Clinical trial NCT03998163
Conditions: Uremic Pruritus
Keywords: Hemodialysis Pruritus Uremic Pruritus Dialysis CR845 Chronic Itch CKD CKD-associated pruritus CKD-aP ESRD (end stage renal disease) difelikefalin Itch Itching KALM Chronic Kidney Disease Kidney failure, chronic Kidney dysfunction Generalized pruritus
Sponsor: Cara Therapeutics, Inc.
Start date: 2019-05-06; Completion date: 2020-03-06
Enrollment: 222 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label study to evaluate the safety and effectiveness of intravenous (IV) CR845 at a dose of 0.5 mcg/kg administered after each dialysis session. The study includes an up to 12-week Treatment Period.

Detailed description:
Screening Period: The Screening Period includes a Screening Visit and a Run-In Period. Informed consent will be obtained prior to performing any study-specific procedures. The Screening Visit will occur within 21 days prior to the start of the Run-in Period. Patients will start the Run-in Period during the week prior to Treatment Period to complete eligibility verification.

Treatment Period: All scheduled study visits during the Treatment Period will be conducted on dialysis days. Patients will be administered CR845 as an IV bolus after the end of their dialysis during a Treatment Period of up to 12 weeks so that each patient will receive CR845 3 times weekly for a total of up to 36 doses. End of treatment (EOT) is defined as the first day of dialysis following the last dose of drug. The EOT procedures will be conducted on the dialysis visit following the last dose of study drug.

Follow-up Visit: A final safety Follow up Visit will be conducted 7-10 days after the EOT/Early Termination Visit.

Arms: arm 1: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)
Interventions: intervention 1: CR845 0.5 mcg/kg
Intervention descriptions: intervention 1: IV CR845 0.5 mcg/kg administered three times/week

Protocol documents:
Prot_000.pdf: 




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INVESTIGATOR APPROVAL STATEMENT 
I have read and understand the protocol (CR845-CLIN3105) and I agree that this 
document contains all ethical, legal, and scientific information necessary to conduct this 
study.  I will oversee the conduct of the study as described in the protocol and any 
amendment(s) made to the protocol.  
I agree to conduct the study as detailed herein and in compliance with the current 
International Council for Harmonization Harmonized Tripartite Guideline for Good 
Clinical Practice and all applicable regulatory requirements. 
Principal Investigator (Refer to Investigator Site File [ISF]) 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
Date: 
 
 


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1.0 
Protocol Synopsis 
STUDY TITLE 
An Open-Label, Multicenter Study to Evaluate the Safety and 
Effectiveness of Intravenous CR845 in Hemodialysis Patients with 
Moderate-to-Severe Pruritus 
PROTOCOL 
NUMBER 
CR845-CLIN3105 
PHASE OF 
DEVELOPMENT 
3 
INVESTIGATIONAL 
PRODUCT 
CR845 Solution (For Clinical Trial Use Only) 
NAME OF ACTIVE 
INGREDIENT 
CR845 
ROUTE OF 
ADMINISTRATION 
Intravenous (IV) 
STUDY CENTERS 
Approximately 80 US and non-US sites  
OBJECTIVES 
 
Primary Objective 
• 
To evaluate the safety of IV CR845 at a dose of 0.5 mcg/kg in 
hemodialysis patients with moderate-to-severe pruritus   
Secondary Objectives 
• 
To evaluate the effectiveness of IV CR845 at a dose of 0.5 
mcg/kg in reducing the intensity of itch in hemodialysis 
patients with moderate-to-severe pruritus 
• 
To evaluate the effectiveness of IV CR845 at a dose of 0.5 
mcg/kg in improving itch-related quality-of-life and quality of 
sleep measures in hemodialysis patients with moderate-to-
severe pruritus.  
NUMBER OF 
PATIENTS 
Approximately 400 male and female hemodialysis patients with 
moderate-to-severe pruritus   
STUDY 
POPULATION 
Inclusion Criteria: 
To be eligible for inclusion into the study, a patient must meet the 
following criteria: 
1. Willing and able to provide written informed consent prior to 
participating in this study; 
2. Able to communicate clearly with the Investigator and staff, 
able to understand the study procedures, and able and willing 
to comply with the study requirements, including providing 
written responses to questionnaires; 
3. Male or female between 18 and 85 years of age, inclusive; 
4. Has end-stage renal disease (ESRD) and has been on 
hemodialysis 3 times per week for at least 3 months prior to 
the start of screening; 
Note 1: Patients who require an occasional additional dialysis 
treatment to manage fluid overload or electrolyte excesses 


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may be enrolled as long as it is anticipated that no more than 
1 such treatment will be required in any given week. Patients 
routinely on 4 dialyses a week will not be eligible. 
Note 2: Patients receiving in-home hemodialysis may 
participate as long as they have switched to in-center 
hemodialysis at least 2 weeks prior to screening and plan to 
remain on in-center hemodialysis for the duration of the 
study.  
Note 3:  Patients receiving alternate dialysis modalities such 
as nocturnal dialysis will not be eligible. 
5. If female, is not pregnant or nursing during any period of the 
study;  
6. If female: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for at least 1 year and is over 
the age of 55 years; or 
c. Has a negative serum pregnancy test within 7 days of 
administration of the first dose of study drug and 
agrees to use acceptable contraceptive measures 
(eg, hormonal contraceptives, barrier with spermicide, 
intrauterine device, vasectomized partner, or 
abstinence from heterosexual intercourse) from the 
time of informed consent until 7 days after the last 
dose of study drug; 
7. If male, agrees not to donate sperm after the first dose of study 
drug until 7 days after the last dose of study drug, and agrees to 
use a condom with spermicide or abstain from heterosexual 
intercourse during the study until 7 days after the last dose of 
study drug;  
Note:  No restrictions are required for a vasectomized 
male provided his vasectomy was performed 
≥4 months prior to screening.  
8. Has a prescription dry body weight ≥40 kg;  
9. Over the last three months prior to screening, has had at least 
one of the following: 
a. At least 2 single-pool Kt/V measurements ≥1.2 on 
different dialysis days;  
b. At least 2 urea reduction ratio measurements ≥65% on 
different dialysis days;  
c. 1 single-pool Kt/V measurement ≥1.2 and 1 urea 
reduction ratio measurement ≥65% on different 
dialysis days;  
10. Prior to treatment: 
a. Has completed at least three Worst Itching Intensity 
Numerical Rating Scale (NRS) questionnaires from the 


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start of the Run-in Period up to and including the pre-
dose assessment on Day 1; 
b. Has a mean baseline Worst Itching Intensity NRS 
score ≥ 5, defined as the average of all non-missing 
scores reported from the start of the Run-in Period up 
to and including the pre-dose assessment on Day 1. 
Exclusion Criteria: 
A patient will be excluded from the study if any of the following 
criteria are met: 
1. Known noncompliance with dialysis treatment that in the 
opinion of the Investigator would impede completion or 
validity of the study; 
2. Scheduled to receive a kidney transplant during the study; 
3. Known history of allergic reaction to opiates, such as hives;  
Note: side effects related to the use of opioids, such as 
constipation or nausea, would not exclude patients 
from the study. 
4. Hypersensitivity to the active substance or any of the 
excipients in the investigational products; 
5. Has a concomitant disease or a history of any medical 
condition that, in the opinion of the Investigator, could pose 
undue risk to the patient, impede completion of the study 
procedures, or would compromise the validity of the study 
measurements, including, but not limited to: 
a. Known or suspected history of alcohol, narcotic, or 
other drug abuse, or substance dependence within 12 
months prior to screening; 
b. Significant systolic or diastolic heart failure (eg, New 
York Heart Association Class IV congestive heart 
failure [Appendix 1, Section 14.1]); 
c. Severe mental illness or cognitive impairment (eg, 
dementia); 
d. Any other relevant acute or chronic medical or 
neuropsychiatric condition within 3 months prior to 
screening (eg, diagnosis of encephalopathy, coma, 
delirium); 
6. New or change of treatment received for itch including 
antihistamines and corticosteroids (oral, IV, or topical) within 
14 days prior to screening; 
7. New or change of prescription for opioids, gabapentin, or 
pregabalin within 14 days prior to screening; 
8. Received another investigational drug within 30 days or five 
half-lives (whichever is longer) prior to the start of dosing or is 
planning to participate in another interventional clinical study 
while enrolled in this study; 


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9. In the opinion of the Investigator, has pruritus attributed to a 
cause other than ESRD or its complications (eg, patients with 
concomitant pruritic dermatological disease or cholestatic liver 
disease);  
Note: Patients whose pruritus is attributed to ESRD 
complications, such as hyperparathyroidism, 
hyperphosphatemia, anemia, or the dialysis procedure 
or prescription may be enrolled. 
10. Has localized itch restricted to the palms of the hands; 
11. Has pruritus only during the dialysis session (by patient 
report); 
12. Is receiving ongoing ultraviolet B treatment and/or anticipates 
receiving such treatment during the study; 
13. Participated in a previous clinical study with CR845. 
STUDY DESIGN 
This is a multicenter, open-label study to evaluate the safety and 
effectiveness of IV CR845 at a dose of 0.5 mcg/kg administered after 
each dialysis session. This study will consist of a Screening Period and 
an up to 12-week Treatment Period. The Screening Period includes a 
Screening Visit and a Run-In Period. After the completion of the 
Treatment Period, patients will be required to complete a Follow-up 
Visit. 
Screening Period 
Screening Visit: 
Informed consent will be obtained prior to performing any study-
specific procedures.  The Screening Visit will occur within 21 days 
prior to the start of the Run-in Period.  Patients should be trained on 
completing patient-reported outcome (PRO) questionnaires prior to the 
start of the Run-in Period. The site has the option of starting the Run-in 
Period on the same day as the Screening Visit at the discretion of the 
Investigator.  
Run-In Period: 
Patients will start the Run-in Period during the week prior to Treatment 
Period to complete eligibility verification. The Run-in Period will start 
on the first dialysis session of that week (i.e, Monday for patients on a 
Monday-Wednesday-Friday dialysis schedule or Tuesday for patients 
on a Tuesday-Thursday-Saturday dialysis schedule). The primary 
purpose of the Run-in Period is to confirm that each patient has 
moderate-to-severe pruritus (ie, weekly average worst itching score 
>5), as measured by the patient reported Worst Itching Intensity NRS 
and to establish a baseline itch intensity. During the Run-in Period, 
patients will complete the Worst Itching Intensity NRS and Sleep 
Quality questionnaires only on the dialysis days and the EQ-5D-5L 
with EQ-PSO bolt on (EQ-5D-5L-P) on the third dialysis session.   


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If patients continue to meet all inclusion criteria and none of the 
exclusion criteria by the end of the Run-in Period, they will enter the 
Treatment Period of the study.   
Treatment Period: Day 1 of the Treatment Period will be defined as 
the day of administration of the first dose of study drug and will occur 
on the first dialysis session of the first treatment week (ie, Monday for 
patients on a Monday-Wednesday-Friday dialysis schedule, or Tuesday 
for patients on a Tuesday-Thursday-Saturday dialysis schedule).  
Before the first dose of CR845, patients will complete their Worst 
Itching Intensity NRS and a series of itch-related quality of life and 
sleep questionnaires (ie, Sleep Quality, 5D Itch, Skindex-10, and EQ-
5D-5L-P questionnaires).   
All scheduled study visits during the Treatment Period will be 
conducted on dialysis days.  Patients will be administered CR845 as an 
IV bolus after the end of their dialysis, either during rinse back or 
after rinse back.  Hospitalizations, infections, missed dialysis 
sessions, clinical laboratory tests, electrocardiograms (ECGs), vital 
signs, adverse events, and concomitant medications will be monitored 
throughout the study.  
End of treatment (EOT) is defined as the first day of dialysis following 
the last dose of drug. The EOT procedures will be conducted on the 
dialysis visit following the last dose of study drug.   
Follow-up Visit 
A final safety Follow-up Visit will be conducted 7-10 days after the 
EOT or Early Termination (ET) Visit.  
  
STUDY DRUG 
Study drug will be supplied in glass vials containing an extractable 
volume of at least 1.3 mL of CR845 at a concentration of 0.05 mg/mL 
in 0.04M isotonic acetate buffer, pH 4.5.  CR845 dose will be 
calculated and adjusted based on prescription dry body weight. 
REFERENCE 
PRODUCT 
No placebo will be used for this study. 
TREATMENT 
REGIMENS 
Patients will be administered 0.5 mcg/kg CR845 as a single IV bolus 
3 times a week after each dialysis session for up to 12 weeks.   
STUDY DURATION 
 
 
 
 
 
Screening Period:  
Screening Visit: up to 21 days prior to Run-In  
Run-In Period: 7 days prior to Treatment Period 
Treatment Period:  up to 12 weeks 
End of Treatment Visit:  First day of Week 13 or at Early Termination 
Follow-up Visit:  7-10 days after the EOT Visit or ET Visit 
Total study duration for a single patient: up to 18 weeks  
STUDY 
ENDPOINTS 
Safety Endpoints 
• 
Adverse events  
• 
ECG 


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• 
Vital signs 
• 
Clinical laboratory values 
Effectiveness Endpoints 
• 
Worst Itching Intensity NRS 
• 
Sleep Quality 
• 
5D-Itch  
• 
Skindex-10  
• 
EQ-5D-5L-P 
Additional Endpoints 
• 
Missed dialysis visits 
• 
Hospitalizations 
• 
Incidence of infections  
STATISTICAL 
ANALYSIS 
Enrolled population is defined as the group of patients who sign 
informed consent. 
Safety population is defined as the group of patients who received at 
least 1 dose of CR845 in the study.   
Full Analysis population is defined as the group of patients who 
received at least 1 dose of CR845 and have least one non-missing 
effective endpoint assessment after baseline.  
All summaries and analysis of safety will be conducted using the 
Safety population. 
Effectiveness endpoints analysis will be conducted using the Full 
Analysis population. 
Safety data will be summarized descriptively. No inferential statistics 
are planned. Analyses of safety data will include summaries of 
treatment-emergent adverse events including Adverse Events of 
Special Interest (AESI), serious adverse events, and adverse events 
resulting in study drug discontinuation. Vital signs, chemistry and 
hematology, ECG data will be presented by visit as applicable, in 
addition to change from baseline. 


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2.0 
Table of Contents 
1.0 Protocol Synopsis.......................................................................................................... 4 
2.0 Table of Contents ........................................................................................................ 10 
3.0 List of Abbreviations .................................................................................................. 15 
4.0 Introduction ................................................................................................................. 16 
4.1 
Background and Rationale ................................................................................. 16 
4.2 
Clinical Experience ............................................................................................ 17 
4.2.1 
Overall Exposure ........................................................................................ 17 
4.2.2 
Safety in Hemodialysis Patients.................................................................. 17 
4.2.3 
Efficacy of CR845 in Hemodialysis Patients with Uremic Pruritus ........... 18 
4.2.4 
Pharmacokinetics in Hemodialysis Patients ............................................... 19 
4.3 
Summary of Potential Risks and Benefits .......................................................... 19 
5.0 Objectives ................................................................................................................... 21 
6.0 Investigational Plan ..................................................................................................... 22 
6.1 
Overall Study Design and Plan:  Description ..................................................... 22 
6.1.1 
Screening Period ......................................................................................... 22 
6.1.1.1 
Screening Visit ........................................................................................ 22 
6.1.1.2 
Run-in Period .......................................................................................... 22 
6.1.1.3 
Treatment Period .................................................................................... 23 
6.1.1.4 
Follow-up Visit ....................................................................................... 24 
6.2 
Selection of Study Population ............................................................................ 25 
6.2.1 
Eligibility Criteria ....................................................................................... 25 
6.3 
Removal of Patients from Therapy or Assessment ............................................ 27 
6.3.1 
Discontinuation of Individual Patients........................................................ 27 
6.3.2 
Discontinuation or Suspension of Entire Study .......................................... 28 
6.4 
Treatments .......................................................................................................... 28 
6.4.1 
Treatments Administered ............................................................................ 28 
6.4.2 
Identity of Investigational Product(s) ......................................................... 29 
6.4.2.1 
Formulation of Study Drug ..................................................................... 29 
6.4.2.2 
Packaging, Labeling, and Storage Stability of Study Drug .................... 29 
6.4.2.3 
Individual Dose Labeling ....................................................................... 29 


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6.4.3 
Drug Accountability.................................................................................... 29 
6.4.4 
Preparation of CR845 ................................................................................. 30 
6.4.5 
Management of Missed Doses .................................................................... 30 
6.4.6 
Treatment Compliance ................................................................................ 30 
6.4.7 
Prior, Concomitant, and Prohibited Medications ........................................ 30 
6.4.7.1 
Prior and Concomitant Medications ....................................................... 30 
6.4.7.2 
Restricted and Prohibited Medications ................................................... 30 
6.5 
Study Assessments and Procedures .................................................................... 31 
6.5.1 
Schedule of Events for the Treatment Period ............................................. 31 
6.5.2 
Effectiveness Assessments.......................................................................... 34 
6.5.2.1 
Worst Itching Intensity Numerical Rating Questionnaire ...................... 34 
6.5.2.2 
Sleep Quality Questionnaire ................................................................... 34 
6.5.2.3 
Skindex-10 Questionnaire ...................................................................... 34 
6.5.2.4 
5-D Itch Questionnaire ........................................................................... 35 
6.5.2.5 
EQ-5D-5L-P Questionnaire .................................................................... 35 
6.5.3 
Safety Assessments ..................................................................................... 35 
6.5.3.1 
Adverse Events ....................................................................................... 36 
6.5.3.2 
Physical Examination ............................................................................. 39 
6.5.3.3 
Vital Signs .............................................................................................. 40 
6.5.3.4 
Electrocardiogram ................................................................................... 40 
6.5.3.5 
Clinical Laboratory Tests ....................................................................... 40 
6.5.3.6 
Contraception and Pregnancy ................................................................. 41 
6.6 
Additional Assessments ..................................................................................... 42 
6.6.1.1 
Missed Dialysis Visits ............................................................................ 42 
6.6.1.2 
Hospitalization ........................................................................................ 42 
6.6.1.3 
Infections ................................................................................................ 42 
7.0 Discussion and Justification of Study Design ............................................................. 43 
7.1 
Selection of Doses in the Study .......................................................................... 43 
7.2 
Appropriateness of Measurements ..................................................................... 43 
8.0 Statistical Methods ...................................................................................................... 44 
8.1 
General Considerations ...................................................................................... 44 
8.2 
Determination of Sample Size ............................................................................ 44 


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8.3 
Interim Analysis ................................................................................................. 44 
8.4 
Analysis Populations .......................................................................................... 44 
8.5 
Statistical Summary and Analysis ...................................................................... 45 
8.5.1 
Patient Disposition ...................................................................................... 45 
8.5.2 
Protocol Deviations ..................................................................................... 45 
8.5.3 
Demographic and Baseline Characteristics ................................................ 45 
8.5.4 
Medical History .......................................................................................... 45 
8.5.5 
Prior and Concomitant Medications ........................................................... 45 
8.5.6 
Antipruritic Medication .............................................................................. 46 
8.6 
Effectiveness Endpoints and Analysis ............................................................... 46 
8.6.1 
Endpoints .................................................................................................... 46 
8.6.2 
Analysis....................................................................................................... 47 
8.7 
Safety Analysis ................................................................................................... 48 
8.7.1 
Exposure to Study Drug and Compliance ................................................... 48 
8.7.2 
Adverse Events ........................................................................................... 49 
8.7.3 
Clinical Laboratory Evaluations ................................................................. 50 
8.7.4 
Vital Signs and ECGs ................................................................................. 50 
8.8 
Additional Analyses ........................................................................................... 51 
8.8.1 
Missed Dialysis Visits, Hospitalizations and Incidence of Infection ......... 51 
9.0 Quality Control and Quality Assurance ...................................................................... 52 
9.1 
Study Monitoring Plan ....................................................................................... 52 
9.2 
Audits and Inspections ....................................................................................... 52 
9.3 
Data Collection, Validation, and Analysis ......................................................... 53 
10.0 Ethics and Regulatory Compliance ............................................................................. 54 
10.1 
Independent Ethics Committee or Institutional Review Board .......................... 54 
10.2 
Ethical Conduct of the Study .............................................................................. 54 
10.3 
Informed Consent Process .................................................................................. 55 
10.4 
Patient Confidentiality ........................................................................................ 55 
11.0 Data Handling and Quality Assurance ........................................................................ 56 
12.0 Administrative Procedures .......................................................................................... 57 
12.1 
Protocol Adherence ............................................................................................ 57 
12.2 
Publication of Study Findings ............................................................................ 57 


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13.0 References ................................................................................................................... 58 
14.0 Appendix ..................................................................................................................... 60 
14.1 
Appendix 1:  New York Heart Association Classification of Heart Failure ...... 60 
14.2 
Appendix 2:  Worst Itching Intensity Numerical Rating Scale (NRS) .............. 61 
14.3 
Appendix 3:  Sleep Quality Questionnaire ......................................................... 62 
14.4 
Appendix 4:  Skindex-10 Questionnaire ............................................................ 63 
14.5 
Appendix 5:  5-D Itch Questionnaire ................................................................. 64 
14.6 
Appendix 6:  EQ-5D-5L-P Questionnaire .......................................................... 66 
 


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LIST OF TABLES 
Table 1. 
Restricted and Prohibited Medications ..................................................... 31 
Table 2. 
Schedule of Events .................................................................................... 32 
 
LIST OF FIGURES 
Figure 1. 
CR845-CLIN3105 Study Schematic......................................................... 24 
 


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3.0 
List of Abbreviations 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
CFR 
Code of Federal Regulations 
CKD 
Chronic Kidney Disease 
CKD-aP 
Chronic Kidney Disease-associated Pruritus 
CI 
Confidence Interval 
CNS 
Central Nervous System 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESRD 
End-Stage Renal Disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H 
Above the Laboratory Parameter’s Reference Range 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IV 
Intravenous 
KOR 
Kappa-Opioid Receptor 
L 
Below the Laboratory Parameter’s Reference Range 
LS 
Least Squares 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Effects Model with Repeated Measures 
N 
Within the Laboratory Parameter’s Reference Range 
NRS 
Numerical Rating Scale 
PRO 
Patient-Reported Outcome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
Abbreviations that occur only in tables or figures are defined within the appropriate table or figure. 




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In nonclinical studies, CR845 has been shown to exhibit antipruritic and 
anti-inflammatory properties [Investigator’s Brochure].   Thus, CR845 is intended to 
reduce the severity of itching in hemodialysis patients and thereby decrease the likelihood 
of developing additional serious conditions associated with pruritus. 
4.2 
Clinical Experience 
4.2.1 
Overall Exposure 
As of October 2018, the intravenous (IV) formulation of CR845 has been evaluated in 
>1440 patients and healthy volunteers across 17 studies (including two Phase 2 studies for 
the relief of moderate-to-severe pruritus and an ongoing long-term safety trials in 
hemodialysis patients conducted in the US).  CR845 has been evaluated both as an IV 
bolus and a 15-minute infusion of single or repeated doses ranging from 
0.25 to 40 mcg/kg. 
Of the patients exposed to IV CR845 to date, >450 hemodialysis patients have received 
single or repeated IV injections of CR845 doses (for up to 1 year) ranging from 0.25 to 6 
mcg/kg across Phase 1 to Phase 3 studies with > 90 and > 30 hemodialysis patients 
exposed to the intended therapeutic dose of 0.5 mcg/kg for 6 months and for one year, 
respectively. 
4.2.2 
Safety in Hemodialysis Patients 
A review of the aggregate safety data in completed Phase 1 and Phase 2 trials shows that 
CR845 was generally well tolerated in hemodialysis patients when administered after each 
dialysis session for up to 8 weeks at IV doses ranging from 0.5 mcg/kg to 6 mcg/kg.  
Although patients exposed to CR845 reported more adverse events compared with placebo 
patients, most events were mild or moderate in nature.  Generally mild, transient 
paresthesias (facial tingling) and/or hypoesthesias (in different anatomic locations), mostly 
on the first week of dosing, as well as headache, dizziness, and somnolence, were the most 
frequently reported adverse events associated with CR845 administration. Consistent with 
its lack of affinity for mu-opioid receptors, CR845 did not cause euphoria or respiratory 
depression.  
The study CR845-CLIN2101 evaluated the safety, pharmacokinetics, and efficacy of 
repeated IV doses of CR845 compared to placebo over an 8-week treatment period in 
174 hemodialysis patients.  As expected with patients on hemodialysis, a significant 
number of the reported serious adverse events (SAEs) were considered not treatment-
related, but related to the disease and/or comorbid conditions.  Of the 174 patients 
randomized and treated on the study, 31 (17.8%) had treatment-emergent SAEs. Out of 
these SAE reports, 4 (9%) occurred in 45 placebo-treated patients and 27 (21%) in 
129 CR845-treated patients.  Only 1 SAE of mental status changes (moderate in severity) 
in a patient who received CR845 1.5 mcg/kg IV was considered by the Investigator to be 
probably related to study drug.  However, based on the Sponsor’s medical review, an 
alternate etiology of urgent/emergent hypertension offers a more plausible explanation for 
the acute change in mental status.  There were 4 patient deaths (1 in placebo group, 1 in 


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CR845 0.5 mcg/kg group, and 2 in CR845 1.5 mcg/kg group; 2.3% of the total study 
population) in the study, all of which were considered not related to the study drug. In 
patients with normal renal function, CR845 can cause free-water diuresis (aquaresis) and 
increased serum sodium.  However, as would be expected in patients undergoing dialysis 
in whom there are few functioning nephrons, there was no evidence of aquaresis or 
significant increases in serum sodium concentrations.  There were no adverse trends in 
clinical chemistry or hematology values (drawn pre-dialysis), including no apparent 
differences between the placebo and CR845 groups in serum sodium.  There were no 
discernable differences between treatment groups in vital sign results.  Of particular note, 
among patients receiving CR845, there was no apparent reduction in blood pressure or 
respiratory rate following dosing. 
Adverse event summary tables can be found in the Investigator’s Brochure, with further 
details of the safety profile of CR845.   
4.2.3 
Efficacy of CR845 in Hemodialysis Patients with Uremic Pruritus 
The efficacy of CR845 at reducing itch was evaluated in two Phase 2, randomized, 
double-blind, placebo-controlled studies (CR845-CLIN2005 [Part B] and 
CR845-CLIN2101). 
CR845-CLIN2005 (Part B) included 65 hemodialysis patients with moderate-to-severe 
pruritus who received either IV CR845 1.0 mcg/kg (n=33) or placebo (n=32) 3 times per 
week for 2 weeks, after each hemodialysis session.  CR845 significantly decreased itching 
intensity compared with placebo (p=0.016), as measured by a visual analog scale (VAS) 
and significantly improved quality of life related to itching (Skindex-10) (see 
Investigator’s Brochure for details).  Furthermore, CR845-treated patients exhibited 
statistically significant reductions in both daytime (p=0.03) and nighttime (p=0.007) worst 
itching scores compared with placebo, and the reduction in itching intensity scores was 
similar on dialysis and nondialysis days.  The mean change from baseline VAS curves 
over time showed numerical separation between the treatment groups within the first week 
of treatment. 
CR845-CLIN2101 evaluated the safety, pharmacokinetics, and efficacy of repeated IV 
doses of CR845 compared to placebo over an 8-week treatment period in 
174 hemodialysis patients experiencing moderate-to-severe pruritus daily or near-daily for 
4.4 years on average.  The study was conducted at 33 dialysis centers and assessed the 
effect of 3 doses of CR845 (ie, 0.5 mcg/kg, n=44; 1 mcg/kg, n=41 and 1.5 mcg/kg, n=44) 
or placebo (n=45) administered at the end of each dialysis session (ie, 3 times/week).  The 
primary efficacy endpoint for Study CR845-CLIN2101 was based on itch intensity 
measurement and defined as the change from a 1-week baseline recorded prior to the start 
of study drug to the last week of the 8-week treatment period with respect to the weekly 
mean of the daily 24-hour Worst Itching Intensity numerical rating scale (NRS) score.  
The least squares (LS) mean (±standard error [SE]) treatment group difference from 
placebo at Week 8 across all CR845 doses was -1.3 (±0.41) (95% confidence interval [CI]:  
-2.1 to -0.5) (p=0.002) with an average NRS score reduction from baseline of -3.2 (±0.22) 
(LS mean ±SE) and 95% CI ranging from -3.7 to -2.8.  Examination of the individual 


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CR845 dose group results for the Full Analysis Population indicates that a substantial 
improvement over placebo was observed with all 3 doses.  These differences from placebo 
were statistically significant for the lower dose group of 0.5 mcg/kg (p<0.001) and the 1.5 
mcg/kg group (p=0.019), with an effect size estimated as 0.82, 0.39, and 0.62 for the 0.5, 
1.0, and 1.5 mcg/kg doses, respectively.  Average reduction from baseline (LS mean ± SE) 
ranged from -2.8 (±0.38) in the 1.0 mcg/kg dose group (95% CI ranging from -3.5 to -2.0) 
to -3.8 (±0.38) in the 0.5 mcg/kg dose group (95% CI ranging from -4.5 to -3.1).  The 
reduction in itch intensity directly correlated with a significant improvement in itch-
related quality of life and sleep measurements (see Investigator’s Brochure, with further 
details of the efficacy profile of CR845).   
4.2.4 
Pharmacokinetics in Hemodialysis Patients 
CR845 is eliminated primarily through the kidney and no major metabolites have been 
identified in humans.  Consequently, total body clearance of CR845 in patients with 
severe renal impairment is reduced relative to healthy, matched, control patients 
(CR845-CLIN1005) such that plasma levels of CR845 remain relatively constant until 
cleared during dialysis in hemodialysis patients (CR845-CLIN1003 and 
CR845-CLIN2005 [Part A]).  Half-life ranges between 26 and 34 hours in hemodialysis 
patients compared to a typical range of 2 to 3 hours in patients with normal renal function.  
Thus, lower doses of CR845 can be administered at a less frequent interval in 
hemodialysis patients to achieve the same or higher overall exposure compared to 
individuals with normal renal function.  Based on this pharmacokinetic profile, CR845 
does not need to be administered more than 3 times a week after each hemodialysis 
session, which is convenient for this patient population and ensures treatment compliance 
in a population already burdened with complex medication schedules.  
The pharmacokinetic profile of repeat-dose CR845 was studied in 24 hemodialysis 
patients who received doses of 0.5, 1.0, or 2.5 mcg/kg 3 times per week for 1 week 
(CR845-CLIN2005 [Part A]).  In this study, there were dose-proportional increases in 
maximum concentration and area under the curve, and minimal to no accumulation with 
repeat doses due to clearance of the drug by hemodialysis (see Investigator’s Brochure for 
details).  
4.3 
Summary of Potential Risks and Benefits 
During preclinical development, no specific safety findings to preclude the use of CR845 
in humans were observed.  During early clinical development, IV CR845 was 
administered to healthy volunteers; patients with mild, moderate, or severe renal 
impairment, including end-stage renal disease (ESRD) and hemodialysis patients; 
recreational poly-drug users; and postsurgical patients.  The effects of CR845 have been 
shown to be in line with the underlying pharmacological mechanism of KOR activity.  
Consistent with the nonclinical abuse liability studies conducted to date, the results of an 
abuse-potential study in humans indicated that CR845 is different from typical opioid 
medications as it does not attach to the mu receptors and therefore cannot produce mu 
receptor mediated side-effects such as addiction.  


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Overall, tingling/numbness, headache, dizziness, fatigue and/or drowsiness/somnolence 
have been the most common adverse events.  Precaution is recommended in the operation 
of machinery for patients who experience dizziness, fatigue, and/or 
drowsiness/somnolence.  This is described in the informed consent form (ICF), as 
appropriate, and will be discussed with each patient prior to initiation of the study.  In 
general, CR845 appeared to be generally well tolerated in both single- and repeat-dose 
clinical studies in hemodialysis patients, which support continued study and development 
of this compound. 


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5.0 
Objectives 
Primary Objective  
• To evaluate the safety of IV CR845 at a dose of 0.5 mcg/kg in hemodialysis 
patients with moderate-to-severe pruritus   
Secondary Objectives  
• To evaluate the effectiveness of IV CR845 at a dose of 0.5 mcg/kg in reducing the 
intensity of itch in hemodialysis patients with moderate-to-severe pruritus 
• To evaluate the effectiveness of IV CR845 at a dose of 0.5 mcg/kg in improving 
itch-related quality-of-life and quality of sleep measures in hemodialysis patients 
with moderate-to-severe pruritus. 


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6.0 
Investigational Plan 
6.1 
Overall Study Design and Plan:  Description 
This is a multicenter, open-label study to evaluate the safety and effectiveness of IV 
CR845 at a dose of 0.5 mcg/kg administered after each dialysis session. This study will 
consist of a Screening Period, an up to 12-week Treatment Period and a Follow Up Visit.  
 
6.1.1 
Screening Period 
The Screening Period can occur within 28 days prior to treatment to assess eligibility. It 
consists of a Screening Visit and a Run-in Period.  
6.1.1.1 
Screening Visit 
The Screening Visit will occur within 21 days prior to the Run-In Period. During this visit, 
patients will sign the Informed Consent Form and then will be evaluated for eligibility by 
assessment of inclusion/exclusion criteria.  
Serum pregnancy test for females of childbearing potential must be performed within 7 
days prior to the first study dose.  
Medical history, including total number of missed dialysis sessions over the past month 
and the conditions of special interest (ie, gait disturbance, fall, dizziness, somnolence, 
seizure, syncope, mental status changes, mood altered, feeling abnormal, tachycardia, and 
palpitations) will be recorded during screening. During screening and before the first visit 
of the Run-in Period, patients will be trained on completion of the Worst Itching Intensity 
NRS, EQ-5D-5L with EQ-PSO bolt-on (EQ-5D-5L-P) and Sleep Quality questionnaires.  
Patients may also be trained on other patient-reported outcome (PRO) questionnaires 
during the Screening Period prior to treatment on Day 1 (ie, Skindex-10 and 5-D itch 
questionnaires).  
6.1.1.2 
Run-in Period 
Eligible patients will begin the Run-in Period during the week prior to Treatment Period to 
complete eligibility verification, starting on the first dialysis session of that week 
(ie, Monday for patients on a Monday-Wednesday-Friday dialysis schedule or Tuesday for 
patients on a Tuesday-Thursday-Saturday dialysis schedule).  The purpose of the Run-in 
Period will be to confirm that each patient has moderate-to-severe pruritus (ie, weekly 
average worst itching score >5), as measured by the patient reported Worst Itching 
Intensity NRS, and to establish a baseline itch intensity.  These criteria for eligibility 
should not be communicated to the patients.  This period will also be used to record each 
patient’s use of antipruritic medications.   
During the first dialysis visit of the Run-in Period, patients will start the reporting of their 
Worst Itching Intensity NRS scores and will continue to do so at every dialysis session. 
For consistency the Worst Itching Intensity NRS scores will be collected at approximately 
the same time around the start of the dialysis session preferably within one hour of starting 


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dialysis. After the completion of the Worst Itching Intensity NRS, patients will complete 
the Sleep Quality Questionnaire. On the third dialysis session of the Run-in Period (Friday 
or Saturday), patients will complete the EQ-5D-5L-P questionnaire. Preferably, the 
patients will complete the sleep questionnaire followed by the EQ-5D-5L and then the 
EQ-PSO bolt on. Patients may continue to be trained on PRO questionnaires during the 
Run-in Period. 
The site has the option of starting the Run-in Period on the same day as the Screening 
Visit at the discretion of the Investigator. In these cases, all screening procedures should 
be conducted first, and then Run-in procedures should be conducted after confirmation of 
eligibility with exception of the lab results, which will be reviewed during the Run-in 
Period. 
6.1.1.3 
Treatment Period 
If patients continue to meet all inclusion and no exclusion criteria at the end of the Run-in 
Period, they will be able to start the Treatment Period and begin IV CR845 0.5 mcg/kg.   
Day 1 of the Treatment Period will be defined as the day of administration of the first dose 
of study drug and will occur on the first dialysis day of the first treatment week 
(ie, Monday for patients on a Monday-Wednesday-Friday dialysis schedule or Tuesday for 
patients on a Tuesday-Thursday-Saturday dialysis schedule).   
All scheduled study visits during the Treatment Period will be conducted on dialysis days. 
Patients will be administered CR845 as an IV bolus after the end of their dialysis, either 
during rinse back or after rinse back, during a Treatment Period of up to 12-week so that 
each patient will receive CR845 3 times weekly for a total of up to 36 doses. 
On Day 1, before the first dose of CR845, patients will complete the Worst Itching 
Intensity NRS, Sleep Quality, 5-D Itch, and Skindex-10 questionnaires.  
The Worst Itching Intensity NRS and Sleep Quality will also be completed at each dialysis 
session (Monday/Wednesday/Friday or Tuesday/Thursday/Saturday) during Week 12. In 
addition, the EQ-5D-5L-P questionnaire should be performed during the third dialysis 
session (Friday/Saturday) of Week 12. 
At the End of Treatment visit (the first dialysis session after last dose of CR845), patients 
will complete the Worst Itching Intensity NRS, Sleep Quality, 5-D Itch, and Skindex-10 
questionnaires preferably within one hour of starting dialysis. 
All questionnaires will be performed at Early Termination. 
On days when multiple questionnaires are to be completed, the following sequence should 
be adhered to: 
1. Itching Intensity NRS questionnaire  
2. Sleep Quality questionnaire 
3. 5-D Itch 
4. Skindex-10 


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5. EQ-5D-5L-P 
All questionnaires are to be completed preferably within one hour of starting dialysis but 
before the completion of dialysis. 
Clinical laboratory tests (see detail in Section 6.5.3.5) will be collected during first day of 
treatment and at End of Treatment or Early Termination Visit. Pre-dialysis vital signs will 
be monitored and recorded on the third dialysis session of the week for Week 1 and every 
four weeks after Week 1. Adverse events, infection assessment, and concomitant 
medications will be continuously recorded during the Treatment Period. 
Electrocardiograms (ECGs) will be monitored at the Screening Visit and at End of 
Treatment or Early Termination Visit. 
The number and reason(s) for missed dialysis, hospitalizations (including duration) and 
the use of antipruritic medications will be recorded throughout the study. 
End of Treatment or Early Termination is defined as the first dialysis day following the 
last dose of study drug.  
6.1.1.4 
Follow-up Visit  
Patients will have a final safety Follow-up Visit conducted 7-10 days after the Early 
Termination or End of Treatment Visit. 
 
The study schematic is shown in Figure 1. 
 
Figure 1. 
CR845-CLIN3105 Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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6.2 
Selection of Study Population 
Patients with ESRD receiving hemodialysis 3 times a week and experiencing 
moderate-to-severe pruritus will be considered for participation in this study. 
A screening log of potential study candidates will be maintained at each study site. 
Patients providing informed consent will be screened for inclusion in the study.  All 
eligibility criteria must be met before a patient receives the first dose of study medication.  
Rescreening will be considered on an individual patient basis and must first be approved 
by the Sponsor or designee.  However, rescreening will not be permitted if a patient 
missed the entry criteria for itch intensity, ie mean Worst Itching Intensity NRS score > 5. 
A patient can only be rescreened once. Rescreening can only occur after at least two 
weeks from original Screening Visit. 
6.2.1 
Eligibility Criteria 
To be eligible for inclusion into the study, a patient must meet the following criteria: 
1. Willing and able to provide written informed consent prior to participating in this 
study; 
2. Able to communicate clearly with the Investigator and staff, able to understand the 
study procedures, and able and willing to comply with the study requirements, 
including providing written responses to questionnaires; 
3. Male or female between 18 and 85 years of age; 
4. Has end-stage renal disease (ESRD) and has been on hemodialysis 3 times per 
week for at least 3 months prior to the start of screening; 
Note 1: Patients who require an occasional additional dialysis treatment to 
manage fluid overload or electrolyte excesses may be enrolled as long as it is 
anticipated that no more than 1 such treatment will be required in any given week. 
Patients routinely on 4 dialyses a week will not be eligible. 
Note 2: Patients receiving in-home hemodialysis may participate as long as they 
have switched to in-center hemodialysis at least 2 weeks prior to screening and 
plan to remain on in-center hemodialysis for the duration of the study.  
Note 3: Patients receiving alternate dialysis modalities such as nocturnal dialysis 
will not be eligible. 
5. If female, is not pregnant or nursing during any period of the study;  
6. If female: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for at least 1 year and is over the age of 55 years; 
or 
c. Has a negative serum pregnancy test within 7 days of administration of the 
first dose of study drug and agrees to use acceptable contraceptive 
measures (eg, hormonal contraceptives, barrier with spermicide, 
intrauterine device, vasectomized partner, or abstinence from heterosexual 


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intercourse) from the time of informed consent until 7 days after the last 
dose of study drug; 
7. If male, agrees not to donate sperm after the first dose of study drug until 7 days 
after the last dose of study drug, and agrees to use a condom with spermicide or 
abstain from heterosexual intercourse during the study until 7 days after the last 
dose of study drug;  
Note:  No restrictions are required for a vasectomized male provided his 
vasectomy was performed ≥4 months prior to screening.  
8. Has a prescription dry body weight ≥40 kg;  
9. Over the last three months prior to screening, has had at least one of the following: 
a. At least 2 single-pool Kt/V measurements ≥1.2 on different dialysis days;  
b. At least 2 urea reduction ratio measurements ≥65% on different dialysis 
days;  
c. 1 single-pool Kt/V measurement ≥1.2 and 1 urea reduction ratio 
measurement ≥65% on different dialysis days;  
10. Prior to treatment: 
a. Has completed at least three Worst Itching Intensity Numerical Rating 
Scale (NRS) questionnaires from the start of the Run-in Period up to and 
including the assessment on Day 1; 
b. Has a mean baseline Worst Itching Intensity NRS score > 5, defined as the 
average of all non-missing scores reported from the start of the Run-in 
Period up to and including the pre-dose assessment on Day 1. 
Exclusion Criteria: 
A patient will be excluded from the study if any of the following criteria are met: 
1. Known noncompliance with dialysis treatment that in the opinion of the 
Investigator would impede completion or validity of the study; 
2. Scheduled to receive a kidney transplant during the study; 
3. Known history of allergic reaction to opiates, such as hives;  
Note: side effects related to the use of opioids, such as constipation or 
nausea, would not exclude patients from the study. 
4. Hypersensitivity to the active substance or any of the excipients in the 
investigational products; 
5. Has a concomitant disease or a history of any medical condition that, in the 
opinion of the Investigator, could pose undue risk to the patient, impede 
completion of the study procedures, or would compromise the validity of the study 
measurements, including, but not limited to: 
a. Known or suspected history of alcohol, narcotic, or other drug abuse, or 
substance dependence within 12 months prior to screening; 
b. Significant systolic or diastolic heart failure (eg, New York Heart 
Association Class IV congestive heart failure [Appendix 1, Section 14.1]); 
c. Severe mental illness or cognitive impairment (eg, dementia); 


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d. Any other relevant acute or chronic medical or neuropsychiatric condition 
within 3 months prior to screening (eg, diagnosis of encephalopathy, coma, 
delirium); 
6. New or change of treatment received for itch including antihistamines and 
corticosteroids (oral, IV, or topical) within 14 days prior to screening; 
7. New or change of prescription for opioids, gabapentin, or pregabalin within 14 
days prior to screening; 
8. Received another investigational drug within 30 days or five half-lives (whichever 
is longer) prior to the start of dosing or is planning to participate in another 
interventional clinical study while enrolled in this study; 
9. In the opinion of the Investigator, has pruritus attributed to a cause other than 
ESRD or its complications (eg, patients with concomitant pruritic dermatological 
disease or cholestatic liver disease);  
Note: Patients whose pruritus is attributed to ESRD complications, such as 
hyperparathyroidism, hyperphosphatemia, anemia, or the dialysis 
procedure or prescription may be enrolled). 
10. Has localized itch restricted to the palms of the hands; 
11. Has pruritus only during the dialysis session (by patient report); 
12. Is receiving ongoing ultraviolet B treatment and anticipates receiving such 
treatment during the study; 
13. Participated in a previous clinical study with CR845. 
6.3 
Removal of Patients from Therapy or Assessment 
6.3.1 
Discontinuation of Individual Patients 
A patient may be withdrawn at any time and at the discretion of the Investigator or the 
Sponsor for safety, behavioural, compliance, or administrative reasons, including, but not 
limited to: 
• Lost to follow-up 
• Adverse event 
• Lack of therapeutic efficacy 
• Pregnancy 
• Eligibility (inclusion/exclusion criteria) 
• Patient non-compliance 
• Informed consent is withdrawn 
Whenever possible, withdrawal of a patient from study drug by the Investigator should be 
discussed with the Medical Monitor before the patient stops study drug.  
If study drug is discontinued, regardless of the reason, an Early Termination Visit should 
be completed at the first dialysis after the last dose of study drug or, if not feasible during 
that timeframe, as soon as feasible.  A Follow-up Visit should be completed 7-10 days 
after the Early Termination Visit.  


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A patient may withdraw from the study at any time at his/her own request. Although a 
patient will not be obliged to give a reason for withdrawing prematurely, the Investigator 
must make a reasonable effort to obtain the reason while fully respecting the patient’s 
rights.  The reason(s) for termination and date of stopping study drug must be recorded on 
the electronic case report form (eCRF) and source documents. 
If a patient discontinues early due to an adverse event, the event will be followed until 
resolution, the patient returns to baseline status, the condition stabilizes, or the patient is 
lost to follow-up. 
A patient will be considered lost to follow-up when no response is received from the 
patient after at least 3 documented attempts to contact the patient over a minimum time of 
2 weeks by the study site. 
If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data already collected before such a withdrawal of consent. 
6.3.2 
Discontinuation or Suspension of Entire Study 
The Sponsor may suspend or terminate the study or part of the study at any time for any 
reason. Reasons may include the following, among others: 
• Investigators have not been able to enroll patients within a reasonable period of 
time or according to inclusion/exclusion criteria; 
• The target number of patients required for the study is enrolled earlier than 
expected; 
• Unexpected safety concern.   
If the study is suspended or terminated, the Sponsor will ensure that applicable regulatory 
agencies and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) 
are notified, as appropriate.  
Should the study be closed prematurely, all study materials must be returned to the 
Sponsor or destroyed at the site according to instructions provided by the Sponsor, as 
applicable.  
6.4 
Treatments 
Detailed information on the study drug and its preparation, administration, storage, supply, 
disposition, and accountability can be found in the Pharmacy Manual. 
6.4.1 
Treatments Administered 
The study drug will be dispensed by qualified staff members who have received training 
on study drug handling and administration and as per local regulations.   
Patients will receive CR845 three times per week for up to 12 weeks, for a total of up to 
36 doses. CR845 will be administered as a 0.5 mcg/kg IV bolus into the venous line at the 
end of their dialysis, either during rinse back or after rinse back. If the study drug is 


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administered after rinse back, the line MUST be flushed with an additional 10ml normal 
saline to ensure study drug doesn’t get stuck in the line. 
Patients who require an extra hemodialysis session in a given week should receive an 
additional dose of CR845; if the extra session is ultrafiltration only, no additional CR845 
dose should be given. 
A maximum of four doses a week are allowed but patients who routinely receive 4 
dialysis/ultrafiltration treatments per week will not be eligible for the study. 
The patient’s prescription dry body weight (ie, the target post-dialysis weight at the end of 
screening, as determined by the Investigator) will be used to calculate the dose of the 
study drug to be administered during the Treatment Period. 
6.4.2 
Identity of Investigational Product(s) 
6.4.2.1 
Formulation of Study Drug 
Study drug will be supplied by the Sponsor as a solution in 2-mL glass vials containing a 
minimum extractable volume of 1.3 mL of CR845 at a concentration of 0.05 mg/mL in 
0.04 M isotonic acetate buffer, pH 4.5.  The composition of the CR845 solution is CR845 
(free base), acetic acid, sodium acetate trihydrate, sodium chloride, hydrochloric acid, and 
water for injection. 
6.4.2.2 
Packaging, Labeling, and Storage Stability of Study Drug 
Temperature will be monitored during shipment and verified and recorded by the 
pharmacist upon arrival at the site.  The vials must be stored per pharmacy manual defined 
guidelines upon receipt and the temperature will be monitored accordingly. Labeling of 
the vials and kits will conform to the regulations required by each country.  
Refer to the Pharmacy Manual for details.  
6.4.2.3 
Individual Dose Labeling 
One syringe will be prepared for each patient on each dosing day.  Syringes and syringe 
labels will be provided.   
Refer to the Pharmacy Manual for details. 
6.4.3 
Drug Accountability 
All supplies will be maintained under adequate security by the approved staff at the 
investigational site.  Study monitor will perform drug accountability on a regular basis.  
Details of study drug accountability are provided in the Pharmacy Manual.  
The Sponsor (or delegated person) will be permitted, at intervals and upon request during 
the study, to check the supplies, storage and dispensing procedures, and records. 


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6.4.4 
Preparation of CR845 
A single vial of CR845 will be used for patients with a prescription dry body weight 
≤135.0 kg.  For patients with a prescription dry body weight >135.0 kg, 2 vials of CR845 
will be used to ensure that the full volume of study drug can be prepared. The syringes can 
be prepared up to an hour in advance of dosing.    
Information on the study drug preparation can be found in the Pharmacy Manual. 
6.4.5 
Management of Missed Doses  
If a patient misses a dialysis visit, dosing of study drug should resume at the next dialysis 
visit.  
Contact the Medical Monitor if patient compliance or safety is of concern. 
6.4.6 
Treatment Compliance 
Patient compliance with study drug is documented as part of standard procedures at the 
dialysis units where study drug is administered.  
6.4.7 
Prior, Concomitant, and Prohibited Medications 
6.4.7.1 
Prior and Concomitant Medications 
Prior medications (including over-the-counter medications, vitamins and herbal 
supplements) are defined as those that the patient has taken any time during the 3 months 
prior to the first dose of study drug.  Concomitant medications are medications that are 
taken from after the first dose of study drug on Day 1 of the Treatment Period through the 
end of the Follow-up Visit.   
Use of antipruritic medications during the study will be recorded on an ongoing basis, 
starting at screening. Medications known for potential antipruritic effects but used for a 
different indication (ex. use of gabapentin for pain management) will not be reported as 
antipruritic medications.  
All prior and concomitant medications are to be recorded in the appropriate page of the 
eCRF, as applicable.  
6.4.7.2 
Restricted and Prohibited Medications 
During the Screening and Treatment Periods (as applicable), the following medications 
will be restricted or prohibited (Table 1). 


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Table 1. 
Restricted and Prohibited Medications  
Drug, Drug Class, or Treatment 
Restrictions During the Treatment Period 
Investigational drug (other than the study 
drug) 
Not allowed 
Ultraviolet B treatments 
Not allowed 
Naloxone, naltrexone, or mixed 
agonist-antagonists (eg, buprenorphine, 
nalfurafine and nalbuphine) 
Not allowed from screening to the end of the 
Treatment Period unless needed to treat an 
adverse event or emergent medical condition 
acutely (in this case, notify the study medical 
monitor and, as appropriate, report adverse 
events). 
Antihistamines (oral, IV, or topical) 
Corticosteroids (oral, IV, or topical) 
treatments 
Opioids 
Gabapentin, pregabalin 
Changes to current prescription are not 
allowed from screening to the end of the 
Treatment Period unless for the acute 
treatment of an adverse event or emergent 
medical condition (in this case, notify the 
study medical monitor and, as appropriate, 
report adverse events). 
No new medication to treat itch should be 
initiated during the Treatment Period. 
All new concomitant medications or change of frequency and doses of a concomitant 
medication will be recorded. 
 
6.5 
Study Assessments and Procedures 
6.5.1 
Schedule of Events for the Treatment Period 
Study procedures are summarized in Table 2.   
An ICF will need to be signed prior to initiation of the Screening Visit and any procedures 
that follow.  


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Table 2. 
Schedule of Events 
 
 
  
Screening Period  
(days) 
Treatment Period f (weeks) 
Early 
Termination 
Visit d 
End of 
Treatment 
Visit g  
Follow-
Up Visit 
Screening 
Visit  
Run-in  
Day -28 
to Day -7 
Day -7 to 
Day 1 
Week 1 
Week 5 
Week 9 
Week 12 
_ _ _ 
Week 13 
Week 13-
14 
 Procedures 
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria a 
X 
  
X 
  
  
  
  
  
  
Medical History/Demographic a,h 
X 
  
X 
  
  
  
  
  
  
Prior Medications a 
X 
X 
X 
  
  
  
  
  
  
Pre-dialysis 12-lead ECG b 
X 
  
  
  
  
  
X 
X 
  
Pre-dialysis Vital Signs c 
X 
  
X 
X 
X 
  
X 
X 
X 
Serum pregnancy (females of childbearing potential) e 
X 
  
  
  
  
X 
X 
  
Patient training on PRO worksheets 
X o 
X p 
X p 
  
  
  
  
  
  
Questionnaires i,j,k,l 
  
X  
X  
  
  
X  
X 
X 
  
Physical Exam 
X 
  
  
  
  
  
  
  
  
Prescription dry body weight 
X 
  
  
  
  
  
  
  
  
Hematology, serum chemistry (pre-dialysis) 
X 
  
X 
  
  
  
X 
X 
  
IV administration of study drug 
  
  
Dose after each dialysis up to W12 inclusive 
  
  
  
Adverse event monitoring m 
X 
X 
Record on an ongoing basis 
X 
X 
X 
Concomitant medications n 
  
  
Record on an ongoing basis 
X 
X 
X 
Record number of missed dialysis visits and reason(s)   
  
     Record on an ongoing basis  
 
Record of In-patient hospitalization and reason(s) 
           Record on an ongoing basis 
  
 


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a 
Medical history, demographic and prior medications will be recorded during screening and updated on Day 1 with any changes since the Screening Visit, and inclusion/exclusion 
criteria will be confirmed prior to starting treatment on Day 1 
b 
Electrocardiograms must be performed prior to the start of dialysis at screening and EOT/Early Termination Visit 
c 
Pre-dialysis (prior to start of dialysis) vital signs, including body temperature, heart rate, and blood pressure, will be recorded when the patient is in a sitting or semi-recumbent 
position on the third dialysis session (Fri/Sat) of the specified week.  Heart rate will be measured at each dialysis; if heart rate is clinically significant and outside the prespecified 
visits per the Schedule of Events, the heart rate will be recorded on the relevant CRF page 
d 
Early Termination procedures need to be performed following the first dialysis visit after the last study dose if the patient discontinues study prior to the completion of full 12-week 
treatment period  
e 
Serum pregnancy must be performed and resulted within 7 day prior to first study dose and should test for human chorionic gonadotropin (HCG) 
f 
Each visit during the Treatment Period will coincide with the patient’s normal dialysis treatments 
g 
The End-of-Treatment Visit will be the first dialysis visit following the last dose of study drug after the patient completed the treatment period of 12 weeks 
h 
In addition to providing a general medical history, patients will be specifically asked if they have conditions of special interest (ie, gait disturbance, fall, dizziness, somnolence, 
seizure, syncope, mental status changes, mood altered, feeling abnormal, tachycardia, and palpitations) and number of missed dialysis visits four weeks prior to Day 1 of run-in   
i 
Worst Itching Intensity NRS and Sleep quality questionnaires should be completed around the start of each dialysis visit (all three sessions) during the Run-In Period & Week12. 
They should also be performed on the first dialysis visit (Monday/Tuesday) during Week 1 & on the first dialysis visit after the last dose of CR845. Worst Itching Intensity NRS 
should be completed prior to the Sleep Quality Questionnaire.  
j 
Patients will be requested to complete their PRO questionnaires at a similar time (preferably within one hour of starting dialysis). The worksheets will be completed prior to or during 
dialysis, but must be completed prior to dosing 
k 
5-D Itch and Skindex-10 questionnaires should be completed at the first dialysis visit of Week 1 and on the first dialysis visit after the last dose of CR845. If the first visit of the week 
is missed, the patient may complete the worksheets at their next visit for the same week. Preferably, the 5-D Itch questionnaire is to be completed first. 
l 
EQ-5D-5L-P questionnaire should be completed around the start of the third dialysis visit of the Run-In Period and around the start of the third dialysis visit of week 12 
m 
Infections will be recorded as per standard procedures at the dialysis sites and reported on the adverse event eCRF page. Information pertaining to the nature of the infections will be 
collected 
n 
Concomitant medications including antipruritic medication will be updated at each dialysis visit until the end of the Follow-up Visit 
o 
Training on Worst Itching Intensity NRS, Sleep Quality, and EQ-5D-5L-P questionnaires will be conducted prior to the start of the Run-in Period 
p 
Training on 5-D Itch and Skindex-10 questionnaires may be performed at any time during Screening Period prior to treatment on Day 1 


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6.5.2 
Effectiveness Assessments 
The effect of CR845 on itch and itch-related quality of life and quality of sleep will be 
measured by means of the following PRO questionnaires:  
• Worst Itching Intensity NRS  
• Sleep Quality  
• Skindex-10  
• 5-D Itch  
• EQ-5D-5L-P 
Patients will be trained on completion of the Worst Itching Intensity NRS, Sleep Quality, 
and EQ-5D-5L-P questionnaires prior to the first visit of the Run-in Period, and will be 
trained on the other itch-related PRO measures at any time prior to dosing on Day 1 of 
the Treatment Period.  All questionnaires must be completed in strict adherence to the 
Training Manual for Patient Reported Assessments. Patients will be provided with these 
questionnaires to complete at the clinic on specific dialysis days per the schedule of 
events (Table 2).  
 
6.5.2.1 
Worst Itching Intensity Numerical Rating Questionnaire 
Intensity of itch will be measured using an NRS scale (Appendix 2, Section 14.2) on a 
worksheet on which patients will be asked to indicate the intensity of the worst itching 
they experienced over the past 24 hours by marking one of 11 numbers, from 0 to 10, that 
best describes it, where “0” is labeled with the anchor phrase “no itching” and “10” is 
labeled “worst itching imaginable.”   
The Worst Itching Intensity NRS has been widely utilized for evaluation of chronic itch, 
including pruritus in hemodialysis patients [Kumagai 2010; Pisoni 2006; Mathur 2010; 
Ständer 2013]. 
6.5.2.2 
Sleep Quality Questionnaire 
The impact of itch on patients’ quality of sleep will be measured using an NRS scale 
(Appendix 3, Section 14.3) on a worksheet on which patients will be asked to indicate 
how their itch interferes with their sleep over the past 24 hours by marking one of 11 
numbers, from 0 to 10, that best describes it, where “0” is labeled with the anchor phrase 
“did not interfere” and “10” is labeled “completely interfered”   
6.5.2.3 
Skindex-10 Questionnaire 
Developed specifically for pruritus associated with chronic kidney disease, the Skindex-
10 (Appendix 4, Section 14.4) is an instrument for measurement of quality-of-life that 
correlates with itch intensity [Mathur 2010].  Patients are asked to mark 1 of 7 boxes 




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• 12-lead ECGs 
• Clinical laboratory tests 
 
6.5.3.1 
Adverse Events 
Definition of Adverse Events 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigational patient administered a medicinal product and which does not necessarily 
have to have a causal relationship with this treatment.  An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
In this study, adverse events will be captured from the time a patient signs the ICF to the 
Follow-up Visit and include the following: 
• Any new sign, symptom, or disease; 
• Any new clinically significant or symptomatic laboratory/diagnostic test 
abnormality; 
• Any clinically significant worsening of laboratory/diagnostic test abnormality; 
• Any worsening (ie, clinically significant change in frequency, nature, and/or 
intensity) of a pre-existing condition.  
A pre-existing condition is a condition that is present prior to signing the ICF for the 
study.  Pre-existing conditions, such as illnesses, symptoms, reactions, progression of 
disease states, and other comorbidities, as well as laboratory/diagnostic test 
abnormalities, will be documented in the patient’s record as medical history. In addition 
to general history, patients will be specifically asked if they have a history of certain 
conditions including but not limited to gait disturbances, falls, dizziness, somnolence, 
seizures, syncope, mental status changes, mood alterations, palpitations and tachycardia.  
Signs and symptoms will be reported individually as adverse events (non-serious), unless 
a medical diagnosis was provided.  Medical diagnosis, whenever provided, will be 
reported rather than individual signs and symptoms.   
Any adverse event that satisfies any of the seriousness criteria described below will be 
reported as an SAE using the SAE Report Form, in addition to documenting in the eCRF.  
Serious adverse events that occurred up to 30 days after the last dose of study drug need 
to be documented on an SAE Report Form if they are deemed by the Investigator to be 
“Related” to study drug. 
An SAE that occurred after a period of 30 days from the last dose of study drug must be 
reported when the investigator becomes aware of it if there is a possible relationship to 
the study drug or the conduct of the study. 


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Adverse Event Severity Assessment 
The Investigator will assess the severity (ie, intensity) of each adverse event (serious and 
non-serious) reported during the study based on his/her clinical judgment.  The severity 
of each adverse event will be assigned to one of the following categories: 
Mild: 
Transient, requires no special treatment, is easily tolerated by the 
patient, causes minimal discomfort, and does not interfere with the 
patient’s daily activities 
Moderate: 
Introduces a level of inconvenience or concern to the patient that may 
interfere with daily activities, but usually is ameliorated by simple 
therapeutic measures 
Severe: 
Interrupts a patient’s usual daily activity and requires systemic drug 
therapy or other treatment 
 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
• Results in death; 
• Is life-threatening; 
NOTE:  The term "life-threatening" in the definition of "serious" refers to an 
event in which the patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were 
more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; or 
• Is a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization, but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These are usually considered serious. 
Severe versus Serious Adverse Event 
The term “severe” is used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  An adverse event as 
well as an SAE must be assessed for severity.  An adverse event that is assessed as severe 
should not be confused with an SAE.  “Severity” is not the same as “Serious,” which is 
based on patient outcome or reaction criteria usually associated with events that pose a 


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threat to a patient’s life or functioning.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
Adverse Event Causality or Relatedness to the Study Drug 
Every effort should be made by the Investigator to explain each adverse event and assess 
its relationship, if any, to study drug.  The Investigator should consider many factors, 
including, but not limited to, temporal association of the event and date/time of study 
drug, duration of study drug, medical/biologic plausibility, pharmacology and adverse 
event profile of study drug, medical history (past medical history, underlying disease, 
comorbidities, intercurrent illness), concomitant medications, medical judgment, 
dechallenge, rechallenge, drug interaction, other plausible causes, etc., to determine the 
causality assessment of an event.   
The Investigator as well as the Sponsor will determine adverse event/SAE causality as 
‘Related’ or ‘Not Related’ to study drug.  Although there is no international consensus on 
how to define ‘Related’ and ‘Not Related,’ in general, an event is considered ‘Related’ if 
there is reasonable possibility that the event is related to study drug rather than to any 
other possible cause(s).  Conversely, an event is considered ‘Not Related’ if there is 
reasonable possibility that the event is related to other factors than the study drug. 
Adverse Event Documentation and Follow-up 
All adverse events, including observed, elicited, or volunteered problems, complaints, or 
symptoms are to be recorded on the adverse event page in the patient’s eCRF from the 
time the patient signs the ICF and until the Follow-up Visit/early termination, whether or 
not judged by the Investigator to be related to study drug.  The need to capture this 
information is not dependent upon whether adverse events are related to study drug.  
Serious adverse events that occurred up to 30 days after the last dose of study drug need 
to be documented on an SAE Report Form if they are deemed by the Investigator to be 
“Related” to study drug. 
Each adverse event is to be documented with a verbatim/reported term, start and stop date 
and time, severity, causal relationship to study drug, action taken with study drug, and 
outcome (resolved, resolved with sequelae, resolving, fatal, unknown).  The Investigator 
must review new adverse events and the outcome of ongoing adverse events frequently 
throughout the study.  
In addition to recording all adverse events (serious and non-serious) in the patient’s 
eCRF, all SAEs must also be documented on the SAE Report Form for the study. 
The Investigator will follow all adverse events until they resolve, the Investigator 
assesses them to be stable, or the patient’s participation in the study ends, whichever 
comes first.  In addition, the Investigator will follow all adverse events assessed as related 
to study drug that are ongoing at the time of the patient’s last visit, until they resolve or 
the Investigator assesses them as stable, even if the patient's participation in the study has 
ended.  Resolution of such events is to be documented in the patient’s record as 
appropriate.  


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It is anticipated that some patients may undergo procedures and/or experience events that 
are common in the study population under investigation, independent of study therapy.  
Preplanned procedures and procedures (eg, kidney transplant, catheter replacement) or 
events that are independent of study therapy, according to the Investigator’s assessment, 
will be documented as specified in the Safety Management Plan.   
Serious Adverse Event Notification, Documentation, and Reporting 
The Investigator will report an SAE within 24 hours of becoming aware of the event.  An 
SAE Report Form will be completed regardless of relationship to the study drug.  The 
initial report will not be delayed in order to obtain additional information.  Any additional 
information will be reported as a follow-up to the initial report within 24 hours of 
collection. 
Details for reporting and follow-up of SAEs are provided in the ISF. 
In the event of any SAE (other than death) occurring after the last dose of study drug and 
prior to the Follow-up Visit, the patient will be instructed to contact the Investigator or 
designee immediately using the instructions provided on the ICF.   
The Medical Monitor will review reported SAEs and may contact the Investigator 
directly for further information. 
The Sponsor will comply with the applicable local regulatory requirements related to 
reporting of SAEs to the appropriate regulatory authorities in the countries and regions 
this study is conducted, while the Investigator and designated study personnel will 
comply with the applicable local regulatory requirements related to reporting of SAEs to 
the IRB/IEC and the Sponsor.   
It is the responsibility of the Sponsor or designee to send all regulatory reports to the 
appropriate regulatory authorities.  Adverse events that are serious, related to the study 
drug, and unexpected (per the Investigator’s Brochure) will be reported to the regulatory 
authorities as specified in the Safety Management Plan. 
As applicable, the Sponsor will also notify other participating Investigator(s) of SUSARs 
to ensure prompt notification of significant new adverse events or risks with respect to 
study drug.  This notification will occur as soon as possible and in compliance with 
country-specific regulations. 
Refer to the Safety Management Plan for further details about SAE reporting and 
processing.  The Medical Monitor should be contacted by study sites requiring additional 
clarification on an SAE. 
6.5.3.2 
Physical Examination 
Physical examinations at Screening will include an examination of the heart, lungs, 
abdomen, extremities, and neurological and vascular systems. Any findings should be 
reported in the medical history.   


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6.5.3.3 
Vital Signs 
Vital signs (sitting or semi-recumbent body temperature, heart rate, and blood pressure) 
will be measured prior to start of dialysis as per schedule presented in Table 2.   
Measurements will be repeated if a value is out of the reference range due to a technical 
issue, considered abnormal for the patient, or for other medical concerns.  Only the 
repeated measurement will be recorded. 
In the event of a clinically significant change in blood pressure and/or heart rate, the 
Investigator and dialysis staff will evaluate and manage the patient per standard dialysis 
unit practices with knowledge of the patient’s typical blood pressure and heart rate 
excursions. 
Heart rate will be collected at each dialysis; if clinically significant and outside the 
prespecified visits per schedule of events, the heart rate will be recorded on the relevant 
CRF page. 
6.5.3.4 
Electrocardiogram 
The 12-lead ECGs will be obtained prior to the start of dialysis and will be read locally 
by the Investigator or qualified designee as per schedule presented in Table 2.  
Electrocardiograms read by a qualified designee must be endorsed by the Investigator.  
Clinically significant abnormalities or worsening findings observed after the first dose of 
study drug will be reported as treatment-emergent adverse events (TEAEs).  
6.5.3.5 
Clinical Laboratory Tests 
Blood samples for clinical laboratory tests including hematology, serum chemistry, and 
serum pregnancy will be taken prior to dialysis as per schedule presented in Table 2 and 
will be analyzed by a central laboratory.  The laboratory tests include the following: 
Assessment 
Parameters to be analysed 
Serum Chemistry 
 
Albumin, Alkaline Phosphatase, ALT/SGPT, AST/SGOT, 
Bilirubin (Total), BUN, Calcium, Chloride, Creatinine, 
Glucose, Phosphorus, Potassium, Sodium 
Hematology 
Basophil %, Basophil (Absolute), Eosinophil %, Eosinophil 
(Absolute), Hematocrit, Hemoglobin, Lymphocyte %, 
Lymphocyte (Absolute), MCH, MCHC, MCV, Monocyte %, 
Monocyte (Absolute), Neutrophil %, Neutrophil (Absolute), 
Platelet, RDW, Red Blood Cells, White Blood Cells 


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Serum Pregnancy (females 
of childbearing potential 
only) 
Human chorionic gonadotropin (HCG) 
No more than 10 mL will be taken for each blood test. Processing and shipment of central 
laboratory samples will be described in the Laboratory Manual.  
6.5.3.6 
Contraception and Pregnancy 
All females of childbearing potential will have blood samples taken at Screening for 
serum pregnancy testing and at the end of the study as per Table 2.  Females are 
considered to be of childbearing potential unless they are:  
• Surgically sterile (ie, tubal ligation, bilateral oophorectomy, and/or 
hysterectomy); or 
• Over 55 years of age and have not had a menstrual period in at least 1 year 
Once they have consented to participate in the study, all women of childbearing potential 
will be counseled on the importance of avoiding pregnancy and on the need to practice 
adequate birth control for the duration of the study, from screening until 7 days after the 
last dose of study drug. 
Medically acceptable methods of birth control include abstinence, vasectomized partner, 
hormonal contraceptives for at least 1 cycle of treatment before study enrollment, an 
intrauterine device, and barrier with spermicide (eg, male or female condom, or 
diaphragm).  
Per inclusion criteria, male patients will agree not to donate sperm after the first dose of 
study drug until seven days after the last dose of study drug, and will agree to use a 
condom with spermicide or abstain from heterosexual intercourse during the study until 
seven days after the last dose of study drug.  No restrictions are required for a 
vasectomized male, provided his vasectomy was performed ≥4 months prior to dosing. If 
sexual abstinence is chosen by the patient, it must be the preferred and usual lifestyle of 
the patient and must be practiced for the entire duration of the study. 
Women will be counseled to contact the Investigator or his/her staff immediately if 
pregnancy is suspected.  Males will be instructed to report to the Investigator if their 
partner becomes pregnant during the study. 
If a patient becomes pregnant from start of treatment to seven days after the last dose of 
study drug, the Investigator will immediately discontinue the patient from the study and 
contact the Sponsor or designee.  Diligent efforts will be made to determine the outcome 
for all pregnancies in the clinical study.  Information on the status of the mother and the 
child will be forwarded to the Sponsor.  Generally, follow-up will occur within 6 to 
8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.  Both maternal and paternal exposure will be collected.  For 
exposure involving the female partner of a male patient, the necessary information must 


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be collected from the patient while respecting the confidentiality of the partner.  A 
pregnancy report will be completed. 
6.6 
Additional Assessments 
The following additional assessments will be collected during the Treatment Period: 
• Missed dialysis visits 
• Hospitalizations 
• Infections 
6.6.1.1 
Missed Dialysis Visits 
The number and reason(s) for missed dialysis will be recorded. 
6.6.1.2 
Hospitalization  
In-patient hospitalizations (including duration) will be collected on the SAE and eCRF 
forms.  
6.6.1.3 
Infections 
Infections will be recorded as per standard procedures at the dialysis sites and reported on 
the adverse event eCRF page. Additional information pertaining to the nature of the 
infections will be collected as applicable.   


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7.0 
Discussion and Justification of Study Design 
This is an open-label study designed to evaluate the safety and effectiveness of CR845 
0.5 mcg/kg IV administered after each dialysis session (generally 3 times per week for up 
to 12 weeks) in hemodialysis patients. This design is commonly used in clinical 
development to obtain additional safety information regarding a novel investigational 
drug.  
7.1 
Selection of Doses in the Study 
The combined safety, pharmacokinetic, and efficacy data from CR845-CLIN2101 
provided the basis for the selection of the dose and dose regimen of CR845 to be used in 
this study.  The lowest dose tested (0.5 mcg/kg IV) in CR845-CLIN2101 appeared to be 
well tolerated and effective at reducing itch intensity over a period of 8 weeks. 
 
7.2 
Appropriateness of Measurements 
Standard clinical, laboratory, and statistical procedures and methodology will be utilized 
in this study.  The PRO assessments to be used in this study are appropriate. 
 


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8.0 
Statistical Methods 
8.1 
General Considerations 
This section describes the statistical analysis of safety, effectiveness, and additional 
endpoints collected during the study.  
 
The statistical analysis plan (SAP) will provide a detailed description for the handling of 
missing data, patient eligibility criteria for the analysis, and statistical methodology. If 
differences occur between analyses of data described in the SAP and the current protocol, 
those found in the SAP will assume primacy.  
 
Unless otherwise noted, continuous variables will be summarized using number of 
non-missing observations, mean, standard deviation, median, minimum, and maximum; 
categorical variables will be summarized using the frequency count and the percentage of 
patients in each category. In addition to the descriptive summaries, pertinent data listings 
will be provided. 
 
All analyses will be performed using SAS® version 9.2 or higher, unless otherwise 
specified. 
8.2 
Determination of Sample Size 
Up to 400 male and female hemodialysis patients who have not been previously exposed 
to CR845 will be enrolled in this study.  No sample size calculation was performed to 
select this sample size.   
8.3 
Interim Analysis 
No interim analysis is planned.  However, an ongoing review of the cumulative safety 
data for this study will be conducted by the Sponsor or designee. 
8.4 
Analysis Populations 
The Enrolled population is defined as the group of patients who sign informed consent. 
The Safety population is defined as the group of patients who received at least 1 dose of 
CR845 in the study.  
The Full Analysis population is defined as the group of patients who received at least 1 
dose of CR845 and have least one non-missing effective endpoint assessment after 
baseline.  
All summaries and analysis of safety will be conducted using the Safety population. 
Effectiveness endpoints analysis will be conducted using the Full Analysis population. 
There will be two sets of analysis for the effectiveness endpoints: main analysis and 


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ancillary analysis.  Patients who complete the study and do not have missing data will be 
included in the main analysis.  Patients who either discontinue early or have missing data 
will be include in the ancillary analysis. 
 
8.5 
Statistical Summary and Analysis 
8.5.1 
Patient Disposition 
The number of patients who enrolled in the study, who received at least one dose of study 
drug, completed, or discontinued from the study drug prematurely, along with the reason 
for discontinuation, will be presented.  The percentage of patients who completed or 
discontinued will be based on the safety population.  
8.5.2 
Protocol Deviations 
Protocol deviations will be identified in several ways:  through programmatic checks, 
through medical reviews, and by clinical research associates during site monitoring.  
Protocol deviations will be classified as minor or major prior to the database lock.  Major 
protocol deviations will be summarized.  All protocol deviations will be listed.   
8.5.3 
Demographic and Baseline Characteristics 
Demographic and baseline patient characteristics to be summarized, will include age at 
screening, age category (<45, 45 to >65, 65 to <75, ≥75), gender, ethnicity, race, and 
prescription dry body weight (kg).   
Baseline characteristics of the disease to be summarized, will include variables such as 
etiology of chronic kidney disease, years since ESRD, duration of pruritus, and time on 
chronic hemodialysis. 
8.5.4 
Medical History 
Medical history data will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by MedDRA System Organ Class (SOC) and Preferred 
Term.  The data will also be listed, including the verbatim investigator description of the 
relevant medical condition, the coded terms (SOC, Preferred Term), start date, end date, 
and whether or not the condition is ongoing. 
A separate coding listing will be created with all the distinct levels of SOC, Preferred 
Terms, and the verbatim investigator description reported in the study.  Sorting will be 
alphabetically by SOC, Preferred Term, and then verbatim description. 
8.5.5 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary.  All 
prior and concomitant medications will be listed and summarized separately by 


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Anatomical Therapeutic Chemical class 3 (ATC 3) and Preferred Term.  Additionally, a 
coding listing of unique medications and their corresponding coding will be presented. 
8.5.6 
Antipruritic Medication 
Antipruritic medications are identified as medications where ‘Yes’ is checked on the 
Previous or Concomitant Medications CRF page to the question ‘Medication was given 
to treat pruritus’.   
Prior and concomitant antipruritic medications will be summarized separately. 
Summaries will be presented by ingredient rather than by ATC codes. 
8.6 
Effectiveness Endpoints and Analysis 
8.6.1 
Endpoints 
24-hour Worst Itching Intensity NRS score 
• Change from baseline in the weekly mean of the 24-hour Worst Itching 
Intensity NRS score to Week 12. 
• Proportion of patients achieving >0, ≥1, ≥2, ≥3, and ≥4-point improvement 
from baseline with respect to the weekly mean of the daily 24-hour Worst 
Itching Intensity NRS at Week 12. 
Sleep Quality Questionnaire 
• Change from baseline in the weekly mean of the 24-hour Sleep Quality score 
to Week 12.   
5-D Itch and Skindex-10 Questionnaires 
• Change from baseline in itch-related quality of life to Week 12 as assessed by 
the 5-D Itch total score and each 5-D Itch individual questions. 
• Change from baseline in itch-related quality of life to Week 12 as assessed by 
the total Skindex-10 total score and each Skindex-10 subdomain score 
(disease, mood/emotional distress, social functioning). 
EQ-5D-5L Questionnaire 
• Proportion of patients with reported problems by level (1 to 5) and EQ-5D-5L 
dimension will be summarized at baseline and Week 12. 
• Proportion of patients with no problems (i.e. with a level 1 response) by EQ-
5D-5L dimension will be summarized at baseline and Week 12. 
• Overall Self-Rated Health Status EQ VAS will be summarized (mean, SD, 
median, Q25-Q75) at baseline and at Week 12 along with the change from 
baseline.   


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• Patients health state will be expressed using the 5 dimensions: mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression.  Each 
dimension is evaluated using 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems.  Response to these 5 
dimensions will be converted into 1 of 3125 unique EQ-5D-5L health state 
descriptions, which ranges between no problems on all 5 dimensions (11111) 
to extreme problems on all 5 dimensions (55555).  The patients’ health state 
will be displayed in a listing.  
EQ-PSO Questionnaire 
• Proportion of patients with reported problems by level (1 to 5) and EQ-PSO 
dimension will be summarized at baseline and Week 12. 
• Proportion of patients with no problems (i.e. with a level 1 response) by EQ-
PSO dimension will be summarized at baseline and Week 12. 
8.6.2 
Analysis 
The weekly mean of the 24-hour Worst Itching Intensity NRS score at Week 12 will be 
defined as the sum of the Worst Itching Intensity NRS scores collected on each dialysis 
visit of Week 12 and on the first dialysis visit of Week 13, divided by the number of days 
with non-missing scores for that week.  The baseline score will be defined as the average 
of the daily 24-hour Worst Itching Intensity NRS scores collected over the Run-in Period, 
including assessments collected on Day 1 prior to the first dose of the Treatment Period.  
For the analysis of NRS, if the 24-hour daily Worst Itching Intensity score is missing for 
>2 dialysis during the collection period on Weeks 12 and 13 then the corresponding 
weekly mean worst itching score will be set to missing.  
Summary statistics (n, mean, SD, min, max) for the weekly mean of the 24-hour Worst 
Itching Intensity NRS score at baseline and at Week 12 of the Treatment Period along 
with the change from baseline will be produced. In addition, the change from baseline in 
the weekly mean of the 24-hour Worst Itching Intensity NRS score to Week 12 
Treatment Period will be analyzed using analysis of covariance (ANCOVA).  The model 
will contain baseline score as covariate.  LS means, standard errors, and 95% confidence 
intervals (CI) derived from the model will be presented. The same procedure will be used 
to analyse Sleep Quality. 
The proportion of patients who have an improvement from baseline with respect to the 
weekly mean of the daily 24-hour Worst Itching Intensity NRS score >0, ≥1, ≥2, ≥3, and 
≥4 points at Week 12 will be analysed using a logistic regression model containing 
baseline NRS score.  A figure presenting the proportion of patients who have an 
improvement from baseline in NRS scores at Week 12 that is >0, ≥1, ≥2, ≥3, and ≥4 will 
be prepared.  
The 5-D Itch and the Skindex-10 questionnaires total score and domains/individual 
questions will be summarized using summary statistics and analysed using a ANCOVA 


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as described for the 24-hour Worst Itching Intensity NRS score. For the analysis of 5-D 
Itch and the Skindex-10 scores, missing scores will not be imputed. 
It is important to note that, in HD patients, the study drug administered during the last 
dialysis of a particular week does not begin to be cleared until the first dialysis of the next 
week.  Therefore, measurements that would reflect treatment effect at the end of a 
specific week (eg. Week 12) will actually be collected during the first day of the next 
week (eg, Week 13). 
Counts and percentages of subjects for each response will be reported as well as a count 
of subjects with missing values. 
8.7 
Safety Analysis 
Analysis of all safety data collected during the Treatment Period will be performed on the 
Safety Population.  The SAP will provide further detail for the analyses to be applied to 
each safety parameter.  No statistical hypothesis testing will be carried out and no 
inferential statistical analysis of the safety parameters will be performed.  
The baseline value for all analyses of Treatment Period safety parameters will be defined 
as the last value obtained prior to the first dose of study drug and will include both 
scheduled and repeat (unscheduled) observations. 
8.7.1 
Exposure to Study Drug and Compliance 
For this study, the duration of treatment for each individual patient may be up to 12 
weeks, for a total of up to 36 doses of study drug administered immediately following 
each dialysis session.  Day 1 of the Treatment Period will be defined as the day of 
administration of the first dose of study drug.  The last day of the Treatment Period will 
be defined as the day of the dialysis session immediately following the last injection of 
study drug. 
Exposure and treatment compliance during the Treatment Period will be summarized by 
the following parameters: 
• Duration of treatment (days) 
• Total number of doses actually received  
• Number of missed doses 
Duration of treatment (days) = (date of first dialysis after last dose) – (date of first dose) 
+ 1. 
If a patient receives additional dialysis during a given week for any reason, an additional 
dose of CR845 will be administered following dialysis.  A maximum of 4 doses per week 
is allowed if an infrequent occurrence.  No additional doses will be given for patients 


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receiving an additional unscheduled ultrafiltration treatment.  The number of patients 
getting such an extra treatment will be summarized. 
8.7.2 
Adverse Events 
All adverse events, as reported by the site, will be coded using MedDRA to MedDRA 
SOC and Preferred Term for standardization and summary purposes. 
All reported adverse events (whether or not treatment-emergent) will be included in a 
by-patient adverse event listing.  Only TEAEs will be included in summary tables. 
Adverse events that are considered “treatment emergent” relative to the Run-in Period are 
identified as any adverse event with an onset date after the start of the Run-in Period and 
up to the first dose of study drug. 
Adverse events that are considered “treatment emergent” relative to the Treatment Period 
are identified as any adverse event with an onset date after the first dose of the study drug 
up to the Follow-up Visit or Early Termination Visit (or 7 days after the last dose if no 
Early Termination Visit was conducted), whichever is later. 
The number and percentage of patients experiencing TEAEs will be summarized.  A 
patient will be counted only once in the incidence count for a MedDRA SOC or Preferred 
Term, although a patient may have multiple occurrences (start and stop) of an event 
associated with a specific MedDRA Preferred Term or SOC.  The most frequent TEAEs 
(≥5% of patients) will also be tabulated by SOC and Preferred Term. 
The incidence and percentage of patients experiencing treatment-emergent SAEs and 
TEAEs leading to study discontinuation will be presented by the appropriate MedDRA 
SOC and Preferred Term.  Adverse events that result in death will also be summarized. 
Treatment-emergent adverse events will also be summarized by severity and by 
relationship to study drug.  If the severity and/or relationship to the study drug of an 
adverse event is missing, a worst-case scenario will be assumed (ie, the adverse event 
will be categorized as “severe” and/or “related” to the study drug).  If a patient reports the 
same TEAE multiple times the event with the worst severity and the strongest 
relationship to study drug will be tabulated. 
An overall summary table will be provided including the number and percentage of 
patients with an adverse event (both treatment and non-treatment emergent), a TEAE, 
serious TEAE, related TEAE, severe TEAE, TEAE leading to dose interruption, and 
TEAE leading to study drug discontinuation.  This table will also include the number of 
events for each specific Preferred Term.  
Separate tables summarizing the incidence of AESIs will be presented for Run-In and 
Treatment Period. Selected preferred terms will be determined prior to database lock and 
combined into the following categories:  
• Gait disturbance                     
• Fall 


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• Dizziness 
• Somnolence 
• Seizure 
• Syncope 
• Mental status changes 
• Mood altered 
• Feeling abnormal  
• Tachycardia 
• Palpitations 
All adverse events will be listed in chronological order, including patient identifier, age, 
race, gender, a flag indicating whether the event was treatment-emergent, and all related 
event status information (start and stop dates, whether the event was ongoing, study day 
of onset, severity, seriousness, relationship to study medication, action taken with study 
treatment, and outcome).  Separate listings will be generated for SAEs, deaths, and 
adverse events leading to study drug discontinuation.  Additionally, a coding list of 
Preferred Terms and the verbatim text associated with them will be produced. 
8.7.3 
Clinical Laboratory Evaluations 
Summary statistics for each scheduled time point measured and mean changes from 
baseline to each time point (when applicable) will be presented for clinical laboratory 
results.   
All laboratory evaluation summaries will include the patients in the Safety Population 
who have at least 1 postbaseline time point (for criteria based on postbaseline 
assessments) and with both a baseline and at least 1 postbaseline time point (for criteria 
evaluating changes from baseline). 
Laboratory values will be reported in Système International units.   
Laboratory test results will be assigned an L/N/H classification according to whether the 
value was below (L), within (N), or above (H) the laboratory parameter’s reference range.  
Comparisons will be based on 3×3 tables (shift tables) that, for a particular laboratory 
test, compare the baseline L/N/H classification to the highest and/or lowest L/N/H 
classification during the Treatment Period.  Clinically important laboratory values based 
on prespecified criteria defined in the SAP will also be summarized. 
Additionally, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline 
phosphatase will be presented in a separate listing, with 3× and 5×ULN flagged for 
alanine aminotransferase and aspartate aminotransferase; 2×ULN flagged for bilirubin, 
and 1.5×ULN flagged for alkaline phosphatase. 
8.7.4 
Vital Signs and ECGs 
Summary tables will include descriptive statistics for baseline and each postbaseline 
assessment.  Descriptive statistics will be calculated on both the actual score and the 


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change from baseline score.  Baseline is defined as the last measurement taken on or prior 
to the first day of dosing.  Note that the Day 1 assessment can be included in the 
evaluation of baseline if that the assessment is performed prior to dosing.  
If two or more evaluations occur in the same visit window, the evaluation closest to the 
target visit day will be selected for inclusion in the analysis.  If multiple evaluations are 
equally close to the target visit day, then the latest evaluation will be selected for 
inclusion in the analysis.   
All vital sign summaries will include the patients in the Safety Population who have at 
least a postbaseline time point (for criteria based on postbaseline assessments) and with 
both a baseline and at least one postbaseline time point (for criteria evaluating changes 
from baseline). 
Clinically notable vital signs will be identified based on the criteria defined in the SAP.  
For each vital sign parameter, the number and percentage of patients with at least one 
notable value will be tabulated by week and overall for the Treatment Period. 
All vital signs will be listed in by-patient listings, including visit and collection date/time, 
and will be sorted by patient identifier and date/time of assessment.   
Electrocardiogram results include an overall interpretation of ‘normal,’ ‘abnormal but not 
clinically significant,’ or ‘abnormal and clinically significant.’  These results will be 
tabulated at each time point.   
Electrocardiogram results will be listed for each visit, including visit, whether ECG was 
performed (yes/no), explanation (if not performed), assessment date/time, study date, 
overall interpretation, and relevant medical history number or adverse event number, if 
deemed a clinically significant abnormality. 
8.8 
Additional Analyses 
8.8.1 
Missed Dialysis Visits, Hospitalizations and Incidence of Infection  
The number and percentage of patients who missed one or more dialysis visits during the 
Treatment Period, and the total number of missed dialyses visits will be tabulated.   
Incidence of infections based on adverse events and/or use of antibiotics for treatment of 
infection overall or related to pruritus will be presented. 
The number and percentage of patients hospitalized during the Treatment Period, and the 
total number of hospitalization days will be tabulated.   
 


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9.0 
Quality Control and Quality Assurance 
9.1 
Study Monitoring Plan 
Monitoring and auditing procedures that comply with current Good Clinical Practice 
(GCP) guidelines will be followed, including but not limited to remote and onsite review 
of the eCRFs via an electronic data capture system for completeness and clarity, source 
document verification, evaluation of protocol adherence, appropriate documentation of 
informed consent procedures, safety reporting, study drug storage, and dispensation.  The 
study will be monitored by the Sponsor or its designee (contract research organization).  
Monitoring will be performed by a representative of the Sponsor or its designee (site 
monitor) who will review patient enrollment, eCRFs, source documents, drug 
accountability records, and reporting and recording of adverse events.  The site monitor 
will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent site visits and communications (letter, telephone, and 
facsimile). 
The site monitor(s) will follow written standard operating procedures as agreed with the 
contract research organization and the Sponsor.  The site monitor(s) will verify that the 
clinical study is conducted and data are generated, documented (recorded), and reported 
in compliance with the protocol, GCP, and the applicable regulatory requirements.  
Monitoring reports will be submitted to the Sponsor in a timely fashion as per details 
described in a clinical monitoring plan for this study. 
Name and contact information for monitors will be included in the ISF. 
9.2 
Audits and Inspections 
The investigational site will maintain appropriate medical and research records for this 
study, in compliance with ICH-GCP, regulatory, and institutional requirements for the 
protection of confidentiality of participants.  The Investigator must allow access to 
authorized persons or institutions to complete data source verification.  Source data are 
all information, original records of clinical findings, observations, or other activities in a 
clinical study necessary for the reconstruction and evaluation of the study.  Examples of 
these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participants’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
participant files and records kept at the pharmacy, laboratories, or medical-technical 
departments involved in the clinical study, as applicable.  
The investigational site will provide access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor 
and inspection by local and regulatory authorities. 


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9.3 
Data Collection, Validation, and Analysis 
A data management vendor will ensure that quality assurance procedures are 
implemented, beginning with the data entry system and generation of data quality control 
checks that will be run on the database.   


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10.0 
Ethics and Regulatory Compliance 
10.1 
Independent Ethics Committee or Institutional Review Board 
A properly constituted, valid IRB/IEC, and the national regulatory authority, if required 
by the applicable laws in the country must review and approve the protocol, the 
Investigator’s Brochure, ICF, and related patient information and recruitment materials 
(if applicable) before the start of the study.  It is the responsibility of the Investigator to 
ensure that written informed consent is obtained from the patient before any activity or 
procedure is undertaken that is not part of routine care. 
The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the patients.  The study will only be conducted at a site 
where IRB/IEC approval has been obtained.   
If it is necessary to amend the protocol and/or ICF during the course of the study, the 
Investigator must ensure that the IRB/IEC/the national regulatory authority, if required by 
the applicable laws in the country reviews and approves these amended documents.  
Except for changes necessary to eliminate an immediate hazard to study patients, or when 
the change involves only logistical or administrative aspects of the study (eg, change in 
monitor, change of telephone number), no amendments to the study protocol will be 
made without the prior written agreement of the Sponsor and acknowledgement by the 
Investigator and, as applicable, the IRB/IEC/the national regulatory authority, if required 
by the applicable laws in the country.  
The Investigator(s) will maintain documentation of the composition of the IRB/IEC as 
well as all correspondence with the IRB/IEC.  The Investigator(s) will comply with local 
requirements for routine reporting to the IRB/IEC as well as local and government 
requirements for notifying the IRB/IEC of SAEs.  The Investigator will provide the 
Sponsor or its designee copies of all IRB/IEC approval notices, correspondence, annual 
reports, and final study progress reports. 
10.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 2013), FDA (CFR, Sections 312.50 and 312.56), EU (536/2014) and 
UK regulations (The Medicines for Human Use [Clinical Trials] Regulations 2004 
[No.1031]), ICH GCP (CPMP 135/95), and with the applicable regulations of the 
countries in which the study is conducted. 
The Investigator will be thoroughly familiar with the appropriate use of the study drug as 
described in the protocol, Investigator’s Brochure, and any other study-related manual(s).  
Essential clinical documents will be maintained to demonstrate the validity of the study 
and the integrity of the data collected.  A study master file must be established for the 
study, and retained according to the appropriate regulations. 


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10.3 
Informed Consent Process 
Informed consent is required for all patients participating in this study.  In obtaining and 
documenting informed consent, the Investigator must comply with applicable regulatory 
requirements and must adhere to GCP regulations.  It is the responsibility of the 
Investigator to ensure that written informed consent is obtained from the patient before 
any activity or procedure is undertaken that is not part of routine care. 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and that continues throughout the individual’s study participation.  
The Investigator or designee will discuss extensively with the participant patient the 
study risks.  Copies of the current, IRB/IEC-approved ICF detailing the risks and benefits 
of study participation will be provided to the participants.  Consent forms describing in 
detail the study drug and study procedures/intervention and risks will be fully explained 
to the patient and written documentation of informed consent will be required prior to 
starting participation in the study.  Upon reviewing the document, the Investigator or 
designee will explain the research study to the participant and answer any questions that 
may arise.  The participants will sign the ICF prior to any procedures being performed 
specifically for the study.  The participants should have sufficient opportunity to discuss 
the study and process the information in the consent process prior to agreeing to 
participate.  The participants may withdraw consent at any time throughout the course of 
the study.  A signed copy of the ICF will be given to the participants for their records. 
Participants must be re-consented to the most current version of the ICF during their 
participation in the study. 
10.4 
Patient Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study 
reports, and communications will identify the patient by assigned patient number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and 
regulatory authority(ies) access to the patient’s original medical records for verification 
of data gathered on the eCRFs and to audit the data collection process.  The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. 
Participant confidentiality is strictly held in trust by the participating Investigators, their 
staff, and the Sponsor(s) and their agents.  This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information 
relating to participating patients. 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence.  No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including, but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. 


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11.0 
Data Handling and Quality Assurance 
All participant data relating to the study will be recorded on eCRFs unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  No data are to be recorded 
directly in the eCRFs (eg, all data will have a unique source).  The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 2 years after the marketing approval of the study 
drug or after discontinuing clinical development unless local regulations or institutional 
policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the Sponsor.  No records may be 
transferred to another location or party without written notification to the Sponsor.  If the 
Investigator withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person willing to accept the responsibility.  If a custodial change or a 
change in record location occurs, the Sponsor must be notified in writing. 


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12.0 
Administrative Procedures 
12.1 
Protocol Adherence 
It is vital to the success of the study that the Investigator adhere to the details of the 
protocol, and thus to keep to a minimum the number of cases later classified as 
“incomplete,” “unusable,” or “not evaluable.”  If, in the interest of safety and/or 
well-being of a particular patient, it is necessary to depart from the protocol, then that 
protocol deviation will pertain to that individual patient only and will be documented.  
Protocol deviations due to lack of patient compliance must also be documented.   
The site monitor will review protocol deviations throughout the course of monitoring 
visits and document new findings of deviations.  The monitor will notify the Investigators 
of deviations verbally or in writing.  The IRB/IEC should be notified of all protocol 
deviations in a timely manner according to IRB/IEC requirements. 
12.2 
Publication of Study Findings 
All information regarding CR845 provided by Sponsor to the Investigator is privileged 
and confidential information.  By conducting this study, the Investigator affirms to the 
Sponsor that he/she will maintain, in strict confidence, information furnished by the 
Sponsor, including data generated from this study, except as exempted for regulatory 
purposes.  All data generated during the conduct of this study are owned by Sponsor.  
The Investigator agrees to use the information to conduct the study and will not use it for 
other purposes without written permission from Sponsor.  Partial or full data or results 
from this study cannot be published without express written consent from Sponsor.  It is 
understood that there is an obligation to provide Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used toward 
the development of CR845 and may be disclosed to regulatory authority, other 
Investigators, corporate partners, or consultants, as required. 


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13.0 
References 
Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. Edition Number 9. Little, Brown & 
Co; Boston, Mass: 1994. pp. 253–6. 
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical 
trials: IMMPACT recommendations. Pain. 2005;113(1-2):9–19. 
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus.  
Br J Dermatol. 2010;162(3):587-93. 
Guidance for Industry. Determining the extent of safety data collection needed in late-
stage premarket and postapproval clinical investigations. US Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER). February 
2016. 
Investigator’s Brochure. CR845 (Difelikefalin). Edition Number 8. 7 November 2017. 
Kimmel M, Alscher DM, Dunst R, et al. The role of micro-inflammation in the 
pathogenesis of uraemic pruritus in haemodialysis patients. Nephrol Dial Transplant. 
2006;21(3):749-55. 
Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H. Effect of a 
novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 
337 haemodialysis patients:  a Phase III, randomized, double-blind, placebo-controlled 
study. NDT. 2010;25(4):1251-7. 
Mathur VS, Lindberg J, Germain M, et al. A longitudinal study of uremic pruritus in 
hemodialysis patients. Clin J Am Soc Nephrol. 2010;5(8):1410-9. 
Mettang T, Pauli-Magnus C, Alscher DM. Uraemic pruritus-new perspectives and 
insights from recent trials. Nephrol Dial Transplant. 2002;17(9):1558-63. 
Narita I, Alchi B, Omori K, et al. Etiology and prognostic significance of severe uremic 
pruritus in chronic hemodialysis patients. Kidney Int. 2006;69(9):1626-32. 
Patel TS, Freedman BI, Yosipovitch G. An update on pruritus associated with CKD. 
Am J Kidney Dis. 2007;50(1):11-20. 
Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: prospective study on 
validity and reliability of the visual analogue scale, numerical rating scale and verbal 
rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92(5):502-7. 
Pisoni RL, Wikstrom B, Elder SJ, et al.  Pruritus in haemodialysis patients: International 
results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial 
Transplant. 2006;21(12):3495-505. 


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Swinburn P, Lloyd A, et al. Development of a Disease-Specific Version of the EQ-5D-5L 
for Use in Patients Suffering from Psoriasis: Lessons Learned from a Feasibility Study in 
the UK. Value in Health. 2013;16:1156-62 
Ständer S, Augustin M, Reich A, et al. Pruritus Assessment in clinical trials: consensus 
recommendations from the International Forum for the Study of Itch (IFSI) Special 
Interest Group Scoring Itch in Clinical Trials. Acta Derm Venereol. 2013;93(5):509-14. 
Tey HL, Yosipovitch G. Targeted treatment of pruritus: a look into the future. Br J 
Dermatol. 2011;165(1):5-17. 


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14.0 
Appendix 
14.1 
Appendix 1:  New York Heart Association Classification of Heart 
Failure 
 
[Criteria Committee of the New York Heart Association 1994] 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 




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14.3 
Appendix 3:  Sleep Quality Questionnaire 
This is a representation of the content of the instrument to be used.  Please refer to the 
Study Reference Manual for the instrument to be administered to patients and 
instructions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
 
 
 
 
 








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14.6 
Appendix 6:  EQ-5D-5L-P Questionnaire  
This is a representation of the content of the instrument to be used.  Please refer to the 
Study Reference Manual for the instrument to be administered to patients and 
instructions. 
 
EQ-5D-5L: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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EQ VAS: 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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EQ-PSO Bolt on: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 1 of 48 
 
STATISTICAL ANALYSIS PLAN 
 09 March 2020 Final 
 
 
 
 
 
AN OPEN LABEL, MULTICENTER, STUDY TO EVALUATE THE SAFETY 
AND EFFECTIVENESS OF INTRAVENOUS CR845 IN HEMODIALYSIS 
PATIENTS WITH MODERATE-TO-SEVERE PRURITUS 
 
 
 
 
 
PROTOCOL NUMBER CR845-CLIN3105 
 
 
 
 
 
 
 
SPONSORED BY 
 
Cara Therapeutics, Inc. 
4 Stamford Plaza 
Stamford, CT 06902 
Telephone:  (203) 406-3700 
 
 
PREPARED BY 
 
Rho, Inc. 
2635 E NC Hwy 54 
Durham, NC 27713 
Telephone:  (919) 408-8000 
Fax: (919) 408-0999 
 
 
 
This document is confidential and proprietary to Cara Therapeutics. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be reproduced, published, 
or otherwise disclosed without the prior written approval of Cara Therapeutics, except that this document 
may be disclosed to appropriate Institutional Review Boards under the condition that they keep the 
information confidential. 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 2 of 48 
DOCUMENT VERSION CONTROL 
Version 
Number 
Date 
Comments/Changes 
1.0 
13 December 2019 
 
1.1 
09 March 2020 
 SMQ analyses removed 
 Correction to potassium normal range and 
hemoglobin units 
 Added AE analyses by region 
 Added WI-NRS and Sleep Questionnaire 
analyses by region 
 Removed ANCOVA and logistic regression 
 Minor edits and clarifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 5 of 48 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 7 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 9 
2. 
PROTOCOL SUMMARY ........................................................................................ 10 
2.1 
Study Objectives ......................................................................................... 10 
2.2 
Overall Study Design and Plan ................................................................... 10 
2.2.1 
Screening Period ............................................................................... 10 
2.2.2 
Treatment Period ............................................................................... 10 
2.3 
Study Population ......................................................................................... 11 
2.4 
Treatment Regimens................................................................................... 11 
2.5 
Treatment Group Assignments or Randomization ....................................... 12 
2.6 
Sample Size Determination ......................................................................... 12 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 13 
3.1 
Assessment Time Windows ........................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 15 
5. 
STUDY SUBJECTS ............................................................................................... 16 
5.1 
Disposition of Subjects ................................................................................ 16 
5.2 
Protocol Deviations ..................................................................................... 16 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 17 
6.1 
Demographic Characteristics ...................................................................... 17 
6.2 
Baseline Characteristics .............................................................................. 17 
6.3 
Medical History ........................................................................................... 18 
6.4 
Prior and Concomitant Medications ............................................................. 18 
6.4.1 
Prior Medication ................................................................................. 18 
6.4.2 
Concomitant Medication .................................................................... 19 
6.4.3 
Anti-itch Medication ........................................................................... 19 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 20 
8. 
EFFECTIVENESS EVALUATION .......................................................................... 22 
8.1 
Overview of Effectiveness Analysis Issues .................................................. 22 
8.1.1 
Handling of Dropouts or Missing Data ................................................ 22 
8.1.2 
Multicenter Studies ............................................................................ 22 
8.1.3 
Assessment Time Windows ............................................................... 22 
8.1.4 
Multiplicity Handling ........................................................................... 22 
8.2 
Effectiveness Variables ............................................................................... 22 
8.2.1 
WI-NRS Score ................................................................................... 24 
8.2.2 
Sleep Quality Questionnaire .............................................................. 26 
8.2.3 
5D-Itch Scale ..................................................................................... 26 
8.2.4 
Skindex-10 ......................................................................................... 27 
8.2.5 
EQ-5D-5L-P ....................................................................................... 28 
8.2.5.1 
EQ-5D Descriptive System .................................................... 28 
8.2.5.2 
EQ VAS ................................................................................ 29 
8.2.5.3 
EQ-PSO ................................................................................ 29 
9. 
SAFETY EVALUATION ......................................................................................... 31 
9.1 
Overview of Safety Analysis Methods ......................................................... 31 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
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9.2 
Adverse Events ........................................................................................... 31 
9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 33 
9.4 
Clinical Laboratory Evaluation ..................................................................... 34 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 35 
9.5.1 
Vital Signs .......................................................................................... 35 
9.5.2 
12-Lead Electrocardiograms .............................................................. 36 
10. OTHER ANALYSES .............................................................................................. 37 
10.1 
Hospitalizations, Emergency Department Encounters ................................. 37 
10.2 
Missed Dialysis Visits and Incidence of Infection ......................................... 37 
11. INTERIM ANALYSES AND DATA MONITORING ................................................. 38 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 39 
13. STATISTICAL APPENDIX ..................................................................................... 40 
14. REFERENCES ....................................................................................................... 41 
15. APPENDICES ........................................................................................................ 42 
15.1 
Schedule of Events ..................................................................................... 42 
15.2 
Custom MedDRA Query (CMQ) Categories and Preferred Terms .............. 44 
15.3 
Treatment-emergent Adverse Events of Special Interest and Preferred 
Terms ......................................................................................................... 48 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 7 of 48 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AESI 
adverse event of special interest 
CI 
confidence interval 
CKD 
chronic kidney disease 
CMQ 
Custom MedDRA Query 
CRF 
case report form 
ECG 
electrocardiogram 
ESRD 
end-stage renal disease 
EQ-5D-5L 
5-level EQ-5D version 
EQ-5D-5L-P 
EQ-PSO 
EQ VAS 
EQ-5D-5L with EQ-PSO bolt-on 
EQ Pruritus Bolt-on 
EQ visual analogue scale 
H 
above laboratory reference range 
IV 
intravenous or intravenously 
L 
below laboratory reference range 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
within laboratory reference range 
QALY 
quality-adjusted life year 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WI-NRS 
Worst Itching Intensity numerical rating scale 
 
 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 8 of 48 
LIST OF IN-TEXT TABLES 
Table 1 
Effectiveness Variables ................................................................. 23 
Table 2 
Schedule of Events ....................................................................... 42 
 
 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 9 of 48 
1. 
PURPOSE OF THE ANALYSES 
CR845-CLIN3105 is an open-label, multicenter study to evaluate the safety and 
effectiveness of IV CR845 in hemodialysis subjects with moderate-to-severe pruritus.  
Treatment with IV CR845 at a dose of 0.5 mcg/kg is administered after each dialysis 
session over a Treatment Period of up to 12 weeks.  This study is sponsored by Cara 
Therapeutics, Inc. (“Sponsor”). 
This statistical analysis plan (SAP) provides a detailed description of the strategy and 
statistical methodology to be used for analysis of data in the CR845-CLIN3105 protocol.  
The purpose of the SAP is to ensure the credibility of the study findings by 
pre-specifying the statistical approaches to the analysis of study data prior to database 
lock.  This analysis plan is meant to supplement the study protocol.  If differences occur 
between analyses described in the SAP and the current protocol, those found in this SAP 
will assume primacy.  Any deviations from this plan will be described in the Clinical 
Study Report. 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
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2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
The primary objective of the study is to evaluate the safety of IV CR845 at a dose of 
0.5 mcg/kg in hemodialysis subjects with moderate-to-severe pruritus.  The secondary 
objectives are to evaluate the effectiveness of IV CR845 at a dose of 0.5 mcg/kg in 
reducing the intensity of itch in hemodialysis subjects with moderate-to-severe pruritus 
and in improving itch-related quality-of-life and quality of sleep measures in 
hemodialysis subjects with moderate-to-severe pruritus.    
2.2 
Overall Study Design and Plan 
This is a multicenter, open-label study to evaluate the safety and effectiveness of 
IV CR845 at a dose of 0.5 mcg/kg administered after each dialysis session.  This study 
will consist of a Screening Period and an up to 12-week Treatment Period.  The 
Screening Period includes a Screening Visit and a Run-In Period.  After the completion 
of the Treatment Period, subjects will be required to complete a Follow-up Visit. 
2.2.1 Screening Period 
The Screening Visit will occur within 21 days prior to the start of the Run-in Period.  The 
site has the option of starting the Run-in Period on the same day as the Screening Visit at 
the discretion of the investigator. 
Subjects will start the Run-in Period during the week prior to the Treatment Period to 
complete eligibility verification.  The Run-in Period will start on the first dialysis session 
of that week (ie, Monday for subjects on a Monday-Wednesday-Friday dialysis schedule 
or Tuesday for subjects on a Tuesday-Thursday-Saturday dialysis schedule).  The 
primary purpose of the Run-in Period is to confirm that each subject has 
moderate-to-severe pruritus (ie, weekly average Worst Itching Intensity Numerical 
Rating Scale (WI-NRS) ≥5) and to establish a baseline itch intensity.  
If subjects continue to meet all inclusion criteria and none of the exclusion criteria by the 
end of the Run-in Period, they will enter the Treatment Period of the study.   
2.2.2 Treatment Period 
Day 1 of the Treatment Period will be defined as the day of administration of the first 
dose of study drug and will occur on the first dialysis day of the first treatment week.  
Each subject will receive CR845 at a dose of 0.5 mcg/kg after each dialysis session, 
3 times per week for up to 12 weeks and up to 36 doses of study drug.  All scheduled 
study visits during the Treatment Period will be conducted on dialysis days.  Subjects 
will be administered CR845 as an IV bolus after the end of their dialysis, either during 
rinse back or after rinse back.   


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 11 of 48 
Hospitalizations, infections, missed dialysis sessions, clinical laboratory tests, 
electrocardiograms (ECGs), vital signs, adverse events, and concomitant medications will 
be monitored throughout the study.  
End of Treatment is defined as the first day of dialysis following the last dose of drug and 
will be considered the last day of the Treatment Period.  The End of Treatment 
procedures will be conducted at the dialysis visit following the last dose.   
A final safety Follow-up Visit will be conducted 7 to 10 days after the End of Treatment 
or Early Termination Visit.  
The study schematic is shown below: 
 
2.3 
Study Population 
The study population includes males and females between 18 and 85 years of age, 
inclusive, with end-stage renal disease (ESRD) who have been on hemodialysis 3 times 
per week for at least 3 months prior to start of screening, have moderate-to-severe 
pruritus (mean baseline WI-NRS score ≥5 with at least 3 worksheets completed from the 
start of the Run-in Period up to and including the pre-dose assessment on Day 1), and 
meet additional eligibility criteria.  A full list of the inclusion and exclusion criteria can 
be found in the CR845-CLIN3105 protocol (v2.0 12FEB2019). 
Subjects providing informed consent will be screened for inclusion in the study; all 
eligibility criteria must be met before a subject receives the first dose of study drug.  
Rescreening will be considered on an individual-subject basis and must first be approved 
by the Sponsor or Medical Monitor, provided that rescreening will not be permitted if a 
subject misses the entry criteria for itch intensity.  A subject can only be rescreened once, 
and rescreening can only occur after at least 2 weeks from original Screening Visit.   
2.4 
Treatment Regimens 
Subjects will be administered 0.5 mcg/kg CR845 as a single IV bolus 3 times a week 
after each dialysis session for up to 12 weeks.  Subjects who require an extra 
hemodialysis session in a given week should receive an additional dose of CR845, unless 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 12 of 48 
the extra session is ultrafiltration only.  A maximum of 4 doses a week are allowed, but 
subjects who routinely receive 4 dialysis/ultrafiltration treatments per week will not be 
eligible for the study. 
2.5 
Treatment Group Assignments or Randomization 
As this is an open-label, single-arm treatment study, all subjects will be assigned to a 
dose of 0.5 mcg/kg, and no randomization will occur.   
2.6 
Sample Size Determination 
Approximately 200 male and female hemodialysis subjects with moderate-to-severe 
pruritus will be enrolled in this study at approximately 50 U.S. and non-U.S. clinical 
sites.  No sample size calculation was performed to select this sample size. 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the 
data from the study.  Departures from these general policies may be given in the specific 
detailed sections of this SAP.  When this situation occurs, the rules set forth in the 
specific section take precedence over the general policies. 
Treatment groups:  All subjects will receive open-label CR845 0.5 mcg/kg; thus displays 
will present tabulations of all subjects in a single column. 
For categorical variables, summary statistics will consist of the number and percentage of 
subjects in each category.  All percentages will be rounded to 1 decimal point.  The 
number and percentage of subjects will always be presented in the form XX (XX.X%) 
with the percentage in parentheses.  To ensure completeness, all summaries for 
categorical and discrete variables will include all categories, even if none of the subjects 
had a response in a particular category.  Unless otherwise noted, for all percentages, the 
number of subjects in the specified analysis population will be the denominator. 
For continuous variables, summary statistics will consist of the number of subjects with 
data, mean, median, standard deviation, minimum value, and maximum value.  The 
summary statistic n will be the number of subjects with non-missing values.  All means 
and medians will be reported to 1 more significant digits than the values being analyzed. 
Standard errors will be reported to 2 more significant digits than the values being 
analyzed.  The minimum and maximum will be reported to the same number of 
significant digits as the values being analyzed. 
No formal hypothesis tests are planned; however, should they be performed as part of 
exploratory and ad hoc analyses, the associated P value will be reported.  All P values 
will be rounded to 3 decimal places; P values that round to 0.000 will be presented as 
“<.001”.  No leading zero will be shown for P values.  P values will be considered 
descriptive in nature; there will be no adjustments for multiple comparisons.  
In general, and unless otherwise specified, the baseline value will be considered the last 
non-missing measurement observed prior to the first dose of study drug  
Data from all sites will be pooled for the purpose of analysis. 
In general, listings will be sorted in the order that columns are displayed, starting with the 
first column on the left (treatment).  Subject listings of data will be presented for all 
enrolled subjects unless specified otherwise. 
SAS statistical software, version 9.4 or higher, will be used for all analyses. 
3.1 
Assessment Time Windows 
Assessments collected by study week that are collected at the Early Termination Visit or 
unscheduled visits will be assigned to a planned visit window, if the Early Termination 
Visit or unscheduled visit day falls between ±3 days of the planned visit.  Exceptions to 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
Page 14 of 48 
this assignment include the Week 13 visit, which will use a window of +1/-3; Day 1, 
which is anchored by the first dose; run-in WI-NRS and Sleep Quality scores, which will 
be assigned to the nearest planned visit; and where otherwise specified in this SAP.   
Should more than 1 measurement fall within a visit window, priority will be given first to 
the measurement with a non-missing value in the following order:  first the scheduled 
assessment, second to an Early Termination Visit, and then the unscheduled assessment 
closest to the planned day.  In the case that 2 unscheduled visits are equidistant, the latest 
will be used.   
This rule will be applied to both effectiveness and safety endpoints. 
   
 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
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4. 
ANALYSIS POPULATIONS 
The Enrolled Population is defined as the group of subjects who signed informed consent. 
The Safety Population is defined as the group of subjects who received at least 1 dose of 
CR845 in the study.  
All summaries and analyses of safety, effectiveness and additional endpoints will be 
conducted using the Safety Population. 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number of subjects enrolled, screen failed, treated, completed, or discontinued from 
the study treatment, along with the reasons for treatment discontinuation and screen 
failure, will be presented.  Subjects completing follow-up will also be presented.  The 
number of subjects included the Safety Population will also be tabulated. 
The following definitions apply to the afore-mentioned groups: 
 Enrolled subjects are all subjects who signed informed consent (see Section 4).  
 Subjects who failed screening are all subjects who failed screening due to 
inclusion/exclusion criteria and are marked as such on the disposition CRF.  
Subjects who fail screening and are rescreened and enrolled will be counted both 
here and with the applicable outcome of their successful enrollment.  Those who 
screen fail twice will be counted only once here; their reported reasons for failure 
will be from their final failure. 
 Treated subjects are all subjects who received at least 1 dose of study drug. 
 Treatment completers are treated subjects with “Yes” noted for the question “Did 
the Subject complete the Treatment Period?” on the Study Completion Status case 
report form (CRF) page.  
 Subjects who discontinued the treatment are subjects with “No” noted for the 
question “Did the Subject complete the Treatment Period?” on the Study 
Completion Status CRF page.  Reasons for treatment discontinuation are also 
collected on this CRF. 
 Follow-up completers are treated subjects with “Yes” noted for the question “Did 
the Subject complete the Follow-up Visit?” on the Study Completion Status CRF 
page.  
 Safety Population includes any treated subject (see Section 4). 
For all categories of subjects (except for enrolled subjects and screen failure subjects), 
percentages will be calculated using the number of subjects in the Safety Population as 
the denominator. 
 
5.2 
Protocol Deviations 
Protocol deviations will be identified in several ways:  through programmatic checks, 
through medical reviews, and by clinical research associates during site monitoring. 
Deviations will be classified as minor or major prior to the database lock.  Protocol 
deviations/violations will be summarized.  All protocol deviations will be listed. 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN3105 
 
09 March 2020 
Version:  CARA_CR845-CLIN3105_final_v1_1_SAP_20200309.docx 
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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics are collected during the Screening Visit. 
Descriptive statistics will be provided for all demographic and baseline characteristics 
based on the Safety Population.  For categorical variables, the number and percentage of 
subjects in each category will be presented.  For continuous variables, summaries will 
include the number of subjects with data, mean, median, standard deviation, minimum, 
and maximum. 
All demographic and other baseline characteristics will be provided in a listing. 
6.1 
Demographic Characteristics 
Demographic and baseline variables will be summarized and include the following: 
 Age at screening (years) as recorded on the CRF 
 Age category at screening (<45, 45-<65, 65-<75, ≥75 years) 
 Gender 
 Ethnicity  
 Race  
 Target dry body weight (kg) 
 Country 
 Region: USA, Western (Canada, UK, Germany, Australia, New Zealand), Eastern 
EU (Poland, Hungary, Romania, Czech Republic), Asia (Taiwan, South Korea) 
 
6.2 
Baseline Characteristics 
Baseline characteristics of the disease will also be summarized and include the following: 
 Prior anti-itch medication use 
 Duration of pruritus (years) 
 Years since diagnosis of ESRD 
 Years since diagnosis of chronic kidney disease (CKD) 
 Years on chronic hemodialysis 
 Etiology of CKD 
 Baseline WI-NRS Score 
 Dialysis type 
 Dialysis type by region 
 
 


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09 March 2020 
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Duration of pruritus (years) will be calculated as: 
(Date of the Screening Visit – the start date of the pruritus + 1)/365.25 
Similarly, years since diagnosis of ESRD will be calculated as: 
(Date of the Screening Visit – first date of ESRD diagnosis + 1)/365.25  
Years since diagnosis of CKD will be calculated as: 
 (Date of the Screening Visit – first date of CKD diagnosis + 1)/365.25 
Years on chronic hemodialysis will be calculated as: 
(Date of the Screening Visit – date of first chronic hemodialysis + 1)/365.25 
For each of the above, if partial dates are recorded, the first day of the month will be 
imputed for missing day, and January for missing month. 
The baseline WI-NRS score is defined as the average of the WI-NRS scores collected 
over the Run-in Period starting at Day -7, including assessments collected on Day 1 prior 
to the first dose of the Treatment Period.   Subjects should provide at least three NRS 
values in the period from Day -7 to Day 1; however, if fewer are present in the data, any 
available values will be used for establishing the baseline. 
6.3 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.0 and summarized by MedDRA System Organ Class (SOC) and 
Preferred Term.  The data will also be listed, including the verbatim investigator 
description of the relevant medical condition, the coded terms (SOC, preferred term), 
start date, end date, and whether or not the condition is ongoing. 
A separate coding listing will be created with all the distinct levels of SOC, preferred 
terms, and the verbatim investigator description reported in the study.  Sorting will be 
alphabetically by SOC, preferred term, and then verbatim description. 
6.4 
Prior and Concomitant Medications 
All medications, including any anti-itch medications, are recorded at screening, and the 
record is updated at each dialysis visit until the end of the Follow-up Visit.  These will be 
coded using the March 2019 World Health Organization Drug Dictionary.  All prior and 
concomitant medications will be listed.  Additionally, a listing for unique medications 
and their corresponding coding will be presented. 
6.4.1 Prior Medication 
Prior medications (including vitamins and herbal supplements) are defined as 
medications collected on the Previous or Concomitant Medications CRF page that the 
subject has taken any time during the last 3 months prior to the first dose of study drug on 


Cara Therapeutics 
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09 March 2020 
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Day 1.  If the medication started prior to treatment start date, but was ongoing or ended 
after treatment start date, the medication will be counted as both prior and concomitant.  
Prior medications will be summarized in a table using the Safety Population.  
Medications will be reported by drug class (Anatomical Therapeutic Chemical Level 3) 
and ingredient; a subject will be counted only once for each medication.  In the case of 
partial dates, if the available information is consistent with a date prior to the first dose, 
then the medication will be included on the summary of prior medications. 
6.4.2 Concomitant Medication  
Concomitant medications are defined as medications collected on the Previous or 
Concomitant Medications CRF page that are taken (regardless of when they started) from 
after the start of the first dose of study drug on Day 1 through the end of the study (ie, 
Follow-Up Visit).  Concomitant medications will be summarized for the Safety 
Population.  Medications will be reported by drug class (Anatomical Therapeutic 
Chemical Level 3) and ingredient; a subject will be counted only once for each 
medication.  In the case of partial dates, if the available information is consistent with 
dates overlapping with the period study drug was taken, then the medication will be 
included on the summary of concomitant medications. 
6.4.3 Anti-itch Medication 
Anti-itch medications are identified as medications where “Yes” is checked on the 
Previous or Concomitant Medications CRF page to the question “…Medication was 
given to treat pruritus?” or if “Pruritus” was listed on the CRF page under “Other 
Indication”.    
The prior and concomitant medication summaries described in Sections 6.4.1 and 6.4.2 
will be repeated for the anti-itch medications but will be reported by ingredient only and 
not by drug class.   


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09 March 2020 
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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
For this study, the duration of treatment for each individual subject is expected to be 
12 weeks, for a total of approximately 36 doses of study drug administered immediately 
following each dialysis session.   
The following variables will be summarized:  
 Duration of treatment (days)  
 Duration of study, from first dose to end of participation date (days) 
 Average dose per administration (mcg/kg)  
 Total number of doses actually received (1-3, 4-6, 7-9, etc.) 
 Number of missed doses  
 Total number of dialysis visits logged (1-3, 4-6, 7-9, etc.) 
 Number of missed dialysis visits 
 Total treatment exposure in subject-years 
 % Compliance (Doses) 
 % Compliance (Dialyses) 
 Number of subjects with extra doses 
 Number of subjects with extra dialysis visits 
 
Duration of treatment (days) = [(Date of first dialysis after last dose) – (Date of first dose) 
+ 1]. 
Duration of study (days) = [(End of participation date, including follow-up) – (Date of 
first dose) + 1].   The end of participation date is derived as the latest of the last visit date, 
the last drug exposure, the latest disposition date, or the death date.  If the subject has a 
death date, any later dates in the database are ignored. 
Subject-years = Duration of treatment (days) of all subjects divided by 365.25. 
 
% Compliance (Doses) = 100* {1 – [number of missed doses / (number of actual doses + 
number of missed doses – number of extra doses)]}. 
  
% Compliance (Dialyses) = 100* {1 – [number of missed dialysis visits / (number of 
actual dialysis visits + number of missed dialysis visits – number of extra dialysis 
visits)]}. 
If a subject receives additional dialysis during a given week for any reason, an additional 
dose of CR845 will be administered following dialysis.  A maximum of 4 doses per week 
is allowed.  No additional doses will be given for subjects receiving an additional 
unscheduled ultrafiltration treatment.  The number of subjects getting such an extra 
treatment will be summarized. 


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Missed and extra doses/dialysis will be determined as follows: 
1. Individual weeks for each subject are examined. 
2. Each subject should have 3 doses per week up to Week 12.  Anything more will 
be counted as extra doses; anything less will be counted as missed doses. 
3. Subjects who do not complete through Week 12 will be checked for how far they 
were into the week that they discontinued:  1 or 2 days means that they should 
have 1 dose; 3 or 4 days = 2 doses; 5 or more days = 3 doses.  This will be 
compared with actual doses for that week to determine missed/extra. 
4. The missed and extra doses are then summed across each subject’s weeks to get 
the total missed and extra doses/dialysis. 


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8. 
EFFECTIVENESS EVALUATION 
8.1 
Overview of Effectiveness Analysis Issues 
8.1.1 Handling of Dropouts or Missing Data 
Missing data will not be imputed.  Data from subjects who terminated prematurely will 
be included in any analyses for which their data is available, unless otherwise specified.  
Further details on the methodological approaches to handling missing data will be 
provided in Section 8.2. 
8.1.2 Multicenter Studies 
Data from all sites will be pooled for the purpose of analyses.  
8.1.3 Assessment Time Windows 
The assessment time windows in Section 3.1 will be applied to the effectiveness 
endpoints, unless otherwise specified in the relevant subsections of Section 8.2. 
8.1.4 Multiplicity Handling 
No adjustments for multiple comparison will be made. 
8.2 
Effectiveness Variables 
Table 1 presents a summary of the study effectiveness variables.  
 


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Table 1 
Effectiveness Variables 
Effectiveness Variables  
Summary 
Statistics  
24-hour WI-NRS Score 
 
Change from baseline in the weekly mean of the 24-hour WI-NRS score to Week 12 
X 
Percentage of subjects achieving >0, ≥1, ≥2, ≥3, ≥4, ≥5 and ≥6-point improvement from baseline with respect to the weekly 
mean of the 24-hour WI-NRS at Week 12  (with ≥3- and ≥4- point improvement also reported by region) 
X 
Sleep Quality Questionnaire 
 
Change from baseline in the weekly mean of the 24-hour Sleep Quality score to Week 12 
X 
Percentage of subjects achieving >0, ≥1, ≥2, ≥3, ≥4, ≥5 and ≥6-point improvement from baseline with respect to the weekly 
mean of the 24-hour Sleep Quality Score at Week 12  (with ≥3- and ≥4- point improvement also reported by region) 
X 
5-D Itch Scale and Skindex-10 Scale 
 
Change from baseline in itch-related quality of life to Week 12 as assessed by the 5-D Itch Scale total score and each 5-D 
Itch Scale individual domain 
X 
Change from baseline in itch-related quality of life to Week 12 as assessed by the total Skindex-10 total score and each 
Skindex-10 subdomain score (disease, mood/emotional distress, social functioning) 
X 
EQ-5D-5L-P Questionnaire 
 
Percentage of subjects with reported problems by level (1 to 5) and EQ-5D-5L dimension at baseline and Week 12 
X 
Percentage of subjects with no problems (ie, with a level 1 response) by EQ-5D-5L dimension at baseline and Week 12 
X 
QALY weight at baseline and Week 12 
X 
Overall Self-Rated Health Status EQ VAS at baseline and at Week 12, along with the change from baseline   
X 
Subject’s health state expressed using the 5 EQ-5D dimensions:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression 
X 
Percentage of subjects with reported problems by level (1 to 5) by EQ-PSO dimension at baseline and Week 12 
X 
Percentage of subjects with no problems (ie, level 1) by EQ-PSO dimension at baseline and Week 12 
X 
EQ-5D-5L = 5-level EQ-5D version; EQ-5D-5L-P = EQ-5D-5L with EQ-PSO; EQ-PSO = EQ Pruritus Bolt-on; EQ VAS = EQ visual analogue scale; WI-NRS = Worst 
Itching Intensity numerical rating scale


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This study uses the following 5 instruments to assess effectiveness: 
 
 WI-NRS  
 Sleep Quality 
 5D-Itch Scale 
 Skindex-10  
 EQ-5D-5L-P 
 
The following effectiveness endpoints are derived from these instruments: 
 
 Change from baseline in the weekly mean of the 24 hour WI-NRS score to 
Week 12 
 Percentage of subjects achieving >0, ≥1, ≥2, ≥3, ≥4, ≥5 and ≥6-point 
improvement from baseline with respect to the weekly mean of the 24-hour 
WI-NRS at Week 12 
 Change from baseline in the weekly mean of the 24-hour Sleep Quality score 
to Week 12 
 Percentage of subjects achieving >0, ≥1, ≥2, ≥3, ≥4, ≥5 and ≥6-point 
improvement from baseline with respect to the weekly mean of the 24-hour 
Sleep Quality score at Week 12 
 Change from baseline in itch-related quality of life to Week 12 as assessed by 
the 5-D Itch total score and each 5-D Itch domain score 
 Change from baseline in itch-related quality of life to Week 12 as assessed by 
the total Skindex-10 total score and each Skindex-10 subdomain score 
 Percentage of subjects with reported problems by level (1 to 5) and by 5-level 
EQ-5D version (EQ-5D-5L) dimension at baseline and Week 12 
 Percentage of subjects with no problems (ie, with a level 1 response) by 
EQ-5D-5L dimension at baseline and Week 12 
 Overall Self-Rated Health Status EQ visual analogue scale (VAS) at baseline 
and at Week 12, along with the change from baseline 
 Subjects’ health state expressed using the 5 EQ-5D-5L dimensions  
 Percentage of subjects with reported problems by level (1 to 5) and by EQ 
Pruritus Bolt-on (EQ-PSO) dimension at baseline and Week 12 
 Percentage of subjects with no problems (ie, with a level 1 response) by 
EQ-PSO dimension at baseline and Week 12 
 Quality-adjusted life year (QALY) weights using the United States value set  
 
No primary efficacy endpoint will be defined.  All effectiveness analyses will be 
performed on the Safety Population. 
 
8.2.1 WI-NRS Score 
Intensity of itch will be measured using the 24-hour WI-NRS (see Appendix 2 of the 
protocol).  Subjects will indicate on a worksheet the intensity of the worst itching they 
experienced over the past 24 hours by marking 1 of 11 numbers, from 0 to 10, that best 


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describes the intensity, where “0” is labeled with the anchor phrase “no itching” and “10” 
is labeled “worst itching imaginable.”   
The baseline WI-NRS score is defined as the average of the 24-hour WI-NRS scores 
collected over the Run-in Period, including assessments collected on Day 1 prior to the 
first dose (see Section 6.2).  The Week 12 WI-NRS score is defined as the sum of the WI-
NRS scores collected on each dialysis visit of Week 12 and on the first dialysis visit of 
Week 13, divided by the number of days with non-missing scores over the same time 
period.   
WI-NRS scores will be collected on dialysis visits during the Run-in Period, on Day 1, on 
dialysis visits during Week 12, and on the Early Termination Visit or the End of 
Treatment Visit.  A subject is expected to have 3 dialysis visits a week; therefore, a total 
of 4 scores are expected to contribute to each of the baseline WI-NRS score and the 
Week 12 WI-NRS score.  WI-NRS scores collected at the Early Termination Visit or 
unscheduled visits will contribute to the Week 12 WI-NRS Score if collected from Day 
76 to Day 86, inclusive.  WI-NRS scores collected at unscheduled visits during the Run-
in Period will be assigned to the nearest planned visit.  If >4 scores are collected in each 
of these respective time periods, the extra score(s) will be factored into the calculation of 
the baseline WI-NRS score or the Week 12 WI-NRS score, as applicable.   
If the WI-NRS scores are missing for >2 dialysis visits during the collection period on 
Week 12 through the first dialysis visit of Week 13, then the Week 12 WI-NRS score will 
be set to missing.  If a subject terminates treatment prematurely, but has at least 1 non-
missing scores collected during that period, the Week 12 WI-NRS score will not be set to 
missing. 
According to the protocol, the subject must have ≥3 non-missing WI-NRS scores from 
the start of the Run-in Period up to and including the assessment on Day 1 to be eligible 
for the study (ie, at most 1 score may be missing).  Regardless, a subject’s baseline WI-
NRS score will only be set to missing if the subject is missing >2 scores collected during 
this baseline collection period. 
Summary statistics (n, mean, standard deviation, minimum, maximum) for the baseline 
WI-NRS score and the Week 12 WI-NRS score will be produced, along with the change 
from baseline.  Missing values will not be imputed. 
The count and percentage of subjects who have an improvement from baseline of >0, ≥1, 
≥2, ≥3, ≥4, ≥5 and ≥6 points at Week 12 will be reported.  The count and percentage of 
subjects with an improvement from baseline of ≥3 and ≥4 points at Week 12 will also be 
reported by region.  A figure presenting the percentages of subjects who have an 
improvement from baseline of >0, ≥1, ≥2, ≥3, ≥4, ≥5 and ≥6 points at Week 12 will also 
be prepared.  
Individual WI-NRS scores will be presented in a by-subject listing. 


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It is important to note that, in patients undergoing hemodialysis, the study drug 
administered during the last dialysis of a particular week does not begin to be cleared 
until the first dialysis of the next week.  Therefore, measurements that would reflect 
treatment effect at the end of a specific week (eg, Week 12) may actually be collected in 
part or in whole during the first day of the next week (eg, Week 13). 
8.2.2 Sleep Quality Questionnaire 
The impact of itch on subjects’ quality of sleep will be measured using the Sleep Quality 
Questionnaire which utilizes a numeric rating scale (see Appendix 3 of the protocol).  
Subjects will indicate on a worksheet how their itch interferes with their sleep over the 
past 24 hours by marking 1 of 11 numbers, from 0 to 10, that best describes the 
interference, where “0” is labeled with the anchor phrase “did not interfere” and “10” is 
labeled “completely interfered.” 
The baseline Sleep Quality score is defined as the average of the Sleep Quality scores 
collected over the Run-in Period, including assessments collected on Day 1 prior to the 
first dose.  The Week 12 Sleep Quality score is defined as the sum of the Sleep Quality 
scores collected on each dialysis visit of Week 12 and on the first dialysis visit of Week 
13, divided by the number of days with non-missing scores over the same time period.   
The Sleep Quality Questionnaire will be administered on the same days as the WI-NRS 
(see Section 8.2.1).  The same rules as in Section 8.2.1 for missing and extra scores will 
be applied to the management of Sleep Quality scores.   
Summary statistics (n, mean, standard deviation, minimum, maximum) for the baseline 
Sleep Quality score and the Week 12 Sleep Quality score will be produced, along with 
the change from baseline.  
The percentages of subjects who have an improvement from baseline of >0, ≥1, ≥2, ≥3, 
≥4, ≥5 and ≥6 points at Week 12 will be analyzed and presented in the same manner as 
that for the WI-NRS scores presented in Section 8.2.1.  The count and percentage of 
subjects with an improvement from baseline of ≥3 and ≥4 points at Week 12 will also be 
reported by region. 
Individual Sleep Quality scores will be presented in a by-subject listing. 
8.2.3 5D-Itch Scale 
The 5-D Itch Scale was developed as a brief but multidimensional questionnaire designed 
to be useful as an outcome measure in clinical trials.  The 5 dimensions of itch assessed 
are degree, duration, direction, disability, and distribution (see Appendix 5 of the 
protocol).  
The duration, degree, and direction domains each include 1 item, while the disability 
domain has 4 items.  All items of the first 4 domains were measured on a 5-point Likert 
scale.  The distribution domain includes 16 potential locations of itch, including 15 body 
part items and 1 point of contact with clothing or bandages.  Single-item domain scores 


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(duration, degree, and direction) are equal to the value indicated below the response 
choice (range 1–5).  The disability domain includes 4 items that assess the impact of 
itching on daily activities:  sleep, leisure/social activities, housework/errands, and 
work/school.  The score for the disability domain is achieved by taking the highest score 
on any of the 4 items.  For the distribution domain, the number of affected body parts is 
tallied (potential sum 0–16), and the sum is sorted into 5 scoring bins:  sum of 0–2 = 
score of 1, sum of 3–5 = score of 2, sum of 6–10 = score of 3, sum of 11–13 = score of 4, 
and sum of 14–16 = score of 5.  The scores of each of the 5 domains are achieved 
separately and then summed together to obtain a total 5-D score.  5-D scores can 
potentially range between 5 (no pruritus) and 25 (most severe pruritus). 
Total 5-D Itch Scale score = duration score (single item) + degree score (single item) + 
duration score (single item) + maximum (4 disability items) + category score based on 
sum of affected body parts. 
The scoring manual does not give specific direction regarding scoring when some 
questions are missing; therefore, each domain and the total score will be set to missing 
when any of their individual components are missing, with the exception of the disability 
domain.  The maximum of any items present for disability will be used for that domain. 
5-D Itch Scale questionnaires should be completed at the first dialysis visit of Week 1 
(for the baseline scores) and the first dialysis visit after the last dose of CR845 (for the 
Week 12 scores).  For the total 5-D Itch Scale score and each respective domain score, 
the Week 12 score would come from the Week 13 End of Treatment visit if non-missing; 
otherwise, it would come from an unscheduled visit or Early Termination Visit collected 
from Day 82 to Day 86, inclusive.     
For the total 5-D Itch Scale score and each domain score, summary statistics (n, mean, 
standard deviation, minimum, maximum) for the respective baseline and Week 12 score 
will be produced, along with the change from baseline.  Missing scores will not be 
imputed. 
Individual scores will be presented in a by-subject listing. 
8.2.4 Skindex-10  
Developed specifically for uremic pruritus, the Skindex-10 (see Appendix 4 of the 
protocol) is an instrument for measurement of quality of life.  Subjects are asked the 
question “During the past week, how often have you been bothered by” and respond by 
filling in 1 of 7 circles numbered from 0 (labeled with the anchor phrase “never 
bothered”) to 6 (labeled as “always bothered”) for each of the 10 questions.  
The total score is the sum of the numeric value of each answered question.  The total 
score is subdivided into 3 domain scores, which are sums of the scores of the following 
questions:  disease domain (questions 1 to 3), mood/emotional distress domain 
(questions 4 to 6), and social functioning domain (questions 7 to 10). 


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Skindex-10 questionnaires should be completed on the same days as the 5-D Itch Scale 
questionnaires (see Section 8.2.3).   
The scoring manual for the Skindex-10 does not give specific direction regarding scoring 
when some questions are missing; therefore, the 3 domains and the total score will be set 
to missing when any of their individual components are missing.  Otherwise, the same 
rules for missing and extra questionnaires in Section 8.2.3 apply to the Skindex-10.  
The same summary statistics presented in Section 8.2.3 for the 5-D Itch Scale scores will 
be applied to and reported for the Skindex-10 scores, both for the total score and each 
domain.  Missing scores will not be imputed.  
Individual scores will be presented in a by-subject listing. 
 
8.2.5 EQ-5D-5L-P 
The EQ-5D-5L-P questionnaire consists of 3 component parts:  the EQ-5D descriptive 
system, the EQ VAS, and the EQ-PSO.  The EQ-5D descriptive system and the EQ VAS 
make up the EQ-5D-5L questionnaire, which was introduced by the EuroQol Group in 
2009.  The EQ-PSO is a 2-dimension questionnaire that was added on to the EQ-5D-5L.  
(See Appendix 6 of the protocol.)  
All 3 questionnaires measure the subject’s perceived state of health as of the day the test 
is taken.  Only descriptive analyses will be conducted for these scores.   
The EQ-5D-5L-P questionnaire should be completed around the start of the third dialysis 
visit of the Run-In Period and around the start of the third dialysis visit of Week 12.  The 
baseline value for each of the 3 component parts (and dimension, in the case of the 
EQ-5D descriptive system and the EQ-PSO) would come from the third dialysis visit of 
the Run-In Period if non-missing.  Similarly, the Week 12 value for each component part 
or dimension would come from third dialysis visit of Week 12 if non-missing. Otherwise, 
questionnaires collected at the Early Termination Visit or unscheduled visits will 
contribute to the Week 12 value if collected from Day 79 to Day 83, inclusive.   
8.2.5.1 
EQ-5D Descriptive System 
The EQ-5D descriptive system comprises 5 dimensions:  mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  Each dimension has 5 levels that can 
be coded as single-digit numbers ranging from 1 to 5 (indicated parenthetically):  no 
problems (1), slight problems (2), moderate problems (3), severe problems (4) and 
extreme problems (5).   
These coded numbers can be reported as 5-digit codes corresponding to the 5 dimensions 
in the following order:  mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression.  The code ranges between no problems on all 5 dimensions (11111) 
to extreme problems on all 5 dimensions (55555).  Missing values for specific 


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dimensions will be coded as 9, unless the entire EQ-5D descriptive system questionnaire 
is missing, in which case the 5-digit code will be missing.   
For each of the 5 dimensions, the number and percentage of subjects with each reported 
level (1 to 5) will be tabulated for baseline and Week 12.  Also, the count and percentage 
of subjects with no problems (ie, level 1) and with problems (ie, levels 2 to 5) by EQ-5D-
5L dimension will be separately summarized for baseline and Week 12.  Histograms will 
be created for the percentage of responses by level of severity for EQ-5D-5L dimensions 
at baseline and at Week 12. 
The Euroqol Group developed a EQ-5D-5L Crosswalk Index Value Calculator that maps 
the 5-digit codes to QALY weights that range in value from 0 to 1.  Although the 
crosswalk provides values for 6 countries, only values presented in the crosswalk for the 
United States will be used for this study.  Each subject’s 5-digit codes will be mapped by 
referencing the crosswalk available on the Euroqol Group’s website (see hyperlink in 
Section 14).  Summary statistics (n, mean, standard deviation, minimum, maximum) for 
the baseline and Week 12 QALY weights will be produced, along with change from 
baseline.    
A listing will be created that displays the subjects’ 5-digits codes and associated QALY 
weights.   
8.2.5.2 
EQ VAS 
The EQ VAS records the subject’s self-rated health on a vertical visual analogue scale, 
with values ranging from 0 (“The worst health you can imagine”) to 100 (“The best 
health you can imagine”).   
A summary table for EQ VAS will include descriptive statistics (number of subjects, 
mean, standard deviation, median, minimum, maximum, 25th percentile, and 75th 
percentile) for the baseline and Week 12 values, along with the change from baseline.   
Individual scores will be presented in a by-subject listing. 
8.2.5.3 
EQ-PSO 
The EQ-PSO will be added to the EQ-5D-5L and includes 2 additional dimensions “skin 
irritation” and “self-confidence” to better capture the itch-associated burdens [Swinburn 
2013].  Like the EQ-5D descriptive system, each dimension has 5 levels of severity 
ranging from 1 to 5.  The levels for the itching dimension are as follows: no itching (1), 
slight itching (2), moderate itching (3), severe itching (4), and extreme itching (5).  The 
levels for the self-confidence dimension are as follows:  no problems with 
self-confidence (1), slight problems with self-confidence (2), moderate problems with 
self-confidence (3), severe problems with self-confidence (4), and extreme problems with 
self-confidence (5). 
For each of the 2 dimensions, the number and percentage of subjects with each reported 
level (1 to 5) will be tabulated for baseline and Week 12.  Subjects with missing values at 


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baseline will still be included in the Week 12 summary, and subjects with missing values 
at Week 12 will still be included in the baseline summary.  
Also, the number and percentage of subjects with no problems (ie, with a level 1 
response) by dimension will be summarized for baseline and Week 12 in a separate table.   
These coded numbers will be reported as 2-digit codes in the same manner as that of the 
EQ-5D descriptive system, in the order of “skin irritation” followed by “self-confidence.”  
A listing will be created that displays the subjects’ 2-digit codes. 
 


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9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
The following assessments will be used to evaluate the safety of CR845 in hemodialysis 
subjects with moderate-to-severe pruritus: 
 Adverse events  
 Clinical laboratory parameters  
 Vital signs 
 12-lead ECG 
Analysis of all safety data collected during the Treatment Period will be performed on the 
Safety Population.  Any analysis of safety data collected during the Screening Period will 
be performed on the Enrolled Population.    
The baseline value for all analyses of Treatment Period safety parameters will be defined 
as the last value obtained prior to the first dose of study drug and will include both 
scheduled and repeat (unscheduled) observations. 
9.2 
Adverse Events 
The period of adverse event reporting will start after the signing of the informed consent 
form through the Follow-up Visit, or Early Termination Visit if the Follow-up Visit was 
not conducted, or 7 days after the last dose if the Early Termination Visit and Follow-up 
Visit were both missing.  All adverse events that occur during this reporting period will 
be collected for all subjects, including subjects who are deemed to be screen failures.  All 
tabular adverse event summaries will be for treatment-emergent adverse events (TEAEs) 
relative to the Treatment Period, unless otherwise specified.  Treatment-emergent adverse 
events are defined as those adverse event that start any time after the first dose of study 
drug up to the Follow-up Visit or Early Termination Visit (or 7 days after the last dose if 
no Early Termination Visit was conducted), whichever is later.  
For events with missing start dates, the following criteria will be used: 
 If the start date for a particular event is missing, then the event is considered 
treatment emergent. 
 If the start time is missing and the start date is the same as the first dosing date, 
then the event is considered treatment emergent. 
If it cannot be determined whether or not an event is treatment emergent due to a missing 
or partial date, then the event will be assumed to be treatment emergent. 
All adverse events will be coded to SOC and preferred term using MedDRA version 22.0.  
MedDRA will be used to map adverse events verbatim to SOC and preferred term for 
standardization and summary purposes. 
The incidence of TEAEs will be summarized.  If a subject experienced more than 
1 episode of an adverse event, the subject will be counted once for that preferred term.  If 


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a subject had more than 1 adverse event in a SOC, the subject will be counted only once 
in that SOC.  The summary tables will include the incidences of SOCs, as well as the 
incidences of preferred terms within each SOC.  Incidence for SOC will be presented by 
decreasing frequency overall and then alphabetically, and for preferred term within each 
SOC, by decreasing frequency overall and then alphabetically. 
The investigator is to record the severity of each adverse event as mild, moderate, or 
severe.  If the same TEAE occurs for a subject on multiple occasions, the TEAE will be 
categorized according to the highest severity rating for that TEAE in that subject.  If the 
severity of the TEAE is not reported, then the severity of the TEAE will be counted as 
severe.  The incidence within each category will be presented.   
The investigator is to record their opinion on the relationship of each adverse event to 
study drug (not related and related).  If a subject experiences the same adverse event 
multiple times, the event with the strongest relationship to study drug will be counted. 
The incidence within each category will be presented.  For the summary of TEAEs by 
relationship to study drug, if the relationship is missing, it will be counted as related. 
Separate tables summarizing the incidence of adverse events of special interest (AESIs) 
be presented for the Treatment Period.  Selected preferred terms shown in Appendix 15.3 
are combined into the following categories:  

Gait disturbance

Fall

Dizziness

Somnolence

Seizure

Syncope

Mental status changes

Mood changes

Unusual feeling, sensation

Tachycardia

Palpitation
To explore the duration and temporal relationship of treatment-emergent AESIs, a 
graphical representation of occurrences and durations of adverse events within each AESI 
will be presented with subjects on the y-axis and time on the x-axis (Swimmer plot).   
The incidence of infections related to uremic pruritus based on adverse events, 
hospitalizations, and/or use of antibiotics for treatment of infection related to uremic 
pruritus will be also be reported with counts and percentages.  The incidence of all 
infections will be summarized by preferred term. 
The following summary tables will be presented for the Safety Population: 


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 An overall summary showing the number and percentage of subjects with a(n) 
TEAE, serious TEAE, adverse events resulting in death (regardless of treatment 
emergence), related TEAE, related serious TEAE, severe TEAE, TEAE leading to 
dose interruption, TEAE leading to study drug discontinuation, and TEAE of 
special interest.  This table will also include number of events. This display will 
be repeated for subgroups by region.   
 Incidence of TEAEs by SOC and preferred term 
 Incidence of serious TEAEs by SOC and preferred term 
 Incidence of related TEAEs by SOC and preferred term 
 Incidence of TEAEs by SOC, preferred term, and maximum severity 
 Incidence of TEAEs leading to study drug discontinuation by SOC and preferred 
term 
 TEAEs by region, SOC, and preferred term 
 Incidence of most common TEAEs (2% or more of subjects) by preferred term 
 Incidence of treatment-emergent AESIs by preferred term 
 Incidence of TEAEs categorized based on custom MedDRA query (CMQ) events 
 Incidence of infections by preferred term 
 Incidence of infections potentially related to uremic pruritus by preferred term, 
where infections are deemed “potentially related to uremic pruritus” based on 
adverse events, hospitalizations, and/or use of antibiotics. 
The incidence of TEAEs in each CMQ category (see Appendix 15.2) will be 
summarized.  If a subject experienced more than 1 episode of an adverse event, the 
subject is counted once for that preferred term; the total number of subjects reporting an 
event in the category will also be reported.   
In addition, all adverse events for each subject will be listed in chronological order 
including subject identifier, age, race, gender, a flag indicating whether the event was 
treatment-emergent, and all related event status information (start and stop dates, whether 
the event was ongoing, study day of onset, severity, seriousness, relationship to study 
drug, action taken with study drug, and outcome).  Note:  For the all adverse event listing 
only, any screen failure subject who has an adverse event after signing the informed 
consent form will be included for completeness.  Separate listings will be generated for 
serious adverse events (SAEs), deaths, adverse events leading to treatment 
discontinuation, and adverse events of special interest.  Additionally, a coding list of 
preferred terms and the verbatim text associated with them will be produced. 
No statistical tests will be performed on adverse events. 
9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
An SAE is defined as any adverse event occurring at any dose and regardless of causality 
that results in death, is life threatening, requires in-patient hospitalization or prolongation 


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of existing hospitalization, results in persistent or significant disability/incapacity, is a 
congenital anomaly/birth defect, or is an important medical event.   
Serious adverse events will be collected from date the informed consent form is signed up 
to the Follow-up Visit or 7 days following the last dose of study drug, whichever is later.  
Serious adverse events that occur up to 30 days after the last dose of study drug should 
also be documented on an SAE form if they are deemed by the investigator to be 
“related” to the study drug.  Serious adverse events that occur after the Follow-up Visit or 
30 days after the last dose of study drug, whichever is later, do not need to be 
documented on an SAE form if they are deemed by the investigator to be “not related” to 
study drug or the conduct of the study.  A more detailed definition of SAEs is provided in 
Protocol Section 6.5.3.1.   
Subject deaths are captured on the Adverse Events CRF page.  Subject death listings will 
include all death data available including date of death and cause of death.  Additionally, 
SAEs and adverse events resulting in study drug discontinuation will be listed. 
9.4 
Clinical Laboratory Evaluation 
Blood samples will be collected during screening, on Day 1 and at End of 
Treatment/Early Termination.  Summaries of actual values and the changes from baseline 
to each time point (when applicable) and the last post-baseline treatment visit will be 
presented for quantitative laboratory parameters (eg, white blood cell count, lymphocyte 
count).  Only data from the central laboratory will be used.  The last post-baseline 
treatment visit will be latest value recorded for a given parameter, not including the 
Follow-up Visit and unscheduled visits following the End of Treatment/Early 
Termination Visit.  
Baseline is defined as the last measurement taken on or prior to the first day of dosing. 
Note that the Day 1 assessment can be included in the evaluation of baseline if the 
assessment is performed prior to dosing. 
All laboratory evaluation summaries will include the subjects in the Safety Population 
who have at least 1 post-baseline time point (for criteria based on post-baseline 
assessments) and with both a baseline and at least 1 post-baseline time point (for criteria 
evaluating changes from baseline).   
Laboratory values will be reported in Système International units, unless otherwise 
specified.   
Laboratory test results will be classified according to whether the value was below (L), 
within (N), or above (H) the laboratory parameter reference range.  A summary of 
treatment-emergent shifts will compare the baseline L/N/H classification for each 
laboratory test to the highest and/or lowest L/N/H classification during the Treatment 
Period.   


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Additionally, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline 
phosphatase will be presented in a separate table with:  3× and 5× upper limit of normal 
(ULN) flagged for alanine aminotransferase and aspartate aminotransferase; 2×ULN 
flagged for bilirubin, and 1.5×ULN flagged for alkaline phosphatase.  Additionally, 
subjects that have alanine aminotransferase or aspartate aminotransferase >3×ULN and 
total bilirubin >2×ULN will be flagged as potential Hy’s Law cases and summarized.  
These liver function values will be presented in a separate listing with 3 and 5ULN 
flagged for alanine aminotransferase and aspartate aminotransferase; 2ULN flagged for 
total bilirubin; and 1.5ULN flagged for alkaline phosphatase. 
Additionally, clinically significant shifts from baseline for hemoglobin, calcium, serum 
albumin, phosphate, and potassium will be reported.  Ranges are given below. 
Test 
Low 
High 
Hemoglobin (g/dL) 
<7 
>14 
Calcium (mg/dL) 
<7 
>10.5 
Serum albumin (g/dL) 
<3 
>5.5 
Phosphate (mg/dL) 
<2.5 
>8 
Potassium (mmol/L) 
<2.5 
>7 
 
All clinical laboratory values will be presented in a listing. 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.5.1 Vital Signs 
Vital signs (including body temperature, heart rate, and systolic and diastolic blood 
pressure) will be collected prior to dialysis during screening; at the third dialysis session 
of Weeks 1, 5, 9; at the End of Treatment Visit or Early Termination Visit; and at the 
Follow-up Visit.  Heart rate will be collected at each dialysis visit; if clinically significant 
and outside the pre-specified visits mentioned above, the heart rate will be recorded on 
the relevant CRF page.  Dry body weight will be collected during screening   
Baseline is defined as the last measurement taken on or prior to the first day of dosing.  
Note that the Day 1 assessment can be included in the evaluation of baseline given that 
the assessment is performed prior to dosing.   
Summary tables will include descriptive statistics (number of subjects, mean, standard 
deviation, median, minimum, and maximum) for baseline and each post-baseline 
assessment and the last post-baseline treatment visit.  Descriptive statistics will be 
calculated on both the actual value and the change from baseline score.  The last 
post-baseline treatment visit will be latest value recorded for a given parameter, not 
including the Follow-up Visit and unscheduled visits following the End of 
Treatment/Early Termination Visit.  


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All vital sign summaries (including the analysis of clinically notable values below) will 
include the subjects in the Safety Population who have at least a post-baseline assessment 
(for criteria based on post-baseline assessments) and subjects who have both a baseline 
and at least 1 post-baseline assessment (for criteria evaluating changes from baseline). 
Clinically notable vital signs will be identified based on the criteria below.  For each vital 
sign parameter, the number and percentage of subjects with at least 1 notable value will 
be tabulated by week and overall for the Treatment Period. 
Vital Sign Parameter 
Value 
Systolic blood pressure 
≥180 mm Hg 
≤90 mm Hg 
Diastolic blood pressure 
≥100 mm Hg 
≤60 mm Hg 
Heart rate 
>130 beats per minute 
<55 beats per minute 
 
All vital signs will be listed in by subject, including visit and collection date/time, and 
will be sorted by subject identifier and date/time of assessment. 
9.5.2 12-Lead Electrocardiograms 
Standard 12-lead ECGs will be performed prior to dialysis during screening and at End of 
Treatment/Early Termination. 
Electrocardiogram results include an overall interpretation of “normal,” “abnormal but 
not clinically significant,” or “abnormal and clinically significant.”  These results will be 
tabulated at each time point, including the last post-baseline treatment visit.  The last 
post-baseline treatment visit will be latest value recorded, not including unscheduled 
visits following the End of Treatment/Early Termination.  The worst post-baseline result 
across all visits will be flagged and reported separately; this may include measurements 
that were not in the individual visit summaries.  
Electrocardiogram results will be listed for each visit, including visit, whether ECG was 
performed (yes/no), explanation (if not performed), assessment date/time, study date, 
overall interpretation, and relevant medical history number or adverse event number if 
deemed a clinically significant abnormality. 


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10. 
OTHER ANALYSES 
10.1 
Hospitalizations, Emergency Department Encounters  
The count and percentage of subjects who were hospitalized as in-patients, the count and 
percentage of subjects who underwent dialysis during hospitalization, and summary 
statistics for duration of hospital stay will be reported.  In addition, a listing will be 
generated that includes the date of admission, date and time of discharge, reason for 
hospitalization, the total number of dialysis procedures completed during the hospital 
stay, whether the subject received any medications administered or had a procedure 
during the hospital stay, and whether the subject had any other medical conditions noted 
during the hospital stay.  
A parallel summary and listing will also be created for emergency room visits. 
10.2 
Missed Dialysis Visits and Incidence of Infection 
The analysis of missed dialysis visits is described in Section 7, Measurements of 
Treatment Compliance.  The analysis of incidence of infection is described in 
Section 9.2, Adverse Events. 
 


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11. 
INTERIM ANALYSES AND DATA MONITORING 
No interim analysis is planned.  However, an ongoing review of the cumulative safety 
data for this study will be conducted by the Sponsor or designee 
 


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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
All changes below are in reference to version 2.0 (12FEB2019) of the protocol 
 The protocol states that approximately 400 subjects will be enrolled at 
approximately 80 sites, while Section 2.6 of this SAP states that approximately 
200 subjects will be enrolled at approximately 50 clinical sites. 
 Effectiveness analyses will be performed on the Safety Population rather than on 
the Full Analysis Population as defined in the protocol.  Main and ancillary 
analyses as described in Section 6.4 of the protocol will not be performed. 
 The incidence of AESIs will not be presented for the Run-In Period. 
 “Most common TEAEs” will be defined as 2% or more of subjects rather than 5% 
or more. 
 The derivation and analyses of EQ-5D-5L QALY weights were added. 
 The percentage of subjects achieving >0, ≥1, ≥2, ≥3, ≥4, ≥5 and ≥6-point 
improvement from baseline with respect to the Sleep Quality score and the WI-
NRS score at Week 12 are reported, while the protocol only specifies the 
percentage of subjects achieving >0, ≥1, ≥2, ≥3, and ≥4-point improvement from 
baseline with respect to the WI-NRS score at Week 12 
 The protocol included analysis of covariance (ANCOVA) analyses of continuous 
efficacy variables, however, with only the baseline as a covariate, the model least 
squares mean yields the same value as the raw mean. 
 The protocol included logistic regression for dichotomous efficacy variables, 
however, with a single treatment group, there are no meaningful odds ratios to be 
reported. 
 


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13. 
STATISTICAL APPENDIX 
Not applicable. 


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14. 
REFERENCES 
Swinburn P, Lloyd A, et al. Development of a Disease-Specific Version of the EQ-5D-5L 
for Use in Patients Suffering from Psoriasis: Lessons Learned from a Feasibility Study in 
the UK. Value in Health. 2013;16:1156-62 
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-
sets/crosswalk-index-value-calculator/ [downloaded November 2019]


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15. 
APPENDICES 
15.1 
Schedule of Events 
Table 2 
Schedule of Events 
 
  
Screening Period  
(days) 
Treatment Period f (weeks) 
Early 
Termination 
Visit d 
End of 
Treatment 
Visit g  
Follow-
Up Visit 
Screening 
Visit  
Run-in  
Day -28 
to Day -7 
Day -7 to 
Day 1 
Week 1 
Week 5 
Week 9 
Week 12 
_ _ _ 
Week 13 
Week 13-
14 
 Procedures 
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria a 
X 
  
X 
  
  
  
  
  
  
Medical History/Demographic a,h 
X 
  
X 
  
  
  
  
  
  
Prior Medications a 
X 
X 
X 
  
  
  
  
  
  
Pre-dialysis 12-lead ECG b 
X 
  
  
  
  
  
X 
X 
  
Pre-dialysis Vital Signs c 
X 
  
X 
X 
X 
  
X 
X 
X 
Serum pregnancy (females of childbearing potential) e 
X 
  
  
  
  
X 
X 
  
Patient training on PRO worksheets 
X o 
X p 
X p 
  
  
  
  
  
  
Questionnaires i,j,k,l 
  
X  
X  
  
  
X  
X 
X 
  
Physical Exam 
X 
  
  
  
  
  
  
  
  
Prescription dry body weight 
X 
  
  
  
  
  
  
  
  
Hematology, serum chemistry (pre-dialysis) 
X 
  
X 
  
  
  
X 
X 
  
IV administration of study drug 
  
  
Dose after each dialysis up to Week 12 inclusive 
  
  
  
Adverse event monitoring m 
X 
X 
Record on an ongoing basis 
X 
X 
X 
Concomitant medications n 
  
  
Record on an ongoing basis 
X 
X 
X 
Record number of missed dialysis visits and reason(s)   
  
     Record on an ongoing basis  
 
Record of In-patient hospitalization and reason(s) 
           Record on an ongoing basis 
  
CRF = case report form; ECG = electrocardiogram; EOT = end of treatment; EQ-5D-5L-P = EQ-5D-5L with EQ-PSO bolt-on;  IV = intravenous; PRO = patient reported outcome; WI-
NRS=Worst Itching Intensity numeric response scale 
a Medical history, demographic and prior medications will be recorded during screening and updated on Day 1 with any changes since the Screening Visit, and inclusion/exclusion 
criteria will be confirmed prior to starting treatment on Day 1 
b Electrocardiograms must be performed prior to the start of dialysis at screening and EOT/Early Termination Visit 


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c Pre-dialysis (prior to start of dialysis) vital signs, including body temperature, heart rate, and blood pressure, will be recorded when the patient is in a sitting or semi-recumbent position 
on the third dialysis session (Fri/Sat) of the specified week.  Heart rate will be measured at each dialysis; if heart rate is clinically significant and outside the prespecified visits per the 
Schedule of Events, the heart rate will be recorded on the relevant CRF page 
d Early Termination procedures need to be performed following the first dialysis visit after the last study dose if the patient discontinues study prior to the completion of full 12-week 
treatment period  
e Serum pregnancy must be performed and resulted within 7 day prior to first study dose and should test for human chorionic gonadotropin 
f 
Each visit during the Treatment Period will coincide with the patient’s normal dialysis treatments 
g The End-of-Treatment Visit will be the first dialysis visit following the last dose of study drug after the patient completed the treatment period of 12 weeks 
h In addition to providing a general medical history, patients will be specifically asked if they have conditions of special interest (ie, gait disturbance, fall, dizziness, somnolence, seizure, 
syncope, mental status changes, mood altered, feeling abnormal, tachycardia, and palpitations) and number of missed dialysis visits four weeks prior to Day 1 of run-in   
i 
WI-NRS and Sleep quality questionnaires should be completed around the start of each dialysis visit (all three sessions) during the Run-In Period & Week12. They should also be 
performed on the first dialysis visit (Monday/Tuesday) during Week 1 & on the first dialysis visit after the last dose of CR845. WI-NRS should be completed prior to the Sleep Quality 
Questionnaire.  
j 
Patients will be requested to complete their PRO questionnaires at a similar time (preferably within one hour of starting dialysis). The worksheets will be completed prior to or during 
dialysis, but must be completed prior to dosing 
k 5-D Itch and Skindex-10 questionnaires should be completed at the first dialysis visit of Week 1 and on the first dialysis visit after the last dose of CR845. If the first visit of the week 
is missed, the patient may complete the worksheets at their next visit for the same week. Preferably, the 5-D Itch questionnaire is to be completed first. 
l 
EQ-5D-5L-P questionnaire should be completed around the start of the third dialysis visit of the Run-In Period and around the start of the third dialysis visit of week 12 
m Infections will be recorded as per standard procedures at the dialysis sites and reported on the adverse event eCRF page. Information pertaining to the nature of the infections will be 
collected 
n Concomitant medications including antipruritic medication will be updated at each dialysis visit until the end of the Follow-up Visit 
o Training on WI-NRS, Sleep Quality, and EQ-5D-5L-P questionnaires will be conducted prior to the start of the Run-in Period 
p Training on 5-D Itch and Skindex-10 questionnaires may be performed at any time during Screening Period prior to treatment on Day 1 
Source:  Table 2, Schedule of Events, of the CR845-CLIN3105 protocol. 
 
 


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15.2 
Custom MedDRA Query (CMQ) Categories and Preferred Terms 
CMQs 
 
Gait Disturbance 
Ataxia 
Balance disorder 
Coordination abnormal 
Gait disturbance 
Gait inability 
Tandem gait test abnormal 
 
Dizziness 
Dizziness 
Dizziness Postural 
Vertigo 
 
Syncope 
Presyncope 
Syncope 
 
Fall & Potentially Drug Related Injury 
Accident 
Back injury 
Contusion 
Fall 
Fracture (all preferred terms containing “fracture”) 
Head injury 
Injury 
Limb injury 
Muscle contusion 
Muscle injury 
Road traffic accident 
Skeletal injury 
Haematoma 
Subdural hematoma 
Epidural haematoma 
Traumatic haematoma 
Periorbital haematoma 
Ecchymosis 
Subdural hematoma 
Subdural haemorrhage 
 
Mood Changes & Behavioral Changes 
Abnormal behavior 


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Affect lability 
Aggression 
Agitation 
Anger 
Anxiety 
Apathy 
Blunted affect 
Crying 
Depressed mood 
Disinhibition 
Dysphoria 
Emotional distress 
Emotional poverty 
Euphoric mood 
Flat affect 
 
Grandiosity 
Hostility 
Inappropriate affect 
 
Listless 
Mood altered 
Mood swings 
Morose 
Nervousness 
Patient uncooperative 
Restlessness 
Social avoidant behavior 
 
Seizures 
Autonomic seizure 
Clonic convulsion 
Drug withdrawal convulsions 
Epilepsy 
Epileptic aura 
Focal dyscognitive seizures 
Generalised tonic-clonic seizure 
Partial seizures 
Partial seizures with secondary generalisation 
 
Seizure 
Seizure cluster 
Simple partial seizures 
Status epilepticus 
Tonic convulsion 
 


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Mental Status & Cognitive Changes 
Acute psychosis 
Delirium 
Altered state of consciousness 
Hallucination (any preferred term containing “Hallucination”) 
Bradyphrenia 
Change in sustained attention 
Cognitive disorder 
Confusional state 
Delusion (any preferred term containing “Delusion”) 
Depressed level of consciousness 
Disorientation 
Encephalopathy 
Illusion 
Judgment impaired 
Lethargy 
Mental impairment 
Mental status changes 
Stupor 
Thinking abnormal 
 
Unusual Feeling, Sensation 
Asthenia 
Depersonalisation/derealisation disorder 
Derealisation 
Dissociation 
Feeling abnormal 
Feeling cold 
Feeling despair 
Feeling drunk 
Feeling guilty 
Feeling hot 
Feeling jittery 
Feeling of body temperature change 
Feeling of despair 
Feeling of relaxation 
Feelings of worthlessness 
Malaise 
Psychiatric symptom 
Sensation of foreign body 
Suffocation feeling 
 
Palpitations & Tachychardia 
Palpitations 
Heart rate irregular 
Heart rate increased 


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Tachycardia 
Atrial tachycardia 
Junctional ectopic tachycardia 
Supraventricular tachycardia 
Ventricular tachycardia 
Sinus tachycardia 
Tachycardia paroxysmal 
Tachyarrhythmia 
Ventricular tachyarrhythmia 
 
Somnolence 
Somnolence 
Sleep disorder 
Abnormal sleep related event 
Microsleep 
Sleep attacks 
Sedation 
 
 
 


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15.3 
Treatment-emergent Adverse Events of Special Interest and 
Preferred Terms 
TEAE of Special Interest 
Terms 
Preferred Terms 
Gait disturbance 
Gait disturbance                      
Falls 
Fall 
Dizziness 
Dizziness 
Somnolence 
Somnolence 
Seizures 
Seizure 
Syncope 
Syncope 
Mental status changes 
Mental status changes 
Mood changes 
Mood altered 
Unusual feeling/sensation 
Feeling abnormal 
Tachycardia 
Sinus tachycardia, Tachycardia, Tachyarrhythmia 
Palpitation 
Palpitations 
TEAE = treatment emergent adverse event