A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Intravenous CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus, With a 52-Week Open Label Extension
Phase: PHASE3
Conditions: Uremic Pruritus
Sponsor: Cara Therapeutics, Inc.

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A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS 
WITH MODERATE-TO-SEVERE PRURITUS, WITH A 52-WEEK 
OPEN-LABEL EXTENSION 
 
Protocol number:   
CR845-CLIN3102 
Phase: 
3 
IND number: 
123140 
Protocol version: 
Version 1.0 
Date: 
December 21, 2017 
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-CLIN3102) 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) and 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 Intravenous CR845 in 
Hemodialysis Patients with Moderate-to-Severe Pruritus, with a 
52-Week Open-label Extension 
PROTOCOL 
NUMBER 
CR845-CLIN3102 
PHASE OF 
DEVELOPMENT 
3 
INVESTIGATIONAL 
PRODUCT 
CR845 Solution 
NAME OF ACTIVE 
INGREDIENT 
CR845 
ROUTE OF 
ADMINISTRATION 
Intravenous (IV) 
STUDY CENTERS 
Up to 80 sites in the United States 
OBJECTIVES 
 
Primary Objective 
• 
To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg 
compared to placebo in reducing the intensity of itch in 
hemodialysis patients with moderate-to-severe pruritus.   
Secondary Objectives 
• 
To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg 
compared to placebo in improving itch-related quality-of-life 
measures in hemodialysis patients with moderate-to-severe 
pruritus.  
• 
To evaluate the safety of IV CR845 at a dose of 0.5 mcg/kg in 
hemodialysis patients with moderate-to-severe pruritus. 
NUMBER OF 
PATIENTS 
The planned sample size is 350 (175 per treatment group) male and 
female hemodialysis patients with moderate-to-severe pruritus.  The 
sample size may be increased to 500 patients (250 per treatment group) 
based on the results of a planned interim assessment conducted when 
approximately 50% of the planned 350 patients have been randomized 
and have either completed the 12-week Treatment Period or have 
discontinued study drug early. 
STUDY 
POPULATION 
Inclusion Criteria: 
To be eligible for inclusion into the Double-blind Phase of 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; 
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3. Male or female 18 years of age or older; 
4. Has end-stage renal disease (ESRD) and has been on 
hemodialysis 3 times per week for at least 3 months prior to 
the start of screening; 
Note 1: Patients who require an occasional additional dialysis 
treatment to manage fluid overload may be enrolled as long as 
it is anticipated that no more than 1 such treatment will be 
required in any given week. 
Note 2: Patients receiving in-home hemodialysis may 
participate as long as they have switched to in-center 
hemodialysis at least 2 weeks prior to screening and plan to 
remain on in-center hemodialysis for the duration of the 
study.  
5. If female, is not pregnant or nursing during any period of the 
study;  
6. If female: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for at least 1 year and is over the 
age of 55 years; or 
c. Has a negative serum pregnancy test 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 prescription dry body weight between 40.0 and 135.0 kg, 
inclusive;  
9. Has at least 2 single-pool Kt/V measurements ≥1.2, or 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 months period prior to screening; 
10. Prior to randomization: 
a. Has completed at least 4 Worst Itching Intensity NRS 
worksheets from the start of the 7-day Run-in Period up to 
and including the pre-randomization assessment on Day 1; 
b. Has a mean baseline Worst Itching Intensity NRS score 
>4, defined as the average of all non-missing scores 
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reported from the start of the 7-day Run-in Period up to 
and including the pre-randomization assessment on Day 1. 
To be eligible for inclusion into the Open-label Extension Phase of 
the study, each patient will have to fulfill the additional following 
criteria at the time of entry into the Open-label Extension Phase:  
11. Has received at least 30 doses of the planned 36 doses of study 
drug during the Double-blind Phase of this study; 
12. Has a prescription dry body weight ≥40 kg; 
13. Continues to meet inclusion criteria 1 through 7. 
Exclusion Criteria: 
A patient will be excluded from the Double-blind Phase of the study if 
any of the following criteria are met: 
1. Known noncompliance with dialysis treatment that in the 
opinion of the investigator would impede completion or 
validity of the study; 
2. Scheduled to receive a kidney transplant during the study; 
3. Known history of allergic reaction to opiates, such as hives 
(Note: side effects related to the use of opioids, such as 
constipation or nausea, would not exclude patients from the 
study). 
4. Has a concomitant disease or a history of any medical 
condition that, in the opinion of the Investigator, could pose 
undue risk to the patient, impede completion of the study 
procedures, or would compromise the validity of the study 
measurements, including, but not limited to: 
a. Known or suspected history of alcohol, narcotic, or other 
drug abuse, or substance dependence within 12 months 
prior to screening; 
b. Significant systolic or diastolic heart failure (eg, New 
York Heart Association Class IV congestive heart failure 
[Appendix 1, Section 14.1]); 
c. Severe mental illness or cognitive impairment (eg, 
dementia); 
d. Any other relevant acute or chronic medical or 
neuropsychiatric condition within 3 months prior to 
screening (eg, diagnosis of encephalopathy, coma, 
delirium); 
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. 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; 
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8. In the opinion of the Investigator, has pruritus attributed to a 
cause other than ESRD or its complications (eg, patients with 
concomitant pruritic dermatological disease or cholestatic liver 
disease) (Note: Patients whose pruritus is attributed to ESRD 
complications, such as hyperparathyroidism, 
hyperphosphatemia, anemia, or the dialysis procedure or 
prescription may be enrolled); 
9. Has localized itch restricted to the palms of the hands; 
10. Has pruritus only during the dialysis session (by patient 
report); 
11. Is receiving ongoing ultraviolet B treatment and anticipates 
receiving such treatment during the study; 
12. Participated in a previous clinical study with CR845. 
A patient will be excluded from the Open-label Extension Phase of 
the study if any of the additional following criteria are met at the 
time of entry into the Open-label Extension Phase: 
13. Completed the Double-blind Phase of this study but exhibited 
adverse events during the course of the Treatment Period that 
may preclude continued exposure to the study drug; 
14. Was noncompliant with protocol procedures during the 
Double-blind Phase of this study which is indicative of an 
inability to follow protocol procedures; 
15. Has developed 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. 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled 
study to evaluate the safety and efficacy of IV CR845 at a dose of 
0.5 mcg/kg administered after each dialysis session.  The study 
includes a Double-blind Phase and an Open-label Extension Phase. 
Double-blind Phase 
The Double-blind Phase of the study will consist of a Screening Visit, a 
7-day Run-in Period, a 12-week Double-blind Treatment Period, and a 
2-week Discontinuation Period.  Informed consent will be obtained 
prior to performing any study-specific procedures.  The Screening Visit 
will occur within 7 to 28 days prior to randomization to assess 
eligibility.  The site has the option to conduct the Screening Visit 
within the Run-in Period at the discretion of the Investigator. 
Eligible patients will complete a 7-day Run-in Period during the week 
prior to randomization to confirm eligibility, starting on the first 
dialysis session of that week (ie, Monday for patients on a 
Monday-Wednesday-Friday dialysis schedule or Tuesday for patients 
on a Tuesday-Thursday-Saturday dialysis schedule).  The purpose of 
the Run-in Period is to confirm that each patient has 
moderate-to-severe pruritus (ie, weekly average worst itch score >4), as 
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measured by the patient-daily reported 24-hour Worst Itching Intensity 
NRS, and to establish a baseline itch intensity.  Patients must not be 
informed that they need to report a weekly average worst itch score 
>4 to be enrolled in the study.  During the first visit of the Run-in 
Period, patients will be trained on completion of the 24-hour Worst 
Itching Intensity numerical rating scale (NRS) and will start the 
reporting of their Worst Itching Intensity NRS daily score.  For 
consistency, patients will be requested to complete the NRS 
worksheets (either at home or in the dialysis unit, as required) each day 
at a similar time of day around the normal start time of their dialysis. 
Patients will be trained on other itch-related patient-reported outcome 
(PRO) worksheets during the Run-in Period or on Day 1 of the 
Double-blind Treatment Period. 
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 into the 
Double-blind Treatment Period in a 1:1 ratio to receive either IV 
CR845 0.5 mcg/kg or placebo.  Patients will be stratified according to 
their use or non-use of concomitant medications to treat their itch 
during the week prior to randomization (Run-in Period) as well as the 
presence or absence of specific medical conditions.  These specific 
medical conditions include: 
• 
History of fall or fracture (related to fall) 
• 
Confusional state or mental status change or altered mental 
status or disorientation 
• 
Gait disturbance or movement disorder 
Day 1 of the Double-blind Treatment Period will be defined as the day 
of administration of the first dose of study drug and will occur on the 
first dialysis session of the first treatment week (ie, Monday for 
patients on a Monday-Wednesday-Friday dialysis schedule, or Tuesday 
for patients on a Tuesday-Thursday-Saturday dialysis schedule).  
Patients will be administered CR845 or matched placebo as an IV 
bolus after the end of each dialysis session during the 12-week 
Double-blind Treatment Period.  Each patient is to receive CR845 or 
placebo 3 times weekly for a total of up to 36 doses.   
During the Double-blind Treatment Period, patients will continue to 
report their daily Worst Itching Intensity NRS score over the previous 
24 hours.  In addition, during selected study visits (Day 1 and first day 
of Weeks 5, 9, 11, and 13; ie Days 29, 57, 71, and 85), they will 
complete other PRO measures (Skindex-10 Scale, 5-D Itch Scale, and 
Patient Global Impression of Change).  Patients will be instructed to 
record patient-reported outcome measurements at a similar time of day, 
whether in the dialysis unit (on dialysis days) or at home 
(on non-dialysis days). 
Blood samples for clinical laboratory tests will be collected at the 
Screening Visit, Days 1 and 85.  Blood samples for biomarkers will be 
collected at Days 1 and 85.  Electrocardiograms (ECGs) will be 
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monitored at the Screening Visit and Day 85.  Vital signs will be 
monitored periodically, and adverse events and concomitant 
medications will be continuously recorded starting at the Screening 
Visit until the end of the Discontinuation Period or Early Termination 
Visit.  Use of antipruritic medications, iron, and 
erythropoiesis-stimulating agents (ESAs) and missed dialysis will be 
recorded throughout the Double-blind Phase. 
The Double-blind Treatment Period will be followed by a 2-week 
Discontinuation Period, during which no study drug will be 
administered.  Patients will be monitored and evaluated for potential 
physical dependence by completing a Short Opiate Withdrawal Scale 
(ShOWS) daily on dialysis days and on non-dialysis days.  Objective 
Opiate Withdrawal Scale (OOWS) score, adverse events, concomitant 
medication, body temperature, and vital signs measurements will also 
be collected at each dialysis visit.  During this period, patients will 
continue to report their NRS scores but only on the dialysis visit. 
A Structured Safety Evaluation will be performed once during the 
Run-in Period and weekly (preferably on Wednesday/Thursday) during 
the Double-blind Treatment Period and Discontinuation Period.  The 
Structured Safety Evaluation is performed by study staff using a list of 
specific signs/symptoms (eg, mental status change, falls, gait 
disturbance). 
Open-label Extension Phase 
Patients who received at least 30 doses of study drug (either active or 
placebo) during the 12-week Double-blind Treatment Period and 
continue to meet other eligibility criteria will have the option to receive 
open-label CR845 for an additional 52 weeks.  The Open-label 
Extension Phase will be comprised of the Open-label Treatment Period 
and the Follow-up Period.  
Each patient will receive CR845 at a dose of 0.5 mcg/kg after each 
dialysis session, 3 times per week for up to 52 weeks, regardless of 
whether they had been previously administered placebo or CR845.  
Prescription dry weight will be recorded every 12 weeks; if there is a 
>10% change from the previous recorded dry weight, then the CR845 
dose will be adjusted.  
The first visit and first dosing for the Open-label Extension Phase of 
the study will occur during the week (+1-week window) following the 
Discontinuation Period. 
Patients will complete the 5-D Itch Scale during Weeks 4, 8, 12, 24, 
36, and 52 (preferably at the end of the specified weeks).  
Clinical laboratory tests, vital signs, adverse events, and concomitant 
medications will be monitored throughout the Open-label Treatment 
Period.  Blood samples for inflammatory biomarkers will be collected 
periodically until the Open-label End-of-Treatment or Early 
Termination Visit.  ECGs will be monitored at the Open-label 
End-of-Treatment or Early Termination Visit. 
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The number and reason(s) for missed dialysis as well as the use of 
antipruritic medications, ESAs and iron will be recorded throughout 
the Open-label Treatment Period.  
The last dose of open-label study drug will be administered at the last 
dialysis visit on Week 52, or Early Termination.  A final safety 
Follow-up Visit will be conducted 7-10 days after the 
End-of-Treatment/Early Termination Visit. 
STUDY DRUG 
Study drug will be supplied in glass vials containing an extractable 
volume of at least 1.3 mL of CR845 at a concentration of 0.05 mg/mL 
in 0.04M isotonic acetate buffer, pH 4.5. 
REFERENCE 
PRODUCT 
Matching placebo (0.04M isotonic acetate buffer, pH 4.5) will be 
provided in glass vials containing an extractable volume of at least 
1.3 mL. 
TREATMENT 
REGIMENS 
Patients will be administered CR845 0.5 mcg/kg or placebo as a single 
IV bolus 3 times a week after each dialysis session for 12 weeks during 
the Double-blind Treatment Period. 
No study drug will be administered during the Discontinuation Period.  
During the Open-label Treatment Period, patients will be administered 
CR845 0.5 mcg/kg as a single IV bolus 3 times a week after each 
dialysis session for up to 52 weeks. 
STUDY DURATION 
 
 
 
 
 
Double-blind Phase:   
Screening Period:  up to 4 weeks (may occur during Run-in Period at 
the discretion of Investigator) inclusive of the 7-day Run-in Period 
Double-blind Treatment Period:  12 weeks 
Discontinuation Period: 2 weeks 
Open-label Extension Phase: 
Open-label Treatment Period:  up to 52 weeks  
Follow-up Period: 2 weeks 
Total study duration for a single patient:  up to approximately 72 weeks 
STUDY 
ENDPOINTS 
Efficacy Endpoints 
Primary Efficacy Endpoint 
• 
Proportion of patients achieving at least a 3-point improvement 
from baseline with respect to the weekly mean of the daily 24-
hour Worst Itching Intensity NRS score at Week 12 of the 
Double-blind Treatment Period 
Secondary Efficacy Endpoints 
• 
Change from baseline in itch-related quality of life at the end 
of Week 12 of the Double-blind Treatment Period, as assessed 
by the 5-D Itch Scale total score 
• 
Change from baseline in itch-related quality of life at the end 
of Week 12 of the Double-blind Treatment Period, as assessed 
by the Skindex-10 Scale total score 
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• 
Proportion of patients achieving ≥4-point improvement from 
baseline with respect to the weekly mean of the daily 24-hour 
Worst Itching Intensity NRS at Week 12 of the Double-blind 
Treatment Period.  
 
Additional efficacy endpoints are described in Section 8.7.4. 
Safety Endpoints 
The safety endpoints used to evaluate the overall safety and tolerability 
of CR845 will be adverse events, ECG, vital signs, and clinical safety 
laboratory evaluations. 
INTERIM 
ASSESSMENT 
(Double-blind Phase) 
Safety data will be reviewed on an ongoing basis by the Sponsor and a 
Data Safety Monitoring Board (DSMB). The operation of the DSMB 
will be governed by a charter that will describe the group’s meeting 
frequency, procedures, and requirements for reporting its observations 
to the Sponsor. 
A single interim assessment for sample size re-estimation is planned 
after approximately 50% of the first 350 randomized patients either 
complete the 12-week Double-blind Treatment Period or discontinue 
study drug prematurely.  The interim assessment will be conducted by 
an Independent Data Monitoring Committee (IDMC).  Members of the 
IDMC will not participate in the DSMB and will not be members of the 
study team.  During the interim assessment, the study team will remain 
blinded to the data; however, the IDMC will receive unblinded 
summary results to implement the decision rule for sample size re-
estimation. The IDMC will only communicate the decision to either 
keep the original sample size or to increase it; no other results will be 
provided to blinded staff.   The DSMB will be made aware of the 
decision, but not given the results that were the basis of the decision. 
 
STATISTICAL 
ANALYSIS 
Analysis Populations 
The Enrolled Population is defined as the group of patients who sign 
informed consent. 
The ITT Population is defined as the group of patients who are 
randomized to a treatment group. The Double-blind Safety Population 
is defined as the group of randomized patients who received at least 1 
dose of study drug during the Double-blind Treatment Period.  
Following the intent-to-treat principle, patients in the ITT will be 
analyzed according to their randomized treatment, regardless of the 
actual treatment received.  Patients in the Double-blind Safety Analysis 
Population will be analyzed according to the actual treatment received.  
The Double-blind Safety Population will be used to analyze all safety 
endpoints collected during the Double-blind Phase, while the ITT 
Population will be used to analyze all efficacy endpoints collected 
during the Double-blind Phase. 
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The Per-Protocol Population is defined as the subset of patients in the 
ITT who do not have any major protocol deviations that could affect 
the efficacy analyses of the double-blind data.   
Inclusion in the Per-Protocol Population will be determined prior to 
unblinding the data and will be detailed in the statistical analysis plan. 
The Open-label Safety Population is defined as the group of patients 
who receive at least 1 dose of study drug in the Open-label Phase.  The 
Open-label Safety Population will be used to analyze all safety 
endpoints collected during the Open-label Phase, and during exposure 
to CR845 combining data from both the Double-blind and the 
Open-label Phases.   
 
Safety Analyses 
Safety data will be summarized descriptively.  No inferential statistics 
are planned.  Analyses of safety data will include summaries of 
treatment-emergent adverse events including Adverse Events of 
Special Interest (AESI), serious adverse events, and adverse events 
resulting in study drug discontinuation.  Vital signs, chemistry and 
hematology data, ECG data will be presented by visit as applicable, in 
addition to change from baseline. 
 
Efficacy Analyses (Double-blind Treatment Period) 
All efficacy analyses will be conducted on the ITT Population.  An 
analysis of the primary and secondary efficacy variables for the Per-
Protocol Population will also be performed. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the proportion of patients 
achieving at least a 3-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour Worst Itching Intensity NRS 
score at Week 12 (Days 79-85) of the Double-blind Treatment Period.  
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 Double-blind 
Treatment Period (eg, Days 2 to 8, Days 9 to 15, Days 16 to 22, etc,. 
Days 79 to 85) 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 
collected over the Run-in Period, including pre-randomization 
assessments collected on Day 1.  
In the primary efficacy analysis, missing NRS data will be imputed 
using a multiple imputation (MI) approach, assuming that patients who 
discontinue double-blind treatment early would have similar Worst 
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Itching Intensity NRS scores as other patients in their respective 
treatment arm that have complete data:  
• 
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).  
• 
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. Differences between CR845 0.5 mcg/kg and 
placebo with respect to the primary endpoint will be compared 
using a logistic regression model containing terms for treatment 
group, baseline NRS score, use of prior anti-itch medication, and 
presence of specific medical conditions 
• 
Results of the logistic regression 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 (Section 8.7.1). 
Secondary Efficacy Endpoints 
The Skindex-10 Scale total score and the 5-D Itch Scale total score will 
be analyzed using a mixed effects model with repeated measures 
(MMRM) that will contain treatment, week, and treatment-by-week 
interaction as fixed effects; baseline score, prior anti-itch medication 
usage and presence of specific medical conditions as covariates; and 
patient as a random effect.  Repeated measures will include values 
collected at the end of Weeks 4, 8, 10, and 12 (end of treatment).  The 
mean treatment difference between CR845 0.5 mcg/kg and placebo 
will be estimated as the simple contrast in the treatment effect at 
Double-blind Treatment Period Week 12. 
It is important to note that, in HD patients, the study drug administered 
during the last dialysis of a particular week is not cleared until the first 
dialysis of the next week. Therefore, measurements that would reflect 
treatment effect at the end of a specific week (eg. Week 4) will actually 
be collected during the first day of the next week (eg. Week 5). 
The proportion of patients achieving ≥4-point improvement from 
baseline with respect to the weekly mean of the daily 24-hour Worst 
Itching Intensity NRS at Week 12 of the Double-blind Treatment 
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Period will be analyzed follow a similar mehtodology to the one 
employed in the primary analysis of the primary 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 in the primary efficacy analysis 
of the primary endpoint (proportion of patients with a ≥3-point 
improvement from baseline at Week 12 of the Double-blind Treatment 
Period with respect to the Worst Itching Intensity NRS) is rejected in 
favor of the alternative that patients randomized to CR845 experience 
significantly less itching compared to patients randomized to placebo.  
To protect the Type 1 error, a gate-keeping strategy will be 
implemented.  Although the p-values corresponding to the hypothesis 
testing of the secondary variables will be reported, they will only be 
considered inferential if the primary analysis is statistically significant.  
Testing of the secondary efficacy endpoints will be performed 
sequentially at a 2-sided 5% error level.  The difference between 
CR845 0.5 mcg/kg and placebo with respect to the 5-D Itch total score 
will be tested first.  If results are statistically significant in favor of 
CR845, testing with respect to the Skindex-10 total score will proceed 
and be inferential.  The proportion of patients achieving ≥4-point 
improvement from baseline with respect to the weekly mean of the 
daily 24-hour Worst Itching Intensity NRS at Week 12 of the Double- 
blind Treatment Period will be tested only if the results of Skindex-10 
total score are statistically significant in favor of CR845. 
Details and methods of analysis are found in Section 8.0 and will be 
described further in the statistical analysis plan. 
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2.0 
Table of Contents 
1.0 Protocol Synopsis........................................................................................................ 4 
2.0 Table of Contents ...................................................................................................... 15 
3.0 List of Abbreviations ................................................................................................ 20 
4.0 Introduction ............................................................................................................... 21 
4.1 
Background and Rationale ................................................................................21 
4.2 
Clinical Experience ...........................................................................................22 
4.2.1 
Overall Exposure .......................................................................................22 
4.2.2 
Safety in Hemodialysis Patients.................................................................22 
4.2.3 
Efficacy of CR845 in Hemodialysis Patients with Uremic Pruritus ..........23 
4.2.4 
Pharmacokinetics in Hemodialysis Patients ..............................................24 
4.3 
Summary of Potential Risks and Benefits .........................................................25 
5.0 Objectives ................................................................................................................. 26 
6.0 Investigational Plan ................................................................................................... 27 
6.1 
Overall Study Design and Plan:  Description ....................................................27 
6.1.1 
Double-blind Phase ....................................................................................27 
6.1.1.1 
Screening Visit ...................................................................................... 27 
6.1.1.2 
Run-in Period ........................................................................................ 27 
6.1.1.3 
Double-blind Treatment Period ............................................................ 28 
6.1.1.4 
Double-blind Discontinuation Period ................................................... 29 
6.1.2 
Open-label Extension Phase ......................................................................30 
6.2 
Selection of Study Population ...........................................................................32 
6.2.1 
Inclusion Criteria .......................................................................................32 
6.2.2 
Exclusion Criteria ......................................................................................33 
6.3 
Removal of Patients from Therapy or Assessment ...........................................34 
6.3.1 
Discontinuation of Individual Patients.......................................................34 
6.3.2 
Discontinuation or Suspension of Entire Study .........................................35 
6.4 
Treatments .........................................................................................................36 
6.4.1 
Treatments Administered ...........................................................................36 
6.4.2 
Identity of Investigational Product(s) ........................................................36 
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6.4.2.1 
Formulation of Study Drug ................................................................... 36 
6.4.2.2 
Packaging, Labeling, and Storage Stability of Study Drug .................. 37 
6.4.2.3 
Individual Dose Labeling ...................................................................... 38 
6.4.3 
Drug Accountability...................................................................................38 
6.4.4 
Method of Assigning Patients to Treatment Groups..................................38 
6.4.5 
Preparation of CR845 ................................................................................38 
6.4.6 
Management of Missed Doses ...................................................................39 
6.4.7 
Treatment Compliance ...............................................................................39 
6.4.8 
Blinding......................................................................................................39 
6.4.9 
Prior, Concomitant, and Prohibited Medications .......................................39 
6.4.9.1 
Prior and Concomitant Medications ..................................................... 39 
6.4.9.2 
Restricted and Prohibited Medications ................................................. 39 
6.5 
Study Assessments and Procedures ...................................................................40 
6.5.1 
Schedule of Events for the Double-blind Phase ........................................40 
6.5.2 
Schedule of Events for the Open-label Extension Phase ...........................44 
6.5.3 
Efficacy Assessments.................................................................................48 
6.5.3.1 
Worst Itching Intensity Numerical Rating Scale .................................. 48 
6.5.3.2 
Skindex-10 Scale .................................................................................. 48 
6.5.3.3 
5-D Itch Scale ....................................................................................... 48 
6.5.3.4 
Patient Global Impression of Change ................................................... 49 
6.5.4 
Safety Assessments ....................................................................................49 
6.5.4.1 
Adverse Events ..................................................................................... 49 
6.5.4.2 
Structured Safety Evaluation ................................................................ 53 
6.5.4.3 
Physical Examination............................................................................ 53 
6.5.4.4 
Vital Signs ............................................................................................. 54 
6.5.4.5 
Electrocardiogram ................................................................................. 54 
6.5.4.6 
Clinical Laboratory Tests ...................................................................... 54 
6.5.4.7 
Contraception and Pregnancy ............................................................... 54 
6.5.5 
Additional Assessments .............................................................................55 
6.5.5.1 
Inflammatory Biomarkers ..................................................................... 55 
6.5.5.2 
Missed Dialysis Visits........................................................................... 56 
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6.5.5.3 
ESAs and IV Iron .................................................................................. 56 
6.5.5.4 
Discontinuation Period Additional Assessments .................................. 56 
7.0 Discussion and Justification of Study Design ........................................................... 57 
7.1 
Discussion of Study Design and Choice of Control Groups .............................57 
7.2 
Selection of Doses in the Study .........................................................................57 
7.3 
Appropriateness of Measurements ....................................................................57 
8.0 Statistical Methods .................................................................................................... 58 
8.1 
General Considerations .....................................................................................58 
8.2 
Determination of Sample Size ...........................................................................58 
8.3 
Randomization ...................................................................................................59 
8.4 
Interim Analysis ................................................................................................60 
8.4.1 
Sample Size Re-estimation ........................................................................60 
8.4.2 
Safety Data Review....................................................................................61 
8.5 
Analysis Populations .........................................................................................61 
8.6 
Statistical Summary and Analysis .....................................................................62 
8.6.1 
Patient Disposition .....................................................................................62 
8.6.2 
Protocol Deviations ....................................................................................62 
8.6.3 
Demographic and Baseline Characteristics ...............................................62 
8.6.4 
Medical History .........................................................................................62 
8.6.5 
Prior and Concomitant Medications ..........................................................63 
8.6.6 
Antipruritic Medication .............................................................................63 
8.7 
Efficacy Analysis ..............................................................................................63 
8.7.1 
Primary Efficacy Endpoint ........................................................................63 
8.7.2 
Secondary Efficacy Endpoints ...................................................................65 
8.7.3 
Hypothesis Testing Strategy ......................................................................66 
8.7.4 
Additional Efficacy Endpoints ...................................................................67 
8.7.4.1 
Itch-intensity Measures ......................................................................... 67 
8.7.4.2 
Itch-related Quality-of-Life Measures .................................................. 67 
8.8 
Safety Analysis ..................................................................................................68 
8.8.1 
Exposure to Study Drug .............................................................................68 
8.8.2 
Adverse Events ..........................................................................................69 
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8.8.3 
Clinical Laboratory Evaluations ................................................................70 
8.8.4 
Vital Signs and ECGs ................................................................................70 
8.9 
Additional Analyses ..........................................................................................72 
8.9.1 
Inflammatory Biomarkers ..........................................................................72 
8.9.2 
Missed Dialysis Visits and Incidence of Infection ....................................72 
8.9.3 
ESA and IV Iron ........................................................................................72 
8.9.4 
Discontinuation Period Additional Assessments .......................................72 
9.0 Quality Control and Quality Assurance .................................................................... 74 
9.1 
Study Monitoring Plan ......................................................................................74 
9.2 
Audits and Inspections ......................................................................................74 
9.3 
Data Collection, Validation, and Analysis ........................................................75 
10.0 Ethics and Regulatory Compliance ........................................................................... 76 
10.1 
Independent Ethics Committee or Institutional Review Board .........................76 
10.2 
Ethical Conduct of the Study .............................................................................76 
10.3 
Informed Consent Process .................................................................................77 
10.4 
Patient Confidentiality .......................................................................................77 
11.0 Data Handling and Quality Assurance ...................................................................... 79 
12.0 Administrative Procedures ........................................................................................ 80 
12.1 
Protocol Adherence ...........................................................................................80 
12.2 
Publication of Study Findings ...........................................................................80 
13.0 References ................................................................................................................. 81 
14.0 Appendix ................................................................................................................... 83 
14.1 
Appendix 1:  New York Heart Association Classification of Heart Failure .....83 
14.2 
Appendix 2:  Worst Itching Intensity Numerical Rating Scale (NRS) .............84 
14.3 
Appendix 3:  Skindex-10 Scale .........................................................................85 
14.4 
Appendix 4:  5-D Itch Scale ..............................................................................86 
14.5 
Appendix 5:  Patient Global Impression of Change ..........................................88 
14.6 
Appendix 6:  Short Opiate Withdrawal Scale ...................................................89 
14.7 
Appendix 7:  Objective Opiate Withdrawal Scale ............................................90 
15.0 Statistical Appendix .................................................................................................. 91 
 
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LIST OF TABLES 
Table 1. 
Restricted and Prohibited Medications ..................................................... 40 
Table 2. 
Schedule of Events:  Double-blind Phase ................................................. 41 
Table 3. 
Schedule of Events:  Open-label Extension Phase ................................... 45 
Table 4. 
Power as a Function of Effect Size (N = 175 per arm) ............................. 59 
Table 5. 
Sample Size as a Function of Odds Ratio (90% Power) ........................... 59 
Table 6. 
Criteria Used to Identify Clinically Notable Vital Sign Abnormalities .... 71 
 
LIST OF FIGURES 
Figure 1. 
CR845-CLIN3102 Study Schematic......................................................... 31 
 
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3.0 
List of Abbreviations 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H 
above the laboratory parameter’s reference range 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IL 
interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IV 
intravenous 
IVRS/IWRS 
interactive voice or web response system 
KOR 
kappa-opioid receptor 
L 
below the laboratory parameter’s reference range 
LS 
least squares 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed effects model with repeated measures 
MNAR 
missing not at random 
N 
within the laboratory parameter’s reference range 
NRS 
numerical rating scale 
OOWS 
Objective Opiate Withdrawal Scale 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error 
ShOWS 
Short Opiate Withdrawal Scale 
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 for references and further details).  
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 no activity at mu- and delta-opioid 
receptors or other receptors, ion channels, or transporters.  CR845’s unique peptidic 
structure 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 
kappa agonists. 
Uremic pruritus is a chronic, unremitting, and highly bothersome condition in patients 
with chronic kidney disease that adversely affects sleep, mood, and ability to socialize 
[Kumagai 2010].  Patients with uremic pruritus frequently exhibit considerable 
mechanical skin damage because of continuous scratching with excoriations, 
superimposed infections, and chronic lesions of prurigo nodularis or skin lichenification 
often occurring.  The mechanical skin damage can become an additional source of 
itching.  Consequently, these patients are at increased risk of related morbidities 
associated with infection, eg, cellulitis, sepsis, bacteremia, cutaneous infections, and 
infections of the dialysis access, and are at higher mortality risk (>15%) 
[Pisoni 2006; Narita 2006].  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.  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 
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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].  
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 hemodialysis patients.   
In nonclinical studies, CR845 has been shown to exhibit antipruritic and 
anti-inflammatory properties [Investigator’s Brochure].  Thus, CR845 is intended to 
reduce the severity of itching in hemodialysis patients and thereby decrease the likelihood 
of developing additional serious conditions associated with uremic pruritus. 
4.2 
Clinical Experience 
4.2.1 
Overall Exposure 
As of the writing of this protocol, the intravenous (IV) formulation of CR845 has been 
evaluated in 722 patients and healthy volunteers across eight Phase 1 studies (including 
2 studies conducted in Japan), three Phase 2 studies for the relief of moderate-to-severe, 
acute postoperative pain, and two Phase 2 studies for the relief of moderate-to-severe 
pruritus in hemodialysis patients.  In the United States, CR845 has been evaluated both as 
an IV bolus and a 15-minute infusion of single or repeated doses ranging from 
0.5 to 40 mcg/kg. 
Of the patients exposed to IV CR845 to date, 213 hemodialysis patients (127 males and 
86 females) have received single or repeated IV injections of CR845 doses (for up to 
8 weeks) ranging from 0.5 to 6 mcg/kg across two Phase 1 studies and two Phase 2 safety 
and efficacy studies. 
The most current information is contained in the current Investigator’s Brochure. 
4.2.2 
Safety in Hemodialysis Patients 
A review of the aggregate safety data shows that CR845 was well tolerated in 
hemodialysis patients when administered after each dialysis session for up to 8 weeks at 
IV doses ranging from 0.5 mcg/kg to 6 mcg/kg.  Although patients exposed to CR845 
reported more adverse events compared with placebo patients, most events were mild or 
moderate in nature.  Generally mild, transient paresthesias (facial tingling) and/or 
hypoesthesias (in different anatomic locations), mostly on the first week of dosing, as 
well as headache, dizziness, and somnolence, were the most frequently reported adverse 
events associated with CR845 administration.  Of note, side effects (eg, dysphoria and 
hallucinations) commonly associated with centrally-acting kappa opioids were not 
reported in patients exposed to CR845.  Consistent with its lack of affinity for mu-opioid 
receptors, CR845 did not cause euphoria, respiratory depression, or reduction in oxygen 
saturation.  
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CR845-CLIN2101 (Part A) evaluated the safety, pharmacokinetics, and efficacy of 
repeated IV doses of CR845 compared to placebo over an 8-week treatment period in 
174 hemodialysis patients.  This study is the longest treatment period evaluated to date in 
hemodialysis patients and no clinically important or significant safety findings related to 
CR845 were noted.  As expected with patients on hemodialysis, a significant number of 
the reported serious adverse events (SAEs) were considered not treatment-related, but 
related to the disease and/or comorbid conditions.  There were 31 (17.8%) of 174 patients 
randomized and treated in the study who had treatment-emergent SAEs.  Of the 31 SAE 
reports, 4 (9%) occurred in 45 placebo-treated patients and 27 (21%) in 
129 CR845-treated patients.  Only 1 SAE of mental status changes (moderate in severity) 
in a patient who received CR845 1.5 mcg/kg IV was considered by the Investigator to be 
probably related to study drug.  However, based on the Sponsor’s medical review, an 
alternate etiology of urgent/emergent hypertension offers a more plausible explanation 
for the acute change in mental status.  There were 4 patient deaths (2.3%) in the study, all 
of which were considered not related to the study drug. 
In patients with normal renal function, CR845 can cause free-water diuresis (aquaresis) 
and increased serum sodium.  However, as would be expected in patients undergoing 
dialysis in whom there are few functioning nephrons, there was no evidence of aquaresis 
or significant increases in serum sodium concentrations.  There were no adverse trends in 
clinical chemistry or hematology values (drawn pre-dialysis), including, no apparent 
differences between the placebo and CR845 groups in serum sodium.  There were no 
discernable differences between treatment groups in vital sign results.  Of particular note, 
among patients receiving CR845, there was no apparent reduction in blood pressure or 
respiratory rate following dosing. 
Adverse event summary tables can be found in the Investigator’s Brochure, with further 
details of the safety profile of CR845.   
4.2.3 
Efficacy of CR845 in Hemodialysis Patients with Uremic Pruritus 
The efficacy of CR845 in uremic pruritus was evaluated in two Phase 2, randomized, 
double-blind, placebo-controlled studies (CR845-CLIN2005 [Part B] and 
CR845-CLIN2101 [Part A]). 
CR845-CLIN2005 (Part B) included 65 hemodialysis patients with moderate-to-severe 
uremic pruritus who received either IV CR845 1.0 mcg/kg (n=33) or placebo (n=32) 
3 times per week for 2 weeks, after each hemodialysis session.  CR845 significantly 
decreased itching intensity compared with placebo (p=0.016), as measured by a visual 
analog scale (VAS) and significantly improved quality of life related to itching 
(Skindex-10 Scale) (see Investigator’s Brochure for details).  Furthermore, 
CR845-treated patients exhibited statistically significant reductions in both daytime 
(p=0.03) and nighttime (p=0.007) worst itching scores compared with placebo, and the 
reduction in itching intensity scores was similar on dialysis and nondialysis days.  The 
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mean change from baseline VAS curves over time showed numerical separation between 
the treatment groups within the first week of treatment. 
CR845-CLIN2101 (Part A) evaluated the safety, pharmacokinetics, and efficacy of 
repeated IV doses of CR845 compared to placebo over an 8-week treatment period in 
174 hemodialysis patients experiencing moderate-to-severe uremic pruritus daily or 
near-daily for 4.4 years on average.  The study was conducted at 33 dialysis centers and 
assessed the effect of 3 doses of CR845 (ie, 0.5 mcg/kg, n=44; 1 mcg/kg, n=41 and 
1.5 mcg/kg, n=44) or placebo (n=45) administered at the end of each dialysis session 
(ie, 3 times/week).  The primary efficacy endpoint for Study CR845-CLIN2101 (Part A) 
was based on itch intensity measurement and defined as the change from a 1-week 
baseline recorded prior to the start of study drug to the last week of the 8-week treatment 
period with respect to the weekly mean of the daily 24-hour Worst Itching Intensity 
numerical rating scale (NRS) score.  The least squares (LS) mean (±standard error [SE]) 
treatment group difference from placebo at Week 8 across all CR845 doses 
was -1.3 (±0.41) (95% confidence interval [CI]:  -2.1 to -0.5) (p=0.002) with an average 
NRS score reduction from baseline of -3.2 (±0.22) (LS mean ±SE) and 95% CI ranging 
from -3.7 to -2.8.  Examination of the individual CR845 dose group results for the Full 
Analysis Population indicates that a substantial improvement over placebo was observed 
with all 3 doses.  These differences from placebo were statistically significant for the 
lower dose group of 0.5 mcg/kg (p<0.001) and the 1.5 mcg/kg group (p=0.019), with an 
effect size estimated as 0.82, 0.39, and 0.62 for the 0.5, 1.0, and 1.5 mcg/kg doses, 
respectively.  Average reduction from baseline (LS mean ± SE) ranged from -2.8 (±0.38) 
in the 1.0 mcg/kg dose group (95% CI ranging from -3.5 to -2.0) to -3.8 (±0.38) in the 
0.5 mcg/kg dose group (95% CI ranging from -4.5 to -3.1).   
4.2.4 
Pharmacokinetics in Hemodialysis Patients 
CR845 is eliminated primarily through the kidney and no major metabolites have been 
identified in humans.  Consequently, total body clearance of CR845 in patients with 
severe renal impairment is reduced relative to healthy, matched, control patients 
(CR845-CLIN1005) such that plasma levels of CR845 remain relatively constant until 
cleared during dialysis in hemodialysis patients (CR845-CLIN1003 and 
CR845-CLIN2005 [Part A]).  Half-life ranges between 26 and 34 hours in hemodialysis 
patients compared to a typical range of 2 to 3 hours in patients with normal renal 
function.  Thus, lower doses of CR845 can be administered at a less frequent interval in 
hemodialysis patients to achieve the same or higher overall exposure compared to 
individuals with normal renal function.  Based on this pharmacokinetic profile, CR845 
does not need to be administered more than 3 times a week after each hemodialysis 
session, which is convenient for this patient population and ensures treatment compliance 
in a population already burdened with complex medication schedules.  
The pharmacokinetic profile of repeat-dose CR845 was studied in 24 hemodialysis 
patients who received doses of 0.5, 1.0, or 2.5 mcg/kg 3 times per week for 1 week 
(CR845-CLIN2005 [Part A]).  In this study, there were dose-proportional increases in 
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maximum concentration and area under the curve, and minimal to no accumulation with 
repeat doses due to clearance of the drug by hemodialysis (see Investigator’s Brochure 
for details). 
4.3 
Summary of Potential Risks and Benefits 
During preclinical development, no specific safety findings to preclude the use of CR845 
in humans were observed.  During early clinical development, IV CR845 was 
administered to healthy volunteers; patients with mild, moderate, or severe renal 
impairment, including end-stage renal disease (ESRD) and hemodialysis patients; 
recreational poly-drug users; and postsurgical patients.  The effects of CR845 have been 
shown to be in line with the underlying pharmacological mechanism of KOR activity.  
Consistent with the nonclinical abuse liability studies conducted to date, the results of an 
abuse-potential study in humans indicated that CR845 appears to present a low risk for 
abuse potential in humans in comparison to currently clinically used opioids.  
Overall, tingling/numbness, dizziness, fatigue and/or drowsiness/somnolence have been 
the most common adverse events.  Precaution is recommended in the operation of 
machinery for patients who experience dizziness, fatigue, and/or drowsiness/somnolence.  
This is described in the informed consent form (ICF), as appropriate, and will be 
discussed with each patient prior to initiation of the study.  In general, CR845 appeared to 
be well tolerated in both single- and repeat-dose clinical studies, which support continued 
study and development of this compound. 
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5.0 
Objectives 
Primary Objective  
• To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg compared to 
placebo in reducing the intensity of itch in hemodialysis patients with 
moderate-to-severe pruritus.   
Secondary Objectives  
• To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg compared to 
placebo in improving itch-related quality-of-life measures in hemodialysis 
patients with moderate-to-severe pruritus.   
• To evaluate the safety of IV CR845 at a dose of 0.5 mcg/kg in hemodialysis 
patients with moderate-to-severe pruritus. 
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6.0 
Investigational Plan 
6.1 
Overall Study Design and Plan:  Description 
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
safety and efficacy of IV CR845 at a dose of 0.5 mcg/kg administered after each dialysis 
session.  The study includes a Double-blind Phase and an Open-label Extension Phase.  
CR845 will be evaluated relative to placebo over a 12-week Double-blind Treatment 
Period in hemodialysis patients with moderate-to-severe pruritus followed by a 2-week 
monitored Discontinuation Period.  At the end of the Discontinuation Period, patients 
who received at least 30 doses of study drug during the 12-week Double-blind Treatment 
Period will have the option to receive open-label CR845 for an additional 52 weeks.   
6.1.1 
Double-blind Phase 
The Double-blind Phase of the study will consist of a Screening Visit, a 7-day Run-in 
Period, a 12-week Double-blind Treatment Period, and a 2-week Discontinuation Period.  
Informed consent will be obtained prior to performing any study-specific procedures.  
The Screening Visit will occur within 7 to 28 days prior to randomization in order to 
assess eligibility.  The Screening Visit can be conducted during the Run-in Period at the 
discretion of the Investigator. 
6.1.1.1 
Screening Visit 
During the Screening Visit, patients will sign the Informed Consent, and will be 
evaluated for eligibility by assessment of inclusion/exclusion criteria, medical history, 
physical examination, prescription dry body weight, pre-dialysis 12-lead 
electrocardiogram, pre-dialysis vital signs, pre-dialysis hematology and serum chemistry, 
serum pregnancy test for females of childbearing potential, adverse events, and ESA and 
IV iron doses, and prior medications. 
6.1.1.2 
Run-in Period 
Eligible patients will complete a 7-day Run-in Period during the week prior to 
randomization to confirm eligibility, starting on the first dialysis session of that week 
(ie, Monday for patients on a Monday-Wednesday-Friday dialysis schedule or Tuesday 
for patients on a Tuesday-Thursday-Saturday dialysis schedule).  The purpose of the 
Run-in Period will be to confirm that each patient has moderate-to-severe pruritus 
(ie, weekly average score >4), as measured by the 24-hour Worst Itching Intensity NRS, 
and to establish a baseline itch intensity.  These criteria for eligibility should not be 
communicated to the patients.  This period will also be used to record each patient’s use 
of itch medications.   
During the first visit of the Run-in Period, patients will be trained on completion of the 
24-hour Worst Itching Intensity NRS scale and will start the reporting of their Worst 
Itching Intensity NRS daily score.  For consistency, patients will be requested to 
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complete the NRS worksheets (either at home or in the dialysis unit, as required) at a 
similar time of day around the normal start time of their dialysis.   
Patients will also be trained on other itch-related patient-reported outcome (PRO) and 
patient health assessment worksheets during the Run-in Period or on Day 1 of the 
Double-blind Treatment Period.  
A Structured Safety Evaluation will be performed during the Run-in Period (preferably 
on Wednesday/Thursday).  The Structured Safety Evaluation is performed by study staff 
using a list of specific signs/symptoms (eg, mental status change, falls, gait disturbance).  
6.1.1.3 
Double-blind Treatment Period 
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 into the Double-blind Treatment Period in a 
1:1 ratio to receive either IV CR845 0.5 mcg/kg or placebo.  Patients will be stratified 
according to their use or non-use of concomitant medications to treat their itch during the 
week prior to randomization (Run-in Period) as well as the presence or absence of 
specific medical conditions. 
Day 1 of the Double-blind Treatment Period will be defined as the day of administration 
of the first dose of study drug and will occur on the first dialysis session day of the first 
treatment week (ie, Monday for patients on a Monday-Wednesday-Friday dialysis 
schedule or Tuesday for patients on a Tuesday-Thursday-Saturday dialysis schedule).   
Patients will be administered CR845 or matched placebo as an IV bolus after the end of 
each dialysis session during the 12-week Double-blind Treatment Period so that each 
patient will receive CR845 or placebo 3 times weekly for a total of up to 36 doses. 
During the Double-blind Treatment Period, patients will continue to report their Worst 
Itching Intensity NRS score on a daily basis, covering the previous 24 hours.  In addition, 
during selected study visits, they will complete other PRO measures (Skindex-10 Scale, 
5-D Itch Scale, and Patient Global Impression of Change).  Patients will be instructed to 
record patient-reported outcome measurements, including Worst Itching Intensity NRS 
scores, at a similar time of day, whether in the dialysis unit (on dialysis days) or at home 
(on non-dialysis days). 
Blood samples for inflammatory biomarkers will be collected for all randomized patients 
prior to dialysis on Day 1 and prior to the last dialysis at the End-of-Treatment Visit for 
the Double-blind Treatment Period (Day 85). 
Clinical laboratory tests and vital signs will be monitored periodically, and adverse 
events and concomitant medications will be continuously recorded starting at the 
Screening Visit until the end of the Discontinuation Period or Early Termination Visit.  
Electrocardiograms (ECGs) will be monitored at Screening Visit and Day 85 or Early 
Termination Visit. 
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The number and reason(s) for missed dialysis as well as the use of antipruritic 
medications, iron, and erythropoiesis-stimulating agents (ESAs) will be recorded 
throughout the study. 
A Structured Safety Evaluation will be performed weekly (preferably on 
Wednesday/Thursday) during the Double-blind Treatment Period.  The Structured Safety 
Evaluation is performed by study staff using a list of specific signs/symptoms (eg, mental 
status change, falls, gait disturbance).  
6.1.1.4 
Double-blind Discontinuation Period 
The Double-blind Treatment Period will be followed by a 2-week Discontinuation 
Period, during which no study drug will be administered and patients will be monitored 
for potential physical dependence, as follows: 
•
Daily patient completion of the Short Opiate Withdrawal Scale
(ShOWS-Gossop 1990) (paper worksheet to be filled by each patient at home on 
nondialysis days and at the dialysis unit on dialysis days at similar time of the day 
for a given patient) (see worksheet in Appendix 6, Section 14.6)
•
Completion of an Objective Opiate Withdrawal Scale (OOWS) worksheet
(Handelsman 1987) by a trained observer at each dialysis visit (ie, 3 times a week) 
(see worksheet in Appendix 7, Section 14.7) (training of observer will be 
recorded)
•
Recording of adverse events, medication used, body temperature, and vital signs 
at each dialysis visit. 
Measurements will be taken starting at the end of the Treatment Period (Day 85) and then 
at each dialysis visit for up to 2 weeks following study drug discontinuation until Day 98 
(Table 2). 
During this Discontinuation Period, at each dialysis visit, patients will be asked to 
continue to report their daily Worst Itching Intensity NRS score over the previous 
24 hours.  In order to minimize bias, the OOWS and ShOWS will be introduced to the 
patients as health-assessment scales. 
On the day of a dialysis visit, the OOWS and the ShOWS will be completed during the 
first hour (+1-hour window allowed) of dialysis so that dialysis-associated patient fatigue 
should minimally interfere with the completion of the scales.  Double-blind study drug 
treatment assignment will remain blinded throughout the course of the Discontinuation 
Period.  For patients who withdraw from the Double-blind Treatment Period early, every 
attempt will be made to conduct the 2-week Discontinuation Period. 
A Structured Safety Evaluation will be performed weekly (preferably on 
Wednesday/Thursday) during the Discontinuation Period.  The Structured Safety 
Evaluation is performed by study staff using a list of specific signs/symptoms (eg, mental 
status change, falls, gait disturbance).  
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6.1.2 
Open-label Extension Phase 
Patients who received at least 30 doses of study drug (either placebo or active) during the 
12-week Double-blind Treatment Period and continue to meet other eligibility criteria 
will have the option to receive open-label CR845 for an additional 52 weeks.  The Open-
label Extension Phase will be comprised of the Open-label Treatment Period and the Follow-up 
Period.  The first visit and first dosing for the Open-label Extension Phase of the study 
will occur during the week (+1-week window) following the Discontinuation Period.  
Each patient will receive CR845 at a dose of 0.5 mcg/kg after each dialysis session, 
3 times per week for up to 52 weeks, whether they had been previously administered 
placebo or CR845.  Prescription dry weight will be recorded every 12 weeks; if there is a 
>10% change from the previous recorded dry weight, then the CR845 dose will be 
adjusted.  
During selected study weeks, patients will complete the 5-D Itch Scale. 
Clinical laboratory tests, vital signs, adverse events, and concomitant medications will be 
monitored throughout the Open-label Treatment Period.  Blood samples for inflammatory 
biomarkers will be collected periodically until the End-of-Treatment or Early 
Termination Visit.  An electrocardiogram will be monitored at the End-of-Treatment or 
Early Termination Visit. 
The number and reason(s) for missed dialysis will be recorded throughout the study.  Use 
of antipruritic medications, iron, and ESAs will be recorded throughout the Open-label 
Treatment Period. 
The last dose of open-label study drug will be administered at the last dialysis visit in 
Week 52.  A final safety Follow-up Visit will be conducted 7-10 days after the 
End-of-Treatment/Early Termination Visit. 
The study schematic is shown in Figure 1. 
 
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6.2 
Selection of Study Population 
Patients with ESRD receiving hemodialysis 3 times a week and experiencing 
moderate-to-severe pruritus will be considered for participation in this study. 
A screening log of potential study candidates will be maintained at each study site. 
Patients providing informed consent will be screened for inclusion in the study.  All 
eligibility criteria must be met before a patient is randomized.   
Rescreening will be considered on an individual patient basis and must first be approved 
by the Sponsor.   
6.2.1 
Inclusion Criteria 
To be eligible for inclusion into the Double-blind Phase of 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. Has ESRD and has been on hemodialysis 3 times per week for at least 3 months 
prior to the start of screening;  
Note 1:  Patients who require an occasional additional dialysis treatment to 
manage fluid overload may be enrolled as long as it is anticipated that no more 
than 1 such treatment will be required in any given week. 
Note 2:  Patients receiving in-home hemodialysis may participate as long as they 
have switched to in-center hemodialysis at least 2 weeks prior to screening and 
plan to remain on in-center hemodialysis for the duration of the study. 
5. If female, is not pregnant or nursing during any period of the study;  
6. If female: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for at least 1 year and is over the age of 55 years; 
or 
c. Has a negative serum pregnancy test 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 
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dose of study drug. (Note:  No restrictions are required for a vasectomized male 
provided his vasectomy was performed ≥4 months prior to screening); 
8. Has a prescription dry body weight between 40.0 and 135.0 kg, inclusive; 
9. Has at least 2 single-pool Kt/V measurements ≥1.2, or 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 months 
period prior to screening; 
10. Prior to randomization:  
a. Has completed at least 4 Worst Itching Intensity NRS worksheets from the 
start of the 7-day Run-in Period up to and including the pre-randomization 
assessment on Day 1;  
b. Has a mean baseline Worst Itching Intensity NRS score >4, defined as the 
average of all non-missing scores reported from the start of the 7-day 
Run-in Period up to and including the pre-randomization assessment on 
Day 1. 
To be eligible for inclusion into the Open-label Extension Phase of the study, each 
patient will have to fulfill the additional following criteria at the time of entry into 
the Open-label Extension Phase: 
11. Has received at least 30 doses of the planned 36 doses of study drug during the 
Double-blind Phase of this study; 
12. Has a prescription dry body weight ≥40 kg; 
13. Continues to meet inclusion criteria 1 through 7. 
 
6.2.2 
Exclusion Criteria 
A patient will be excluded from the Double-blind Phase of the study if any of the 
following criteria are met: 
1. Known noncompliance with dialysis treatment that in the opinion of the 
investigator would impede completion or validity of the study; 
2. Scheduled to receive a kidney transplant during the study; 
3. Known history of allergic reaction to opiates, such as hives (Note:  side effects 
related to the use of opioids, such as constipation or nausea, would not exclude 
patients from the study); 
4. Has a concomitant disease or a history of any medical condition that, in the 
opinion of the Investigator, could pose undue risk to the patient, impede 
completion of the study procedures, or would compromise the validity of the 
study measurements, including, but not limited to: 
a. Known or suspected history of alcohol, narcotic, or other drug abuse, or 
substance dependence within 12 months prior to screening; 
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b. Significant systolic or diastolic heart failure (eg, New York Heart 
Association Class IV congestive heart failure [Appendix 1, Section 14.1]); 
c. Severe mental illness or cognitive impairment (eg, dementia); 
d. Any other relevant acute or chronic medical or neuropsychiatric condition 
within 3 months prior to screening (eg, diagnosis of encephalopathy, coma, 
delirium); 
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. 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; 
8. In the opinion of the Investigator has pruritus attributed to a cause other than 
ESRD or its complications (eg, patients with concomitant pruritic dermatological 
disease or cholestatic liver disease) (Note:  Patients whose pruritus is attributed to 
ESRD complications, such as hyperparathyroidism, hyperphosphatemia, anemia, 
or the dialysis procedure or prescription may be enrolled); 
9. Has localized itch restricted to the palms of the hands; 
10. Has pruritus only during the dialysis session (by patient report); 
11. Is receiving ongoing ultraviolet B and anticipates receiving such treatment during 
the study; 
12. Participated in a previous clinical study with CR845. 
A patient will be excluded from the Open-label Extension Phase of the study if any of 
the additional following criteria are met at the time of entry into the Open-label 
Extension Phase: 
13. Completed the Double-blind Phase of this study but exhibited adverse events 
during the course of the Treatment Period that may preclude continued exposure 
to the study drug; 
14. Was noncompliant with protocol procedures during the Double-blind Phase of 
this study which is indicative of an inability to follow protocol procedures;  
15. Has developed 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. 
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.   
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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. If a patient misses 3 consecutive doses either on Week 11 or Week 12 of the 
Double-blind Treatment Period (these patients may still be eligible for the 
Open-label Phase at the discretion of the Investigator in consultation with the 
Sponsor).  
3. If patient misses 6 consecutive doses at any time; 
4. At the discretion of the Sponsor/Medical Monitor, if a patient receives a 
prohibited concomitant medication according to Table 1. 
5. Any patient who becomes pregnant during treatment must be withdrawn from 
the study (see Section 6.5.4.7). 
Whenever possible, withdrawal of a patient from study drug by the Investigator should be 
discussed with the Medical Monitor before the patient stops study drug.  
If study drug is discontinued, regardless of the reason, an Early Termination Visit should 
be completed at the first dialysis after the last dose of study drug or, if not feasible during 
that timeframe, as soon as feasible.  If at all possible, a monitored 2-week Discontinuation 
Period is to be completed after the Early Termination Visit in the Double-blind Phase.  
Although a patient will not be obliged to give a reason for withdrawing prematurely, the 
Investigator must make a reasonable effort to obtain the reason while fully respecting the 
patient’s rights.  The reason(s) for termination and date of stopping study drug must be 
recorded on the electronic case report form (eCRF) and source documents. 
If a patient discontinues early due to an adverse event, the event will be followed until 
resolution, the patient returns to baseline status, the condition stabilizes, or the patient is 
lost to follow-up. 
A patient will be considered lost to follow-up when no response is received from the 
patient after at least 3 documented attempts to contact the patient over a minimum time of 
2 weeks by the study site. 
If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data 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 
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regulatory agencies and Institutional Review Boards (IRBs)/Independent Ethics 
Committees are notified, as appropriate.  
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 the Sponsor or 
destroyed at the site according to instructions which will be provided by the Sponsor, as 
applicable.  
6.4 
Treatments 
Additional information on the study drug and its preparation, administration, storage, 
supply, disposition, and accountability can be found in the Pharmacy Section of the 
Investigator Site File (ISF). 
6.4.1 
Treatments Administered 
The study drug will be dispensed by qualified staff members who have received training 
on study drug handling and administration.   
Patients will receive IV CR845 at a dose of 0.5 mcg/kg or placebo after each dialysis 
session, generally 3 times per week for up to 64 weeks (ie, 12 weeks double-blind and 
52 weeks open-label) as an IV bolus into the venous line of the dialysis circuit at the end 
of each dialysis session and may be given either during or after rinse back of the dialysis 
circuit.  If a patient receives additional dialysis during a given week for any reason, an 
additional dose of CR845 or placebo will be administered following dialysis.  A maximum 
of 4 doses per week is allowed.  No additional doses will be given for patients receiving 
an additional unscheduled ultrafiltration treatment. 
Following the IV push of study drug, the venous line must be flushed with at least 10 mL 
of normal saline.   
The patient’s prescription dry body weight (ie, the target post-dialysis weight, as 
determined by the patient’s nephrologist or dialysis unit during screening) will be used to 
calculate the dose of the study drug to be administered throughout the Double-blind 
Treatment Period. 
During the Open-label Treatment Period, the volume of CR845 to be administered will be 
based on patient’s prescription target dry body weight recorded on Day 1 of the 
Open-label Treatment Period, and adjusted if prescription dry body weight changes by 
±10% or more from dry body weight being used for calculation of CR845 dose.  
6.4.2 
Identity of Investigational Product(s) 
6.4.2.1 
Formulation of Study Drug 
Study drug will be supplied by the Sponsor as a solution in 2-mL glass vials containing a 
minimum extractable volume of 1.3 mL of CR845 at a concentration of 0.05 mg/mL in 
0.04 M isotonic acetate buffer, pH 4.5.  The composition of the CR845 solution contains 
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CR845 (free base), acetic acid, sodium acetate trihydrate, sodium chloride, hydrochloric 
acid, and water for injection. 
Matching placebo (0.04M isotonic acetate buffer, pH 4.5) will be provided in 2-mL glass 
vials containing a minimum extractable volume of 1.3 mL.  The composition of the 
placebo buffer solution is acetic acid, sodium acetate trihydrate, sodium chloride, 
hydrochloric acid, and water for injection.  The placebo buffer is identical to the buffer 
solution used in the CR845 solution and has identical appearance as the solution 
containing the active ingredient.  The placebo buffer solution will be packaged, stored, 
and shipped identically to the CR845 solution. 
6.4.2.2 
Packaging, Labeling, and Storage Stability of Study Drug 
Study drug will be shipped at 15°C to 30°C.  Temperature will be monitored during 
shipment and verified and recorded in the pharmacy log by pharmacist upon arrival at the 
site.  The vials must be stored at temperature ranging from 15°C to 30°C upon receipt and 
temperature will be monitored accordingly. 
For the Double-blind Treatment Period vials will be packaged (blinded) in boxed kits (also 
blinded) containing 40 vials per box (4 extra vials for backup).  Kits will be labeled with 
patient ID number and kit number.  A single box of vials will be assigned to a patient. 
For the Open-label Treatment Period, vials will be packaged in boxed kits containing 
12 vials per box.  Kits will be labeled with patient ID number and kit number.  A single 
box of vials will be assigned to a patient. 
Labeling of the vials will include, but is not limited to, the following: 
• Study protocol number (CR845-CLIN3102) 
• Blinded name of study drug (CR845 0.5 mcg/kg or placebo IV solution) for the 
Double-blind Treatment Period or name and concentration of study drug (CR845 
0.5 mcg/kg) for the Open-label Treatment Period 
• Batch or lot number (open-label only) 
• Temperature storage instructions (store at 15°C to 30°C) 
• Extractable volume:  at least 1.3 mL 
• Name and location of Sponsor 
• Administer according to protocol 
• For Clinical Trial Use Only 
The label on each kit will be the same as the label on an individual vial, and in addition, 
will provide the number of vials contained per box (12 or 40).  It will also include 
“Caution: New Drug- Limited by Federal (or United States) Law to Investigational Use.” 
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6.4.2.3 
Individual Dose Labeling 
One syringe will be prepared for each patient on each dosing day.  Patients weighing 
>135.0 kg require modified preparation of CR845.  Syringes and syringe labels will be 
provided.  Refer to the ISF for details. 
6.4.3 
Drug Accountability 
All supplies will be maintained under adequate security by the pharmacist or approved 
staff at the investigational site.  At the end of each injection, the used vials will be stored 
until the study monitor performs accountability.  Details of study drug accountability and 
return are provided in the ISF.  
The Sponsor (or delegated person) will be permitted, at intervals and upon request during 
the study, to check the supplies, storage and dispensing procedures, and records. 
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 ratio to receive either CR845 
0.5 mcg/kg IV or matching placebo IV during the Double-blind Treatment Period.  
Patients will be stratified into 2 strata according to their use or non-use of concomitant 
medications to treat their itch during the pre-randomization week (Run-in Period) as well 
as the presence or absence of specific medical conditions.  These specific medical 
conditions include: 
• History of fall or fracture (related to fall) 
• Confusional state or mental status change or altered mental status or disorientation 
• Gait disturbance or movement disorder 
All eligible patients providing consent for participation in the Open-label Treatment 
Period will receive CR845 at a dose of 0.5 mcg/kg starting on Day 1 of the Open-label 
Treatment Period. 
6.4.5 
Preparation of CR845 
In the Double-blind Phase of the study, a single vial of study drug will be used for each 
patient.  Each patient’s prescription dry body weight will not exceed 135.0 kg. 
In the Open-label Extension Phase of the study, 1 vial of CR845 will be used for patients 
with a prescription dry body weight ≤135.0 kg.  For patients with a prescription dry body 
weight >135.0 kg, 2 vials of CR845 will be used to ensure that the full volume of study 
drug can be prepared.  Further details will be provided in the ISF.   
Information on the study drug preparation can be found in the Pharmacy Manual. 
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6.4.6 
Management of Missed Doses  
If a patient misses a dialysis visit and the planned dose of CR845 for that visit, dosing 
should resume at the next dialysis visit.   
Contact the Medical Monitor if patient compliance or safety is of concern. 
6.4.7 
Treatment Compliance 
Patient compliance with study drug is documented as part of standard procedures at the 
dialysis units where study drug is administered. 
6.4.8 
Blinding 
During the Double-blind Treatment Period, 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. 
6.4.9 
Prior, Concomitant, and Prohibited Medications 
6.4.9.1 
Prior and Concomitant Medications 
Prior medications (including vitamins and herbal supplements) are defined as those that 
the patient has taken any time during the 3 months prior to the first dose of study drug on 
Day 1 of the Double-blind Treatment Period.  Concomitant medications are medications 
that are taken from after the start of the first dose of study drug on Day 1 of the 
Double-blind Treatment Period through the end of the Open-label Treatment Period or 
early termination (ie, End-of-Treatment/Early Termination Visit).   
Erythropoiesis-stimulating agents and IV iron administered to the patient will be recorded 
as per the schedule of events (Table 2 and Table 3). 
Use of antipruritic medications during the study will be recorded on an ongoing basis, 
starting at screening. 
All prior and concomitant medications, including over-the-counter medications used by 
patients during this study, are to be recorded in the appropriate page of the eCRF, as 
applicable. 
6.4.9.2 
Restricted and Prohibited Medications 
During the Treatment Period for either the Double-blind Phase or Open-label Extension 
Phase, the following medications will be restricted or prohibited (Table 1). 
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Table 1. 
Restricted and Prohibited Medications  
Drug, Drug Class, or Treatment 
Restrictions During the Treatment Period 
Investigational drug (other than the study 
drug) 
Not allowed 
Ultraviolet light-B treatments 
Not allowed 
Naloxone, naltrexone, or mixed 
agonist-antagonists (eg, buprenorphine and 
nalbuphine) 
Not allowed from the start of dosing of the 
Double-blind Treatment Period to the end of 
the Open-label Treatment Period, 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 screening to the end of the 
Double-blind Treatment Period unless for the 
acute treatment of an adverse event or 
emergent medical condition (in this case, 
notify the study medical monitor and, as 
appropriate, report adverse events). 
No new medication to treat itch should be 
initiated. 
All new concomitant medications or change of frequency and doses of a concomitant 
medication will be recorded. 
6.5 
Study Assessments and Procedures 
6.5.1 
Schedule of Events for the Double-blind Phase 
Study procedures for the Double-blind Treatment Period are summarized in Table 2.   
An ICF will need to be signed prior to initiation of the Screening Visit and any procedures 
that follow.  
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a. 
Each visit during the Double-blind Treatment Period will coincide with the patient’s normal dialysis treatments. 
b. 
The End-of-Treatment Visit in the Double-blind Phase will be the first dialysis visit following the last dose of study drug (ie, first dialysis on Week 13 [Day 85]), which also corresponds to Day 1 
of the Discontinuation Period (DP Day 1).  
c. 
Medical history will be updated on Day 1 with any changes since the Screening Visit, and inclusion/exclusion criteria will be confirmed prior to randomization.  Antipruritic medication will be 
updated at each dialysis visit during the Run-in Period. 
d. 
Electrocardiogram must be performed prior to the start of dialysis at screening, Day 85 (End of Treatment), or at Early Termination visit. 
e. 
Pre-dialysis vital signs, including body temperature, heart rate, and blood pressure, will be recorded on Days 1, 15, 29, 43, 57, 71 and 85 (End of Treatment), or at Early Termination visit only 
when the patient is in a sitting or semi-recumbent position.  Heart rate will be measured at each dialysis; if heart rate is clinically significant and outside the prespecified visits per Schedule of 
Events, the heart rate will be recorded on the relevant CRF page.  
f. 
Pre-dialysis vital signs, including body temperature, heart rate, and blood pressure, will be recorded at each dialysis visit during the Discontinuation Period.  Heart rate will be measured at each 
dialysis. 
g. 
Blood samples for clinical laboratory evaluation will be taken at screening, and on Days 1 and 85 (End of Treatment), or at Early Termination visit only.  
h. 
Training on Worst Itching Intensity NRS will be conducted on the first day of the Run-in Period (Day -7).   
i. 
Training on ShOWS on Day -7 and first day of Week 13. 
j. 
Training on Skindex-10 Scale and 5-D Itch Scale may be performed at any time during the week prior to randomization or on Day 1 of the Double-blind Treatment Period 
k. 
Patients will be requested to complete their Worst Itching Intensity NRS worksheets each day at a similar time (either at home on non-dialysis days around the normal start time of their dialysis or 
in the dialysis unit).  On dialysis days, the worksheets will be completed prior to or during dialysis, but must be completed prior to dosing. 
l. 
 During the Discontinuation Period, Worst Itching Intensity NRS worksheets will be completed on dialysis days only. 
m. 
5-D Itch Scale and Skindex-10 Scale completed on Day 1 and the first visit of Weeks 5, 9 and 11 (on Days 29, 57 and 71) and Week 13 (Day 85).  5-D Itch scale will preferably be completed first.  
If the first visit of the week is missed, the patient may complete the worksheets at their next visit for the same week.  The worksheets will be completed prior to or during dialysis (preferably within 
1 hour of the dialysis), but must be completed prior to dosing. 
n. 
ShOWS worksheets will be completed daily through the entire Discontinuation Period starting on Day 85.  The OOWS worksheets will be completed at each dialysis visit during the 
Discontinuation Period starting on Day 85.  On the day of a dialysis visit, the OOWS and the ShOWS will be completed during the first hour (+1-hour window allowed) of dialysis so that dialysis-
associated patient fatigue and other potential side effects related to the dialysis procedure should minimally interfere with the completion of the scales.   
o. 
Biomarker samples must be collected prior to the start of dialysis on Day 1 and Day 85. 
p 
Concomitant medications including antipruritic medication will be updated at each dialysis visit during the Double-blind Treatment Period, and until the end of the Discontinuation Period.  
q. 
Sites have the option to conduct the Screening Visit during the Run-in Period at the discretion of the Investigator 
r. 
A list of specific signs/symptoms will be verified with the patient by qualified site staff, preferably to be completed on Wednesday/Thursday each week during the Run-in Period, the Double-blind 
Treatment Period and the Discontinuation Period.  Not to be completed on Monday/Tuesday.  
 
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6.5.2 
Schedule of Events for the Open-label Extension Phase 
Study procedures for the Open-label Extension Phase are summarized in Table 3.  
The safety assessment visit may occur on any chosen dialysis day of a scheduled week as 
long as all assessments are completed during that visit.  Patients who miss one of the 
scheduled study visit weeks (eg, Week 4 of open-label treatment) may complete this visit 
at their next dialysis treatment if conducted within 2 weeks of the scheduled visit.  
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, the adverse events reported, as 
well as changes to concomitant medications, as applicable.  Additional testing 
(eg, laboratory tests, vital signs, ECGs) will be performed as clinically indicated. 
 
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i. 
Administered after each dialysis as an IV bolus.   
j. 
To be completed in the dialysis unit at any time prior to or during dialysis, but must be done prior to dosing.  Preferably at the end of the specified week, which corresponds to 
the beginning of the following calendar week (ie, end of Week 4 is the Monday/Tuesday of Week 5). 
k. 
Biomarker samples must be collected prior to the start of dialysis. 
l. 
Adverse events and concomitant medications will be recorded starting on Day 1 of the Open-label Treatment Period.   
 
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6.5.3 
Efficacy Assessments 
The effect of CR845 on itch will be measured by means of the following PRO measures:  
• Worst Itching Intensity NRS score 
• Skindex-10 Scale 
• 5-D Itch Scale  
• Patient Global Impression of Change 
Patients will be trained on completion of the Worst Itching Intensity NRS scale at the 
first visit of the Run-in Period, and will be trained on the other itch-related PRO measures 
at any time during the Run-in Period or on Day 1 of the Double-blind Treatment Period.  
All questionnaires must be completed in strict adherence to the Training Manual for 
Patient Reported and Observer-reported Assessments. 
6.5.3.1 
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, both at the clinic on dialysis days 
and at home on nondialysis days.   
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]. 
6.5.3.2 
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 itch 
intensity [Mathur 2010].  Patients are asked to mark 1 of 7 boxes numbered from 0 
(labeled with the anchor phrase “never bothered”) to 6 (labeled as “always bothered”) for 
each of the 10 questions describing how often they have been bothered by their itch and 
its impact over the past week.  The total score is the sum of the numeric value of each 
answered question.  The total score is subdivided into 3 domain scores, which are sums 
of the scores of the following questions:  disease domain (questions 1 to 3), 
mood/emotional distress domain (questions 4 to 6), and social functioning domain 
(questions 7 to 10). 
6.5.3.3 
5-D Itch Scale 
The 5-D Itch Scale was developed as a brief, multidimensional questionnaire designed to 
be useful as an outcome measure in clinical studies.  The 5 dimensions of itch assessed 
are degree, duration, direction, disability, and distribution (Appendix 4, Section 14.4).  
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Patients are asked to mark boxes that best describe the impact of their itch over the past 
2 weeks.  The scale has been validated in patients with chronic pruritus, including 
hemodialysis patients and has been shown to be sensitive to changes in pruritus over time 
[Elman 2010]. 
6.5.3.4 
Patient Global Impression of Change 
The Patient Global Impression of Change is a global PRO measure that assesses the 
change in itch (no change, improvement or worsening) overall relative to the start of the 
study [Dworkin 2005].  The scale has only 1 item, and the patient is asked to mark the 
category that best describes the change in itch ranging from “Very Much Improved” to 
“Very Much Worse” (Appendix 5, Section 14.5). 
6.5.4 
Safety Assessments 
During both the Double-blind and Open-label Phases, the safety assessments for each 
patient are the following: 
• Severity, seriousness, and relationship of adverse events to study drug  
• Structured Safety Evaluation by site staff  
• Physical examination 
• Vital signs  
• 12-lead ECGs 
• Clinical laboratory tests 
 
6.5.4.1 
Adverse Events 
Definition of Adverse Events 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigational patient administered a medicinal product and which does not necessarily 
have to have a causal relationship with this treatment.  An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
In this study, adverse events will be captured from the time a patient signs the ICF to the 
Follow-up Visit and include the following: 
• Any new sign, symptom, or disease; 
• Any new clinically significant or symptomatic laboratory/diagnostic test 
abnormality; 
• Any clinically significant worsening of laboratory/diagnostic test abnormality; 
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• Any worsening (ie, clinically significant change in frequency, nature, and/or 
intensity) of a pre-existing condition.  
A pre-existing condition is a condition that is present prior to signing the ICF for the 
study.  Pre-existing conditions, such as illnesses, symptoms, reactions, progression of 
disease states, and other comorbidities, as well as laboratory/diagnostic test 
abnormalities, will be documented in the patient’s record as medical history.  
Signs and symptoms will be reported individually as adverse events (non-serious), unless 
a medical diagnosis was provided.  Medical diagnosis, whenever provided, will be 
reported rather than individual signs and symptoms.   
Any adverse event that satisfies any of the seriousness criteria described below will be 
reported as an SAE using the SAE Report Form, in addition to documenting in the eCRF.  
Serious adverse events that occurred up to 30 days after the last dose of study drug need 
to be documented on an SAE Report Form if they are deemed by the Investigator to be 
“Related” to study drug. 
Adverse Event Severity Assessment 
The Investigator will assess the severity (ie, intensity) of each adverse event (serious and 
non-serious) reported during the study based on his/her clinical judgment.  The severity 
of each adverse event will be assigned to one of the following categories: 
Mild: 
Transient, requires no special treatment, is easily tolerated by the 
patient, causes minimal discomfort, and does not interfere with the 
patient’s daily activities 
Moderate: 
Introduces a level of inconvenience or concern to the patient that may 
interfere with daily activities, but usually is ameliorated by simple 
therapeutic measures 
Severe: 
Interrupts a patient’s usual daily activity and requires systemic drug 
therapy or other treatment 
 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
• Results in death; 
• Is life-threatening; 
NOTE:  The term "life-threatening" in the definition of "serious" refers to an 
event in which the patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were 
more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; or 
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• Is a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization, but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These are usually considered serious. 
Severe versus Serious Adverse Event 
The term “severe” is used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  An adverse event as 
well as an SAE must be assessed for severity.  An adverse event that is assessed as severe 
should not be confused with an SAE.  “Severity” is not the same as “Serious,” which is 
based on patient outcome or reaction criteria usually associated with events that pose a 
threat to a patient’s life or functioning.  Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
Adverse Event Causality or Relatedness to the Study Drug 
Every effort should be made by the Investigator to explain each adverse event and assess 
its relationship, if any, to study drug.  The Investigator should consider many factors, 
including, but not limited to, temporal association of the event and date/time of study 
drug, duration of study drug, medical/biologic plausibility, pharmacology and adverse 
event profile of study drug, medical history (past medical history, underlying disease, 
comorbidities, intercurrent illness), concomitant medications, medical judgment, 
dechallenge, rechallenge, drug interaction, other plausible causes, etc., to determine the 
causality assessment of an event.   
The Investigator as well as the Sponsor will determine adverse event/SAE causality as 
‘Related’ or ‘Not Related’ to study drug.  Although there is no international consensus on 
how to define ‘Related’ and ‘Not Related,’ in general, an event is considered ‘Related’ if 
there is reasonable possibility that the event is related to study drug than to any other 
possible cause(s).  Conversely, an event is considered ‘Not Related’ if there is reasonable 
possibility that the event is related to other factors than the study drug. 
Adverse Event Documentation and Follow-up 
All adverse events, including observed, elicited, or volunteered problems, complaints, or 
symptoms are to be recorded on the adverse event page in the patient’s eCRF from the 
time the patient signs the ICF and until the Follow-up Visit/early termination, whether or 
not judged by the Investigator to be related to study drug.  The need to capture this 
information is not dependent upon whether adverse events are related to study drug.  
Serious adverse events that occurred up to 30 days after the last dose of study drug need 
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to be documented on an SAE Report Form if they are deemed by the Investigator to be 
“Related” to study drug. 
Each adverse event is to be documented with a verbatim/reported term, start and stop date 
and time, severity, causal relationship to study drug, action taken with study drug, and 
outcome (resolved, resolved with sequelae, resolving, fatal, unknown).  The Investigator 
must review new adverse events and the outcome of ongoing adverse events frequently 
throughout the study.  
In addition to recording all adverse events (serious and non-serious) in the patient’s 
eCRF, all SAEs must also be documented on the SAE Report Form for the study. 
The Investigator will follow all adverse events until they resolve, the Investigator 
assesses them to be stable, or the patient’s participation in the study ends, whichever 
comes first.  In addition, the Investigator will follow all adverse events assessed as related 
to study drug that are ongoing at the time of the patient’s last visit, until they resolve or 
the Investigator assesses them as stable, even if the patient's participation in the study has 
ended.  Resolution of such events is to be documented in the patient’s record as 
appropriate.  
It is anticipated that some patients may undergo procedures and/or experience events that 
are common in the study population under investigation, independent of study therapy.  
Preplanned procedures and procedures (eg, kidney transplant, catheter replacement) or 
events that are independent of study therapy, according to the Investigator’s assessment, 
will be documented as specified in the Safety Management Plan.  Common procedures or 
events (new or ongoing) for which the Investigator cannot rule out the role of study drug 
in their evolution, either because their nature or severity is not consistent with that 
generally seen in the study population or because of other valid medical/scientific 
rationale, will be recorded and reported as adverse events with all the attributes required 
for appropriate medical assessment. 
Serious Adverse Event Notification, Documentation, and Reporting 
The Investigator will report an SAE within 24 hours of becoming aware of the event.  An 
SAE Report Form will be completed regardless of relationship to the study drug.  The 
initial report will not be delayed in order to obtain additional information.  Any additional 
information will be reported as a follow-up to the initial report within 24 hours of 
collection. 
Details for reporting and follow-up of SAEs are provided in the ISF. 
In the event of any SAE (other than death) occurring after the last dose of study drug and 
prior to the Follow-up Visit, the patient will be instructed to contact the Investigator or 
designee immediately using the instructions provided on the ICF.   
The Medical Monitor will review reported SAEs and may contact the Investigator 
directly for further information. 
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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 the Sponsor 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 
(CFR) 21 CFR 312.32 on Investigational New Drug (IND) safety reporting and as 
specified in the Safety Management Plan. 
For regulatory reporting purposes, the Sponsor can upgrade the Investigator’s assessment 
(eg, from not related to related); however, Cara Therapeutics cannot downgrade the 
Investigator’s assessment unless the Investigator determines that a re-assessment of 
causality is necessary.  The Medical Monitor will review and comment on any upgrade 
made to a report.  If there is any doubt concerning the relationship between study drug 
and the event, then the relationship should be considered to be related to study drug. 
As applicable, the Sponsor will also notify other participating Investigator(s) of all IND 
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. 
6.5.4.2 
Structured Safety Evaluation 
A weekly Structured Safety Evaluation will also be used during the Double-Blind Phase 
to proactively identify and monitor adverse events of special interest. 
The Structured Safety Evaluation will be performed once during the Run-in Period and 
weekly (preferably on Wednesday/Thursday) during the Double-blind Treatment Period 
and Discontinuation Period.  The Structured Safety Evaluation will be performed by 
qualified study staff using a list of specific signs/symptoms, including mental status 
change, falls and gait disturbance. 
6.5.4.3 
Physical Examination 
Physical examinations will include an examination of the heart, lungs, abdomen, 
extremities, and neurological and vascular systems.  Clinically significant abnormalities 
or worsening findings observed after the first dose of study drug will be reported as 
treatment-emergent adverse events (TEAEs).  
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6.5.4.4 
Vital Signs 
Vital signs include sitting or semi-recumbent body temperature, heart rate, and blood 
pressure and will be measured prior to start of dialysis.   
Measurements will be repeated if a value is out of the reference range due to a technical 
issue, considered abnormal for the patient, or for other medical concerns.  Only the 
repeated measurement will be recorded. 
In the event of a clinically significant change in blood pressure and/or heart rate, the 
Investigator and dialysis staff will evaluate and manage the patient per standard dialysis 
unit practices with knowledge of the patient’s typical blood pressure and heart rate 
excursions. 
Heart rate will be collected at each dialysis; if clinically significant and outside the 
prespecified visits per schedule of events, the heart rate will be recorded on the relevant 
CRF page. 
6.5.4.5 
Electrocardiogram 
The 12-lead ECGs will be obtained prior to the start of dialysis and will be read locally 
by the Investigator or qualified designee.  Electrocardiograms read by a qualified 
designee must be endorsed by the Investigator.  Clinically significant abnormalities or 
worsening findings observed after the first dose of study drug will be reported as 
treatment-emergent adverse events (TEAEs).  
6.5.4.6 
Clinical Laboratory Tests 
Blood samples for clinical laboratory tests including hematology, serum chemistry, and 
serum pregnancy will be taken prior to dialysis and will be analyzed by a central 
laboratory.  Processing and shipment of central laboratory samples will be described in 
the Laboratory Manual, along with the final list of laboratory tests.  
6.5.4.7 
Contraception and Pregnancy 
All females of childbearing potential will have blood samples taken at Screening for 
serum pregnancy testing.  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. 
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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 
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 Double-blind or Open-label Treatment Periods 
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. 
6.5.5 
Additional Assessments 
The following additional assessments will be collected during the Double-blind and 
Open-label Extension Phases: 
• Inflammatory biomarkers 
• Missed dialysis visits 
• ESAs and IV iron 
 
6.5.5.1 
Inflammatory Biomarkers 
Inflammatory biomarkers, such as interleukin (IL)-6, IL-8, and granulocyte 
macrophage-colony stimulating factor will be measured, as defined in the statistical 
analysis plan (SAP).  A blood sample of sufficient volume to provide for replicate assays 
of each biomarker will be collected prior to dialysis per the schedules of events.   
Detailed instructions for biomarker sample collection and processing will be provided in 
the laboratory manual. 
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6.5.5.2 
Missed Dialysis Visits 
The number and reason(s) for missed dialysis will be recorded. 
6.5.5.3 
ESAs and IV Iron 
Use of ESA and iron will be recorded and reported on the appropriate eCRF page. 
6.5.5.4 
Discontinuation Period Additional Assessments 
Short Opiate Withdrawal Scale 
The SOWS-Gossop (or ShOWS) is a self-administered scale for grading opioid 
withdrawal symptoms over a 24-hour period.  It was chosen because of its validation as 
an opioid withdrawal measure [Gossop 1990; Bradley 1988; Vernon 2016] and frequent 
use in clinical studies.  This patient-rated scale consists of 10 items, scored from 0 (none) 
to 3 (severe) (total score range 0–30).  This scale is demonstrated to be a valid and 
reliable indicator of the severity of the opiate withdrawal syndrome over a wide range of 
common signs and symptoms.  The higher the score, the greater the severity of associated 
withdrawal.  
The ShOWS will be presented as a paper worksheet to be filled by each patient at home 
on nondialysis days and at the dialysis unit on dialysis days, at similar time of the day for 
a given patient during the 2-week discontinuation period (during which no study drug 
will be administered). 
Objective Opiate Withdrawal Scale 
The OOWS-Handelsman contains 13 physically observable signs, rated present (score of 
1) or absent (score of 0) (total score range 0–13), based on a timed period of 5 to 
10 minutes of observation of the patients by a rater [Handelsman 1987].  Higher total 
scores will indicate more severe withdrawal signs.  The rater will be a qualified staff 
member who will be trained by the Sponsor.  This scale is demonstrated to be a valid and 
reliable indicator of the severity of the opiate withdrawal syndrome over a wide range of 
common signs and symptoms.   
The OOWS will be presented as a paper worksheet to be filled by a qualified staff 
member at the dialysis unit on dialysis days, at similar time of the day for a given patient 
during the 2-week discontinuation period (during which no study drug will be 
administered). 
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7.0 
Discussion and Justification of Study Design 
7.1 
Discussion of Study Design and Choice of Control Groups 
The double-blind part of the study was designed to evaluate the efficacy and safety of 
IV CR845 in hemodialysis patients with moderate-to-severe pruritus.  A randomized, 
double-blind design was chosen to minimize bias.  A 12-week duration of treatment was 
selected to demonstrate durability of the efficacy observed in a prior 8-week treatment 
study (ie, Study CR845-CLIN2101) and to further evaluate safety during a longer 
exposure.  The primary efficacy endpoint was determined using the Worst Itching 
Intensity NRS scale, which measures itching intensity over 24 hours.  This scale has been 
validated for this patient population and is identical to the primary efficacy endpoint used 
in the dose-ranging, Phase 2 study, CR845-CLIN2101.  The Discontinuation Period of 
the Double-blind Phase of the study has been designed to assess potential physical 
dependence on CR845 in accordance with the FDA abuse liability guidance 
[Guidance for Industry January 2017]. 
The open-label part of the study was designed to evaluate the safety of CR845 
0.5 mcg/kg IV administered after each dialysis session (generally 3 times per week for up 
to 52 weeks) in patients who completed the 12-week Double-blind Treatment Period of 
this study.  This design is commonly used in clinical development to obtain long-term 
safety information.  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 combined safety, pharmacokinetic, and efficacy data from CR845-CLIN2101 
(Part A) provided the basis for the selection of the dose and dose regimen of CR845 to be 
used in this study.  The lowest dose tested (0.5 mcg/kg IV) appeared to be well tolerated 
and effective at reducing itch intensity over a period of 8 weeks. 
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. 
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8.0 
Statistical Methods 
8.1 
General Considerations 
This section describes the statistical analysis of efficacy and safety data collected during 
the Double-blind Phase only.  The analysis of safety and efficacy data collected during 
the Open-label Phase will be included in the SAP. 
The SAP will provide a detailed description for the handling of missing data, patient 
eligibility criteria for the analysis, and statistical methodology.  If differences occur 
between analyses of double-blind data described in the SAP and the current protocol, 
those found in the SAP will assume primacy.  In addition, the SAP will provide details 
for the analysis of data collected during the Open-label Phase, including the analysis of 
safety data during exposure to CR845 across both the Double-blind and the Open-label 
Phases. 
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 planned sample size for this study is 350 (175 per treatment group) male and female 
hemodialysis patients with chronic moderate-to-severe pruritus (mean baseline 24-hour 
Worst Itching Intensity NRS score >4), randomized at approximately 80 clinical sites.  
The sample size may be increased to 500 patients (250 per treatment group) based on the 
results of a planned unblinded interim assessment conducted when approximately 50% of 
the planned 350 first patients have been randomized and have either completed the 
12-week Double-blind Treatment Period or have discontinued from double-blind 
treatment early.  The planned interim assessment will be conducted by an Independent 
Data Monitoring Committee (IDMC).  Details related to the sample size re-estimation are 
included in Section 8.4.1. 
The sample size calculation is based on results of a completed Phase 2 double-blind, 
placebo-controlled study (CR845-CLIN2101) of CR845 in hemodialysis patients with 
ESRD who had moderate-to-severe pruritus.  In this study, 30% of patients randomized 
to the placebo group reported ≥3-point improvement from baseline with respect to the 
24-hour Worst Itching Intensity NRS at the end of treatment (Week 8).  The proportion of 
patients who received CR845 and reported a similar improvement in itch scores ranged 
from approximately 60% to 45% (ie, 30% to 15% difference from placebo), depending 
on the dose of active study drug (0.5 mcg/kg, 1.0 mcg/kg, 1.5 mcg/kg).   
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Given a sample size of 350 patients (175 per treatment group) and assuming a true 
response rate of 30% for the placebo group and a true response rate of 50% for the 
CR845 group (defining response as an improvement from baseline ≥3 points with respect 
to the Worst Itching Intensity NRS at Week 12), a 2-sided continuity corrected 
Chi-square will have 96% power to detect a treatment difference.  The power of this test 
statistic would be ≥84% for differences from placebo as low as 0.16 (Table 4). 
Table 4. 
Power as a Function of Effect Size (N = 175 per arm) 
Placebo Response 
0.30 
0.30 
0.30 
0.30 
CR845 Response 
0.50 
0.48 
0.46 
0.45 
Odds Ratio 
2.333 
2.154 
1.988 
1.909 
Powera 
96% 
92% 
84% 
79% 
a. 
Power for a 2-sided Chi-square continuity-corrected test and a 5% Type 1 error. 
Based on results of a planned interim assessment, the sample size may be increased up to 
500 patients (250 per treatment group).  Given this maximum sample size, and assuming 
a true response rate of 30% in the placebo group, a 2-sided continuity corrected 
Chi-square would have approximately 90% power to detect a treatment difference when 
the CR845 response rate is 45% (a 15% difference from placebo) (Table 5). 
Table 5. 
Sample Size as a Function of Odds Ratio (90% Power) 
Placebo Response 
0.30 
0.30 
0.30 
0.30 
0.30 
CR845 Response 
0.50 
0.48 
0.46 
0.45 
0.44 
Odds Ratio 
2.333 
2.154 
1.988 
1.909 
1.833 
Sample Sizea 
134 
164 
204 
230 
262 
a. 
Sample size for a 2-sided Chi-square continuity-corrected test 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 ratio to receive either CR845 0.5 mcg/kg IV or matching placebo IV 
during the Double-blind Treatment Period.  Patients will be stratified according to their 
use or non-use of concomitant medications to treat their itch during the week prior to 
randomization (Run-in Period) as well as the presence or absence of specific medical 
conditions.  These medical conditions include: 
• History of fall or fracture (related to fall) 
• Confusional state or mental status change or altered mental status or 
disorientation 
• Gait disturbance or movement disorder 
All eligible patients who sign the ICF for participation in the Open-label Treatment 
Period will receive CR845 at a dose of 0.5 mcg/kg starting on Day 1 of the Open-label 
Extension Phase. 
 
 
 
 
 
 
 
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8.4.2 
Safety Data Review 
The operation of the DSMB will be governed by a charter that will describe the meeting 
frequency, procedures, and requirements for reporting its observations to the Sponsor. 
Safety data will be reviewed on an ongoing basis by the Sponsor and a DSMB.  In order 
to actively monitor patient safety, a prospective approach will be taken to collect and 
analyze specific adverse events designated as adverse events of special interest. 
8.5 
Analysis Populations 
The Enrolled Population is defined as the group of patients who sign informed consent. 
The ITT Population is defined as the group of patients who are randomized to a treatment 
group. 
The Double-blind Safety Population is defined as the group of randomized patients who 
received at least 1 dose of double-blind study drug during the Double-blind Treatment 
Period.   
Following the intent-to-treat principle, patients in the ITT population will be analyzed 
according to their randomized treatment, regardless of the actual treatment received.  
Patients in the Double-blind Safety Population will be analyzed according to the actual 
treatment received.  The Double-blind Safety Population will be used to analyze all safety 
endpoints collected during the Double-blind Phase, while the ITT Population will be used 
to analyze all efficacy endpoints collected during the Double-blind Phase. 
The Per-Protocol Population is defined as the subset of patients in the ITT Population 
who do not have any major protocol deviations that could affect the efficacy analyses of 
the double-blind data.  An analysis of the primary and secondary efficacy variables for 
the Per-Protocol Population will be performed.   
Key exclusions from the Per-Protocol population include patients who: 
• Received less than 80% of the planned study drug doses 
• Had a mean baseline Worst Itching Intensity score <= 4.0 
• Had a missing average 24-hour weekly Worst Itching NRS score for ≥25% of 
study weeks  
• Had significant amounts of restricted and prohibited medications (Section 6.4.9) 
based on medical review 
• Received a different treatment than the treatment to which they were randomized  
Inclusion in the Per-Protocol Population will be determined prior to unblinding the data. 
The Open-label Safety Population is defined as the group of patients who receive at least 
1 dose of study drug in the Open-label Phase.  The Open-label Safety Population will be 
used to analyze all safety endpoints collected during the Open-label Phase, and during 
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exposure to CR845 combining data from both the Double-blind and the 
Open-label Phases.  
8.6 
Statistical Summary and Analysis 
8.6.1 
Patient Disposition 
For the Double-blind Phase, the number of patients enrolled, treated, completed, or 
discontinued from the study, 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. 
8.6.2 
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.   
8.6.3 
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 to >65, 65 to 
<75, ≥75), gender, ethnicity, race, prescription dry body weight (kg).  Height will not be 
collected. 
Baseline characteristics of the disease will also be summarized overall and by treatment 
group, and will include variables such as etiology of chronic kidney disease, years since 
ESRD, duration of pruritus, and time on chronic hemodialysis. 
8.6.4 
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 or not the condition is ongoing. 
A separate coding listing will be created with all the distinct levels of SOC, Preferred 
Terms, and the verbatim investigator description reported in the study.  Sorting will be 
alphabetically by SOC, Preferred Term, and then verbatim description. 
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8.6.5 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary.  All 
prior and concomitant medications will be listed and summarized separately by 
Anatomical Therapeutic Chemical class 3 (ATC 3), Preferred Term, and treatment group.  
The use of concomitant medications during the Double-blind and Discontinuation Period 
will be summarized separately.  Additionally, a coding listing of unique medications and 
their corresponding coding will be presented. 
8.6.6 
Antipruritic Medication 
Prior and concomitant antipruritic medications will be summarized separately by study 
period (Run-in, Double-blind, Discontinuation); summaries will be presented by 
ingredient rather than by ATC codes. 
8.7 
Efficacy Analysis 
8.7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the proportion of patients achieving ≥3-point 
improvement from baseline with respect to the weekly mean of the daily 24-hour Worst 
Itching Intensity NRS at Week 12 (Days 79 to 85) of the Double-blind Treatment Period. 
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 scores reported during a specific week 
during the Double-blind Treatment Period (eg, Days 2 to 8, Days 9 to 15, Days 16 to 22, 
Days 79 to 85) divided by the number of days with nonmissing 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 collected over the Run-in Period, including pre-randomization assessments 
collected on Day 1.   
In the primary efficacy analysis, missing NRS data will be imputed using a multiple 
imputation (MI) approach, assuming that patients who discontinue Double-blind 
treatment early would have similar Worst Itching Intensity NRS scores as other patients 
in their respective treatment arm that have complete data: 
• 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).  Details on the MI procedure 
can be found in Appendix 14.8. 
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• 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.  Differences between 
CR845 0.5 mcg/kg and placebo with respect to the primary endpoint will be 
compared using a logistic regression model containing terms for treatment group, 
baseline NRS score, use of prior anti-itch medication, and presence of specific 
medical conditions. 
• Results of the logistic regression on the multiply imputed data sets will be 
summarized by the SAS MIANALYZE procedure.   
The final p-value will be calculated using the Cui, Hung, Wang (CHW) procedure where 
the z-score is a weighted average of the z-score at the interim and the z-score observed 
for data collected after the interim, following the formula below. 
                   Zfinal=Zinterim * √(n/N) + Zpost-interim * √(1- n/N) 
where n is the number of patients at the interim and N is the initial number of patients 
planned (300). 
Sensitivity analyses of the primary efficacy endpoint will be conducted to evaluate the 
robustness of study results under different assumptions and imputation algorithms.  For 
each of these sensitivity analyses, the final p-value will be calculated based on the CWH 
procedure, using the formula specified above. 
• Sensitivity 1: Early discontinuations as nonresponders  
Patients who discontinue study drug early will be considered nonresponders.  The 
imputed data will be analyzed using a logistic regression model similar to the 
primary analysis.  
• Sensitivity 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.   
o 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. 
o For patients who discontinued study drug due to adverse events, NRS scores 
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 4 to 10).  
o For patients who discontinue due to reasons other than adverse event, missing 
NRS scores after patients discontinue study drug early will be multiply 
imputed using multiple calls of the SAS MI procedure using data from 
patients within the same treatment group that have complete data at that time.  
The proportion of patients who have an improvement from baseline with 
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respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS 
score ≥3 points will be calculated for each imputed dataset 
o Similar to the primary analysis, results of the logistic regression on the 
multiply imputed data sets will be summarized by the SAS MIANALYZE 
procedure.   
• Sensitivity 3: Tipping point analysis 
Multiple imputation with mixed missing data mechanisms (MNAR for a missing 
data pattern and MAR for others) will be used to assess the robustness of the 
MAR assumption.  This sensitivity analysis is to investigate the departure from 
MAR assumption by progressively decreasing the treatment differences with 
respect to the NRS scores over the missing visits in active treatment group until 
conclusion from the primary analysis is overturned.  The MI procedure includes 
the following steps: 
o Uses MCMC methodology from PROC MI by treatment group to impute the 
intermittent missing data to a monotone missing pattern 
o Uses a standard MAR-based MI approach from PROC MI to impute data from 
monotone missing data 
o For patients in the active treatment group, shift parameter from PROC MI will 
be progressively applied to impute the missing data, until the p-value >0.05 
To evaluate the potential impact of the IA on the properties of statistical inference at the 
end of the trial, the primary and sensitivity analyses of the primary endpoint will also be 
presented separately for the sample of patients enrolled into the study after the IA. 
8.7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the: 
• Change from baseline in itch-related quality of life at the end of Week 12 of the 
Double-blind Treatment Period, as assessed by the 5-D Itch Scale total score; 
• Change from baseline in itch-related quality of life at the end of Week 12 of the 
Double-blind Treatment Period, as assessed by the total Skindex-10 Scale total 
core; 
• Proportion of patients achieving ≥4-point improvement from baseline with respect 
to the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 12 
(Day 79 to 85) of the Double-blind Treatment Period. 
The 5-D Itch Scale and the Skindex-10 Scale score 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, prior anti-itch medication 
usage and presence of specific medical conditions as covariates; and patient as a random 
effect.  The baseline 5-D total score and the Skindex-10 total score will be defined as the 
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value collected on Day 1, prior to randomization.  Repeated measures will include values 
collected at the end of Weeks 4, 8, 10, and 12 (end of treatment).  The mean treatment 
difference between CR845 0.5 mcg/kg and placebo will be estimated as the simple 
contrast in the treatment effect at Double-blind Treatment Period Week 12.  
It is important to note that, in HD patients, the study drug administered during the last 
dialysis of a particular week is not cleared until the first dialysis of the next week.  
Therefore, measurements that would reflect treatment effect at the end of a specific week 
(eg. Week 4) will actually be collected during the first day of the next week (eg, Week 5). 
For the analysis of 5-D Itch Scale and the Skindex-10 Scale score, 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.  Missing scores will not be 
imputed.  Assuming that the data are MAR, the estimates of the treatment differences 
calculated from the MMRM described above are unbiased.  
The proportion of patients achieving ≥4-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 12 of the 
Double-blind Treatment Period will be analyzed following a methodology similar to the 
one employed for the primary analysis of the primary endpoint. 
8.7.3 
Hypothesis Testing Strategy 
The efficacy of CR845 0.5 mcg/kg compared to placebo in pivotal Phase 3 study 
CLIN3102 will be evaluated based on 1 primary and 3 secondary efficacy endpoints.  
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 in the primary efficacy analysis of the primary endpoint (proportion of patients 
achieving ≥3-point improvement from baseline with respect to the Worst Itching Intensity 
NRS) is rejected in favor of the alternative that patients randomized to CR845 experience 
significantly less itching compared to patients randomized to placebo.  
To protect the Type 1 error, a gate-keeping strategy will be implemented.  Although the 
p-values corresponding to the hypothesis testing of the secondary variables will be 
reported, they will only be considered inferential if the primary analysis is statistically 
significant.  Testing of the 2 secondary efficacy endpoints will be performed sequentially 
at a 2-sided 5% error level.  The difference between CR845 0.5 mcg/kg and placebo with 
respect to the 5-D Itch total score will be tested first.  If results are statistically significant 
in favor of CR845, testing with respect to the Skindex-10 total score will proceed and be 
inferential. 
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The proportion of patients achieving ≥4-point improvement from baseline with respect to 
the weekly mean of the daily 24-hour Worst Itching Intensity NRS at Week 12 of the 
Double-blind Treatment Period will be tested only if the results of Skindex-10 total score 
are statistically significant in favor of CR845. 
8.7.4 
Additional Efficacy Endpoints 
8.7.4.1 
Itch-intensity Measures 
• Proportion of patients who have an improvement from baseline at Week 12 of the 
Double-blind period with respect to the weekly mean of the 24-hour Worst 
Itching Intensity NRS scores ≥1 and ≥2.  The calculation of the proportions will 
be based on the NRS data using a multiple imputation (MI) approach for the 
missing data as in the primary efficacy analysis.  A figure presenting the 
proportion of patients who have an improvement from baseline in NRS scores at 
Week 12 that is ≥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 Double-blind 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 8.7.2. 
• Proportion of patients who rate their itch condition as “Very much improved” or 
“Much Improved” at the end of Week 12 of the Double-blind Treatment 
Period/end of double-blind treatment, as measured by the Patient Global 
Impression of Change.  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). 
8.7.4.2 
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 
Double-blind Treatment Period, as assessed by the 5-D Itch Scale total score.  
Treatment differences between CR845 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 
Double-blind Treatment Period, as assessed by the Skindex-10 Scale total score.  
Treatment differences between CR845 and placebo at each postbaseline time 
point will be evaluated using the same MMRM fitted for the secondary efficacy 
analysis. 
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• Change from baseline in itch-related quality of life at Week 12 of the 
Double-blind Treatment Period and at each of the remaining weeks of the 
Double-blind 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 overall Skindex-10 Scale score (Section 8.7.2). 
8.8 
Safety Analysis 
Analysis of all safety data collected during the Double-blind Phase will be performed on 
the Double-blind Safety Population.  The SAP will provide further detail for the analyses 
to be applied to each safety parameter, and will also include analyses of safety data 
collected during the Open-label Phase and during exposure to CR845 during both the 
Double-blind and Open-label Phases.  No statistical hypothesis testing will be carried out 
and no inferential statistical analysis of the safety parameters will be performed.  
The baseline value for all analyses of double-blind safety parameters will be defined as 
the last value obtained prior to the first dose of double-blind study drug and will include 
both scheduled and repeat (unscheduled) observations.  
8.8.1 
Exposure to Study Drug 
For this study, the duration of double-blind treatment for each individual patient may be 
up to 12 weeks, for a total of approximately 36 doses of study drug administered 
immediately following each dialysis session.  Day 1 of the Double-blind Treatment 
Period will be defined as the day of administration of the first dose of study drug.  The 
last day of the Double-blind Treatment Period will be defined as the day of the dialysis 
session immediately following the last injection of study drug. 
Exposure and treatment compliance during the Double-blind Treatment Period will be 
summarized by the following parameters: 
• Duration of treatment (days) 
• Total number of doses actually received  
• Number of missed doses 
Duration of treatment (days) = (date of first dialysis after last dose) – (date of first dose) 
+ 1. 
If a patient receives additional dialysis during a given week for any reason, an additional 
dose of CR845 will be administered following dialysis.  A maximum of 4 doses per week 
is allowed.  No additional doses will be given for patients receiving an additional 
unscheduled ultrafiltration treatment.  The number of patients getting such an extra 
treatment will be summarized. 
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8.8.2 
Adverse Events 
All adverse events, as reported by the site, will be coded using MedDRA to MedDRA 
SOC and Preferred Term for standardization and summary purposes.   
All reported adverse events (whether or not treatment-emergent) will be included in a 
by-patient adverse event listing.  Only TEAEs will be included in summary tables which 
will present results by treatment group and by study period, as appropriate.   
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 Double-blind Period. 
Adverse events that are considered “treatment emergent” relative to the Double-blind 
Period are identified as any adverse event with an onset date after the first dose of the 
double-blind study drug up to the study Double-blind End of Treatment/Early 
Termination Visit or the start of the Discontinuation Period (or 7 to 10 days after the last 
dose if no Double-blind End of Treatment/Early Termination Visit was conducted), 
whichever is later  
Adverse events that are considered “treatment-emergent” relative to the Discontinuation 
Period are identified as any adverse event with an onset date after and up to 2 weeks post 
the start of the Discontinuation Period or the start of the Open-label Phase, whichever 
comes first 
The number and percentage of patients experiencing TEAEs will be summarized by 
treatment group and by period.  A patient will be counted only once in the incidence 
count for a MedDRA SOC or Preferred Term, although a patient may have multiple 
occurrences (start and stop) of an event associated with a specific MedDRA Preferred 
Term or SOC.  The most frequent TEAEs (≥5% of patients in any treatment group) will 
also be tabulated by SOC and Preferred Term. 
The incidence and percentage of patients experiencing treatment-emergent SAEs and 
TEAEs leading to study discontinuation will be presented by the appropriate MedDRA 
SOC and Preferred Term.  Adverse events that result in death will also be summarized. 
Treatment-emergent adverse events will also be summarized by severity for each study 
period of the Double-blind Phase and by relationship to double-blind study drug for the 
Double-blind Period.  If the severity and/or relationship to the study drug of an adverse 
event is missing, a worst-case scenario will be assumed (ie, the adverse event will be 
categorized as “severe” and/or “related” to the study drug).  If a patient reports the same 
TEAE multiple times the event with the worst severity and the strongest relationship to 
study drug will be tabulated. 
Separate tables summarizing the incidence of AESIs, as defined in the Safety 
Surveillance plan, will be presented for each study period. 
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In addition, to evaluate the potential for physical dependence of CR845, a summary table 
comparing the incidence rate of TEAEs occurring prior to (i.e. during the Double-blind 
Period) and during the Discontinuation Period will be presented.  
For each period of the Double-blind Phase, 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) during that period, a TEAE, 
serious TEAE, related TEAE, severe TEAE, TEAE leading to dose interruption, and 
TEAE leading to study drug discontinuation.  This table will also include the number of 
events for each specific Preferred Term.  
All adverse events will be listed in chronological order, including patient identifier, age, 
race, gender, a flag indicating whether the event was treatment-emergent, and all related 
event status information (start and stop dates, whether the event was ongoing, study day 
of onset, severity, seriousness, relationship to study medication, action taken with study 
treatment, and outcome).  Separate listings will be generated for SAEs, deaths, and 
adverse events leading to study drug discontinuation.  Additionally, a coding list of 
Preferred Terms and the verbatim text associated with them will be produced. 
8.8.3 
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 Double-blind Safety 
Population who have at least 1 postbaseline time point (for criteria based on postbaseline 
assessments) and with both a baseline and at least 1 postbaseline time point (for criteria 
evaluating changes from baseline). 
Laboratory values will be reported in Système International units.   
Laboratory test results will be assigned an L/N/H classification according to whether the 
value was below (L), within (N), or above (H) the laboratory parameter’s reference range.  
Comparisons will be based on 3×3 tables (shift tables) that, for a particular laboratory 
test, compare the baseline L/N/H classification to the highest and/or lowest L/N/H 
classification during the treatment period.  Clinically important laboratory values based 
on prespecified criteria defined in the SAP will also be summarized. 
Additionally, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline 
phosphatase will be presented in a separate listing, with 3× and 5×ULN flagged for 
alanine aminotransferase and aspartate aminotransferase; 2×ULN flagged for bilirubin, 
and 1.5×ULN flagged for alkaline phosphatase. 
8.8.4 
Vital Signs and ECGs 
Summary tables will include descriptive statistics for baseline and each postbaseline 
assessment.  Descriptive statistics will be calculated on both the actual score and the 
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change from baseline score.  Baseline is defined as the last measurement taken on or prior 
to the first day of dosing.  Note that the Day 1 assessment can be included in the 
evaluation of baseline if that the assessment is performed prior to dosing.  
If 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, then the latest evaluation will be selected for 
inclusion in the analysis.   
All vital sign summaries will include the patients in the Double-blind Safety Population 
who have at least a 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).≥ 
Clinically notable vital signs will be identified based on the criteria in Table 6.  For each 
vital sign parameter, the number and percentage of patients with at least 1 notable value 
will be tabulated by week and overall for the Double-blind Phase. 
Table 6. 
Criteria Used to Identify Clinically Notable Vital Sign 
Abnormalities 
Vital Sign Parameter 
Value 
Change from Baselinea 
Systolic blood pressure 
≥180 mm Hg 
Increase or Decrease of ≥40 mm Hg 
 
≤90 mm Hg 
Decrease of ≥60 mm Hg 
Diastolic blood pressure 
≥100 mm Hg 
Increase or Decrease of ≥20 mm Hg 
 
≤60 mm Hg 
Decrease of ≥40 mm Hg 
Heart rate 
>130 bpm 
Increase of ≥30 bpm 
 
 <55 bpm 
Decrease of ≥30 bpm 
a. 
Both value and change from baseline criteria must be met to qualify as a clinically notable 
abnormality. 
All vital signs will be listed in by-patient listings, including visit and collection date/time, 
and will be sorted by patient identifier and date/time of assessment.   
Electrocardiogram results include an overall interpretation of ‘normal,’ ‘abnormal but not 
clinically significant,’ or ‘abnormal and clinically significant.’  These results will be 
tabulated at each time point.   
Electrocardiogram results will be listed for each visit, including visit, whether ECG was 
performed (yes/no), explanation (if not performed), assessment date/time, study date, 
overall interpretation, and relevant medical history number or adverse event number, if 
deemed a clinically significant abnormality. 
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8.9 
Additional Analyses 
8.9.1 
Inflammatory Biomarkers  
The observed value and the change in inflammatory biomarkers (eg, IL-6, IL-8, and 
granulocyte macrophage-colony stimulating factor) from pre-dose to the end of the 
Double-blind Treatment Period (Week 12) will be presented by treatment group.  
Univariate and multivariate analyses of the change in inflammatory biomarkers will be 
described in an analysis plan, separate from the study SAP. 
8.9.2 
Missed Dialysis Visits and Incidence of Infection  
The number and percentage of patients who missed 1 or more dialysis visits during the 
Double-blind Treatment Period, and the total number of missed dialyses visits will be 
tabulated overall and by treatment group.   
Incidence of infections based on adverse events, hospitalizations, and/or use of antibiotics 
for treatment of infection related to uremic pruritus will be analyzed using Fisher’s Exact 
Test.   
8.9.3 
ESA and IV Iron 
Erythropoiesis-stimulating agent and IV Iron use will be summarized descriptively by 
treatment group.  Statistical analyses of changes in use of ESAs or IV iron from pre-dose 
to the end of the Double-blind Treatment Period (Week 12) will be defined in the SAP. 
8.9.4 
Discontinuation Period Additional Assessments 
Baseline ShOWS and OOWS will be the scores collected on the dialysis day on Day 85 
(Double-blind EOT/Early Termination) (Table 2).  Only patients who have a baseline 
ShOWS and OOWS will be included in the analysis. 
Summary statistics for the daily ShOWs and the OOWS collected at each dialysis visit, 
including number of non-missing observations, mean, standard deviation, median, 
minimum, and maximum median of ShOWS and OOWS will be tabulated by treatment 
group.  Figures for the overall mean scores over time will also be presented.  
The ShOWS scores on discontinuation days 1, 2, 3, and >3 will be analyzed to compare 
the treatment groups at each visit, using an Analysis of Covariance (ANCOVA) model, 
with treatment group and baseline value as a covariate.  The OOWS scores will be 
analyzed using a similar ANCOVA model at each day of collection.  In addition, 
between-treatment group comparisons over the overall 2-Week Discontinuation Period 
will be performed using an MMRM with treatment group, discontinuation day, and 
treatment group-by-day interaction as fixed effects, baseline value as the covariate, and 
patient as a random effect.  An unstructured covariance matrix will be used to model the 
covariance of within-patient scores.  These analyses will be performed based on all 
postbaseline scores using only the observed cases without imputation of missing values.  
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Exploratory analyses may be performed, depending on sample size, for the subgroup of 
patients who also stop taking concomitant opioid medications during the 2-week 
Discontinuation Period. 
Adverse events (AEs) and vital signs potentially related to withdrawal that occur during 
the 2-week Discontinuation Period will be identified based on a blinded review of the 
data, and will be summarized by randomized treatment group, and compared to the 
2-week period prior to discontinuation.  
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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 ISF. 
An IDMC will be convened for this study to implement an unblinded sample size 
re-estimation.  In addition, there will be a DSMB that will convene periodically to assess 
accumulating safety data.  Membership into the IDMC will be independent of 
membership into the DSMB.  A contract organization specializing in IDMC management 
will be identified.  The IDMC and the DSMB will be supported on the Sponsor’s behalf 
by an independent unblinded statistician who will not be part of the study team.  Details 
will be in the IDMC and DSMB charters.  
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, 
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clinical and office charts, laboratory notes, memoranda, participants’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
participant files and records kept at the pharmacy, laboratories, or medical-technical 
departments involved in the clinical study, as applicable.  
The investigational site will provide access to all study-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor 
and inspection by local and regulatory authorities. 
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, IB, 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.   
Patients must sign a separate informed consent prior to participating in the Open-label 
Treatment Period. 
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. 
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The study monitor or other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including, but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. 
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11.0 
Data Handling and Quality Assurance 
All participant data relating to the study will be recorded on eCRFs unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  No data are to be recorded 
directly in the eCRFs (eg, all data will have a unique source).  The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/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 and preliminary 
laboratory results, 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 accomplish 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 regulatory authority, other 
Investigators, corporate partners, or consultants, as required. 
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13.0 
References 
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Chapman and Hall/CRC; 2014; p. 183-98. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical 
trials. Biometrics. 1999;55(3):853-7. 
Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. Edition Number 9. Little, Brown & 
Co; Boston, Mass: 1994. pp. 253–6. 
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical 
trials: IMMPACT recommendations. Pain. 2005;113(1-2):9–19. 
Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus.  
Br J Dermatol. 2010;162(3):587-93. 
Gossop M. The development of a Short Opiate Withdrawal Scale (SOWS). Addict 
Behav. 1990;15(5): 487–90. 
Guidance for Industry. Assessment of Abuse Potential of Drugs. US Department of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
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Guidance for Industry. Determining the extent of safety data collection needed in late-
stage premarket and postapproval clinical investigations. US Department of Health and 
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Research (CDER), Center for Biologics Evaluation and Research (CBER). February 
2016. 
Handelsman L, Cochrane KJ, Aronson MJ, Ness RA, Rubinstein KJ, Kanof PD. Two 
new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293–308. 
Investigator’s Brochure. CR845 (Difelikefalin). Edition Number 7. 19 May 2016. 
Kimmel M, Alscher DM, Dunst R, et al. The role of micro-inflammation in the 
pathogenesis of uraemic pruritus in haemodialysis patients. Nephrol Dial Transplant. 
2006;21(3):749-55. 
Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H. Effect of a 
novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 
337 haemodialysis patients:  a Phase III, randomized, double-blind, placebo-controlled 
study. NDT. 2010;25(4):1251-7. 
Mathur VS, Lindberg J, Germain M, et al. A longitudinal study of uremic pruritus in 
hemodialysis patients. Clin J Am Soc Nephrol. 2010;5(8):1410-9. 
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Mettang T, Pauli-Magnus C, Alscher DM. Uraemic pruritus-new perspectives and 
insights from recent trials. Nephrol Dial Transplant. 2002;17(9):1558-63. 
Narita I, Alchi B, Omori K, et al. Etiology and prognostic significance of severe uremic 
pruritus in chronic hemodialysis patients. Kidney Int. 2006;69(9):1626-32. 
Patel TS, Freedman BI, Yosipovitch G. An update on pruritus associated with CKD. 
Am J Kidney Dis. 2007;50(1):11-20. 
Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: prospective study on 
validity and reliability of the visual analogue scale, numerical rating scale and verbal 
rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92(5):502-7. 
Pisoni RL, Wikstrom B, Elder SJ, et al.  Pruritus in haemodialysis patients: International 
results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial 
Transplant. 2006;21(12):3495-505. 
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. 
Vernon MK, Reinders S, Mannix S, Gullo K, Gorodetzky CW, Clinch T. Psychometric 
evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) in 
patients undergoing opioid detoxification. Addict Behav. 2016;60:109-16. 
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14.0 
Appendix 
14.1 
Appendix 1:  New York Heart Association Classification of Heart 
Failure 
 
[Criteria Committee of the New York Heart Association 1994] 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
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14.2 
Appendix 2:  Worst Itching Intensity Numerical Rating Scale 
(NRS) 
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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14.3 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
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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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14.5 
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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14.6 
Appendix 6:  Short Opiate Withdrawal 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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14.7 
Appendix 7:  Objective Opiate Withdrawal 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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15.0 
Statistical Appendix 
This appendix provides further details related to the treatment of missing data for the 
primary and sensitivity analyses of the primary endpoint. 
For multiple imputations and other instances where random seeds are required, the values 
used (in order) are: 
8392857 
2985729 
1843255 
9086284 
5547484 
8017456 
9597295  
2252256 
4821871 
9852467 
5126715 
3232132 
9841654 
3645284 
1587345 
Note that not all seeds may be required in programming the multiple imputations.  If 
additional seeds are needed, they will be chosen by adding 1 to each of the values above, 
again using them in order. 
The number of imputations for the multiple imputations will be 20.  
For the primary analysis, a multi-stage process will be applied: 
Stage 1: Subjects will have their 11-point NRS scores imputed.  First, using all visits, 
intermittent missing data will be imputed using the Markov Chain Monte Carlo (MCMC) 
method implemented with the SAS MI procedure; data imputed following subject 
discontinuation via this process will be censored out of the resulting dataset so that only 
intermittent missing data is imputed via this method.  Second, monotone missing data 
will be imputed following subject discontinuation using SAS proc MI.  For each stage, 
MI will be performed within treatment group with covariates for baseline NRS score, use 
of prior anti-itch medication, and presence of select medical conditions.  Should 
convergence issues occur due to small cell size for the one or both of the categorical 
covariates at either stage, the appropriate covariate(s) will be removed from the model. 
Stage 2: Using the resulting complete datasets, the change from baseline with respect to 
the 11-point NRS will be calculated; patients will be categorized as responder if they 
have a 3-point (or greater) improvement over baseline.  Week 12 values will serve as the 
primary timepoint.  The 20 MI runs will be analyzed independently using a logistic 
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model and the results combined using SAS proc MIANALYZE.  Logistic model 
covariates will include treatment, baseline NRS score, use of prior anti-itch medication, 
and presence of select medical conditions.  As with the MI, should convergence issues 
occur due to small cell sizes, the appropriate categorical covariate(s) will be dropped as 
necessary. 
Should a sample size increase occur, the above process will be implemented completely 
independently among subjects contributing the interim results and those following the 
interim analysis.  
For the tipping point analysis, a shift parameter will be applied to only subjects in the 
active group, running from 0 to 5 points in 0.25-point increments or until the conclusions 
of the analysis “tip” and the results are no longer significant.  This analysis will not be 
performed should the initial primary results fail to achieve significance. 
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