Conditions: Chronic Kidney Diseases Pruritus
Keywords: difelikefalin CR845 Pruritus Chronic Itch Itch Itching uremic pruritus CKD CKD-aP CKD-associated pruritus Chronic Kidney Disease Kidney dysfunction Generalized pruritus Hemodialysis Dialysis ESRD (end stage renal disease) Kidney failure, chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 269
Healthy volunteers: no

Brief summary:
This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of 3 dose levels of oral CR845 compared to placebo in reducing the intensity of itch in chronic kidney disease (CKD) patients with moderate-to-severe pruritus. This study will consist of a Screening Period, a 7-day Run-in Period, a 12 week Treatment Period, and a Follow-up Visit (approximately 7 days after the last dose of study drug).

Detailed description:
This study will consist of a Screening Period, a 7-day Run-in Period, a 12 week Treatment Period, and a Follow-up Visit (approximately 7 to 10 days after the last dose of study drug). Informed consent will be obtained prior to performing any study-specific procedures. Screening will occur within 7 to 28 days prior to randomization to assess eligibility.

If patients continue to meet all inclusion and no exclusion criteria at the end of the 7-day Run-in Period, they will be randomized in a 1:1:1:1 ratio to receive orally once daily either placebo or CR845 tablets at doses of 0.25, 0.5 or 1 mg. Randomization will be stratified according to the patient's renal disease status: moderate CKD; severe CKD non-dialysis; severe CKD on dialysis (ie, 3 categories). A final safety Follow-up Visit will be conducted 7 to 10 days after the last dose of study drug.

Arms:
arm 1: Oral CR845 0.25 mg to be taken orally once daily for 12 weeks arm 2: Oral CR845 0.5 mg to be taken orally once daily for 12 weeks arm 3: Oral CR845 1 mg to be taken orally once daily for 12 weeks arm 4: Oral Placebo to be taken orally once daily

Interventions: intervention 1: CR845 0.25 mg Oral Tablet intervention 2: CR845 0.5 mg Oral Tablet intervention 3: CR845 1 mg Oral Tablet intervention 4: Placebo Oral Tablet
Intervention descriptions: intervention 1: CR845 0.25 mg medication taken orally 1 time/day intervention 2: CR845 0.5 mg medication taken orally 1 time/day intervention 3: CR845 1 mg medication taken orally 1 time/day intervention 4: Placebo tablet taken orally 1 time/day

Protocol document:
Prot_000.pdf: 
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A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF ORAL CR845 IN CHRONIC KIDNEY DISEASE PATIENTS 
WITH MODERATE-TO-SEVERE PRURITUS 
 
Protocol number:   
CR845-210301 
Phase: 
2 
IND number: 
132198 
Protocol version: 
Version 1.2 
Date: 
14 May 2018 
Sponsor: 
 
 
Cara Therapeutics, Inc. 
4 Stamford Plaza 
Stamford, CT  06902 
(203) 406-3700 
 
Information contained in this document is proprietary and confidential information of Cara Therapeutics, 
Inc.  Any distribution, copying, or disclosure is strictly prohibited unless such disclosure is required by 
federal regulations or state law.  Persons receiving the information in this document are hereby given notice 
that the information is confidential and may not be further copied, distributed, disseminated or otherwise 
disclosed to any other person without the express written authorization of Cara Therapeutics, Inc.   
 
 




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INVESTIGATOR APPROVAL STATEMENT 
I have read and understand the protocol (CR845-210301) 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 Harmonisation Harmonised Tripartite Guideline for Good 
Clinical Practice E6 (R1), E6(R2) Good Clinical Practice: Integrated Addendum to ICH 
E6(R1) Integrated, United States Code Title 21 (Food and Drug Administration), and 
applicable regulatory requirements. 
Principal Investigator  
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
Date: 
 
 


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1.0 
Protocol Synopsis 
STUDY TITLE 
A Multicenter, Double-blind, Randomized, Placebo-controlled Study to 
Evaluate the Safety and Efficacy of Oral CR845 in Chronic Kidney 
Disease Patients with Moderate-to-Severe Pruritus 
PROTOCOL 
NUMBER 
CR845-210301 
PHASE OF 
DEVELOPMENT 
2 
INVESTIGATIONAL 
PRODUCT 
CR845 Tablets 
NAME OF ACTIVE 
INGREDIENT 
CR845 
ROUTE OF 
ADMINISTRATION 
Oral 
STUDY CENTERS 
Up to 80 sites 
OBJECTIVES 
 
Primary Objective 
• 
To evaluate the efficacy of 3 dose levels of oral CR845 
compared to placebo in reducing the intensity of itch in chronic 
kidney disease (CKD) patients with moderate-to-severe 
pruritus.   
Secondary Objectives 
• 
To evaluate the efficacy of 3 dose levels of oral CR845 
compared to placebo in improving itch-related quality-of-life 
measures in CKD patients with moderate-to-severe pruritus.   
• 
To evaluate the safety of 3 dose levels of oral CR845 in CKD 
patients with moderate-to-severe pruritus.   
NUMBER OF 
PATIENTS 
The planned sample size is approximately 240 (60 per treatment group) 
male and female CKD patients with moderate-to-severe pruritus (mean 
baseline 24-hour Worst Itching Intensity numerical rating scale (NRS) 
score ≥5).  The sample size may be increased up to 480 patients (120 
per treatment group) based on the results of a planned interim analysis 
(IA) conducted when approximately 50-60% of the planned 
240 patients have been randomized and have either completed the 
12-week Treatment Period or have discontinued study drug early. 
Randomization will be stratified according to the patient’s renal disease 
status: moderate CKD non-dialysis; severe CKD non-dialysis; and 
severe CKD on dialysis (ie, 3 categories).  The randomization of severe 
CKD patients on hemodialysis will be capped at approximately 20% of 
the total sample size (ie, 48 of 240 patients).  
 


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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; 
3. Male or female 18 years of age or older; 
4. CKD patients with stage III, IV, or V disease (ie, moderate 
renal impairment with estimated glomerular filtration rate 
(GFR) ≥30 and <60 mL/min/1.73 m2 or severe renal 
impairment with estimated GFR <30 mL/min/1.73 m2).  For 
severe CKD patients on hemodialysis, they must be receiving 
hemodialysis 3 times per week for at least 3 months prior to 
the start of screening; 
Note 1:  Patients who have received a renal organ transplant 
and who are at least 6 months post-transplant with an estimated 
GFR <60 mL/min/1.73 m2 may participate if clinically stable 
and are on maintenance immunosuppression.  
Note 2:  Severe CKD patients on hemodialysis who require an 
additional hemodialysis treatment to manage fluid overload 
may be enrolled as long as it is anticipated that no more than 
1 such treatment will be required in any given week.  
Note 3:  Severe CKD patients on hemodialysis 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. 
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 amenorrheic for at least 1 year and is over the 
age of 55 years; or 
c. has a negative serum pregnancy test at screening and 
agrees to use acceptable contraceptive measures 
(eg, hormonal contraceptives, barrier with spermicide, 
intrauterine device, vasectomized partner, or abstinence) 
from the time of informed consent until 7 days after the 
last dose of study drug; 
 


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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 body weight between 40.0 and 140.0 kg, inclusive (for 
severe CKD patients on hemodialysis, this is the prescription 
dry body weight); 
9. Self-reports experiencing daily or near-daily pruritus during the 
month prior to screening; 
10. For severe CKD patients on hemodialysis, at least 2 single-pool 
Kt/V measurements ≥1.2, at least 2 urea reduction ratio 
measurements ≥65%, or 1 single-pool Kt/V measurement ≥1.2, 
and 1 urea reduction ratio measurement ≥65% on different 
dialysis days during the 3-month period prior to screening; 
11. Prior to randomization: 
a. Has completed at least 4 Worst Itching Intensity NRS 
worksheets from the start of the 7-day Run-in Period; 
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 7-day Run-in Period. 


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Exclusion Criteria: 
A patient will be excluded from the study if any of the following 
criteria are met:   
1. Patients not currently on dialysis who are likely to initiate 
routine dialysis during study participation; 
2. For severe CKD patients on hemodialysis, noncompliance 
with hemodialysis treatment that, in the opinion of the 
Investigator, would impede completion or validity of the 
study; 
3. Scheduled to receive a kidney transplant during the study; 
4. Has a concomitant disease or 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; 
5. New or change of treatment received for itch including 
antihistamines and corticosteroids (oral, intravenous [IV], or 
topical) within 14 days prior to screening; 
6. New or change of prescription for opioids, gabapentin, or 
pregabalin within 14 days prior to screening; 
7. Serum alanine aminotransferase or aspartate aminotransferase 
greater than 2.5 times the reference upper limit of normal 
(ULN), or total bilirubin greater than 2 times the ULN at 
screening; 
8. Received another investigational drug within 30 days prior to 
the start of screening or is planning to participate in another 
clinical study while enrolled in this study; 
9. Has pruritus attributed to a cause other than CKD (eg, patients 
with concomitant pruritic dermatological disease or 
cholestatic liver disease would be excluded); 
10. Has localized itch restricted to the palms of the hands; 
11. Anticipates receiving an opioid antagonist (eg, naloxone, 
naltrexone) or opioid-mixed agonist-antagonist 


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(eg, buprenorphine, nalbuphine) from the start of screening 
through the end of the Treatment Period; 
12. Received ultraviolet B treatment within 30 days prior to the 
start of screening or anticipates receiving such treatment 
during the study; 
13. Participated in a previous clinical study with CR845. 
14. If currently a patient with a renal transplant: 
a. Has received an increase or a new immunosuppressive 
treatment due to an acute or chronic rejection episode 
4 weeks prior to screening; 
b. Is anticipated to have a change in immunosuppressive 
treatment from screening to the end of the study. 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled 
study to evaluate the safety and efficacy of 3 dose levels (0.25, 0.5, and 
1 mg) of oral CR845 in moderate-to-severe CKD patients with 
moderate-to-severe pruritus.   
This study will consist of a Screening Period, a 7-day Run-in Period, a 
12-week Treatment Period, and a Follow-up Visit (approximately 
7 days after the last dose of study drug).  Informed consent will be 
obtained prior to performing any study-specific procedures.  Screening 
will occur within 7 to 28 days prior to randomization to assess 
eligibility.   
Eligible patients will complete a 7-day Run-in Period during the week 
prior to randomization when they will be required to complete at least 
4 Worst Itching Intensity NRS scale worksheets. The mean baseline 
Worst Itching Intensity NRS score during the 7-day Run-In Period 
must be ≥5.  The mean baseline is defined as the average of all non-
missing scores reported from the start of the 7-day Run-in Period.  For 
consistency, patients will be requested to complete the Worst Itching 
Intensity NRS worksheets at a similar time each day.   
Patients will also be trained on the Skindex-10 Scale, 5-D Itch Scale, 
Patient Global Impression of Worst Itch Severity, and Patient Global 
Impression of Change (PGIC) worksheets at any time during the Run-
in Period or on Day 1 of the Treatment Period.   
Day 1 of the Treatment Period will be defined as the day of the 
administration of the first dose of study drug.   
If patients continue to meet all inclusion and no exclusion criteria at the 
end of the 7-day Run-in Period, they will be randomized in a 
1:1:1:1 ratio to receive orally once daily either placebo or CR845 
tablets at doses of 0.25, 0.5 or 1 mg.  Randomization will be stratified 
according to the patient’s renal disease status.  
Patients will report their Worst Itching Intensity NRS score over the 
last 24 hours daily during the entire Treatment Period.  Patients will be 
instructed to complete the NRS score at a similar time of the day.  In 
addition, patients will complete other patient-reported outcome (PRO) 


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measures (Skindex-10 Scale, 5-D Itch Scale, Patient Global Impression 
of Worst Itch Severity) during the Treatment Period.  The PGIC will be 
completed at end of treatment/early termination. 
Safety assessments tests will be conducted periodically starting at 
Screening until the Follow-up Visit.  Adverse events and concomitant 
medications will be recorded during the study starting at Screening 
until the Follow-up Visit.   
A final safety Follow-up Visit will be conducted 7 to 10 days after the 
last dose of study drug.   
STUDY DRUG 
CR845 will be provided as enteric-coated tablets.  All tablets are white 
in color with no markings and are identical in appearance, regardless of 
dose.   
CR845 tablets will be provided at doses of 0.25, 0.5, and 1 mg.   
REFERENCE 
PRODUCT 
Placebo to match CR845 tablets 
TREATMENT 
REGIMENS 
Patients will take study drug once daily for a total of 12 weeks.  
Each dose should be taken at least 2 hours prior to or after a meal, 
around the same time of day (patient should not lie down for at least 1 
hour after swallowing the tablet).  
For severe CKD patients on hemodialysis, the study drug should not be 
taken until after their dialysis procedure on days when they receive 
dialysis.  Note that the same requirement for meal timing of study drug 
must also be followed. 
STUDY DURATION 
Screening Period:  Day -28 to Day -7  
Run-in Period:  1 week prior to randomization (Day -7 to Day -1) 
Treatment Period:  12 weeks 
Follow-up Visit:  7-10 days after the End-of-Treatment Visit or Early 
Termination Visit 
Total study duration for a single patient:  up to approximately 17 weeks  
STUDY 
ENDPOINTS 
Efficacy Endpoints 
Primary Efficacy Endpoint 
• 
Change from baseline with respect to the weekly mean of the 
daily 24-hour Worst Itching Intensity NRS score during 
Week 12 of the Treatment Period. 
Secondary Efficacy Endpoints 
• 
Change from baseline in itch-related quality of life at the end 
of Week 12, as assessed by the total Skindex-10 Scale score; 
• 
Change from baseline in itch-related quality of life at the end 
of Week 12, as assessed by the 5-D Itch Scale score; 
• 
Proportion of patients achieving an improvement from baseline 
≥3 points with respect to the weekly mean of the daily 24-hour 


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Worst Itching Intensity NRS score at Week 12 of the 
Treatment Period. 
 
Additional efficacy endpoints are described in Section 8.6.4. 
Safety Assessments 
The safety assessments used to evaluate the overall safety of CR845 
will include adverse events, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations. 
INTERIM 
ASSESSMENT 
An unblinded IA will be conducted when approximately 50-60% of the 
planned 240 patients have been randomized and have either completed 
the 12-week Treatment Period or have discontinued study drug early.  
The primary goal of the IA is to identify dose(s) of oral CR845 that are 
both safe and efficacious.  Doses that are found to be unsafe or poorly 
tolerated will be dropped from the study.  The sample size of any dose 
group that is found to be efficacious may be increased to ensure that 
the pairwise comparison against placebo with respect to the primary 
efficacy variable at the end of the study is powered appropriately.  The 
sample size of dose groups that do not separate from placebo at the IA 
may not be increased; however, no dose will be dropped for futility 
reasons.  The sample size will not be increased past 480 total patients 
(120 patients per treatment group). 
Details of the IA will be included in a separate document. 


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STATISTICAL 
ANALYSIS 
Analysis Populations 
The Enrolled Population is defined as the group of patients who sign 
the informed consent form. 
The Safety and Full Analysis Populations are both defined as the group 
of all randomized patients who receive at least 1 dose of study drug.  
Following the intent-to-treat principle, patients in the Full Analysis 
Population will be analyzed according to their randomized treatment, 
regardless of the actual treatment received.  Patients in the Safety 
Analysis Population will be analyzed according to their actual 
treatment.  
The Per-Protocol Population is defined as the subset of patients in the 
Full Analysis Population who do not have any major protocol 
deviations that could affect the efficacy analyses.   
Inclusion in the Per-Protocol Population will be determined prior to 
unblinding the data and will be detailed in the statistical analysis plan. 
 
Efficacy Analyses 
All efficacy analyses will be conducted using the Full Analysis 
Population.  An analysis of the primary and secondary efficacy 
variables for the Per-Protocol Population may be performed if more 
than 20% of the patients in the Full Analysis Population are excluded. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the change from baseline 
to Week 12 of the Treatment Period with respect to the weekly mean of 
the daily 24-hour Worst Itching Intensity NRS score.  The weekly 
mean of the 24-hour Worst Itching Intensity NRS score will be defined 
as the sum of the daily Worst Itching Intensity NRS score reported 
during a specific week during the Treatment Period (eg, Days 2 to 8, 
Days 9 to 15, Days 16 to 22, etc.) divided by the number of days with 
non-missing scores for that week.  If the daily worst itching score is 
missing for >3 days during a specific week, the corresponding weekly 
mean worst itching score will be set to missing.  The baseline score 
will be defined as the average of the daily 24-hour Worst Itching 
Intensity NRS scores over the last 7 days prior to randomization,; at 
least 4 completed Worst Itching Intensity NRS worksheets will be 
required prior to randomization.   
The primary efficacy variable will be analyzed using a mixed effects 
model with repeated measures (MMRM).  The model will contain 
treatment, week, and treatment-by-week interaction as fixed effects; 
baseline score and renal disease status as covariates, and patient as a 
random effect.  For each dose group, the treatment group difference vs 
placebo will be estimated as the simple contrast in the treatment effect 
at Week 12 of the Treatment Period.  


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In the primary efficacy analysis, missing NRS data will be imputed 
using a multiple imputation (MI) approach, assuming that patients who 
discontinue study drug early would have similar Worst Itching 
Intensity NRS scores as other patients in their respective treatment arm 
that have complete data.  
Sensitivity analyses of the primary efficacy endpoint will be conducted 
to evaluate the robustness of study results under different assumptions 
and imputation algorithms (Section 8.6.1). 
 
Secondary Efficacy Endpoints 
The Skindex-10 Scale total score and the 5-D Itch Scale total score will 
be analyzed using an MMRM that will contain treatment, week, and 
treatment-by-week interaction as fixed effects, baseline score and renal 
disease status as covariates, and patient as a random effect.  Repeated 
measures will include values that reflect the Skindex-10 and the 5-D 
total scores at the end of Weeks 4, 8, 10, and 12 (end of treatment).  
The baseline value will be defined as the value of the Skindex-10 or 
5-D total score collected on day 1 prior to randomization.  Missing 
Skindex-10 Itch Scale and 5-D Itch Scales total scores will not be 
imputed.  The mean treatment difference between each CR845 dose 
and placebo will be estimated as the simple contrast in the treatment 
effect at Treatment Period Week 12. 
 
The proportion of patients achieving an improvement from baseline ≥3 
points with respect to the weekly mean of the daily 24-hour Worst 
Itching Intensity NRS score at Week 12 of the Treatment Period will 
be analyzed using logistic regression with terms for treatment group, 
baseline NRS score, and renal disease status.  Missing NRS data will 
be imputed using the same methodology described for the primary 
efficacy endpoint.  
Hypothesis Testing Strategy 
Testing of the primary efficacy endpoint will be 2-sided and conducted 
at the 5% error level.  The study will be considered positive if the null 
hypothesis of no treatment difference is rejected in favor of the 
alternative that patients randomized to CR845 experience significantly 
less itching, as measured by the change from baseline to Week 12 of 
the Treatment Period with respect to the weekly mean of the 24-hour 
Worst Itching Intensity NRS score.  This is a Phase 2 study designed to 
identify a safe and efficacious dose; therefore, each CR845 dose group 
will be compared against placebo.  There will be no adjustment for 
multiple comparisons.  
Safety Analyses 
Analysis of all safety data will be performed using the Safety 
Population.  Safety data will be summarized descriptively.  No 


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inferential statistics are planned.  Analyses of safety data will include 
summaries of treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), and adverse events resulting in study drug 
discontinuation.  Vital signs, clinical laboratory data, and ECG data 
will be descriptively summarized 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 ...................................................................................................... 14 
3.0 List of Abbreviations ................................................................................................ 18 
4.0 Introduction ............................................................................................................... 19 
4.1 
Background and Rationale ................................................................................19 
4.2 
Clinical Experience ...........................................................................................20 
4.3 
Summary of Potential Risks and Benefits .........................................................20 
5.0 Objectives ................................................................................................................. 22 
6.0 Investigational Plan ................................................................................................... 23 
6.1 
Overall Study Design and Plan:  Description ....................................................23 
6.2 
Selection of Study Population ...........................................................................26 
6.2.1 
Inclusion Criteria .......................................................................................26 
6.2.2 
Exclusion Criteria ......................................................................................27 
6.3 
Removal of Patients from Therapy or Assessment ...........................................29 
6.3.1 
Discontinuation of Individual Patients.......................................................29 
6.3.2 
Discontinuation or Suspension of Entire Study .........................................29 
6.4 
Treatments .........................................................................................................31 
6.4.1 
Treatments Administered ...........................................................................31 
6.4.2 
Identity of Investigational Product(s) ........................................................31 
6.4.3 
Drug Accountability...................................................................................31 
6.4.4 
Method of Assigning Patients to Treatment Groups..................................32 
6.4.5 
Treatment Compliance ...............................................................................32 
6.4.6 
Blinding......................................................................................................32 
6.4.7 
Prior, Concomitant, and Prohibited Medications .......................................32 
6.5 
Study Assessments and Procedures ...................................................................34 
6.5.1 
Efficacy Assessments.................................................................................38 
6.5.2 
Safety Assessments ....................................................................................39 
7.0 Discussion and Justification of Study Design ........................................................... 46 
7.1 
Discussion of Study Design and Choice of Control Groups .............................46 


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7.2 
Selection of Doses in the Study .........................................................................46 
7.3 
Appropriateness of Measurements ....................................................................47 
8.0 Statistical Methods .................................................................................................... 48 
8.1 
General Considerations .....................................................................................48 
8.2 
Determination of Sample Size ...........................................................................48 
8.3 
Randomization ...................................................................................................49 
8.4 
Analysis Populations .........................................................................................49 
8.5 
Statistical Summary and Analysis .....................................................................50 
8.5.1 
Patient Disposition .....................................................................................50 
8.5.2 
Protocol Deviations ....................................................................................50 
8.5.3 
Demographic and Baseline Characteristics ...............................................50 
8.5.4 
Medical History .........................................................................................50 
8.5.5 
Prior and Concomitant Medications ..........................................................51 
8.5.6 
Antipruritic Medication .............................................................................51 
8.6 
Efficacy Analyses ..............................................................................................51 
8.6.1 
Primary Efficacy Endpoint ........................................................................51 
8.6.2 
Secondary Efficacy Endpoints ...................................................................52 
8.6.3 
Hypothesis Testing Strategy ......................................................................53 
8.6.4 
Additional Efficacy Endpoints ...................................................................54 
8.7 
Safety Analyses .................................................................................................55 
8.7.1 
Exposure to Study Drug and Compliance ..................................................55 
8.7.2 
Adverse Events ..........................................................................................56 
8.7.3 
Clinical Laboratory Evaluations ................................................................57 
8.7.4 
Vital Signs and Electrocardiograms...........................................................58 
9.0 Quality Control and Quality Assurance .................................................................... 59 
9.1 
Study Monitoring Plan ......................................................................................59 
9.2 
Audits and Inspections ......................................................................................59 
9.3 
Data Collection, Validation, and Analysis ........................................................60 
10.0 Ethics and Regulatory Compliance ........................................................................... 61 
10.1 
Independent Ethics Committee or Institutional Review Board .........................61 


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10.2 
Ethical Conduct of the Study .............................................................................61 
10.3 
Informed Consent Process .................................................................................62 
10.4 
Patient Confidentiality .......................................................................................63 
11.0 Data Handling and Quality Assurance ...................................................................... 64 
12.0 Administrative Procedures ........................................................................................ 65 
12.1 
Protocol Adherence ...........................................................................................65 
12.2 
Publication of Study Findings ...........................................................................65 
13.0 References ................................................................................................................. 66 
14.0 Appendix ................................................................................................................... 68 
14.1 
Appendix 1:  New York Heart Association Classification of Heart Failure .....68 
14.2 
Appendix 2:  Worst Itching Intensity Numerical Rating Scale .........................69 
14.3 
Appendix 3:  Skindex-10 Scale .........................................................................70 
14.4 
Appendix 4:  5-D Itch Scale ..............................................................................71 
14.5 
Appendix 5:  Patient Global Impression of Change ..........................................73 
14.6 
Appendix 6:  Patient Global Impression of Worst Itch Severity .......................74 
 


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LIST OF TABLES 
Table 1. 
Restricted and Prohibited Medications ............................................. 34 
Table 2. 
Schedule of Events ............................................................................ 35 
Table 3. 
Schedule for Patient-reported Outcome Assessments and Training . 37 
Table 4. 
Power as a Function of Effect Size (N = 120 Per Arm)a .................. 49 
 
LIST OF FIGURES 
Figure 1. 
CR845-210301 Study Schematic ...................................................... 25 
 


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3.0 
List of Abbreviations 
ATC 
Anatomical Therapeutic Chemical 
CKD 
chronic kidney disease 
CNS 
central nervous system 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
H 
above the laboratory parameter’s reference range 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS/IWRS 
interactive voice or web response system 
KOR 
kappa-opioid receptor 
L 
below the laboratory parameter’s reference range 
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 
PGIC 
Patient Global Impression of Change 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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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4.0 
Introduction 
4.1 
Background and Rationale 
CR845 is a kappa-opioid receptor (KOR) agonist with a peripheral mechanism of action 
being developed by Cara Therapeutics, Inc. (designated as Cara Therapeutics or Sponsor 
in this protocol) as a novel therapeutic agent for the symptomatic relief of acute and 
chronic pain and pruritus.   
Opioid receptors are involved in the modulation of itch and pain signals and consist of 
3 subtypes:  mu, kappa, and delta.  These receptor subtypes are found in the central 
nervous system (CNS), in peripheral nervous system tissues, such as skin and viscera, 
and in the immune system (see Investigator’s Brochure or references for details).  An 
opioid analgesic like morphine acts primarily via activation of the mu-opioid receptor 
located in the CNS and peripheral nervous system, and as such, is associated with a wide 
array of side effects, including sedation, respiratory depression, abuse liability, and 
constipation.  CR845 was designed to activate KORs located primarily in the peripheral 
nervous system, which are known to modulate itch, pain, and inflammatory signals, 
without producing the side effects associated with the activation of mu-opioid receptors, 
such as respiratory depression, abuse liability, and constipation.   
CR845 is a potent and selective KOR agonist with more than 30,000-fold selectivity over 
mu- and delta-opioid receptors and does not demonstrate activity at other receptors, ion 
channels, or transporters.  The unique peptidic structure of CR845 significantly differs 
from other small molecule KOR agonists developed to date, which, for the most part, are 
CNS-active.  Being a hydrophilic peptide, CR845 has limited membrane permeability by 
passive diffusion, which limits its access to the CNS.  Since CR845 does not activate 
receptors other than KORs, and does not readily enter the CNS, it is expected to be safer 
and better tolerated than other opioid agonists, including centrally-acting kappa agonists. 
Thus far, CR845 has no abuse properties and no respiratory depression effects (see 
Investigator’s Brochure for details).  
Large multinational studies (Dialysis Outcomes and Practice Patterns) and studies based 
in the United States have demonstrated that approximately 30% to 40% of hemodialysis 
patients have moderate-to-severe pruritus.  Though renal transplantation may ameliorate 
pruritic symptoms, up to 38% of renal transplant recipients may have persistent itching 
[Panuccio, 2017].  There are no approved treatments for this condition in the United 
States and current off-label therapies are unable to successfully treat uremic pruritus.   
Although the pathophysiology of moderate-to-severe pruritus in hemodialysis patients is 
not well understood, there is increasing evidence that it is likely multifactorial and that an 
immune system dysfunction (including elevated proinflammatory activity) and imbalance 
in the endogenous opioid system (with over-expression of mu-opioid receptors in dermal 
cells and lymphocytes and concomitant downregulation of KORs) are involved 
[Kimmel 2006; Narita 2006; Phan 2012; Patel 2007; Mettang 2002; Tey 2011].   


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Based on nonclinical pharmacological studies, it was anticipated that CR845 will produce 
a combined anti-itch and anti-inflammatory effect (see Investigator’s Brochure for 
details), which could provide significant relief of itch in patients with chronic kidney 
disease.   
4.2 
Clinical Experience 
To date, more than 1300 healthy volunteers and patients have been exposed to CR845 
either as an intravenous (IV) or oral formulation.  The oral formulation of CR845 has 
been evaluated in 626 patients and healthy volunteers across three Phase 1 studies 
(including 1 study in hemodialysis patients) and two Phase 2 studies in patients with 
osteoarthritis.  CR845 has been evaluated as single or repeated enteric-coated tablets or 
capsules at dosage strengths ranging from 0.1 to 10 mg and with tablets of 1, 2.5, and 
5 mg administered twice daily for 8 weeks in osteoarthritis patients (Study CR845-
CLIN2002-PO).  In a Phase 1 study with hemodialysis patients, CR845 tablets at doses 
ranging from 0.25 to 1 mg administered either once after each dialysis session for 1 week 
(ie, 3 times) or once daily for 1 week was shown to be well-tolerated (Study CR845-
CLIN1301).  A recent Phase 1 study conducted in patients with moderate or severe 
chronic kidney disease (Stage III, IV, or V, not on maintenance dialysis) has also 
demonstrated that once-daily oral administration of CR845 was safe and well tolerated at 
doses of 0.25, 0.5, and 1 mg over a 1-week treatment period (Study CR845-CLIN1303).  
4.3 
Summary of Potential Risks and Benefits 
The potential benefit of CR845 in alleviating the symptoms of pruritus associated with 
chronic kidney disease (CKD) in hemodialysis patients is predicated on its 
pharmacological class and evidence of its effectiveness in multiple animal models of 
pruritus and in two Phase 2 clinical studies with IV CR845 in hemodialysis patients 
experiencing moderate-to-severe pruritus (CR845-CLIN2005 Part B and 
CR845-CLIN2101).   
In humans with normal renal function, CR845 has aquaretic effects that can result in 
dehydration and associated symptoms (eg, tachycardia) and hypernatremia if the fluid 
balance is not managed properly.  However, these effects appear to be absent in the 
dialysis population, many of whom are anuric and all of whom have few functioning 
nephrons.  These effects are also anticipated to be largely reduced in CKD patients stage 
III to IV not yet on dialysis. 
Overall, tingling/numbness, dizziness, fatigue and/or drowsiness/somnolence have been 
the most common adverse events. Due to the potential adverse event of 
fatigue/drowsiness/somnolence, subjects should be cautioned about operating hazardous 
machinery or operating a motor vehicle.   


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Gastrointestinal dysfunction (abdominal discomfort, nausea, constipation) may be 
possible, as it has been frequently reported after oral tablet administration in normal 
healthy volunteers.   
Tingling sensation or facial numbness has been reported shortly after administration of 
CR845.  This effect is transient and does not appear to be a clinically significant issue.   
While it has been demonstrated that CR845 has substantially less access to the CNS than 
previously tested kappa opioid agonists, adverse CNS effects of CR845 (eg, altered 
mental status) could still be considered a possibility (eg, hypothetically, in patients with 
impaired blood-brain barrier functioning).   
A detailed summary of the potential risks and benefits of CR845 is provided in the 
[Investigator’s Brochure].  The Investigator must become familiar with all sections of the 
current Investigator’s Brochure for CR845 before the start of the study.   


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5.0 
Objectives 
Primary Objective  
• To evaluate the efficacy of 3 dose levels of oral CR845 compared to placebo in 
reducing the intensity of itch in CKD patients with moderate-to-severe pruritus.   
Secondary Objectives  
• To evaluate the efficacy of 3 dose levels of oral CR845 compared to placebo in 
improving itch-related quality-of-life measures in CKD patients with 
moderate-to-severe pruritus.   
• To evaluate the safety of 3 dose levels of oral CR845 in CKD 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, randomized, double-blind, placebo-controlled study to evaluate the 
safety and efficacy of 3 dose levels (0.25, 0.5, and 1 mg) of oral CR845 in moderate-to- 
severe CKD patients with moderate-to-severe pruritus.   
This study will consist of a Screening Period, a 7-day Run-in Period, a 12-week 
Treatment Period, and a Follow-up Visit (approximately 7 to 10 days after the last dose 
of study drug).  Informed consent will be obtained prior to performing any study-specific 
procedures.  Screening will occur within 7 to 28 days prior to randomization to assess 
eligibility. 
Eligible patients will complete a 7-day Run-in Period during the week prior to 
randomization when they will be required to complete at least 4 Worst Itching Intensity 
numerical rating scale (NRS) worksheets.  The mean baseline Worst Itching Intensity 
NRS score during the 7-day Run-in Period must be ≥5.  The mean baseline is defined as 
the average of all non-missing scores reported from the start of the 7-day Run-in Period.  
For consistency, patients will be requested to complete the Worst Itching Intensity NRS 
worksheets at a similar time each day.    
Patients will also be trained on the Skindex-10 Scale, 5-D Itch Scale, Patient Global 
Impression of Worst Itch Severity, and Patient Global Impression of Change (PGIC) 
worksheets at any time during the Run-in Period or on Day 1 of the Treatment Period.   
Day 1 of the Treatment Period will be defined as the day of the administration of the first 
dose of study drug.     
If patients continue to meet all inclusion and no exclusion criteria at the end of the 7-day 
Run-in Period, they will be randomized in a 1:1:1:1 ratio to receive orally once daily 
either placebo or CR845 tablets at doses of 0.25, 0.5 or 1 mg.  Randomization will be 
stratified according to the patient’s renal disease status: moderate CKD; severe CKD non-
dialysis; severe CKD on dialysis (ie, 3 categories).  The randomization of severe CKD 
patients on hemodialysis will be capped at approximately 20% of the total sample size 
(ie, 48 of 240 patients). 
Patients will report their Worst Itching Intensity NRS score over the last 24 hours daily 
during the entire Treatment Period.  Patients will be instructed to complete the NRS score 
at a similar time of the day throughout the Treatment Period.  In addition, patients will 
complete other patient-reported outcome (PRO) measures (Skindex-10 Scale, 5-D Itch 
Scale, Patient Global Impression of Worst Itch Severity) during the Treatment Period.  
The PGIC will be completed at end of treatment/early termination.   
 


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Safety assessment will be monitored periodically as per schedule of events (Table 2).  
Adverse events and concomitant medications will be recorded during the study starting at 
Screening until the Follow-up Visit.  A final safety Follow-up Visit will be conducted 7 
to 10 days after the last dose of study drug.   
The study schematic is shown in Figure 1.   
 




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6.2 
Selection of Study Population 
Patients with moderate-to-severe CKD, including patients who have received a renal 
organ transplant, 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 before 
enrollment, randomization, and dosing.  All eligibility criteria must be met before a patient 
is enrolled.   
Rescreening will be considered on an individual patient basis and must first be approved 
by the Sponsor or Medical Monitor.   
6.2.1 
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; 
3. Male or female 18 years of age or older; 
4. CKD patients not currently maintained on hemodialysis with stage III, IV, or V 
disease (ie, moderate renal impairment with estimated glomerular filtration rate 
(GFR) ≥30 and <60 mL/min/1.73 m2 or severe renal impairment with estimated 
GFR <30 mL/min/1.73 m2).  For patients with severe CKD on hemodialysis, they 
must be receiving hemodialysis 3 times per week for at least 3 months prior to the 
start of screening; 
Note 1:  Patients who have received a renal organ transplant and who are at least 
6 months post-transplant with an estimated GFR <60 mL/min/1.73 m2 may 
participate if clinically stable and are on maintenance immunosuppression.  
Note 2:  Severe CKD patients on hemodialysis who require an additional 
hemodialysis treatment to manage fluid overload may be enrolled as long as it is 
anticipated that no more than 1 such treatment will be required in any given week. 
Note 3:  Severe CKD patients on hemodialysis 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. 
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 amenorrheic for at least 1 year and over the age of 55 years; or 


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c. has a negative serum pregnancy test at screening and agrees to use 
acceptable contraceptive measures (eg, hormonal contraceptives, barrier 
with spermicide, intrauterine device, vasectomized partner, or abstinence) 
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 body weight of between 40.0 and 140.0 kg, inclusive (for severe CKD 
patients on hemodialysis, this is the prescription dry body weight);  
9. Self-reports experiencing daily or near-daily pruritus during the month prior to 
screening;  
10. For severe patients on hemodialysis, at least 2 single-pool Kt/V measurements 
≥1.2, at least 2 urea reduction ratio measurements ≥65%, or 1 single-pool Kt/V 
measurement ≥1.2, and 1 urea reduction ratio measurement ≥65% on different 
dialysis days during the 3-month period prior to screening; 
11. Prior to randomization: 
a. Has completed at least 4 Worst Itching Intensity NRS worksheets from the 
start of the 7-day Run-in Period;  
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 7-day 
Run-in Period. 
6.2.2 
Exclusion Criteria 
A patient will be excluded from the study if any of the following criteria are met: 
1. Patients not currently on dialysis who are likely to initiate routine dialysis during 
study participation; 
2. For severe CKD patients on hemodialysis, noncompliance with hemodialysis 
treatment that, in the opinion of the Investigator, would impede completion or 
validity of the study; 
3. Scheduled to receive a kidney transplant during the study;  


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4. Has a concomitant disease or 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; 
5. New or change of treatment received for itch including antihistamines and 
corticosteroids (oral, IV, or topical) within 14 days prior to screening; 
6. New or change of prescription for opioids, gabapentin, or pregabalin within 
14 days prior to screening; 
7. Serum alanine aminotransferase or aspartate aminotransferase greater than 
2.5 times the reference upper limit of normal (ULN), or total bilirubin greater than 
2 times the ULN at screening; 
8. Received another investigational drug within 30 days prior to the start of screening 
or is planning to participate in another clinical study while enrolled in this study; 
9. Has pruritus attributed to a cause other than CKD (eg, patients with concomitant 
pruritic dermatological disease or cholestatic liver disease would be excluded); 
10. Has localized itch restricted to the palms of the hands;  
11. Anticipates receiving an opioid antagonist (eg, naloxone, naltrexone) or 
opioid-mixed agonist-antagonist (eg, buprenorphine, nalbuphine) from the start of 
screening through the end of the Treatment Period; 
12. Received ultraviolet B treatment within 30 days prior to the start of screening or 
anticipates receiving such treatment during the study; 
13. Participated in a previous clinical study with CR845. 
14. If currently a patient with a renal transplant: 
a. Has received an increase or a new immunosuppressive treatment due to an 
acute or chronic rejection episode 4 weeks prior to screening; 
b. Is anticipated to have a change in immunosuppressive treatment from 
screening to the end of the study.   


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6.3 
Removal of Patients from Therapy or Assessment 
6.3.1 
Discontinuation of Individual Patients 
A patient may withdraw from the study at any time at his/her own request for any reason 
without prejudice to future medical care by the physician or at the institution.  A patient 
may be withdrawn at any time due to the following reasons: 
1. At the discretion of the Investigator or the Sponsor for safety, behavioral, 
compliance, or administrative reasons; 
2. At the discretion of the Sponsor/Medical Monitor, if a patient receives a 
prohibited concomitant medication according to Table 1 (Section 6.4.7.2). 
In addition, any patient who becomes pregnant during the Treatment Period or within 
7 days after the last dose of study drug should be withdrawn from the study 
(Section 6.5.2.6). 
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 after the last dose of study drug or, as soon as feasible.  The Follow-up Visit 
is to be completed 7 to 10 days after the Early Termination Visit.   
If study drug is discontinued, 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.   
If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.   
Patients who discontinue after the administration of the first dose of study drug will not be 
replaced.   
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.  If the study is suspended or terminated, the Sponsor will ensure that applicable 
regulatory agencies and Institutional Review Boards (IRBs)/Independent Ethics 
Committees are notified, as appropriate.   


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Should the study be closed prematurely, all study materials (eg, completed, partially 
completed, and blank eCRFs, as well as study drug) must be returned to Cara Therapeutics 
or destroyed at the site according to instructions that will be provided by the Sponsor, as 
applicable.   


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6.4 
Treatments  
6.4.1 
Treatments Administered 
Study drug (placebo tablet or CR845 tablet at a dose of 0.25, 0.5 or 1 mg) should be taken 
once daily at least 2 hours prior to or after a meal, around the same time of day (patient 
should not lie down for at least 1 hour after swallowing the tablet).  
For severe CKD patients on hemodialysis, the study drug should not be taken until after 
following their dialysis procedure on days when they receive dialysis. Note that the same 
requirement for meal timing of study drug must also be followed. 
6.4.2 
Identity of Investigational Product(s) 
6.4.2.1 
Formulation of Study Drug  
CR845 will be provided as enteric-coated tablets at doses of 0.25, 0.5, and 1 mg.  Placebo 
will also be provided as enteric-coated tablets.  All tablets (CR845 and placebo) are white 
in color with no markings and are identical in appearance, regardless of dose.   
6.4.2.2 
Packaging, Labeling, and Storage Stability of Study Drug 
Study drug must be stored refrigerated.  CR845 tablets will be provided in 15-count 
bottles.  
Labeling of the bottles will include but not limited to the following: 
• Study protocol number (CR845-210301) 
• Bottle number 
• Patient identification number 
• Temperature storage instructions 
• Name and location of Sponsor 
• Administer according to protocol 
• Caution:  New Drug Limited by Federal (or United States) Law to Investigational 
Use 
6.4.3 
Drug Accountability 
The study drug is to be used exclusively in the clinical study according to the instructions 
of this protocol.  The Investigator is responsible for dispensing the study drug according to 
the dosing scheme and for ensuring proper storage of the study drug.   
The Investigator must confirm receipt of the study drug with his/her signature.  A copy of 
this receipt must be kept by the Investigator and another copy will be stored at Cara 


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Therapeutics.  Until the study drug is dispensed to the patients, it must be stored at 2°C to 
8°C in a securely locked area that is not generally accessible.   
The key to the storage area is to be kept by the Investigator or designee responsible for the 
study drug.  The storage area will be accessible only to those persons authorized by the 
Investigator to dispense the study drug.   
6.4.4 
Method of Assigning Patients to Treatment Groups 
Before the start of the study, computer-generated randomization schedules will be 
prepared.  Randomization will be performed using an interactive voice or web response 
system (IVRS/IWRS).  Patients will be randomized in a 1:1:1:1 ratio to receive CR845 
0.25 mg, 0.5 mg, 1 mg, or placebo.  Randomization will be stratified according to the 
patient’s renal disease status: moderate CKD non-dialysis; severe CKD non-dialysis; 
severe CKD on dialysis (ie, 3 categories).   
6.4.5 
Treatment Compliance 
Treatment compliance with study drug will be assessed by study personnel via tablet 
counts of returned study drug and by questioning the patient, if necessary, at every visit, as 
applicable.   
In addition, patients will be asked to record their daily intake of study drug.   
6.4.6 
Blinding 
Patients, Investigators, study staff, and the Sponsor will be blinded to study drug 
assignment.   
For medically urgent or emergent situations that necessitate knowledge of study drug 
assignment for patient management, the blind may be broken via the IVRS/IWRS.  
Medical Monitor should be contacted prior to breaking the blind.  The Sponsor and 
Medical Monitor will receive a report whenever a patient blind is broken.   
6.4.7 
Prior, Concomitant, and Prohibited Medications 
6.4.7.1 
Prior and Concomitant Medications 
Prior medications (including vitamins and herbal supplements) are defined as those that 
the patient has taken any time during the 30 days prior to Screening up until the first dose 
of study drug on Day 1.  Concomitant medications are medications that are taken from 
after the start of the first dose of study drug on Day 1 of the Treatment Period through the 
End-of-Treatment/Early Termination Visit.  Only medications that are used for adverse 
events will be recorded from the time after the End-of-Treatment/Early Termination Visit 
through the Follow-up Visit.  


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All prior and concomitant medications, including over-the-counter medications used by 
patients during this study, are to be recorded in the appropriate source documents at each 
scheduled visit and noted on the appropriate page of the eCRF, as applicable.   
All new concomitant medications or change of frequency and doses of a concomitant 
medication will be recorded.   


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6.4.7.2 
Restricted and Prohibited Medications 
During the Treatment Period, the following medications will be restricted or prohibited 
(Table 1). 
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 light-B treatments 
Not allowed 
Naloxone, naltrexone, or mixed agonist-
antagonists (eg, buprenorphine and 
nalbuphine) 
Not allowed, unless needed to treat an adverse 
event or emergent medical condition acutely. 
Antihistamines (oral, IV, or topical) 
Corticosteroids (oral, IV, or topical) 
treatments   
Opioids   
Gabapentin, pregabalin 
Changes to current prescription should be 
avoided from 14 days prior to Screening to 
the end of the Treatment Period unless for the 
treatment of an adverse event or emergent 
medical condition. 
No new medication to treat itch should be 
initiated. 
All new concomitant medications or change of frequency and doses of a concomitant 
medication will be recorded and taken into consideration during the assessment of an 
adverse event.   
6.5 
Study Assessments and Procedures 
Study procedures are summarized in Table 2 and Table 3.   
An informed consent form (ICF) will need to be signed prior to initiation of Screening and 
any procedures that follow.   




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Table 2. 
Schedule of Events (Continued) 
a. 
To be collected/performed prior to the first dose of study drug on Day 1.   
b. 
Vital signs, including body temperature, heart rate, and blood pressure, will be obtained while the patient is in a sitting or semi-recumbent position.   
c. 
Study drug will be dispensed to patients in bottles of 15 tablets following randomization on Day 1 and thereafter at each visit during the Treatment Period until the end of 
treatment/early termination visit.  Patients may be contacted to verify or remind them to take their tablet daily per the protocol. Patients must record when they took the study 
drug in a drug diary every day during the Treatment Period. 
d. 
Training on Worst Itching Intensity NRS on the first day of the Run-in Period.    
e. 
Training on Skindex-10, 5-D Itch, and Patient Global Impression of Worst Itch Severity may be performed at any time during the Run-in Period or on Day 1 of the Treatment 
Period.   
f. 
Patients will be requested to complete the NRS worksheets at a similar time each day.   
g. 
Skindex-10, 5-D Itch, and Patient Global Impression of Worst Itch Severity are to be completed at the clinical site.   
h. 
Concomitant medications will be updated at each study visit following the first dose of study drug on Day 1.   
j. 
A phone follow-up will be conducted, unless otherwise necessary. 




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Unscheduled visits may be necessary for outstanding, unresolved adverse events 
(eg, additional safety laboratory or clinical evaluations).  At minimum, for any 
unscheduled visit, the reason for the visit will be recorded and the adverse event(s) 
reported, as well as changes to concomitant medications, as applicable.  Additional 
testing (eg, laboratory tests, vital signs, ECGs) will be performed, as clinically indicated.   
6.5.1 
Efficacy Assessments 
The effect of CR845 on itch will be measured by the following PRO measures:   
• Worst Itching Intensity NRS score 
• Skindex-10 Scale 
• 5-D Itch Scale  
• Patient Global Impression of Change (PGIC) 
• Patient Global Impression of Worst Itch Severity 
Patients will be trained on completion of the Worst Itching Intensity NRS scale at the 
first day of the Run-in Period, and will be trained on Skindex-10 Scale, 5-D Itch Scale, 
Patient Global Impression of Worst Itch Severity, and PGIC worksheets at any time 
during the Run-In Period or on Day 1 of the Treatment Period.  All questionnaires must 
be completed in strict adherence to the Patient Reported Outcomes Instructions (as per 
Study Reference Manual).   
   
6.5.1.1 
Worst Itching Intensity Numerical Rating Scale 
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.”  Patients will be provided with these worksheets to 
record their 24-hour worst itching assessment scores.   
The Worst Itching Intensity NRS has been widely utilized for evaluation of chronic itch, 
including uremic pruritus [Kumagai 2010; Pisoni 2006; Mathur 2010; Ständer 2013].   


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6.5.1.2 
Skindex-10 Scale 
Developed specifically for uremic pruritus, the Skindex-10 Scale (Appendix 3, 
Section 14.3) is an instrument for measurement of quality of life that correlates with both 
itch intensity as well as other instruments evaluating quality of life in patients with 
uremic pruritus [Mathur 2010].  Patients are asked to fill 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).   
6.5.1.3 
5-D 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 (Appendix 4, 
Section 14.4).  The scale has been validated in patients with chronic pruritus and has been 
shown to be sensitive to changes in pruritus over time [Elman 2010].   
6.5.1.4 
Patient Global Impression of Change 
The PGIC is a global PRO measure that assesses the change (improvement or worsening) 
in overall status relative to the start of the study [Dworkin 2005].  The scale has only 
1 item, with values ranging from 1 (Very Much Improved) to 7 (Very Much Worse) 
(Appendix 5, Section 14.5).   
6.5.1.5 
Patient Global Impression of Worst Itch Severity 
The Patient Global Impression of Worst Itch Severity is a PRO measure that assesses itch 
severity [Guy 2000].  The scale has only 1 item, with 5 possible values ranging from 
none to very severe (Appendix 6, Section 14.6).   
6.5.2 
Safety Assessments 
The safety assessments for each patient are the following: 
• Severity, seriousness, and relationship of adverse events to study drug 
• Physical examination 
• Vital signs 
• 12-lead ECGs 
• Clinical laboratory tests 


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6.5.2.1 
Adverse Events 
6.5.2.1.1 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and that 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 pre-existing laboratory/diagnostic test 
abnormalities, will be documented in the patient’s record as medical history.   
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 in 
Section 6.5.2.1.3 will be reported as a serious adverse event (SAE) using the SAE Report 
Form, in addition to documenting in the eCRF.   
6.5.2.1.2 
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 


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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 
6.5.2.1.3 
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 that 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.   
6.5.2.1.4 
Severe vs 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 
threat to a patient’s life or functioning.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations.   
6.5.2.1.5 
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 


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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 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. 
6.5.2.1.6 
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 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, severity, causal relationship to study drug, action taken with study drug, and 
outcome (resolved, resolved with sequelae, resolving, not resolved, 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.   
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 or 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.   


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6.5.2.1.7 
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 Safety Management Plan.   
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 Food and Drug Administration (FDA), while the Investigator 
and designated study personnel will comply with the applicable local regulatory 
requirements related to reporting of SAEs to the IRB and Sponsor.   
It is the responsibility of Cara Therapeutics to send all regulatory reports to the FDA.  
Adverse events that are serious, related to the study drug, and unexpected (per the 
Investigator’s Brochure) will be reported to the FDA as per Code of Federal Regulations 
21 Code of Federal Regulations (CFR) 312.32 on Investigational New Drug safety 
reporting and as specified in the Safety Management Plan.   
For regulatory reporting purpose, the sponsor will follow “Guidance for Industry and 
Investigators -  Safety Reporting Requirements for INDs and BA/BE Studies” (December 
2012), which states “for serious events that are unexpected, the sponsor considers the 
investigator’s causality assessment but submits an IND safety report only for those events 
for which the sponsor determines there is a reasonable possibility that the drug caused the 
event, regardless of the investigator’s causality assessment.”   
As applicable, the Sponsor will also notify other participating Investigator(s) of all 
Investigational New Drug Safety Reports 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.   


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6.5.2.2 
Physical Examination 
Physical examinations at screening will include an examination of the heart, lungs, 
abdomen, extremities, and neurological and vascular systems.  Clinically significant 
abnormalities will be reported as medical history.   
6.5.2.3 
Vital Signs 
Vital signs include sitting or semi-recumbent body temperature, heart rate, and blood 
pressure.   
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 staff will evaluate and manage the patient per standard practices with 
knowledge of the patient’s typical blood pressure and heart rate excursions.   
6.5.2.4 
Electrocardiogram 
The 12-lead ECGs will be read locally by the Investigator or qualified designee.  An ECG 
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).   
6.5.2.5 
Clinical Laboratory Tests 
Blood samples for clinical laboratory tests, including hematology, serum chemistry and 
serum pregnancy will be analyzed by the central laboratory.  Processing and shipment of 
central laboratory samples will be described in the Laboratory Manual, along with the 
final list of laboratory tests.  
6.5.2.6 
Contraception and Pregnancy 
All 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 are methods with a failure rate of <1% per 
year, and include hormonal contraceptives for at least 1 cycle of treatment before study 


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enrollment, an intrauterine device, and double-barrier method (eg, male or female 
condom, diaphragm).   
Per inclusion criteria, male patients will agree not to donate sperm after the first dose of 
study drug until 7 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 7 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.   
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 during the Treatment Period or within 7 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 
be collected from the patient while respecting the confidentiality of the partner.  A 
pregnancy report will be completed.   


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7.0 
Discussion and Justification of Study Design 
7.1 
Discussion of Study Design and Choice of Control Groups 
This is a multicenter, randomized, double-blind, placebo-controlled study designed to 
evaluate the efficacy and safety of oral CR845 in CKD patients with moderate-to-severe 
pruritus.  A randomized, double-blind design was chosen to minimize bias.  The duration 
of the study is in accordance with International Council for Harmonisation (ICH) and 
FDA guidance [Guidance for Industry February 2016].   
7.2 
Selection of Doses in the Study 
The safety and pharmacokinetic data from Studies CR845-CLIN1301 and 
CR845-CLIN1303 provided the basis for the selection of the doses and dosing regimen of 
oral CR845 to be used in this study.  In Study CR845-CLIN1301 (Part B) conducted in 
hemodialysis patients with once-daily oral administration, CR845 was safe and well 
tolerated at doses of 0.25, 0.5, and 1 mg over a treatment period of 7 days (oral dosing 
was after the end of dialysis on dialysis days).  TEAEs were generally mild to moderate 
in severity and not dose-related. Two patients experienced serious TEAEs (diabetic foot 
ulcer in 1 placebo patient and hypertensive encephalopathy in 1 CR845 1 mg patient), 
neither of which was considered by the Investigator to be related to study drug.  There 
were no deaths and no patient experienced a TEAE that led to premature discontinuation 
from the study.  No clinically important or significant safety findings were observed with 
respect to laboratory, vital sign, or ECG results.  
In Study CR845-CLIN1303 conducted in patients with moderate or severe chronic 
kidney disease (Stage III, IV, or V, not on maintenance dialysis), once-daily oral 
administration of CR845 was safe and well tolerated at doses of 0.25, 0.5, and 1 mg over 
an 8-day treatment period.  TEAEs were generally mild to moderate in severity with no 
treatment-related serious TEAEs reported.  There were no deaths and no patient 
experienced a treatment-related TEAE that led to premature discontinuation from the 
study.  No clinically important or significant safety findings were observed with respect 
to laboratory, vital sign, or ECG results. 
In the Phase 2 Study CR845-CLIN2101, the IV dose of 0.5 mcg/kg of CR845 was 
established as an effective antipruritic dose in hemodialysis patients with moderate-to-
severe pruritus when administered after each dialysis over an 8-week treatment period. 
Based on the crossover phase of study CR845-CLIN1301, it was determined that a single 
oral dose of 1 mg produces comparable exposure in hemodialysis patients to an IV dose 
of 1 mcg/kg.  From the pharmacokinetic data with oral dosing established in the studies 
CR845-CLIN1301 and CR845-CLIN1303, a daily oral dose of CR845 ranging from 0.5 
to 1 mg in patients with moderate-to-severe CKD, as well as CKD patients on dialysis, 
will provide comparable systemic exposure to the 0.5 mcg/kg IV dose established in 
hemodialysis patients.  Therefore, oral doses of 0.25, 0.5, and 1.0 mg were selected to 


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bracket the exposure anticipated to produce an antipruritic effect in this patient 
population. 
7.3 
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  
(see Sections 6.5.1.1 through 6.5.1.5).   


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8.0 
Statistical Methods 
8.1 
General Considerations 
This protocol describes key safety and efficacy analyses of data collected as currently 
planned.  A SAP will be developed based on the clinical protocol and eCRFs and 
finalized prior to unblinding of the study; it will include a detailed description of the 
statistical methodology including the treatment of missing data and the patient eligibility 
criteria.  No database will be locked or analyses completed until the SAP has been 
approved.  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 
The minimum total sample size for this study is N = 240 patients (60 per treatment 
group) and the maximum is N = 480 (120 per treatment group).  An unblinded interim 
analysis (IA) will be conducted when approximately 50-60% of the planned 240 patients 
have been randomized and have either completed the 12-week Treatment Period or have 
discontinued study drug early.  The primary goal of the IA is to identify dose(s) of oral 
CR845 that are both safe and efficacious.  Doses that are found to be unsafe or poorly 
tolerated will be dropped from the study.  The sample size of any dose group that is found 
to be efficacious may be increased to ensure that the pairwise comparison against placebo 
with respect to the primary efficacy variable at the end of the study is powered 
appropriately.  No dose will be dropped for futility reasons.  A sample size of 60 patients 
per treatment group (the minimum sample size) will provide adequate power (≥80%) for 
effect sizes ≥0.52 for a 5% type 1 error and a 2-sided T-test.  Assuming a standard 
deviation of 2.6 for the primary efficacy variable, an effect size of 0.52 corresponds to a 
difference of approximately 1.4 point on a 0- to 10-point scale.   
A sample size of 120 patients per treatment group (the maximum sample size) will 
provide adequate power (≥80%) for effect sizes ≥0.40 for a 5% type 1 error and a 2-sided 
T-test.  Assuming a standard deviation of 2.6 for the primary efficacy variable, an effect 
size of 0.40 corresponds to a difference of approximately 1 point on a 0- to 10-point 
scale.  The power of a 2-sided hypothesis test with a 5% Type 1 error as a function of 
sample size and effect size is presented in Table 4. 


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Table 4. 
Power as a Function of Effect Size (N = 120 Per Arm)a 
Effect Size 
0.55 
0.52 
0.50 
0.45 
0.40 
0.35 
Power (N = 120) 
98% 
97% 
97% 
93% 
86% 
77% 
Power (N = 60) 
84% 
80% 
77% 
68% 
58% 
47% 
a. 
Power for a 2-sided T-test with equal variance and a 5% Type 1 error.   
8.3 
Randomization  
Before the start of the study, a computer-generated randomization schedule will be 
prepared.  Randomization will be performed using an IVRS/IWRS.  Patients will be 
randomized in a 1:1:1:1 ratio to receive either placebo or CR845 tablets at doses of 0.25, 
0.5, or 1 mg.  Randomization will be stratified according to the patient’s renal disease 
status: moderate CKD; severe CKD non-dialysis; severe CKD on dialysis 
(ie, 3 categories).  The randomization of severe CKD patients on hemodialysis will be 
capped at approximately 20% of the total sample size (ie, 48 of 240 patients).  
8.4 
Analysis Populations 
The Enrolled Population is defined as the group of patients who sign the ICF. 
The Safety and Full Analysis Populations are both defined as the group of all randomized 
patients who receive at least 1 dose of study drug.  Following the intent-to-treat principle, 
patients in the Full Analysis Population will be analyzed according to their randomized 
treatment, regardless of the actual treatment received.  Patients in the Safety Analysis 
Population will be analyzed according to their actual treatment.  The Safety Population 
will be used to analyze all safety endpoints, while the Full Analysis Population will be 
used to analyze all efficacy endpoints.   
The Per-Protocol Population is defined as the subset of patients in the Full Analysis 
Population who do not have any major protocol deviations that could affect the efficacy 
analyses.  An analysis of the primary and secondary efficacy variables for the 
Per-Protocol Population may be performed if more than 20% of the patients in the Full 
Analysis Population are excluded.   
Inclusion in the Per-Protocol Population will be determined prior to unblinding the data 
and will be detailed in the SAP.   


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8.5 
Statistical Summary and Analysis 
8.5.1 
Patient Disposition 
The number of patients enrolled, treated, who complete the 12-week treatment, or 
discontinue study drug early, along with the reason for discontinuation, will be 
summarized overall and by treatment group.   
For all categories of patients (except for the screened patients), percentages will be 
calculated using the number of enrolled patients as the denominator.   
In addition, the number of patients in each analysis population will be tabulated.  
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 by treatment group.  All protocol deviations will 
be listed.   
8.5.3 
Demographic and Baseline Characteristics 
Demographic and baseline patient characteristics will be summarized overall and by 
treatment group and will include age at screening, age category (<45, 45->65, 65-<75, 
≥75), gender, ethnicity, race, height, prescription dry body weight (kg) (for severe CKD 
patients on dialysis) or weight (for CKD patients not on dialysis), and body mass index. 
Baseline characteristics of the disease will also be summarized overall and by treatment 
group, and will include variables such as etiology of CKD, renal disease status, years 
since CKD diagnosis, duration of pruritus, and time on chronic hemodialysis (if 
applicable). 
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), Preferred Term, 
and treatment group.  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 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. 


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8.5.5 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary.  All 
prior and concomitant medications (see Section 6.4.7) will be listed and summarized 
separately by Anatomical Therapeutic Chemical (ATC) class 3, Preferred Term, and 
treatment group.  Additionally, a coding listing will be created which will include all 
distinct ATC class 3 codes and Preferred Terms along with the corresponding verbatim 
description of the concomitant medications; sorting will be alphabetically by ATC class 3 
and Preferred Term.  
8.5.6 
Antipruritic Medication 
An additional analysis of prior and concomitant antipruritic medications will be 
conducted.  These medications will be summarized by ingredient rather than by ATC 
codes.   
8.6 
Efficacy Analyses 
8.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the change from baseline to Week 12 of the 
Treatment Period with respect to the weekly mean of the daily 24 hour Worst Itching 
Intensity NRS score.  The weekly mean of the 24-hour Worst Itching Intensity NRS score 
will be defined as the sum of the daily Worst Itching Intensity NRS score reported during 
a specific week during the Treatment Period (eg, Days 2 to 8, Days 9 to 15, Days 16 to 
22, etc.) divided by the number of days with non-missing scores for that week.  If the 
daily worst itching score is missing for >3 days during a specific week, the corresponding 
weekly mean worst itching score will be set to missing.  The baseline score will be 
defined as the average of the daily 24-hour Worst Itching Intensity NRS scores over the 
last 7 days prior to randomization; at least 4 completed Worst Itching Intensity NRS 
worksheets will be required prior to randomization.   
The primary efficacy variable will be analyzed using a mixed effects model with repeated 
measures (MMRM).  The model will contain treatment, week, and treatment-by-week 
interaction as fixed effects; baseline score and renal disease status as covariates, and 
patient as a random effect.  For each dose group, the treatment group difference vs 
placebo will be estimated as the simple contrast in the treatment effect at Week 12 of the 
Treatment Period.   
An appropriate covariance matrix will be used to model the within patient errors.  The 
use of an unstructured covariance matrix structure as well as other structures, such as 
spatial patterns, that require fewer parameters (Toeplitz, autoregressive, or compound 
symmetry) will be examined.  The Akaike information criterion will be used to determine 
the appropriate covariance matrix for the MMRM model.  The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom.  


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In the primary efficacy analysis, missing NRS data will be imputed using a multiple 
imputation (MI) approach, assuming that patients who discontinue study drug early 
would have similar Worst Itching Intensity NRS scores as other patients in their 
respective treatment arm that have complete data.  Specifically, the following steps will 
be followed: 
• 
Intermittent missing NRS scores will first be imputed using the Markov Chain 
Monte Carlo (MCMC) method implemented with the SAS MI procedure, 
which is appropriate for non-monotonic missing data.  
• 
NRS scores missing after patients discontinue study drug early will then be 
multiply imputed with the SAS MI procedure using a method appropriate for 
monotone missingness (eg, regression statement).  
• 
Results of the MMRM on the multiply imputed data sets will be summarized 
by the SAS MIANALYZE procedure.   
Sensitivity analyses of the primary efficacy endpoint will be conducted to evaluate the 
robustness of study results under different assumptions and imputation algorithms, as 
described below: 
• 
Sensitivity analysis 1 (missing at random [MAR]): 
In this sensitivity analysis, missing daily worst itching scores will not be imputed.  
Assuming the data are MAR, the estimates of the treatment differences calculated from 
the MMRM model described above are unbiased.  
• 
Sensitivity analysis 2 (Multiple Imputation; MNAR) 
This sensitivity analysis is an implementation of a pattern mixture model that draws from 
different populations based on the reason for withdrawal.  For patients who discontinue 
study drug due to adverse events, data missing after discontinuation will be imputed 
using the distribution of the baseline value of all patients’ daily worst itching score 
assuming a trimmed normal (from 0 to 10).  For patients who discontinue due to reasons 
other than adverse event, missing data will be imputed using multiple calls of the SAS MI 
procedure.  At each time point, missing data will be imputed using data from patients 
within each group that have complete data at that time.  Results of the MMRM on the 
multiply imputed data sets will be summarized by the SAS MIANALYZE procedure. 
8.6.2 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are the: 
• Change from baseline in itch-related quality of life at the end of Week 12, as 
assessed by the total Skindex-10 Scale score; 
• Change from baseline in itch-related quality of life at the end of Week 12, as 
assessed by the total 5-D Itch Scale score; 


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• Proportion of patients achieving an improvement from baseline ≥3 points with 
respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS 
score at Week 12 of the Treatment Period. 
The Skindex-10 Scale total score and the 5-D Itch Scale total score will be analyzed 
using MMRM that will contain treatment, week, and treatment-by-week interaction as 
fixed effects, baseline score and renal disease status as covariates, and patient as a 
random effect.  Repeated measures will include values that reflect the Skindex-10 and 
5-D total score at the end of Weeks 4, 8, 10, and 12 (end of treatment).  The baseline 
value will be defined as the value of the Skindex-10 or 5-D total score collected on Day 1 
prior to randomization.  Missing Skindex-10 Itch Scale and 5-D Itch Scale total scores 
will not be imputed.  The mean treatment difference between CR845 dose and placebo 
will be estimated as the simple contrast in the treatment effect at Treatment Period 
Week 12.  
An appropriate covariance matrix will be used to model the within-patient errors.  The 
use of an unstructured covariance matrix structure as well as other structures, such as 
spatial patterns, that require fewer parameters (Toeplitz, autoregressive, or compound 
symmetry) will be examined.  The Akaike information criterion will be used to determine 
the appropriate covariance matrix for the MMRM.  The Kenward-Roger approximation 
will be used to estimate the denominator degrees of freedom.  The proportion of patients 
achieving an improvement from baseline ≥3 points with respect to the weekly mean of 
the daily 24-hour Worst Itching Intensity NRS score at Week 12 of the Treatment Period 
will be analyzed using logistic regression with terms for treatment group, baseline NRS 
score, and renal disease status.  
Missing NRS data will be imputed using the same methodology described for the primary 
efficacy endpoint.  Specifically,  
• 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 
≥3 points will be calculated for each imputed dataset derived for the primary 
efficacy analysis (Section 8.6.1).  Differences between each CR845 treatment 
group and placebo will be compared using a logistic regression model containing 
terms for treatment group, baseline NRS score and renal disease status.   
• Results of the logistic regression on the multiply imputed data sets will be 
summarized by the SAS MIANALYZE procedure.   
8.6.3 
Hypothesis Testing Strategy 
Testing of the primary efficacy endpoint will be 2-sided and conducted at the 5% error 
level.  The study will be considered positive if the null hypothesis of no treatment 
difference is rejected in favor of the alternative that patients randomized to CR845 
experience significantly less itching as measured by the change from baseline to Week 12 
of the Treatment Period with respect to the weekly mean of the 24-hour Worst Itching 


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Intensity NRS score.  This is a Phase 2 study designed to identify a safe and efficacious 
dose; therefore, each CR845 dose group will be compared against placebo.  There will be 
no adjustment for multiple comparison. 
8.6.4 
Additional Efficacy Endpoints 
8.6.4.1 
Itch-intensity Measures 
Itch-intensity measures and their analyses will include: 
• Proportion of patients who have an improvement from baseline at Week 12 of the 
Treatment Period with respect to the weekly mean of the 24-hour Worst Itching 
Intensity NRS scores ≥1, ≥2, and ≥4 points.  The calculation of the proportions 
will be based on the NRS data using an MI approach for the missing data as in the 
primary efficacy analysis.  Treatment differences will be compared using a 
logistic regression model with terms for treatment group, baseline NRS score and 
renal disease status.   
• A figure presenting the proportion of patients who have an improvement from 
baseline in NRS scores at Week 12 that are ≥1, ≥2, ≥3, and ≥4 will be prepared. 
• Change from baseline in the weekly mean of the 24-hour Worst Itching Intensity 
NRS score at each week of the Treatment Period (Week 1 to Week 12).  
Treatment differences between CR845 and placebo at each postbaseline time 
point will be evaluated using the same MMRM detailed in Section 8.6.1. 
• Proportion of patients who rate their itch condition as “Very much improved” or 
“Much improved” at the end of Week 12 of the Treatment Period/end of 
treatment, as measured by the PGIC.  Treatment difference will be tested using 
the Cochran-Mantel-Haenszel test, adjusting for strata.  An exact test, such as the 
Fisher’s exact test, may be used if the observed count in a particular cell is small 
(ie, <5). 
• The number and percentage of patients in each of the 5 categories of the Patient 
Global Impression of Worst Itch Severity at baseline and at each week of the 
Treatment Period will be tabulated.  In addition, the proportion of patients who 
have a 1-point improvement or more at each week of the Treatment Period, as 
measured by the Patient Global Impression of Worst Itch Severity.  Pairwise 
treatment differences with respect to this variable will be tested using the Fisher’s 
exact test.   
8.6.4.2 
Itch-related Quality-of-Life Measures 
Itch-related quality-of-life measures and their analyses will include: 
• Change from baseline in itch-related quality of life at each week of the Treatment 
Period, as assessed by the total score of the 5-D Itch Scale.  Treatment differences 


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between each CR845 dose group and placebo at each postbaseline time point will 
be evaluated using the same MMRM fitted for the secondary efficacy analysis. 
• Change from baseline in itch-related quality-of-life at each week of the Treatment 
Period, as assessed by the total score of the Skindex-10 Scale.  Treatment 
differences between each CR845 dose group and placebo at each postbaseline 
time point will be evaluated using the same MMRM fitted for the secondary 
efficacy analysis. 
• Change from baseline in itch-related quality of life at Week 12 of the Treatment 
Period and at each of the remaining weeks of the Treatment Period with respect to 
each of the 3 domains of the Skindex-10 Scale.  Treatment differences with 
respect to each domain will be evaluated using a model similar to the MMRM 
fitted for the analysis of the change from baseline in the total score of the 
Skindex-10 Scale.  
• Change from baseline in itch-related quality of life at Week 12 of the Treatment 
Period and at each of the remaining weeks of the Treatment Period with respect to 
each of the domains of 5-D Itch Scale.  Treatment differences with respect to each 
domain will be evaluated using a model similar to the MMRM fitted for the 
analysis of the change from baseline in the total score of the 5-D Scale.  
8.7 
Safety Analyses 
Analysis of all safety data will be performed using the Safety Population.  Safety data 
will be summarized descriptively.  No inferential statistics are planned.  The baseline 
value for all analyses of 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 84 doses of study drug.  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 last dose taken by the patient 
(determined based on the patient daily dosing diary).  For all patients, the last day of 
study will be defined as the date of the Follow-up Visit. 
Exposure and treatment compliance during the Treatment Period will be summarized by 
the following parameters: 
• Duration of treatment (days) 
• Duration of study (days) 


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• Total number of doses received (based on the patient daily dosing diary) 
• Total number of missed doses (0, 1, ≥2) (based on the patient daily dosing diary) 
• Percent compliance (<80%, 80% to 110%, >110%).  Compliance will be 
calculated in 2 different ways: based on the patient daily dosing diary and using 
drug accountability records 
8.7.2 
Adverse Events 
All adverse events will be coded using MedDRA dictionary to the corresponding 
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 during the Treatment Period. 
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 study End of Treatment/Early Termination Visit (or 7 to 10 days after the last 
dose if no End of Treatment/Early Termination Visit was conducted), whichever is later.   
Treatment-emergent adverse events will be summarized by treatment group and by 
period (Run-in Period vs Treatment Period).  The incidence of TEAEs will be presented 
using counts and percentages of patients with adverse events and tabulated by SOC and 
Preferred Term.  System Organ Class will be sorted alphabetically and Preferred Term 
within SOC will be sorted by descending frequency based on the incidence across 
patients overall.  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 following specific summary tables will be generated: 
• Incidence of TEAEs  
• Incidence of TEAEs related to study drug  
o If the 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 “related” to the study drug).  If a patient reports 2 or more 
adverse events that code to the same Preferred Term, the event with the 
maximum relationship will be included in the table. 
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o If the severity 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”).  If a patient reports 2 or more adverse events that 
code to the same Preferred Term, the event with the maximum severity 
will be included in the table.  
• Incidence of TEAEs occurring in ≥5% of patients in at least 1 treatment group 
• Incidence of treatment-related TEAEs occurring in ≥5% of patients in at least 
1 treatment group 
• Incidence of serious TEAEs 
• Incidence of TEAEs leading to study drug discontinuation 
In addition, an overall summary table will be provided, presenting for each treatment 
group:  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.   
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 drug, action taken with study drug, 
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.   


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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 Electrocardiograms 
Summary tables will include descriptive statistics for baseline and each postbaseline 
assessment.  Descriptive statistics will be calculated on both the actual score and the 
change from baseline score.  Baseline is defined as the last measurement taken prior to 
the first dose of study drug.  If 2 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, the latest evaluation will be 
selected for inclusion in the analysis.   
All vital signs will be listed in 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.   


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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 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 Cara Therapeutics or its designee (contract research organization).  
Monitoring will be done remotely or by personal visits from 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 Investigator Site File.   
Clinical laboratory testing will be completed at a central laboratory.  The central 
laboratory will provide a separate manual.   
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.   


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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.   
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 or Independent Ethics Committee 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 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 approval has been obtained.  The protocol, Investigator’s Brochure, ICF, 
advertisements (if applicable), written information given to the patients, safety updates, 
annual progress reports, and any revisions to these documents will be provided to the IRB 
by the Investigator.   
If it is necessary to amend the protocol and/or ICF during the course of the study, the 
Investigator must ensure that the IRB 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.   
The Investigator(s) will maintain documentation of the composition of the IRB as well as 
all correspondence with the IRB.  The Investigator(s) will comply with local 
requirements for routine reporting to the IRB as well as local and government 
requirements for notifying the IRB of SAEs.  The Investigator will provide Cara 
Therapeutics or its designee copies of all IRB 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 ethical principles founded in the 
Declaration of Helsinki and all accepted amendments, the ICH principles of GCP 
(including archiving of essential study documents), and the applicable regulations of the 
country 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-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 done 
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.   


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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 monitors 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/Independent Ethics 
Committee 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, Cara Therapeutics 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 should be notified of all protocol deviations 
in a timely manner according to IRB requirements. 
12.2 
Publication of Study Findings 
All information regarding CR845 provided by Cara Therapeutics 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 
Cara Therapeutics.  The Investigator agrees to use the information to conduct the study 
and will not use it for other purposes without written permission from Cara Therapeutics.  
Partial or full data or results from this study cannot be published without express written 
consent from Cara Therapeutics.  It is understood that there is an obligation to provide 
Cara Therapeutics 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 a 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 & 
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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. 
Guy W: Clinical Global Impressions (CGI) Scale. Modified From: Rush J, et al.: 
Psychiatric Measures, APA, Washington DC, 2000. 
Investigator’s Brochure. CR845 (Difelikefalin). Edition Number 8. 1 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. Nephrol Dial Transplant. 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. 
Panuccio V, Tripepi R, Bellantoni M, et al. Pruritus and quality of life in renal transplant 
patients. Clin Transplant. 2017;31(3):doi: 10.1111/ctr.12893. Epub 2017 Jan 6. 
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. 


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Version 1.2 
 
 
Pisoni RL, Wikström 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. 
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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CR845-210301 
 
 
14 May 2018 
 
Version 1.2 
 
 
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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Version 1.2 
 
 
14.2 
Appendix 2:  Worst Itching Intensity Numerical Rating Scale 
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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Version 1.2 
 
 
14.3 
Appendix 3:  Skindex-10 Scale 
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.   
 


Cara Therapeutics Inc. 
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Version 1.2 
 
 
14.4 
Appendix 4:  5-D Itch Scale 
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 May 2018 
 
Version 1.2 
 
 
 


Cara Therapeutics Inc. 
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Version 1.2 
 
 
14.5 
Appendix 5:  Patient Global Impression of Change 
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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Version 1.2 
 
 
14.6 
Appendix 6:  Patient Global Impression of Worst Itch Severity  
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. 
 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan  
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
           Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 1 of 57 
 
Protocol Title: 
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF ORAL CR845 IN CHRONIC 
KIDNEY DISEASE PATIENTS WITH MODERATE-TO-
SEVERE PRURITUS 
Protocol Number: 
CR845-210301 
Protocol Version, Date 
Version 1.2, 14May2018 
 
 
Document Version, Date: 
Final 3.0, 18 October 2019  
 
 
 
 
 
 
On behalf of: 
CARA Therapeutics, Inc.  
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons 
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment, which prevents unauthorized access to the document. 
 
 




 
 
 Statistical Analysis Plan (SAP) 
 
 
 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
                                                       Version: Final V3.0,
Date: 18Oct2019
Page 3 of 57
 
REVISION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version/Date 
Version 
name 
Section 
Changes implemented 
Version 1.0/ 
26MAR2019 
Version 1 
N/A 
N/A 
Version 2.0/ 
01JUL2019 
Version 2 
7.1 / 8.6.2 
Update condition to treat the Weekly NRS score as missing based on number 
of non-missing scores rather then number of days with missing scores. 
8.6.3 
Use multiple missing data imputation for secondary endpoints also. 
Version 3.0/ 
18OCT2019 
Version 3 
4.3 / 8.6.3 
/ 8.6.4 
New endpoints added: 
- 
Proportion of “complete responders” with respect to Worst Itching 
Intensity score. 
- 
Proportion of patients who indicate a severity of ‘None’ on the Patient 
Global Impression Worst Itch Severity scale. 
- 
Proportion of patients who either rate the degree of itching intensity 
over the past 2 weeks as ‘Not Present’ or the direction of itching as 
‘Completely Resolved’ from the 5-D Itch Scale. 
- 
Proportion of patients with itching present at each body part and the 
shift from baseline.  
7.1 / 8.1 
Provided further clarification regarding the terms “Baseline”, “On-treatment” 
and “End of Treatment”. 
8.4.2 
Baseline and screen failure summaries added for Glomerular filtration rate. 
8.4.5 
Section for prior/concomitant procedures added. 
8.5.3 
Section for CR845 exposure added. 
8.6.3 / 
8.6.4 
Standardization of the analysis of binary outcomes from non-multiple imputed 
data. Logistic regression model always performed, followed by Cochran-
Mantel-Haenzel test (or equivalent exact test if cell counts < 5). Analyses of 
“End of Treatment” result were ensured for all endpoints. 
8.7.2 
Definitions for “attained” and “sustained” sodium levels added. 


 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 4 of 57 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE ........................................................................................................... 2 
REVISION HISTORY ........................................................................................................ 3 
TABLE OF CONTENTS .................................................................................................... 4 
LIST OF ABBREVIATIONS ............................................................................................. 6 
1 INTRODUCTION ......................................................................................................... 7 
2 STUDY OBJECTIVES ................................................................................................. 8 
2.1 Primary objective .................................................................................................. 8 
2.2 Secondary objective (s) ........................................................................................ 8 
2.3 Exploratory objective ........................................................................................... 8 
3 STUDY DESIGN .......................................................................................................... 9 
3.1 General study design ............................................................................................ 9 
3.2 Randomization and blinding ............................................................................... 10 
3.3 Study treatments and assessments ...................................................................... 10 
4 STUDY ENDPOINTS ................................................................................................. 13 
4.1 Primary efficacy endpoint .................................................................................. 13 
4.2 Secondary efficacy endpoint(s) .......................................................................... 13 
4.3 Additional efficacy endpoint(s) .......................................................................... 13 
4.4 Safety endpoint(s) ............................................................................................... 14 
5 SAMPLE SIZE AND POWER ................................................................................... 15 
6 ANALYSIS POPULATIONS ..................................................................................... 16 
6.1 Enrolled Population ............................................................................................ 16 
6.2 Full Analysis Set (FAS) ...................................................................................... 16 
6.3 Safety population (Safety) .................................................................................. 16 
6.4 Per-Protocol population (PP) .............................................................................. 16 
6.5 Protocol deviations/violations and exclusions from analysis sets ...................... 17 
7 Statistical Considerations and analysis ........................................................................ 18 
7.1 Derived Variables ............................................................................................... 18 
7.2 Handling of missing data and outliers ................................................................ 19 
7.2.1 Missing data analysis methods ............................................................... 19 
7.2.2 Handling of missing or incomplete dates ............................................... 19 
7.3 Assessment Time Windows................................................................................ 20 
8 STATISTICAL METHODS........................................................................................ 21 
8.1 General statistical conventions ........................................................................... 21 
8.2 Subject disposition .............................................................................................. 22 
8.3 Protocol deviations ............................................................................................. 22 
8.4 Demographics and baseline characteristics ........................................................ 22 
8.4.1 Demographics ......................................................................................... 22 
8.4.2 Baseline and disease characteristics ....................................................... 23 
8.4.3 Medical History ...................................................................................... 23 
8.4.4 Prior and concomitant medications ........................................................ 23 
8.4.5 Prior and concomitant procedures .......................................................... 24 
8.5 Extent of exposure .............................................................................................. 24 
8.5.1 Treatment duration ................................................................................. 24 


 
 
Statistical Analysis Plan (SAP) 
 
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              Date: 18Oct2019
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8.5.2 Treatment compliance ............................................................................ 25 
8.5.3 Exposure to CR845 ................................................................................. 25 
8.6 Efficacy analyses ................................................................................................ 25 
8.6.1 Analysis methods .................................................................................... 26 
8.6.1.1 Multiplicity ............................................................................................. 26 
8.6.1.2 Treatment by center interaction analysis (multi-center study) ............... 26 
8.6.2 Analysis of primary efficacy endpoint ................................................... 26 
8.6.3 Analysis of secondary efficacy endpoint(s)............................................ 29 
8.6.4 Analysis of additional efficacy endpoint(s) ............................................ 31 
8.7 Safety analyses ................................................................................................... 34 
8.7.1 Adverse events ........................................................................................ 35 
8.7.2 Clinical laboratory evaluations ............................................................... 36 
8.7.3 Vital signs ............................................................................................... 37 
8.7.4 Electrocardiograms ................................................................................. 38 
8.8 Other analysis ..................................................................................................... 39 
8.8.1 Subgroup analysis ................................................................................... 39 
8.9 Interim analysis .................................................................................................. 39 
8.9.1 General Strategy ..................................................................................... 39 
8.9.2 Interim Analysis Statistical Analysis ...................................................... 41 
8.9.2.1 Subject disposition including study population ...................................... 41 
8.9.2.2 Demographic and Baseline Characteristic .............................................. 41 
8.9.2.3 Summary and analysis of NRS score ..................................................... 41 
8.9.2.4 Summary and analysis of Skindex-10 and 5-D Itch total scale score and 
Responder Analysis ................................................................................ 42 
8.9.2.5 Safety Analysis ....................................................................................... 42 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ................... 43 
10 REFERENCES ............................................................................................................ 44 
11 APPENDICES ............................................................................................................. 45 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 6 of 57 
 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
cm 
Centimeter 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
GFR 
Glomerular filtration rate 
IA 
Interim Analysis 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IVRS/IWRS 
Interactive Voice or Web Response System 
Kg 
Kilogram 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measurements 
MNAR 
Missing Not At Random 
NRS 
Numerical Rating Scale 
PGIC 
Patient Global Impression of Change 
PP 
Per Protocol 
PRO 
Patient-Reported Outcome 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD  
Standard Deviation 
SE 
Standard error 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
ULN 
Upper Limit of Normal 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 7 of 57 
 
1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol CR845- 210301, 
version 1.2, “A multicenter, double-blind, randomized, placebo-controlled study to evaluate 
the safety and efficacy of oral CR845 in chronic kidney disease patients with moderate-to-
severe pruritus” dated 14 May 2018 for Interim and Final analysis. The table of contents and 
templates for the tables, figures and listings (TFLs) will be produced in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report 
(CSR). 
 
The preparation of this SAP has been based on International Conference on Harmonization 
(ICH) E9. 
Unless otherwise specified, all data analyses and generation of TFLs will be performed using 
SAS 9.2® or higher. 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 8 of 57 
 
2 
STUDY OBJECTIVES 
2.1 
Primary objective 
To evaluate the efficacy of 3 dose levels of oral CR845 compared to placebo in reducing the 
intensity of itch in Chronic Kidney Disease (CKD) patients with moderate-to-severe 
pruritus. 
2.2 
Secondary objective (s) 
• To evaluate the efficacy of 3 dose levels of oral CR845 compared to placebo in 
improving itch-related quality-of-life measures in CKD patients with moderate-to-
severe pruritus  
• To evaluate the safety of 3 dose levels of oral CR845 in CKD patients with moderate-
to-severe pruritus.  
2.3 
Exploratory objective 
Not Applicable. 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 9 of 57 
 
3 
STUDY DESIGN 
3.1 
General study design 
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
safety and efficacy of 3 dose levels (0.25, 0.5, and 1 mg) of oral CR845 in moderate-to-
severe CKD patients with moderate-to-severe pruritus. 
 
Total study duration for a single patient: up to approximately 18 weeks  
• Screening Period: 7 to 28 days prior to randomization (Day -28 to Day -8)  
• Run-in Period:1 week prior to randomization (Day -7 to Day -1)  
• Treatment Period: 12 weeks  
• Follow-up Visit: 7-10 days after the End-of-Treatment Visit or Early Termination 
Visit  
Eligible patients will enter a 7-day Run-in period during the week prior to randomization 
when they will be required to complete at least four 24-hr Worst Itching Intensity NRS 
worksheets. If patients continue to meet all inclusion and no exclusion criteria at the end of 
the 7-day Run-in period and their mean baseline Worst Itching Intensity NRS score is ≥5, 
they will be randomized in a 1:1:1:1 ratio to receive orally once daily either placebo or 
CR845 tablets at doses of 0.25, 0.5 or 1 mg. The mean baseline NRS score is defined as the 
average of the non-missing scores reported from the start of the 7-day Run-in period (eligible 
patients cannot have more than 3 missing daily scores during the run-in period). 
Randomization will be stratified according to the patient’s renal disease status: moderate 
CKD non-dialysis; severe CKD non-dialysis; severe CKD on dialysis. The randomization of 
severe CKD patients on hemodialysis will be capped at approximately 20% of the total 
sample size. 
The planned sample size is approximately 240 (60 per treatment group) male and female 
CKD patients with moderate-to-severe pruritus (mean baseline 24-hour Worst Itching 
Intensity numerical rating scale (NRS) score ≥5). The sample size may be increased up to 
480 patients (120 per treatment group) based on the results of a planned interim analysis (IA) 
to be conducted when approximately 50-60% of the planned 240 patients have been 
randomized and have either completed the 12-week Treatment period or have discontinued 
study drug early.  
 
 


 
 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 10 of 57 
 
The study schematic is shown in Figure 1. 
Figure-1 CR845-210301 Study Schematic 
 
 
3.2 
Randomization and blinding 
Before the start of the study, a computer-generated randomization schedule will be prepared. 
Randomization will be performed using an interactive voice or web response system 
(IVRS/IWRS). Patients will be randomized in a 1:1:1:1 ratio to receive either placebo or 
CR845 tablets at doses of 0.25, 0.5, or 1 mg. Randomization will be stratified according to 
the patient’s renal disease status: moderate CKD non-dialysis; severe CKD non-dialysis; 
severe CKD on dialysis (ie, 3 categories). The randomization of severe CKD patients on 
hemodialysis will be capped at approximately 20% of the total sample size (ie, 48 of 240 
patients).  
Patients, investigators, study staff, and the sponsor will be blinded to study drug assignment.  
For medically urgent or emergent situations that necessitate knowledge of study drug 
assignment for patient management, the blind may be broken via the IVRS/IWRS. Whenever 
possible, the medical monitor should be contacted prior to breaking the blind. The sponsor 
and medical monitor will receive a report whenever a patient blind is broken.  
3.3 
Study treatments and assessments 
As described in Section 3.1, randomized patients will take study drug once daily for 12 
weeks and a total of 84 doses of study drug. Each dose should be taken at least 2 hours prior 
to or after a meal, around the same time of day (patient should not lie down for at least 1 
hour after swallowing the tablet).  
For severe CKD patients on hemodialysis, the same requirement for meal timing of study 
drug is required but the study drug must not be taken until after their dialysis procedure on 
days when they receive dialysis.  
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the scheduled of study assessments in Table 1. 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                      Page 11 of 57
 
Table 1: Schedule of Events 
Study Procedures  
 
 
Screening Period 
Treatment Period 
Follow-upj 
 
Screening 
Period  
Run-in 
Period  
 
EOT or Early 
Termination 
Study Week 
 
 
1 
2 
4 
6 
8 
10 
12 
 
Visit Days 
-28 to -7  
-7 to -1  
1 
14 
28 
42 
56 
70 
84 (or following 
discontinuation 
at any time) 
7 to 10 days after 
EOT/Early 
Termination 
 
 
 
 
±2 days 
 
Administrative procedures  
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
X 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Review drug dosing instructions with patient  
 
 
X 
 
 
 
 
 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
Safety and efficacy evaluations  
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
Weight (this is the prescription dry body weight 
for hemodialysis patients) 
X 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram  
X 
 
Xa 
 
 
 
 
 
X 
 
Vital signsb  
X 
 
Xa 
X 
X 
X 
X 
X 
X 
 
Hematology  
X 
 
Xa 
 
 
X 
 
 
X 
 
Serum chemistry   
X 
 
Xa 
 
 
X 
 
 
X 
 
Serum pregnancy (females of childbearing 
potential only)  
X 
 
Xa 
 
 
 
 
 
X 
 
Dispense study drug and drug diaryc  
 
 
X 
X 
X 
X 
X 
X 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
 
 
 
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Protocol Number: CR845-210301 
            Version: Final V3.0,
              Date: 18Oct2019
                                                      Page 12 of 57
 
Study Procedures  
 
 
Screening Period 
Treatment Period 
Follow-upj 
 
Screening 
Period  
Run-in 
Period  
 
EOT or Early 
Termination 
Study Week 
 
 
1 
2 
4 
6 
8 
10 
12 
 
Visit Days 
-28 to -7  
-7 to -1  
1 
14 
28 
42 
56 
70 
84 (or following 
discontinuation 
at any time) 
7 to 10 days after 
EOT/Early 
Termination 
 
 
 
 
±2 days 
 
Patient training on PRO worksheets 
 
Xd,e 
Xe 
 
 
 
 
 
 
 
Worst Itching Intensity NRS (daily)  
 
X 
Xf 
 
 
X 
 
Skindex-10, 5-D Itch Scale, Patient Global 
Impression of Worst Itch Severityg  
 
 
Xa 
 
X 
 
X 
X 
X 
 
Patient Global Impression of Change 
 
 
 
 
 
 
 
 
X 
 
Adverse event assessment  
 
Prior medications 
X 
 
 
 
 
 
 
 
 
Concomitant medicationsh 
 
 
 
CKD = chronic kidney disease; EOT = end of treatment; NRS = numerical rating scale; PRO = patient-reported outcome 
 
a) 
To be collected/performed prior to the first dose of study drug on Day 1.  
b) 
Vital signs, including body temperature, heart rate, and blood pressure, will be obtained while the patient is in a sitting or semi-recumbent position.  
c) 
Study drug will be dispensed to patients in bottles of 15 tablets following randomization on Day 1 and thereafter at each visit during the Treatment Period until the end of 
treatment/early termination visit.  Patients may be contacted to verify or remind them to take their tablet daily per the protocol. Patients must record when they took the study 
drug in a drug diary every day during the Treatment Period.  
d) 
Training on Worst Itching Intensity NRS on the first day of the Run-in Period.  
e) 
Training on Skindex-10, 5-D Itch, and Patient Global Impression of Worst Itch Severity may be performed at any time during the Run-in Period or on Day 1 of the Treatment 
Period.  
f) 
Patients will be requested to complete the NRS worksheets at a similar time each day.  
g) 
Skindex-10, 5-D Itch, and Patient Global Impression of Worst Itch Severity are to be completed at the clinical site.  
h) 
Concomitant medications will be updated at each study visit following the first dose of study drug on Day 1.  
j) 
A phone follow-up will be conducted, unless otherwise necessary.  


 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 13 of 57 
 
4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint 
The primary efficacy endpoint is defined as the change from baseline to week 12 of the 
Treatment period with respect to the weekly mean of the daily 24 hour Worst Itching 
Intensity NRS score. 
4.2 
Secondary efficacy endpoint(s) 
The secondary efficacy endpoints of this study are: 
• Change from baseline in itch-related quality of life at the end of week 12, as assessed 
by the total Skindex-10 scale score;  
 
• Change from baseline in itch-related quality of life at the end of week 12, as assessed 
by the 5-D Itch Scale score;  
 
• Proportion of patients achieving an improvement from baseline ≥3 points with 
respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score 
at Week 12 of the Treatment period.  
4.3 
Additional efficacy endpoint(s) 
The additional efficacy endpoints of this study are: 
Itch-intensity Measures 
 
• Proportion of patients who have an improvement from baseline at each week of the 
Treatment period and end of treatment with respect to the weekly mean of the 24-
hour Worst Itching Intensity NRS scores ≥1, ≥2, ≥3 (excluding week 12) and ≥4 
points.  
 
• Proportion of “complete responders” with respect to Worst Itching Intensity score 
NRS at each week of the Treatment period and at end of treatment. A patient that has 
≥ 80% of the non-missing daily NRS scores in a week equal to 0 or 1 is considered 
a complete responder at that week. 
 
• Change from baseline in the weekly mean of the 24-hour Worst Itching Intensity 
NRS score at each week of the Treatment period (Week 1 to Week 11) and at end of 
treatment.  
 
• Proportion of patients who rate their itch condition as “Very much improved” or 
“Much improved” at Week 12/end of treatment, as measured by the Patient Global 
Impression of Change (PGIC).  
 


 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 14 of 57 
 
• Proportion of patients in each of the 5 categories of the Patient Global Impression of 
worst itch severity at baseline and at each scheduled weekly visit of the Treatment 
period and end of treatment.  
In addition:  
o Proportion of patients who have a 1-point improvement or more from 
baseline 
o Proportion of patients who indicate a severity of ‘None’.  
 
 
Itch-related Quality-of-Life Measures 
 
• Change from baseline in itch-related quality of life at each scheduled weekly visit of 
the Treatment period (excluding Week 12) and end of treatment, as assessed by the 
total score of the 5-D Itch Scale.  
In addition, at each scheduled weekly visit of the Treatment period and end of 
treatment: 
o Proportion of patients who either rate the degree of itching intensity over the 
past 2 weeks as ‘Not Present’ or the direction of itching as ‘Completely 
Resolved’ from the 5-D Itch Scale. 
o Proportion of patients with itching present at each body part and the shift 
from baseline.  
 
• Change from baseline in itch-related quality-of-life at each scheduled weekly visit 
(excluding Week 12) of the Treatment period and end of treatment, as assessed by 
the total score of the Skindex-10 Scale.  
 
• Change from baseline in itch-related quality-of-life at each scheduled weekly visit of 
the Treatment period and end of treatment with respect to each of the 3 domains of 
the Skindex-10 Scale.  
 
• Change from baseline in itch-related quality-of-life at each scheduled weekly visit 
(excluding Week 12) of the Treatment period and end of treatment with respect to 
each of the domains of 5-D Itch Scale.  
4.4 
Safety endpoint(s) 
The safety assessments to evaluate the overall safety of CR845 will include, 
• Adverse events  
• Vital signs  
• 12-lead Electrocardiograms (ECGs)  
• Clinical laboratory evaluations 
• Exposure to Study Drug and Compliance  
 


 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 15 of 57 
 
5 
SAMPLE SIZE AND POWER 
The minimum total sample size for this study is N = 240 patients (60 per treatment group) 
and the maximum is N = 480 (120 per treatment group). An unblinded interim analysis (IA) 
will be conducted when approximately 50-60% of the planned 240 patients have been 
randomized and have either completed the 12-week Treatment period or have discontinued 
study drug early. The primary goal of the IA is to identify dose(s) of oral CR845 that are 
both safe and efficacious. Doses that are found to be unsafe or poorly tolerated will be 
dropped from the study. No dose will be dropped for futility reasons. The details of sample 
size re-estimation based on conditional power are described in section 8.9.1. A sample size 
of 60 patients per treatment group (the minimum sample size) will provide adequate power 
(≥80%) for effect sizes ≥0.52 for a 5% type 1 error and a 2-sided T-test. Assuming a standard 
deviation of 2.6 for the primary efficacy variable, an effect size of 0.52 corresponds to a 
difference of approximately 1.4 point on a 0- to 10-point scale.  
A sample size of 120 patients per treatment group (the maximum sample size) will provide 
adequate power (≥80%) for effect sizes ≥0.40 for a 5% type 1 error and a 2-sided T-test. 
Assuming a standard deviation of 2.6 for the primary efficacy variable, an effect size of 0.40 
corresponds to a difference of approximately 1 point on a 0- to 10-point scale. The power of 
a 2-sided hypothesis test with a 5% Type 1 error as a function of sample size and effect size 
is presented below. 
Power as a Function of Effect Size (N = 120 Per Arm)a 
Effect Size 
0.55 
0.52 
0.50 
0.45 
0.40 
0.35 
Power (N = 120)  
98% 
97% 
97% 
93% 
86% 
77% 
Power (N = 60)  
84% 
80% 
77% 
68% 
58% 
47% 
a Power for a 2-sided T-test with equal variance and a 5% Type 1 error. 


 
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6 
ANALYSIS POPULATIONS 
6.1 
Enrolled Population 
The enrolled population is defined as the group of patients who sign the informed consent 
form (ICF). 
6.2 
Full Analysis Set (FAS) 
The full analysis set is defined as all randomized patients who received at least 1 dose of 
study drug. Patients in the full analysis set will be analyzed according to their randomized 
treatment, regardless of the actual treatment received. The Full Analysis set will be used to 
analyze all efficacy endpoints. 
6.3 
Safety population (Safety) 
The safety analysis population is defined as all randomized patients who received at least 1 
dose of study drug. Patients in the safety analysis population will be analyzed according to 
their actual treatment. The Safety Population will be used to analyze all safety endpoints. 
6.4 
Per-Protocol population (PP) 
The Per-Protocol Population is defined as the subset of patients in the full analysis set who 
do not have any major protocol deviations that could affect the efficacy analyses. An analysis 
of the primary and secondary efficacy variables for the per-protocol population may be 
performed if more than 20% of the patients in the full analysis set are excluded. 
The per protocol population include patients who: 
• Received ≥ 80% and ≤120% of the planned study drug doses 
• Had a mean baseline Worst Itching Intensity NRS score ≥ 5.0 
• Had a non-missing average 24-hour weekly Worst Itching NRS score available for 
at least 75% of study weeks (weeks with >3 missing daily values are missing) 
• Did not have significant amounts of restricted and prohibited medications listed in 
protocol Section 6.4.7.2. 
• Did not have major protocol violations that would impact efficacy outcomes. 
• Satisfied all major inclusion and exclusion criteria on study entry and received 
treatment as planned. 
Patients in the per-protocol population will be analyzed according to their actual treatment. 
 
 
 


 
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6.5 
Protocol deviations/violations and exclusions from analysis sets 
All violations and exclusions of patients from analysis sets will be identified through 
programmatic checks, through medical reviews, and by clinical research associates during 
site monitoring. Protocol deviations will be classified as minor or major and whether they 
result in exclusion of the patient from the PP set, prior to the database lock. 






 
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partial portion of the first dose date and the medication is ongoing, the particular 
medication will be classified as ‘concomitant’.   
Missing or partial medication stop date: 
 If the stop date is completely missing then it will be assumed to be ongoing 
 
If the stop date is partially missing then it will be compared to the partial portion of 
the date of first dose. If the partial medication stop date is greater than the partial 
portion of the first dose date, the particular medication will be classified as 
‘concomitant’. 
 
7.3 
Assessment Time Windows 
For the primary analysis variable, assessment time windows are not needed since the NRS 
Itch Intensity Assessments Log collects the daily individual scores and average NRS score 
for the run-in and each post-baseline visit week are calculated based on these daily scores.  
Assessments collected by study week that are collected at early termination visits and 
unscheduled visits will be assigned to a post-baseline planned visit window, if the early 
termination or unscheduled visit day falls between +/- 2 days of the planned visit. Should 
more than one measurement fall within a visit window, priority is given first to the 
measurement with a non-missing value in the following order, first the scheduled 
assessment, second to an early termination visit, then the unscheduled assessment closest to 
the planned day will be used. In the case that two unscheduled visits are equidistant, the 
latest will be used. This rule will be applied both to efficacy and safety endpoints.  


 
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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.2 or higher. 
Unless otherwise noted, continuous variables will be summarized using descriptive statistics, 
including number of patients with non-missing observation (n), mean, median, standard 
deviation (SD), minimum (min) and maximum (max). Means and medians will be reported 
to one decimal place more than the raw data. Standard deviation will be reported to two more 
decimal places than the raw value. The minimum and maximum will be reported to the same 
decimal as the raw data. 
Categorical variables will be summarized using the frequency count and the percentage of 
patients in each category. All percentages will be rounded to one decimal point. The number 
and percentage of patients will always be presented in the form XX (XX.X%) where the 
percentage is in parentheses. To ensure completeness, all summaries for categorical and 
discrete variables will include all categories, even if none of the patients in a particular 
category. Counts of zero in any category will be presented as “0”. Unless otherwise noted, 
for all percentages, the number of patients in the analysis population for the treatment group 
will be the denominator. 
 “Baseline” will be defined as per section 7.1. For efficacy endpoints, “on-treatment” is 
defined as any assessment following the first dose of study drug and within 2 days from the 
last dose of study drug recorded in the patient diary. For safety endpoints (excluding adverse 
events), any assessment within 7 days after last dose of study drug will be deemed “on-
treatment”. For all endpoints “End of treatment” (EOT), in summaries, will be represented 
by the last non-missing on-treatment value recorded up to and including the Week 12/Early 
Termination visit. Treatment emergence for adverse events is described in section 8.7.1. 
Summaries will be presented across all scheduled visits and EOT unless stated otherwise. 
Only on-treatment data will be used in summaries and statistical analyses (with the exception 
of the Patient Global Impression of Change).  
Unless otherwise stated, all statistical testing will be two-sided and will be performed using 
a significance (alpha) level of 0.05. Two-sided 95% confidence intervals (CI) will be 
provided appropriately. For tests of hypothesis of treatment group differences, the associated 
p-value will be reported. All p-values will be rounded to three decimal places; p-values that 
round to 0.000 will be presented as “< 0.001”. 
All patients data, including those derived, will be presented in individual patient data listings. 
Unless otherwise stated, unscheduled visit results will be included in date/time chronological 
order, within patient listings only. All listings will be sorted by treatment, patient number, 
date/time and visit. Patient listings of efficacy and safety data will be presented for all full 
analysis set and safety set patients respectively unless specified otherwise. 


 
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8.2 
Subject disposition 
The number of enrolments, screen failures, randomizations and treated patients will be 
summarized over all patients. In addition, the number of each reason for screen failure will 
be provided. In this summary table, percentages will be calculated using the number of 
enrolments as the denominator.  
The number and percent of screen failure patients failing each inclusion and exclusion 
criteria at least one once will be summarized. The percentages will be calculated using the 
number of patients in the enrolled population. 
A separate display will present the number and percent of patients who receive study 
treatment, complete the 12-week study treatment, who discontinue from double-blind 
treatment, (and the reason for study treatment discontinuation), and who complete the 
follow-up. For this table, percentages will be calculated using the number in patients in the 
safety population. 
Additionally, the above table will summarize the number and percent of randomized patients 
in the following populations:  
• Full Analysis set; 
• Safety population; 
• Per Protocol population; 
8.3 
Protocol deviations 
Protocol deviations will be classified as minor or major and whether they led to exclusion of 
the patient from the Per Protocol Population prior to the database lock. Major protocol 
deviations overall and major protocol deviations leading to exclusion of the the patient from 
the Per Protocol Population will be summarized by category and overall. All protocol 
deviations will be listed. 
8.4 
Demographics and baseline characteristics 
Demographic and baseline patient characteristics will be summarized overall and by 
treatment group based on the safety population.  
All demographic and other baseline characteristics will be provided in a listing. 
8.4.1 Demographics 
Following demographic characteristics will be summarized  
• Age (years)at screening,  
• Age category (<45, 45-64, 65-74, ≥75 years, Not Reported) 
• Gender (Male, Female) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported) 
• Race (American Indian or Alaska Native, Asian, Black or African American,   Native 
Hawaiian or other Pacific Islander, White, Other, Not Reported) 


 
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• Height (cm)  
• Weight (kg) (for hemodialysis patients- prescription dry body weight)  
• Body mass index (kg/m2) 
• 
Female Reproductive status (Pre-menarche, Sterile, Post-menopausal, Potentially 
able to bear children, Other and Not applicable) 
8.4.2 Baseline and disease characteristics 
Baseline characteristics of the disease will also be summarized. Baseline disease 
characteristics include variables such as 
• Glomerular filtration rate (GFR) (mL/min/1.73m²) 
• Grouped GFR (<30 mL/min/1.73 m2 or ≥30 and <60 mL/min/1.73 m2) 
• Renal disease status (Moderate CKD Non-Dialysis, Severe CKD Non-Dialysis, 
Severe CKD On Dialysis) 
• Baseline NRS score 
As a separate summary, the GFR (mL/min/1.73m²) and grouped GFR (<15 ml/min/1.73m2, 
15-29 ml/min/1.73m2, 30-59 ml/min/1.73m2, 60-89 ml/min/1.73m2, >90 ml/min/1.73m2) 
will be summarized across patients who did not meet inclusion criteria #4 (renal status). If 
multiple GFR results were recorded during the screening/run-in period then the maximum 
will be used. This data will be listed in the screen failure listing (see section 8.2).  
8.4.3 Medical History 
Medical history data will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0. A summary table by treatment group will be presented 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 
the condition is ongoing. 
A separate coding listing will be created with all the distinct levels of SOC, High Level 
Terms, Preferred Terms, Lowest Level Term and the verbatim Investigator description 
reported in the study. Sorting will be alphabetically by SOC, Preferred Term, and then 
verbatim description. 
8.4.4 Prior and concomitant medications 
Prior medications (including vitamins and herbal supplements) are defined as those that the 
patient has taken any time during the 30 days prior to the screening up until the first dose of 
study drug on Day 1. 
Concomitant medications are medications that the patient has taken after the start of the 
first dose of study drug on Day 1 of the Treatment period through the end-of-treatment (i.e., 
12-week Treatment period)/early termination visit. 


 
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All medications will be coded using the World Health Organization Drug Dictionary 
(WHODD) version March 2018. All prior and concomitant medications will be listed and 
summarized separately by Anatomical Therapeutic Chemical (ATC) class 3 and preferred 
term.  
Additionally, a coding listing will be created which will include all distinct ATC class 1, 2 
and 3 codes and preferred terms along with the corresponding verbatim description of the 
medications; sorting will be alphabetically by ATC class 3 and preferred term. Prior and 
concomitant medications will be listed separately. 
 
8.4.5 Prior and concomitant procedures 
Prior procedures are defined as those performed on the patient during the 30 days prior to 
the screening up until the first dose of study drug on Day 1. 
Concomitant procedures are defined as those performed on the patient after the start of the 
first dose of study drug on Day 1 of the Treatment period through the end-of-treatment (i.e., 
12-week Treatment period)/early termination visit. 
All procedures will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 21.0. All prior and concomitant procedures will be listed and summarized separately 
by SOC and preferred term.  
Additionally, a coding listing will be created which will include all distinct SOC, High Level 
Terms, preferred terms and Lowest Level Terms along with the corresponding verbatim 
description of the procedure; sorting will be alphabetically by SOC and preferred term. Prior 
and concomitant procedures will be listed separately. 
 
8.5 
Extent of exposure 
Study drug summary and compliance summaries will be based on the safety population. 
Drug administration details including derived variables will be provided in the form listings 
in addition to the below summaries.  
8.5.1 Treatment duration 
The duration of treatment will be derived using the dates of first/last study drug 
administration from the patient diary as date of last dose – date of first dose + 1.  
Duration of treatment (days) and duration of study (days) will be summarised based on the 
safety population using descriptive statistics. Refer to section 7.1 for the derivation of 
variables. In addition, descriptive summary will be provided for total number of doses taken 
(based on the patient daily dosing diary). This will also be presented in categories “1-7, 8-
14, 15-21, 22-28, 29-35, 36-42, 43-49, 50-56, 57-63, 64-70, 71-77, 78-84” using count and 


 
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percentage. 
Total number of missed doses collected from patient daily dosing diary presented in 
categories 0, 1, ≥2 using count and percentage. 
8.5.2 Treatment compliance 
Compliance will be calculated in 2 different ways: based on the patient daily dosing diary 
and using drug accountability records. 
Study drug compliance based on the number of tablets taken will be calculated as: [(Total 
number of tablet dispensed across all visits-Total number of tablet returned across all visits)/ 
Duration of study drug (days)] ×100.  
Study drug compliance based on the patient daily dosing diary will be calculated as: [(Total 
number of tablet taken as per daily dosing dairy)/ Duration of treatment] ×100.  
Study drug compliance (based on the patient daily dosing diary and using drug accountability 
records) will be summarized. Compliance will also be summarized in categories <80%, 80% 
- 120%, >120% using frequency tables. 
Study drug compliance summaries will be based on the safety population. 
8.5.3 Exposure to CR845 
The exposure to CR845 (mg) will be calculated also using the patient daily dosing diary, 
however, the actual dose levels taken by the patient will be taken into account rather than 
the number of tablets (i.e. for a correctly dosed placebo patient, exposure to CR845 = 0mg). 
8.6 
Efficacy analyses 
This section describes the analysis to be conducted on the primary, secondary and additional 
efficacy variables. All the efficacy analyses will be performed using the full analysis set and 
data that is collected on or prior to the date of treatment discontinuation/completion. An 
analysis of the primary and secondary efficacy variables for the per-protocol population will 
be performed if more than 20% of the FAS patients are excluded in any of the treatment 
groups. Each CR845 dose group, will be compared against placebo for all the endpoints. In 
addition, a separate analysis comparing all CR845 doses pooled against placebo will be 
performed with respect to the primary and key secondary variables. Only the results for the 
all CR845 doses pooled group and the comparison with placebo will be presented from these 
analyses. An analysis of all CR845 doses pooled versus placebo with respect to the rest of 
the secondary variables may also be considered.  A dose response analysis will be performed 
with respect to the primary and key secondary variables. Results for the primary and 
secondary efficacy variables will be presented by renal disease status (moderate CKD non-
dialysis; severe CKD non-dialysis; severe CKD on dialysis). 


 
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8.6.1 Analysis methods 
8.6.1.1 Multiplicity 
There will be no adjustment for multiple comparisons. 
8.6.1.2 Treatment by center interaction analysis (multi-center study) 
Given the large (~60) number of sites with few patients per site, no analysis will be 
conducted to assess the treatment-by-center interaction.  
8.6.2 Analysis of primary efficacy endpoint 
The primary efficacy endpoint is defined as the change from baseline to week 12 of the 
Treatment period with respect to the weekly mean of the daily 24 hour Worst Itching 
Intensity NRS score. Testing of the primary efficacy endpoint will be 2-sided and conducted 
at the 5% error level.  
The study will be considered positive if at least one safe and efficacious dose is identified. 
Effectiveness will be evaluated based on results of the primary efficacy analysis either using 
the estimate of treatment effect or the p-value of the hypothesis tests.   
The null hypotheses H01, H02, H03, and H04 given below will be tested against the alternative 
hypotheses HA1, HA2 and HA3 respectively: 
H01:  µD1 - µP = 0,    H02:      µD2 - µP = 0,  
H03: 
µD3 - µP = 0,             H04: 
µD123 - µP = 0 
HA1: µD1 - µP ≠ 0,     HA2:  
µD2 - µP ≠ 0, 
HA3:  
µD3 - µP ≠ 0,  
 
HA4:  
µD123 - µP ≠ 0 
Where µD1, µD2 and µD3 denote the mean change in Worst Itching Intensity NRS score from 
baseline to week 12 in the three active treatment dose groups and µP denotes the mean change 
from baseline to week 12 in the placebo group (placebo, P). D1 denotes the CR845 0.25mg 
dose group, D2 denotes the CR845 0.5mg dose group and D3 denotes the CR845 1mg dose 
group and D123 denotes the doses (0.25, 0.5 and 1 mg) combined. 
The weekly mean of the 24-hour Worst Itching Intensity NRS score will be defined as the 
sum of the daily Worst Itching Intensity NRS score reported during a specific week of the 
Treatment period (eg, Days 1 to 7, Days 8 to 14, Days 15 to 21, etc. till 78 to 84) divided by 
the number of non-missing scores for that week. If there are <4 non-missing daily worst 
itching scores during a specific week, the corresponding weekly mean worst itching score 
will be set to missing. The baseline score will be defined as the average of the daily 24-hour 
Worst Itching Intensity NRS scores over the last 7 days prior to randomization; at least 4 
completed Worst Itching Intensity NRS worksheets will be required prior to randomization. 
The primary efficacy variable will be analyzed using a mixed effects model with repeated 
measures (MMRM). The model will contain treatment, week, and treatment-by-week 
interaction as fixed effects; baseline score and renal disease status as covariates. For each 


 
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dose group, the treatment group difference vs placebo will be estimated as the simple 
contrast in the treatment effect at Week 12 of the Treatment Period. The treatment difference 
between all doses combined and placebo will be estimated using a similar approach. 
For week 12, the adjusted least square means (LS means) and standard error (SE) from the 
model will be presented for each treatment group. The LS means estimate for the difference, 
standard error, 95% CI, and p-value will also be presented. The primary analysis will be 
conducted using the Full Analysis Set. A summary table including descriptive statistics (n, 
mean, SD, median, minimum, maximum) for the observed value and the change from 
baseline by treatment group will also be provided for the NRS score. 
An unstructured covariance matrix structure will be used to model the within patient errors. 
If there are convergence issues, other structures that require fewer parameters will applied 
in the following order: 1) heterogeneous Toeplitz, 2) autoregressive, 3) compound symmetry 
until convergence is attained. The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom. 
For the MMRM analyses, the missing Weekly NRS score will be imputed using a Multiple 
Imputation (MI) approach, assuming that patients who discontinue study drug early would 
have similar Worst Itching Intensity NRS scores as other patients in their respective 
treatment arm that have complete data. The details of missing data imputations described as 
below.  
• Intermittent missing weekly NRS scores will first be imputed using the Markov 
Chain Monte Carlo (MCMC) method implemented with the SAS MI procedure, 
which is appropriate for non-monotonic missing data. Additional terms for baseline 
NRS score and randomization stratification category (as dummy 0/1 variables) will 
be added. This will be performed within each treatment group separately. 
• The monotone missing weekly NRS values will then be multiply imputed with the 
SAS MI procedure using the monotone regression method. The regression model 
will include terms for treatment group, baseline NRS score, and randomization 
stratification category; all previous non-missing post-baseline NRS scores will be 
included in the model.  Should convergence issues occur due to small cell size for 
the categorical covariates at either stage, they will be removed from the model. 
• The change from baseline at Week 12 with respect to the weekly mean of the daily 
24-hour Worst Itching Intensity will be analyzed for each imputed dataset using an 
MMRM model.  
• One hundred imputations will be performed. 


 
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• Results of the MMRM analysis on the multiply imputed data sets will be summarized 
by the SAS MIANALYZE procedure. 
The details of MI SAS procedure described in Appendix F. 
In addition, sensitivity analyses of the primary efficacy endpoint will be conducted to 
evaluate the robustness of study results under different assumptions and imputation 
algorithms, as described below: 
Sensitivity analysis 1 (No imputation; Missing at Random [MAR]): 
In this sensitivity analysis, missing weekly worst itching scores will not be imputed. 
Assuming the data are MAR, the estimates of the treatment differences calculated from the 
MMRM model described above are unbiased. Details of analysis using SAS described under 
Appendix G. 
Sensitivity analysis 2 (Multiple Imputation; Missing Not at random (MNAR) 
This sensitivity analysis is an implementation of a pattern mixture model that draws from 
different populations based on the reason for withdrawal.   
• Intermittent missing NRS scores will first be imputed using the MCMC method with 
the SAS MI procedure, which is appropriate for non-monotonic missing data. This 
will be performed within each treatment group separately. 
• For patients who discontinue study drug due to adverse events, data missing after 
discontinuation will be imputed using the distribution of the baseline value of all 
patients’ weekly worst itching score with the same renal status assuming a trimmed 
normal (from 5 to 10).   
• For patients who discontinue study drug due to reasons other than adverse event, 
monotone missing weekly NRS values will be multiply imputed with the SAS MI 
procedure using the monotone regression method applied to all patients with data 
available at the particular visit (including those withdrawing due to an adverse event). 
The regression model will include terms for treatment group, baseline NRS score, 
and randomization stratification category; all previous non-missing post-baseline 
NRS scores.  Should convergence issues occur due to small cell size for the 
categorical covariates at either stage, they will be removed from the model. 
• Results of the MMRM on the multiply imputed data sets will be summarized by the 
SAS MIANALYZE procedure.  


 
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• The details of MNAR based imputation using SAS described under Appendix H. 
Descriptive statistics for the primary efficacy endpoint will also be provided by treatment 
group for each renal disease category (moderate CKD non-dialysis; severe CKD non-
dialysis; severe CKD on dialysis). In addition, an analysis of the primary efficacy endpoint 
within each renal disease status will be performed using an MMRM model similar to the one 
implemented for the primary efficacy analysis but without renal disease status as a fixed 
effect. As the renal disease status was included a factor in the multiple missing data 
imputation for the primary analysis, the same multiple imputed datasets as created for the 
primary analysis and methods to combine results will be used for these analyses.  
A linear trend test across the doses based on a MMRM model will also be presented to 
explore the dose response curve. The model will contain treatment as continuous variable 
(Placebo = 0 mg and other doses 0.25, 0.5, and 1.0 mg), week, and treatment-by-week 
interaction as fixed effects; baseline score and renal disease status as covariates. The estimate 
and p-value for overall effect of dose will be provided. An unstructured covariance matrix 
structure will be used to model the within patient errors. 
Listings will be provided for Worst Itching Intensity NRS score for all the available visits. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
The key secondary efficacy endpoints are: 
• Change from baseline in itch-related quality of life at the end of Week 12, as assessed 
by the total Skindex-10 scale score;  
• Change from baseline in itch-related quality of life at the end of Week 12, as assessed 
by the total 5-D Itch scale score; 
• 
Proportion of patients achieving an improvement from baseline ≥3 points with 
respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score 
at Week 12 of the Treatment period. 
The Skindex-10 scale total score and the 5-D Itch total scale score will be analyzed using 
MMRM that will contain treatment, week, and treatment-by-week interaction as fixed 
effects; baseline score and renal disease status as covariates. Repeated measures will include 
values that reflect the Skindex-10 and 5-D total score at the end of weeks 4, 8, 10, and 12.  
The total score derivation for Skindex-10 and 5-D Itch scale detailed in Appendix B and 
Appendix C respectively. 
The baseline value will be defined as the value of the Skindex-10 or 5-D Itch total score 
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total scores will be imputed in a similar fashion as the primary endpoint for the MMRM 
analyses using the MI approach assuming data is missing at random.  The mean treatment 
difference between each CR845 dose and placebo, and between all CR845 doses combined 
and placebo will be estimated as the simple contrast in the treatment effect at Treatment 
period week 12.  
Descriptive statistics will be provided for the observed value and change from baseline at 
week 12 by treatment group for Skindex-10 scale and the 5-D Itch total scores. The adjusted 
LS means and SE from the model will be presented for each treatment group. The LS means 
estimate for the difference, standard error, 95% CI, and p-value will be presented. The 
analysis will be conducted using the Full Analysis Set. 
An unstructured covariance matrix structure will be used to model the within patient errors. 
If there are convergence issues, other structures that require fewer parameters will applied 
in the following order: 1) heterogeneous Toeplitz, 2) autoregressive, 3) compound symmetry 
until convergence is attained. The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom.  
Descriptive statistics for the change from baseline with respect to the Skindex-10 and the 5-
D Itch total score will also be provided by treatment group for each renal disease category 
(moderate CKD non-dialysis; severe CKD non-dialysis; severe CKD on dialysis). In 
addition, an analysis of these key secondary endpoints by renal disease status will be 
performed using an MMRM model and a treatment of missing data similar to the one 
described above.   
A linear trend test across the doses based on a MMRM model will also be presented to 
explore the dose response curve. The model will contain treatment as continuous variable 
(Placebo = 0 mg and other doses 0.25, 0.5, and 1.0 mg), week, and treatment-by-week 
interaction as fixed effects; baseline score and renal disease status as covariates. The estimate 
and p-value for overall effect of dose will be provided. An unstructured covariance matrix 
structure will be used to model the within patient errors. 
Patients achieving improvement from baseline ≥3 points will be summarized using count 
and percentage. The proportion of patients achieving an improvement from baseline ≥3 
points with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS 
score at week 12 of the treatment period will be analyzed using logistic regression with terms 
for treatment group, baseline NRS score, and renal disease status. Odds ratio, and P-value 
based on logistic regression comparing difference in patients achieving NRS response 
between CR845 treatment group and placebo and between all CR845 doses combined and 
placebo at week 12 will be presented. In case of small counts resulting in separation issues 
of the log-likelihood, Firth’s correction will be applied.  


 
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Missing NRS data will be imputed using the same methodology described for the primary 
efficacy endpoint.  Specifically,   
• 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 ≥3 points 
will be calculated for each imputed dataset derived for the primary efficacy analysis.  
Differences between each CR845 treatment group and placebo will be compared 
using a logistic regression model containing terms for treatment group, baseline NRS 
score and renal disease status.  P-value will be presented. 
• Results of the logistic regression on the multiply imputed data sets will be 
summarized by the SAS MIANALYZE procedure (see Appendix I).  
• For comparisons between treatments at end of treatment (not using MI), the same 
logistic regression will be performed on observed data with additional non-
parametric analyses evaluating pairwise treatment differences will be tested using 
the Cochran-Mantel-Haenszel test, adjusting for strata (i.e renal disease status).  An 
exact test of whether the common odds ratio across strata equals 1 will be used if the 
observed count in a particular cell is small (ie, <5) (see Appendix J).  
The proportion of patients achieving an improvement from baseline ≥3 points by each renal 
disease category (moderate CKD non-dialysis; severe CKD non-dialysis; severe CKD on 
dialysis) will be presented. In addition, treatment differences within each subgroup will be 
investigated using logistic regression, including a Fisher’s exact test for the end of treatment 
(not using MI) comparison.  
The proportion of patients achieving an improvement from baseline ≥3 points with respect 
to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score at week 12 of 
the Treatment period will be also be analyzed using logistic regression with terms for 
treatment group as continuous variable (Placebo = 0 mg and other doses 0.25, 0.5, and 1.0 
mg), baseline NRS score, and renal disease status to evaluate the dose response curve. 
Overall effect of treatment group will be presented. 
Listings will be provided for all the collected Skindex-10 scale score and the 5-D Itch Scale 
score separately. 
8.6.4 Analysis of additional efficacy endpoint(s) 
Itch-intensity Measures: 
• Proportion of patients who have an improvement from baseline at week 12 of the 
treatment period with respect to the weekly mean of the 24-hour Worst Itching 
Intensity NRS scores ≥1, ≥2, and ≥4 points will be calculated. Treatment differences 


 
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will be compared using a logistic regression model with terms for treatment group, 
baseline NRS score and renal disease status.  This analysis will be conducted 
separately for each NRS score categories (≥1 vs <1 (no or less improvement 
compared to baseline, or, ≥2 vs <2, and ≥4 vs <4 points). The calculation of the 
proportions will be based on the NRS data using an MI approach for the missing data 
as in the primary efficacy analysis. Results of the logistic regression on the multiple 
imputed data sets will be summarized by the SAS MIANALYZE procedure.  In 
addition, a graph showing the proportion of patients who have an improvement from 
baseline in NRS scores at week 12 that are ≥1, ≥2, ≥3, and ≥4 will be prepared. For 
comparisons between treatments at end of treatment (not using MI), the same logistic 
regression will be performed on observed data with additional non-parametric 
analyses evaluating pairwise treatment differences pairwise treatment differences 
will be tested using the Cochran-Mantel-Haenszel test, adjusting for strata (i.e renal 
disease status).  An exact test of whether the common odds ratio across strata equals 
1 will be used if the observed count in a particular cell is small (ie, <5). 
• Proportion of “complete responders” with respect to Worst Itching Intensity score 
NRS at week 12 and end of treatment. A patient that has ≥ 80% of the non-missing 
daily NRS scores in a week equal to 0 or 1 is considered a complete responder at that 
week. Patients with <4 non-missing NRS scores within a week will be derived as 
missing at that week. Treatment differences will be compared using a logistic 
regression model with terms for treatment group, baseline NRS score and renal 
disease status. In addition, pairwise treatment differences will be tested using the 
Cochran-Mantel-Haenszel test, adjusting for strata (i.e renal disease status).  An exact 
test of whether the common odds ratio across strata equals 1 will be used if the 
observed count in a particular cell is small (ie, <5). 
• Change from baseline in the weekly mean of the 24-hour Worst Itching Intensity 
NRS score at each post baseline week (except week 12) of the treatment period will 
be summarized. Treatment differences between CR845 and placebo at each post 
baseline time point will be evaluated and presented using the same MMRM detailed 
in primary efficacy analysis (see section 8.6.2). Analysis will be based on the NRS 
data using an MI approach for the missing data as in the primary efficacy analysis. 
 
• Proportion of patients who rate their itch condition as “Very much improved” or 
“Much improved” at the end of week 12 of the treatment period and end of treatment, 
as measured by the Patient Global Impression of Change (PGIC).  Treatment 
differences will be compared using a logistic regression model with terms for 
treatment group, baseline Patient Global Impression Worst Severity score and renal 
disease status. In addition, pairwise treatment differences will be tested using the 


 
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Cochran-Mantel-Haenszel test, adjusting for strata (i.e renal disease status). An exact 
test of whether the common odds ratio across strata equals 1 will be used if the 
observed count in a particular cell is small (ie, <5). The PGIC responses at week 12 
and end of treatment will also be presented with count and percentage. 
 
• The number and percentage of patients in each of the 5 categories of the Patient 
Global Impression of Worst Itch Severity at baseline and at each scheduled post 
baseline week of the treatment period will be tabulated.  In addition, the proportion 
of patients who have at least 1-point improvement or more from baseline at each 
week of the Treatment Period, as measured by the Patient Global Impression of 
Worst Itch Severity will be calculated.  Similarly, the proportion of patients who 
indicate a Patient Global Impression of Worst Itch Severity of ‘None’ will be derived 
at Week 12 and end of treatment. Treatment differences will be compared using a 
logistic regression model with terms for treatment group, baseline Worst Itch 
Severity and renal disease status. In addition, pairwise treatment differences will be 
tested using the Cochran-Mantel-Haenszel test, adjusting for strata (i.e renal disease 
status). An exact test of whether the common odds ratio across strata equals 1 will 
be used if the observed count in a particular cell is small (ie, <5).  
Itch-related Quality-of-Life Measures:  
• Change from baseline in itch-related quality of life at each scheduled post baseline 
week of the Treatment period, as assessed by the total score of the 5-D itch scale.  
Treatment differences between each CR845 dose group and placebo at each post 
baseline time points will be evaluated and presented (except week 12) using the 
MMRM fitted for the secondary efficacy analysis section 8.6.3. 
• The proportion of patients who either rate the degree of itching intensity as ‘Not 
Present’ or the direction of itching as ‘Completely Resolved’ over the past 2 weeks 
from the 5-D Itch Scale will be calculated at Week 12 and end of treatment. 
Treatment differences will be compared using a logistic regression model with terms 
for treatment group, baseline 5-D Itch Total Score and renal disease status. In 
addition, pairwise treatment differences will be tested using the Cochran-Mantel-
Haenszel test, adjusting for strata (i.e renal disease status). An exact test of whether 
the common odds ratio across strata equals 1 will be used if the observed count in a 
particular cell is small (ie, <5). 
• The proportion of patients with itching present at each body part will be presented at 
Week 12 and end of treatment along with the shift from baseline (Present or Not 
Present combinations). The presence of itching at each body part at end of treatment 
will be compared between treatments adjusting for strata (i.e renal disease status) and 
presence of itch at baseline (Present/Not Present). An exact test of whether the 


 
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common odds ratio across strata equals 1 will be performed. 
• Change from baseline in itch-related quality-of-life at each week of the Treatment 
period, as assessed by the total score of the Skindex-10 Scale. Treatment differences 
between each CR845 dose group and placebo at each scheduled post baseline time 
points will be evaluated and presented (except week 12) using the same MMRM 
fitted for the secondary efficacy analysis section 8.6.3.  
• The total Skindex-10 score is subdivided into 3 domain scores, which are sums of 
the scores of the following consideration of questions (Appendix B):  disease domain 
(questions 1 to 3), mood/emotional distress domain (questions 4 to 6), and social 
functioning domain (questions 7 to 10). Change from baseline in itch-related quality 
of life at each of the post baseline weeks of the treatment period with respect to each 
of the 3 domains of the Skindex-10 Scale will be calculated.  Treatment differences 
with respect to each domain will be evaluated using a model similar to the MMRM 
fitted for the analysis of the change from baseline in the total score of the Skindex-
10 Scale. 
• Change from baseline in itch-related quality of life at week 12 of the treatment period 
and at each of the remaining weeks of the treatment period with respect to each of 
the domains of 5-D Itch scale.  Treatment differences with respect to each domain 
will be evaluated using a model similar to the MMRM fitted for the analysis of the 
change from baseline in the total score of the 5-D Itch Scale. The domain score 
derivation will be considered as detailed in the Appendix C. 
Listings will be provided for the variables used in the additional efficacy endpoints (which 
are not mentioned in the primary or secondary analysis). 
8.7 
Safety analyses 
The following assessments will be used to evaluate the overall safety of CR845: 
• Adverse events 
• Vital signs  
• 12-lead ECGs  
• Clinical laboratory evaluations.  
All safety analysis will be performed using the safety population. All safety endpoints will 
be summarized by treatment group and overall. Baseline value defined as the last lab value 
obtained prior to treatment. 


 
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8.7.1 Adverse events 
All adverse events (AE) will be coded using MedDRA dictionary to the corresponding 
MedDRA system organ class (SOC) and Preferred Term (PT) for standardization and 
summary purposes. Only treatment emergent adverse events (TEAEs) will be included in 
summary tables, except for a table presenting an overall summary of all AES and of REAEs. 
Summaries will provide results overall and by treatment.  
TEAEs are defined as adverse events (AEs) with an onset date on or after the first dose of 
the study drug up to the End of Treatment/Early Termination visit or 7 days after the last 
dose, whichever is later.  
The incidence of TEAEs will be presented using counts and percentages of patients with 
adverse events and tabulated by SOC and preferred term. System organ class will be sorted 
alphabetically and preferred term within SOC will be sorted by descending frequency based 
on the incidence across all patients in the safety population. 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 following specific summary tables will be generated:  
• An overall summary showing the number and percentage of patients with  
o Any AE (both TEAE and non-TEAE) 
o TEAE  
o Serious TEAE  
o Serious non-TEAE 
o Related TEAE  
o Severe TEAE 
o TEAE leading to drug interruption 
o TEAE leading to dose reduction  
o TEAE leading to study drug discontinuation  
o Number of any events and number of TEAEs (Count only) 
• TEAEs by SOC and preferred term 
• TEAEs related to study drug by SOC and preferred term 
• TEAEs by SOC, preferred term and maximum severity 
• TEAEs occurring in ≥5% of patients in at least 1 treatment group  
• 
Treatment-related TEAEs occurring in ≥5% of patients in at least 1 treatment 
group  


 
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• Serious TEAEs by SOC and preferred term 
• TEAEs leading to study drug discontinuation by SOC and preferred term 
If the relationship to the study drug of an adverse event (AE) is missing, the AE will be 
categorized as “related” to the study drug. If a patient reports 2 or more AEs that code to the 
same preferred term, the event with the maximum relationship will be included in the table.  
If the severity to the study drug of an AE is missing, the AE will be categorized as “severe”. 
If a patient reports 2 or more adverse events that code to the same preferred term, the event 
with the maximum severity will be included in the table.  
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 drug, action taken with study drug, and 
outcome).  
In addition, separate listings will be generated for serious adverse events (SAEs), deaths, and 
adverse events leading to study drug discontinuation.  
A coding list of SOC, high level, preferred and lowest level terms and the verbatim text 
associated with them will also be produced additionally. TEAEs and non-TEAEs will be 
listed separately. 
8.7.2 Clinical laboratory evaluations 
Blood samples for clinical laboratory tests, including hematology, serum chemistry and 
serum pregnancy will be collected during screening and day 1 before study drug 
administration, on week 6 and week 12 (end of treatment). 
All clinical laboratory data will be reported in Système International units.  
Summary statistics for each scheduled time point measured and mean changes from baseline 
to each time point will be presented for hematology and serum chemistry laboratory results.  
The baseline value is defined as the last observation prior to or on the date of the first dose 
of study drug whether scheduled or unscheduled (see section 7.1). 
Hematology and serum chemistry laboratory test results will be assigned as Low (L), Normal 
(N) or High (H) classification according to whether the value was below (L), within (N), or 
above (H) the laboratory parameter’s reference range.  


 
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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 the below specified criteria will also be 
summarized. 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST),  
o >3 × ULN  
o >5 × ULN 
o ALT>3xULN or AST>3xULN 
• Alkaline phosphatase (ALP) 
o >1.5 × ULN 
• Total Bilirubin (TBILI) 
o >2 × ULN 
• AST and Total Bilirubin 
o AST >3xULN and TBILI>2xULN 
• ALT and Total Bilirubin 
o ALT>3xULN and TBILI>2xULN 
• AST or ALT and Total Bilirubin 
o AST or ALT>3xULN and TBILI>2xULN 
A summary of treatment emergent sodium findings will also be provided, categorizing 
results into those <146 mmol/L, 146 - 150 mmol/L, and >150 mmol/L at the 6 and 12 week 
assessments. An additional summary will present these categories for subjects over the full 
study period presenting the highest category attained (at any on-treatment assessment) and 
sustained (at any on-treatment assessment and all subsequent on-treatment assessments); this 
analysis will include both scheduled and unscheduled laboratory test results. 
All clinical laboratory values will be presented in a listing. Additionally, ALT, AST, 
bilirubin, ALP and sodium will be presented in a separate listing, with values >3 × or >5 × 
ULN flagged for alanine aminotransferase and aspartate aminotransferase; 2 × ULN flagged 
for total bilirubin, 1.5 × ULN flagged for alkaline phosphatase and ≥ 146 mmol/L flagged 
for sodium. In each listing, all the data for the patient across the study will be presented for 
any parameter flagged post-baseline. 
8.7.3 Vital signs 
Vital sign parameters include systolic blood pressure (SBP), diastolic blood pressure (DBP), 
body temperature and heart rate. For each scheduled timepoint, descriptive summary 
statistics will be calculated for both the actual and the change from baseline values for all 


 
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vital sign parameters. The baseline value is defined as the last observation prior to or on the 
date of the first dose of study drug whether scheduled or unscheduled (see section 7.1). 
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 Treatment period. This analysis will include results from 
both scheduled and unscheduled assessments. 
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 bpm 
 <55 bpm 
 
All vital signs will be listed in patient listings, including visit and collection date/time, and 
will be sorted by patient identifier and date/time of assessment. 
8.7.4 Electrocardiograms 
ECG assessment will be done at screening, day 1 and end of treatment (EOT). 
ECG 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 using a shift table. 
Electrocardiogram results will be listed for all available visits, including visit, whether ECG 
was performed (yes/no), explanation (if not performed), assessment date/time, overall 
interpretation. 


 
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8.8 
Other analysis 
8.8.1 Subgroup analysis 
The following endpoints will be summarized by strata- patient’s renal disease status: 
moderate CKD non-dialysis; severe CKD non-dialysis; and severe CKD on dialysis. 
• All primary and secondary efficacy endpoints 
o 24-hour Worst Itching Intensity numerical rating scale (NRS) score 
o Total Skindex-10 Scale score 
o 5-D Itch Scale score 
 
• Safety endpoints 
o Overall Adverse Events 
o AEs by SOC and PT 
 
8.9 
Interim analysis 
An unblinded Interim Analysis (IA) will be conducted when approximately 50-60% of the 
planned 240 patients have been randomized and have either completed the 12-week 
Treatment Period or have discontinued study drug early. The primary goal of the IA is to 
identify dose(s) of oral CR845 that are both safe and efficacious across all strata. Doses that 
are found to be unsafe or poorly tolerated will be dropped from the study.  No dose will be 
dropped for futility reasons. The sample size will not be increased past 480 total patients 
(120 patients per treatment group).  
8.9.1 General Strategy 
Since there are 3 CR845 doses, the decision rule for sample size re-estimation to be followed 
for the IA, and described below is designed to address multiple comparisons and protect the 
type 1 error  
The conditional power of each CR845 dose to separate from placebo at the end of study 
(based on the planned sample size of 60 patients per group) will be calculated, assuming that 
estimated treatment effect at interim analysis is the true effect. 
o If the conditional power is >= 80% for at least one dose then the sample size will not 
be increased in any of the doses 
o If the conditional power is < 80% across all doses and ≥ 20% in at least one dose, 


 
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then the following process will be followed 
• For each CR845 dose group the sample size (sizenew) needed to achieve an 
80% power given the observed treatment effect will be calculated 
• The calculated sample sizes will be ordered from lowest to highest as 
min(sizenew), int(sizenew) and max (sizenew) 
• If the smallest re-estimated sample size min(sizenew) is > 120 then the 
recommendation will be to increase the sample size to 120 for all treatment 
groups 
• If min(sizenew) ≤ 120 but {int(sizenew) and max(sizenew)} > 120 (i.e. only the 
minimum sample size is ≤ 120) then the recommendation will be to increase 
the sample size to min(sizenew) for all treatment groups 
• If min(sizenew) and int(sizenew) are both ≤ 120 (i.e. 2 out 3 re-estimated sample 
sizes are ≤ 120) then the recommendation will be to increase the sample size 
for all treatment groups to  
• int(sizenew) if [int(sizenew) – min(sizenew)] ≤ 10   
or  
• min(sizenew) if [int(sizenew) – min(sizenew)] > 10    
• If max(sizenew) ≤ 120 (i.e. 3 out 3 re-estimated sample sizes are ≤ 120), then 
the recommendation will be to increase the sample size for all treatment 
groups to  
• max(sizenew) if [max(sizenew) – min(sizenew)] ≤ 10   
or  
• min(sizenew) if [max(sizenew) – min(sizenew)] > 10  
o  If the conditional power is < 20% for all doses the sample size will not be increase 
for any dose 
Conditional power will be calculated for each CR845 dose assuming that the estimated 
treatment effect at interim analysis is the true effect as proposed by formula in the article by 
Mehta and Pocock3. 
 
Where Z1 is observed test-statistic calculated using the sample included in the IA, n2 is the 
total planned size (i.e. 120 = 60 per group), n1 is the interim size (approximately 50% of the 
target n2), ň2 is the difference (n2 – n1), and delta hat is the observed treatment difference. 


 
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8.9.2 Interim Analysis Statistical Analysis 
The following variables/summaries will be included in the Interim Analysis 
8.9.2.1 Subject disposition including study population 
Subject disposition information will be summarized by treatment group and overall (across 
CR845 doses and across all treatments). The number of patients who are enrolled, the 
number and percent of screen failures, of randomized and treated patients will be 
summarized. In addition, the reason for screen failure will be provided. In this summary 
table, percentages will be calculated using the number of enrolled patients as the 
denominator.  
A separate display will present the number and percent of patients who complete the 12-
week study treatment, who discontinue from double-blind treatment, (and the reason for 
study treatment discontinuation), and who complete the follow-up. For this table, 
percentages will be calculated using the number in patients in the safety population. 
 
Additionally, the above table will summarize the number and percent of randomized patients 
in the following populations:  
• Full Analysis set; 
• Safety population; 
 
8.9.2.2 Demographic and Baseline Characteristic 
Summary of demographic and baseline variable described in section 8.4.1 and 8.4.2. 
 
8.9.2.3 Summary and analysis of NRS score 
The change from baseline in the weekly mean of the 24-hour Worst Itching Intensity NRS 
score at each post baseline week of the treatment period will be summarized. Treatment 
differences between CR845 and placebo at each post baseline time point will be evaluated 
and presented using mixed effects model with repeated measures (MMRM). Refer to section 
8.6.2 for the details of NRS data analysis. 
Summary statistics will be provided for the observed and the change from baseline with 
respect to the weekly mean of the 24-hour Worst Itching Intensity NRS score by strata- renal 
disease status (moderate CKD non-dialysis; severe CKD non-dialysis; and severe CKD on 
dialysis). 
 


 
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8.9.2.4 Summary and analysis of Skindex-10 and 5-D Itch total scale score 
and Responder Analysis 
The secondary efficacy endpoints mentioned below will be summarized for IA.  
• Change from baseline in itch-related quality of life at the end of Week 12, as assessed 
by the total Skindex-10 Scale score;  
• Change from baseline in itch-related quality of life at the end of Week 12, as assessed 
by the total 5-D Itch Scale score; 
• Proportion of patients achieving an improvement from baseline ≥3 points with 
respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score 
at Week 12 of the Treatment Period. 
 
Refer to section 8.6.3 for details of the analysis for the above endpoints. 
 
8.9.2.5 Safety Analysis 
The following summaries will be provided to evaluate the safety profile of CR845. Analysis 
details are provided in section 8.7.1. Except for the first display listed below, only TEAE 
during treatment period will be summarized. 
• Overall summary of Adverse Event 
• AEs summary by SOC and PT 
• AEs related to study drug by SOC and PT 
• AEs leads to study drug discontinuation by SOC and PT 
• AEs by Maximum severity 
• Serious adverse event summary 
• Summary of Clinically important laboratory values 
• Summary of Sodium abnormal findings (<146 mmol/L,   >= 146 mmol/L, <=150 
mmol/L, >150 mmol/L) 
Line plot for the below parameters will also be provided. 
• Change from baseline in selected Laboratory Tests over Time (hemoglobin, 
creatinine, GFR, albumin, phosphate, calcium, sodium) 
• Blood Pressure Measurements (Systolic and diastolic blood pressure) 
• Heart Rate Measurements 
In addition, the following listings will also be provided to support safety data. 
• Listing of Adverse Events 
• Listing of death 
• Listing of Serious Adverse Events 
• AEs leading to study drug discontinuation 
• Listings for clinically important laboratory values 


 
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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
• Antipruritic medications are not identified in the CRF or the database using a Yes/No 
flag. The use antipruritic medications will need to be derived based on the indication 
entered on the CRF. Therefore, a specific analysis of antipruritic medications by 
ingredient will not be completed since it will not be different than the analysis 
summarizing medications by preferred term. 
 
• Section 8.6.1 of the protocol defines the primary endpoint as follows: “The weekly 
mean of the 24-hour Worst Itching Intensity NRS score will be defined as the sum 
of the daily Worst Itching Intensity NRS score reported during a specific week during 
the Treatment Period (eg, Days 2 to 8, Days 9 to 15, Days 16 to 22, etc.) divided by 
the number of days with non-missing scores for that week. If the daily worst itching 
score is missing for >3 days during a specific week, the corresponding weekly mean 
worst itching score will be set to missing.”.  
However, to facilitate patient diary dates anomalies which may result in duplicate 
dates (e.g. patient completes diary shortly after midnight and then again on same 
date) and the fact that only the diary date is used for mapping to a specific week as 
per section 7.1, of this SAP, the underlined text above is replaced with “…divided 
by the number of non-missing scores for that week. If there are <4 non-missing daily 
worst itching scores during a specific week…”. In addition, because in this study the 
Day 1 NRS score is planned to be taken after dosing, weeks are re-defined in this 
SAP one day earlier than stated in the protocol (eg. Days 1 to 7, Days 8 to 14, Days 
15 to 21, etc.).  
 
• Section 8.6.2 of the protocol states that missing Skindex-10 Itch Scale and 5-D Itch 
Scale total scores will not be imputed. To ensure a more unbiased assessment of these 
secondary endpoints, which does not ignore missing data, analyses in this SAP state 
that the same MI method with MAR assumption will be applied to these endpoints 
in similar fashion to the primary endpoint. 
 
• 
Section 8.6.3 of the protocol stated that the study would be considered positive if the 
null hypothesis of no treatment difference is rejected in favor of the alternative that 
patients randomized to CR845 experience significantly less itching as measured by 
the change from baseline in the weekly mean of the Worst Itching Intensity score at 
Week 12. In fact, since this study compares several CR845 doses versus placebo, the 
study will be considered positive if at least one dose is found to be safe and effective. 
Effectiveness will be evaluated based on results of the primary efficacy analysis 
either using the estimate of treatment effect or the p-value of the hypothesis tests.   


 
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10 
REFERENCES 
 
1. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted March 
1998). 
2. 
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. 
3. 
Mehta C. and Pocock J Adaptive increase in sample size when interim results are promising: 
A practical guide with example. 
 
 
 


 
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11 
APPENDICES 
Appendix A: Worst Itching Intensity Numerical Rating Scale 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 46 of 57 
 
 
Appendix B:  Skindex-10 Scale 
 
Patients will be asked to fill 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). 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 47 of 57 
 
Appendix C: 5-D Itch Scale 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 48 of 57 
 
The scores of each of the five domains are achieved separately and then summed together to 
obtain a total 5-D Itch score. 5-D Itch scores can potentially range between 5 (no pruritus) 
and 25 (most severe pruritus)2. 
Single-item domain scores (duration, degree and direction) are equal to the value indicated 
below the response choice (range 1–5)2. The disability domain includes four 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 four items. For the distribution domain, the number of affected body parts is 
tallied (potential sum 0– 16) and the sum is sorted into five 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. 
Total 5-D Itch 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. 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 49 of 57 
 
Appendix D: Patient Global Impression of Change 
 
 
 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: CR845-210301 
              Version: Final V3.0,
              Date: 18Oct2019
                                                     Page 50 of 57 
 
Appendix E: Patient Global Impression of Change