A Phase II Clinical Study of MR13A9 in Hemodialysis Patients With Pruritus.
Phase: PHASE2
Conditions: Uremic Pruritus
Sponsor: Kissei Pharmaceutical Co., Ltd.

Protocol No.: MR13A9-4 
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CLINICAL STUDY PROTOCOL 
 
 
 
Development Code 
: MR13A9 
Study Type 
: Phase II Clinical Study 
Study Population 
: Previously Treated Hemodialysis 
Patients with Pruritus 
 
 
 
 
Study Objectives: 
To determine the dose-response relationship for the efficacy, safety, and 
pharmacokinetics of MR13A9 0.25, 0.5, or 1.0 μg/kg administered to 
previously treated hemodialysis patients with pruritus for 8 weeks in a placebo-
controlled, double-blind design. 
 
Title of Study: 
A phase II clinical study of MR13A9 in previously treated hemodialysis patients 
with pruritus 
 
Development Phase: 
Phase II 
 
Protocol No.: 
MR13A9-4 
 
Version: 
02.00.000 
 
Date of Creation/Amendment: 
November 29, 2018 
 
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unpublished information contained in the document may not be disclosed without 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. 
 
 
 
 

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Protocol Synopsis 
Title of Study: 
A phase II clinical study of MR13A9 in previously treated hemodialysis patients with pruritus 
(Protocol No.: MR13A9-4) 
Development Phase: 
Phase II 
Study Objectives: 
To determine the dose-response relationship for the efficacy, safety, and pharmacokinetics of MR13A9 0.25, 0.5, or 
1.0 μg/kg administered to previously treated hemodialysis patients with pruritus for 8 weeks in a placebo-controlled, double-
blind design. 
 
1. Efficacy endpoints 
1) Primary endpoint 
 Itch NRS score (The primary variable is change from baseline in the mean NRS score at Week 8 of the treatment period) 
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 
3. Pharmacokinetic endpoint 
 Plasma concentration of MR13A9 (unchanged drug) 
Study Population: 
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) Japanese patients providing written informed consent for study participation in person (Their first- and second-degree 
relatives must be all Japanese) 
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 who can continue hemodialysis without changing its frequency or 
method (excluding temporary changes with no changes in treatment strategies) during the study 
4) Patients whose pruritus treatment for 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 not receiving nalfurafine hydrochloride for ≥ 2 weeks prior to the start of the screening period 
6) 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) 
 
 Moisturizing drugs (prescription/nonprescription) 
 
 Products formulated with either of the above 
7) Patients whose NRS score in the 7 days prior to the start of the treatment period (including the score recorded on the day 
at Week 0) meets both of the below: 
 
 NRS scores have been recorded for ≥ 5 days. 
 
 The mean value of the recorded scores exceeds 4. 
8) Patients whose itch score based on the Shiratori’s severity criteria in the 7 days prior to the start of the treatment period 
(including the score recorded on the day at Week 0) 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. 
9) Patients who can record the symptom diary, as instructed by the principal investigator, subinvestigator, or clinical 
research coordinator 

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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 received phototherapy to treat itching within 4 weeks prior to the start of the screening period 
4) Patients who previously received any study drug (including placebo) in a clinical study of MR13A9 
5) Patients with any concurrent or previous disease that could affect the evaluations in this study in the opinion of the 
principal investigator or subinvestigator 
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 meets any of criteria (1) to (3): 
 
(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 whose dry weight is < 24 kg at the start of the screening period 
10) Patients with congestive heart failure (NYHA functional class IV) (Appendix 1) 
11) Patients with concurrent malignancy or a history of malignancy within 5 years prior to the informed consent procedure 
12) Patients with concurrent or previous drug abuse (defined as illicit drug use) 
13) Patients with concurrent or previous alcoholism 
14) Patients with a history of severe drug hypersensitivity 
15) Patients with a mental disorder (i.e., depression, schizophrenia, or dementia) 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 medical device in a clinical study (including clinical studies of 
medical devices) 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 to receive any medical intervention between the informed consent procedure and the 
end of the follow-up period 
20) Patients withdrawn from the study in the screening period because they are found to not meet either inclusion criteria 7) 
or 8) after participation in the study 
21) Patients withdrawn from the study in the screening period after re-registration 
22) Other patients ineligible for study participation in the opinion of the principal investigator or subinvestigator 
Study Design: 
A placebo-controlled, multicenter, randomized, double-blind, parallel-group study 
Study Drugs: 
1. Test drug 
 MR13A9 0.025 mg/mL (injection): 
Each vial contains 1.3 mL of MR13A9 dissolved in 0.04 mol/L isotonic acetate buffer (pH 4.5) at a concentration of 
0.025 mg/mL 
 MR13A9 0.05 mg/mL (injection): 
Each vial contains 1.3 mL of MR13A9 dissolved in 0.04 mol/L isotonic acetate buffer (pH 4.5) at a concentration of 
0.05 mg/mL 
 MR13A9 0.1 mg/mL (injection): 
Each vial contains 1.3 mL of MR13A9 dissolved in 0.04 mol/L isotonic acetate buffer (pH 4.5) at a concentration of 
0.1 mg/mL 
2. Control drug 
 MR13A9 placebo (injection): 
Each vial contains 1.3 mL of 0.04 mol/L isotonic acetate buffer (pH 4.5) 
The MR13A9 placebo is indistinguishable from MR13A9 0.025, 0.05, or 0.1 mg/mL. 

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Dose and Dosing Method: 
1. Screening period 
A 2-week period before entry into the treatment period is defined as the screening period, during which subjects will 
receive no study drug. Subjects will continuously use any restricted concomitant medications (e.g., anti-itch drugs) used at 
the start of the screening period. 
2. Treatment period 
In addition to the use of restricted 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 8 weeks (3 
times weekly, 24 times in total). The injected volume of the study drug will be determined based on the subject’s dry weight 
on the day of dosing according to Table 1. If any dialysis circuit trouble precludes injection through the dialysis circuit, it will 
be permissible to administer the study drug as an intravenous injection. If a fourth dialysis session is extraordinarily 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 
0.25 µg/kg group 
0.5 µg/kg group 
1.0 µg/kg group 
Placebo group 
< 45.0 kg 
0.35 mL 
8.75 μg 
17.5 μg 
35.0 μg 
0 μg 
≥ 45.0 kg, < 65.0 kg 
0.50 mL 
12.50 μg 
25.0 μg 
50.0 μg 
0 μg 
≥ 65.0 kg, < 85.0 kg 
0.70 mL 
17.50 μg 
35.0 μg 
70.0 μg 
0 μg 
≥ 85.0 kg 
0.85 mL 
21.25 μg 
42.5 μg 
85.0 μg 
0 μg 
3. Follow-up period 
A 2-week period after the end of the treatment period or the assessments at discontinuation in the treatment period is 
defined as the follow-up period, during which subjects will receive no study drug. Subjects will continuously use any 
restricted concomitant medications (e.g., anti-itch drugs) used at the start of the screening period. 
Concomitant Treatments: 
1. Concomitant medications 
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. 
It is permissible to change the dosage and administration of any concomitant medication for safety reasons such as the 
occurrence of adverse events. 
2. Restricted concomitant medications 
Between the start of the screening period and the end of the follow-up period, subjects may use the drugs listed below that 
have been used since before the screening period without changing their type or dosage and administration. In addition, do 
not newly use the drugs listed below: 
1) Drugs indicated for the treatment of itching (prescription/nonprescription) 
2) Moisturizing drugs (prescription/nonprescription) 
3) In-hospital drugs formulated with either of the above 
4) Antidepressants, antipsychotics, antiepileptics, hypnotics, anxiolytics, pregabalin, steroids (any route of administration) 
Among the drugs listed in 1) to 3) above, topical use of any prescription/nonprescription drug for purposes other than the 
purpose of treating itching caused by chronic renal failure or any complication of chronic renal failure 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 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 
2) 
Opioid antagonists 
naloxone hydrochloride, eptazocine hydrobromide, naldemedine 
tosylate 
3) 
Investigational products other than MR13A9 
Various kinds 
4. 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. 
Hemodialysis Conditions: 
Between the start of the screening period and the end of the follow-up period, the hemodialysis method (HD, off-line HDF, 
on-line HDF, or I-HDF) may not be changed. The dialysis conditions (frequency of dialysis per week, duration of dialysis, 
dialyzer, vascular access, dialysate flow rate, blood flow rate, and dialysate sodium concentration) should not be changed 
whenever possible, except for temporary changes with no changes in treatment strategies. 

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Dependency Assessment: 
Using the questionnaire shown in Appendix 8, the principal investigator or subinvestigator will rate the dependency on a 4-
level scale from “remarkable” to “none”. 
The dependency assessment members will perform a dependency assessment based on the questionnaire. Details are 
stipulated in a separate procedure. 
Investigations, Observations, Tests, and Evaluations and their Schedules: 
See the study schedule table. 
Sample Size: 
This study will enroll a total of 240 subjects: 60 for each MR13A9 dose group and the placebo group. 
 

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Table of Contents 
1. Rationale and Background for the Investigational Plan ......................................... 11 
1.1 Pruritus in Hemodialysis Patients ...................................................................... 11 
1.2 Treatment of Pruritus in Hemodialysis Patients ................................................. 11 
1.3 History of the Development of MR13A9 ............................................................ 11 
1.4 Summary of Expected Adverse Drug Reactions and Benefits .......................... 15 
2. Study Title and Development Phase ..................................................................... 17 
2.1 Title of Study ..................................................................................................... 17 
2.2 Development Phase ......................................................................................... 17 
3. Study Objectives ................................................................................................... 17 
3.1 Endpoints for Efficacy ....................................................................................... 17 
3.2 Endpoints for Safety ......................................................................................... 18 
3.3 Endpoints for Pharmacokinetics ....................................................................... 18 
4. Study Population .................................................................................................. 18 
4.1 Inclusion Criteria ............................................................................................... 18 
4.2 Exclusion Criteria .............................................................................................. 20 
4.3 Discontinuation of Individual Subjects .............................................................. 21 
5. Subject Consent ................................................................................................... 22 
5.1 Timing of Informed Consent.............................................................................. 22 
5.2 Informed Consent Procedure............................................................................ 23 
6. Study Drugs .......................................................................................................... 23 
6.1 Test Drug and Control Drug .............................................................................. 23 
6.2 Packaging of the Study Drugs .......................................................................... 24 
6.3 Labeling (Samples) ........................................................................................... 24 
6.4 Management of the Study Drugs ...................................................................... 24 
7. Study Methods ...................................................................................................... 25 
7.1 Study Design .................................................................................................... 25 
7.2 Doses and Dosing Method ............................................................................... 25 
7.3 Concomitant Treatments .................................................................................. 26 
7.4 Hemodialysis Conditions .................................................................................. 27 
7.5 Randomization and Blinding ............................................................................. 27 
7.6 Sample Size ..................................................................................................... 29 
8. Subject Instructions and Management.................................................................. 30 
9. Investigations, Observations, Tests, and Evaluations ........................................... 31 
9.1 Subject Demographics ..................................................................................... 31 

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9.2 Treatment Compliance ..................................................................................... 32 
9.3 Concomitant Medications and Concomitant Therapies .................................... 32 
9.4 Efficacy Endpoints ............................................................................................ 33 
9.5 Laboratory Tests ............................................................................................... 34 
9.6 Vital Signs (Blood Pressure, Pulse Rate, Body Temperature) .......................... 34 
9.7 Body Weight ..................................................................................................... 34 
9.8 12-Lead ECG.................................................................................................... 34 
9.9 Dependency Assessment ................................................................................. 34 
9.10 Pregnancy Test ............................................................................................... 35 
9.11 Pharmacokinetics ........................................................................................... 35 
9.12 Adverse Events............................................................................................... 35 
10. Investigations, Observations, Tests, and Evaluations at Each Time 
Point ..................................................................................................................... 39 
10.1 At the Time of Signing Informed Consent ....................................................... 39 
10.2 At Week −2 ..................................................................................................... 39 
10.3 At Week −1 ..................................................................................................... 39 
10.4 At Week 0 ....................................................................................................... 40 
10.5 At Week 1 ....................................................................................................... 40 
10.6 At Week 2 ....................................................................................................... 40 
10.7 At Week 3 ....................................................................................................... 41 
10.8 At Week 4 ....................................................................................................... 41 
10.9 At Weeks 5 and 6 ........................................................................................... 41 
10.10 At Week 7 ..................................................................................................... 41 
10.11 At Week 8 or at the Time of Discontinuation ................................................. 41 
10.12 At Week 9 (Week 1 of the Follow-up Period) or Week 1 after 
Discontinuation ................................................................................................. 42 
10.13 At Week 10 (Week 2 of the Follow-up Period) or Week 2 after 
Discontinuation ................................................................................................. 42 
11. Measures to Ensure the Safety of the Clinical Study .......................................... 43 
11.1 Action to be Taken for Adverse Events............................................................ 43 
11.2 Action to be Taken for and Response to Serious Adverse Events .................. 43 
11.3 Action to be Taken for and Response to Pregnancies..................................... 43 
11.4 Collection and Provision of Safety Information ............................................... 43 
12. Discontinuation/Suspension of the Clinical Study ............................................... 44 
12.1 Discontinuation/Suspension of Parts of the Study or the Entire Study ........... 44 
12.2 Discontinuation Criteria (Discontinuation/Suspension of Parts of the 

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Study or the Entire Study) ................................................................................ 44 
12.3 Procedures for Discontinuation/Suspension ................................................... 45 
13. Statistical Analysis .............................................................................................. 45 
13.1 Analysis Sets .................................................................................................. 45 
13.2 Analysis Groups .............................................................................................. 46 
13.3 Disposition of Subjects ................................................................................... 46 
13.4 Demographic and Other Baseline Characteristics .......................................... 46 
13.5 Efficacy ........................................................................................................... 46 
13.6 Safety ............................................................................................................. 49 
13.7 Pharmacokinetics ........................................................................................... 50 
14. Protocol Agreement and Amendment ................................................................. 50 
14.1 Agreement on the Protocol ............................................................................. 50 
14.2 Amendment of the Protocol ............................................................................ 50 
14.3 Deviation from the Protocol ............................................................................ 50 
15. Direct Access to Source Documents................................................................... 50 
15.1 Source Documents ......................................................................................... 50 
15.2 Direct Access .................................................................................................. 51 
15.3 Consistency Between Source Documents and Case Report Forms ............... 51 
16. Quality Control and Quality Assurance for the Study .......................................... 51 
17. Ethics .................................................................................................................. 51 
17.1 Compliance with GCP .................................................................................... 51 
17.2 Protection of Subject Confidentiality ............................................................... 51 
17.3 Compensation to Subjects .............................................................................. 52 
18. Data Handling, and Record Keeping .................................................................. 52 
18.1 Preparation and Submission of Case Report Forms ...................................... 52 
18.2 Recording of the Symptom Diary .................................................................... 52 
18.3 Preparation and Submission of Forms for 12-Lead ECG Charts .................... 52 
18.4 External Data .................................................................................................. 53 
18.5 Record Keeping .............................................................................................. 53 
19. Monetary Payment.............................................................................................. 53 
20. Publication Policy................................................................................................ 53 
21. Study Administrative Structure ............................................................................ 53 
22. History of Protocol Amendments......................................................................... 54 
23. Literature References ......................................................................................... 55 
24. Appendices ......................................................................................................... 59 

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List of Abbreviations and Terms 
 
Abbreviation/Term 
Definition 
AUClast 
Area under the plasma concentration-time curve from time zero to the last quantifiable concentration 
AUC0-x 
Area under the plasma concentration-time curve from time zero to x hours 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero extrapolated to infinite time 
CYP 
Cytochrome P450 
Cmax 
Maximum plasma concentration 
C0 
Plasma concentration immediately after administration 
DBTC 
Dibutyltin chloride 
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 
nor-BNI 
Nor-binaltorphimine 
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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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 

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injectable formulation and an oral formulation to relieve pain and pruritus. In Japan, Maruishi 
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. A subsequent phase II 
clinical study in hemodialysis patients suggested that MR13A9 relieves pruritus; therefore, 
this late phase II clinical study has been planned to determine dose-response relationships. 
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 
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 

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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. 
The carcinogenicity of MR13A9 is being investigated in animals. The development of 
malignancies in animals given MR13A9 has not been reported to date. 
1.3.2 Clinical study results 
1.3.2.1 Clinical pharmacology studies 
In a clinical pharmacology study in Japanese 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. After the first dose, 
Cmax was 4.38 ± 1.31 and 8.95 ± 2.24 ng/mL and AUC0-∞ was 97.38 ± 35.02 and 
240.05 ± 87.23 hr•ng/mL in the 0.5 and 1 μg/kg groups, respectively. After the third dose, 
Cmax was 5.38 ± 1.84 and 8.69 ± 2.45 ng/mL and AUC0-∞ was 151.34 ± 48.55 and 
316.85 ± 106.67 hr•ng/mL in the 0.5 and 1 μg/kg groups, respectively, showing increases in 
C0, Cmax, AUClast, AUC0-∞, and AUC0-48 with increasing dose. Tmax occurred at the first 

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sampling time, except for 1 patient receiving 0.5 μg/kg. t1/2 was 34.1 to 39.0 hours after the 
first dose and 40.0 to 49.3 hours after the third dose. The accumulation ratio of Day 5 to 
Day 1 calculated using the Cmax, AUC0-48, and trough values indicated a low likelihood of 
accumulation of MR13A9. 
In a clinical pharmacology study in healthy Japanese 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 a clinical pharmacology study in non-Japanese 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. 
1.3.2.2 Efficacy and safety 
In a Japanese phase II clinical study (MR13A9-3), 105 previously treated hemodialysis 
patients with pruritus received intravenous doses of MR13A9 0.25, 0.5, 1.0, or 1.5 μg/kg, or 
placebo 3 times weekly for 2 weeks. With respect to efficacy, 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) (mean ± standard deviation) was 
23.4 ± 20.0 mm, 28.0 ± 18.2 mm, 32.8 ± 25.4 mm, and 41.2 ± 22.8 mm in the 0.25, 0.5, 1.0, 
and 1.5 µg/kg groups, respectively, versus 26.4 ± 22.3 mm in the placebo group. These results 
suggested a dose-dependent improvement by treatment with MR13A9 at doses ≥ 0.5 μg/kg. 
With respect to safety, the incidence of adverse drug reactions was 23.8% (5/21 subjects), 
33.3% (7/21 subjects), 61.9% (13/21 subjects), 47.4% (9/19 subjects), and 82.6% 
(19/23 subjects) in the placebo, 0.25, 0.5, 1.0, and 1.5 µg/kg groups, respectively. Commonly 
reported adverse drug reactions (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. The incidence of these adverse drug reactions was as 
follows: blood thyroid stimulating hormone decreased, 9.5% (2/21 subjects) in the 0.25 μg/kg 
group, 31.6% (6/19 subjects) in the 1.0 µg/kg group, and 30.4% (7/23 subjects) in the 
1.5 μg/kg group; dizziness, 4.8% (1/21 subjects) in the 0.25 μg/kg group, 9.5% (2/21 subjects) 
in the 0.5 µg/kg group, 10.5% (2/19 subjects) in the 1.0 µg/kg group, and 17.4% (4/23 
subjects) in the 1.5 μg/kg group; blood prolactin increased, 4.8% (1/21 subjects) in the 
0.25 μg/kg group, 4.8% (1/21 subjects) in the 0.5 µg/kg group, 5.3% (1/19 subjects) in the 
1.0 µg/kg group, and 17.4% (4/23 subjects) in the 1.5 μg/kg group; nausea, 4.8% (1/21 
subjects) in the 0.25 μg/kg group and 17.4% (4/23 subjects) in the 1.5 μg/kg group; feeling 
abnormal, 4.8% (1/21 subjects) in the 0.5 µg/kg group and 17.4% (4/23 subjects) in the 
1.5 μg/kg group; and somnolence, 4.8% (1/21 subjects) in the 0.25 μg/kg group, 4.8% (1/21 
subjects) in the 0.5 µg/kg group, and 13.0% (3/23 subjects) in the 1.5 μg/kg group. 
Reported serious adverse events included the following: 2 events (encephalopathy and shunt 
stenosis) in 2 subjects in the 0.25 μg/kg group, 8 events (abdominal distension, influenza, 
diverticulitis, dizziness, hyperglycaemia, cholecystitis, hypotension, and muscular weakness) 
in 4 subjects in the 0.5 µg/kg group, and 1 event (dizziness) in 1 subject in the 1.5 μg/kg 
group. Of these events, relationship to study treatment was not ruled out for 4 events 
(diverticulitis, dizziness, hypotension, and hyperglycaemia) in 3 subjects in the 0.5 µg/kg 
group and 1 event (dizziness) in 1 subject in the 1.5 μg/kg group. Study treatment was 
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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 non-Japanese phase II clinical study (CR845-CLIN2005 Part B), 65 hemodialysis 
patients with moderate to severe pruritus received intravenous doses of MR13A9 1.0 μg/kg or 
placebo 3 times weekly for 2 weeks. With respect to efficacy, the primary endpoint of change 
in VAS (i.e., change from baseline in the mean VAS for the most intense itching at Week 2) 
(mean ± standard deviation) was −33.1 ± 23.03 mm in the 1.0 µg/kg group versus 
−21.5 ± 24.79 mm in the placebo group. With respect to safety, the incidence of adverse drug 
reactions was 9.4% (3/32 subjects) in the placebo group and 18.2% (6/33 subjects) in the 
1.0 µg/kg group. Commonly reported adverse drug reactions (in ≥ 5% of subjects in the 
MR13A9 group) included dizziness, hypoaesthesia, and pruritus. 
In a non-Japanese phase II clinical study (CR845-CLIN2101), 174 hemodialysis patients with 
moderate to severe pruritus received intravenous doses of MR13A9 0.5, 1.0, or 1.5 μg/kg, or 
placebo 3 times weekly for 8 weeks. With respect to efficacy, the primary endpoint of change 
in NRS (i.e., change from baseline in the mean itch NRS at 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 mm in the placebo group. With respect to safety, 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. 
1.4 Summary of Expected Adverse Drug Reactions and Benefits 
1.4.1 Expected adverse drug reactions 
In a phase II clinical study in Japanese hemodialysis patients (MR13A9-3), 84 subjects 
received intravenous doses of MR13A9 0.25, 0.5, 1.0, or 1.5 μg/kg 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. Although adverse drug reactions suggesting the 
effects of MR13A9 on the central nervous system tended to occur relatively frequently, most 
of them were mild and none of them were severe in severity. 
In a phase II clinical study in non-Japanese hemodialysis patients (CR845-CLIN2005 Part B), 
33 subjects received intravenous doses of MR13A9 1.0 μg/kg 3 times weekly for 2 weeks. 
Adverse drug reactions reported in ≥ 5% of subjects receiving MR13A9 included dizziness 
and hypoaesthesia. In a phase II clinical study in non-Japanese hemodialysis patients (CR845-
CLIN2101), 129 subjects received intravenous doses of MR13A9 0.5, 1.0, or 1.5 μg/kg 
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. 
In non-Japanese 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 a 
phase I clinical study in healthy Japanese adult males (MR13A9-1), blood sodium increased 
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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 non-Japanese 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 II clinical study of MR13A9 in previously treated hemodialysis patients with pruritus 
(Protocol No.: MR13A9-4) 
2.2 Development Phase 
Phase II 
3. Study Objectives 
To determine the dose-response relationship for the efficacy, safety, and pharmacokinetics of 
MR13A9 0.25, 0.5, or 1.0 μg/kg administered to previously treated hemodialysis patients with 
pruritus for 8 weeks in a placebo-controlled, double-blind design. 
3.1 Endpoints for Efficacy 
3.1.1 Efficacy endpoints 
1) 
Primary endpoint 
 Itch NRS score (The primary variable is change from baseline in the mean NRS score at 
Week 8 of the treatment 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 criteria14) 
 Skindex-16 score15) 
 5-D itch scale score16) 
 Patient Global Impression of Change (PGIC) 
3.1.2 Rationale for the efficacy endpoints 
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. 
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. 

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3.2 Endpoints for Safety 
3.2.1 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 electrocardiography (ECG) 
 Dependency assessment 
3.2.2 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. 
3.3 Endpoints for Pharmacokinetics 
3.3.1 Pharmacokinetic endpoint 
 Plasma concentration of MR13A9 (unchanged drug) 
3.3.2 Rationale for the pharmacokinetic endpoint 
This endpoint has been established to determine the pharmacokinetic dose-response 
relationship in Japanese hemodialysis patients with pruritus. 
4. Study Population 
This study will enroll previously treated hemodialysis patients with pruritus who meet all of 
the inclusion criteria and none of the exclusion criteria below. 
4.1 Inclusion Criteria 
4.1.1 Inclusion criteria 
1) 
Patients aged 20 years or older (at the time of signing informed consent) 
2) 
Japanese patients providing written informed consent for study participation in person 
(Their first- and second-degree relatives must be all Japanese) 
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 
who can continue hemodialysis without changing its frequency or method (excluding 
temporary changes with no changes in treatment strategies) during the study 
4) 
Patients whose pruritus treatment for 1 year prior to the informed consent procedure 

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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 not receiving nalfurafine hydrochloride for ≥ 2 weeks prior to the start of the 
screening period 
6) 
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) 
 Moisturizing drugs (prescription/nonprescription) 
 Products formulated with either of the above 
7) 
Patients whose NRS score in the 7 days prior to the start of the treatment period 
(including the score recorded on the day at Week 0) meets both of the below: 
 NRS scores have been recorded for ≥ 5 days. 
 The mean value of the recorded scores exceeds 4. 
8) 
Patients whose itch score based on the Shiratori’s severity criteria in the 7 days prior to 
the start of the treatment period (including the score recorded on the day at Week 0) 
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. 
9) 
Patients who can record the symptom diary, as instructed by the principal investigator, 
subinvestigator, or clinical research coordinator 
4.1.2 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 and GCP. 
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) 
To exclude the effects of nalfurafine hydrochloride on the efficacy and safety of 
MR13A9. 

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6)-8) 
To include patients who have a certain degree of itching continuously. 
9) 
To include patients who can perform appropriate assessment using a symptom diary. 
4.2 Exclusion Criteria 
4.2.1 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 received phototherapy to treat itching within 4 weeks prior to the start of 
the screening period 
4) 
Patients who previously received any study drug (including placebo) in a clinical study 
of MR13A9 
5) 
Patients with any concurrent or previous disease that could affect the evaluations in this 
study in the opinion of the principal investigator or subinvestigator 
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 whose dry weight is < 24 kg at the start of the screening period 
10) Patients with congestive heart failure (NYHA functional class IV) (Appendix 1) 
11) Patients with concurrent malignancy or a history of malignancy within 5 years prior to 
the informed consent procedure 
12) Patients with concurrent or previous drug abuse (defined as illicit drug use) 
13) Patients with concurrent or previous alcoholism 
14) Patients with a history of severe drug hypersensitivity 
15) Patients with mental disorder (i.e., depression, schizophrenia, or dementia) 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 

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18) Patients who received treatment with any study drug or medical device in a clinical study 
(including clinical studies of medical devices) 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 to receive any medical intervention between the 
informed consent procedure and the end of the follow-up period 
20) Patients withdrawn from the study in the screening period because they are found not 
meeting either of inclusion criteria 7) or 8) after participation in the study 
21) Patients withdrawn from the study in the screening period after re-registration 
22) Other patients ineligible for study participation in the opinion of the principal 
investigator or subinvestigator 
4.2.2 Rationale for the exclusion criteria 
1)-5) 
To perform the efficacy evaluation of MR13A9 appropriately. 
6)-8), 10)-14), 19), 
22) 
To ensure the safety of subjects. 
9) 
To prevent the dose of the investigational product from exceeding the 
prespecified dose. 
15) 
To exclude the effect of this condition on protocol adherence. 
16), 17) 
To ensure the safety of pregnant women, fetuses, and infants 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 the 
ethical aspect. 
20), 21) 
Re-registration will not be permitted because it could affect the 
efficacy evaluation. 
4.3 Discontinuation of Individual Subjects 
4.3.1 Discontinuation criteria (discontinuation of individual subjects) 
1) 
Adverse event (The name of the adverse event should be recorded in the case report 
form): 
 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 

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categorized as 2) above) 
4) 
Significant protocol deviation during the study 
 Any GCP violation is found 
 After registration, the subject is found not meeting any of the inclusion criteria or 
meeting any of the exclusion criteria stipulated in the protocol 
 Study continuation may cause injury to the subject because of the subject’s protocol 
noncompliance in the opinion of the principal investigator or subinvestigator 
5) 
Four consecutive missed doses of the study drug 
6) 
Pregnancy 
7) 
Discontinuation of the entire study 
8) 
Discontinuation of the study at the study site 
9) 
Lost to observation or follow-up 
 Study continuation becomes impossible because of failure to contact the subject 
10) 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) 
4.3.2 Responses to the discontinuation of any individual subject 
If a subject meets any of the criteria described in “4.3.1 Discontinuation criteria 
(discontinuation of individual subjects)” during the study, the principal investigator or 
subinvestigator will immediately decide to discontinue the study. On the day of dialysis 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 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 “9.12.9 Follow-up investigation” 
If the study is discontinued during the treatment period, the next day of the assessments at 
discontinuation will be regarded as the start date of the follow-up period. 
4.3.3 Investigation of subjects not returning to the study site 
If a subject fails to return to the study site as scheduled, the principal investigator, 
subinvestigator, or clinical research coordinator will immediately investigate the reason for 
missed visits and the subsequent course. 
5. Subject Consent 
5.1 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). 

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5.2 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). 
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. 
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. 
6. Study Drugs 
6.1 Test Drug and Control Drug 
6.1.1 Test drug 
1) 
Code name: MR13A9 
2) 
Nonproprietary name: Difelikefalin (INN) 
3) 
Strength and dosage form: 
 MR13A9 0.025 mg/mL (injection): Each vial contains 1.3 mL of MR13A9 dissolved in 
0.04 mol/L isotonic acetate buffer (pH 4.5) at a concentration of 0.025 mg/mL. 
 MR13A9 0.05 mg/mL (injection): Each vial contains 1.3 mL of MR13A9 dissolved in 
0.04 mol/L isotonic acetate buffer (pH 4.5) at a concentration of 0.05 mg/mL. 
 MR13A9 0.1 mg/mL (injection): Each vial contains 1.3 mL of MR13A9 dissolved in 
0.04 mol/L isotonic acetate buffer (pH 4.5) at a concentration of 0.1 mg/mL. 
4) 
Storage conditions: Store at room temperature (1°C to 30°C) 
6.1.2 Control drug 
1) 
Strength and dosage form: 
MR13A9 placebo (injection): Each vial contains 1.3 mL of 0.04 mol/L isotonic acetate buffer 

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(pH 4.5). 
The MR13A9 placebo is indistinguishable from MR13A9 0.025, 0.05, or 0.1 mg/mL. 
2) Storage conditions: Store at room temperature (1°C to 30°C) 
6.1.3 Rationale for the control drug 
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 control drug 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). 
6.2 Packaging of the Study Drugs 
A total of 27 vials of MR13A9 0.025, 0.05, 0.1 mg/mL, or placebo (24 vials for 8 weeks + 
3 spare vials) will be packed in 1 carton to prepare a carton per subject. 
6.3 Labeling (Samples) 
 
MR13A9 
 
 
Storage: Store at room temperature 
(1°C to 30°C) 
Serial No.: E8181 
 
 
Kissei Pharmaceutical Co., Ltd. 
Figure 6.3-1 
Vial Label 
 
MR13A9 
 
 
Storage: Store at room temperature (1°C to 30°C) 
Serial No.: E8181 
 
 
Kissei Pharmaceutical Co., Ltd. 
Clinical Development 
3-1-3 Koishikawa, Bunkyo-ku, Tokyo 
Tel: 03-5684-3533 
 
 
Drug Number 
 
                   
 
 
Subject Identification Code 
 
                   
Figure 6.3-2 
Carton label 
6.4 Management of the Study Drugs 
The study drug manager will manage and store the study drugs appropriately, as stipulated 
For 
investigational 
use 
D r u g  N u mb e r 
For 
investigational 
use 

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separately in the written procedure. 
7. Study Methods 
7.1 Study Design 
A placebo-controlled, multicenter, randomized, double-blind, parallel-group study 
 
Figure 7.1-1 
Study Design 
7.2 Doses and Dosing Method 
7.2.1 Screening period 
A 2-week period before entry into the treatment period is defined as the screening period, 
during which subjects will receive no study drug. Subjects will continuously use any 
restricted concomitant medications (e.g., anti-itch drugs) used at the start of the screening 
period. 
7.2.2 Treatment period 
In addition to the use of restricted 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 8 weeks (3 times weekly, 24 times in total). The 
injected volume of the study drug will be determined based on the subject’s dry weight on the 
day of dosing according to Table 7.2.2-1. If any dialysis circuit trouble precludes injection 
through the dialysis circuit, it will be permissible to administer the study drug as an 
intravenous injection. If a fourth dialysis session is extraordinarily 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. Details are stipulated in 
a separate procedure. 
 
Table 7.2.2-1 
Doses 
Dry weight 
Injected volume 
MR13A9 dose 
0.25 μg/kg 
group 
0.5 µg/kg 
group 
1.0 µg/kg 
group 
Placebo 
group 
< 45.0 kg 
0.35 mL 
8.75 μg 
17.5 μg 
35.0 μg 
0 μg 
≥ 45.0 kg, < 65.0 kg 
0.50 mL 
12.50 μg 
25.0 μg 
50.0 μg 
0 μg 
≥ 65.0 kg, < 85.0 kg 
0.70 mL 
17.50 μg 
35.0 μg 
70.0 μg 
0 μg 
≥ 85.0 kg 
0.85 mL 
21.25 μg 
42.5 μg 
85.0 μg 
0 μg 
Screening period  
2 weeks 
Treatment period 
8 weeks 
Follow-up period 
2 weeks 
Placebo group  
MR13A9 0.25-μg/kg group 
MR13A9 0.5-μg/kg group 
MR13A9 1.0-μg/kg group 
Restricted concomitant medications (anti-itch drugs) 

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7.2.3 Follow-up period 
A 2-week period after the end of the treatment period or the assessments at discontinuation in 
the treatment period is defined as the follow-up period, during which subjects will receive no 
study drug. Subjects will continuously use any restricted concomitant medications (e.g., anti-
itch drugs) used at the start of the screening period. 
7.2.4 Rationale for the doses 
A dose-dependent improvement in itching was suggested in the Japanese phase II clinical 
study in hemodialysis patients with pruritus receiving MR13A9 0.25, 0.5, 1.0, or 1.5 μg/kg for 
2 weeks (MR13A9-3). As for safety, all of these doses were tolerated, but the dose of 
1.5 μg/kg was not considered suitable for a clinical dose, taking the occurrence of adverse 
drug reactions into account. It was thus determined that the efficacy and safety profiles of 
MR13A9 at 0.25, 0.5, and 1.0 μg/kg would be investigated in detail to determine the 
recommended clinical doses of MR13A9. For dose selection, body weight categories based on 
dry weight were established, taking the convenience of drug preparation into account. 
In addition, an 8-week period that allows the efficacy evaluation of MR13A9 was established, 
provided that pruritus associated with hemodialysis requires prolonged treatment and that the 
improvement in itching was maintained after Week 2 in the non-Japanese phase II clinical 
study of MR13A9 that was administered for 8 weeks (CR845-CLIN2101). 
7.3 Concomitant Treatments 
7.3.1 Concomitant medications 
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. It is permissible to 
change the dosage and administration of any concomitant medication for safety reasons such 
as the occurrence of adverse events. 
7.3.2 Restricted concomitant medications 
Between the start of the screening period and the end of the follow-up period, subjects may 
use the drugs listed below that have been used since before the screening period without 
changing their type or dosage and administration. In addition, do not newly use the drugs 
listed below: 
1) 
Drugs indicated for the treatment of itching (prescription/nonprescription) 
2) 
Moisturizing drugs (prescription/nonprescription) 
3) 
In-hospital drugs formulated with either of the above 
4) 
Antidepressants, antipsychotics, antiepileptics, hypnotics, anxiolytics, pregabalin, 
steroids (any route of administration) 
Among the drugs listed in 1) to 3) above, topical use of any prescription/nonprescription drug 
for purposes other than the purpose of treating itching caused by chronic renal failure or any 
complication of chronic renal failure 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. 

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7.3.3 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 7.3.3-1 will be prohibited. 
Table 7.3.3-1 
Prohibited concomitant medications 
Class 
Common drugs 
1) 
Opioids 
Nalfurafine hydrochloride, morphine, fentanyl, oxycodone, 
buprenorphine, pentazocine, codeine phosphate, dihydrocodeine 
2) 
Opioid antagonists 
Naloxone hydrochloride, eptazocine hydrobromide, naldemedine 
tosylate 
3) 
Investigational product other than 
MR13A9 
Various kinds 
7.3.4 Rationale for the prohibited concomitant medications 
1), 2) 
To exclude their effects on the efficacy evaluation of MR13A9. 
3) 
To exclude their effects when coadministered with MR13A9 on the safety 
evaluation of MR13A9. 
7.3.5 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. 
7.3.6 Rationale for the prohibited concomitant therapies 
To exclude the effect of phototherapy on the efficacy evaluation of MR13A9. 
7.4 Hemodialysis Conditions 
Between the start of the screening period and the end of the follow-up period, the 
hemodialysis method (HD, off-line HDF, on-line HDF, or I-HDF) may not be changed. The 
dialysis conditions (frequency of dialysis per week, duration of dialysis, dialyzer, vascular 
access, dialysate flow rate, blood flow rate, and dialysate sodium concentration) may not be 
changed whenever possible, except for temporary changes with no changes in treatment 
strategies. 
7.5 Randomization and Blinding 
7.5.1 Treatment Assignment 
The person responsible for treatment assignment will prepare a treatment assignment table to 
assign subjects to MR13A9 0.25, 0.5, or 1.0 μg/kg, or placebo at a ratio of 1:1:1:1. 
7.5.2 Preparation 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. 
7.5.3 Retention of the treatment assignment table and the emergency key 
codes 
The person responsible for treatment assignment will seal the treatment assignment table and 
the emergency key codes so that blind-breaking can be detected, and retain them until 

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unblinding, as stipulated separately in the written procedure. 
7.5.4 Subject registration 
7.5.4.1 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 “4. Study Population”), enter 
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. 
The completed primary subject registration form and the primary subject registration 
confirmation form obtained from the subject registration center will be retained at the study 
site. 
7.5.4.2 Secondary subject registration 
The principal investigator or subinvestigator will assess the eligibility of each subject at the 
start of the screening period (see “4. 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. 
The completed secondary subject registration form and the secondary subject registration 
confirmation form obtained from the subject registration center will be retained at the study 
site. 
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. 
7.5.4.3 Tertiary subject registration 
The principal investigator or subinvestigator will assess the final eligibility of each subject at 
the start of the treatment period (see “4. Study Population”), enter necessary information in a 
tertiary subject registration form, and register the each 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. 
The completed tertiary subject registration form and the tertiary subject registration 
confirmation form obtained from the subject registration center will be retained at the study 
site. 
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. 

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7.5.4.4 Randomization of subjects 
Based on the treatment assignment table, the subject registration center will randomly assign 
subjects eligible for tertiary registration to 4 treatment groups by a dynamic allocation method 
using 2 stratification factors: prior treatment with nalfurafine hydrochloride (for ≥ 
2 consecutive weeks in the year prior to the informed consent procedure) and specific signs or 
symptoms during the screening period (Appendix 2) confirmed before dialysis at Week 0. 
7.5.5 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 
to open the emergency key code by telephone or other means. 
2) 
If requested by the principal investigator or subinvestigator to open the emergency key 
code or if the sponsor considered necessary to open the emergency key code, the sponsor 
will open the emergency key code for the drug number, as stipulated separately in the 
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. 
7.5.6 Unblinding 
The person responsible for treatment assignment will confirm that the blind has been 
maintained throughout the study period and then unblind the treatment assignment table. 
7.5.7 Maintenance of the blind 
To maintain the blind, the results of measurement of plasma drug concentrations will be kept 
and managed at the measurement organization until the unblinding of the treatment 
assignment table. Any information that can identify treatment groups or individual subjects 
will be reported to the sponsor and the study site after the unblinding of the treatment 
assignment table. 
7.6 Sample Size 
7.6.1 Sample size 
This study will enroll 60 subjects for each MR13A9 dose group and the placebo group, 
240 subjects in total. 
7.6.2 Rationale for the sample size 
In the non-Japanese phase II clinical study (CR845-CLIN2101), the change from baseline in 
NRS score at Week 8 (mean ± standard deviation) was −3.9 ± 2.48, −2.8 ± 2.24, and 
−3.4 ± 2.34 in the MR13A9 0.5 µg/kg, 1.0 µg/kg, and combined (CR845 all doses) groups, 
respectively, versus −1.9 ± 2.29 in the placebo group. The difference in the change from 

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baseline in NRS score (least squares mean ± standard error) in each of the MR13A9 0.5 µg/kg, 
1.0 µg/kg, and combined groups versus the placebo group was −1.8 ± 0.50, −0.8 ± 0.52, and 
−1.3 ± 0.41, respectively. 
For the present study, the MR13A9 0.5 and 1.0 µg/kg groups were assumed to have a similar 
change in NRS score at Week 8 of the treatment period to that observed in the MR13A9 
combined group in the non-Japanese phase II clinical study. The MR13A9 0.25 μg/kg group, 
for which no efficacy results were obtained, was assumed to have about half the change in 
NRS score assumed above. The mean difference in NRS score between each of the MR13A9 
0.25, 0.5, and 1.0 µg/kg groups and the placebo group was assumed to be −0.6, −1.3, and −1.3, 
respectively, with a common standard deviation of 2.5. When the dose-response relationship 
for the MR13A9 0.25, 0.5, and 1.0 µg/kg groups was evaluated using the contrast patterns 
shown in “13.5.2.1.1 Primary analysis,” with a two-sided significance level of 5% and a 
sample size of 60 subjects per group, a contrast pattern of 3, 1, −2, −2 (placebo, 0.25, 0.5, 
1.0 μg/kg) produced a statistical power of 91.7%. Statistical power is more than 80% when 
the MR13A9 0.5 or 1.0 µg/kg group (60 subjects per groups) was compared with the placebo 
group. 
With respect to the mean difference in NRS score at Week 2 of the treatment period, the 
MR13A9 0.5 and 1.0 µg/kg groups were assumed to show a difference considered clinically 
meaningful versus the placebo group, and the MR13A9 0.25 μg/kg group was assumed to 
show about half the difference above. The mean difference in NRS score versus the placebo 
group was assumed to be −0.4, −0.8, and −0.8 in the MR13A9 0.25, 0.5, and 1.0 µg/kg groups, 
respectively, with a common standard deviation of 1.9. As with the evaluation of the dose-
response relationship at Week 8 of the treatment period, when the dose-response relationship 
for the MR13A9 0.25, 0.5, and 1.0 µg/kg groups was evaluated using the contrast patterns, 
with a two-sided significance level of 5% and a sample size of 60 subjects per group, a 
contrast pattern of 3, 1, −2, −2 (placebo, 0.25, 0.5, 1.0 μg/kg) produced a statistical power of 
76.4%. 
8. 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 
subinvestigator. Pay attention during hazardous machine operation and automobile 
driving during the treatment period. Avoid hazardous machine operation and automobile 
driving on the day of study treatment. 
2) 
Maintain the symptom diary in subject every day. Record symptoms in the designated 
form and bring it at visit dates if any electronic diary system trouble makes the 
maintenance of the symptom diary impossible. 
3) 
Take all prescribed drugs other than the study drug properly as instructed. 
4) 
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. Visit the study site at the same time at 
every visit whenever possible. 
5) 
Report the drug(s) used currently to the principal investigator or subinvestigator before 
participation in the study. Consult the principal investigator or subinvestigator before use 
about any new drug prescribed at other medical departments or hospitals or any over-the-

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counter drug to be started. Report to the principal investigator or subinvestigator 
immediately if it was inevitable to use any drug without consultation. 
6) 
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 or pharmacist 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. 
7) 
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 time of 
discontinuation) or at the end of the follow-up investigation. 
8) 
Women of childbearing potential must avoid intercourse during the study period or use 
appropriate contraceptive methods when having intercourse. Immediately inform the 
principal investigator or subinvestigator about any suspected pregnancy during the study 
period. 
9) 
Men must avoid intercourse during the study period 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. 
10) 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). 
9. Investigations, Observations, Tests, and Evaluations 
The principal investigator and subinvestigator will perform investigations, observations, tests, 
and evaluations according to the study schedule (pages 49 and 50) and the respective 
procedures of investigations, observations, and tests. 
9.1 Subject Demographics 
The following subject demographics will be investigated and recorded in the case report form: 
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) 
Hemodialysis method (HD, off-line HDF, on-line HDF, or I-HDF) and dialysis 
conditions (frequency of dialysis per week, duration of dialysis, dialyzer, vascular access, 
dialysate flow rate, blood flow rate, and dialysate sodium concentration) 
7) 
Dry weight at the start of the screening period 
8) 
Medical history (any concurrent disease at the time of signing informed consent); if yes, 
the name of the disease 

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9) 
Time of onset of itching 
10) Prior treatment with nalfurafine hydrochloride within 1 year of the time of signing 
informed consent; if yes, the duration of treatment and dose 
11) Remaining renal function 
12) Need for pregnancy testing 
13) Information related to the inclusion/exclusion criteria 
9.2 Treatment Compliance 
The principal investigator or subinvestigator will record compliance with study treatment (day 
of dosing, time of dosing, route of dosing, dry weight on the day of dosing, drug number, and 
injected volume) in the case report form. 
9.3 Concomitant Medications and Concomitant Therapies 
9.3.1 Concomitant medications 
For all drugs (including over-the-counter drugs, Chinese herbal drugs, vitamins) 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 restricted 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, dialysate) 
 
Infusion solution used to establish access 
 
Diluents for injection 
 
Vehicles used for in-hospital dispensing (other than drugs of which main effect is 
expected) 
 
Pretreatment drugs for tests 
9.3.2 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. 
9.3.3 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 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) 

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9.4 Efficacy Endpoints 
9.4.1 Symptom diary (electronic diary) 
The principal investigator, subinvestigator, or clinical research coordinator will instruct each 
subject 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. The subject will record the 
following information 1) and 2) in the symptom diary from the next day of the start date of 
the screening period until the end date of the follow-up period. 
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 3, the most severe itching within the day 
will be assessed in integer 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 4, the symptoms during the day and the night will be assessed 
on a scale ranging from 0 to 4, where 0 represents no symptoms and 4 represents severe 
itching. 
 Degree of the symptom during the day: Degree of the most severe itching during the 
day between the time of awakening on the previous day of assessment and the time of 
going to bed on the previous day of assessment 
 Degree of the symptom during the night: Degree of the most severe itching during the 
night between the time of going to bed on the previous day and the time of awakening 
on the day of assessment 
9.4.2 Skindex-16 
At the first visit of each week (before dosing of the study drug), 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 assessed on a scale ranging from 0 
to 6, where 0 represents never bothered and 6 represents always bothered. 
9.4.3 5-D itch scale 
At the first visit of each week (before dosing of the study drug), subjects will look back on the 
condition of itching in the past 2 weeks and assess the 5 components of itching (duration, 
degree, direction, disability, distribution) according to Appendix 6. 
9.4.4 PGIC 
At the first visit of each week, subjects will compare the overall symptom of itching with the 
symptom in the screening period, and assess 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. 

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9.5 Laboratory Tests 
Blood samples will be collected for the tests listed below before the first dialysis of each week. 
Laboratory test values will be determined centrally at the laboratory testing facility. Only the 
presence or absence of collected samples will be recorded in the case report form. 
9.5.1 Hematology 
Red blood cell count, hemoglobin, hematocrit, white blood cell count, differential white blood 
cell count (neutrophil, eosinophil, basophil, monocyte, lymphocyte), platelet count 
9.5.2 Blood biochemistry 
AST, ALT, γ-GTP, CRP, LDH, ALP, total protein, albumin, glycoalbumin (only in subjects 
with concurrent diabetes mellitus), glucose, total cholesterol, total bilirubin, direct bilirubin, 
creatinine, BUN (before and after dialysis), Na, K, Cl, Ca, P, serum iron, UIBC, TIBC, TSAT, 
ferritin 
9.5.3 Endocrinology 
Testosterone, free testosterone, prolactin, TSH, FT3, FT4, intact-PTH, antidiuretic hormone 
9.6 Vital Signs (Blood Pressure, Pulse Rate, Body Temperature) 
Before the first dialysis of each week, sitting systolic blood pressure, diastolic blood pressure, 
and pulse rate will be measured after a period of rest. Body temperature will also be measured 
before dialysis. 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. 
9.7 Body Weight 
Before and after the first dialysis of each week, body weight will be measured. The date, 
timing, and result of measurement will be recorded in the case report form. 
9.8 12-Lead ECG 
Before the first dialysis and before blood sampling of each week, 12-lead ECGs will be 
obtained in the supine position after a period of rest, and the date of measurement and the 
presence/absence of abnormal findings will be recorded in the case report form. ECG charts 
will be retained at the study site. 
The same testing device will be used in the same subject throughout the study period in 
principle. 
9.9 Dependency Assessment 
Using the questionnaire shown in Appendix 8, the principal investigator or subinvestigator 
will rate the dependency on a 4-level scale from remarkable to none.18) 
The dependency assessment members will perform dependency assessment based on the 
questionnaire. Details are stipulated in a separate written procedure. 

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9.10 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. 
9.11 Pharmacokinetics 
Plasma concentrations of MR13A9 (unchanged drug) will be measured. Plasma 
concentrations of MR13A9 will be determined using an LC-MS/MS method at the 
bioanalytical laboratory. The date and time of blood sampling will be recorded in the case 
report form. Details are stipulated in a separate study plan. 
9.12 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. 
9.12.1 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. 
9.12.1.1 Adverse event collection period 
Adverse events will be collected between the time of signing informed consent and the final 
visit in the follow-up period. 
9.12.1.2 History of adverse events 
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 
visit?” 
9.12.1.3 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. 

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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. 
9.12.2 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 
9.12.3 Severity of adverse events 
The severity of adverse events will be categorized into 3 grades according to Table 9.12.3-1. 
For an adverse event in which the severity changes, the highest severity will be recorded. 
 
Table 9.12.3-1 
Severity of adverse events 
Severity 
Criteria 
Mild 
Not or minimally interfering with daily activitiesa) and requiring no special treatment or simple 
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Moderate 
Somewhat interfering with daily activitiesa) and requiring treatment 
Severe 
Largely interfering with daily activitiesa) or requiring systemic treatment 
a) Include sleeping, movements, work, going out, eating, exercise, bathing 
 
9.12.4 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. 
9.12.5 Adverse events of special interest 
On the day of the first dialysis of each week, 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 2. Any specific sign or symptom corresponding to an adverse event will 
be recorded as an adverse event of special interest (of any seriousness). Details are stipulated 
in a separate procedure. 
 
Considerations for the recording of adverse events of special interest 
1) 
Any new sign or symptom (i.e., never occurred before or not included in the subject’s 
medical history) will be recorded as an adverse event in the case report form. 
2) 
Any sign or symptom already present within 3 months prior to the start of the screening 
period (i.e., included in the subject’s medical history) will be recorded as an adverse 
event in the case report form only when its severity or frequency has increased compared 
with baseline. 
3) 
For any sign or symptom that is part of a definitive diagnosis, the diagnosis will be 
recorded as an adverse event. 
4) 
Any sign or symptom that does not meet the criteria 1) or 2) above will not be recorded 
as an adverse event. 
9.12.6 Action taken with study treatment 
Actions taken with study treatment are defined in Table 9.12.6-1. 
 

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Table 9.12.6-1 
Action taken with study treatment 
Action 
Definition 
Drug withdrawn 
Study treatment is discontinued due to the adverse event, including at the subject’s 
request. 
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 for reasons other than the 
adverse event at the time when the adverse event occurred 
Drug Interrupted 
Study treatment is interrupted due to the adverse event, including at the subject’s 
request. 
9.12.7 Outcome of adverse events 
The outcome of each adverse event will be assessed according to Table 9.12.7-1. 
 
Table 9.12.7-1 
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. 
Fatal 
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. 
9.12.8 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 9.12.8-1. Any adverse 
event occurring after the start of study treatment of which 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 9.12.8-1 
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 causal 
relationship with the study drug, specifically when the event falls into one of the following 
criterion: 
 
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 

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subject’s medical history or condition, concomitant medications or therapies, and diet. 
9.12.9 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 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, until either 
of the time points below: 
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 
10. 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 the study schedule and their 
respective procedures. Tests and evaluations will be performed on the day of the first dialysis 
of each week, unless prescribed otherwise. 
10.1 At the Time of Signing Informed Consent 
 Confirmation of written informed consent 
 Confirmation of subject demographics 
10.2 At Week −2 
 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) 
 Confirmation of eligibility and subject registration 
 Instructions for the symptom diary 
10.3 At Week −1 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 

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 Confirmation of the implementation status of hemodialysis 
10.4 At Week 0 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 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 and subject registration 
 Confirmation of the compliance with study treatment 
10.5 At Week 1 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Confirmation of the implementation status of hemodialysis 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
 Pharmacokinetics (before the first dialysis and at 5 minutes after administration of the 
week, before the second dialysis) 
10.6 At Week 2 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Confirmation of the implementation status of hemodialysis 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
 Pharmacokinetics (before the first dialysis of the week) 

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10.7 At Week 3 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Confirmation of the implementation status of hemodialysis 
10.8 At Week 4 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Confirmation of the implementation status of hemodialysis 
 Skindex-16 
 5-D itch scale 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 
 Confirmation of the compliance with study treatment 
 Pharmacokinetics (before the first dialysis and at 5 minutes after administration of the 
week, before the second dialysis) 
10.9 At Weeks 5 and 6 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Confirmation of the implementation status of hemodialysis 
10.10 At Week 7 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Confirmation of the implementation status of hemodialysis 
 Confirmation of the compliance with study treatment 
 Pharmacokinetics (before the first dialysis, and at 5 minutes and at least 1 hour* after 
administration of the week, before the second dialysis) 
*: To be performed only in subjects from whom blood can be collected. 
10.11 At Week 8 or at the Time of Discontinuation 
 Review of the symptom diary 

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 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Dependency assessment (before the first dialysis of Week 8 or before dialysis on the day 
of the assessments at discontinuation) 
 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) 
 Pharmacokinetics (before the first dialysis of Week 8 or before dialysis on the day of the 
assessments at discontinuation) 
10.12 At Week 9 (Week 1 of the Follow-up Period) or Week 1 after 
Discontinuation 
Assessments at Week 1 after discontinuation will be performed on the same day of the week 
for the assessments at discontinuation. 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Examination of specific signs and symptoms 
 Dependency assessment (before the first dialysis of Week 9 or before dialysis at Week 1 
after discontinuation) 
 Confirmation of the implementation status of hemodialysis 
10.13 At Week 10 (Week 2 of the Follow-up Period) or Week 2 after 
Discontinuation 
 Review of the symptom diary 
 Confirmation of adverse events, concomitant medications, and concomitant therapies 
 Confirmation of the implementation status of hemodialysis 
 Examination of specific signs and symptoms 
 Vital signs 
 Laboratory tests (hematology, blood biochemistry, endocrinology) 

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11. Measures to Ensure the Safety of the Clinical Study 
11.1 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 “9.12.9 Follow-up investigation” will be followed up, 
as instructed in the section. 
11.2 Action to be Taken for and Response to Serious Adverse 
Events 
11.2.1 Action to be taken for serious adverse events 
If any serious adverse event described in “9.12.4 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. 
11.2.2 Response to serious adverse events 
The principal investigator or subinvestigator will inform the monitor of a serious adverse 
event within 24 hours of knowledge of its occurrence, and the principal investigator will 
submit a prespecified document within 3 days of knowledge of the occurrence. 
In addition, the principal investigator will immediately report the event to the head of the 
study site, as instructed by the study site’s procedure. 
11.3 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. 
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 
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. 
11.4 Collection and Provision of Safety Information 
11.4.1 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. 

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11.4.2 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 
on the safety of the investigational product that is considered necessary to be reported to the 
principal investigator or subinvestigator. 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. Discontinuation/Suspension of the Clinical Study 
12.1 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. 
12.2 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. 

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12.3 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. 
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. 
13. Statistical Analysis 
Data will be analyzed by the person in charge of statistical analysis as instructed by the 
statistical analysis manager. Major analysis methods are described below, and details of the 
statistical analyses will be defined in a statistical analysis plan prepared separately before the 
database lock. Any necessary analysis other than the prespecified analyses will be performed 
using an appropriate method at the discretion of the statistical analysis manager. 
Handling of subjects and data will be determined before the database lock. 
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 imbalance. 
Summary statistics will be presented 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. 
13.1 Analysis Sets 
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 group to which each subject has been 
assigned. When the safety set (SS) and the pharmacokinetic analysis set (PKS) are used as 
analysis sets, analyses will be performed based on the treatment group in which each subject 
has been treated actually. 
 FAS: Population of subjects, excluding the following subjects: subjects with GCP 
violations, untreated subjects, discontinued subjects before entry to the treatment period, 
some of the ineligible subjects, and subjects with no available mean NRS score at 
baseline (Week 0) 
 PPS: Population of subjects, excluding the following subjects from the FAS: ineligible 
subjects, discontinued subjects, deviators, and subjects with broken emergency key 

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codes, as the subjects to be excluded from the PPS 
 SS: Population of subjects, excluding the following subjects: subjects with GCP 
violations, untreated subjects, and discontinued subjects before entry to the treatment 
period 
 PKS: Population of subjects, excluding the following subjects from the SS subjects with 
no available plasma drug concentration data 
13.2 Analysis Groups 
 MR13A9 0.25 μg/kg group: Subjects allocated to or treated with MR13A9 0.25 μg/kg 
 MR13A9 0.5 µg/kg group: Subjects allocated to or treated with MR13A9 0.5 μg/kg 
 MR13A9 1.0 µg/kg group: Subjects allocated to or treated with MR13A9 1.0 μg/kg 
 Placebo group: Subjects allocated to or treated with placebo 
13.3 Disposition of Subjects 
For the each analysis set and the presence/absence of discontinuation, numbers and 
percentages of subjects will be presented and the imbalance between the groups will be 
examined. 
13.4 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, and 
imbalance between the groups will be examined. 
13.5 Efficacy 
The FAS will be used as the primary analysis set. 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. 
13.5.1 Primary endpoint 
The primary endpoint is the NRS score. The assessment time points and their evaluated time 
windows in the treatment period and the follow-up period are shown in Table 13.5.1-1 and 
Table 13.5.1-2, respectively. 
Table 13.5.1-1 
Assessment time points and evaluated time windows in the 
treatment period 
Time point 
Evaluated time windowa) 
Week 0 (baseline) 
From Day −6 to Day 1 
Week 1 
From Day 2 to Day 8 
Week 2 
From Day 9 to Day 15 
Week 3 
From Day 16 to Day 22 
Week 4 
From Day 23 to Day 29 
Week 5 
From Day 30 to Day 36 
Week 6 
From Day 37 to Day 43 
Week 7 
From Day 44 to Day 50 
Week 8 
From Day 51 to Day 57 
a) The start date of the treatment period will be regarded as Day 1 and the previous day of the start date of the treatment 
period will be regarded as Day −1. 

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Table 13.5.1-2 
Assessment time points and evaluated time windows in the 
follow-up period 
Time point 
Evaluated time windowa) 
Week 1 
From Day 1 to Day 7 
Week 2 
From Day 8 to Day 14 
a) The start date of the follow-up period (the date of treatment period completion 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: 
Mean NRS score at each time point = Sum of the NRS score observed during the evaluated 
time window ÷ Number of days when NRS score was observed during the evaluated 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 
13.5.2 Primary variable 
Change from baseline in the mean NRS score at Week 8 of the treatment period 
13.5.2.1 Analysis of the primary variable 
13.5.2.1.1 Primary analysis 
The primary analysis will be performed 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 dynamic allocation factors, presence of prior 
treatment with nalfurafine hydrochloride, and presence of specific signs or symptoms to be 
confirmed in the screening period, as covariates; and subject as a random effect. 
The analysis will include all available data obtained at each time point between Week 1 and 
Week 8 of the treatment period. 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’s 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. 
For the primary variable and the change from baseline in the mean NRS score at Week 2 of 
the treatment period, contrasts will be used to determine the dose-response relationship for the 
placebo group and the MR13A9 0.25, 0.5 and 1.0 µg/kg groups. Contrast patterns (placebo, 
0.25, 0.5, 1.0 μg/kg) to be used will include (3, 1, −1, −3), (2, 2, −1, −3), (1, 1, 1, −3), (1, 1, 
−1, −1), (3, −1, −1, −1), and (3, 1, −2, −2). 
The adjusted mean change at each time point for each group and its two-sided 95% 
confidence interval will be presented. The adjusted mean between-difference in the change at 
each time point for the placebo group and the MR13A9 0.25, 0.5, and 1.0 µg/kg groups and 
its two-sided 95% confidence interval as well as the p value will be presented. 

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13.5.2.1.2 Sensitivity analysis 
The sensitivity analyses shown below 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 sensitivity analyses, as with the primary analysis, contrasts will be used to 
determine dose-response relationships and estimate treatment effects. 
1) 
MI – MMRM 
Multiple imputed data will be generated in the MI 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 Week 0 and Week 8 of the treatment 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 MI 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 Week 0 and Week 8 of the treatment 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. 
13.5.2.2 Other assessment variables 
1) 
Mean NRS score 
For changes from baseline, summary statistics will be presented. A one-sample t-test will be 
used for comparisons within each group. A two-sample t-test will be used for comparisons 
between the placebo group and each of the MR13A9 0.25, 0.5, and 1.0 µg/kg groups. 
For the mean NRS score, summary statistics will be presented. 
13.5.3 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 
“13.5.1 Primary endpoint.” 
For changes from baseline, summary statistics will be presented. A one-sample t-test will be 
used for comparisons within each group. A two-sample t-test will be used for comparisons 
between the placebo group and each of the MR13A9 0.25, 0.5, and 1.0 µg/kg groups. 
For mean itch scores, summary statistics will be presented. 
2) 
Total Skindex-16 score and total 5-D itch scale score 

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For changes from baseline, summary statistics will be presented. A one-sample t-test will be 
used for comparisons within each group. A two-sample t-test will be used for comparisons 
between the placebo group and each of the MR13A9 0.25, 0.5, and 1.0 µg/kg groups. 
For measurements, summary statistics will be presented. 
3) 
Patient Global Impression of Change (PGIC) 
For measurements, the number and percentage of subjects will be presented. A two-sample 
Wilcoxon test will be used for comparisons between the placebo group and each of the 
MR13A9 0.25, 0.5, and 1.0 µg/kg groups. 
13.6 Safety 
The SS will be used as the analysis set. 
13.6.1 Adverse events and adverse drug reactions 
Analysis will include events occurring between the start of study treatment and the end of the 
follow-up period. Analysis of adverse drug reactions will be similar to adverse events. 
1) 
Incidence of adverse events and adverse drug reactions 
The number of events, the number of subjects experiencing events, the incidence of events 
and its two-sided 95% confidence interval will be presented. Fisher’s exact test will be used 
for comparisons between the placebo group and each of the MR13A9 0.25, 0.5, and 1.0 µg/kg 
groups. The between-group difference in the incidence of events and its two-sided 95% 
confidence interval will be presented. 
2) 
Incidences of adverse events and adverse drug reactions (serious events and events led to 
discontinuation) 
The numbers of events, the numbers of subjects experiencing events, and the incidences of 
events will be presented for all events, events led to death, serious events other than death, 
and events led 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. 
13.6.2 Vital signs and body weight 
Summary statistics will be presented. Scatterplots before and after treatment will be presented. 
13.6.3 Laboratory tests 
For quantitative values, summary statistics will be presented. Scatterplots before and after 
treatment will be presented. Shift tables before and after treatment will be presented. 
For qualitative values, the number and percentage of subjects will be presented. Shift tables 
before and after treatment will be presented. 

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13.6.4 Dependency assessment 
The number and percentage of subjects with or without dependency will be presented. 
13.7 Pharmacokinetics 
The PKS will be used as the analysis set. 
13.7.1 Plasma drug concentration 
For plasma concentrations of MR13A9 (unchanged drug), summary statistics, geometric 
means, and geometric CVs will be presented. Geometric means and individual values will be 
illustrated by dose group. 
14. Protocol Agreement and Amendment 
14.1 Agreement on the Protocol 
To confirm the agreement on the content of the protocol and the compliance with the protocol, 
the principal investigator and the sponsor will affix their name and seal to or sign, and date 
the protocol or an alternative document. 
14.2 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. 
14.3 Deviation 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. The principal investigator 
or subinvestigator will document all deviations from the protocol. 
15. Direct Access to Source Documents 
15.1 Source Documents 
Source documents refer to original documents, data, and records that contain source 

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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. In 
addition, the study site will consult with the sponsor and specify source documents. 
15.2 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. 
15.3 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. 
16. 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. 
17. Ethics 
17.1 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. 
17.2 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’ 

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source data. 
17.3 Compensation to Subjects 
1) 
The study site will provide treatment or other necessary measures for a subject 
experiencing any study-related injury. 
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. 
18. Data Handling, and Record Keeping 
18.1 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 treatment period, only the information on the date of written informed 
consent, the information on the investigations, observations, tests, and evaluations performed 
at Week −2, adverse events, concomitant medications, concomitant therapies, implementation 
status of dialysis, and the information on the discontinuation of the study will be collected and 
recorded. Case report forms will be completed as instructed separately in the written 
procedure. 
18.2 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. Record forms prepared at the time of electronic diary 
system troubles will be checked by the principal investigator or subinvestigator during 
interviews. These record forms will be retained at the study site. The symptom diary will be 
recorded and amended as instructed separately in the written procedure. 
18.3 Preparation and Submission of Forms for 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 attach copies of all ECG charts for the subject obtained 
during the study to a 12-lead ECG chart form, and submit the form to the sponsor. 
The principal investigator, subinvestigator, or clinical research coordinator will attach copies 

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of 12-lead ECG charts to a 12-lead ECG chart form, and enter the subject identification code 
and the time of measurement in the form. The principal investigator or subinvestigator will 
check all the entries, enter the date of confirmation and sign (or affix the name and seal to) the 
form, and submit the form to the sponsor. 
18.4 External Data 
For measurements at an external laboratory testing facility, the sponsor will obtain their 
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. 
18.5 Record Keeping 
18.5.1 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. 
18.5.2 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. 
18.5.3 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. 
19. 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. 
20. 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. 
21. Study Administrative Structure 
This study will be planned and conducted by the organizations shown in the attachment. Any 

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amendment of the attachment will be managed separately from the protocol. 
22. History of Protocol Amendments 
Version 02.00.000: created on November 29, 2018 
 

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23. 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: 203-210. 
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. 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. 94-108. 
11) Suzuki H. 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. 49-55. 
12) Toray Industries, Inc. Drug Interview Form for REMITCH® Capsules 2.5 μg, OD 
Tablets 2.5 μg. Revised in September 2017 (13th 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) Shinzato T, et al., A View on Kt/V and Protein Catabolic Rate (PCR) and % Creatinine 
Production Rate, Journal of Japanese Society for Dialysis Therapy 1996; 29(12), 1511-
6. 
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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Study Schedule 
 
Screening period 
Treatment period 
Follow-up period 
Visita) 
(weeks after initial dose) 
 
Week −2 Week −1 
Week 0 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5–6 
Week 7 
Week 8 
Week 9 
Week 10 
Visit 
— 
1 
— 
2 
— 
— 
3 
4 
— 
5 
— 
— 
— 
— 
— 
6 
7 
— 
— 
— 
— 
8 
9 
— 
10 
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— 
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12 
Day of the week 
— 
Mon 
/Tue 
Mon 
/Tue 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Mon 
/Tue 
Informed consentb) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demographics 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject registration 
Primary Seconda
ry 
 
Tertiary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
NRSc) 
Shiratori’s severity 
criteriac) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
Concomitant 
medications/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific signs/symptomsd) 
 
 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
Prohibited concomitant 
medications 
Hemodialysis conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skindex-16 
5-D itch scale 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
Body weighte) 
12-lead ECGe) 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
Vital signse) 
Laboratory testse) 
 
● 
 
● 
 
 
● 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
Postdialysis BUN 
Postdialysis weight 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dependency assessmentf) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
 
 
 
Serum pregnancy testg) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
Pharmacokineticsh) 
 
 
 
 
 
 
● 
● 
 
● 
 
 
 
 
 
● 
● 
 
 
 
 
● 
● 
 
● 
 
 
 
 
 
 
a) 
Assessments and tests will be performed on the day of the first dialysis of each week, unless prescribed otherwise. 
b) 
Consent for study participation must be obtained prior to the start of the screening period. 
c) 
To be recorded in the symptom diary once daily from the next day of the start date of the screening period until the visit day at Week 10. 
d) 
Subjects will be examined for specific signs/symptoms every week (Monday or Tuesday) from Week −1 until Week 10. 
e) 
To be performed before dialysis. 
f) 
To be performed before dialysis at Week 8. 
g) 
To be performed only in women of childbearing potential (within 1 year of their last menstrual period and who have not undergone total hysterectomy or bilateral total ovariectomy). 
h) 
Blood samples will be collected at Week 1 (before the first dialysis, at 5 minutes after administration of the week, before the second dialysis), Week 2 (before the first dialysis of the week), 
Week 4 (before the first dialysis, at 5 minutes after administration of the week, before the second dialysis), Week 7 (before the first dialysis, at 5 minutes and of the week, at least 1 hour after 
administration, before the second dialysis), and Week 8 (before the first dialysis of the week). At least 1 hour after administration at Week 7, blood sampling will be performed only in subjects 
from whom blood can be collected. 

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Study Schedule (at the time of discontinuation) 
 
Treatment 
period 
Follow-up period 
Visit 
(weeks after initial dose) 
At 
discontinuation a) 
Week 1 after 
discontinuation 
Week 2 after 
discontinuation 
Visit 
— 
— 
— 
Day of the week 
— 
  — b) 
Mon 
/Tue 
Wed 
/Thu 
Fri 
/Sat 
Study treatment 
 
 
 
 
 
NRSc) 
Shiratori’s severity criteriac) 
 
 
 
 
 
Adverse events 
Concomitant medications/therapies 
 
 
 
 
 
Specific signs/symptomsd) 
● 
● 
● 
 
 
Prohibited concomitant 
medications 
Hemodialysis conditions 
 
 
 
 
 
Skindex-16 
5-D itch scale 
● 
 
 
 
 
PGIC 
● 
 
 
 
 
Body weighte) 
12-lead ECGe) 
● 
 
 
 
 
Vital signse) 
Laboratory testse) 
● 
 
● 
 
 
Postdialysis BUN 
Postdialysis weight 
 
 
 
 
 
Dependency assessment 
 ●e) 
● 
 
 
 
Serum pregnancy testf) 
● 
 
 
 
 
Pharmacokineticse) 
● 
 
 
 
 
a) 
Assessments and tests will be performed on the day of dialysis after discontinuation has been decided. 
b) 
Assessments at Week 1 after discontinuation will be performed on the same day of the week as the day of the assessments at discontinuation. 
c) 
To be recorded in the symptom diary once daily from the next day of the start date of the screening period until the visit day at Week 2 after discontinuation. 
d) 
Subjects will be examined for specific signs/symptoms at the time of discontinuation, at Week 1 after discontinuation, and at Week 2 after discontinuation. 
e) 
To be performed before dialysis. 
f) 
To be performed only in women of childbearing potential (within 1 year of their last menstrual period and who have not undergone total hysterectomy or bilateral total ovariectomy). 
* 
Subjects discontinuing the study in the treatment period will undergo the assessments at discontinuation and enter into the follow-up period. 
 

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24. Appendices 
Appendix 1 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. 
Appendix 2 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) 
 
 

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Appendix 3 Numerical Rating Scale (NRS) 
 
 
Appendix 4 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 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 is categorized into questions concerning symptoms, No. 5 to 11 are categorized into questions concerning 
emotions, and No. 12 to 16 is categorized into questions concerning functioning. Patients choose 1 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. 
0  1  2  3  4  5  6  7  8  9  10 
No itching 
Worst itching 
imaginable 

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Appendix 6 5-D itch scale 
 
1. Duration 
During the past 2 weeks, how many hours a day have you been itching? 
(1) 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 
 
 

Protocol No.: MR13A9-4 
CONFIDENTIAL 
Version: 02.00.000 
 
- 62 - 
Appendix 8 Dependency assessment 
Questionnaire on the study drug (before dialysis at Week 8 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 9 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) 

      
 
 
CERTIFICATE OF TRANSLATION 
 
 
 
This document is the translated version of the source document below written in Japanese. 
It is hereby certified that this document is a true and accurate translation of the source 
document from Japanese into English. 
 
 
 
 
 
Source document: 
MR13A9-4 Clinical Study Protocol (Ver 02.00.000) 
File name: mr13a9-4-p-jp.pdf 
Name of representative: 
 
 
Signature and Date of signature: 
Refer to Signature Page 
 

 
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