A Phase III Clinical Study of MR13A9 in Hemodialysis Patients With Pruritus
Phase: PHASE3
Conditions: Uremic Pruritus
Sponsor: Kissei Pharmaceutical Co., Ltd.

CONFIDENTIAL 
Protocol No.: MR13A9-5 
Version: 1.0 
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CLINICAL STUDY PROTOCOL 
 
 
 
 
Title of Study: 
A phase III clinical study of MR13A9 in previously treated 
hemodialysis patients with pruritus 
Protocol No.: 
MR13A9-5 
 
Version: 
1.0 
 
Date of 
Creation/Amendment: 
October 28, 2020 
 
Sponsor: 
Kissei Pharmaceutical Co., Ltd. 
 
 
 
Confidentiality Statement 
This confidential document contains the sponsor’s proprietary information. Any 
unpublished information contained in the document may not be disclosed without 
written consent of the sponsor. 

CONFIDENTIAL 
Protocol No.: MR13A9-5 
Version: 1.0 
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CONFIDENTIAL 
Protocol No.: MR13A9-5 
Version: 1.0 
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Protocol Synopsis 
Title of Study: 
A phase III clinical study of MR13A9 in previously treated hemodialysis patients with pruritus 
(Protocol No.: MR13A9-5) 
Development Phase: 
Phase III 
Study Objectives: 
1. Primary Objective 
To confirm the superiority of MR13A9 0.5 μg/kg administered for 4 weeks in improving itching in previously treated 
hemodialysis patients with pruritus versus placebo in a double-blind design. 
2. Secondary Objectives 
1) To determine the efficacy of MR13A9 0.5 μg/kg in improving the following in previously treated hemodialysis patients 
with pruritus: 
• 
Degree of itching 
• 
Itching-related QOL 
2) To determine the safety of MR13A9 0.5 μg/kg in previously treated hemodialysis patients with pruritus. 
Endpoints: 
1. Efficacy endpoints 
1) Primary endpoint 
Itch NRS score (The primary variable is change from baseline in the mean 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. 
2) Secondary endpoints 
• 
Itch score based on the Shiratori’s severity criteria 
• 
Skindex-16 score 
• 
5-D itch scale score 
• 
Patient Global Impression of Change (PGIC) 
2. Safety endpoints 
• 
Occurrence of adverse events 
• 
Occurrence of adverse drug reactions 
• 
Occurrence of adverse events of special interest 
• 
Laboratory tests (hematology, blood biochemistry, endocrinology) 
• 
Vital signs (blood pressure, pulse rate, body temperature) 
• 
Body weight 
• 
12-lead ECG 
• 
Dependency assessment 
Study Population: 
Double-blind period 
The double-blind period of this study will enroll previously treated hemodialysis patients with pruritus who meet all of the 
inclusion criteria and none of the exclusion criteria below. 
1. Inclusion criteria 
1) Patients aged 20 years or older (at the time of signing informed consent) 
2) Patients providing written informed consent for study participation in person 
3) Patients with chronic renal failure on periodic hemodialysis (HD, off-line HDF, on-line HDF, or I-HDF) 3 times weekly 
for ≥ 12 weeks prior to the informed consent procedure (including the date of informed consent) who can continue 
hemodialysis without changing its frequency or method (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 
4) Patients whose pruritus treatment within 1 year prior to the informed consent procedure meets either (1) or (2) below: 
(1) Drug therapy with nalfurafine hydrochloride for ≥ 2 consecutive weeks 
(2) Inadequate response to both drug therapies a) and b) below: 
a) Systemic (e.g., oral, injection) therapy with antihistamines or antiallergics contained in prescription drugs 
indicated for the treatment of itching for ≥ 2 consecutive weeks 
b) Local (topical) therapy with prescription drugs indicated for the treatment of itching or moisturizers prescribed 
by physicians 
5) Patients whose pruritus has been treated with 1 or more drugs listed below since prior to the start of the screening period: 
• 
Drugs indicated for the treatment of itching (prescription/nonprescription) (excluding nalfurafine hydrochloride) 
• 
Drugs to treat itching (prescription/nonprescription) 
• 
Moisturizing drugs (prescription/nonprescription) 
• 
Products formulated with any of the above 
6) Patients whose NRS score (Appendix 1) in the 7 days prior to the start of the double-blind period (7 days including the 

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Protocol No.: MR13A9-5 
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score recorded on the start day of treatment) meets both of the below: 
• 
NRS scores have been recorded for ≥ 5 days. 
• 
The mean value of the recorded scores exceeds 4.0 (not including 4.0). 
7) Patients whose itch score based on the Shiratori’s severity criteria (Appendix 2) in the 7 days prior to the start of the 
double-blind period (7 days including the score recorded on the start day of treatment) meets both of the below: 
• 
Itch scores during the day and the night have been recorded for ≥ 5 days. 
• 
The larger itch score either during the day or the night is “3. Moderate itching” or greater for ≥ 2 days. 
8) Patients who can record the symptom diary, as instructed by the principal investigator, subinvestigator, or clinical 
research coordinator 
2. Exclusion criteria 
1) Patients 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 principal investigator or subinvestigator (e.g., atopic 
dermatitis, chronic urticaria) 
2) Patients with concurrent hepatic cirrhosis 
3) Patients who used nalfurafine hydrochloride within 2 weeks prior to the start of the screening period 
4) Patients who received phototherapy to treat itching within 4 weeks prior to the start of the screening period 
5) Patients who previously received any study drug (including placebo) in a clinical study of MR13A9 
6) Patients with any adverse drug reaction to nalfurafine hydrochloride in the past who are ineligible for study participation 
in the opinion of the principal investigator or subinvestigator 
7) Patients with drug hypersensitivity to opioids 
8) Patients whose laboratory data at the start of the screening period meet any of the criteria (1) to (3) below: 
(1). ALT: > 2.5 times the upper limit of normal 
(2) AST: > 2.5 times the upper limit of normal 
(3) Total bilirubin: > 2 times the upper limit of normal 
9) Patients with congestive heart failure (NYHA functional class IV) (Appendix 3) 
10) Patients with concurrent malignancy or a history of malignancy within 5 years prior to the informed consent procedure 
11) Patients with concurrent or previous drug abuse (defined as illicit drug use) 
12) Patients with concurrent or previous alcoholism 
13) Patients with a history of severe drug hypersensitivity (anaphylactic shock, etc.) 
14) Patients with concurrent depression, schizophrenia, or dementia 
15) Patients with a concurrent mental disorder that could affect the evaluation of the investigational product 
16) Female patients who are pregnant, breastfeeding, intending to become pregnant between the informed consent procedure 
and the end of the follow-up period, or unwilling to use appropriate methods to prevent conception 
17) Male patients who are unwilling to use appropriate methods to prevent conception between the start of study treatment 
and 12 weeks after the day of the final dose 
18) Patients who received treatment with any study drug or studyl device in a clinical study (including clinical studies of 
medical devices or cellular and tissue-based products) within 12 weeks 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 
19) Patients scheduled to be hospitalized (over at least 1 night) to receive any medical intervention between the informed 
consent procedure and the end of the follow-up period 
20) Patients withdrawn from the study during the screening period because they are found not meeting either of inclusion 
criteria 6) or 7) after participation in the study 
21) Patients withdrawn from the study during the screening period after re-registration 
22) Other patients ineligible for study participation in the opinion of the principal investigator or subinvestigator 
Extension period 
Subjects meeting all of the following criteria for entrance at the Week 6 visit during the double-blind period will enter into 
the extension period. Subjects not meeting the criteria for entrance will be withdrawn from the study and undergo the 
assessments at discontinuation promptly. 
1) Subjects not withdrawn during the double-blind period 
2) Subjects receiving at least 14 doses of the study drug during the double-blind period 
3) Subjects completing at least 70% of the symptom diary during the double-blind period 
4) Subjects who are not inappropriate to enter into the extension period for safety or other reasons in the opinion of the 
principal investigator or subinvestigator 
Study Design: 
• 
Double-blind period 
A placebo-controlled, multicenter, randomized, double-blind, parallel-group study 
• 
Extension period 
A multicenter, open-label study 
Study Drugs: 
1. Test drug 
• 
MR13A9 17.5 μg: Pre-filled syringe containing 17.5 μg of MR13A9 per syringe 
• 
MR13A9 25.0 μg: Pre-filled syringe containing 25.0 μg of MR13A9 per syringe 
• 
MR13A9 35.0 μg: Pre-filled syringe containing 35.0 μg of MR13A9 per syringe 
• 
MR13A9 42.5 μg: Pre-filled syringe containing 42.5 μg of MR13A9 per syringe 

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Protocol No.: MR13A9-5 
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2. Comparator 
• 
MR13A9 placebo: Pre-filled syringe not containing MR13A9 
The MR13A9 placebo is indistinguishable from MR13A9 17.5, 25.0, 35.0, or 42.5 µg. 
Dosage and Administration: 
1. Screening period 
A 2-week period before entry into the double-blind period is defined as the screening period, during which subjects will 
receive no study drug. 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 study drug will be injected into the venous line of the dialysis circuit at the end of each dialysis session 
for 6 weeks (3 times weekly, 18 times in total). The dose of the study drug will be determined according to Table 1 based on 
the subject’s dry weight before dialysis on the start day of the screening period. 
If any dialysis circuit trouble precludes injection through the dialysis circuit, the study drug will be administered directly 
intravenously. If an extra fourth dialysis session required within the week, the study drug will be administered (up to 4 times 
weekly). If only the extracorporeal ultrafiltration method is used, the study drug will not be administered. 
Table 1 Doses 
Dry weight 
Injected volume 
MR13A9 dose 
0.5 µg/kg group 
Placebo group 
< 45.0 kg 
0.35 mL 
17.5 μg 
0 μg 
≥ 45.0 kg, < 65.0 kg 
0.35 mL 
25.0 μg 
0 μg 
≥ 65.0 kg, < 85.0 kg 
0.35 mL 
35.0 μg 
0 μg 
≥ 85.0 kg 
0.35 mL 
42.5 μg 
0 μg 
3. 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, the study drug will be injected into the venous line of the dialysis circuit at the end of each dialysis session 
for 52 weeks (3 times weekly, 156 times in total). Study treatment in the extension period will be started at Week 6. The dose 
of the study drug will be determined according to Table 1, and the dose of the study drug from Week 6 to immediately before 
Week 34 will be determined based on the subject’s dry weight before dialysis at Week 6. The dose of the study drug after 
Week 34 will be determined based on the subject’s dry weight before dialysis at Week 34. The study drug will not be 
administered at Week 58. 
If any dialysis circuit trouble precludes injection through the dialysis circuit, the study drug will be administered directly 
intravenously. If an extra fourth dialysis session is required within the week, the study drug will be administered (up to 4 
times weekly). If only the extracorporeal ultrafiltration method is used, the study drug will not be administered. 
4. Follow-up period 
A 1-week period after the assessments at discontinuation or a 1-week period after the end of the extension period is defined 
as the follow-up period, during which subjects will receive no study drug. 
Concomitant Treatments: 
Subjects may use any drug used to treat symptoms of chronic renal failure or drug used to treat complications at the start of 
the screening period without changing its dosage and administration whenever possible until the end of the follow-up period. 
I he dosage and administration of any concomitant medication may be changed for safety reasons including adverse events. 
Any centrally acting concomitant drug should be used with attention to possible central adverse events. 
1. Prohibited concomitant medications 
Between the start of the screening period and the end of the follow-up period, use of the drugs listed in Table 2 will be 
prohibited. 
Table 2 Prohibited concomitant medications 
Class 
Common drugs 
1) Opioids 
Nalfurafine hydrochloride, morphine, fentanyl, oxycodone, buprenorphine, 
pentazocine, codeine phosphate, dihydrocodeine, etc. 
2) Opioid antagonists 
Naloxone hydrochloride, eptazocine hydrobromide, naldemedine tosylate, etc. 
3) Investigational products other 
than MR13A9 
Various kinds 
2. Conditionally permitted concomitant medications 
Between the start of the screening period and the end of the double-blind period (or the time of withdrawal during the 
double-blind period), subjects may use the drugs listed below that have been used since before the screening period without 
changing their dosage and administration. In addition, the drugs listed below should not be newly used. The dosage and 
administration at the start of the screening period should not be changed or newly used. 
Between the start of the extension period and the end of the follow-up period, the dosage administration should not be 
changed or newly used whenever possible. 
1) Drugs indicated for the treatment of itching (prescription/nonprescription) 
2) Drugs to treat itching (prescription/nonprescription) 
3) Moisturizing drugs (prescription/nonprescription) 
4) Steroids (excluding inhalants, nasal drops, ear drops, eye drops, and eye ointments) 

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Protocol No.: MR13A9-5 
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5) Capsaicin (topical) 
6) In-hospital drugs formulated with any of the drugs listed 1) to 5) above 
7) Pregabalin, gabapentin 
8) Antidepressants, anxiolytics 
Among the drugs listed in 1) to 6) above, however, topical use of any prescription/nonprescription drug 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). 
Use of any combination product that contains ingredients indicated for itching but is not indicated itself for itching will not 
be restricted. 
3. 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. 
Hemodialysis Conditions: 
Between the start of the screening period and the end of the follow-up period, the frequency of dialysis per week and the 
hemodialysis method (HD, off-line HDF, on-line HDF, or I-HDF) may not be changed. Any temporary change in dialysis 
frequency or hemodialysis method associated with travel or admission to other hospitals with no changes in treatment 
strategies is acceptable. The hemodialysis conditions (duration of dialysis and dialyzer) should not be changed whenever 
possible. 
Investigations, Observations, Tests, and Evaluations and their Schedules: 
See the study schedule. 
Sample Size: 
• 
Double-blind period: The study will enroll 86 subjects each MR13A9 0.5 μg/kg group and the placebo group (172 in 
total). 
• 
Extension period: The study will enroll 100 subjects who complete 58-week treatment. 

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Protocol No.: MR13A9-5 
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Study Schedule 
 
 
Screening period 
Double-blind period 
Extension period 
Follow-up period 
Visit (weeks after initial dose) 
 
Week −2 
Week −1 
Initial dose 
Week 1 
Week 2 
Week 4 
Week 6 
Week 7 
Week 8 
Week 10 Week 12 Week 18 Week 26 Week 34 Week 46 Week 58 Week 59 
Acceptable time window a) 
 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Week 17–
19 
Week 
25–27 
Week 
33–35 
Week 
45–47 
Week 
57–59 
— 
Visit 
 
1 
— 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Day of the week a) 
 
Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue Mon/Tue 
Mon/Tue 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject registration 
Primary Secondary 
 
Tertiary 
 
 
 
Entering into 
the extension 
period 
 
 
 
 
 
 
 
 
 
 
Study treatment b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of DW/dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRSc) 
Shiratori’s severity criteria c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skindex-16 
5-D itch scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs d) 
Laboratory tests d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Postdialysis BUN 
Postdialysis weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight d) 
12-lead ECG d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dependency assessment 
 
 
 
 
 
 
 
 
 
 
 
 
d) 
 
d) 
 
d) 
 
Adverse events 
Concomitant 
medications/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific signs/symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prohibited concomitant 
medications 
Prohibited concomitant 
therapies 
Hemodialysis method 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conditionally permitted 
concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) Assessments and tests will be performed on the day of first dialysis of each week (Monday or Tuesday). 
b) The study drug will not be administered in Week 58. 
c) Subjects will record these data in the symptom diary once daily from the next day of the start date of the screening period until the end of the follow-up period. 
d) To be performed before dialysis. 
e) To be performed only in women of childbearing potential (within 1 year of their last menstrual period and who have not undergone hysterectomy or bilateral total ovariectomy). 

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Study Schedule (at the time of discontinuation) 
 
Double-blind period 
or extension period 
Follow-up period f) 
Visit 
(weeks after initial dose) 
At discontinuation 
Week 1 after 
discontinuation 
Visit 
— 
— 
Day of the week 
— e) 
— g) 
Informed consent 
 
 
Eligibility assessment 
 
 
Subject demographics 
 
 
Subject registration a) 
 
 
Study treatment 
 
 
Confirmation of DW/dose 
 
 
NRS b) 
Shiratori’s severity criteria b) 
 
 
Skindex-16 
5-D itch scale 
 
 
PGIC 
 
 
Vital signs c) 
Laboratory tests c) 
 
 
Postdialysis BUN 
Postdialysis weight 
 
 
Serum pregnancy test d) 
 
 
Body weight c) 
12-lead ECG c) 
 
 
Dependency assessment 
c) 
 
Adverse events 
Concomitant 
medications/therapies 
 
 
Specific signs/symptoms 
 
 
Prohibited concomitant 
medications 
Prohibited concomitant 
therapies 
Hemodialysis method 
 
 
Conditionally permitted 
concomitant medications 
 
 
a) To be performed only in subjects withdrawing from the study during the double-blind period. 
b) Subjects will record these data in the symptom diary once daily until the end of the follow-up period. 
c) To be performed before dialysis. 
d) To be performed only in women of childbearing potential (within 1 year of their last menstrual period and who have not undergone hysterectomy or bilateral total ovariectomy). 
e) Assessments and tests will be performed on the next dialysis day after discontinuation has been decided. 
f) Excluding those withdrawing from the study during the screening period. 
g) To be performed on the same day of the week as the day of the assessments at discontinuation. 

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Protocol No.: MR13A9-5 
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Table of Contents 
1. Rationale and Background for the Investigational Plan ........................................ 14 
1.1 Pruritus in Hemodialysis Patients ..................................................................... 14 
1.2 Treatment of Pruritus in Hemodialysis Patients ................................................ 14 
1.3 History of the Development of MR13A9 ........................................................... 14 
1.4 Summary of Expected Adverse Drug Reactions and Benefits .......................... 18 
2. Study Title and Development Phase ..................................................................... 20 
2.1 Title of Study ..................................................................................................... 20 
2.2 Development Phase ......................................................................................... 20 
3. Study Objectives ................................................................................................... 20 
3.1 Primary Objective ............................................................................................. 20 
3.2 Secondary Objectives ....................................................................................... 20 
4. Endpoints .............................................................................................................. 20 
4.1 Endpoints for Efficacy ....................................................................................... 20 
4.2 Endpoints for Safety ......................................................................................... 21 
5. Study Population .................................................................................................. 21 
5.1 Double-blind period .......................................................................................... 21 
5.2 Extension Period .............................................................................................. 24 
5.3 Discontinuation of Individual Subjects .............................................................. 25 
6. Subject Consent ................................................................................................... 26 
6.1 Timing of Informed Consent.............................................................................. 26 
6.2 Informed Consent Procedure............................................................................ 26 
7. Study Drugs .......................................................................................................... 27 
7.1 Test Drug and Comparator ............................................................................... 27 
7.2 Packaging of the Study Drugs .......................................................................... 27 
7.3 Labeling ............................................................................................................ 28 
7.4 Management of the Study Drugs ...................................................................... 28 
8. Study Methods ...................................................................................................... 28 
8.1 Study Design .................................................................................................... 28 
8.2 Dosage and Administration ............................................................................... 28 
8.3 Concomitant Treatments .................................................................................. 30 
8.4 Hemodialysis Conditions .................................................................................. 31 
8.5 Randomization and Blinding ............................................................................. 31 
8.6 Sample size ...................................................................................................... 33 
9. Subject Instructions and Management.................................................................. 33 

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10. Investigations, Observations, Tests, and Evaluations ......................................... 34 
10.1 Subject Demographics ................................................................................... 34 
10.2 Treatment Compliance ................................................................................... 35 
10.3 Dry Weight ...................................................................................................... 35 
10.4 Concomitant Medications and Concomitant Therapies .................................. 35 
10.5 Implementation Status of Dialysis ................................................................... 36 
10.6 Efficacy Endpoints .......................................................................................... 36 
10.7 Laboratory Tests ............................................................................................. 37 
10.8 Vital Signs (Blood Pressure, Pulse Rate, Body Temperature) ........................ 37 
10.9 Body Weight ................................................................................................... 37 
10.10 12-lead ECG ................................................................................................. 38 
10.11 Dependency Assessment ............................................................................. 38 
10.12 Pregnancy Test ............................................................................................. 38 
10.13 Adverse Events ............................................................................................. 38 
11. Investigations, Observations, Tests, and Evaluations at Each Time 
Point ..................................................................................................................... 42 
11.1 At the Time of Signing Informed Consent........................................................ 42 
11.2 Visit 1 (Week −2, at the Start of the Screening Period) ................................... 42 
11.3 Visit 2 (Start Day of Administration, at Start of the Double-blind 
Period) .............................................................................................................. 43 
11.4 Visit 3 (Week 1) ............................................................................................... 43 
11.5 Visit 4 (Week 2) ............................................................................................... 43 
11.6 Visit 5 (Week 4) ............................................................................................... 43 
11.7 Visit 6 (Week 6, at the Start of the Extension Period) ..................................... 44 
11.8 Visit 7 (Week 7) ............................................................................................... 44 
11.9 Visit 8 (Week 8) ............................................................................................... 44 
11.10 Visit 9 (Week 10) ........................................................................................... 45 
11.11 Visit 10 (Week 12) ......................................................................................... 45 
11.12 Visit 11 (Week 18) ......................................................................................... 45 
11.13 Visit 12 (Week 26) ......................................................................................... 45 
11.14 Visit 13 (Week 34) ......................................................................................... 46 
11.15 Visit 14 (Week 46) ......................................................................................... 46 
11.16 Visit 15 (Week 58, at the Start of the Follow-up Period) ............................... 46 
11.17 Visit 16 (Week 59 [at the End of the Follow-up Period]) or 1 Week 
after Discontinuation ......................................................................................... 47 
11.18 At Discontinuation ......................................................................................... 47 

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12. Measures to Ensure the Safety of the Clinical Study .......................................... 48 
12.1 Action to be Taken for Adverse Events ........................................................... 48 
12.2 Action to be Taken for and Response to Serious Adverse Events .................. 48 
12.3 Response to Serious Adverse Events Caused by Device 
Deficiencies ...................................................................................................... 48 
12.4 Action to be Taken for and Response to Pregnancies .................................... 48 
12.5 Collection and Provision of Safety Information ............................................... 49 
12.6 Opening of Emergency Key Codes ................................................................ 49 
13. Discontinuation/Suspension of the Clinical Study ............................................... 50 
13.1 Discontinuation/Suspension of Parts of the Study or the Entire Study ........... 50 
13.2 Discontinuation Criteria (Discontinuation/Suspension of Parts of the 
Study or the Entire Study) ................................................................................ 50 
13.3 Procedures for Discontinuation/Suspension ................................................... 50 
14. Statistical Analysis .............................................................................................. 51 
14.1 Analysis Sets .................................................................................................. 51 
14.2 Analysis Groups .............................................................................................. 52 
14.3 Disposition of Subjects ................................................................................... 52 
14.4 Demographic and Other Baseline Characteristics .......................................... 52 
14.5 Efficacy ........................................................................................................... 52 
14.6 Safety ............................................................................................................. 55 
14.7 Timing of Analyses .......................................................................................... 56 
15. Compliance with the Protocol, etc....................................................................... 57 
15.1 Agreement on the Protocol ............................................................................. 57 
15.2 Amendment of the Protocol ............................................................................ 57 
15.3 Deviation from the Protocol ............................................................................ 57 
16. Direct Access to Source Documents................................................................... 57 
16.1 Source Documents and Source Data ............................................................. 57 
16.2 Direct Access .................................................................................................. 58 
16.3 Consistency Between Source Documents and Case Report Forms ............... 58 
17. Quality Control and Quality Assurance for the Study .......................................... 58 
18. Ethics .................................................................................................................. 58 
18.1 Compliance with GCP .................................................................................... 58 
18.2 Protection of Subject Confidentiality ............................................................... 58 
18.3 Compensation to Subjects .............................................................................. 58 
19. Data Handling, and Record Keeping .................................................................. 59 
19.1 Preparation and Submission of Case Report Forms ...................................... 59 

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19.2 Recording of the Symptom Diary .................................................................... 59 
19.3 Submission of 12-lead ECG charts ................................................................. 59 
19.4 External Data .................................................................................................. 59 
19.5 Record Keeping .............................................................................................. 60 
20. Monetary Payment.............................................................................................. 60 
21. Publication Policy................................................................................................ 60 
22. Study Administrative Structure ............................................................................ 60 
23. History of Protocol Amendments......................................................................... 60 
24. Literature References ......................................................................................... 61 
25. Appendices ......................................................................................................... 63 

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List of Abbreviations and Terms 
Abbreviation/Term 
Definition 
AUC0-x 
Area under the plasma concentration-time curve from time zero to x hours 
Cmax 
Maximum plasma concentration 
CYP 
Cytochrome P450 
EC50 
50% effective concentration 
ECG 
Electrocardiography 
FOB 
Functional observational battery 
HD 
Hemodialysis 
HDF 
Hemodiafiltration 
hERG 
Human ether-a-go-go related gene 
IL-(x) 
Interleukin 
KOR 
κ opioid receptor 
LPS 
Lipopolysaccharide 
MATE 
Multidrug and toxin extrusion protein 
MIP 
Macrophage inflammatory protein 
MOR 
μ opioid receptor 
NRS 
Numerical Rating Scale 
NYHA 
New York Heart Association 
PGIC 
Patient Global Impression of Change 
QOL 
Quality of life 
t1/2 
Terminal-phase elimination half-life 
Tmax 
Time to reach peak concentration 
TNF 
Tumor necrosis factor 
UGT 
UDP-glucuronosyltransferase 
VAS 
Visual analog scale 
 

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Protocol No.: MR13A9-5 
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1. Rationale and Background for the Investigational Plan 
1.1 Pruritus in Hemodialysis Patients 
Pruritus is a common symptom in patients with chronic renal failure receiving hemodialysis 
treatment. In Japan, approximately 35% of hemodialysis patients are distressed by moderate 
or severe pruritus.1) In hemodialysis patients, pruritus can occur anywhere on the body, 
causing widespread, symmetric, intermittent itching. Itching is most prominent at night in 
general, and it deprives patients with more severe pruritus of about 2 hours of sleep on 
average.2) It has been reported that decreased sleep quality and fatigue occur more frequently 
by 1.9 to 3.7 times and 2.2 to 5.8 times, respectively, in patients with moderate to severe 
pruritus than in patients with no pruritus, and that the risk of death is 22% higher in patients 
with moderate to severe pruritus than in patients with no pruritus.3) Thus, pruritus in 
hemodialysis patients affects their physical and mental health by causing sleep disorder and 
depression, reduces their QOL markedly, and increases their risk of death. 
The cause of pruritus in hemodialysis patients is not well understood, and this condition is 
considered intractable. The development of pruritus involves multiple factors, which include 
dry skin, accumulation of endogenous substances, and overproduction of chemical mediators 
such as histamine and substance P.4),5) Other possible causes of pruritus include altered 
immune function and collapsed opioid balance. Opioid receptors are divided into 3 subtypes 
involved in the regulation of pain and itching signals (μ, κ, and δ).The μ opioid receptor 
(MOR) binds to β-endorphin and inhibits pain and induces itching, and the κ opioid receptor 
(KOR) binds to dynorphin and inhibits pain and itching.6)-8) In dialysis patients with pruritus, 
the μ opioid system that induces itching is believed to be predominant over the κ opioid 
system that inhibits itching.9),10) 
1.2 Treatment of Pruritus in Hemodialysis Patients 
Main treatments of pruritus in hemodialysis patients include topical therapy with moisturizers, 
such as milky lotion and cream, and with steroids, and topical or internal therapy with 
antihistamines and antiallergics.11) However, many patients have an inadequate response to 
these existing treatments such as topical and internal therapies, and these patients are treated 
with an oral KOR agonist, nalfurafine hydrochloride. This drug activates KOR in the central 
nervous system, thereby exerting antipruritic effects on pruritus refractory to existing 
treatments. Nalfurafine hydrochloride is effective in treating pruritus; however, because of the 
oral formulation, dialysis patients have to take a larger number of tablets, which increases the 
burden of these patients taking many oral drugs to treat their complications. In addition, 
dialysis patients may have difficulty in taking this drug because of their decreased salivary 
secretion and restricted fluid intake. Furthermore, nalfurafine hydrochloride activates KOR in 
the central nervous system and the gastrointestinal tract, thereby inducing adverse drug 
reactions, such as sleep loss and constipation, frequently.12) 
Under these circumstances, patients with an inadequate response to existing treatments have 
hoped the development of a new treatment that relieves itching, is more convenient for use, 
and causes fewer adverse drug reactions. 
1.3 History of the Development of MR13A9 
MR13A9 (non-Japanese investigational product code: CR845), a novel peptide KOR agonist 
developed by Cara Therapeutics, Inc. in the United States, is under development as an 
injectable formulation and an oral formulation to relieve pain and pruritus. In Japan, Maruishi 

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Pharmaceutical Co., Ltd. and Kissei Pharmaceutical Co., Ltd. have jointly undertaken its 
development as an injectable formulation to relieve pruritus. MR13A9 has been designed to 
activate KOR in peripheral nerves and immune cells, thereby relieving visceral and 
inflammatory pain and itching and regulating inflammatory signals. MR13A9, which has 
potent agonist effects on human and rodent KOR, is expected to be effective in treating 
pruritus based on the results of identification of its pharmacological class and animal 
experiments. In addition, MR13A9 is expected to be safer and more tolerable than existing 
KOR agonists because of the limited membrane permeability and central nervous system 
penetration as indicated by its physicochemical properties. Furthermore, MR13A9 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. 
Being expected to become a treatment of pruritus in hemodialysis patients from nonclinical 
study results, MR13A9 was evaluated in a phase I clinical study in healthy Japanese adults 
and a clinical pharmacology study in hemodialysis patients in Japan. Subsequently, a phase II 
clinical study in hemodialysis patients was conducted to investigate the dose-response 
relationship for the efficacy and safety of MR13A9. There was a dose-response relationship 
showing a constant effect of MR13A9 at doses of 0.5 μg/kg and higher, indicating that the 
recommended clinical dose was 0.5 μg/kg. Based on these results, this phase III clinical study 
has been planned to confirm the superiority of MR13A9 0.5 μg/kg to placebo as well as to 
confirm its long-term safety. 
Outside Japan, phase I clinical studies were conducted in healthy adults, patients with 
impaired renal function, patients with end-stage renal disease, and recreational drug users, 
which were followed by a phase II clinical study in hemodialysis patients with moderate to 
severe pruritus. A phase III clinical study in hemodialysis patients with moderate to severe 
pruritus is ongoing currently. 
1.3.1 Nonclinical study results 
In in vitro primary pharmacodynamic studies, MR13A9 showed an EC50 of 0.048 and 0.16 
nmol/L against mouse and human KOR, respectively, and did not have any effects on human 
MOR or human δ opioid receptors at levels up to 10 μmol/L. These results suggested that 
MR13A9 is a KOR-specific full agonist. At levels up to 10 μmol/L, MR13A9 exhibited no 
affinity for human or rodent receptors, enzymes, transporters, or ion channels, other than 
KOR. 
In in vivo primary pharmacodynamic studies, MR13A9 showed dose-dependent antipruritic 
effects on mouse models of histamine-induced pruritus, substance P-induced pruritus, 
compound 
48/80-induced 
pruritus 
through 
mast 
cell 
stimulations, 
and 
guanidinonaltrindole-induced pruritus through KOR inhibition. MR13A9 dose-dependently 
reduced the release of TNFα induced by LPS in mice and also reduced the release of IL-1β, 
IL-2, MIP-1β, and IL-12 (p40/p70) in mice. In addition, MR13A9 dose-dependently reduced 
paw edema in a rat carrageenan-induced paw edema model. These results suggested that 
MR13A9 has anti-inflammatory effects. 
Safety pharmacology studies of MR13A9 showed the following findings. With respect to the 
central nervous system effects of MR13A9, a functional observational battery study in rats 
revealed a sedation-like effect in all treatment groups (1, 5, and 25 mg/kg iv), but this effect 
was not dose-dependent and resolved at 48 hours after administration. In a rotarod study in 

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rats, motor coordination was affected in animals given ≥ 3 mg/kg. With respect to its 
cardiovascular effects, inhibition of hERG potassium channel current was 7.2% even at 1 
mmol/L. In a telemetry study in conscious monkeys, animals exhibited decreases in blood 
pressure, body temperature, and pulse rate as well as lethargy and hunchback posture. 
MR13A9 did not affect any ECG parameters. 
With respect to organ and tissue concentrations of MR13A9, a study of radioactivity tissue 
distribution following repeated intravenous doses in rats showed that the radioactivity was 
eliminated from the plasma in a biphasic manner. Radioactivity distribution was prominent in 
the renal medulla and cortex and minimal in the central nervous system. 
With respect to its drug interaction, MR13A9 did not inhibit the metabolism of CYP, UGT, or 
renal excretion transporters (MATE1 and MATE2K), suggesting that it does not serve as their 
substrate. MR13A9 was therefore considered less likely to cause drug interactions via these 
isoforms and transporters. 
In a 26-week repeated intravenous dose toxicity study of MR13A9 in rats, animals receiving ≥ 
0.25 mg/kg/day exhibited decreased locomotor activity, staggering gait, abducted forelimbs, 
and decreases in body weight and food consumption, all of which were transient changes 
observed in early weeks of treatment. Histopathological examination revealed proximal 
tubular basophilic degeneration, seminiferous tubule atrophy, and epididymal intraluminal cell 
debris in male animals receiving 25 mg/kg/day. The no-observed-adverse-effect level was 2.5 
mg/kg/day in males and 25 mg/kg/day in females. A 39-week repeated intravenous dose 
toxicity study of MR13A9 in monkeys showed the following findings: Sedation, somnolence, 
decreased locomotor activity, and vomiting in animals receiving ≥ 0.25 mg/kg/day; lethargy in 
male animals receiving 1 mg/kg/day; decreased body weight in animals receiving 1 
mg/kg/day; and decreases in food consumption and urine volume in animals receiving ≥ 0.06 
mg/kg/day. All of these were transient changes observed in early weeks of treatment. The no-
observed-adverse-effect level was ≥ 1 mg/kg/day in both males and females. 
The reproductive toxicity of MR13A9 was investigated in a study on fertility and early 
embryonic development to implantation in rats, studies on embryo-fetal development in rats 
and rabbits, and a study on pre- and postnatal development, including maternal function, in 
rats. None of these studies revealed potentially MR13A9–related abnormalities in early 
embryonic development, embryo-fetal development, maternal animals, pups (F1), or fetuses 
(F2). 
The genotoxicity of MR13A9 was investigated in a bacterial reverse mutation test, a 
chromosomal aberration test with cultured mammalian cells, and a mouse micronucleus test. 
None of these tests revealed findings suggestive of its genotoxicity. 
In a 26-week repeated subcutaneous dose carcinogenicity study of MR13A9 in mice and a 
2-year repeated subcutaneous dose carcinogenicity study in rats, MR13A9 was not 
carcinogenic in mice or rats. 
1.3.2 Clinical study results 
1.3.2.1 Clinical pharmacology studies 
In a Japanese clinical pharmacology study in hemodialysis patients (MR13A9-2), plasma 
MR13A9 concentrations after the first and third intravenous doses showed a biphasic 
elimination pattern: A rapid initial phase and a slow elimination phase. The t1/2 of MR13A9 
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accumulation ratio of Day 5 to Day 1 calculated using the Cmax, AUC0-48, and trough values 
indicated a low likelihood of accumulation of MR13A9. 
In a Japanese clinical pharmacology study in healthy subjects (MR13A9-1), 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 an overseas clinical pharmacology study in hemodialysis patients (CR845-CLIN1003), 
postdialysis plasma concentrations of MR13A9 decreased by 75% to 80% on average down 
below 2 ng/mL on average in all treatment groups (1, 3, and 6 μg/kg). These results suggested 
that unchanged MR13A9 is eliminated primarily through the kidneys. 
In an overseas QT/QTc evaluation study (CR845-100201), 58 healthy adults (26 males and 32 
females) received a single dose of MR13A9 0.5 or 3.0 μg/kg, placebo, or moxifloxacin 400 
mg. The upper limit of the 90% confidence interval of ΔΔQTcF in the MR13A9 0.5 and 3.0 
μg/kg groups was below 10 msec at all time points. No clinically significant QTc interval 
prolongation was observed at any dose. 
In an overseas mass balance study (CR845-100302), a single dose of [14C]-MR13A9 was 
administered to 6 healthy adults (males) and 6 hemodialysis patients (males). In the healthy 
adults, [14C]-MR13A9 was excreted mainly in urine, and 80.5% and 11.3% of radioactivity 
were recovered in urine and feces, respectively. In the hemodialysis patients, [14C]-MR13A9 
was excreted mainly in feces, and 11.2%, 58.8%, and 19.5% of radioactivity were recovered 
in urine, feces, and dialysate, respectively. In the healthy adults and hemodialysis patients, 
over 99% of MR13A9 was present as unchanged drug in their plasma. In addition, no 
metabolites detected in urine or feces accounted for more than 10% of the administered dose 
in any subject group. 
1.3.2.2 Efficacy and safety 
In a Japanese phase II clinical study (MR13A9-3), 105 previously treated hemodialysis 
patients with pruritus received MR13A9 0.25, 0.5, 1.0, or 1.5 μg/kg, or placebo injected into 
the venous line of the dialysis circuit at the end of each dialysis session 3 times weekly for 2 
weeks. The primary endpoint of change in VAS (i.e., change based on the larger VAS 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 MR13A9 at doses ≥ 0.5 μg/kg. 
Common adverse drug reactions (reported in ≥ 10% of subjects in any of the MR13A9 
groups) 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 MR13A9 0.5 µg/kg group. 
In a Japanese phase II clinical study (MR13A9-4), 247 previously treated hemodialysis 
patients with pruritus received MR13A9 0.25, 0.5, or 1.0 μg/kg, or placebo injected into the 
venous line of the dialysis circuit at the end of each dialysis session 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 MR13A9 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 

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improvement in the MR13A9 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. 
Adverse drug reactions reported in ≥ 3% of subjects in any group during the treatment period 
included somnolence, dizziness, palpitations, vomiting, nausea, and blood thyroid stimulating 
hormone decreased. Study treatment was discontinued or interrupted due to 5 events in 4 of 
61 subjects in the MR13A9 0.5 μg/kg group and 6 events in 5 of 62 subjects in the 1.0 μg/kg 
group. Dependency was assessed as being absent in all evaluable subjects. 
In an overseas phase II clinical study (CR845-CLIN2101), 174 hemodialysis patients with 
moderate to severe pruritus received MR13A9 0.5, 1.0, or 1.5 μg/kg, or placebo injected into 
the venous line of the dialysis circuit at the end of each dialysis session 3 times weekly for 8 
weeks. The primary endpoint of change from baseline in the weekly mean 24-hour Worst 
Itching Intensity NRS score at the final week of the treatment period (Week 8) (mean ± 
standard deviation) was −3.9 ± 2.48, −2.8 ± 2.24, and −3.3 ± 2.18 in the 0.5, 1.0, and 1.5 
μg/kg groups, respectively, versus −1.9 ± 2.29 in the placebo group. The incidence of adverse 
drug reactions was 2.2% (1/45 subjects), 27.3% (12/44 subjects), 26.8% (11/41 subjects), and 
22.7% (10/44 subjects) in the placebo, 0.5, 1.0, and 1.5 μg/kg groups, respectively. 
Commonly reported adverse drug reactions (in ≥ 5% of subjects in any of the MR13A9 
groups) included dizziness, somnolence, headache, paraesthesia, fatigue, and hyperglycaemia. 
In the verification part of an overseas phase III clinical study (CR845-CLIN3102), 377 
hemodialysis patients with moderate to severe pruritus received MR13A9 0.5 μg/kg or 
placebo injected into the venous line of the dialysis circuit at the end of each dialysis session 
3 times weekly for 12 weeks. The primary endpoint of proportion of subjects with a ≥ 3 points 
improvement in NRS score (Week 12) was 51.0% in the MR13A9 0.5 μg/kg group and 27.6% 
in the placebo group. MR13A9 0.5 μg/kg group showed significant improvement compared 
with the placebo group. The incidence of adverse drug reactions was 5.3% (10/188 subjects) 
in the placebo group and 6.9% (13/188 subjects) in the 0.5 μg/kg group. Common adverse 
drug reactions (reported in ≥ 1% of the subjects in the MR13A9 group) included dizziness, 
somnolence, constipation, headache, hypoaesthesia, paraesthesia, and confusional state. 
1.4 Summary of Expected Adverse Drug Reactions and Benefits 
1.4.1 Expected adverse drug reactions 
In the Japanese phase II clinical study (MR13A9-3), 84 patients received MR13A9 0.25, 0.5, 
1.0, or 1.5 μg/kg injected into the venous line of the dialysis circuit at the end of each dialysis 
session 3 times weekly for 2 weeks. Adverse drug reactions reported in ≥ 10% of subjects in 
any of the MR13A9 groups included blood thyroid stimulating hormone decreased, dizziness, 
blood prolactin increased, nausea, feeling abnormal, and somnolence. 
In the Japanese phase II clinical study (MR13A9-4), 184 patients received MR13A9 0.25, 0.5, 
or 1.0 μg/kg injected into the venous line of the dialysis circuit at the end of each dialysis 
session 3 times weekly for 8 weeks. Adverse drug reactions reported in ≥ 3% of subjects in 
any of the MR13A9 groups included somnolence, dizziness, palpitations, vomiting, nausea, 
and blood thyroid stimulating hormone decreased. 
In the overseas phase II clinical study (CR845-CLIN2101), 129 patients received MR13A9 
0.5, 1.0, or 1.5 μg/kg injected into the venous line of the dialysis circuit at the end of each 
dialysis session 3 times weekly for 8 weeks. Adverse drug reactions reported in ≥ 5% of 
subjects in any of the MR13A9 groups included dizziness, somnolence, headache, 
paraesthesia, fatigue, and hyperglycaemia. 

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In the overseas phase III clinical study (verification part of CR845-CLIN3102), 188 patients 
received MR13A9 0.5 μg/kg injected into the venous line of the dialysis circuit at the end of 
each dialysis session 3 times weekly for 12 weeks. Adverse drug reactions reported in ≥ 1% of 
subjects in the MR13A9 group included dizziness, somnolence, constipation, headache, 
hypoaesthesia, paraesthesia, and confusional state. 
In overseas clinical studies, an adverse event of serum sodium increased associated with the 
aquaretic effect of KOR agonists13) was reported in subjects receiving ≥ 5 μg/kg. In addition, 
an adverse event of tachycardia associated with the same effect was reported. 
In the Japanese phase I clinical study in healthy adult males (MR13A9-1), blood sodium 
increased was reported in 4 of 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 hemodialysis patients. 
1.4.2 Expected benefits 
The Japanese and overseas phase II clinical studies in hemodialysis patients with pruritus 
have suggested the efficacy of MR13A9 for pruritus in hemodialysis patients. Treatment with 
MR13A9 is also expected to relieve pruritus in hemodialysis patients in the present study. 

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2. Study Title and Development Phase 
2.1 Title of Study 
A phase III clinical study of MR13A9 in previously treated hemodialysis patients with 
pruritus 
2.2 Development Phase 
Phase III 
3. Study Objectives 
3.1 Primary Objective 
To confirm the superiority of MR13A9 0.5 μg/kg administered for 4 weeks in improving 
itching in previously treated hemodialysis patients with pruritus versus placebo in a double-
blind design. 
3.2 Secondary Objectives 
1) 
To determine the efficacy of MR13A9 0.5 μg/kg in improving the following in 
previously treated hemodialysis patients with pruritus: 
 Degree of itching 
 Itching-related QOL 
2) 
To determine the safety of MR13A9 0.5 μg/kg in previously treated hemodialysis 
patients with pruritus. 
4. Endpoints 
4.1 Endpoints for Efficacy 
4.1.1 Efficacy endpoints 
4.1.1.1 Primary endpoint 
Itch NRS score (The primary variable is change from baseline in the mean 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. 
4.1.1.2 Secondary endpoints 
 Itch score based on the Shiratori’s severity criteria14) 
 Skindex-16 score15) 
 5-D itch scale score16) 
 Patient Global Impression of Change(PGIC) 

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4.1.2 Rationale for the efficacy endpoints 
4.1.2.1 Primary endpoint 
The itch NRS score has been selected as the primary endpoint because it is used widely as a 
pruritus assessment method in clinical studies2) and is also used as the primary endpoint of the 
non-Japanese phase III clinical study. 
4.1.2.2 Secondary endpoints 
 The Shiratori’s severity criteria have been selected as an endpoint for pruritus, provided 
that they are used widely to assess the degree of itching by dermatologists in Japan and 
that they can also be used to assess sleep disorder because they use the effects on daily 
activities as the criteria for severity. 
 Skindex-16 and 5-D itch scale have been selected as QOL endpoints for pruritus 
because they are used to assess the skin disease-related QOL. 
 PGIC has been selected as an endpoint for treatment effects assessed by subjects. 
4.2 Endpoints for Safety 
4.2.1 Safety endpoints 
 Occurrence of adverse events 
 Occurrence of adverse drug reactions 
 Occurrence of adverse events of special interest 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Vital signs (blood pressure, pulse rate, body temperature) 
 Body weight 
 12-lead ECG 
 Dependency assessment 
4.2.2 Rationale for the safety endpoints 
In addition to the endpoints generally used for safety evaluation, endocrinology testing and 
dependency assessment have been selected because these endpoints could be affected by 
opioids. In addition, for careful assessment of their effects on the central nervous system, 
adverse events of special interest have been established. 
5. Study Population 
5.1 Double-blind period 
The double-blind period of this study will enroll previously treated hemodialysis patients with 
pruritus who meet all of the inclusion criteria and none of the exclusion criteria below. 
5.1.1 Inclusion criteria 
1) 
Patients aged 20 years or older (at the time of signing informed consent) 
2) 
Patients providing written informed consent for study participation in person 

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3) 
Patients with chronic renal failure on periodic hemodialysis (HD, off-line HDF, on-line 
HDF, or I-HDF) 3 times weekly for ≥ 12 weeks prior to the informed consent procedure 
(including the date of informed consent) who can continue hemodialysis without 
changing its frequency or method (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 
4) 
Patients whose pruritus treatment within 1 year prior to the informed consent procedure 
meets either (1) or (2) below: 
(1) Drug therapy with nalfurafine hydrochloride for ≥ 2 consecutive weeks 
(2) Inadequate response to both drug therapies a) and b) below: 
a) 
Systemic (e.g., oral, injection) therapy with antihistamines or antiallergics 
contained in prescription drugs indicated for the treatment of itching for ≥ 2 
consecutive weeks 
b) 
Local (topical) therapy with prescription drugs indicated for the treatment of 
itching or moisturizers prescribed by physicians 
5) 
Patients whose pruritus has been treated with 1 or more drugs listed below since prior to 
the start of the screening period: 
 Drugs indicated for the treatment of itching (prescription/nonprescription) (excluding 
nalfurafine hydrochloride) 
 Drugs to treat itching (prescription/nonprescription) 
 Moisturizing drugs (prescription/nonprescription) 
 Products formulated with any of the above 
6) 
Patients whose NRS score in the 7 days prior to the start of the double-blind period (7 
days including the score recorded on the start day of treatment) (Appendix 1) meets both 
of the below: 
 NRS scores have been recorded for ≥ 5 days. 
 The mean value of the recorded scores exceeds 4.0 (not including 4.0). 
7) 
Patients whose itch score based on the Shiratori’s severity criteria (Appendix 2) in the 7 
days prior to the start of the double-blind period (7 days including the score recorded on 
the start day of treatment) meets both of the below: 
 Itch scores during the day and the night have been recorded for ≥ 5 days. 
 The larger itch score either during the day or the night is “3. Moderate itching” or 
greater for ≥ 2 days. 
8) 
Patients who can record the symptom diary, as instructed by the principal investigator, 
subinvestigator, or clinical research coordinator 
5.1.2 Rationale for the inclusion criteria 
1) 
To include patients old enough to provide consent in person legally. 
2) 
To comply with the ethical principles that have their origin in the Declaration of Helsinki 
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3) 
To include patients on stable hemodialysis. 
4) 
To include patients whose pruritus has been treated with drug therapy and who have had 
an inadequate response to the drug therapy other than nalfurafine hydrochloride. Patients 
previously treated with nalfurafine hydrochloride will be included because it is assumed 
that they have not responded to drugs other than nalfurafine hydrochloride. 
5)-7) To include patients who have a certain degree of itching continuously. 
8) 
To include patients who can perform appropriate assessment using a symptom diary. 
5.1.3 Exclusion criteria 
1) 
Patients 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 principal investigator or subinvestigator (e.g., atopic dermatitis, chronic 
urticaria) 
2) 
Patients with concurrent hepatic cirrhosis 
3) 
Patients who used nalfurafine hydrochloride within 2 weeks prior to the start of the 
screening period 
4) 
Patients who received phototherapy to treat itching within 4 weeks prior to the start of 
the screening period 
5) 
Patients who previously received any study drug (including placebo) in a clinical study 
of MR13A9 
6) 
Patients with any adverse drug reaction to nalfurafine hydrochloride in the past who are 
ineligible for study participation in the opinion of the principal investigator or 
subinvestigator 
7) 
Patients with drug hypersensitivity to opioids 
8) 
Patients whose laboratory data at the start of the screening period meet any of the criteria 
(1) to (3) below: 
(1) ALT: > 2.5 times the upper limit of normal 
(2) AST: > 2.5 times the upper limit of normal 
(3) Total bilirubin: > 2 times the upper limit of normal 
9) 
Patients with congestive heart failure (NYHA functional class IV) (Appendix 3) 
10) Patients with concurrent malignancy or a history of malignancy within 5 years prior to 
the informed consent procedure 
11) Patients with concurrent or previous drug abuse (defined as illicit drug use) 
12) Patients with concurrent or previous alcoholism 
13) Patients with a history of severe drug hypersensitivity (anaphylactic shock, etc.) 
14) Patients with concurrent depression, schizophrenia, or dementia 
15) Patients with a concurrent mental disorder that could affect the evaluation of the 
investigational product 
16) Female patients who are pregnant, breastfeeding, intending to become pregnant between 
the informed consent procedure and the end of the follow-up period, or unwilling to use 
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17) Male patients who are unwilling to use appropriate methods to prevent conception 
between the start of study treatment and 12 weeks after the day of the final dose 
18) Patients who received treatment with any study drug or study device in a clinical study 
(including clinical studies of medical devices or cellular and tissue-based products) 
within 12 weeks 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 
19) Patients scheduled to be hospitalized (over at least 1 night) to receive any medical 
intervention between the informed consent procedure and the end of the follow-up period 
20) Patients withdrawn from the study during  the screening period because they are found 
not meeting either of inclusion criteria 6) or 7) after participation in the study 
21) Patients withdrawn from the study during  the screening period after re-registration 
22) Other patients ineligible for study participation in the opinion of the principal 
investigator or subinvestigator 
5.1.4 Rationale for the exclusion criteria 
1)-5) 
To perform the efficacy evaluation of MR13A9 appropriately. 
6)-13), 19), 21), 22) 
To ensure the safety of subjects. 
14), 15) 
To exclude the effect of this condition on protocol adherence. 
16) 
To ensure the safety of pregnant women, fetuses, and infants 
because the safety of MR13A9 in them has not been established. 
17) 
To ensure the safety of female partners of childbearing potential and 
female partners who are pregnant because the safety of MR13A9 in 
them has not been established. 
18) 
To establish a certain time interval for subjects, between 
administration of another study drug and administration of MR13A9 
because it is impossible to rule out the possibility of an interaction 
between these drugs and the development of delayed adverse 
reactions of another investigational product as well as it is necessary 
to do so from an ethical aspect. 
20) 
Re-registration will not be permitted because it could affect the 
efficacy evaluation. 
5.2 Extension Period 
Subjects meeting all of the following criteria for entrance at the Week 6 visit during the 
double-blind period will enter into the extension period. Subjects not meeting the criteria for 
entrance will be withdrawn from the study and undergo the assessments at discontinuation 
promptly. 
5.2.1 Criteria for entrance 
1) 
Subjects not withdrawn during the double-blind period 
2) 
Subjects receiving at least 14 doses of the study drug during the double-blind period 
3) 
Subjects completing at least 70% of the symptom diary during the double-blind period 

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4) 
Subjects who are not inappropriate to enter into the extension period for safety or other 
reasons in the opinion of the principal investigator or subinvestigator 
5.2.2 Rationale for the criteria for entrance 
1), 2) 
To perform the efficacy evaluation of MR13A9 appropriately. 
3) 
To include subjects who can perform appropriate assessment using a symptom diary. 
4) 
To ensure the safety of subjects. 
5.3 Discontinuation of Individual Subjects 
5.3.1 Discontinuation criteria (discontinuation of individual subjects) 
1) 
Adverse events 
 It is necessary to withdraw the subject from the study because of the adverse event in 
the opinion of the principal investigator or subinvestigator. 
 The subject does not want to continue the study due to the adverse event. 
2) 
Lack of efficacy (inadequate response): 
 Study continuation may cause an unacceptable risk to the subject because of the lack of 
efficacy of the study drug in the opinion of the principal investigator or subinvestigator. 
3) 
Voluntary request for study discontinuation by the subject (Discontinuation due to an 
adverse event is categorized as 1) above and discontinuation due to the lack of efficacy is 
categorized as 2) above). 
4) 
Significant protocol deviation during the study (between the date of informed consent 
and the end of the follow-up period) 
 Any GCP violation is found 
 After the initial study treatment, the subject is found not meeting any of the inclusion 
criteria or meeting any of the exclusion criteria stipulated in the protocol 
 A subject has received the study drug with drug number other than specified 
5) 
Four consecutive missed doses of the study drug during the double-blind period 
6) 
Seven consecutive missed doses of the study drug during the extension period 
7) 
Not meeting the criteria for entrance at the Week 6 visit of the double-blind period 
8) 
Pregnancy 
9) 
Discontinuation of the entire study 
10) Discontinuation of the study at the study site 
11) Lost to observation or follow-up 
 Study continuation becomes impossible because of failure to contact the subject. 
12) Any other cases where it is necessary to withdraw the subject from the study in the 
opinion of the principal investigator or subinvestigator (A detailed reason should be 
recorded in the case report form) 

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5.3.2 Responses to the discontinuation of any individual subject 
 If a subject meets any of the criteria described in “5.3.1 Discontinuation criteria 
(discontinuation of individual subjects)” during the study, the principal investigator or 
subinvestigator will immediately decide to discontinue the study. On the next dialysis 
day after the decision to discontinue, the prespecified assessment items at 
discontinuation will be measured and assessed and the date of discontinuation and the 
reason for discontinuation will be recorded in the case report form. The date of 
discontinuation will be the day when the principal investigator or subinvestigator 
decides to discontinue the study. If the study is discontinued during the double-blind 
period or the extension period, the next day of the assessments at discontinuation will be 
regarded as the start date of the follow-up period. 
 If the study is discontinued because of the occurrence of an adverse event, the principal 
investigator or subinvestigator will promptly provide appropriate treatment for the 
subject and perform a follow-up investigation, as instructed in “10.13.9 Follow-up 
investigation.” 
 If a subject does not return to the study site, the principal investigator, subinvestigator, 
or clinical research coordinator will immediately investigate the reason for missed visits 
and the subsequent course. 
6. Subject Consent 
6.1 Timing of Informed Consent 
Written informed consent must be obtained before the start of the screening period (before 
any protocol-specified testing, and before the start of washout for patients on nalfurafine 
hydrochloride). 
6.2 Informed Consent Procedure 
The principal investigator will prepare written information and consent forms with reference 
to the materials and information necessary to prepare these documents provided by the 
sponsor (e.g., examples of written information and informed consent forms), and obtain 
approval of the institutional review board (IRB) in advance. 
The principal investigator or subinvestigator will select subjects who have sufficiently 
considered the objectives of the study from the ethical and scientific standpoints. Individuals 
incapable of giving consent will not be selected as subjects. When selecting an individual who 
may have an unreasonable disadvantage because he/she does not participate in the study, the 
principal investigator or subinvestigator must ensure that consent is given voluntarily by the 
subject. 
Prior to the participation of each subject in the study, the principal investigator or 
subinvestigator will provide the subject with a thorough explanation using the written 
information. The principal investigator or subinvestigator will obtain voluntary written 
consent for study participation (informed consent form) from the subject after giving a chance 
to ask questions, answering to the questions sufficiently, and confirming that the subject has 
understood the information sufficiently. The informed consent form will be dated and signed 
(or affix name and seal) by the principal investigator or subinvestigator giving the explanation 
and dated and signed by the subject. Any clinical research coordinator giving a supplementary 
explanation will also date and sign (or affix name and seal) the informed consent form. 

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The principal investigator or subinvestigator will hand the written information and a copy of 
the informed consent form to the subject and retain the original informed consent form at the 
study site. 
7. Study Drugs 
7.1 Test Drug and Comparator 
7.1.1 Test drug 
1) 
Code name: MR13A9 
2) 
Nonproprietary name: Difelikefalin acetate (JAN) 
3) 
Strength and dosage form: 
 MR13A9 17.5 μg: Pre-filled syringe containing 17.5 μg of MR13A9 per syringe 
 MR13A9 25.0 μg: Pre-filled syringe containing 25.0 μg of MR13A9 per syringe 
 MR13A9 35.0 μg: Pre-filled syringe containing 35.0 μg of MR13A9 per syringe 
 MR13A9 42.5 μg: Pre-filled syringe containing 42.5 μg of MR13A9 per syringe 
4) 
Storage conditions: Store at room temperature (1°C to 30°C) 
7.1.2 Comparator 
1) 
Strength and dosage form: 
MR13A9 placebo: Pre-filled syringe not containing MR13A9 
The MR13A9 placebo is indistinguishable from MR13A9 17.5, 25.0, 35.0, or 42.5 µg. 
2) 
Storage conditions: Store at room temperature (1°C to 30°C) 
7.1.3 Rationale for the comparator 
With reference to the “Choice of Control Group and Related Issues in Clinical Trials” 
(MHLW PFSB/ELD Notification No. 136 dated February 27, 2001), a placebo has been 
selected as a comparator to control all potential influences on the actual or apparent course of 
the disease other than those arising from the pharmacologic action of the test drug (natural 
history of the disease, subject or investigator expectations, the effect of being in a trial, use of 
other therapy, and subjective elements of diagnosis or assessment). 
7.2 Packaging of the Study Drugs 
 Double-blind period 
A total of 21 prefilled syringes containing MR13A9 0.5 μg/kg or placebo packaged in blister 
packs (18 syringes for 6-week treatment + 3 spare syringes) will be packed in 1 carton. 
 Extension period 
A total of 10 prefilled syringes containing MR13A9 0.5 μg/kg packaged in blister packs (9 
syringes for 3-week treatment + 1 spare syringe) will be packed in 1 carton. 

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7.3 Labeling 
Details of labeling will be provided in a separate written procedure. 
7.4 Management of the Study Drugs 
The study drug manager will manage and store the study drugs appropriately, as stipulated 
separately in the written procedure. 
8. Study Methods 
8.1 Study Design 
 Double-blind period 
A placebo-controlled, multicenter, randomized, double-blind, parallel-group study 
 Extension period 
A multicenter, open-label study 
 
Screening 
period 
2 weeks 
Double-blind period 
6 weeks 
Extension period 
52 weeks 
Follow-up 
period 
1 week 
Placebo group 
 
 
 
 
Placebo 
MR13A9 0.5 μg/kg 
Conditionally permitted concomitant medications (anti-itch drugs) 
 
 
 
 
MR13A9  
0.5 μg/kg group 
 
 
 
 
MR13A9 0.5 μg/kg 
MR13A9 0.5 μg/kg 
Conditionally permitted concomitant medications (anti-itch drugs) 
 
 
 
 
Figure 8.1-1 Study Design 
8.2 Dosage and Administration 
8.2.1 Screening period 
A 2-week period before entry into the double-blind period is defined as the screening period, 
during which subjects will receive no study drug. Subjects will continuously use any 
conditionally permitted concomitant medications (e.g., anti-itch drugs) used at the start of the 
screening period. 
8.2.2 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 study drug will be injected into the venous 
line of the dialysis circuit at the end of each dialysis session for 6 weeks (3 times weekly, 18 
times in total). The dose of the study drug will be determined based on the subject’s dry 
weight before dialysis on the start day of the screening period according to Table 8.2.2-1. 
If any dialysis circuit trouble precludes injection through the dialysis circuit, the study drug 
will be administered directly intravenously. If an extra fourth dialysis session is required 
within the week, the study drug will be administered (up to 4 times weekly). If only the 
extracorporeal ultrafiltration method is used, the study drug will not be administered. 

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Table 8.2.2-1 Doses 
Dry weight 
Injected volume 
MR13A9 dose 
0.5 µg/kg group 
Placebo group 
< 45.0 kg 
0.35 mL 
17.5 μg 
0 μg 
≥ 45.0 kg, < 65.0 kg 
0.35 mL 
25.0 μg 
0 μg 
≥ 65.0 kg, < 85.0 kg 
0.35 mL 
35.0 μg 
0 μg 
≥ 85.0 kg 
0.35 mL 
42.5 μg 
0 μg 
8.2.3 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, the study drug will be injected into the venous 
line of the dialysis circuit at the end of each dialysis session for 52 weeks (3 times weekly, 
156 times in total). Study treatment in the extension period will be started at Week 6. The dose 
of the study drug will be determined according to Table 8.2.2-1, and the dose of the study 
drug from Week 6 to immediately before Week 34 will be determined based on the subject’s 
dry weight before dialysis at Week 6. The dose of the study drug after Week 34 will be 
determined based on the subject’s dry weight before dialysis at Week 34. The study drug will 
not be administered at Week 58. 
If any dialysis circuit trouble precludes injection through the dialysis circuit, the study drug 
will be administered directly intravenously. If an extra fourth dialysis session is required 
within the week, the study drug will be administered (up to 4 times weekly). If only the 
extracorporeal ultrafiltration method is used, the study drug will not be administered. 
8.2.4 Follow-up period 
A 1-week period after the assessments at discontinuation or a 1-week period after the end of 
the extension period is defined as the follow-up period, during which subjects will receive no 
study drug. 
8.2.5 Rationale for the doses and the duration of treatment 
In a Japanese phase II clinical study (Study MR13A9-4), intravenous administration of 
MR13A9 0.25, 0.5, and 1.0 μg/kg or placebo 3 times weekly for 8 weeks resulted in 
significant improvement of pruritus in 0.5 and 1.0 μg/kg groups compared with the placebo 
group. In addition, there was a dose-response relationship showing a constant effect of 
MR13A9 at doses of 0.5 μg/kg and higher. As for safety, MR13A9 at up to 1.0 μg/kg was 
tolerated, but adverse events occurred frequently in the 1.0 μg/kg group. The phase II study in 
the  United State (Study CLIN2101) and phase III study (Study CLIN3102) also confirmed 
the superiority of the MR13A9 0.5 μg/kg group to the placebo group. Based on the above, it 
was considered appropriate to select 0.5 μg/kg of MR13A9 as the recommended clinical dose. 
In Study MR13A9-4, the effect of MR13A9 to improve itching was constant after Week 4, 
and all adverse drug reactions occurred before Week 6. Accordingly, 4-week and 6-week 
periods in the double-blind period were established to allow the efficacy and safety 
evaluations of MR13A9, respectively. In addition, a 52-week extension period was 
established to assess the safety of long-term treatment with MR13A9 with reference to the 
“Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term 
Treatment of Non-Life-Threatening Conditions” (ELD Notification No. 592 dated May 24, 
1995). 

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8.3 Concomitant Treatments 
Subjects may use any drug used to treat symptoms of chronic renal failure or drug used to 
treat complications at the start of the screening period without changing its dosage and 
administration 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. Any centrally acting concomitant drug should be used with attention to 
possible central adverse events. 
A summary of concomitant treatments is shown in Table 8.3-1. 
Table 8.3-1 
Concomitant Treatments 
8.3.1 Prohibited concomitant medications 
Between the start of the screening period and the end of the follow-up period, use of the drugs 
listed in Table 8.3.1-1 will be prohibited. 
Table 8.3.1-1 Prohibited concomitant medications 
Class 
Common drugs 
1) Opioids 
Nalfurafine hydrochloride, morphine, fentanyl, oxycodone, buprenorphine, 
pentazocine, codeine phosphate, dihydrocodeine, etc. 
2) Opioid antagonists 
Naloxone hydrochloride, eptazocine hydrobromide, naldemedine tosylate, etc. 
3) Investigational products 
other than MR13A9 
Various kinds 
8.3.2 Conditionally permitted concomitant medications 
Between the start of the screening period and the end of the double-blind period (or the time 
of withdrawal during the double-blind period), subjects may use the drugs listed below that 
have been used since before the screening period without changing their dosage and 
administration. In addition, the drugs listed below should not be newly used. The dosage and 
administration at the start of the screening period should not be changed or newly used. 
Between the start of the extension period and the end of the follow-up period, the dosage 
administration should not be changed or newly used whenever possible. 
1) 
Drugs indicated for the treatment of itching (prescription/nonprescription) 
2) 
Drugs to treat itching (prescription/nonprescription) 
3) 
Moisturizing drugs (prescription/nonprescription) 
4) 
Steroids (excluding inhalants, nasal drops, ear drops, eye drops, and eye ointments) 
 
Screening period 
Double-blind period 
Extension period 
Follow-up period 
Concomitant 
medications 
Permitted 
(The dosage and administration should not be changed whenever possible.) 
Prohibited 
concomitant 
medications 
Not permitted 
Conditionally 
permitted 
concomitant 
medications 
Permitted 
(The dosage and administration should not be 
changed or newly used.) 
Permitted 
(The dosage and administration should not be 
changed or newly used whenever possible.) 
Prohibited 
concomitant 
therapies 
Not permitted 

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5) 
Capsaicin (topical) 
6) 
In-hospital drugs formulated with any of the drugs listed 1) to 5) above 
7) 
Pregabalin, gabapentin 
8) 
Antidepressants, anxiolytics 
Among the drugs listed 
in 1) to 6) above, however, topical use of any 
prescription/nonprescription drug 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). 
Use of any combination product that contains ingredients indicated for itching but is not 
indicated itself for itching will not be restricted. 
8.3.3 Prohibited concomitant therapies 
Between the start of the screening period and the end of the follow-up period, use of 
phototherapy to treat itching will be prohibited. 
8.3.4 Rationale for the prohibited concomitant medications, conditionally 
permitted 
concomitant 
medications, 
and 
prohibited 
concomitant 
therapies 
To exclude their effects on the efficacy evaluation of MR13A9. 
8.4 Hemodialysis Conditions 
Between the start of the screening period and the end of the follow-up period, the frequency 
of dialysis per week and the hemodialysis method (HD, off-line HDF, on-line HDF, or I-HDF) 
may not be changed. Any temporary change in dialysis frequency or hemodialysis method 
associated with travel or admission to other hospitals with no changes in treatment strategies 
is acceptable. The hemodialysis conditions (duration of dialysis and dialyzer) should not be 
changed whenever possible. 
8.5 Randomization and Blinding 
8.5.1 Preparation and retention of a treatment assignment table 
The person responsible for treatment assignment will prepare a treatment assignment table 
and retain it until unblinding, as stipulated separately in the written procedure. 
8.5.2 Preparation and retention of emergency key codes 
The person responsible for treatment assignment will prepare emergency key codes to allow 
immediate identification of the treatment assigned to each subject in emergencies and retain 
them until unblinding, as stipulated separately in the written procedure. 
8.5.3 Subject registration 
8.5.3.1 Primary subject registration 
The principal investigator or subinvestigator will assess the eligibility of all subjects 
providing consent at the time of signing informed consent (see “5. Study Population”), enter 

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necessary information in a primary subject registration form, and register the subjects by the 
next day. 
The subject registration center will notify the principal investigator or subinvestigator about 
the acceptance or rejection of the primary subject registration for each subject. 
8.5.3.2 Secondary subject registration 
The principal investigator or subinvestigator will assess the eligibility of each subject at the 
start of the screening period (see “5. Study Population”), enter necessary information in a 
secondary subject registration form, and register the subject by the next day. 
The subject registration center will notify the principal investigator or subinvestigator about 
the acceptance or rejection of the secondary subject registration of each subject. 
For any subject eligible for primary registration but ineligible for secondary registration, the 
principal investigator or subinvestigator will notify the subject registration center about the 
reason for ineligibility. 
8.5.3.3 Tertiary subject registration 
The principal investigator or subinvestigator will assess the eligibility of each subject at the 
start of the double-blind period (see “5. Study Population”), enter necessary information in a 
tertiary subject registration form, and register the subject promptly. 
The subject registration center will notify the principal investigator or subinvestigator about 
the acceptance or rejection of the tertiary subject registration of each subject, and the drug 
number for the subject when the registration of the subject has been accepted. The principal 
investigator or subinvestigator will prescribe the study drug of the drug number notified by 
the subject registration center for the subject. 
For any subject eligible for secondary registration but ineligible for tertiary registration, the 
principal investigator or subinvestigator will notify the subject registration center about the 
reason for ineligibility. 
8.5.3.4 Registration for the extension period 
The principal investigator or subinvestigator will assess the eligibility of each subject at the 
start of the extension period (see “5. Study Population”), enter necessary information in a 
registration form for the extension period, and register the subject by the next day. 
The subject registration center will notify the principal investigator or subinvestigator about 
the acceptance or rejection of the registration for the extension period of each subject. 
For any subject eligible for tertiary registration but ineligible for registration for the extension 
period, the principal investigator or subinvestigator will notify the subject registration center 
about the reason for ineligibility. 
8.5.3.5 Randomization of subjects 
Based on the treatment assignment table prepared by the person responsible for treatment 
assignment, the subject registration center will randomly assign subjects eligible for tertiary 
registration to either the MR13A9 0.5 μg/kg or placebo group at a ratio of 1:1 by a dynamic 
allocation method using two stratification factors: Prior treatment with nalfurafine 
hydrochloride notified by the medical institution (for ≥ 2 consecutive weeks in the year prior 

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to the informed consent procedure) and specific signs or symptoms occurring during the 
screening period (Appendix 4) confirmed before dialysis on the start day of treatment. 
8.5.4 Unblinding 
The person responsible for treatment assignment will confirm that the blind has been 
maintained throughout the double-blind period and then unblind the treatment assignment 
table. 
8.6 Sample size 
8.6.1 Sample size 
 Double-blind period 
The study will enroll 86 subjects each MR13A9 0.5 μg/kg group and the placebo group (172 
in total). 
 Extension period 
The study will enroll 100 subjects who complete 58-week treatment. 
8.6.2 Rationale for the sample size 
8.6.2.1 Double-blind period 
In a Japanese phase II clinical study (MR13A9-4), the change from baseline in the mean NRS 
score at Week 4 of the treatment period (mean ± standard deviation) was −2.15 ± 1.98 in the 
placebo group and −3.22 ± 2.09 in the MR13A9 0.5 μg/kg group. The difference for the 
MR13A9 0.5 μg/kg group versus the placebo group at Week 4 of the treatment period was 
−1.04 ± 0.35 (adjusted mean ± standard error). 
For the primary variable of change from baseline in the mean NRS score at Week 4 of the 
double-blind period, its mean difference for the MR13A9 0.5 μg/kg group versus the placebo 
group was assumed to be −1.0, with a common standard deviation of 2.0. Assuming a 
two-sided significance level of 5% and a statistical power of 90%, the sample size required to 
confirm the superiority of the MR13A9 0.5 μg/kg group to the placebo group using a 
two-sample t-test was calculated to be 86 subjects per group. 
8.6.2.2 Extension period 
With reference to the “The Extent of Population Exposure to Assess Clinical Safety for Drugs 
Intended for Long-Term Treatment of Non-Life-Threatening Conditions” (ELD Notification 
No. 592 dated May 24, 1995), 100 subjects were assumed to complete 58-week treatment. 
9. Subject Instructions and Management 
The principal investigator or subinvestigator should sufficiently explain the significance and 
objectives of the study to subjects, and instruct and manage them especially for the following: 
1) 
Confirm the absence of somnolence, dizziness, or similar symptoms after receiving the 
study drug and return home. Report any symptoms to the principal investigator or 
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2) 
Pay attention during hazardous machine operation and automobile driving during the 
treatment period. 
3) 
Maintain the symptom diary in subject every day. Report any device deficiencies to the 
principal investigator or subinvestigator. 
4) 
Take all prescribed drugs other than the study drug properly as instructed. 
5) 
Be sure to visit the study site as scheduled. Inform the study site in advance if it is 
impossible to visit for some unavoidable reason. 
6) 
Visit the study site at the same time at every visit whenever possible during the study 
period. 
7) 
Report the drug(s) used currently to the principal investigator or subinvestigator before 
participation in the study. Consult the principal investigator or subinvestigator about any 
new drug prescribed at other medical departments or hospitals or any over-the-counter 
drug before use. Report to the principal investigator or subinvestigator immediately if it 
was inevitable to use any drug without consultation. 
8) 
Be sure to report in advance any visit to another department or hospital during the study 
period to the principal investigator or subinvestigator and report your participation in the 
study to the doctor at the department or hospital. If it is impossible to report in advance 
for unavoidable reasons such as an emergency visit, report your participation in the study 
to the doctor at the department or hospital and immediately report the visit to the 
department or hospital as well as prescribed drugs and other information to the principal 
investigator or subinvestigator. 
9) 
Immediately inform the principal investigator or subinvestigator about any abnormalities 
in your body after undergoing tests at the end of the follow-up period or at the end of the 
follow-up investigation. 
10) Women of childbearing potential must avoid intercourse or use appropriate contraceptive 
methods when having intercourse during the study period. Immediately inform the 
principal investigator or subinvestigator about any suspected pregnancy during the study 
period. 
11) Men must avoid intercourse or use appropriate contraceptive methods when having 
intercourse. Immediately inform the principal investigator or subinvestigator about any 
suspected pregnancy of your partner between the start of study treatment and 12 weeks 
after the final dose. 
12) Avoid disclosing any information related to this study, such as data used during the study, 
adverse events reported during the study, tests performed during the study, and personal 
remarks about administration of the study drug, on the Internet (e.g., Facebook, Twitter, 
blogs) or other information media (e.g., newspapers, magazines, advertisements). 
10. Investigations, Observations, Tests, and Evaluations 
The principal investigator, subinvestigator, and clinical research coordinator will perform 
investigations, observations, tests, and evaluations according to the study schedule and the 
following procedures. 
10.1 Subject Demographics 
The following subject demographics will be investigated and recorded in the case report form: 

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1) 
Date of written informed consent 
2) 
Month of birth, sex, race 
3) 
Body height 
4) 
Etiology of chronic renal failure 
5) 
Time when hemodialysis was started 
6) 
Frequency of dialysis per week at the start of the screening period, hemodialysis methods 
(HD, off-line HDF, online HDF, I-HDF), and hemodialysis conditions (duration of 
dialysis, dialyzer) 
7) 
Medical history (any concurrent disease at the time of signing informed consent); if yes, 
the name of the disease 
8) 
Time of onset of itching associated with chronic renal failure 
9) 
Prior treatment with nalfurafine hydrochloride between 1 year before the time of signing 
informed consent and the start of the screening period (Week −2); if yes, the duration of 
treatment and dose 
10) Remaining renal function 
11) Need for pregnancy testing 
12) Information related to the inclusion/exclusion criteria 
13) Specific signs or symptoms occurring during the screening period 
10.2 Treatment Compliance 
Compliance with study treatment (day of dosing and route of dosing) will be recorded in the 
case report form. Also, the drug number and the dose of the study drug will be recorded in the 
case report form during the double-blind period and the extension period, respectively. 
10.3 Dry Weight 
The dry weight before dialysis at Week −2, Week 6, and Week 34 will be recorded in the case 
report form. 
10.4 Concomitant Medications and Concomitant Therapies 
10.4.1 Concomitant medications 
For all drugs (including over-the-counter drugs) used between the informed consent procedure 
and the end of the follow-up period, information on use (drug name, route of administration, 
duration of use, indication) will be recorded in the case report form. For any change in the 
drug name, dose, or dosing frequency of conditionally permitted concomitant medications, the 
date, detail, and reason for the change will be recorded in the case report form. The drugs 
listed below will require no recording in the case report form. 
 Drugs used for dialysis (anticoagulants, local anesthetics, disinfectants, physiological 
saline used for priming and blood return, dialysate) 
 Infusion solution used to establish access 
 Diluents for injection 

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 Vehicles used for in-hospital dispensing (other than drugs of which main effect is 
expected) 
 Pretreatment drugs for tests 
 Nalfurafine hydrochloride used between the time of informed consent and the start of 
the screening period (Week −2) 
10.4.2 Concomitant therapies 
If phototherapy to treat itching is performed between the time of signing informed consent 
and the end of the follow-up period, implementation status of the therapy (name and duration 
of treatment) will be recorded in the case report form. 
10.5 Implementation Status of Dialysis 
The dates of dialysis between the start of the screening period and the end of the follow-up 
period will be recorded in the case report form. For any change in the frequency of dialysis 
per week or the hemodialysis method (HD, off-line HDF, on-line HDF, or I-HDF), the date, 
detail, and reason for the change will be recorded in the case report form. 
The sponsor will calculate the single-pool Kt/V at the start of the screening period. The 
single-pool Kt/V will be calculated using the Daugirdas formula.17) 
10.6 Efficacy Endpoints 
10.6.1 Symptom diary (electronic diary) 
The principal investigator, subinvestigator, or clinical research coordinator will instruct each 
subject on how to record the symptom diary, as well as register the information on each 
subject in the electronic diary system to prepare for the start of recording. 
1) 
NRS score 
Looking back on the period between the time of awakening on the previous day of assessment 
and the time of awakening on the day of assessment (including sleeping hours) once daily, 
subjects will assess the NRS score for the most severe itching by themselves and record the 
score in the symptom diary. According to Appendix 1, the most severe itching within the day 
will be recorded in integers on a scale ranging from 0 to 10, where 0 represents no itching and 
10 represents worst itching imaginable. 
2) 
Shiratori’s severity criteria 
Looking back on the period between the time of awakening on the previous day of assessment 
and the time of awakening on the day of assessment (including sleeping hours) once daily, 
subjects will assess the degree of itching by themselves and record the score in the symptom 
diary. According to Appendix 2, the symptoms during the day and the night will be recorded 
on a scale ranging from 0 to 4, where 0 represents no symptoms and 4 represents severe 
itching. 
10.6.2 Skindex-16 
At the first visit (before dosing of the study drug) of each week (Monday or Tuesday), 
subjects will look back on the condition of itching in the past week and assess how often they 
were bothered by itching. According to Appendix 5, the frequency of itching will be recorded 

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based on a scale ranging from 0 to 6, where 0 represents never bothered and 6 represents 
always bothered. The date of recording and the result will be recorded in the case report form. 
10.6.3 5-D itch scale 
At the first visit (before dosing of the study drug) of each week (Monday or Tuesday), 
subjects will look back on the condition of itching in the past 2 weeks and record the 5 
components of itching (duration, degree, direction, disability, distribution) according to 
Appendix 6. The date of recording and the result will be recorded in the case report form. 
10.6.4 PGIC 
At the first visit of each week (Monday or Tuesday), subjects will compare the overall 
symptom of itching with the symptom in the screening period, and record it on a 7-level scale 
consisting of very much improved, much improved, minimally improved, no change, 
minimally worsened, much worsened, and very much worsened, according to Appendix 7. 
The date of recording and the result will be recorded in the case report form. 
10.7 Laboratory Tests 
Blood samples will be collected for the tests listed below before the first dialysis of each week 
(Monday or Tuesday). Laboratory test values will be determined centrally at the laboratory 
testing facility. The presence or absence of collected samples will be recorded in the case 
report form. 
10.7.1 Hematology 
Red blood cell count, hemoglobin, hematocrit, white blood cell count, differential white blood 
cell count (neutrophil, eosinophil, basophil, monocyte, lymphocyte), and platelet count 
10.7.2 Blood biochemistry 
AST, ALT, γ-GTP, CRP, LDH, ALP, total protein, albumin, glycoalbumin, glucose, total 
cholesterol, total bilirubin, direct bilirubin, creatinine, BUN (before and after dialysis), Na, K, 
Cl, Ca, P, serum iron, UIBC, TIBC, TSAT, and ferritin 
10.7.3 Endocrinology 
Testosterone, free testosterone, prolactin, TSH, FT3, FT4, intact-PTH, and antidiuretic 
hormone 
10.8 Vital Signs (Blood Pressure, Pulse Rate, Body Temperature) 
Systolic blood pressure, diastolic blood pressure, pulse rate, and body temperature will be 
measured after a period of rest before the first dialysis each week (Monday or Tuesday). The 
date and result of measurement will be recorded in the case report form. The same testing 
device will be used in the same subject throughout the study period in principle. 
10.9 Body Weight 
Body weight will be measured before the first dialysis of each week (Monday or Tuesday). 
The date and result of measurement will be recorded in the case report form. At the start of the 
screening period, body weight will also be measured after dialysis, and the date and result of 
measurement will be recorded in the case report form. 

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10.10 12-lead ECG 
Before dialysis and blood sampling on the first day of each week (Monday or Tuesday), 
12-lead ECGs will be obtained in the supine position after a period of rest, and the date of 
measurement and the assessment by the doctor will be recorded in the case report form. The 
same testing device will be used in the same subject throughout the study period in principle. 
10.11 Dependency Assessment 
The investigator or subinvestigator will interview each subject using the questionnaire shown 
in Appendix 8 and record the result of the interview.18) The dependency assessment members 
will perform dependency assessment based on the questionnaire. 
Details are stipulated in a separate procedure. 
10.12 Pregnancy Test 
In women of childbearing potential (those who have not undergone total hysterectomy or 
bilateral total ovariectomy and within 1 year of their last menstrual period), a pregnancy test 
(serum HCG) will be performed to determine whether the subject is pregnant or not. 
Pregnancy will be determined centrally at the laboratory testing facility. The presence or 
absence of collected samples and the presence or absence of pregnancy will be recorded in the 
case report form. 
10.13 Adverse Events 
An adverse event is defined as any unfavorable or unintended sign, symptom, exacerbation of 
a complication, or disease in a subject, whether or not considered related to the study drug. 
Exacerbation of any variable used for individual efficacy evaluations will not be regarded as 
an adverse event. 
10.13.1 Collection of adverse events 
Adverse event information to be recorded in the case report form will include adverse event 
term, date of onset, date of resolution (when the outcome of an adverse event is resolved, 
resolved with sequelae, or fatal), severity, seriousness assessment, action taken with study 
treatment and other actions taken, outcome, causal relationship with study treatment, and 
assessment of adverse events of special interest. For any adverse event reported between the 
time of signing informed consent and the start of study treatment, adverse event term, 
seriousness assessment, and assessment of adverse events of special interest will be recorded 
in the case report form. 
10.13.1.1 Adverse event collection period 
Adverse events will be collected between the time of signing informed consent and the end of 
the follow-up period. 
10.13.1.2 Adverse event interview 
When interviewing each subject about his/her condition, the principal investigator or 
subinvestigator will pay due attention not to influence spontaneous reporting from the subject; 
for example, asking a general question such as “How have you been doing since the previous 
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10.13.1.3 Considerations for the recording of adverse events 
1) 
Any diagnosis identified from signs and/or symptoms will be recorded as an adverse 
event term. The laboratory abnormality, abnormal finding, or symptom associated with 
the adverse event will not be regarded as the adverse event. 
2) 
If no diagnosis can be identified from signs and/or symptoms, the laboratory abnormality, 
abnormal finding, or symptom will be regarded as the adverse event. 
3) 
A laboratory abnormality or abnormal finding will be regarded as an adverse event when 
it is regarded as a clinically significant variation or change by the principal investigator 
or subinvestigator. A clinically significant variation or change is defined as a laboratory 
abnormality or abnormal finding that requires a medical intervention or treatment or is 
considered to be a variation or change that exceeds the normal range of the subject’s 
physiological variation by the principal investigator or subinvestigator. 
4) 
Any laboratory abnormality or abnormal finding in a test at the start of the screening 
period will not be regarded as an adverse event. 
5) 
Any disease, symptom, or finding that has been present since before the informed 
consent procedure will not be regarded as an adverse event. 
6) 
Any exacerbation of a complication, preexisting symptom, or finding will be regarded as 
an adverse event. Exacerbation of a complication, preexisting symptom, or finding is 
defined as an exacerbation of a disease, symptom, or finding present before study 
participation considered to be greater than expected by the principal investigator or 
subinvestigator, or an increased frequency or an increased seriousness or severity of a 
seasonal or intermittent symptom or finding. 
7) 
Any exacerbation after the start of study treatment of an adverse event that has occurred 
between the time of signing informed consent and the start of study treatment will be 
regarded as a new adverse event. 
8) 
Any operation or treatment scheduled before the time of signing informed consent will 
not be regarded as an adverse event. 
9) 
Any elective operation or treatment that will not alter the disease condition (e.g., dental 
implant, cosmetic surgery, or suture removal after skin suture at the request of the 
subject) will not be regarded as an adverse event. However, if any of these interventions 
causes a clinically significant finding or symptom, the event will be regarded as an 
adverse event. 
10.13.2 Date of onset of adverse events 
 Day when the subject, principal investigator or subinvestigator becomes aware of the 
sign or symptom of an adverse event 
 Day when the subject, principal investigator or subinvestigator becomes aware of the 
exacerbation of a complication, preexisting symptom, or finding 
 Day of confirmed diagnosis of an asymptomatic disease, of which time of onset can be 
estimated 
 Day of a test that yields a laboratory abnormality or abnormal finding considered to be a 
clinically significant variation or change by the principal investigator or subinvestigator 

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10.13.3 Severity of adverse events 
The severity of adverse events will be categorized into 3 grades according to Table 10.13.3-1. 
For an adverse event in which the severity changes, the highest severity will be recorded. 
Table 10.13.3-1 Severity of adverse events 
Severity 
Criteria 
Mild 
Not or minimally interfering with daily activities a) and requiring no special treatment or 
simple treatment 
Moderate 
Somewhat interfering with daily activities a) and requiring treatment 
Severe 
Largely interfering with daily activities a) or requiring systemic treatment 
a) Include sleeping, movements, work, going out, eating, exercise, and bathing 
10.13.4 Serious adverse events 
All adverse events, including those occurring between the time of signing informed consent 
and the start of study treatment, that meet any of the following criteria will be regarded as 
serious adverse events. For any serious adverse event, its symptom or laboratory test and the 
reason for assessing it as serious will be recorded in the case report form. 
1) 
Results in death 
2) 
Is life-threatening 
3) 
Requires inpatient hospitalization or prolongation of existing hospitalization 
4) 
Results in persistent or significant disability/incapacity 
5) 
Is a congenital anomaly/birth defect 
6) 
Is a serious condition corresponding to 1) to 5) above 
A serious condition corresponding to 1) to 5) above refers to any important medical event that 
might not be immediately life-threatening or result in death or hospitalization but might 
jeopardize the patient or might require intervention or treatment to prevent the outcomes 
listed in the definitions 1) to 5) above. 
10.13.5 Adverse events of special interest 
On the first dialysis day of each week (Monday or Tuesday) between Week −1 and the end of 
the follow-up period, the principal investigator or subinvestigator will ask each subject about 
specific signs or symptoms occurring in the past week and record them, referring to Appendix 
4. Then, the principal investigator or subinvestigator will determine and record the presence 
or absence of specific signs or symptoms occurring in the past week based on the results of 
interview and the observation of the subject. If any particular sign or symptom is considered 
to be present, the principal investigator or subinvestigator will determine and record whether 
the particular sign or symptom is an adverse event. A adverse event of special interest is 
defined as a specific sign or symptom that is determined to be an adverse event by the 
principal investigator or subinvestigator. Details are stipulated in a separate procedure. 
10.13.6 Action taken with study treatment 
Actions taken with study treatment are defined in Table 10.13.6-1. 

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Table 10.13.6-1 Action taken with study treatment 
Action 
Definition 
Drug withdrawn 
Study treatment is discontinued due to the adverse event, including at the subject’s request. 
Drug Interrupted 
Study treatment is interrupted due to the adverse event, including at the subject’s request. 
Dose not changed 
No action is taken and study treatment is continued. 
Unknown 
Action taken with study treatment is unknown. 
Not applicable 
Study treatment is already completed or discontinued before the onset of the adverse event. 
10.13.7 Outcome of adverse events 
The outcome of each adverse event will be assessed according to Table 10.13.7-1. 
Table 10.13.7-1 Outcome of adverse events 
Outcome 
Criteria 
Recovered/Resolved 
The symptom has disappeared or resolved. The test value has returned to normal or 
baseline level. 
Recovering/Resolving 
The severity of the symptom/abnormal value has reduced or has been improving. 
Not recovered/Not 
resolved 
The symptom/abnormal value has changed little or worsened. 
Recovered/Resolved with 
sequelae 
The symptom/abnormal value has caused dysfunction that interferes with daily 
activities. 
Results in death 
The symptom/abnormal value has caused death. 
* This category will not be selected if the subject’s death is not related to the symptom/abnormal value. 
Unknown 
Confirmation of outcome is impossible despite efforts to follow-up the 
symptom/abnormal value. 
10.13.8 Causal relationship between adverse events and study treatment 
Based on the subject’s condition, complications, past history, concomitant medications, and 
temporal relationship with time to onset, the causal relationship between an adverse event and 
study treatment will be classified into 2 categories according to Table 10.13.8-1. Any adverse 
event occurring after the start of study treatment of which the causal relationship with study 
treatment is assessed as related will be regarded as an adverse drug reaction. 
The causal relationship between any adverse event occurring secondary to another adverse 
event and study treatment will be assessed separately. 
Table 10.13.8-1 Causal relationship between adverse events and study treatment 
Causality 
Criteria 
Related 
The adverse event is believed to be related to study treatment because the onset of the adverse 
event can be explained easily from the subject’s condition, complications, past history, 
concomitant medications, and the temporal relationship with time to onset. 
Not related 
The adverse event that does not fall into the above criterion of the presence of a causal 
relationship with the study drug, specifically when the event falls into one of the following 
criteria: 
• It is clear that the adverse event is attributable to factors other than study treatment. 
• No temporal correlation or a discrepancy is found between the onset/resolution of the adverse 
event and study treatment. 
• The onset of the adverse event is considered to be incidental (e.g., the same event was 
observed repeatedly before the study, and the adverse event occurring during the study is also 
considered to be in the same range). 
• The adverse event is attributable to factors other than study treatment, such as the subject’s 
medical history or condition, concomitant medications or therapies, and diet. 

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10.13.9 Follow-up investigation 
The principal investigator or subinvestigator will follow up any serious adverse event 
occurring between the informed consent procedure and the start of study treatment or any 
adverse event occurring after the start of study treatment, when considering that its symptom 
(including test values) has not recovered to the state before its onset or resolved by the end of 
the follow-up period. The follow-up investigation will be terminated if either of the following 
criteria is met as a result of the follow-up investigation: 
1) 
When the principal investigator or subinvestigator deems that the event has recovered or 
resolved 
2) 
When the principal investigator or subinvestigator deems further follow-up investigation 
as unnecessary 
11. Investigations, Observations, Tests, and Evaluations at 
Each Time Point 
The principal investigator, subinvestigator, and clinical research coordinator will perform 
investigations, observations, tests, and evaluations according to “10. Investigations, 
Observations, Tests, and Evaluations.” 
11.1 At the Time of Signing Informed Consent 
 Confirmation of written informed consent 
 Confirmation of subject demographics 
 Confirmation of eligibility 
 Primary subject registration 
11.2 Visit 1 (Week −2, at the Start of the Screening Period) 
 Confirmation of subject demographics 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Body weight (before and after dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology, postdialysis BUN) 
 Pregnancy test (only in women of childbearing potential) 
 Instructions for the symptom diary 
 Confirmation of the dry weight and the dose 
 Confirmation of eligibility 
 Secondary subject registration 

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11.3 Visit 2 (Start Day of Administration, at Start of the Double-blind 
Period) 
 Confirmation of subject demographics 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 Body weight (before dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of eligibility 
 Tertiary subject registration 
 Confirmation of the compliance with study treatment 
11.4 Visit 3 (Week 1) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.5 Visit 4 (Week 2) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.6 Visit 5 (Week 4) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 

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 Skindex-16 
 5-D itch scale 
 PGIC 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.7 Visit 6 (Week 6, at the Start of the Extension Period) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Body weight (before dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of eligibility 
 Registration for the extension period 
 Confirmation of the dry weight and the dose 
 Confirmation of the compliance with study treatment 
11.8 Visit 7 (Week 7) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.9 Visit 8 (Week 8) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 

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11.10 Visit 9 (Week 10) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.11 Visit 10 (Week 12) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Body weight (before dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.12 Visit 11 (Week 18) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Dependency assessment (before dialysis) 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.13 Visit 12 (Week 26) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 

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 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.14 Visit 13 (Week 34) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Dependency assessment (before dialysis) 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Body weight (before dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the dry weight and the dose 
 Confirmation of the compliance with study treatment 
11.15 Visit 14 (Week 46) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
11.16 Visit 15 (Week 58, at the Start of the Follow-up Period) 
 Review of the symptom diary 

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 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Dependency assessment (before dialysis) 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Body weight (before dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Pregnancy test (only in women of childbearing potential) 
 Confirmation of the compliance with study treatment 
11.17 Visit 16 (Week 59 [at the End of the Follow-up Period]) or 1 
Week after Discontinuation 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Dependency assessment 
 Confirmation of the implementation status of hemodialysis 
11.18 At Discontinuation 
 Registration for the extension period (only in subjects withdrawing from the study 
during the double-blind period) 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Dependency assessment (before dialysis) 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 PGIC 
 Body weight (before dialysis) 
 12-lead ECG 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Pregnancy test (only in women of childbearing potential) 
 Confirmation of the compliance with study treatment 

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12. Measures to Ensure the Safety of the Clinical Study 
12.1 Action to be Taken for Adverse Events 
If any adverse event occurs in a subject during the study period, the principal investigator or 
subinvestigator will take appropriate action to ensure the safety of the subject. Any adverse 
event that meets the criteria described in “10.13.9 Follow-up investigation” will be followed 
up, as instructed in the section. 
12.2 Action to be Taken for and Response to Serious Adverse 
Events 
12.2.1 Action to be taken for serious adverse events 
If any serious adverse event described in “10.13.4 Serious adverse events” occurs in a subject, 
the principal investigator or subinvestigator will make efforts to provide the subject with 
appropriate emergency treatment for recovery. 
12.2.2 Response to serious adverse events 
The principal investigator or subinvestigator will notify the sponsor of a serious adverse event 
within 24 hours of knowledge of its occurrence. In addition, the principal investigator will 
submit a prespecified document to the sponsor within 3 days, and promptly report the event to 
the head of the study site, as instructed by the study site’s procedure. 
12.3 Response to Serious Adverse Events Caused by Device 
Deficiencies 
A device deficiency refers to a deficiency related to quality, safety, performance, etc. in a 
broad sense such as breakage, malfunction, etc. occurring at the device part of the study drug. 
If any serious adverse event caused by a device deficiency occurs, the principal investigator or 
subinvestigator will respond to it according to “12.2 Action to be Taken for and Response to 
Serious Adverse Events.” If becoming aware of any deficiency that could cause a serious 
adverse event, the principal investigator will submit a prespecified document to the sponsor 
within 1 week, and promptly report the deficiency to the head of the study site, as instructed 
by the study site’s procedure. 
12.4 Action to be Taken for and Response to Pregnancies 
If a female subject is found or suspected to be pregnant during the study period, the principal 
investigator or subinvestigator will immediately discontinue study treatment in the subject. If 
obtained any information about a suspected pregnancy, the principal investigator or 
subinvestigator will immediately provide the sponsor with the information. In addition, the 
principal investigator or subinvestigator will follow up the course from pregnancy until 
delivery as well as the postnatal development of her baby for about one and half years, and 
provide obtained information for the sponsor. However, it is unnecessary to follow up the 
subject if she is found to have been in the placebo group after unblinding and has not entered 
into the extension period. 
If obtained information about a pregnancy or suspected pregnancy of the partner of a male 
subject during the period between the start of study treatment and 12 weeks after the day of 
the final dose, the principal investigator or subinvestigator will immediately provide the 

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sponsor with the information. In addition, the principal investigator or subinvestigator will 
follow up the course of the partner’s pregnancy whenever possible and provide obtained 
information for the sponsor. However, it is unnecessary to follow up the subject if she is found 
to have been in the placebo group after unblinding and has not entered into the extension 
period. 
12.5 Collection and Provision of Safety Information 
12.5.1 Collection of new safety information 
The sponsor will continuously collect and assess information that may adversely affect the 
safety of subjects, influence the conduct of the clinical study, or require changes to the 
approval of the IRB for continuation of the study. 
12.5.2 Provision of new safety information 
The sponsor will promptly notify all the principal investigators involved in the study, the head 
of the study site, and the IRB via the head of the study site in writing of any new information 
that could affect the safety of subjects or the conduct of the study. If any agreement has been 
made in advance among the sponsor, the IRB, and the head of the study site, the sponsor may 
also notify the IRB at one time of only notifications concerning Article 20, Paragraphs 2 and 3 
of the GCP ordinance. 
When considering that any information may affect the subject’s willingness to continue 
participation in the study, the principal investigator or subinvestigator will immediately notify 
the subject of the information and reconfirm the subject’s willingness to continue participation 
in the study. At this time, the communication of the information to the subject and the result of 
reconfirmation of the subject’s willingness to continue participation in the study will be 
documented in writing (such as in medical records). In addition, when considering it 
necessary to revise the informed consent form, the principal investigator will promptly revise 
the informed consent form on the basis of the information and obtain approval of the IRB in 
advance. For subjects already participating in the study, the principal investigator or 
subinvestigator will provide an explanation about details again using the revised informed 
consent form and obtain voluntary consent in writing for continuation of participation in the 
study from the subjects. In principle, new subjects will not be enrolled in the study until the 
revised informed consent form is approved. However, enrollment will be permitted when the 
sponsor or the principal investigator consider it unnecessary to change, terminate, or suspend 
the study. In this case, the informed consent form before revision will be used, and any new 
safety information that may affect the subject’s willingness to continue participation in the 
study will be conveyed and documented. After given approval by the IRB, reconsent will be 
obtained using the revised informed consent form. 
12.6 Opening of Emergency Key Codes 
If the study drug assigned to a subject needs to be identified immediately in emergencies, the 
emergency key code for the drug number will be opened to identify the treatment, as 
instructed below: 
1) 
In an emergency, the principal investigator or subinvestigator will promptly provide 
appropriate treatment for the subject, confirm his/her health condition, and report to the 
sponsor. If it is considered necessary to open the emergency key code for the subject to 
assure his/her safety, the principal investigator or subinvestigator will request the sponsor 
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2) 
If requested by the principal investigator or subinvestigator to open the emergency key 
code or if the sponsor considered it necessary to open the emergency key code, the 
sponsor will open the emergency key code for the drug number, as stipulated separately 
in the written procedure, and report the drug number to the principal investigator. 
3) 
For the subject with the relevant drug number, the principal investigator will complete a 
case report form and a “record of premature opening of a treatment assignment code” 
and submit the documents to the sponsor. 
13. Discontinuation/Suspension of the Clinical Study 
13.1 Discontinuation/Suspension of Parts of the Study or the Entire 
Study 
If any of the following discontinuation criteria are met during the study, the sponsor or the 
principal investigator will determine measures to be taken, taking into consideration 
discontinuation/suspension of parts of the study or the entire study. 
13.2 Discontinuation Criteria (Discontinuation/Suspension of Parts 
of the Study or the Entire Study) 
1) 
It is considered difficult to continue the study because of new safety information 
(including the occurrence of a serious adverse event). 
2) 
It is considered difficult to properly continue the study because of a serious violation of 
GCP, the protocol, or the agreement by the sponsor, study site, or principal investigator. 
3) 
It is considered difficult to continue the study because of a change in the study 
administrative structure (e.g., transfer of the principal investigator). 
4) 
It is considered inappropriate to continue the study for other reasons such as new 
information or a change in circumstances during the study. 
13.3 Procedures for Discontinuation/Suspension 
The study will be discontinued or suspended in the following procedures: 
1) 
When the sponsor discontinues/suspends parts of the study or the entire study, the 
sponsor will immediately notify the head of the study site in writing of the decision on 
discontinuation/suspension and the reason for the decision. 
2) 
When the principal investigator discontinues/suspends the study, the principal 
investigator will immediately notify the head of the study site in writing of the decision 
on discontinuation/suspension and the reason for the decision. 
3) 
When the sponsor decides to discontinue/suspend parts of the study or the entire study 
and notifies the head of the study site of the decision, the head of the study site will 
immediately notify the principal investigator and the IRB in writing of the decision and 
the reason for the decision. When the principal investigator discontinues/suspends the 
study and notifies the head of the study site of the decision, the head of the study site will 
immediately notify the sponsor and the IRB in writing of the decision and the reason for 
the decision. 

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When receiving the notice of discontinuation/suspension of the study, the principal 
investigator will immediately convey the notice to subjects on treatment and take appropriate 
action for them. 
14. Statistical Analysis 
Major analysis methods are described below. Details will be specified in a statistical analysis 
plan prepared separately before the informed consent procedure of the first subject. 
For the double-blind period, data from the start of the screening period to the end of the 
double-blind period will be analyzed. Over the entire study period, data from the start of the 
screening period to the end of the follow-up period will be analyzed. 
Handling of subjects and data in the double-blind period and over the entire study period will 
be determined before the respective database lock points in the double-blind period and over 
the entire study period. 
All statistical tests will be performed using a two-sided significance level of 5%; however, a 
two-sided significance level of 15% will be used for the analysis of between-group 
demographic imbalance. Summary statistics to be presented include the number of subjects, 
mean, standard deviation, minimum, median, maximum, and quartile. 
Data will be tabulated by group and by time point, unless otherwise specified. Baseline is 
defined as the start date of treatment. 
14.1 Analysis Sets 
Analysis sets are defined as follows: When the full analysis set (FAS) and the per protocol set 
(PPS) are used as analysis sets, analyses will be performed based on the treatment to which 
each subject has been assigned. When the safety set (SS) is used as an analysis set, analyses 
will be performed based on the treatment provided to each subject actually. 
1) 
FAS 
Population of subjects given at least one dose of the study drug, meeting the inclusion 
criterion related to NRS score, and having a baseline mean NRS score. 
2) 
PPS (only in the double-blind period) 
Population of subjects excluding the following subjects from the FAS: 
 Subjects not meeting the inclusion criteria 
 Subjects meeting any of the exclusion criteria related to efficacy evaluation 
 Subjects withdrawing from the study before Week 4 in the double-blind period 
 Subjects given < 9 or > 15 doses of the study drug before Week 4 in the double-blind 
period 
 Subjects changing the dosage and administration of a conditionally permitted 
concomitant medication or newly using a conditionally permitted concomitant 
medication before Week 4 in the double-blind period 
 Subjects using a prohibited concomitant drug or therapy before Week 4 in the double-
blind period 
 Subjects changing the frequency of dialysis per week or the hemodialysis method 
before Week 4 in the double-blind period 

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3) 
SS 
Population of subjects given at least one dose of the study drug 
14.2 Analysis Groups 
14.2.1 Double-blind period 
The analysis sets and subjects included in the analysis sets for the analysis groups are shown 
in Table 14.2.1-1. 
Table 14.2.1-1 Analysis sets and subjects included in the analysis sets for the 
analysis groups 
Analysis Groups 
Analysis Sets 
Subjects included in the analysis set 
MR13A9 0.5 μg/kg 
group 
FAS, PPS 
Subjects randomized to MR13A9 0.5 μg/kg 
SS 
Subjects given MR13A9 0.5 μg/kg 
Placebo group 
FAS, PPS 
Subjects randomized to placebo 
SS 
Subjects given placebo 
14.2.2 Entire study period 
The analysis sets and subjects included in the analysis sets for the analysis groups are shown 
in Table 14.2.2-1. 
Table 14.2.2-1 Analysis sets and subjects included in the analysis sets for the 
analysis groups 
Analysis Groups 
Analysis Sets 
Subjects included in the analysis set 
MR-MR group 
FAS 
Subjects randomized to MR13A9 0.5 μg/kg in the double-blind 
period and entering into the extension period 
SS 
Subjects given MR13A9 0.5 μg/kg in the double-blind period and 
entering into the extension period 
P-MR group 
FAS 
Subjects randomized to placebo in the double-blind period and 
entering into the extension period 
SS 
Subjects given placebo in the double-blind period and entering into 
the extension period 
14.3 Disposition of Subjects 
For each analysis set and the presence/absence of discontinuation, numbers and percentages 
of subjects will be presented. For the double-blind period, differences between the groups will 
be examined. 
14.4 Demographic and Other Baseline Characteristics 
For major subject demographics, summary statistics or numbers and percentages of subjects 
will be presented overall and by group according to the characteristics of individual data. For 
the double-blind period, imbalance between the groups will be examined. 
14.5 Efficacy 
The FAS will be used as the primary analysis set for the double-blind period. As a 
supplementary analysis, the PPS will be used for the primary analysis of the primary variable 
to determine the robustness of the analysis results. 
The FAS will be used as the analysis set for the entire study period. 

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14.5.1 Primary endpoint 
The primary endpoint is the NRS score. The assessment time points and their time windows 
in the screening period, the double-blind period, and the extension period are shown in Table 
14.5.1-1. The assessment time point and its time window in the follow-up period are shown in 
Table 14.5.1-2. 
Table 14.5.1-1 Assessment time points and their time windows in the screening 
period, the double-blind period, and the extension period 
Period 
Assessment time point 
Assessment time window a) 
Screening period 
At Week −1 
From Day −13 to Day −7 
Double-blind period 
At baseline 
From Day −6 to Day 1 
At Weeks 1 to 6 
From Day 7 × x − 5 to Day 7 × x + 1 b) 
Extension period 
At Weeks 7 to 58 
From Day 7 × x − 5 to Day 7 × x + 1 b) 
a) The start date of the double-blind period will be regarded as Day 1 and the previous day of the start date of the double-
blind period will be regarded as Day −1. 
b) x: Number of weeks 
Table 14.5.1-2 Assessment time point and its time window in the follow-up period 
Period 
Assessment time point 
Assessment time window a) 
Follow-up period 
At Week 1 of the follow-
up period 
From Day 1 to Day 7 
a) The start date of the follow-up period (the completion date of the extension period or the next day of the date of 
discontinuation) will be regarded as Day 1. 
The mean NRS score at each time point will be calculated as follows. However, if the number 
of observation days during the assessment period is less than 4 days at the time of calculation 
of the score at each time point, the data will be deemed as missing: 
Mean NRS score at each time point = Sum of the NRS score observed during the assessment 
time window ÷ Number of days when NRS score was observed during the assessment time 
window 
The change from baseline in the mean NRS score at each time point will be calculated as 
follows: 
Change from baseline in the mean NRS score at each time point = Mean NRS score at each 
time point − Mean NRS score at baseline 
14.5.2 Primary variable 
The primary variable will be the change from baseline in the mean NRS score at Week 4 of 
the double-blind period. 
14.5.3 Analysis of the primary variable 
Data obtained up to Week 4 of the double-blind period will be analyzed. 
14.5.3.1 Primary analysis 
The superiority of the MR13A9 0.5 μg/kg group to the placebo group will be confirmed by 
performing the analysis using a mixed-effects model for repeated measures (MMRM) with 
change from baseline in the mean NRS score at each time point as an objective variable; 
treatment group, time point, and treatment group-by-time point interaction as fixed effects; 
baseline mean NRS score and the presence or absence of prior treatment with nalfurafine 
hydrochloride as a dynamic allocation factor as covariates; and subject as a random effect. 

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The analysis will include all available data obtained at each time point from Week 1 to Week 
4 of the double-blind period as objective variables. Estimation will be performed using a 
restricted maximum likelihood method. An unstructured covariance structure will be used to 
estimate error variance. If the unstructured covariance structure fails to provide convergence, 
the structure that minimizes Akaike Information Criterion (AIC), among the Toeplitz, first-
order autoregressive, and compound symmetry structures, will be used. The degree of 
freedom will be adjusted with the Kenward-Roger method. 
The adjusted mean change at each time point for each group and its two-sided 95% 
confidence interval will be presented. The adjusted mean difference in the change at each time 
point between the placebo group and the MR13A9 0.5 µg/kg group and its two-sided 95% 
confidence interval as well as the p value will be presented. 
14.5.3.2 Sensitivity analysis 
Sensitivity analyses will be performed to determine the robustness of the analysis results. 
Details of the multiple imputation (MI) method are described separately in the statistical 
analysis plan. 
In the individual analyses, treatment effects will be estimated as in the primary analysis. 
1) 
MI – MMRM 
Multiple imputed data will be generated in the procedures shown below. Each imputation data 
will be analyzed using the same MMRM model as that for the primary analysis, and the 
results of the analyses will be combined. Imputation will be performed for all available data 
obtained at each time point between the baseline and Week 4 of the double-blind period. 
(1) Non-monotone missing data will be imputed with a Markov Chain Monte Carlo 
(MCMC) method. 
(2) Monotone missing data will be imputed with an imputation formula generated using a 
regression model developed based on the data from all the groups. 
2) 
Placebo MI – MMRM 
Multiple imputed data will be generated in the procedures shown below. Each imputation data 
will be analyzed using the same MMRM model as that for the primary analysis, and the 
results of the analyses will be combined. Imputation will be performed for all available data 
obtained at each time point between the baseline and Week 4 of the double-blind period. 
(1) Non-monotone missing data will be imputed with an MCMC method. 
(2) Monotone missing data will be imputed with an imputation formula generated using a 
regression model developed based on the data from the placebo group. 
14.5.3.3 Other assessment variables 
1) 
Change from baseline in the mean NRS score 
Summary statistics will be presented. A one-sample t-test will be used for comparisons within 
each group. For the double-blind period, a two-sample t-test will be used for comparisons 
between the placebo group and the MR13A9 0.5 µg/kg group. 
2) 
Mean NRS score 
Summary statistics will be presented. 

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3) 
Percentage of subjects with improvement in the mean NRS score 
The number and percentage of subjects with improvement in the mean NRS score will be 
presented. For the double-blind period, a Fisher’s exact test will be used for comparisons 
between the placebo group and the MR13A9 0.5 µg/kg group. Subjects with improvement are 
defined as shown below. 
 Subjects with 3-point improvement: Change from baseline in the mean NRS score is 
≤ −3 
 Subjects with 4-point improvement: Change from baseline in the mean NRS score is 
≤ −4 
14.5.4 Secondary endpoints 
1) 
Itch score based on the Shiratori’s severity criteria 
The mean itch score and change from baseline at each time point will be calculated using the 
same calculation formula as that for the mean NRS score and change from baseline shown in 
“14.5.1 Primary endpoint.” 
For changes from baseline, the same analysis as “14.5.3.1 Primary analysis” will be 
performed on the data obtained up to Week 4 of the double-blind period. However, the 
covariate of the model will be the baseline of the data to be analyzed. The same analysis as 
“14.5.3.3 1) Change from baseline in the mean NRS score“ will be performed. 
For measurements, the same analysis as “14.5.3.3 2) Mean NRS score“ will be performed. 
2) 
Overall Skindex-16 score and total 5-D itch scale score 
For changes from baseline, analysis of covariance with treatment group as a fixed effect and 
baseline score as a covariate will be performed on the data obtained at the end of the double-
blind period. The same analysis as “14.5.3.3 1) Change from baseline in the mean NRS 
score“ will be performed. 
For measurements, the same analysis as “14.5.3.3 2) Mean NRS score“ will be performed. 
3) 
PGIC(Patient Global Impression of Change) 
The number and percentage of subjects with global symptoms will be presented. For the 
double-blind period, a two-sample Wilcoxon test will be used for comparisons between the 
placebo group and the MR13A9 0.5 µg/kg group. 
14.6 Safety 
The SS will be used as the analysis set. 
14.6.1 Adverse events and adverse drug reactions 
For the double-blind period, analysis will include events occurring between the start of study 
treatment in the double-blind period and the end of the double-blind period. For the entire 
study period, analysis will include events occurring between the start of study treatment in the 
double-blind period and the end of the follow-up period. 
Adverse events of special interest will also be summarized in the same manner. 
1) 
Incidence of adverse events and adverse drug reactions 

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The number of events, the number of subjects experiencing events, the incidence of events 
and its two-sided 95% confidence interval will be presented. For the double-blind period, a 
Fisher’s exact test will be used for comparisons between the placebo group and the MR13A9 
0.5 µg/kg group, and the between-group difference in incidence and its 95% confidence 
interval will be presented. 
2) 
Incidences of adverse events and adverse drug reactions (serious events and events 
leading to discontinuation) 
The numbers of events, the numbers of subjects experiencing events, and the incidences of 
events will be presented for all events, events leading to death, serious events other than death, 
and events leading to discontinuation. 
3) 
Occurrence of adverse events and adverse drug reactions 
The number of subjects experiencing events and the incidence of events will be presented for 
all events and by primary SOC and PT. 
4) 
Occurrence of adverse events and adverse drug reactions (by severity) 
The numbers of events by severity will be presented for all events and by primary SOC and 
PT. 
5) 
Occurrence of adverse events and adverse drug reactions (by time of onset) 
For the entire study period, the number of subjects experiencing events and the incidence of 
events for all events and by primary SOC and PT will be presented by time of onset. 
14.6.2 Vital signs and body weight 
Summary statistics as well as scatter plots before and after treatment will be presented. 
14.6.3 Laboratory tests 
For quantitative values, summary statistics as well as scatter plots and shift tables before and 
after treatment will be presented. 
For qualitative values, the number and percentage of subjects as well as shift tables before and 
after treatment will be presented. 
14.6.4 Dependency assessment 
The number and percentage of subjects with or without dependency will be presented. 
14.7 Timing of Analyses 
When all data obtained in the double-blind period are locked, an interim analysis of the data 
in the double-blind period will be performed. When data obtained up to Week 34 of the 
extension period are locked, interim tabulation of the data up to Week 34 will be performed. 
When all data obtained in the extension period are locked, the final tabulation of the data over 
the entire study period will be performed. 

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15. Compliance with the Protocol, etc. 
15.1 Agreement on the Protocol 
To confirm the agreement on the content of the protocol and the compliance with the protocol, 
the principal investigator will affix their name and seal to or sign, and date the protocol or an 
alternative document. 
15.2 Amendment of the Protocol 
The sponsor will revise the protocol as necessary when becoming aware of information on the 
quality, efficacy, and safety of the test drug and other important information for the proper 
conduct of the study. In such cases and in cases where the protocol is revised on the order of 
the head of the study site based on IRB’s opinion, the sponsor will agree with the principal 
investigator on the revision of the protocol. 
The principal investigator or subinvestigator must not implement any deviation from or 
changes of the protocol unless the principal investigator obtains prior written agreement from 
the sponsor and written approval from the IRB based on its prior review, except where 
medically necessary to eliminate immediate hazards to subjects, or when the change involves 
only administrative aspects of the study. 
15.3 Deviation from the Protocol 
The principal investigator or subinvestigator will document all deviations from the protocol. 
When having implemented a deviation from or a change to the protocol to eliminate 
immediate hazards to subjects or for other inevitable medical reasons, the principal 
investigator will submit a document describing the deviation or change and the reason for it, 
as well as a proposed protocol revision when protocol revision is necessary, as soon as 
possible, to the sponsor, the head of the study site, and the IRB via the head of the study site. 
By doing so, the principal investigator will obtain approval from the head of the study site and 
written agreement from the sponsor via the head of the study site. 
16. Direct Access to Source Documents 
16.1 Source Documents and Source Data 
“Source documents” refer to information on the course of events in the study as well as 
original documents, data, and records that contain source information for case report forms. 
More specifically, source documents refer to records, such as informed consent forms, 
subject’s medical records, laboratory data, and study treatment records, necessary for the 
reconstruction and evaluation of the course of events in the study. 
“Source data” refer to all information recorded in the original records on clinical findings, 
observations, and other activities in a clinical study and their certified copies, which are 
necessary for the reconstruction and evaluation of the course of events in the clinical study. 
“Source data” are contained in the source documents (original records or their certified 
copies). 
Source data must be attributable, legible, contemporaneous, original, accurate, and complete, 
and any changes made to the source data may be traceable and may not obscure the original 
entry. 

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16.2 Direct Access 
The head of the study site and the principal investigator must allow monitoring and auditing 
by the sponsor and inspections by the IRB and regulatory authorities in and outside Japan, 
providing direct access to source documents. 
The sponsor will confirm that each subject has consented in writing to direct access to their 
original medical records at the time of monitoring, auditing, and inspections by the IRB and 
regulatory authorities in and outside Japan. 
16.3 Consistency Between Source Documents and Case Report 
Forms 
The sponsor will confirm that the entries in case report forms completed by the principal 
investigator and study-related records such as source documents are accurate by checking 
them against each other. 
The entries in case report forms must be consistent with the contents in source documents. 
The principal investigator will prepare a record explaining the reason for any discrepancy 
between case report forms and source documents and submit the record to the sponsor. A copy 
of the record will be retained at the study site. 
17. Quality Control and Quality Assurance for the Study 
The sponsor will implement quality control and quality assurance for this study according to 
the standard operating procedures. The sponsor’s auditor will assess whether this study is 
being conducted in compliance with GCP, protocol, and written procedures, independently 
and separately from the routine monitoring and study quality control activities. 
18. Ethics 
18.1 Compliance with GCP 
This study will be conducted in accordance with the ethical principles that have their origin in 
the latest Declaration of Helsinki and in compliance with Article 14-3 and Article 80-2 of the 
Law for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices, the 
standards related to the conduct of clinical studies of drugs stipulated by the Ministry of 
Health, Labour and Welfare, the MHLW Ordinance on Good Clinical Practice, and this 
protocol. 
18.2 Protection of Subject Confidentiality 
The head of the study site will take necessary measures to guarantee the protection of subject 
confidentiality. Sufficient care for the protection of human rights will be taken, including 
identification of subjects by subject identifiers in documentation of subject data in the case 
report form. In addition, measures will be taken to ensure that subject confidentiality is 
protected when the monitors, auditors, IRB, and regulatory authorities access the subjects’ 
source data. 
18.3 Compensation to Subjects 
1) 
The study site will provide treatment or other necessary measures for a subject 
experiencing any study-related injury. 

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2) 
If a subject makes or may make a claim for compensation or indemnification from the 
study site for a study-related injury, the study site will immediately notify the sponsor, 
and the study site and the sponsor will cooperate to settle the issue. 
3) 
The sponsor will compensate a subject experiencing any study-related injury in 
accordance with the compensation rules specified by the sponsor. 
4) 
If responsibilities arise later for damage from a study-related injury to a subject in this 
study, the compensation will be the responsibility of and at the expense of the party 
liable for the damage. 
5) 
The sponsor will insure against the compensation or indemnification mentioned above. 
19. Data Handling, and Record Keeping 
19.1 Preparation and Submission of Case Report Forms 
In this study, clinical study data on investigations, observations, tests, and evaluations will be 
collected and recorded electronically to complete case report forms. The principal investigator 
or subinvestigator will complete case report forms for all subjects who have provided 
informed consent, and the principal investigator will review all entered data. For subjects not 
entering into the double-blind period, at least the information on the date of written informed 
consent, sex, year and month of birth, race, adverse events, and discontinuation of the study 
will be collected and recorded in the case report form. Case report forms will be completed as 
instructed separately in the written procedure. 
19.2 Recording of the Symptom Diary 
Subjects will record their symptoms in the symptom diary based on the electronic diary 
system. Data recorded by subjects will be transferred to electronic case report forms, and the 
case report forms will be regarded as source documents. The contents of the case report forms 
will be checked by the principal investigator, subinvestigator, or clinical research coordinator 
during interviews and when necessary. The symptom diary will be recorded as instructed 
separately in the written procedure. 
19.3 Submission of 12-lead ECG charts 
If any abnormal finding corresponding to an adverse event is observed in a subject after 
administration of the study drug and the sponsor considers it necessary to do so, the principal 
investigator or subinvestigator will submit copies of all ECG charts for the subject obtained 
during the study to the sponsor. 
19.4 External Data 
If obtaining any measurements at an external laboratory testing facility as electronic data, the 
sponsor will obtain such electronic data directly from the external laboratory testing facility. 
The method and time of data generation will be in accordance with a procedure established 
between the sponsor and the external laboratory testing facility. 

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19.5 Record Keeping 
19.5.1 Study site 
The head of the study site will retain study-related documents and records until notified by the 
sponsor that the retention of study-related documents and records is no longer necessary. The 
head of the study site or the record retention manager will take measures to prevent the loss or 
disposal of these records during a time period of retention and to make these records available 
upon request. 
The principal investigator will retain study-related documents, as instructed by the head of the 
study site. 
19.5.2 Institutional review board 
The founder of the IRB will retain study-related documents and records until notified by the 
sponsor that the retention of study-related documents and records is no longer necessary. 
These records must be made available upon request from the regulatory authorities. 
19.5.3 Notice from the sponsor 
When the retention of study-related documents and records by the head of the study site or the 
founder of the IRB is no longer needed, the sponsor will notify the head of the study site and 
the founder of the IRB via the head of the study site. 
20. Monetary Payment 
The study site and the sponsor will discuss any monetary payment to a subject in advance and 
obtain approval of the IRB. If the IRB’s approval is obtained, money should be paid to the 
subject based on the documented rules for payment to subjects. 
21. Publication Policy 
Information, including unpublished data included in this protocol, is the property of the 
sponsor and may not be disclosed to any third party without written consent of the sponsor. 
Disclosure of the results of the study to outside parties such as academic societies or journals, 
in part or in whole, will require the prior approval of the sponsor. 
22. Study Administrative Structure 
This study will be planned and conducted by the organizations described in the separate 
volume of the protocol. The separate volume will be revised separately from this protocol. 
23. History of Protocol Amendments 
Version: 1.0: created on October 28, 2020 

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24. Literature References 
1) Rayner HC, Larkina M, Wang M, et al. International Comparisons of Prevalence, 
Awareness, and Treatment of Pruritus in People on Hemodialysis. Clin J Am Soc 
Nephrol. 2017;12:2000-7. 
2) Mathur VS, Lindberg J, Germain M, et al. A longitudinal study of uremic pruritus in 
hemodialysis patients. Clin J Am Soc Nephrol. 2010;5:1410-19. 
3) Kimata N, Fuller DS, Saito A, et al. Pruritus in haemodialysis patients: Results from 
Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS). Hemodial Int. 
2014;18:657-67. 
4) Monkawa T. Management of Hemodialysis Patients for Residents. 2nd Edition. Tokyo. 
Igaku-Shoin Ltd.; 2014. p. 110-1. 
5) Kaneko T. Itchy skin, skin abnormalities. In: Edited by Iida N and Akiba T. Guidebook 
for Dialysis Therapy. 4th Edition. Tokyo. Ishiyaku Pub, Inc.; 2014. p. 137-8. 
6) Mansour A, Hoversten MT, Taylor LP, et al. The cloned μ, δ and κ receptors and their 
endogenous ligands: evidence for two opioid peptide recognition cores. Brain Res. 
1995;700:89-98. 
7) Minami M, Markawa K, Yabuuchi K, et al. Double in situ hybridization study on 
coexistence of μ-, δ- and κ-opioid receptor mRNAs with preprotachykinin A mRNA in 
the rat dorsal root ganglia. Brain Res Mol Brain Res, 1995;30:203-10. 
8) Stein C. Opioid receptors on peripheral sensory neurons. Adv Exp Med Biol. 
2003;521:69-76. 
9) Takamori K, Nemoto O. Mechanism of Itching in Dialysis Patients. In: Edited by 
Akiba T and Akisawa T. Dialysis Therapy Next XII, Front-line Therapy for Dialysis 
Pruritus. Tokyo. Igakutosho-Shuppan Ltd.; 2011.p.34-41. 
10) Kumagai H, Maruyama S, Ebata T, et al. Clinical Development of a New Itching Drug 
(REMITCH®) and its Efficacy. In: Edited by Akiba T and Akisawa T. Dialysis Therapy 
Next XII, Front-line Therapy for Dialysis Pruritus. Tokyo. Igakutosho-Shuppan Ltd.; 
2011.p. 94-108. 
11) Suzuki H. Current Treatment of Dialysis Itching. In: Edited by Akiba T and Akisawa T. 
Dialysis Therapy Next XII, Front-line Therapy for Dialysis Pruritus. Tokyo. 
Igakutosho-Shuppan Ltd.; 2011.p. 49-55. 
12) Toray Industries, Inc. Drug Interview Form for REMITCH® Capsules 2.5 μg, OD 
Tablets 2.5 μg. Revised in September 2020 (16th version). 
13) Ohnishi A, Mihara M, Yasuda S, et al. Aquaretic effect of the stable dynorphin-A 
analog E2078 in the human. J Pharmacol Exp Ther. 1994;270:342-7. 
14) Shiratori A, et al., Clinical Evaluation of Oxatomide for Pruritus–Multicenter, Double-
blind Study–, Nishinihon Journal of Dermatology 1983;45: 1042-51. 
15) Higaki Y, Kawamoto K, Kamo T, et al. The Japanese Version of Skindex-16: A Brief 
Quality-of-Life Measure for Patients with Skin Disease. J Dermatol. 2002;29:693-8 

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16) Ebata T, et al., Development of the Japanese Version of the 5-D itch scale, Japanese 
Journal of Dermatology 2015; 125, 1035-40. 
17) JT Daugirdas. Second Generation Logarithmic Estimates of Single-Pool Variable 
Volume Kt/V: An Analysis of Error. J. Am. Soc. Nephrol. 1993;4:1205-13. 
18) Kurihara M, et al. Double-blind comparison of clinical effects of ID-540 
(fludiazepam), diazepam, and placebo on psychoneurotic patients and a tentative draft 
of dependency questionnaire. Clinical Evaluation. 1977; 5, 341-68. 

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25. Appendices 
Appendix 1 
NRS (numerical rating scale) 
 
Appendix 2 
Shiratori’s severity criteria 
Severity 
Daytime symptom 
Nighttime symptom 
4: Severe itching 
Intolerable itch, not relieved by scratching 
but instead worsens. Cannot focus on work 
or study. 
Can hardly sleep because of itch. 
Scratching all the time, but itch intensifies 
with scratching. 
3: Moderate itching 
Scratching even in the presence of others. 
Irritation as a result of itch, continuous 
scratching. 
Wake up because of itch. Can fall asleep 
again after scratching, but continue to 
scratch unconsciously while sleeping. 
2: Mild itching 
Itch sensation is relieved by light, 
occasional scratching. Not too disturbing. 
Feel somewhat itchy, but can obtain relief 
by scratching. Do not wake up because of 
itch sensations. 
1: Slight itching 
Feel itchy sometimes, but tolerable without 
scratching. 
Feel slightly itchy when going to sleep, but 
do not need to scratch. Sleeping well. 
0: No symptom 
Hardly feel itchy or do not feel itchy at all. Hardly feel itchy or do not feel itchy at all. 
Source: Shiratori A, et al., Clinical Evaluation of Oxatomide for Pruritus–Multicenter, Double-blind Study–, Nishinihon 
Journal of Dermatology 1983;45:1042-51. 
Appendix 3 
New York Heart Association (NYHA) Classification 
Class I: Patients with cardiac disease but without resulting in limitation of physical activity. 
 Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
Class II: Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. 
 Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III: Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. 
 Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV: Patients with cardiac disease resulting in the inability to carry on any physical 
activity without discomfort. 
 Symptoms of heart failure or the anginal pain may be present even at rest. If any 
physical activity is undertaken, discomfort increases. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No itching 
Worst itching 
imaginable 

CONFIDENTIAL 
Protocol No.: MR13A9-5 
Version: 1.0 
64 
Appendix 4 
Specific signs or symptoms 
1) 
Dizziness (e.g., lightheadedness, vertigo) 
2) 
Syncope (e.g., fainting spells) 
3) 
Palpitation (e.g., heart pounding) 
4) 
Tachycardia (as per vital sign assessment) 
5) 
Falls (including fractures due to falls) 
6) 
Seizures (including convulsions) 
7) 
Gait disturbance (e.g., unsteady gait, unsteady on feet while walking) 
8) 
Mental status change (e.g., patient appears confused, spatially or temporally disoriented, 
forgetful) 
9) 
Somnolence (e.g., patient appears sleepier, drowsy, sedated, groggy) 
10) Mood changes (e.g., patient appears more anxious, agitated, aggressive, uncooperative, 
restless, withdrawn) 
Appendix 5 
Skindex-16 
During the past 1 week, how often have you been bothered by the following? 
1. Skin itching 
2. Skin burning or stinging 
3. Skin hurting 
4. Skin irritated 
5. Persistence or recurrence of condition 
6. Worry about condition (e.g., that it will get worse) 
7. Appearance of skin 
8. Frustration about skin 
9. Embarrassment about skin 
10. Annoyed about skin 
11. Feeling depressed 
12. Effect of skin on interaction with others (e.g., family members, friends, familiar people) 
13. Effect of skin in desire to be with people 
14. Skin making it hard to show affection 
15. Effect of skin on daily activities 
16. Skin making it hard to work/have enjoyment 
No. 1 to 4 are categorized into questions concerning symptoms, No. 5 to 11 are categorized 
into questions concerning emotions, and No. 12 to 16 are categorized into questions 
concerning functioning. Patients choose one answer to each question from among 7 scales, 
where 0 indicates never bothered and 6 indicates always bothered. 
Copyright holder for the Japanese version: Higaki Y (Tokyo Women's Medical University), 
Publisher: Medical Professional Relations K.K. 

CONFIDENTIAL 
Protocol No.: MR13A9-5 
Version: 1.0 
65 
Appendix 6 
5-D itch scale 
1. Duration 
During the past 2 weeks, how many hours a day have you been itching? 
Less than 6 hours/day, (2) 6-12 hours/day, (3) 12-18 hours/day, (4) 18-23 hours/day, (5) All day 
 
2. Degree 
Rate the intensity of your itching over the past 2 weeks. 
(1) Not present, (2) Mild, (3) Moderate, (4) Severe, (5) Unbearable 
 
3. Direction 
Over the past 2 weeks, has your itching gotten better or worse compared to the previous 
month? 
(1) Completely resolved, (2) Much better, but still present, (3) Little bit better, but still 
present, (4) Unchanged, (5) Getting worse 
 
4. Disability 
Rate the impact of your itching on the following activities over the past 2 weeks. 
 
Sleep 
(1) Never affects sleep, (2) Occasionally delays falling asleep, (3) Frequently delays falling 
asleep, (4) Delays falling asleep and occasionally wakes me up at night, (5) Delays falling 
asleep and frequently wakes me up at night 
 
Leisure/Social 
(1) Never affects this activity, (2) Rarely affects this activity, (3) Occasionally affects this 
activity, (4) Frequently affects this activity, (5) Always affects this activity, (*) Not applicable 
 
Housework/Errands 
(1) Never affects this activity, (2) Rarely affects this activity, (3) Occasionally affects this 
activity, (4) Frequently affects this activity, (5) Always affects this activity, (*) Not applicable 
 
Work/School 
(1) Never affects this activity, (2) Rarely affects this activity, (3) Occasionally affects this 
activity, (4) Frequently affects this activity, (5) Always affects this activity, (*) Not applicable 
 
5. Distribution 
Mark whether itching has been present in the following parts of your body over the past 2 
weeks. If a body part is not listed, choose the one that is closest. 
Head/Scalp ( ), Face ( ), Chest ( ), Abdomen ( ), Back ( ), Buttocks ( ), Thighs ( ), Lower legs 
( ), Tops of feet/Toes ( ), Soles ( ), Palms ( ), Tops of hands/Fingers ( ), Forearms (below the 
elbow) ( ), Upper arms (from the elbow to the shoulder) ( ), Points of contact with clothing 
(e.g., waistband, undergarment) ( ), Groin ( ) 
Source: Ebata T, et al., Development of the Japanese Version of the 5-D itch scale, Japanese Journal of Dermatology 
2015;125,1035-40. 
Appendix 7 
Patient Global Impression of Change (PGIC) 
1) 
Very much improved 
2) 
Much improved 
3) 
Minimally improved 
4) 
No change 
5) 
Minimally worse 
6) 
Much worse 
7) 
Very much worse 

CONFIDENTIAL 
Protocol No.: MR13A9-5 
Version: 1.0 
66 
Appendix 8 
Dependency assessment 
Questionnaire on the study drug (before dialysis at Weeks 18, 34, and 58 or at the time of 
discontinuation) 
Question 
Remarkable Moderate 
Slight 
None 
Remarks 
Specify reason for 
Remarkable and Moderate 
Do you feel clearheaded when using 
the study drug? 
 
 
 
 
 
Do you feel indifferent to disliked 
persons or things when using the study 
drug? 
 
 
 
 
 
Do you become hyperactive or 
talkative when using the study drug? 
 
 
 
 
 
Do you become broad-minded when 
using the study drug? 
 
 
 
 
 
Do you feel intoxicated when using the 
study drug? 
 
 
 
 
 
Do you feel irritable or somewhat 
lonely when the effect of the study 
drug runs out? 
 
 
 
 
 
Do you want to continue using the 
study drug? 
 
 
 
 
□ To relieve pruritus 
□ To improve mood 
Do you think this drug has become less 
effective? 
 
 
 
 
 
Do you want to use the study drug in 
larger doses? 
 
 
 
 
□ To relieve pruritus 
□ To improve mood 
Do you feel nauseated or tremulous 
when the effect of the study drug runs 
out? 
 
 
 
 
 
Adapted from Literature Reference 18) 
Questionnaire on the study drug (at Week 59 or at Week 1 after discontinuation) 
Question 
Remarkable Moderate 
Slight 
None 
Remarks 
Specify reason for 
Remarkable and Moderate 
Did you feel irritable or unstable after 
you discontinued the study drug? 
 
 
 
 
 
Did you have more difficulty in 
sleeping after you discontinued the 
study drug? 
 
 
 
 
 
Did you have nausea, vomiting, 
tremors of limb or perspiration after 
you discontinued the study drug? 
 
 
 
 
 
Do you really want to use the study 
drug? 
 
 
 
 
 To relieve pruritus 
 To improve mood 
Did you have convulsions after you 
discontinued the study drug? 
 
 
 
 
 
Did you have a clouded mind or heard 
or seen anything unusual after you 
discontinued the study drug? 
 
 
 
 
 
Adapted from Literature Reference 18) 

 
SI G N A T U R E P A G E  
 
 
D o c u m e nt I D:   
 
 
 
 
U s er  
 
D at e (U T C ) 
 
R e a s o n  
2 0 1 4/ 0 9/ 0 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 9 0 1 8 6 a 1 8 0 0 b c d 7 e
2 0 2 1/ 0 1/ 2 8
0 8: 3 5: 5 8
治験総括責任者として承認する。