .........................................................................................86 
10.8.4.2 
AESI Reporting and Recording .......................................................................86 
11. DATA AND SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE PROCEDURES .............................................................................87 
12. STATISTICAL ANALYSIS ...................................................................................88 
12.1 
Statistical Methods .................................................................................................88 
12.2 
Sample Size and Power Calculations .....................................................................88 
12.3 
Randomisation .......................................................................................................89 
12.4 
Analysis Populations ..............................................................................................89 
12.4.1 
Double-blind Safety Analysis Set .......................................................................89 
12.4.2 
Full Analysis Set .................................................................................................89 
12.4.3 
Per-Protocol Set ..................................................................................................90 
12.4.4 
Open-label Safety Analysis Set ..........................................................................90 
12.5 
Background and Demographic Characteristics ......................................................90 
12.6 
Exposure to Investigational Product ......................................................................91 
12.7 
Concomitant Therapy.............................................................................................91 
12.8 
Efficacy Evaluations ..............................................................................................92 
12.8.1 
Primary Efficacy Evaluations .............................................................................92 
12.8.2 
Secondary Efficacy Evaluations .........................................................................94 
12.9 
Safety Evaluations .................................................................................................96 
12.9.1 
Adverse Events ...................................................................................................96 
12.9.2 
Special Situations ................................................................................................98 
12.9.3 
Vital Signs...........................................................................................................98 
12.9.4 
12-lead ECG .......................................................................................................98 
12.9.5 
Physical Examination .........................................................................................98 
12.9.6 
Clinical Laboratory Tests....................................................................................98 
12.10 Interim Analyses ....................................................................................................99 
12.11 Handling of Missing Data ......................................................................................99 
13. STUDY ETHICAL CONSIDERATIONS ...........................................................100 
13.1 
Ethical Conduct of the Study ...............................................................................100 
13.2 
Informed Consent.................................................................................................100 
13.3 
Independent Ethics Committee ............................................................................100 

 
 
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13.4 
Insurance ..............................................................................................................100 
14. QUALITY CONTROL AND QUALITY ASSURANCE ...................................102 
14.1 
Quality Management: Critical Processes and Data ..............................................102 
15. REPORTING AND RECORDING OF DATA ...................................................104 
15.1.1 
Source Documentation ......................................................................................104 
15.1.2 
Records Retention .............................................................................................104 
15.1.3 
Site Documentation...........................................................................................105 
16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .....................................................................106 
16.1 
Protocol Deviations ..............................................................................................106 
16.2 
Protocol Amendments ..........................................................................................106 
16.3 
Study Termination ...............................................................................................106 
17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ..............107 
18. REFERENCES .......................................................................................................108 
 

 
 
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LIST OF TABLES 
Page 
Table 1 
Schedule of Events and Assessments for the Double-blind Period ...........19 
Table 2 
Schedule of Events and Assessments for the Open-label Extension 
Period .........................................................................................................22 
Table 3 
Total Dose Volumes per Weight Range ....................................................53 
 

 
 
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LIST OF FIGURES 
Page 
Figure 1 
Study Design ..............................................................................................18 
 

 
 
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LIST OF APPENDICES 
Page 
Appendix 1 
Worst Itching Intensity-Numerical Rating Scale .....................................110 
Appendix 2 
New York Heart Association Classification of Heart Failure .................111 
Appendix 3 
Skindex-10 Scale .....................................................................................112 
Appendix 4 
5-D Itch Scale ..........................................................................................113 
Appendix 5 
Patient Global Impression of Change ......................................................115 

 
 
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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 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-aP 
chronic kidney disease-associated pruritus 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRO 
Contract Research Organisation 
DB-SAF 
double-blind safety analysis set 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
electronic data capture 
ESRD 
end-stage renal disease 
EU 
European Union 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
Hb 
haemoglobin 
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 

 
 
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MAR 
missing at random 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-effect model for repeated measures 
NRS 
Numerical Rating Scale 
OL-SAF 
open-label safety analysis set 
PK 
pharmacokinetic 
PPS 
per-protocol set 
PRO 
patient reported outcome 
PT 
preferred term 
QoL 
quality of life 
RBCs 
red blood cells 
RDW 
red blood cell distribution width 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
US 
United States 
WBCs 
white blood cells 
WI-NRS 
Worst Itching Intensity Numerical Rating Scale 

 
 
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1. INTRODUCTION AND BACKGROUND 
Difelikefalin is a novel, selective 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 CKD patients undergoing HD [1]. 
However, there are currently no approved treatments for CKD-aP in 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. Difelikefalin has been approved 
for marketing in the US on 23 August 2021 and it is expected to be approved in the EU in 
May 2022. 
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 QoL 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, or 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; 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]. 
This creates the need to develop new treatments that are more convenient for use and cause 
fewer ADRs. 

 
 
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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. 
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. 
• 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. 

 
 
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• 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 pharmacokinetics (PK) in systemic exposure were 
observed following single IV or oral doses, with t½ ranging from 1.1-5.5 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 3 clinical trial of difelikefalin in HD Chinese subjects with 
moderate-to-severe pruritus. 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 4,037 subjects; 2,672 subjects have received IV 
formulation, and 1,365 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 the product in patients with CKD-aP 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. 
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. 

 
 
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Following single-dose IV administration of (14C)-difelikefalin to healthy volunteers or 
subjects on HD, >99% of circulating plasma radioactivity remained as unchanged 
difelikefalin. 
In both healthy volunteers and subjects on HD, 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. 
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, 

 
 
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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-P1-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 CKD-aP 
subjects on HD receiving difelikefalin), 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 CKD-aP 
subjects on HD receiving difelikefalin), 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 QoL 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). 
• 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. 

 
 
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• 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 NRS 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 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 QoL 
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 QoL were also observed in 
this global study. 
• 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 QoL 
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 HD subjects with CKD-aP. Study KOR-CHINA-301 will be the first clinical trial 
of IV difelikefalin for the treatment of subjects with CKD-aP on HD to be conducted in 
China.  
Clinical data outside of China have shown the benefits of difelikefalin in CKD-aP 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. 
Treatment with difelikefalin is also expected to relieve pruritus in HD patients in the present 
study. 
2.2 
Study Design 
This study is designed to evaluate efficacy and safety of 0.5 µg/kg IV difelikefalin in 
Chinese subjects with CKD on HD (3 times weekly) and with moderate-to-severe 
associated pruritus. A dialysis frequency of 3 times a week (versus twice weekly), is 
prevalent for the dialysis practice in China [14]. 
IV administration of difelikefalin will occur at the end of HD by using the return HD line 
or via injection directly into a vein. 
This study design (dose, investigational product administration, duration of treatment) is 
based on Phase 2 and Phase 3 clinical trials with difelikefalin in subjects with CKD-aP on 
HD conducted by Cara Therapeutics, Inc. previously outside of China (including clinical 
trials conducted in Japan by licensees of Cara Therapeutics, Inc.). 
This study consists of a double-blind, randomised, placebo-controlled, parallel group 
treatment period, and an optional open-label extension period.  
During the double-blind period, subjects will be administered investigational product 
(difelikefalin or placebo) at the end of each dialysis session for 12 weeks (3 times weekly, 
36 times in total). The duration of the double-blind period is enough for the evaluation of 
the efficacy and safety in comparison with placebo. In a Phase 2 study in Japan 
(MR13A9-4), the difference between difelikefalin (0.5 µg/kg) and placebo in reducing 
NRS score increased until Week 3 and remained about constant at later time points (until 
Week 8). Based on these results, in an ongoing Phase 3 study in Japan, the primary efficacy 

 
 
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endpoint will be evaluated at Week 4; the same approach is used in this study. Twelve-week 
double-blind treatment is also considered enough for the assessment of difelikefalin safety 
in comparison with placebo, as adverse reactions occur early during difelikefalin treatment.  
At the end of the double-blind period, subjects will have the option to enter an open-label 
extension period, during which, difelikefalin will be administered at the end of each dialysis 
session for 14 weeks (3 times weekly, 42 times in total). Thus, all subjects completing the 
double-blind period will be given the chance to receive the active treatment during the 
open-label phase. The inclusion of 14 weeks open-label treatment will increase the total 
duration of exposure to 26 weeks (for subjects receiving difelikefalin during the 
double-blind and open-label phases) and will also increase the safety population, allowing 
for collection of more safety data. After last administration of investigational product (end 
of double-blind period or end of open-label extension period or early discontinuation), 
subjects will enter a 1-week follow-up period (1 week to 10 days). 
This study design (dose, investigational product administration, duration of treatment) is 
based on Phase 2 and Phase 3 clinical trials with difelikefalin in subjects with CKD-aP on 
HD conducted by Cara Therapeutics, Inc. previously outside of China (including clinical 
trials conducted in Japan by licensees of Cara Therapeutics, Inc.).  
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 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 reducing itch in HD subjects with CKD-aP 
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 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 efficacy of difelikefalin 0.5 µg/kg compared to placebo in reducing the 
intensity of itch in HD Chinese subjects with moderate-to-severe pruritus. 
3.2 
Secondary Objectives 
• To evaluate the efficacy of difelikefalin 0.5 µg/kg compared to placebo in improving 
the itch-related QoL in HD Chinese subjects with moderate-to-severe pruritus. 
• To evaluate the safety of difelikefalin 0.5 µg/kg in HD Chinese subjects with 
moderate-to-severe pruritus. 
3.3 
Primary Efficacy Endpoint 
• Change from baseline in the weekly mean of the daily 24-hour WI-NRS score at 
Week 4 of the double-blind period*. 
*The degree of the most intense itching within a day will be assessed using NRS scores. 
3.4 
Secondary Efficacy Endpoints 
• Proportion of subjects achieving ≥3-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour WI-NRS at Week 4 of the double-blind period. 
• Proportion of subjects achieving ≥3-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour WI-NRS at Week 8 of the double-blind period. 
• Proportion of subjects achieving ≥3-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour WI-NRS at Week 12 of the double-blind period. 
• Proportion of subjects achieving ≥4-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour WI-NRS at Week 4 of the double-blind period. 
• Proportion of subjects achieving ≥4-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour WI-NRS at Week 8 of the double-blind period. 
• Proportion of subjects achieving ≥4-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour WI-NRS at Week 12 of the double-blind period. 
• Change from baseline in itch-related QoL at the end of Week 12 of the double-blind 
period, as assessed by the 5-D itch scale total score. 
• Change from baseline in itch-related QoL at the end of Week 12 of the double-blind 
period, as assessed by the Skindex-10 scale total score. 

 
 
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• Change from baseline in the weekly mean of the 24-hour WI-NRS score at each week 
of the double-blind period. 
• Change from baseline in itch-related QoL at each time point of the double-blind period 
and open-label extension phase, as assessed by the 5-D itch scale total score. 
• Change from baseline in itch-related QoL at each time point of the double-blind period 
and open-label extension phase, as assessed by the Skindex-10 scale total score. 
• Patient Global Impression of Change. 
3.5 
Safety Endpoints 
Overall safety and tolerability of difelikefalin as assessed by incidence of AEs, 12-lead 
ECG vital signs, 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 3, multicentre, controlled, randomised study to evaluate the efficacy and 
safety of difelikefalin 0.5 µg/kg compared to placebo in reducing the intensity of itch in 
adult Chinese HD subjects with moderate-to-severe pruritus (Figure 1). 
The study includes a 12-week double-blind placebo-controlled treatment period and a 
14-week optional open-label extension period. A 4-week period (including a 7-day run-in 
period during the week prior to randomisation) before entry into the double-blind period is 
defined as the screening period, during which subjects will receive no investigational 
product.  
Subjects eligible for randomisation in the double-blind part of the study will be randomised 
1:1 to either difelikefalin or placebo treatment groups and will receive a randomisation 
number. Subjects will be stratified according to their use or non-use of concomitant 
medications to treat their itch during the week prior to randomisation (run-in period) as 
well as the presence or absence of specific medical conditions. These specific medical 
conditions include: 
• History of fall or fracture (related to fall) 
• Confusional state or mental status change or altered mental status or disorientation  
• Gait disturbance or movement disorder 
Randomised subjects who terminate their study participation for any reason regardless of 
whether the investigational product was administered or not, will retain their randomisation 
number. The next subject will be given the next randomisation number.  
During the double-blind period, the investigational product will be injected into the venous 
line of the dialysis circuit at the end of each dialysis session for 12 weeks (3 times weekly, 
36 times in total). The dose of the investigational product will be determined based on the 
subject’s prescription dry body weight (i.e., the target post-dialysis weight, as determined 
by the patient’s nephrologist or dialysis unit) at the start day of the double-blind treatment 
period. The first dose of investigational product will be administered on Day 1, which will 
occur preferably on the first dialysis session of the first treatment week (i.e., Monday for 
subjects on a Monday-Wednesday-Friday dialysis schedule, or Tuesday for subjects on a 
Tuesday-Thursday-Saturday dialysis schedule).  
During the open-label extension period, difelikefalin will be administered for 14 weeks 
(3 times weekly), starting at Week 13, and will be given until Week 26 inclusive. The first 
visit and first dosing for the open-label extension phase of the study will occur immediately 
on the day of the last visit of the double-blind period or up to 1 week after the end of the 
double-blind period. The participation in the open-label extension period is optional. 

 
 
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The study also includes a 1-week (1 week to 10 days) follow-up period after last 
administration of investigational product (end of double-blind period or end of open-label 
extension period or early discontinuation). 
Throughout the study, subjects will continuously use any conditionally permitted 
concomitant medications (e.g., to treat symptoms of chronic renal failure or other 
comorbidities) used at the start of the screening period. Please refer to Section 6.8 for details 
on concomitant treatments and therapies. 
The schedule of assessments is provided in Table 1. 
4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is 31 to 32 weeks: screening period duration 
is 4 weeks (including a 7-day run-in period); treatment period duration is 12 weeks; 
open-label extension period (optional) is 14 weeks (starting within 1 week after the end of 
double-blind period), and follow-up period is 1 week (1 week to 10 days). For subjects not 
participating in the open-label extension period, the total study duration is 17 weeks. 
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 
5.1.1 
Double-blind Period 
Based on the results observed at the end of Week 4 in a Japanese Phase 2 clinical study 
(MR13A9-4) and in the pooled data of 2 Phase 3 clinical studies (CLIN3102 and 
CLIN3103), a mean difference of −0.9 with a common SD of 2.1 is assumed between 
difelikefalin and placebo group regarding the primary endpoint. Assuming a 2-sided 
significance level of 5% and a statistical power of 90%, 116 subjects per group will be 
required to detect a difference of -0.9, with a common SD of 2.1, between the difelikefalin 
and the placebo group using a 2-sample t-test. In addition, assuming a 10% drop out rate, 
258 subjects in total need to be enrolled in the double-blind study period, i.e., 129 subjects 
per group. 
5.1.2 
Open-label Extension Period 
All subjects who completed the double-blind period may continue into the 14-week 
open-label extension period provided they meet the eligibility criteria on Day 1 of the open-
label extension period. 
5.2 
Inclusion Criteria 
Double-blind Period 
The double-blind period of this study will enrol HD subjects with pruritus who meet all the 
inclusion criteria and none of the exclusion criteria listed below. 
1. Subject (or legally accepted representative) has provided written informed consent. 
Written informed consent must be provided before any study-specific procedures are 
performed including screening procedures. 
2. Chinese subjects aged ≥18 to 85 years (inclusive) at the time of consent. 
3. Able to communicate clearly with the Investigator and staff, able to understand the 
study procedures, and able and willing to comply with the study requirements, 
including providing written responses to questionnaires. 
4. Subjects with CKD on HD 3 times weekly for ≥12 weeks prior to the informed consent 
procedure (including the date of informed consent) who can continue HD without 
changing its frequency or method.  
Note 1: Any temporary change in dialysis frequency or method associated with travel 
or admission to other hospitals with no changes in treatment strategies is acceptable, 
from the date of informed consent until the end of the follow-up period. Subjects 
routinely on 4 dialyses a week will not be eligible. 

 
 
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Note 2: Subjects receiving in-home HD may participate as long as they have switched 
to in-centre HD at least 2 weeks prior to screening and plan to remain on in-centre HD 
for the duration of the study. 
Note 3: Subjects receiving alternate dialysis modalities such as nocturnal dialysis will 
not be eligible. 
5. If female, is not pregnant, or nursing.  
6. 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 acceptable contraceptive measures (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. 
7. If male, agrees not to donate sperm after the first dose of investigational product 
administration until 7 days after the last dose of investigational product, 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. 
8. Subjects whose NRS score (Appendix 1) in the 7-days run-in period (7 days including 
the score recorded on the start day of treatment) meets both of the below: 
a. NRS scores have been recorded for at least 4 days through a 7-day run-in period. 
b. The mean value of the recorded scores is ≥5.0 (moderate-to-severe pruritus). 
9. Subjects with a prescription dry body weight between 40 and 100 kg, inclusive. 
10. Over the last 3 months prior to screening, has had at least 1 of the following: 
a. At least 2 single-pool Kt/V measurements ≥1.2 on different dialysis days 
b. At least 2 urea reduction ratio measurements ≥65% on different dialysis days 

 
 
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c. 1 single-pool Kt/V measurement ≥1.2 and 1 urea reduction ratio measurement 
≥65% on different dialysis days 
Open-label Extension Period 
Subjects meeting all of the following inclusion criteria at the end of Week 12 of the 
double-blind period will enter the extension period. Subjects not meeting these inclusion 
criteria will be withdrawn from the study and undergo the follow-up assessments. 
11. Subjects not withdrawn during the double-blind period. 
12. Subjects receiving at least 30 doses of the planned 36 doses of investigational product 
during the double-blind period. 
13. Has a prescription dry body weight ≥40 kg. 
14. Continues to meet inclusion criteria 1 through 7. 
15. Subjects do not have any safety or other reasons, which in the opinion of the 
Investigator, should exclude them from entering the open-label extension period. 
5.3 
Exclusion Criteria 
1. Known noncompliance with dialysis treatment that in the opinion of the Investigator 
would impede completion or validity of the study. 
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. Subjects with itching caused by conditions other than chronic renal failure or 
complications of chronic renal failure, which could affect the efficacy evaluation in the 
opinion of the Investigator (e.g., atopic dermatitis, chronic urticaria). Note: Subjects 
whose pruritus is attributed to ESRD complications, such as hyperparathyroidism, 
hyperphosphataemia, anaemia, or the dialysis procedure, or prescription may be 
enrolled. 
4. Has localised itch restricted to the palms of the hands. 
5. Has pruritus only during the dialysis session (by subject report). 
6. Subjects with severe hepatic impairment (Child-Pugh Class C) or concurrent hepatic 
cirrhosis. 
7. Subject is receiving ongoing ultraviolet B treatment and anticipates receiving such 
treatment during the study. 
8. Subjects who previously were enrolled in any clinical study of difelikefalin and 
received at least 1 dose of difelikefalin. 

 
 
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9. Significant systolic or diastolic heart failure (e.g., New York Heart Association 
Class IV congestive heart failure) (Appendix 2). 
10. Subjects with concurrent malignancy except excised basal cell or squamous cell 
carcinoma of the skin, or carcinoma in situ that has been excised or resected completely. 
11. Known or suspected history of alcohol, narcotic, or other drug abuse, or substance 
dependence within 12 months prior to screening. 
12. Severe mental illness or cognitive impairment (e.g., dementia) or other concurrent 
mental disorder that, in the opinion of the Investigator, would compromise the validity 
of study measurements.  
13. Any other relevant acute or chronic medical or neuropsychiatric condition within 
3 months prior to screening (e.g., diagnosis of encephalopathy, coma, delirium). 
14. New or change of treatment received for itch including antihistamines and 
corticosteroids (oral, IV, or topical) within 14 days prior to screening. 
15. New or change of prescription for opioids, gabapentin, or pregabalin within 14 days 
prior to screening. 
16. Subject is receiving prohibited medication (e.g., nalfurafine hydrochloride, opioid 
antagonists) 
17. Subjects who received treatment with any investigational product or study device in a 
clinical study (including clinical studies of medical devices or cellular and tissue-based 
products) within 30 days prior to the informed consent procedure, or who are planning 
to participate in another clinical study before the end of the follow-up period of 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 
condition requiring care or medications prohibited by the protocol, unacceptable AEs, 
refusal to continue treatment, major noncompliance 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. 

 
 
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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”. 
5.5 
Rescreening of Subjects 
A subject can only be randomised once in the trial. Randomised 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.  
• Rescreening will be considered on an individual subject basis and must be first 
approved by the Sponsor or designee. However, rescreening will not be permitted if a 
subject missed the entry criteria for itch intensity, i.e., the weekly mean of the daily 
24-hour WI-NRS score <5. A subject can only be rescreened once. Rescreening can 
only occur after at least 2 weeks from screening. 

 
 
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6. STUDY TREATMENTS 
6.1 
Treatment Blinding 
During the double-blind period, study participants, Investigators, site study staff, and the 
Sponsor/Contract Research Organisation (CRO) will be blinded to investigational product 
assignment. Treatment randomisation information will be kept confidential by an unblinded 
biostatistician until the study database has been locked. 
Clinical trial supply management staff will have access to overall difelikefalin/placebo 
usage at a site level for oversight of investigational product stock levels. 
If the Investigator or site study staff become aware of a subject’s investigational product 
assignment, efforts should be made to not disclose treatment assignments to other study 
site staff, subjects, or their caregivers. 
During the double-blind period, the blind will only be broken under the conditions specified 
in Section 6.1.1. 
6.1.1 
Treatment Unblinding 
During the double-blind period, the study blind will be broken for an individual subject 
only in the following situations: 
• For medically urgent or emergent situations that necessitate knowledge of 
investigational product assignment for subject management. 
• When reporting of the treatment arm to the Health Authorities is required, e.g., for 
reporting a suspected unexpected serious adverse reaction (SUSAR) (see 
Section 10.7.3). 
• If a subject becomes pregnant during the study, the knowledge of the treatment arm is 
therefore necessary (see Section 10.8.3). 
Except for when subject’s care requires the treatment assignment immediately, the 
Investigator must submit a written report, including all pertinent details, to the Medical 
Monitor within 24 hours of the unblinding. The Sponsor and Medical Monitor will receive 
a report whenever a subject blind is broken. 
If breaking of the blind is required, the unblinded information should be, wherever possible, 
accessible only to those of site study staff who need to be involved in the diagnostic 
workup, treatment, or medical follow-up of the subject (e.g., in case of a medical 
emergency or a pregnancy), or in the safety reporting to external regulatory bodies (e.g., in 
case of a SUSAR or a pregnancy). 
Unblinding must always be performed according to the procedures that are specified in the 
applicable Standard Operating Procedures effective for this study. 

 
 
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6.2 
Dosage Forms/Formulation 
All investigational products used in this study have been manufactured in accordance with 
current Good Manufacturing Practice and will be provided by the Sponsor. 
6.2.1 
Difelikefalin (IV Formulation) 
Difelikefalin (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. 
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 store above 30°C. Do not freeze. 
6.2.2 
Placebo 
Placebo will be provided in 2 R glass vials. 
Content: 
Acetic acid, sodium acetate trihydrate, sodium chloride, and water 
for injection 
Appearance: 
Clear, colourless solution 
Dosage Form: 
Injection 
Manufacturers: 
Siegfried Hameln GmbH or Patheon Manufacturing Services LLC 
Storage: 
Do not store above 30°C. Do not freeze. 

 
 
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6.3 
Investigational Product Dosage and Administration 
The investigational product will be dispensed by qualified site study staff who have 
received training on handling and administration of investigational product.  
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. 
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.  
Investigational product will be administered by IV bolus injection within 15 minutes 
following the end of the dialysis on the scheduled investigational product administration 
day. Investigational product may be given either during or after rinse back of the dialysis 
circuit. Administration of investigational product 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. 
If any dialysis circuit trouble precludes injection through the dialysis circuit, the 
investigational product will be administered directly intravenously. If in exceptional cases 
an extra fourth dialysis session is required within the week, the investigational product will 

 
 
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be administered (up to 4 times weekly); if only the extracorporeal ultrafiltration method is 
used at this fourth dialysis session, the investigational product will not be administered. 
Additional details on dose preparation and administration will be provided in the Pharmacy 
Manual.  
6.4 
Package and Labelling 
Investigational product will be packaged and labelled in accordance with local regulations 
for investigational products.  
6.5 
Study Treatment Allocation 
After obtaining informed consent, subjects will be screened according to the inclusion and 
exclusion criteria. The subjects will receive a screening number, as allocated by the 
electronic data capture (EDC) system. Eligible subjects will be randomised into the double-
blind period in a 1:1 ratio to receive either difelikefalin or placebo (see Section 12.3), i.e., 
a randomisation number will be allocated via a validated centralised procedure (IWRS). 
For the open-label extension period, all eligible subjects who agree to participate to the 
open-label extension period will receive open-label difelikefalin. 
6.6 
Site Supply, Storage, Accountability 
6.6.1 
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. 
6.6.2 
Storage 
All investigational products must not be stored above 30ºC and must not be frozen. 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. 
6.6.3 
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 

 
 
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(including kit and/or 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. 
6.7 
Drug Dose Modification 
Dose modifications are not allowed in this study. 
6.7.1 
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). 
6.8 
Prohibited Therapy and 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. 
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. 

 
 
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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 vaccine is unlikely. 
6.8.1 
Concomitant Treatments 
Subjects may continuously use any medication used to treat symptoms of chronic renal 
failure or other comorbidities at the start of the screening period without changing its 
dosage and administration regimen whenever possible until the end of the follow-up period. 
The dosage and administration of any concomitant medication may be changed for safety 
reasons including AEs. Any centrally acting concomitant drug should be used with caution 
due to possible central AEs that might confound the safety profile of difelikefalin. 
6.8.1.1 
Prohibited Concomitant Treatments 
Between the start of the screening period and the end of the follow-up period, use of the 
following drugs will be prohibited: 
• Other KOR agonists, e.g., nalfurafine hydrochloride 
• Opioid antagonists: naloxone hydrochloride, eptazocine hydrobromide, naldemedine 
tosylate, etc., or mixed agonists-antagonists (e.g., buprenorphine and nalbuphine) 
• Investigational products other than the investigational products described in this 
protocol. 
6.8.1.2 
Conditionally Permitted Concomitant Treatments 
Between the start of the screening period and the end of the follow-up period, subjects may 
use the drugs listed below that have been used before the screening period without changing 
their dosage and administration. However, treatment with these drugs should not be 
initiated during the same time window defined above. 
1. Drugs indicated for the treatment of itching (prescription/non-prescription) except 
prohibited concomitant medications 
2. Drugs to treat itching including traditional Chinese medications (prescription/non-
prescription) except prohibited concomitant medications 
3. Moisturising drugs (prescription/non-prescription) 
4. Steroids 
Note: Local steroids, such as inhalants, nasal drops, ear drops, eye drops, and eye 
ointments are allowed. 

 
 
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5. Capsaicin (topical) 
6. Opioids 
7. Pregabalin, gabapentin  
8. Antidepressants, anxiolytics 
9. Drugs formulated with any of the drugs listed above 
Topical use of any prescription/non-prescription drugs listed in 1) to 5) above that are used 
to treat itching caused by chronic renal failure or any complication of chronic renal failure 
will not be restricted (concomitant medications for local itching caused by insect stings, 
chilblains, contact dermatitis, etc. will not be restricted).  
The use of any combination products that contain ingredients indicated for itching but are 
not indicated itself for itching will not be restricted. 
6.8.1.3 
Prohibited Concomitant Therapy 
Between the start of the screening period and the end of the follow-up period, phototherapy 
to treat itching will be prohibited. 
6.8.2 
HD Conditions 
Between the start of the screening period and the end of the follow-up period, the frequency 
of dialysis per week and the HD method may not be changed. Any temporary change in 
dialysis frequency or HD method associated with travel or admission to other hospitals with 
no changes in treatment strategies is acceptable. The HD conditions (duration of dialysis 
and dialyser) should not be changed whenever possible. 

 
 
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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) AEs reported from clinical studies with IV 
difelikefalin in subjects with CKD on HD with an incidence ≥1.0% greater compared with 
placebo were, in descending frequency, diarrhoea, nausea, fall, hypotension, dizziness, 
vomiting, abdominal pain, hyperkalaemia, headache, pneumonia, dyspnoea, constipation, 
somnolence, pyrexia, and blood thyroid stimulating hormone decreased. 
Risk of Driving and Operating Machinery 
Dizziness, somnolence, and mental status changes have occurred in subjects taking IV 
difelikefalin. IV difelikefalin may impair the mental or physical abilities needed to perform 
potentially hazardous activities, such as driving a car and operating machinery. Subjects 
should be advised not to drive or operate dangerous machinery until the effect of IV 
difelikefalin on a subject’s ability to drive or operate machinery is known. 
Dizziness, Somnolence, Mental Status Changes, and Gait Disturbances 
Dizziness, somnolence, mental status changes, and gait disturbances, including falls, have 
occurred in subjects taking IV difelikefalin and may subside over time with continued 
treatment. 
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). 
The incidence of somnolence was higher in IV difelikefalin-treated subjects (in the Phase3 
studies) ≥65 years of age (7.0%) than in IV difelikefalin-treated subjects <65 years of age 
(2.8%). Concomitant use of centrally acting depressant medications, sedating 
antihistamines, and opioid analgesics may increase the likelihood of these adverse reactions 
and should be used with caution during treatment with IV difelikefalin. 
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. 

 
 
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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. 
7.2.3 
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. 
7.2.4 
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 Visit (Day -28 to Day -7) 
The screening visit is to occur 28 to 7 calendar days before the start of treatment; it should 
be on a dialysis day (for assessments to be performed pre-dialysis). Sites have the option 
to conduct the screening visit during the run-in period (within 7 days before start of 
treatment) at the discretion of the Investigator. 
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: 
• Dispense subject identification card 
• Eligibility criteria 
• Demographics 
• Medical history/prior medications (including antipruritic medications) 
• Physical examination 
• Prescription dry body weight 
• 12-lead ECG obtained before starting dialysis 
• Vital signs (body temperature, heart rate, and blood pressure) obtained before starting 
dialysis with the subject in a sitting or semi-recumbent position 
• Samples for serum chemistry (for central laboratory assessment) obtained before 
starting dialysis to include: 
− 
Albumin, alkaline phosphatase (AP), ALT, AST, bilirubin (total), BUN, creatinine, 
glucose 
− 
Electrolytes (calcium, chloride, phosphorus, potassium, and sodium) 
• Haematology obtained before starting dialysis to include basophil %, basophil 
(absolute), eosinophil %, eosinophil (absolute), haematocrit, haemoglobin (Hb), 
lymphocyte %, lymphocyte (absolute), MCH, MCHC, MCV, monocyte %, monocyte 
(absolute), neutrophil %, neutrophil (absolute), platelet, RDW, red blood cells (RBCs), 
white blood cells (WBCs). Assessment to be performed via central laboratory 
• Serum pregnancy in women of childbearing potential (central laboratory assessment) 
within 7 days prior to the first dose of investigational product 
• AEs assessment 

 
 
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8.3 
Run-in Period (Day -7 to Day -1) 
Eligible subjects will complete a 7-day run-in period before randomisation to confirm that 
each subject has moderate-to-severe pruritus (i.e., weekly average worst itch score ≥5), as 
measured by the subject-daily reported 24-hour WI-NRS, and to establish a baseline itch 
intensity. Subjects must not be informed that they need to report a weekly average worst 
itch score ≥5 to be enrolled in the study. 
The following assessments/events will take place during the run-in period: 
• Medical history/prior medications (including antipruritic medications). Medical history 
will be updated on Day 1 with any changes since the screening visit, and 
inclusion/exclusion criteria will be confirmed prior to randomisation. Antipruritic 
medication will be updated at each dialysis visit during the run-in period 
• WI-NRS questionnaire 
− 
During the first visit (Day -7) of the run-in period, subjects will be trained on 
completion of the 24-hour WI-NRS 
− 
Subjects will start the reporting of their WI-NRS daily score on Day −7 until 
Day −1. For consistency, subjects will be requested to complete the NRS 
worksheets (either at home or in the dialysis unit, as required) each day at a similar 
time of day around the normal start time of their dialysis. 
• Subject training on PRO worksheets. Training on Skindex-10 scale and 5-D itch scale 
may be performed at any time during the week prior to randomisation or at the latest on 
Day 1 of the double-blind period 
• AEs assessment 
• Structured safety evaluation: A list of specific signs/symptoms will be verified with the 
subject 
by 
qualified 
site 
study 
staff, 
preferably 
to 
be 
completed 
on 
Wednesday/Thursday (not to be completed on Monday/Tuesday) 
8.4 
Double-blind Period 
If subjects continue to meet all inclusion and no exclusion criteria at the end of the 7-day 
run-in period, they will be randomised on Day 1 into the double-blind period in a 1:1 ratio 
to receive either difelikefalin or placebo. Subjects will be stratified according to their use 
or non-use of concomitant medications to treat their itch during the week prior to 
randomisation (run-in period) as well as the presence or absence of specific medical 
conditions (See Section 12.3). 
Each visit during the double-blind period will coincide with the subject’s normal dialysis 
treatments. 

 
 
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8.4.1 
Week 1/Day 1 
Day 1 of the double-blind period will be defined as the day of administration of the first 
dose of investigational product and will occur preferably on the first dialysis session of the 
first treatment week (i.e., Monday for subjects on a Monday-Wednesday-Friday dialysis 
schedule, or Tuesday for subjects on a Tuesday-Thursday-Saturday dialysis schedule). 
Subjects will be administered investigational product after the end of each dialysis session 
during the 12-week double-blind period. Each subject is to receive investigational product 
3 times weekly for a total of 36 doses. 
The following assessments and procedures will be performed on Day 1: 
• Medical history/prior medications; medical history will be updated with any changes 
since the screening visit  
• Confirm eligibility criteria before randomisation 
• Randomisation  
• Prescription dry body weight  
• Pre-dialysis vital signs, including body temperature, heart rate, and blood pressure, to 
be assessed when the subject is in a sitting or semi-recumbent position 
• Samples for serum chemistry (central laboratory assessment) obtained before starting 
dialysis to include:  
− 
Albumin, AP, ALT, AST, bilirubin (total), BUN, creatinine, glucose 
− 
Electrolytes (calcium, chloride, phosphorus, potassium, and sodium) 
• Haematology samples (central laboratory assessment) obtained before starting dialysis 
to include basophil %, basophil (absolute), eosinophil %, eosinophil (absolute), 
haematocrit, Hb, lymphocyte %, lymphocyte (absolute), MCH, MCHC, MCV, 
monocyte %, monocyte (absolute), neutrophil %, neutrophil (absolute), platelet, RDW, 
RBCs, WBCs 
• Subject training on PRO worksheets (Skindex-10 scale and 5-D itch scale) if not done 
previously during the week before randomisation 
• WI-NRS questionnaire 
− 
Subjects can complete the questionnaire before or during dialysis but before dosing 
− 
Remind subjects to complete the questionnaire daily at home on non-dialysis days 
around the normal start time of their dialysis 

 
 
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• Subjects to complete 5-D itch scale (preferably first) and Skindex-10 scale. If the first 
visit of the week is missed, the subject may complete the worksheets at their next visit 
for the same week. The questionnaires could be completed before or during dialysis 
(preferably within 1 hour of the dialysis) but before dosing 
• IV administration of investigational product within 15 minutes after completion of 
dialysis session 
• AEs assessment 
• Concomitant medications (including antipruritic medications) 
8.4.2 
Week 1/Day 3 
• WI-NRS questionnaire 
− 
Subjects can complete the questionnaire before or during dialysis but before dosing 
− 
Remind subjects to complete the questionnaire daily at home on non-dialysis days 
around the normal start time of their dialysis 
• IV administration of investigational product within 15 minutes after completion of 
dialysis session 
• AEs assessment 
• Concomitant medications (including antipruritic medications) 
• Structured safety evaluation: A list of specific signs/symptoms will be verified with the 
subject by qualified site study staff 
8.4.3 
Week 1/Day 5 
• WI-NRS questionnaire 
− 
Subjects can complete the questionnaire before or during dialysis but before dosing 
− 
Remind subjects to complete the questionnaire daily at home on non-dialysis days 
around the normal start time of their dialysis 
• IV administration of investigational product within 15 minutes after completion of 
dialysis session 
• AEs assessment 
• Concomitant medications (including antipruritic medications) 

 
 
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8.4.4 
Week 2 to Week 12 
• Record vital signs Week 3/Day 15, Week 5/Day 29, Week 7/Day 43, Week 9/Day 57 
and Week 11/Day 71 
− 
Vital signs include body temperature, heart rate, and blood pressure 
− 
Assess before dialysis with the subject in a sitting or semi-recumbent position 
− 
Measure heart rate at each dialysis; if heart rate is clinically significant at visits 
outside the pre-specified visits per Table 1, the heart rate will be recorded in the 
eCRF 
• Serum potassium assessment at Week 3/Day 15, Week 5/Day 29, Week 7/Day 43, 
Week 9/Day 57 and Week 11/Day 71 (central laboratory) 
• WI-NRS questionnaire to be completed daily (from Week 2 to Week 12) 
• Subjects can complete the questionnaire before or during dialysis but before dosing 
− 
Remind subjects to complete the questionnaire daily at home on non-dialysis days 
around the normal start time of their dialysis 
• Subjects to complete 5-D itch scale (preferably completed first) and Skindex-10 on the 
first visit of Week 5/Day 29 and of Week 9/Day 57. If the first visit of the week is 
missed, the subject may complete the worksheets at their next visit for the same week. 
The questionnaires can be completed before or during dialysis (preferably within 1 hour 
of the dialysis) but before dosing 
• IV administration of the investigational product (3 times a week within 15 minutes after 
completion of the dialysis sessions) 
• AEs assessment 
• Concomitant medications (including antipruritic medications) to be recorded at each 
dialysis visit 
• Structured safety evaluation: A list of specific signs/symptoms will be verified with the 
subject 
by 
qualified 
site 
study 
staff, 
preferably 
to 
be 
completed 
on 
Wednesday/Thursday each week during the double-blind period (not to be completed 
on Monday/Tuesday) 
8.5 
Double-blind Period End of Treatment/Early Termination/Day 85 
On completion of the double-blind period (i.e., last study visit Day 85), or if subject is 
discontinued/withdrawn early, the following assessments and procedures should be 
performed: 

 
 
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• 12-lead ECG obtained before starting dialysis 
• Vital signs (body temperature, heart rate, and blood pressure) obtained before starting 
dialysis with the subject in a sitting or semi-recumbent position 
• Samples for serum chemistry (central laboratory assessment) obtained before starting 
dialysis to include: 
− 
Albumin, AP, ALT, AST, bilirubin (total), BUN, creatinine, glucose 
− 
Electrolytes (calcium, chloride, phosphorus, potassium, and sodium) 
• Haematology samples (central laboratory assessment) obtained before starting dialysis 
to include basophil %, basophil (absolute), eosinophil %, eosinophil (absolute), 
haematocrit, Hb, lymphocyte %, lymphocyte (absolute), MCH, MCHC, MCV, 
monocyte %, monocyte (absolute), neutrophil %, neutrophil (absolute), platelet, RDW, 
RBCs, WBCs 
• Serum pregnancy in women of childbearing potential (central laboratory assessment) 
• Subject training on PRO worksheet Patient Global Impression of Change 
• WI-NRS questionnaire 
− 
Subjects can complete the questionnaire before or during dialysis but before dosing 
− 
Remind subjects to complete the questionnaire daily at home on non-dialysis days 
around the normal start time of their dialysis 
• Subjects to complete 5-D itch scale (preferably first) and Skindex-10 scale. If the first 
visit of the week is missed, the subject may complete the worksheets at their next visit 
for the same week. The questionnaires could be completed before or during dialysis 
(preferably within 1 hour of the dialysis) but before dosing 
• Patient Global Impression of Change 
• AE assessment 
• Concomitant medications (including antipruritic medications) 
Note: The end-of-treatment visit in the double-blind period will be the first dialysis visit 
following the last dose of investigational product, i.e., first dialysis on Week 13/Day 85, 
which also corresponds to Day 1 of the open-label extension period. 

 
 
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8.6 
Follow-up Period (ONLY for Subjects not Participating in the 
Open-label Extension Phase)/Day 85 to Day 95  
• Pre-dialysis vital signs, including body temperature, heart rate, and blood pressure, will 
be recorded at the follow-up visit (at 7 to 10 days after end-of-treatment/early 
termination visit). Heart rate will be measured at each dialysis visit during the follow-up 
period; if heart rate is clinically significant at visits outside the follow-up visit, the heart 
rate will be recorded in the eCRF 
• WI-NRS worksheets to be completed only on dialysis days 
• AEs assessment 
• Concomitant medications 
• Structured safety evaluation: A list of specific signs/symptoms will be verified with the 
subject by qualified site study staff once during the follow-up period 
8.7 
Open-label Extension Period 
Subjects who received at least 30 doses of investigational product during the 12-week 
double-blind period and continue to meet other eligibility criteria will be eligible to receive 
open-label difelikefalin for an additional 14 weeks. Each subject will receive difelikefalin 
at a dose of 0.5 µg/kg after the end of each dialysis session, 3 times per week for up to 
14 weeks, regardless of whether they had been previously administered placebo or 
difelikefalin. Prescription dry body weight will be recorded at the start of the open-label 
extension phase; if there is a ±10% or more change from the prescription dry body weight 
recorded at screening, then the difelikefalin dose will be adjusted according to the newly 
recorded dry body weight.  
8.7.1 
Day 1/Open-label Extension 
The first visit and first dosing for the open-label extension phase of the study will occur 
immediately on the day of the last visit of the double-blind period or up to 1 week following 
the double-blind treatment period. 
The following assessments will be performed: 
• Eligibility criteria assessment for entry into the open-label phase 
• Physical examination 
• Prescription dry body weight to be captured from the dialysis prescription. If there is a 
>10% change in prescription dry body weight compared to the last value, then the 
difelikefalin dose will be adjusted 

 
 
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• Pre-dialysis vital signs (body temperature, heart rate, and blood pressure) to be obtained 
while the subject is in a sitting or semi-recumbent position prior to the start of dialysis  
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
sessions) 
• AEs assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis 
8.7.2 
Week 2/Open-label Extension 
The study visit may occur on any chosen dialysis day of a scheduled week as long as all 
assessments are completed during that visit. The following assessments will take place: 
• Assessment of serum potassium before starting of dialysis (central laboratory) 
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
session) 
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis  
8.7.3 
Week 4/Open-label Extension 
The study visit may occur on any chosen dialysis day of a scheduled week as long as all 
assessments are completed during that visit. The following assessments will take place: 
• Pre-dialysis vital signs (body temperature, heart rate, and blood pressure) to be obtained 
while the subject is in a sitting or semi-recumbent position prior to the start of dialysis. 
Heart rate will be measured at each dialysis; if the heart rate is clinically significant at 
visits outside the pre-specified visits per Table 2, the heart rate will be recorded in the 
eCRF 
• Assessment of serum potassium before starting of dialysis (central laboratory) 
• Subjects to complete 5-D itch scale and Skindex-10 scale before or during dialysis 
(preferably within 1 hour of the dialysis but before dosing). 5-D itch scale will 
preferably be completed first.  
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
session) 
• AE assessment on an ongoing basis 

 
 
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• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis  
8.7.4 
Week 6/Open-label Extension 
The study visit may occur on any chosen dialysis day of a scheduled week as long as all 
assessments are completed during that visit. The following assessments will take place: 
• Assessment of serum potassium before starting of dialysis (central laboratory) 
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
session) 
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis  
8.7.5 
Week 8/Open-label Extension 
The study visit may occur on any chosen dialysis day of a scheduled week if all assessments 
are completed during that visit. The following assessments will take place: 
• Pre-dialysis vital signs (body temperature, heart rate, and blood pressure) to be obtained 
while the subject is in a sitting or semi-recumbent position prior to the start of dialysis. 
Heart rate will be measured at each dialysis; if the heart rate is clinically significant at 
visits outside the pre-specified visits per Table 2, the heart rate will be recorded in the 
eCRF 
• Assessment of serum potassium before starting of dialysis (central laboratory) 
• Subjects to complete 5-D itch scale and Skindex-10 scale before or during dialysis 
(preferably within 1 hour of the dialysis but before dosing). 5-D itch scale will 
preferably be completed first 
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
session) 
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis 
8.7.6 
Week 10/Open-label Extension 
The study visit may occur on any chosen dialysis day of a scheduled week as long as all 
assessments are completed during that visit. The following assessments will take place: 

 
 
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• Assessment of serum potassium before starting of dialysis (central laboratory) 
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
session) 
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis  
8.7.7 
Week 12/Open-label Extension 
The study visit may occur on any chosen dialysis day of a scheduled week if all assessments 
are completed during that visit. The following assessments will take place: 
• Prescription dry body weight to be captured from the dialysis prescription. If there is a 
>10% change in prescription dry body weight compared to the last value, then the 
difelikefalin dose will be adjusted 
• Pre-dialysis vital signs (body temperature, heart rate, and blood pressure) to be obtained 
while the subject is in a sitting or semi-recumbent position prior to the start of dialysis. 
Heart rate will be measured at each dialysis; if the heart rate is clinically significant at 
visits outside the pre-specified visits per Table 2, the heart rate will be recorded in the 
eCRF 
• Assessment of serum potassium before starting of dialysis (central laboratory) 
• Subjects to complete 5-D itch scale and Skindex-10 scale before or during dialysis 
(preferably within 1 hour of the dialysis but before dosing). 5-D itch scale will 
preferably be completed first 
• IV administration of difelikefalin (within 15 minutes after completion of dialysis 
session) 
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis 
8.7.8 
First Dialysis of Week 15/Open-label Extension End of 
Treatment/Early Termination 
The end-of-treatment visit will be the first dialysis visit following the last dose of 
investigational product (i.e., first dialysis on Week 15). The following assessments will be 
performed: 
• Pre-dialysis 12-lead ECG 

 
 
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• Pre-dialysis vital signs (body temperature, heart rate, and blood pressure) to be obtained 
while the subject is in a sitting or semi-recumbent position prior to the start of dialysis  
• Samples for serum chemistry (central laboratory assessment) obtained before starting 
dialysis to include: 
− 
Albumin, AP, ALT, AST, bilirubin (total), BUN, creatinine, glucose 
− 
Electrolytes (calcium, chloride, phosphorus, potassium, and sodium) 
• Haematology samples (central laboratory assessment) obtained before starting dialysis 
to include basophil %, basophil (absolute), eosinophil %, eosinophil (absolute), 
haematocrit, Hb, lymphocyte %, lymphocyte (absolute), MCH, MCHC, MCV, 
monocyte %, monocyte (absolute), neutrophil %, neutrophil (absolute), platelet, RDW, 
RBCs, WBCs  
• Serum pregnancy test for women of childbearing potential only (central laboratory 
assessment) 
• 5-D itch scale and Skindex-10 scale (to be completed in the dialysis unit at any time 
before or during dialysis)  
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis 
8.7.9 
Follow-up for Subjects Participating in the Open-label Period 
A follow-up visit will be performed 7 to 10 days after end of treatment/early termination 
on a dialysis day. The following assessments will take place: 
• Pre-dialysis vital signs (body temperature, heart rate, and blood pressure) to be obtained 
while the subject is in a sitting or semi-recumbent position prior to the start of dialysis  
• AE assessment on an ongoing basis 
• Concomitant medications (including antipruritic medications) recorded on an ongoing 
basis 

 
 
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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, and race) 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 before 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 before 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 before obtaining the informed consent must be documented in the eCRF, 
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). 
9.2 
Physical Examination and Vital Signs 
Physical examination will include general appearance, cardiovascular, respiratory, 
abdominal, musculoskeletal, neurological, lymph nodes, and skin. Any findings at 
screening should be reported in the medical history; clinically significant changes should 
be reported as AEs. 
Vital signs will include oral 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.  
An AE form must be completed for all changes identified as clinically noteworthy. 
9.3 
12-lead ECG 
Standard 12-lead ECGs will be measured after the subject has been resting for minimum of 
5 minutes.  

 
 
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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 and in the subject’s hospital records. 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 via central laboratory as 
indicated in the Schedule of Events (Table 1 and Table 2). 
• Serum chemistry: 
− 
Albumin, bilirubin (total), AP, ALT, AST, glucose, creatinine, BUN 
− 
Electrolytes (sodium, potassium*, chloride, calcium, and phosphorus) 
• Haematology: 
− 
Basophil %, basophil (absolute), eosinophil %, eosinophil (absolute), haematocrit, 
Hb, lymphocyte %, lymphocyte (absolute), MCH, MCHC, MCV, monocyte %, 
monocyte (absolute), neutrophil %, neutrophil (absolute), platelet, RDW, RBCs, 
WBCs 
• Other: 
− 
Serum pregnancy test in women of childbearing potential 
*Serum potassium will be additionally assessed at time points as noted in the Schedule of 
Events (Table 1 and Table 2).  
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. 
9.5 
Adverse Events 
See Section 10. 

 
 
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9.6 
Prior, Concomitant, and Prohibited Medications 
Prior medications (including over-the-counter drugs and herbal supplements reported by 
the subjects) are defined as prescription and non-prescription medications taken any time 
during the last 3 months prior to the first dose of investigational product (Day 1 of the 
double-blind period) and ending before Day 1. 
Concomitant medications are defined as all drugs and therapies used on Day 1 of the 
double-blind period or after the first dose of the investigational product on Day 1 and 
through the end of the follow-up period. 
Use of antipruritic medications during the study will be recorded on an ongoing basis, 
starting at screening. Subjects having a prescription for the use of anti-itch medication will 
be stratified as using anti-itch medication even if such medications were not reported to be 
used during the run-in period. Medications known for potential antipruritic effects but used 
for a different indication (e.g., use of gabapentin for pain management) will not be reported 
as antipruritic medications. 
All prior and concomitant medications, including over-the-counter medications used by 
subjects during this study, are to be recorded in the appropriate page of the eCRF, as 
applicable.  
For a list of conditionally permitted concomitant treatment see Section 6.8.1.2. 
For a list of prohibited concomitant treatment see Section 6.8.1.1. 
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 vaccination or an impact of the vaccination on difelikefalin are unlikely.  
9.7 
PRO Measures 
The effect of difelikefalin on itch will be measured by means of the following PRO 
measures: 
• WI-NRS score 
• Skindex-10 scale 
• 5-D itch scale 
Patient Global Impression of Change Subjects will be trained on completion of the WI-NRS 
scale before the first visit of the run-in period and will be trained on the other itch-related 
PRO measures at any time before Day 1 of the double-blind period. All questionnaires must 
be completed in strict adherence to the training manual for patient reported assessments. 

 
 
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9.7.1 
WI-NRS 
Intensity of itch will be measured using an NRS scale (Appendix 1) on a worksheet on 
which subjects will be asked to indicate the intensity of the worst itching they have 
experienced over the past 24 hours by marking one of 11 numbers, from 0 to 10, that best 
describes it, where 0 is labelled with the anchor phrase “no itching” and “10” is labelled 
“worst itching imaginable.” Subjects will be provided with the WI-NRS worksheets to 
record their 24-hour worst itching assessment scores, both at the clinic on dialysis days and 
at home on non-dialysis days. 
The WI-NRS has been widely utilised for evaluation of chronic itch, including uraemic 
pruritus [15-18]. 
9.7.2 
Skindex-10 Scale 
Developed specifically for uraemic pruritus, the Skindex-10 scale (Appendix 3) is an 
instrument for measurement of QoL that correlates with itch intensity [17]. Subjects are 
asked to mark 1 of 7 boxes numbered from 0 (labelled with the anchor phrase “never 
bothered”) to 6 (labelled as “always bothered”) for each of the 10 questions describing how 
often they have been bothered by their itch and its impact over the past week. The total 
score is the sum of the numeric value of each answered question. The total score is 
subdivided into 3 domain scores, which are sums of the scores of the following questions: 
disease domain (questions 1 to 3), mood/emotional distress domain (questions 4 to 6), and 
social functioning domain (questions 7 to 10). 
9.7.3 
5-D Itch Scale 
The 5-D itch scale was developed as a brief, multidimensional questionnaire designed to 
be useful as an outcome measure in clinical studies. The 5 dimensions of itch assessed are 
degree, duration, direction, disability, and distribution (Appendix 4). Subjects are asked to 
mark boxes that best describe the impact of their itch over the past 2 weeks. The scale has 
been validated in patients with chronic pruritus, including HD patients and has been shown 
to be sensitive to changes in pruritus over time [19]. 
9.7.4 
Patient Global Impression of Change  
The Patient Global Impression of Change is a global PRO measure that assesses the change 
in itch (no change, improvement or worsening) overall relative to the start of the study [20]. 
The scale has only 1 item, and the subject is asked to mark the category that best describes 
the change in itch ranging from “Very Much Improved” to “Very Much Worse” 
(Appendix 5). 

 
 
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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 his or her 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 toxicity 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., 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 
for the admission 

 
 
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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 by using the study-specific Sponsor SAE form/via 
SAE CRF/eCRF in the 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 SUSAR 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.  
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 difelikefalin IB. 

 
 
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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 or elderly population (if this is not the 
population under investigation) 
• 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. 
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 

 
 
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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 Medical Monitor 
must be contacted immediately to break the blind (if applicable). 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.  
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). 

 
 
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10.8.4 Adverse Events of Special Interest 
10.8.4.1 
Definition of AESIs 
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 established for this study. 

 
 
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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). The level of significance to be used will be set an alpha of 
0.05 (2-sided). 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 database 
lock. 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. 
12.2 Sample Size and Power Calculations 
Double-blind Period 
In a Japanese Phase 2 clinical study (MR13A9-4), a mean difference of –1.0 was observed 
between the difelikefalin and placebo groups with an SD of 2.09 and 1.98 in the 
difelikefalin and placebo group, respectively, regarding the change from baseline in the 
weekly mean of the daily 24-hour WI-NRS score at end of Week 4. 
In the pooled data of 2 Phase 2 clinical studies (CLIN3102 and CLIN3103), a mean 
difference of –0.8 was observed between difelikefalin and placebo group with an SD of 
2.15 and 1.99 in the difelikefalin and placebo group, respectively, regarding the change 
from baseline in the weekly mean of the daily 24-hour WI-NRS score at end of Week 4. 
Based on the results observed at the end of Week 4 in previous studies as mentioned in the 
above paragraphs, a mean difference of −0.9 with a common SD of 2.1 is assumed between 
difelikefalin and placebo group regarding the primary endpoint. Assuming a 2-sided 
significance level of 5% and a statistical power of 90%, 116 subjects per group will be 
required to detect a difference of −0.9, with a common SD of 2.1, between the difelikefalin 
and the placebo group using a 2-sample t-test. In addition, assuming, a 10% drop out rate, 
258 subjects in total need to be enrolled in the double-blind study period, i.e., 129 subjects 
per group. 
The sample size calculation was done with the software nQuery Version 8.6 using a 
2-sample t-test to compare means.  
Open-label Extension Period 
All subjects who completed the double-blind period may continue into the 14-week 
open-label extension period if they meet the eligibility criteria at Day 1 of the open-label 
extension period. 

 
 
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12.3 Randomisation 
All subjects enrolled must be identifiable throughout the study. 
Randomisation of subjects will be performed on Day 1 before start of treatment with study 
drug.  
Each eligible subject will be randomised during the double-blind period in a 1:1 allocation 
ratio to receive either difelikefalin or matching placebo using a validated centralised 
procedure (IWRS) that automates the random assignment of treatment groups to 
randomisation numbers. Subjects will be stratified according to their use or non-use of 
concomitant medications to treat their itch (refer to Section 6.8.1) during the week prior to 
randomisation (run-in period) as well as the presence or absence of specific medical 
conditions. These specific medical conditions include: 
• History of fall or fracture (related to fall) 
• Confusional state or mental status change or altered mental status or disorientation  
• Gait disturbance or movement disorder  
Randomised subjects who terminate their study participation for any reason regardless of 
whether the investigational product was taken or not, will retain their randomisation 
number. The next subject will be given the next randomisation number. 
Before the start of the study, a randomisation list will be created for each stratum. The 
randomisation lists will be kept strictly confidential, accessible only to authorised persons, 
until the time of unblinding. 
12.4 Analysis Populations 
12.4.1 Double-blind Safety Analysis Set 
The DB-SAF consists of all randomised subjects who receive at least 1 dose of 
investigational product during the double-blind period. Subjects in the DB-SAF will be 
analysed according to the actual treatment received. The DB-SAF will be used to analyse 
exposure data as well as all safety endpoints collected during the double-blind period. 
12.4.2 Full Analysis Set 
The FAS is defined as all subjects who satisfy the following criteria: 
• Randomised to treatment 
• Received at least 1 dose of investigational product 
• Had a non-missing baseline assessment for the weekly mean of the daily 24-hour 
WI-NRS score 

 
 
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• Had at least 1 post-baseline assessment for the weekly mean of the daily 24-hour 
WI-NRS score 
Subjects in the FAS will be analysed according to their randomised treatment, regardless 
of the actual treatment received. The FAS will be used to analyse all efficacy endpoints 
collected during the double-blind period. 
12.4.3 Per-Protocol Set 
The PPS consists of all subjects who, in addition to the FAS criteria, do not have any major 
protocol deviations that will be defined and reviewed during the blinded data review 
meeting prior to unblinding the data. Subjects in the PPS will be analysed according to their 
randomised treatment, regardless of the actual treatment received. The PPS will be used to 
analyse efficacy endpoints collected during the double-blind period and will act as 
supportive analyses. 
12.4.4 Open-label Safety Analysis Set 
The OL-SAF consists of all subjects who receive at least 1 dose of investigational product 
in the open-label extension period. Subjects in the OL-SAF will be analysed according to 
the actual treatment sequence received during the double-blind and open-label extension 
periods. The OL-SAF will be used to analyse exposure data to difelikefalin, efficacy as 
well as all safety endpoints collected during the open-label extension period. 
12.5 Background and Demographic Characteristics 
For the double-blind period, the number of subjects enrolled, randomised, treated, 
completed, or discontinued from the treatment and from the study, along with the reason 
for discontinuation, will be summarised by treatment group and overall. 
In addition, the number of subjects in each analysis set will be tabulated.  
Subject demographics and baseline characteristics will be summarised by treatment group 
and overall using descriptive statistics; no formal statistical analysis tests will be performed. 
Demographic variables to be summarised will include sex, race, age (years) at informed 
consent as continuous and categorical variable (18 to <65, ≥65 to <85, ≥85 years) and 
baseline prescription dry body weight (kg). Height will not be collected.  
Baseline characteristics of the disease will also be summarised by treatment group and 
overall and will include variables such as baseline weekly mean of the daily 24-hour 
WI-NRS score, use/non-use of anti-itch medication, presence/absence of specific medical 
conditions, aetiology of CKD, duration of pruritus (years), and years on HD. 
Medical history data will be coded using MedDRA and summarised by MedDRA SOC, 
PT, and treatment group. The data will also be listed, including the verbatim Investigator 

 
 
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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 Exposure to Investigational Product 
For this study, the duration of double-blind period for each individual subject may be up to 
12 weeks, for a total of approximately 36 doses of investigational product administered 
immediately following each dialysis session. Day 1 of the double-blind period will be 
defined as the day of administration of the first dose of investigational product. The last 
day of the double-blind period will be defined as the day of the dialysis session immediately 
following the last injection of investigational product.  
Exposure and treatment compliance during the double-blind period will be summarised by 
treatment group and by the following parameters:  
• Duration of double-blind treatment (days)  
• Total number of doses actually received  
• Total number of dialysis visits logged 
• Number of missed doses 
• Number of missed dialysis visits 
• Number of subjects with extra doses 
• Number of subjects with extra dialysis visits  
• Compliance (%) 
Duration of double-blind treatment (days) = (date of first dialysis after last dose) – (date of 
first dose) + 1.  
Compliance (%)=actual doses/planned doses 
If a subject receives additional dialysis during a given week for any reason, an additional 
dose of investigational product will be administered following dialysis. A maximum of 
4 doses per week is allowed. No additional doses will be given for subjects receiving an 
additional unscheduled ultrafiltration treatment. The number of subjects getting extra doses 
will be summarised. 
12.7 Concomitant Therapy 
All medications will be coded using the World Health Organization Drug Dictionary. 
Counts and percentages of subject use for each concomitant medication will be tabulated 
separately by study period, by appropriate World Health Organization Drug Dictionary 

 
 
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classifications and by treatment group. Prior medications will be presented in a listing only. 
Traditional Chinese medicines should also be recorded. 
In addition, prior and concomitant antipruritic medications will be summarised separately 
by study period; summaries will be presented by ingredient rather than by Anatomical 
Therapeutic Chemical codes. 
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 dose administration of investigational product or as any medication/therapy with a 
missing end date. If missing, the medication will be assumed to be ongoing and considered 
as concomitant. 
12.8 Efficacy Evaluations 
12.8.1 Primary Efficacy Evaluations 
The primary efficacy endpoint is defined as the change from baseline in the weekly mean 
of the daily 24-hour WI-NRS score at Week 4 (Days 23 to 29) of the double-blind period. 
The FAS will be used as the primary population for the analysis of the primary efficacy 
endpoint as well as for its sensitivity analysis. The PPS will be used as a secondary 
population. 
The weekly mean of the 24-hour WI-NRS score will be defined as the sum of the daily 
WI-NRS score reported during a specific week during the double-blind period (e.g., Days 2 
to 8, Days 9 to 15, Days 16 to 22, Days 23 to 29) divided by the number of days with 
non-missing scores for that week. If the daily WI-NRS is missing for >3 days during a 
specific week, the corresponding weekly mean WI-NRS will be set to missing. The baseline 
score will be defined as the average of the daily 24-hour WI-NRS scores collected over the 
run-in period, including pre-randomisation assessments collected on Day 1. 
The change from baseline in the weekly mean of the daily 24-hour WI-NRS score at 
Week 4 (Days 23 to 29) of the double-blind period will be analysed using a MMRM. 
Missing scores will not be imputed. Assuming that the data are MAR, the estimates of the 
treatment differences calculated from the MMRM described below are unbiased. The 
model will contain treatment, week, and treatment-by-week interaction as fixed effects; 
baseline NRS score, use of prior anti-itch medication and presence of specific medical 
conditions as covariates.  
Repeated measures will include values collected at the end of Weeks 1, 2, 3, and 4. 
An unstructured covariance matrix will be used to model the within-subject errors. Should 
the model fail to converge, a compound symmetric covariance matrix will be used instead.  

 
 
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The Kenward-Roger2 approximation will be used to estimate the denominator degrees of 
freedom. 
Standard descriptive statistics will be reported on the values and changes from baseline at 
Week 4 of the double-blind period along with the adjusted mean change at Week 4 for each 
group and its 2-sided 95% CI. The adjusted mean treatment difference in the change 
between difelikefalin and placebo groups will be estimated at Week 4 of the double-blind 
period as the simple contrast in the treatment effect. Its 2-sided 95% CI as well as its p-value 
will be presented 
Testing of the primary efficacy endpoint will be 2-sided and conducted at the 5% error 
level. The null hypothesis in this study is that there is no treatment difference in the primary 
efficacy analysis of the primary endpoint, i.e., the change from baseline in the weekly mean 
of the daily 24-hour WI-NRS score at Week 4 of the double-blind period. The alternative 
hypothesis is that subjects randomised to difelikefalin experience significantly less itching 
compared to subjects randomised to placebo. 
In the primary efficacy analysis, missing NRS data will not be imputed. 
Sensitivity analyses of the primary efficacy endpoint will be conducted to evaluate the 
robustness of study results under different assumptions and imputation algorithms.  
For both sensitivity analyses described below, the adjusted mean change at Week 4 for each 
group and its 2-sided 95% CI, the adjusted mean treatment difference in the change between 
difelikefalin and placebo groups at Week 4 of the double-blind period, its 2-sided 95% CI 
as well as its p-value will be estimated as in the primary efficacy analysis. 
Sensitivity 1: Multiple Imputation (MI) – MMRM 
Multiple imputed data will be generated using the approach described below. Each 
imputation data will be analysed using the same MMRM model as the one used for the 
primary efficacy analysis, and the results of the analyses will be combined. Imputation will 
be performed using all available data collected at each time point between Week 1 and 
Week 4 of the double-blind period. 
• Intermittent missing NRS scores will first be imputed using the Markov Chain Monte 
Carlo method implemented with the SAS MI procedure, which is appropriate for 
non-monotonic missing data.  
• The monotone missing NRS values will then be multiply imputed with the SAS MI 
procedure using the monotone regression method.  

 
 
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• For each stage, MI will be performed within treatment group with covariates for 
baseline NRS score, both randomisation stratification factors and all non-missing NRS 
scores for each week. Should convergence issues occur due to small cell size for the 
categorical covariates corresponding to strata (at either stage), those specific covariates 
will be removed from the model.  
Sensitivity 2: Placebo MI – MMRM  
Multiple imputed data will be generated using the approach described below. Each 
imputation data will be analysed using the same MMRM model as the one used for the 
primary efficacy analysis, and the results of the analyses will be combined. Imputation will 
be performed using all available data collected at each time point between Week 1 and 
Week 4 of the double-blind period. 
• Intermittent missing NRS scores will first be imputed using the Markov Chain Monte 
Carlo method implemented with the SAS MI procedure, which is appropriate for 
non-monotonic missing data. Covariates for baseline NRS score, both randomisation 
stratification factors and all non-missing NRS scores for each week will be included. 
• The monotone missing NRS values will then be multiply imputed with the SAS MI 
procedure using the monotone regression method. Covariates for baseline NRS score, 
both randomisation stratification factors and all non-missing NRS scores for each week 
will be included. 
• The MNAR option in Proc MI will be used with the visit values and will reference the 
placebo group for informing the imputation. 
• For each stage, should convergence issues occur due to small cell size for the 
categorical covariates corresponding to strata, those specific covariates will be removed 
from the model. 
12.8.2 Secondary Efficacy Evaluations 
Secondary and other efficacy endpoints will be analysed using the FAS, as the primary 
population, and PPS, as a secondary population. 
Significance level is set at an alpha of 0.05 (2-sided) and no adjustment will be made for 
testing multiple secondary outcomes. Some significant findings are expected to occur by 
chance so undue consideration will not be given to any particular significant difference. 
Moreover, interpretation of the results will be based on patterns of differences and in 
conjunction with the results of the primary analyses. 
The proportion of subjects achieving ≥3-point and ≥4-point improvement, respectively, 
from baseline with respect to the weekly mean of the daily 24-hour WI-NRS at Week 4, 8 
and 12 of the double-blind period will be analysed using a logistic regression model 
containing terms for treatment group, baseline WI-NRS score, use of prior anti-itch 

 
 
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medication, and presence of specific medical conditions. Missing NRS data will be imputed 
using a MI approach, assuming that subjects who discontinue double-blind period early 
would have similar WI-NRS scores as other subjects in their respective treatment arm that 
have complete data. The observed number and proportion of subjects with ≥3-point and 
≥4-point improvement, respectively, among the non-imputed data will be reported along 
with the imputed data logistic regression model-based estimates of the proportions of 
responders (as defined above) with their 2-sided 95% CIs, odds ratio as well as 2-sided 
Wald 95% CIs and p-value. A sensitivity analysis will be performed. The same logistic 
regression model will be used as the one specified above; the only difference is that subjects 
who discontinue investigational product early will be considered non-responders. Further 
details will be specified in the SAP.  
Change from baseline in itch-related QoL at end of Week 12 of the double-blind period, as 
assessed by the 5-D itch scale total score will be analysed using a MMRM. Missing scores 
will not be imputed. Assuming that the data are MAR, the estimates of the treatment 
differences calculated from the MMRM described below are unbiased. The model will 
contain treatment, week, and treatment-by-week interaction as fixed effects; baseline score, 
use of prior anti-itch medication and presence of specific medical conditions as covariates. 
The baseline 5-D total score will be defined as the value collected on Day 1, prior to 
randomisation. Repeated measures will include values collected at each time point of the 
double-blind period. An unstructured covariance matrix will be used to model the within-
subject errors. Should the model fail to converge, a compound symmetric covariance matrix 
will be used instead. The Kenward-Roger2 approximation will be used to estimate the 
denominator degrees of freedom. Standard descriptive statistics will be reported on the 
values and changes from baseline at end of Week 12 along with the adjusted mean at end 
of Week 12 for each group and its 2-sided 95% CI. The adjusted mean treatment difference 
between difelikefalin and placebo groups will be estimated at end of Week 12 of the 
double-blind period as the simple contrast in the treatment effect as well as its 2-sided 95% 
CI and its p-value. 
Change from baseline in itch-related QoL at end of Week 12 of the double-blind period, as 
assessed by the Skindex-10 scale total score will be analysed using the same approach as 
described above fitted for the change from baseline in itch-related QoL at end of Week 12 
of the double-blind period, as assessed by the 5-D itch scale total score. The baseline 
Skindex-10 scale total score will be defined as the value collected on Day 1, prior to 
randomisation. 
Change from baseline in the weekly mean of the 24-hour WI-NRS score at each week of 
the double-blind period will be analysed following a methodology similar to the one 
employed for the primary analysis of the primary efficacy endpoint. Repeated measures 
will include values collected at the end of each week from Week 1 until Week 12 of the 
double-blind period. 
Change from baseline in itch-related QoL at each time point of the double-blind period and 
of the open-label extension period, as assessed by the Skindex-10 scale total score will be 

 
 
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analysed using the same approach as described above fitted for the change from baseline 
in itch-related QoL at end of Week 12 of the double-blind period, as assessed by the 5-D 
itch scale total score. Repeated measures will include all values collected during each 
period separately. 
Change from baseline in itch-related QoL at each time point of the double-blind period and 
of the open-label extension period, as assessed by the 5-D itch scale total score will be 
analysed separately using the same approach as described above fitted for the change from 
baseline in itch-related QoL at end of Week 12 of the double-blind period, as assessed by 
the 5-D itch scale total score. Repeated measures will include all values collected during 
each period separately. 
The number and percentage of subjects for each response of the Patient Global Impression 
of Change will be reported as well as the count of subjects with missing values. The number 
and percentage of subjects who rate their itch condition as “Very much improved” or 
“Much Improved” at the end of Week 12 of the double-blind period/end of double-blind 
will be reported together. The Mantel-Haenszel estimate, adjusting for the randomisation 
stratification variables, of common odds ratio with its 2-sided 95% CI will be reported. 
Additionally, the 2-sided exact Clopper Pearson 95% CI for the proportion of subjects who 
rate their itch condition as “Very much improved” or “Much Improved” will be presented. 
12.9 Safety Evaluations 
The objective of the evaluation of the safety variables is to investigate the data for any 
effects on clinical tolerability and laboratory safety variables. All such variables will be 
summarised by treatment group and by study period (and time point as appropriate). No 
inferential statistics are planned. Safety data will be summarised descriptively.  
12.9.1 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 by treatment group and by study 
period, as appropriate. AEs will also be presented in by-subject AE listings.  
AEs relative to the double-blind period are identified as any AE: 
• With an onset date after the first dose of the investigational product in the double-blind 
period for subjects who do not enter the open-label extension period. 
• With an onset date after the first dose of the investigational product in the double-blind 
period up to the first dose of difelikefalin in the open-label extension period for subjects 
who continue into the open-label extension period. 
AEs relative to the open-label extension period are identified as any AE with an onset date 
after the first dose of difelikefalin in the open-label extension period. 

 
 
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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 will be summarised by treatment 
group and by study period. 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.  
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 for 
each study period. 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 “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.  
For each study period, an overall summary table will be provided, presenting for each 
treatment group, 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 interruption, 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 
• Most common AEs (≥2% or more of subjects in any treatment group) by PT 
• AESIs by PT 
• Related AESIs by PT 
All AEs will be listed in chronological order, including information such as treatment 
group/treatment sequence, subject identifier, age, sex, use/non-use of anti-itch medication, 

 
 
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presence/absence of specific medical conditions a flag indicating whether the AE was 
relative to the double-blind or to the open-label extension period, and all related AE status 
information (start and stop dates, whether the event was ongoing, study day of onset, 
severity, seriousness, relationship to study medication, action taken with study treatment, 
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. 
12.9.2 Special Situations 
All special situations will be coded using MedDRA (when applicable). All reported special 
situations will be included in a by-subject listing. 
12.9.3 Vital Signs 
For each study period, summary tables for vital signs will include descriptive statistics for 
baseline and each post-baseline assessment. Descriptive statistics will be calculated on both 
the actual values and the change from baseline. Baseline is defined as the last measurement 
taken on or prior to the first day of dosing for each study period. Note that the Day 1 
assessment can be included in the evaluation of baseline if that the assessment is performed 
prior to dosing.  
All vital signs will be listed in by-subject listings, including information such as visit, 
collection date, and will be sorted by subject identifier and date of assessment.  
12.9.4 12-lead ECG 
For each study period, baseline and change from baseline in ECG parameters will be 
summarised at each time point. 
All 12-lead ECG data will be listed in a by-subject listing. 
12.9.5 Physical Examination 
Not applicable as physical examination finding will be recorded through medical history or 
AEs if clinically relevant. 
12.9.6 Clinical Laboratory Tests 
For each study period, summaries of actual values and the change from baseline to each 
time point (when applicable) will be presented for quantitative laboratory parameters. 
Laboratory values will be reported in Système International units.  
Laboratory test results will be classified according to whether the value was below (L), 
within (N), or above (H) the laboratory parameter reference range. A summary of 
treatment-emergent shifts will compare the baseline L/N/H classification for each 
laboratory test to the L/N/H classification at end of the treatment for each study period. For 

 
 
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serum potassium, shift table comparing the baseline L/N/H classification to each 
post-baseline L/N/H classification will also be provided.  
12.10 Interim Analyses 
An interim analysis may be performed. Details will be defined in the SAP. 
12.11 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 [21], and the International Council for Harmonisation (ICH) 
guidelines for Good Clinical Practice (GCP) [22] 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 [23]. 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 [24]. 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 
1. 
Rayner HC, Larkina M, Wang M, Graham-Brown M, van der Veer SN, Ecder T, et 
al. International comparisons of prevalence, awareness, and treatment of pruritus in 
people on hemodialysis. Clin J Am Soc Nephrol. 2017 Dec;12:2000-7. 
2. 
Li J, Guo Q, Lin J, Yi C, Yang X, Yu X. Prevalence and associated factors of 
uraemic pruritus in continuous ambulatory peritoneal dialysis patients. Intern Med. 
2015 Mar 1;54:2827-33.  
3. 
Wen Y, Liu C, Lin Z, Zhang Z, Sun W, Qin X, et al. Uremic pruritus in Chinese 
chronic haemodialysis population: a single-centre series study. Acta Medica 
Mediterranea. 2020;36:1569. 
4. 
Swarna S, Aziz K, Zubair T, Qadir N, Khan M. Pruritus associated with chronic 
kidney disease: a comprehensive literature review. Cureus. 2019 Jul 
28;11(7):e5256. 
5. 
Verduzco HA and Shirazian S. CKD-associated pruritus: new insights into 
diagnosis, pathogenesis, and management. Kidney Int Rep. 2020;5:1387-402. Epub 
2020 May 8. 
6. 
Weisshaar E, Szepietowski JC, Dalgard F, Garcovich S, Gieler U, Giménez-Arnau 
A, et al. European S2k guideline on chronic pruritus. Acta Derm Venereol. 
2019;99:469-506. 
7. 
Kozono H, Yoshitani H, Nakano R Post-marketing surveillance study of the safety 
and efficacy of nalfurafine hydrochloride (Remitch® capsules 2.5 μg) in 3,762 
hemodialysis patients with intractable pruritus. Int J Nephrol Renovasc Dis. 2018 
15;11:9-24. 
8. 
Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H, Watson SJ. Mu, 
delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ 
hybridization study. J Comp Neurol. 1994;350:412-38. 
9. 
Stein C, Schäfer M, Machelska H. Attacking pain at its source: new perspectives on 
opioids. Nat Med. 2003 Aug;9(8):1003-8. 
10. 
Albert-Vartanian A, Boyd MR, Hall AL, Morgado SJ, Nguyen E, Nguyen VPH, et 
al. Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve 
pain with less opioid adverse effects and abuse potential? J Clin Pharm Ther. 
2016;41:371–82. 
11. 
Yaksh T, Wallace M. Chapter 20: Opioids, analgesia, and pain management. In: 
Brunton LL, Hilal-Dandan R, Knollmann BC, editors. The pharmacological basis 
of therapeutics. 13th ed. New York: McGraw-Hill Education; 2018. p. 355-86. 
12. 
Lipman ZM, Yosipovitch G. An evaluation of difelikefalin as a treatment option for 
moderate-to-severe pruritus in end stage renal disease. Expert Opin Pharmacother. 
2021;22(5):549-55. Epub 2020 Nov 16. 

 
 
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13. 
Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F. A phase 3 trial of 
difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020 Jan 
16;382(3):222-32. 
14. 
Zhao X, Niu Q, Gan L, Hou FF, Liang X, Ni Z, et al. Baseline data report of the 
China Dialysis Outcomes and Practice Patterns Study (DOPPS). Sci Rep. 
2021;11(1):873. 
15. 
Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H. Effect of 
a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 
haemodialysis patients: a phase III, randomized, double-blind, placebo-controlled 
study. Nephrol Dial Transplant. 2010;25:1251-7. Epub 2009 Nov 19. 
16. 
Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al. Pruritus 
in haemodialysis patients: international results from the Dialysis Outcomes and 
Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2006;21:3495-505. 
Epub 2006 Sep 12. 
17. 
Mathur VS, Lindberg J, Germain M, Block G, Tumlin J, Smith M, et al. A 
longitudinal study of uremic pruritus in hemodialysis patients. Clin J Am Soc 
Nephrol. 2010;5:1410-9. 
18. 
Ständer S, Augustin M, Reich A, Blome C, Ebata T, Phan NQ, et al. Pruritus 
assessment in clinical trials: consensus recommendations from the International 
Forum for the Study of Itch (IFSI) special interest group scoring itch in clinical 
trials. Acta Derm Venereol. 2013;93:509-14. 
19. 
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of 
pruritus. Br J Dermatol. 2010;162:587-93. 
20. 
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. 
Core outcome measures for chronic pain clinical trials: IMMPACT 
recommendations. Pain. 2005;113:9-19. 
21. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. October 2013. 
22. 
ICH Harmonised Guideline. ICH E6(R2): Integrated addendum to ICH E6(R1) 
guideline for good clinical practice. 2016 Nov 9. 
23. 
PhRMA. Principles on conduct of clinical trials. Communication of clinical trial 
results. Pharmaceutical Research and Manufacturers of America [Internet]. 2014 
Dec. Available from: https://www.phrma.org/-/media/Project/PhRMA/PhRMA-
Org/PhRMA-Org/PDF/0-9/042009_clinical_trial_principles_final_0.pdf. 
24. 
International Committee of Medicinal Journal Editors [Internet]. Recommendations 
for the conduct, reporting, editing, and publication of scholarly work in medical 
journals. 2019 Dec. p. 1-19. Available from: http://www.icmje.org. 

SUBJECT 
NUMBER: 
WORST ITCHING INTENSITY 
NUMERICAL RATING SCALE (NRS) 
Completed in Dialysis Unit or at Home? (please mark only one)
Dialysis Unit 
Home 
INSTRUCTIONS 
Please indicate the intensity of the WORST ITCHING you experienced over the 
past 24 hours by marking the box with the number that best describes it. After 
completing the scale below, please provide your initials in the SUBJECT INITIALS 
box indicating that you completed the scale by yourself and the DATE and TIME 
you completed the scale. 
Worst Itching Over the Past 24 Hours 
Please indicate the intensity of the WORST ITCHING you experienced over the 
past 24 hours. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
NO 
WORST 
ITCHING 
ITCHING 
IMAGINABLE 
Note: Section to be completed by the site staff after form has been collected from subject 
STUDY DAY NUMBER: 
Site Staff Initials: 
 - Patient Related Outcome (PRO) Worksheet 
Version 1.0 , 10 Oct 2017 
Page 1 of 1 
Date Completed: 
Time: 
2 
0 
D 
D 
M 
M 
M 
Y 
Y 
Y 
Y 
 
AM 
PM 
SUBJECT INITIALS 
First 
Middle 
Last 
- 
Appendix 1 Worst Itching Intensity-Numerical Rating Scale
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Appendix 2 
New York Heart Association Classification of Heart Failure 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
 
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SKINDEX-10 QUESTIONNAIRE 
SUBJECT 
NUMBER: 
INSTRUCTIONS: During the past WEEK, how often have you been bothered by: 
0 
1 
2 
3 
4 
5 
6 
(Never 
bothered) 
(Always 
bothered) 
1. Your itching
2. The persistence/reoccurrence
of your itching
3. The appearance of your skin
from scratching
4. Frustration about your itching
5. Being annoyed about your
itching
6. Feeling depressed about your
itching
7. Feeling embarrassed about
your itching
8. The effects of your itching on
your interactions with others
(for example: interactions with
family, friends, close
relationships, etc.)
9. The effects of your itching on
your desire to be with people
10. The effect of your itching
making it hard to work or do
what you enjoy
Note: Section to be completed by the site staff after form has been collected from subject 
STUDY DAY NUMBER: 
Site Staff Initials: 
 - Patient Related Outcome (PRO) Worksheet 
Version 1.0 , 10 Oct 2017 
Page 1 of 1 
Date Completed: 
Time: 
2 
0 
D 
D 
M 
M 
M 
Y 
Y 
Y 
Y 
 
AM 
PM 
SUBJECT INITIALS 
First 
Middle 
Last 
-
Appendix 3 Skindex-10 Scale
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Appendix 4 
5-D Itch Scale 
1. DURATION: 
During the last 2 weeks, how many hours a day have you been itching? 
Less than 
6 hrs/day 
6-12 hrs/ 
day 
12-18 hrs/day 
18-23 hrs/day 
All day 
 
 
 
 
2. DEGREE: 
Please rate the intensity of your itching over the past 2 weeks 
Not present 
Mild 
Moderate 
Severe 
Unbearable 
3. DIRECTION: 
Over the past 2 weeks has your itching gotten better or worse compared to the 
previous month? 
Completely 
resolved 
Much better, 
but still present 
Little bit better, 
but still present 
Unchanged 
Getting Worse 
4. DISABILITY: 
Rate the impact of your itching on the following activities over the last 2 weeks 
Sleep 
Never affects 
sleep 
Occasionally 
delays falling 
asleep 
Frequently 
delays falling 
asleep 
Delays falling 
asleep and 
occasionally 
wakes me up at 
night 
Delays falling 
asleep and 
frequently 
wakes me up at 
night 
 
N/A 
Never 
affects this 
activity 
Rarely affects 
this activity 
Occasionally 
affects this 
activity 
Frequently 
affects this 
activity 
Always 
affects this 
activity 
Leisure/Social 
Housework/ 
Errands 
 
 
 
 
 
 
Work/School 
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5. DISTRIBUTION: Mark whether itching has been present in the following parts of 
your body over the last 2 weeks. If a body part is not listed, 
choose the one that is closest anatomically. 
Head/Scalp 
 
 
Soles 
 
 
Face 
 
 
Palms 
 
 
Chest 
 
 
Tops of Hands/Fingers 
 
 
Abdomen 
 
 
Forearms 
 
 
Back 
 
 
Upper Arms 
 
 
Buttocks 
 
 
Points of Contact w/ Clothing 
(e.g., waistband, 
undergarment) 
 
 
 
Thighs 
 
 
Lower legs 
 
 
Groin 
 
 
Tops of Feet/Toes 
 
  
 
 
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Appendix 5 
Patient Global Impression Change 
Since the start of the study, my overall status is: 
✓ one box only: 
[1]  Very Much Improved 
[2]  Much Improved 
[3]  Minimally Improved 
[4]  No Change 
[5]  Minimally Worse 
[6]  Much Worse 
[7]  Very Much Worse 
 
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