Clinical trial NCT02858726
Conditions: Uremic Pruritus
Keywords: Hemodialysis CR845 Kappa opioid Anti-itch difelikefalin
Sponsor: Cara Therapeutics, Inc.
Start date: 2016-06-01; Completion date: 2017-03-14
Enrollment: 226 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
2 Part Study: Part A will assess 3 different dosing levels of IV CR845 versus placebo in patient on hemodialysis who have moderate-to-severe itching due to uremic pruritus. Patients will receive either CR845 or placebo after each dialysis session for eight weeks. The safety and efficacy of CR845 will be monitored throughout the study. A sub-group of patients will also have pharmacokinetic assessments completed. Part B of the study will assess one dose of IVCR845 versus placebo for 12 weeks in patients on hemodialysis who have moderate-to-severe itching. The dose of CR845 used in Part B will be based on safety and efficacy found in Part A.

Detailed description:
This is a two-part study. Patients participating in Part A will be consented and trained on the completion of questionnaires about the severity of itching and overall health. Patients will be required to complete questionnaires during their visits to the dialysis center and also while at home on other days. Results of the screening questionnaires will assess eligibility for the study. Additional laboratory tests and measurements for safety will also be completed during the screening period. Patients meeting all criteria for entry into Part A of the study will be randomized to receive either one of three different doses of CR845 or a placebo. Patients will receive the study drug for eight weeks IV after each hemodialysis treatment (i.e. 3 times per week). Assessments for intensity of itch and safety will also be completed during the 8 week treatment period. When patients have completed treatment, a Follow-up visit will be completed 7 days later.

Patients participating in Part B will be consented and trained on the completion of questionnaires about itching and overall health. Patients will be required to complete questionnaires during their visits to the dialysis center and also while at home on other days. Laboratory tests and measurements for safety will also be completed during the screening period to determine study eligibility. Patients meeting all criteria for entry into Part B of the study will be randomized to receive either CR845 or a placebo. The dose of CR845 used will have been determined based on the safety and efficacy from Part A. Patients will be dosed with either CR845 or placebo for twelve weeks after each hemodialysis treatment (i.e. 3 times per week). Assessments for intensity of itch and safety will be completed during the treatment period also. When patients have completed treatment, a Follow-up visit will be completed 7 days later.

Arms: arm 1: Part A of study: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week) arm 2: Part A of study: IV CR845 1 mcg/kg administered after each dialysis session (3 times/week) arm 3: Part A of study: IV CR845 1.5 mcg/kg administered after each dialysis session (3 times/week) arm 4: Part A of study: IV Placebo administered after each dialysis session (3 times/week)
Interventions: intervention 1: CR845 0.5 mcg/kg intervention 2: CR845 1 mcg/kg intervention 3: CR845 1.5mcg/kg intervention 4: Placebo
Intervention descriptions: intervention 1: IV medication delivered three times/week intervention 2: IV medication delivered three times/week intervention 3: IV medication delivered three times/week intervention 4: IV medication delivered three times/week

Protocol documents:
Prot_000.pdf: 
Cara Therapeutics Inc. 
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Final, Version 1.0 
 
 
 
 
A TWO-PART, MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS 
WITH MODERATE-TO-SEVERE PRURITUS 
 
PROTOCOL 
NUMBER:   
CR845-CLIN2101 
IND NUMBER: 
123140 
PROTOCOL 
STATUS: 
 
DATE: 
 
 
Final, Version 1.0 
 
May 19, 2016 
 
SPONSORED BY: 
 
 
 
 
MEDICAL 
MONITOR: 
 
Cara Therapeutics, Inc. 
4 Stamford Plaza 
Stamford, CT 06902 
 (203) 406-3700 
 
 
 
  
 
 
 
CONTRACT 
RESEARCH 
ORGANIZATION: 
Biorasi 
One Turnberry Place 
19495 Biscayne Blvd., Suite 900 
Aventura, FL  33180 
(786) 888-0700 
 
 
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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Statement of Compliance 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) 
E6 (R1) dated 10 June 1996, and the appropriate regulatory requirement(s).  The 
Investigator will be thoroughly familiar with the appropriate use of the study drug as 
described in the protocol and Investigator’s Brochure (IB).  Essential clinical documents 
will be maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files should be established at the beginning of the study, maintained for 
the duration of the study, and retained according to the appropriate regulations. 
The Institutional Review Board (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 the clinical site if IRB approval has been obtained.  The protocol, IB, 
informed consent form (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.  
No amendments to the study protocol should be made without the prior written 
agreement of both the Investigator and the Sponsor, and the IRB where applicable. 
The Investigator will maintain documentation of the composition of the IRB as well as all 
correspondence with the IRB.  The Investigator will comply with local requirements for 
routine reporting to the IRB, as well as local and government requirements for notifying 
the IRB and Sponsor of any serious adverse event.  The Investigator will provide Cara 
Therapeutics, Inc. or its designee copies of all IRB approval notices, correspondence, 
annual reports, and final study progress reports. 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................5 
1.0 
INVESTIGATOR APPROVAL STATEMENT .......................................................9 
2.0 
PROTOCOL SYNOPSIS ........................................................................................10 
3.0 
LIST OF ABBREVIATIONS .................................................................................22 
4.0 
INTRODUCTION ...................................................................................................23 
4.1 Background and Rationale ................................................................................23 
4.2 Clinical Experience ...........................................................................................24 
4.3 Summary of Potential Risks and Benefits .........................................................26 
5.0 
SAFETY MONITORING PLAN ............................................................................28 
6.0 
OBJECTIVES .........................................................................................................29 
6.1 Part A .................................................................................................................29 
6.2 Part B .................................................................................................................29 
7.0 
INVESTIGATIONAL PLAN .................................................................................31 
7.1 Study Design and Rationale ..............................................................................31 
7.2 Number of Patients and Sites ............................................................................34 
7.3 Randomization ...................................................................................................34 
7.4 Blinding .............................................................................................................34 
7.5 Endpoints ...........................................................................................................35 
7.5.1 Safety Endpoints ....................................................................................35 
7.5.2 Pharmacokinetic Endpoints ...................................................................35 
7.5.3 Primary Efficacy Endpoint ....................................................................35 
7.5.4 Secondary Efficacy Endpoint ................................................................35 
7.5.5 Other Efficacy Endpoints ......................................................................35 
7.6 Duration of Treatment .......................................................................................37 
7.7 Selection of the Patient Population ...................................................................37 
7.7.1 Inclusion Criteria ...................................................................................38 
7.7.2 Exclusion Criteria ..................................................................................39 
7.8 Withdrawal of Patients from Therapy or Assessment .......................................40 
7.9 Contraception, Pregnancy, and Sperm Donation ..............................................41 
7.10 Data Monitoring Committee .............................................................................43 
8.0 
STUDY PROCEDURES .........................................................................................44 
8.1 Screening (Part A and Part B) ...........................................................................44 
8.2 Treatment Period ...............................................................................................45 
8.2.1 Week 1 (Part A and Part B) ...................................................................46 


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8.2.2 Weeks 2 through 8 (Part A and Part B) .................................................48 
8.2.3 Weeks 9 through 12 (Part B only) .........................................................49 
8.3 End-of-Treatment (Day 57 of Part A or Day 85 of Part B) or Early Termination 
Visit ...................................................................................................................51 
8.4 Follow-Up Visit .................................................................................................52 
8.5 Unscheduled Visits ............................................................................................52 
9.0 
STUDY DRUG ADMINISTRATION ....................................................................53 
9.1 Identity of Investigational Product(s) ................................................................53 
9.1.1 Formulation of CR845 and Placebo ......................................................53 
9.1.2 Packaging, Labeling, and Storage Stability of CR845 and Placebo .....53 
9.2 Preparation, Blinding, Administration, and Dosage of CR845 and Placebo ....54 
9.2.1 Individual Dose Labeling (CR845 and Placebo) ...................................55 
9.2.2 Selection of Doses Used in the Study ...................................................56 
9.3 Drug Accountability ..........................................................................................56 
10.0 PRIOR, CONCOMITANT, AND PROHIBITED MEDICATIONS ......................58 
10.1 Prior and Concomitant Medications ..................................................................58 
10.2 Restricted and Prohibited Medications ..............................................................58 
11.0 ASSESSMENTS .....................................................................................................60 
11.1 Efficacy Assessments ........................................................................................60 
11.1.1 Worst Itching Intensity Numerical Rating Scale ...................................60 
11.1.2 Patient Self-categorization of Pruritus Disease Severity .......................60 
11.1.3 Skindex-10 Scale ...................................................................................61 
11.1.4 MOS Sleep Scale ...................................................................................61 
11.1.5 5-D Itch Scale ........................................................................................61 
11.1.6 Patient Global Impression of Worst Itch Severity .................................62 
11.1.7 Patient Global Impression of Change ....................................................62 
11.2 Safety Assessments ...........................................................................................62 
11.2.1 Physical Examination ............................................................................62 
11.2.2 Vital Signs .............................................................................................63 
11.2.3 Electrocardiogram .................................................................................63 
11.2.4 Clinical Laboratory Tests ......................................................................63 
11.3 Adverse Events ..................................................................................................64 
11.3.1 Definition of Adverse Events ................................................................64 
11.3.2 Adverse Event Intensity Assessment ....................................................65 
11.3.3 Definition of Serious Adverse Events ...................................................66 
11.3.4 Adverse Event Causality or Relatedness to the Study Drug .................67 


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11.3.5 Adverse Event Documentation and Follow-Up ....................................68 
11.3.6 Serious Adverse Event Notification, Documentation, and Reporting ...69 
11.4 Pharmacokinetic Evaluation ..............................................................................71 
11.5 Inflammatory Biomarker Evaluation .................................................................71 
12.0 STATISTICAL METHODS ...................................................................................73 
12.1 General Considerations .....................................................................................73 
12.2 Determination of Sample Size ...........................................................................73 
12.3 Interim Analysis ................................................................................................75 
12.4 Analysis Populations .........................................................................................75 
12.5 Statistical Summary and Analysis .....................................................................76 
12.5.1 Patient Disposition ................................................................................76 
12.5.2 Protocol Deviations ...............................................................................76 
12.5.3 Demographic and Baseline Characteristics ...........................................76 
12.6 Efficacy Analysis ..............................................................................................76 
12.6.1 Primary Efficacy Endpoint ....................................................................76 
12.6.2 Secondary Efficacy Endpoint ................................................................79 
12.6.3 Hypothesis Testing Strategy ..................................................................79 
12.6.4 Other Efficacy Endpoints ......................................................................80 
12.6.5 Additional Statistical Considerations ....................................................83 
12.7 Pharmacokinetic Analysis .................................................................................83 
12.8 Safety Analysis ..................................................................................................84 
12.8.1 Adverse Events ......................................................................................84 
12.8.2 Other Safety Analyses ...........................................................................85 
12.8.3 Prior and Concomitant Medications ......................................................86 
13.0 QUALITY CONTROL AND QUALITY ASSURANCE ......................................87 
13.1 Study Monitoring Plan ......................................................................................87 
13.2 Audits and Inspections ......................................................................................87 
13.3 Data Collection, Validation and Analysis .........................................................88 
14.0 ETHICS AND REGULATORY COMPLIANCE ..................................................89 
14.1 Ethics .................................................................................................................89 
14.2 Good Clinical Practices .....................................................................................89 
14.3 Institutional Review Board ................................................................................90 
14.4 Informed Consent Process .................................................................................90 
14.5 Patient Confidentiality .......................................................................................91 
14.6 Study Suspension, Termination and Completion ..............................................91 
15.0 DATA HANDLING AND RECORD KEEPING ...................................................93 


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15.1 Case Report Form Completion ..........................................................................93 
15.2 Data Management Responsibilities ...................................................................93 
16.0 ADMINISTRATIVE PROCEDURES ....................................................................94 
16.1 Study Records Retention ...................................................................................94 
16.2 Protocol Adherence ...........................................................................................94 
16.3 Publication of Study Findings ...........................................................................94 
17.0 REFERENCES ........................................................................................................96 
18.0 APPENDICES .........................................................................................................98 
18.1 APPENDIX I Schedule of Events .....................................................................99 
18.2 APPENDIX II Pharmacokinetic Blood Sampling Schedule ...........................106 
18.3 APPENDIX III Worst Itching Intensity Numerical Rating Scale (NRS) .......107 
18.4 APPENDIX IV Patient Self-Categorization of Pruritus Disease Severity ......108 
18.5 APPENDIX V Skindex-10 Scale ....................................................................109 
18.6 APPENDIX VI Medical Outcomes Study (MOS) Sleep Scale ......................110 
18.7 APPENDIX VII 5-D Itch Scale .......................................................................111 
18.8 APPENDIX VIII Patient Global Impression of Worst Itch Severity ..............112 
18.9 APPENDIX IX Patient Global Impression of Change ....................................113 
 


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1.0 
Investigator Approval Statement 
I have read and understand the protocol (CR845-CLIN2101) and the Investigator’s 
Brochure (IB, Edition No. 7) and I agree that these documents contain all ethical, legal, 
and scientific information necessary to conduct this study.  I will personally conduct 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 International 
Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical 
Practice (GCP) E6 (R1) dated 10 June 1996 and applicable regulatory requirements. 
I will ensure that all individuals assisting with the study are adequately trained and 
informed about the protocol, investigational product(s), procedures and their study related 
duties and functions. 
I agree not to deviate from the protocol without prior agreement from the Sponsor except 
to eliminate an immediate safety hazard to the study patients. 
I further agree that the Sponsor, Sponsor designees, and federal agencies shall have 
access to all source documents and records associated with the study for review and 
monitoring of the investigational trial. 
 
Principal 
Investigator:  
 
 
 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
Date: 
 
 
 
 
 


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2.0 
Protocol Synopsis 
STUDY TITLE 
A Two-Part, Multicenter, Double-Blind, Randomized, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy of 
Intravenous CR845 in Hemodialysis Patients with Moderate-to-Severe 
Pruritus 
PROTOCOL 
NUMBER 
CR845-CLIN2101 
PHASE OF 
DEVELOPMENT 
2 (Part A) and 3 (Part B) 
INVESTIGATIONAL 
PRODUCT 
CR845 Solution 
NAME OF ACTIVE 
INGREDIENT 
CR845 
ROUTE OF 
ADMINISTRATION 
Intravenous (IV) 
STUDY CENTERS 
Part A:  Up to 40 sites in United States 
Part B:  Up to 60 sites in United States 
OBJECTIVES 
PART A 
Primary Objective 
 
To evaluate the efficacy of 3 dose levels of IV CR845 
administered after each dialysis session, compared to placebo, 
in reducing the intensity of itch as assessed by the change from 
baseline to the last week of the 8-week Treatment Period with 
respect to the Worst Itching Intensity Numerical Rating Scale 
(NRS) score of in hemodialysis patients with 
moderate-to-severe pruritus. 
Secondary Objectives 
 
To evaluate the efficacy of 3 dose levels of IV CR845 
administered after each dialysis session, compared to placebo, 
in improving itch-related quality-of-life measures as assessed 
by the Skindex-10 Scale over an 8-week Treatment Period in 
hemodialysis patients with moderate-to-severe pruritus. 
 
To evaluate the safety of 3 dose levels of IV CR845 
administered after each dialysis session over an 8-week 
Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus. 
 
To evaluate the pharmacokinetics (PK) of 3 dose levels of IV 
CR845 administered after each dialysis session over an 8-week 
Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus. 


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OBJECTIVES 
PART B  
One dose level will be tested in Part B after selection from the doses 
tested in part .A  
 
Primary Objective 
 
To evaluate the efficacy of 1 dose level of IV CR845 
administered after each dialysis session, compared to placebo, 
in reducing the intensity of itch as assessed by the change from 
baseline to the last week of the 12-week Treatment Period with 
respect to the Worst Itching Intensity NRS score in 
hemodialysis patients with moderate-to-severe pruritus.   
Secondary Objectives 
 
To evaluate the efficacy of 1 dose level of IV CR845 
administered after each dialysis session, compared to placebo, 
in improving itch-related quality-of-life measures as assessed 
by the Skindex-10 Scale over a 12-week Treatment Period in 
hemodialysis patients with moderate-to-severe pruritus.  
 
To evaluate the safety of 1 dose level of IV CR845 
administered after each dialysis session over a 12-week 
Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus. 
NUMBER OF 
PATIENTS 
The planned overall (Part A + Part B) sample size for this clinical 
investigation is approximately 400 male and female hemodialysis 
patients with persistent moderate-to-severe pruritus (mean baseline 
24-hour Worst Itching Intensity NRS score > 4).   
Part A:  Approximately 160 male and female hemodialysis patients 
with moderate-to-severe pruritus will be randomized at approximately 
40 clinical sites.  
Part B:  Approximately 240 male and female hemodialysis patients 
with moderate-to-severe pruritus will be randomized at approximately 
60 clinical sites. 
STUDY 
POPULATION 
Inclusion criteria: 
To be eligible for inclusion into either Part A or Part B of the study, 
each patient will have to fulfill 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 read, complete questionnaires, and understand the 
study procedures; 
3. Males or females 18 years of age or older; 
4. End stage renal disease (ESRD) patients who have 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. 


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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. Female patients who are surgically sterile; or amenorrheic for 
at least 1 year and over the age of 55 years; or amenorrheic 
for at least 1 year, between the ages of 45 and 55 years, and 
have a serum follicle-stimulating hormone (FSH) level in the 
post-menopausal range at Screening; or have a negative serum 
pregnancy test at Screening and agree to use acceptable 
contraceptive measures (e.g., hormonal contraceptives, barrier 
with spermicide, intrauterine device, vasectomized partner, or 
abstinence) from the time of informed consent until the safety 
Follow-Up Visit or at least 7 days after the last dose, 
whichever is later. (Note: If the result from serum pregnancy 
testing at Screening is indeterminate because of possible 
human chorionic gonadotropin elevation secondary to ESRD 
unrelated to pregnancy, 1 or more serum pregnancy re-tests 
will be performed and reported to the Investigator prior to 
first dosing with the study drug to establish if a negative test 
result for pregnancy can be confirmed); 
6. If male, agrees not to donate sperm after the first dose of 
study drug until 7 days after the last dose, and agrees to use a 
condom with spermicide or abstain from heterosexual 
intercourse during the study until 7 days after study drug 
administration. (Note: No restrictions are required for a 
vasectomized male provided his vasectomy has been 
performed ≥ 4 months prior to dosing); 
7. Has a body weight of between 40.0 kg and 135.0 kg, inclusive 
(dry body weight);  
8. Patient who self-reports experiencing pruritus during the 
month prior to Screening;  
9. If currently using antihistamines (oral, IV, or topical), topical 
non-drug treatments (e.g., emollients, creams, oils), or oral or 
intravenous corticosteroids for itch, the current regimen (i.e., 
same drug, same dose, same route of administration, and same 
frequency) has been stable for 14 days prior to Screening and 
no change to the regimen is anticipated from Screening 
through the end of the Treatment Period; 
10. If currently using opioids, gabapentin or pregabalin, the 
current regimen (i.e., same drug, same dose, same route of 
administration, and same frequency) has been stable for at 
least 14 days prior to Screening and no change to the regimen 
is anticipated from Screening through the end of the 
Treatment Period; 
11. At least 2 single-pool Kt/V measurements ≥ 1.2, or at least 
2 urea reduction ratio measurements ≥ 65%, or 1 single-pool 


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Kt/V measurement ≥ 1.2 and 1 urea reduction ratio 
measurement ≥ 65% on different dialysis days during the 
3 months period prior to Screening; 
12. Patient who self-categorizes on the Patient Self-categorization 
of Pruritus Disease Severity questionnaire as a B or C profile 
at Screening;  
13. At the end of the Screening Period prior to randomization: 
a. Patient has completed at least 4 Worst Itching Intensity 
NRS scores out of 7 possible daily assessments during 
the last 7 days prior to randomization (0-10 NRS scale 
where 0 = “No itching” and 10 = “Worst itching 
imaginable”).  
b. Patient has a mean baseline Worst Itching Intensity 
NRS score > 4, defined as the average of all 
non-missing scores reported during the last 7 days 
prior to randomization (including scores collected on 
Day 1, prior to randomization). 
 
Exclusion criteria: 
A patient will be excluded from either Part A or Part B of the study if 
any of the following criteria are met: 
1. Known to be non-compliant with dialysis treatment (i.e., has 
missed more than 2 dialysis sessions in the past 2 months 
because of non-compliance); 
2. Anticipated 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. Known or suspected history of Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition-diagnosed alcohol, 
narcotic, or other drug abuse or dependence within 12 months 
prior to Screening; 
5. Patient has any clinically relevant acute or chronic medical or 
neuropsychiatric condition including, but not limited to, 
severe co-morbid condition such as congestive heart failure 
(New York Heart Association class IV), severe mental illness, 
or cognitive impairment which, in the opinion of the 
Investigator, would pose undue risk to the patient, would 
impede completion of the study procedures, or would 
compromise the validity of the study measurements; 
6. Serum alanine aminotransferase or aspartate aminotransferase 
greater than 2.5 times the reference upper limit of normal 
(ULN), or total bilirubin greater than 2 times ULN at 
Screening; 


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7. Received another investigational drug within 30 days prior to 
the start of Screening or has planned to participate in another 
clinical trial while enrolled in this study; 
8. Has pruritus probably or definitely attributed to a cause other 
than ESRD or its complications (e.g., patients with 
concomitant pruritic dermatological disease or cholestatic 
liver disease would be excluded).  (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. Anticipated to receive opioid antagonists (e.g., naloxone, 
naltrexone), or opioid mixed agonist-antagonist 
(e.g., buprenorphine, nalbuphine) from the start of Screening 
through the end of the Treatment Period; 
12. Used Salvia divinorum or Salvinorin A within 30 days prior to 
the start of Screening or is anticipated to use it during the 
study; 
13. Received ultraviolet B treatment within 30 days prior to the 
start of Screening or is anticipated to receive such treatment 
during the study; 
14. Participated in a previous clinical trial with CR845. 
STUDY 
DESIGN 
This is a two-part, multicenter, randomized, double-blind, 
placebo-controlled study to evaluate the safety and efficacy of IV 
CR845 administered after each dialysis session.  In Part A, 3 dose 
levels of CR845 will be evaluated relative to placebo over an 8-week 
Treatment Period in hemodialysis patients with moderate-to-severe 
pruritus.  A subset of patients (approximately 10 patients per treatment 
group) will also be consented for the collection of blood samples for 
evaluating the PK profile of CR845.  Based on the overall safety and 
efficacy profile from Part A, 1 dose of CR845 will be selected for 
Part B and evaluated relative to placebo over a 12-week Treatment 
Period in hemodialysis patients with moderate-to-severe pruritus.  
Part A consists of a Screening Period, an 8-week Treatment Period, an 
End-of-Treatment Visit (approximately 3 days after the last dose), and 
a Follow-Up Visit (approximately 1 week after the last dose).  
Part B consists of a Screening Period, a 12-week Treatment Period, an 
End-of-Treatment Visit (approximately 3 days after the last dose), and 
a Follow-Up Visit (approximately 1 week after the last dose).  Part B 
will not be initiated until an unblinded review of the safety and efficacy 
data from Part A has been completed. 
The Screening Period will occur between 8 and 14 days prior to 
randomization following the signing of the informed consent form.  


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Eligible patients will then be trained on completion of the 24-hour 
Worst Itching Intensity NRS scale and required to record their Worst 
Itching Intensity NRS score each day for 7 days prior to randomization.  
For consistency, patients will be requested to 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.  
During the week prior to randomization up to the first day of study 
drug (Day 1), patients will be trained on other PRO measures, 
including quality-of-life measurements. 
Day 1 of the Treatment Period will be defined as the day of the first 
dose of administration of study drug.   
All study visits (scheduled and unscheduled) will be conducted on 
dialysis days, including the end of study visit.   
For Part A, patients will be randomized in a 1:1:1:1 ratio to receive 
either CR845 1.5 mcg/kg, CR845 1.0 mcg/kg, CR845 0.5 mcg/kg, or 
placebo.  For statistical analysis, patients will be stratified into 
1 stratum according to their use or non-use of concomitant medications 
to treat their itch.  Patients who have consented to IV blood sampling 
will be included in the PK sample, with approximately 10 patients per 
treatment arm.  For Part B, patients will be randomized in a 1:1 ratio to 
receive either CR845 or placebo, with the dose of CR845 determined 
from an assessment of safety and efficacy observed in Part A.  Patients 
enrolled in Part B will also be stratified according to their use or 
non-use of concomitant medications to treat their itch. 
Patients will be administered CR845 or matched placebo as an IV 
bolus immediately after the end of the dialysis session during the 
8-week (Part A) or 12-week (Part B) Treatment Period so that each 
patient will receive CR845 3 times weekly.  During the Treatment 
Period, PRO measurements, including Worst Itching Intensity NRS 
scores, will be obtained at the similar time of day (daily or bi-weekly) 
for a given patient, either in the dialysis unit on dialysis days or at 
home. 
Patients will report their Worst Itching Intensity NRS score over the 
last 24 hours daily during Screening and during the entire Treatment 
Period.  In addition, during selected study visits, they will complete 
other PRO measures (Skindex-10 Scale, MOS-Sleep Scale, 5-D Itch 
Scale, Patient Global Impression of Worst Itch Severity, and Patient 
Global Impression of Change). 
Patients who are still in the study but miss their last on-treatment 
dialysis day (Week 8 for Part A; Week 12 for Part B) due to a 
competing medical conflict (e.g., hospitalization due to ESRD 
complications) will be allowed to complete the end of study visit if 
they return to the site within 3 days of the scheduled visit.  The end of 
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Blood samples for inflammatory biomarkers will be collected for all 
randomized patients prior to dialysis on Day 1 and prior to the last 
dialysis of the Treatment Period. 
For Part A only, blood samples for evaluating the PK of CR845 will be 
collected in up to 40 patients (approximately 10 patients per treatment 
group) who have consented for this purpose, and will be collected prior 
to dosing on Day 1, and at pre-specified time points after the first dose 
of study drug.  For Part B, blood samples for evaluating the PK of 
CR845 will be collected by sparse-sampling, using a more limited set 
of time points than in Part A.  
Vital signs and clinical laboratory tests will be monitored periodically, 
and adverse events and concomitant medications will be continuously 
recorded during the study starting at the Screening Visit until the end 
of the Follow-up Period.  
A final safety Follow-Up Visit will be conducted 7 days (+3) after the 
last dose of study drug.  
STUDY DRUG 
Study drug will be supplied in glass vials containing an extractable 
volume of 1.3 mL of CR845 at concentrations of 0.05 mg/mL, 
0.10 mg/mL and 0.15 mg/mL in 0.04M isotonic acetate buffer, pH 4.5.  
The study drug will be labeled for a blinded study. 
REFERENCE 
PRODUCT 
Matching placebo (0.04M isotonic acetate buffer, pH 4.5) will be 
provided in glass vials containing an extractable volume of 1.3 mL. 
TREATMENT 
REGIMENS 
Part A: Four groups with a sample size of approximately 40 patients 
each will be administered CR845 0.5, 1, or 1.5 mcg/kg, or placebo as a 
single IV bolus 3 times a week immediately after each dialysis session 
for 8 weeks.   
Part B: Two groups with a sample size of approximately 120 patients 
each will be administered CR845 or placebo as a single IV bolus 
3 times a week immediately after each dialysis session for 12 weeks.  
The dose of CR845 and the total sample size will be confirmed based 
on an unblinded review of the safety and efficacy data collected in 
Part A. 
STUDY DURATION 
Screening Period: Up to 14 days prior to Randomization 
Treatment Period:  Part A, 8 weeks; Part B, 12 weeks 
Follow-Up Visit: 1 week (+3 days)  
Total study duration for a single patient: Part A up to 11.5 weeks; 
Part B, up to 15.5 weeks 
STUDY 
ENDPOINTS 
Safety Endpoints (Parts A and B) 
The safety assessments used to evaluate the overall safety of CR845 
include the frequency and severity of adverse events by treatment 
group, physical examination, 12-lead electrocardiogram (ECG), vital 
signs, and clinical safety laboratory evaluations.  
 


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Pharmacokinetic Endpoints (Part A) 
The PK profile of CR845 will be determined between Week 1 and 
Week 8, and calculation of the accumulation ratio between the first and 
last doses with respect to maximum concentration (Cmax) and area 
under the curve (AUC) will be reported.  The PK profile will be used to 
determine the sparse sampling schedule for Part B of the study. 
 
Efficacy Endpoints (Parts A and B) 
Primary Efficacy Endpoint 
 
Change from baseline with respect to the weekly mean of the 
daily 24-hour Worst Itching Intensity NRS score during 
Week 8 (Part A) or Week 12 (Part B) of the Treatment Period 
Secondary Efficacy Endpoint 
 
Change from baseline in itch-related quality-of-life at the end 
of Week 8 (Part A) or Week 12 (Part B) as assessed by the 
total Skindex-10 Scale score 
 
Other Efficacy Endpoints 
 
Itch-intensity measures: 
o Change from baseline with respect to the weekly mean 
of the daily Worst Itching Intensity NRS score from 
Week 2 through the end of the Treatment Period 
(Week 8 for Part A or Week 12 for Part B) 
o Treatment Response, defined as the percent 
improvement from baseline with respect to the weekly 
mean of the daily Worst Itching Intensity NRS score 
during the last week of the Treatment Period (Week 8 
for Part A or Week 12 for Part B) 
 
Itch-related quality-of-life measures: 
o Change from baseline in itch-related quality-of-life 
from Week 2 through the last week of the Treatment 
Period (Week 8 for Part A or Week 12 for Part B) as 
assessed by the total Skindex-10 Scale score 
o Change from baseline in itch-related quality-of-life at 
the end of the last week of the Treatment Period 
(Week 8 for Part A or Week 12 for Part B), and over 
each week of the Treatment Period within each of the 
3 domains of the Skindex-10 Scale 
o Change from baseline to the end of Week 8 (Part A) or 
Week 12 (Part B) in itch-related quality-of-life, as 
measured by the 5-D Itch Scale 
o Change from baseline to the end of Week 8 (Part A) or 
Week 12 (Part B) in itch-related sleep disturbance, as 


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measured by the Sleep Disturbance Subscale of the 
Medical Outcomes Study Sleep Scale 
o Proportion of patients who rate their itch condition as 
“Very much improved” or “Much Improved”, as 
measured by the Patient Global Impression of Change 
at the end of the Treatment Period (Week 8 for Part A 
or Week 12 for Part B) 
o The number and percentage of patients in each of the 
5 categories of the Patient Global Impression of Worst 
Itch Severity at baseline, Weeks 2, 4, and 8 (Part A), or 
baseline, Weeks 2, 4, 8, and 12 (Part B).  In addition, 
the proportion of patients who have a 1-point 
improvement or more at Week 2, 4, 8, and Week 12 
(Part B only), as measured by the Patient Global 
Impression of Worst Itch Severity 
 
Missed Dialysis Visits and Incidence of Infection: 
o Missed dialysis visits based on percentage of patients 
who missed 1 or more visits at the dialysis unit and 
total number of missed dialysis visits during the 
Treatment Period 
o Incidence of infection based on adverse events, 
hospitalizations, and/or use of antibiotics for treatment 
of infection related to uremic pruritus 
 
Inflammatory Biomarkers: 
o Changes in blood levels of  inflammatory biomarkers, 
including but not limited to hepcidin, interleukin [IL]-
2, IL-6, IL-31, pre-albumin, C-reactive protein from 
pre-dose to the end of the Treatment Period (Week 8 
for Part A or Week 12 for Part B) 
 
Iron Status and use of Erythropoiesis-Stimulating Agents 
and IV Iron 
o Changes in ferritin and transferrin saturation from pre-
dose to the end of the Treatment Period (Week 8 for 
Part A or Week 12 for Part B) 
o Changes in erythropoiesis-stimulating agents 
and/or IV iron dose, and erythropoiesis resistive 
index from pre-dose to the end of the Treatment 
Period (Week 8 for Part A or Week 12 for Part B) 


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INTERIM 
ASSESSMENT 
Safety data will be reviewed on an ongoing basis by the Sponsor and a 
Data Monitoring Committee (DMC). No formal interim analysis of 
efficacy data is planned for Part A or Part B. 
Following completion of Part A, there will be an unblinded analysis to 
determine the dose of CR845 to be used in Part B.  This analysis will 
not affect the Type I error for Part B, as it will represent the final 
analysis for Part A. 
STATISTICAL 
ANALYSIS 
The data from Part A of the study will be summarized and analyzed 
separately from the data collected in Part B of the study. 
 
Analysis Population(s) 
The Safety and Full Analysis Populations are both defined as the group 
of all randomized patients who received at least 1 dose of double-blind 
study drug.  Following the intent-to-treat principle, patients in the Full 
Analysis Population will be analyzed according to their randomized 
treatment, regardless of the actual treatment received.  However, 
patients in the Safety Analysis Population will be analyzed according 
to their actual treatment.  The Safety Population will be used to analyze 
all safety endpoints while the Full Analysis Population will be used to 
analyze all efficacy endpoints. 
The Per-Protocol Population is defined as the subset of patients in the 
Full Analysis Population who do not have any major protocol 
deviations that could affect the efficacy analyses.  An analysis of the 
primary and secondary efficacy variables for the Per-Protocol 
Population may be performed if more than 20% of the patients in the 
Full Analysis Population are excluded.   
The Pharmacokinetic Evaluable Population is defined as all patients 
who received CR845 and have sufficient plasma concentrations for PK 
analysis.   
Safety Analyses 
Safety data will be summarized descriptively.  No inferential statistics 
are planned.  Analyses of adverse event data will be summarized by 
Medical Dictionary for Regulatory Activities system organ class (SOC) 
and preferred term by treatment group, and will include summaries of 
treatment-emergent adverse events, serious adverse events, and adverse 
events resulting in study drug discontinuation.  Vital signs, clinical 
safety laboratory, physical examination findings, and ECG data will be 
descriptively summarized by visit as applicable, in addition to change 
from baseline.  


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Pharmacokinetic Analyses 
Plasma concentrations will be summarized descriptively and 
graphically by nominal time.  Pharmacokinetic parameters (Cmax, time 
to Cmax, AUC, clearance, steady state volume of distribution, etc.) will 
be calculated based on the actual time of blood sampling.  
Accumulation ratios for Cmax (RCmax) and AUC (RAUC) will also be 
calculated.  Individual plasma CR845 concentrations will be listed and 
plotted by patient and compared across dose groups. 
Efficacy Analyses 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the change from baseline 
to the last week of the Treatment Period (Week 8 for Part A, and 
Week 12 for Part B) with respect to the weekly mean of the daily 
24-hour Worst Itching Intensity NRS score.  The baseline score will be 
defined as the average of the daily 24-hour Worst Itching Intensity 
NRS scores over the last 7 days prior to randomization, including 
pre-treatment assessments collected on Day 1.   
The primary efficacy variable will be analyzed using a mixed effects 
model with repeated measures (MMRM).  The model will contain 
treatment, week, and treatment-by-week interaction as fixed effects; 
baseline as a covariate, and patient as a random effect.  For each dose 
group (Part A) or for the selected dose of CR845 (Part B), the 
treatment group difference versus placebo will be estimated as the 
simple contrast in the treatment effect on the last week of treatment.   
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 [1], or compound 
symmetry) will be examined.  The Akaike information criterion will be 
used to determine the appropriate covariance matrix for the MMRM 
model.  The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom.  
In the primary efficacy analysis (Part A or B), missing daily worst 
itching scores will not be imputed.  Assuming that the data are missing 
at random (MAR), the estimates of the treatment differences calculated 
from the MMRM model described above are unbiased.  
Sensitivity analyses will be conducted to evaluate the effect of the 
MAR assumption on the study results for Part B.  Depending on the 
pattern and the amount of early treatment discontinuations in Part A, 
similar sensitivity analyses may also be performed for Part A in order 
to provide estimates of treatment effect under different imputation 
algorithms and help refine the sample size for Part B. 
Secondary Efficacy Endpoint 
The secondary efficacy variable is the change from baseline in the 
(total) Skindex-10 Scale score.  An MMRM, similar to that used for the 
primary efficacy analysis, will be fitted to the data.  The baseline value 


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will be defined as the value of the Skindex-10 Scale score collected on 
Day 1, prior to randomization.   
Missing Skindex-10 Scale scores will not be imputed.  Assuming that 
the data are MAR, the estimates of the treatment differences calculated 
from the MMRM models above are unbiased. 
Hypothesis Testing Strategy 
PART A 
The primary goal for Part A of this clinical investigation is to evaluate 
the efficacy of different dose levels of IV CR845 administered after 
each dialysis session in reducing the intensity of itch over an 8-week 
Treatment Period in hemodialysis patients with moderate-to-severe 
pruritus.  Three doses will be studied (1.5 mcg/kg, 1.0 mcg/kg, and 
0.5 mcg/kg), and each will be compared against placebo.  One of these 
doses will be selected for further evaluation compared to placebo in 
Part B.  Although a hypothesis test of each CR845 dose against placebo 
will be performed for each of the primary, secondary and exploratory 
variables, these hypothesis tests are not expected to be statistically 
significant based on the planned sample size of approximately 
40 patients per treatment group and effect size data from previous 
studies of CR845 in the same population.  Nevertheless, the estimates 
of treatment effect and p-values resulting from these hypothesis tests 
will be used, in addition to a review of safety data, to select the most 
appropriate dose for Part B.  A sample size of 40 patients per group is 
adequate to provide an appropriate estimate of the magnitude and 
variability of treatment effect at each dose. 
PART B 
Each hypothesis test will be 2-sided and conducted at the 5% 
significance level.  The study will be considered positive if the null 
hypothesis of no treatment difference is rejected in favor of the 
alternative that patients randomized to CR845 experience significantly 
less itching as measured by the change from baseline to Week 12 of the 
Treatment Period with respect to the weekly mean of the 24-hour 
Worst Itching Intensity NRS score.   
Further details and analysis methods are found in Section 12.0 and will 
be described further in the Statistical Analysis Plan. 


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3.0 
List of Abbreviations 
 
AUC 
area under the curve 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRF 
case report form 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end stage renal disease  
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
H 
above laboratory reference range 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS/IWRS 
interactive voice response system/interactive web response system 
L 
below laboratory reference range 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed effects model with repeated measures 
MOS 
Medical Outcomes Study 
N 
within laboratory reference range 
NRS 
numerical rating scale 
PK 
pharmacokinetic(s) 
PNS 
peripheral nervous system 
PRO 
patient reported outcome 
RAUC 
accumulation ratio for AUC 
RCmax 
accumulation ratio for Cmax  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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4.0 
Introduction 
4.1 
Background and Rationale 
CR845 is a kappa-opioid receptor agonist with a peripheral mechanism of action, 
currently being developed by Cara Therapeutics, Inc. (designated as Cara Therapeutics 
and Sponsor in this protocol) as a novel therapeutic agent for the treatment of acute and 
chronic pain, and pruritus. 
Opioid receptors are involved in the modulation of 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 (PNS) tissues such as skin and viscera, and in the 
immune system (see Investigator’s Brochure [IB]1 for references and further details).  
Morphine, the most widely used opiate analgesic, acts primarily via activation of the mu 
opioid receptor located in the CNS and PNS, and as such, is associated with a wide array 
of side effects, including sedation, respiratory depression, abuse liability, and 
constipation.  As a way to avoid these undesirable effects, CR845 was designed to 
activate kappa opioid receptors, located in the PNS, which are known to modulate itch, 
pain, and inflammatory signals without producing the side effects associated with the 
activation of mu opioid receptors. 
CR845 is a potent and selective kappa receptor agonist with more than 30,000-fold 
selectivity over mu and delta opioid receptors and does not demonstrate activity at other 
receptors, ion channels, or transporters.  CR845’s unique peptidic structure significantly 
differs from other small molecule kappa agonists developed thus far, which, for the most 
part, are CNS-active.  Being a hydrophilic tetrapeptide, CR845 has limited membrane 
permeability by passive diffusion, which limits its access to the CNS, and thus, the 
compound preferentially activates kappa receptors located outside the CNS. 
Based on nonclinical pharmacological studies, it is anticipated that CR845 could produce 
a combined analgesic, anti-itch, and anti-inflammatory effect (see IB1 for details).   
Uremic pruritus is a chronic, unremitting, and highly bothersome condition in patients 
with chronic kidney disease which adversely affects sleep, mood, and ability to 
socialize2, and is associated with increased mortality3,4.  Large multinational studies 
(Dialysis Outcomes and Practice Patterns) and studies based in the United States have 
demonstrated that approximately 30-40% hemodialysis patients have moderate-to-severe 


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pruritus.  There are no approved treatments for this condition in the United States, 
although kappa opioid agonists are known to modulate pruritus in human5 and the mixed 
non-selective mu partial agonist and kappa opioid agonist nalfurafine (Remitch™) has 
been recently approved in Japan for the treatment of pruritus in hemodialysis patients.  
Thus, evaluation of the efficacy of CR845 at reducing itch in a hemodialysis population 
could be beneficial as it could support further clinical development for the treatment of 
pruritus in this population.   
4.2 
Clinical Experience 
Overall Exposure 
To date, the intravenous (IV) formulation of CR845 has been evaluated in 495 patients 
and healthy volunteers (231 males and 264 females) across 6 Phase 1 studies (including 
1 Phase 1a/b study conducted in Japan), 3 Phase 2 studies for the relief of 
moderate-to-severe acute post-operative pain, and 1 Phase 2 study for the relief of 
moderate-to-severe pruritus in hemodialysis patients.  CR845 has been evaluated both as 
IV bolus and 15-minute infusion of single or repeated doses ranging from 0.5 to 
40 mcg/kg.   
Out of the 495 subjects exposed to CR845 to date, 70 hemodialysis patients (41 males 
and 29 females) have received IV injection of single or repeated CR845 doses (for up to 
2 weeks) ranging from 0.5 to 6 mcg/kg across one Phase 1 study and one Phase 2 safety 
and efficacy study. 
Safety in Hemodialysis Patients 
A review of the aggregate safety data for hemodialysis patients shows that CR845 was 
safe and well-tolerated in a complex population of hemodialysis patients with multiple 
comorbidities when administered after each dialysis session for a period of up to 2 weeks 
at IV doses ranging from 0.5 mcg/kg to 6 mcg/kg.  Although patients exposed to CR845 
reported more adverse events compared to placebo patients, most were mild or moderate 
in nature.   
Generally mild, transient paresthesias (facial tingling) and/or hypoesthesias (in different 
anatomic locations), mostly on the first day of dosing, as well as headache, dizziness, and 
somnolence, were the most frequently reported adverse events associated with CR845 


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administration.  However, psychiatric side effects (e.g., dysphoria and hallucinations) 
commonly associated with centrally-acting kappa opioids were not reported in patients 
exposed to CR845.  Other common mu-opioid side effects such as vomiting, 
constipation, and euphoria were also not observed; nausea occurred with a frequency 
similar to that in the placebo group.  Consistent with its lack of affinity for the mu-opioid 
receptor, CR845 did not cause respiratory depression, reduction in oxygen saturation, or 
decreased blood pressure.  
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, as noted, no 
apparent differences between the placebo and CR845 groups in serum sodium.  There 
were no discernable differences between treatment groups in vital signs.  Of particular 
note, among patients receiving CR845, there was no apparent reduction in blood pressure 
or respiratory rate following dosing, in contrast to the expected effects of mu-opioid 
agonists. 
Adverse event summary tables can be found in the IB1 with further details of the safety 
profile of CR845 established to date in this population.   
Efficacy of CR845 in Hemodialysis Patients with Uremic Pruritus 
The efficacy of CR845 in uremic pruritus was evaluated in a Phase 2, randomized, 
double-blind, placebo-controlled trial (CR845-CLIN2005, Part B) that 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 during that time period.  CR845 significantly decreased itching 
intensity (P=0.016 versus placebo) and significantly improved the quality-of-life related 
to itching (Skindex-10 Scale) (see IB1 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 on non-dialysis days.  The separation of 
CR845-treated patients from placebo-treated patients in itching intensity was evident by 
Day 3 of treatment and continued to increase into Week 2. 


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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 subjects (Study 
CR845-CLIN1005) such that plasma levels of CR845 remain relatively constant until 
cleared during dialysis in hemodialysis patients (Study CR845-CLIN1003 and 
CR845-CLIN2005), with half-life ranging between 18 to 24 hours in hemodialysis 
patients compared to a typical range of 2 to 3 hours in subjects 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 (PK) profile, it 
was established that 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 PK profile of repeat-dose CR845 was studied in 24 hemodialysis patients who 
received doses of 0.5, 1.0, or 2.5 mcg/kg 3 times per week for 1 week 
(CR845-CLIN2005, Part A).  In this study, there were dose-proportional increases in 
maximum concentration (Cmax) and area under the curve (AUC), and minimum to no 
accumulation with repeat doses due to clearance of the drug by hemodialysis (see IB1 for 
details). 
4.3 
Summary of Potential Risks and Benefits 
The potential benefit of CR845 in alleviating the symptoms of uremic pruritus is 
predicated on its pharmacological class and evidence of its effectiveness in multiple 
animal models of pruritus and in one Phase 2 clinical trial with hemodialysis patients 
experiencing moderate-to-severe pruritus (CR845-CLIN2005, Part B) 
In humans with normal renal function, CR845 has aquaretic effects which can result in 
dehydration and associated symptoms (e.g., dizziness, tachycardia) and hypernatremia if 
the fluid balance is not managed properly.  However, these effects appear to be absent in 
the dialysis population, many of whom are anuric and all of whom have few functioning 
nephrons.   


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Potential risks of CR845 include the possible occurrence of adverse events of mild 
somnolence and transient mild or moderate dizziness following the first dose, which have 
been reported in 3-6% of patients at doses planned for this trial.  Therefore, as a 
precaution, investigators should advise patients not to drive or operate machinery on 
Day 1 following the first dose, until it is determined that the patient does not experience 
these possible adverse events.  While it has been demonstrated that CR845 has 
substantially less access to the CNS than previously tested kappa opioid agonists, adverse 
neurobehavioral effects of CR845 could still be considered a possibility (e.g., 
hypothetically, in patients with impaired blood-brain barrier functioning). 
A more detailed summary of the potential risks of CR845 is provided in the IB.1  The 
Investigator must become familiar with all sections of the current IB for CR845 before 
the start of the study. 


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5.0 
Safety Monitoring Plan 
The safety monitoring plan is intended to minimize risk for patients participating in this 
study.  General safety monitoring will include assessment of adverse events, 
measurements of serum chemistry, hematology, vital signs, 12-lead electrocardiograms 
(ECGs), and physical examinations.  Following completion of study drug treatment, 
patients will return for a safety Follow-Up Visit.  Based on the safety profile of CR845 
observed in a 2-week treatment study, this study aims to further evaluate safety as well as 
efficacy during treatment with CR845 for 8 weeks (Part A) and 12 weeks (Part B).  The 
doses selected for this study include the 1 mcg/kg dose, which was found to be effective 
and to have a good safety profile, a lower dose (0.5 mcg/kg), and a higher dose 
(1.5 mcg/kg), which has not been previously studied, but is well within the range of doses 
previously studied in hemodialysis patients (0.5 mcg/kg to 6 mcg/kg) (See Section 
9.2.2.).  Frequent study visits (3 times/week) permit close safety monitoring of patients.  
Because CR845 is effectively cleared by hemodialysis (CR845-CLIN1003 and CR845-
CLIN2005), this procedure enables removal of the drug in situations of unintentional 
overdose or if a patient is experiencing a severe or serious adverse event (SAE) that, in 
the opinion of the Investigator, could possibly, probably or definitely be drug-related, 
such that removal of the drug could potentially be of benefit to the patient.   


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6.0 
Objectives 
6.1 
Part A 
Primary Objective  
The primary objective is to evaluate the efficacy of 3 dose levels of IV CR845 
administered after each dialysis session, compared to placebo, in reducing the intensity of 
itch as assessed by the change from baseline to the last week of the 8-week Treatment 
Period with respect to the Worst Itching Intensity Numerical Rating Scale (NRS) score of 
in hemodialysis patients with moderate-to-severe pruritus.   
Secondary Objectives 
The secondary objectives are: 
 To evaluate the efficacy of 3 dose levels of IV CR845 administered after each 
dialysis session, compared to placebo, in improving itch-related quality-of-life 
measures as assessed by the Skindex-10 Scale over an 8-week Treatment Period 
in hemodialysis patients with moderate-to-severe pruritus. 
 To evaluate the safety of 3 dose levels of IV CR845 administered after each 
dialysis session over an 8-week Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus.  
 To evaluate the PK of 3 dose levels of IV CR845 administered after each dialysis 
session over an 8-week Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus.  
6.2 
Part B 
One dose level will be tested in Part B after selection from the doses tested in part A and 
which will be the dose which represents best efficacy and safety 
Primary Objective  
The primary objective is to evaluate the efficacy of 1 dose level of IV CR845 
administered after each dialysis session, compared to placebo, in reducing the intensity of 
itch as assessed by the change from baseline to the last week of the 12-week Treatment 


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Period with respect to the Worst Itching Intensity NRS score in hemodialysis patients 
with moderate-to-severe pruritus.   
Secondary Objectives 
The secondary objectives are: 
 To evaluate the efficacy of 1 dose level of IV CR845 administered after each 
dialysis session, compared to placebo, in improving itch-related quality-of-life 
measures as assessed by the Skindex-10 Scale over a 12-week Treatment Period 
in hemodialysis patients with moderate-to-severe pruritus. 
 To evaluate the safety of 1 dose level of IV CR845 administered after each 
dialysis session over a 12-week Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus. 


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7.0 
Investigational Plan 
This is a two-part, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety and efficacy of IV CR845 administered after each dialysis session.  In 
Part A, 3 dose levels of CR845 will be evaluated relative to placebo over an 8-week 
Treatment Period in hemodialysis patients with moderate-to-severe pruritus.  A subset of 
patients (approximately 10 patients per treatment group) will also be consented for the 
collection of blood samples for evaluating the PK profile of CR845.  Based on the overall 
safety and efficacy profile of the 3 doses in Part A, 1 dose of CR845 will be selected for 
further evaluation relative to placebo over a 12-week Treatment Period in hemodialysis 
patients with moderate-to-severe pruritus in Part B. 
7.1 
Study Design and Rationale 
The present study is designed to further evaluate the efficacy and safety of IV CR845 in 
end stage renal disease (ESRD) patients on hemodialysis with uremic pruritus.  A 
randomized, double-blind design was chosen to minimize bias.  In Part A, an 8-week 
duration was selected to demonstrate durability of the efficacy observed in a prior 2-week 
treatment trial and to further evaluate safety following a longer exposure.  The primary 
efficacy endpoint is the Worst Itching Intensity NRS scale, which measures itching 
intensity over 24 hours.  Although prior studies [Mathur 20106; CR845-CLIN2005] 
utilized separate measures of the worst itching intensity during the daytime and 
nighttime, based on the similarity of the daytime and nighttime scores in the prior study 
CR845-CLIN2005, only a single measurement to describe itching during the entire 
24-hour period will be used in this study.  A 24-hour recall period is a standard recall 
period for the evaluation of other chronic conditions such as chronic pain or 
osteoarthritis. Prior to the initiation of this clinical trial, Cara will conduct a study to 
confirm the appropriateness of a 24-hour recall period in hemodialysis patients.  Daily 
Worst Itching Intensity NRS scores will be collected to evaluate pruritus efficacy on both 
dialysis and non-dialysis days as was done in the prior study CR845-CLIN2005. 
Part A consists of a Screening Period, an 8-week Treatment Period, an End-of-Treatment 
Visit (approximately 3 days after the last dose), and a Follow-Up Visit (approximately 
1 week after the last dose).  
Part B consists of a Screening Period, a 12-week Treatment Period, an End-of-Treatment 
Visit (approximately 3 days after the last dose), and a Follow-Up Visit (approximately 


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1 week after the last dose).  Part B will not be initiated until an unblinded review of the 
safety and efficacy data from Part A has been completed. 
The Screening Period will occur within 14 days prior to randomization following the 
signing of the informed consent form (ICF). 
Eligible patients will then be trained on completion of the 24-hour Worst Itching 
Intensity NRS scale and required to record their Worst Itching Intensity NRS scale each 
day for 7 days prior to randomization.  For consistency, patients will be requested to 
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.  During the week prior 
to randomization up to the first day of study drug (Day 1), patients will be trained on 
other PRO measures, including quality-of-life measurements. 
Day 1 of the Treatment Period will be defined as the day the first dose of administration 
of study drug.  Study weeks will begin on the same day of the week as randomization 
(e.g., for a patient randomized on a Tuesday, all study weeks will start on Tuesday and 
end on Monday).  
All study visits (scheduled and unscheduled) will be conducted on dialysis days, 
including the end of study visit.  
For Part A, patients will be randomized in a 1:1:1:1 ratio to receive either CR845 
1.5 mcg/kg, CR845 1.0 mcg/kg, CR845 0.5 mcg/kg, or placebo.  For statistical analysis, 
patients will be stratified into 1 strata according to their use or non-use of concomitant 
medications to treat their itch.  Patients who have consented to IV blood sampling will be 
included in the PK sample, with approximately 10 patients per treatment arm.  For Part B, 
patients will be randomized in a 1:1 ratio to receive either CR845 or placebo, with the 
dose of CR845 determined from an assessment of safety and efficacy observed in Part A.  
Patients enrolled in Part B will also be stratified according to their use or non-use of 
concomitant medications to treat their itch. 
Patients will be administered CR845 or matched placebo as an IV bolus immediately 
after the end of the dialysis session during the 8-week (Part A) or 12-week (Part B) 
Treatment Period so that each patient will receive CR845 3 times weekly.  Patients 
receiving a 4th dialysis treatment during a given week (e.g., for fluid overload) should 
receive an extra dose of CR845 following dialysis after this treatment.  During the 


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Treatment Period, PRO measurements, including Worst Itching Intensity NRS scores, 
will be obtained at the similar time of day (daily or bi-weekly) for a given patient, either 
in the dialysis unit on dialysis days or at home.  
Patients will report their Worst Itching Intensity NRS score over the last 24 hours daily 
during Screening and during the entire Treatment Period.  In addition, during selected 
study visits, they will complete other PRO measures (Skindex-10 Scale, MOS-Sleep 
Scale, 5-D Itch Scale, Patient Global Impression of Worst Itch Severity, and Patient 
Global Impression of Change). 
Patients who are still in the study but miss their last on-treatment dialysis day (Week 8 
for Part A; Week 12 for Part B) due to a competing medical conflict (e.g., hospitalization 
due to ESRD complications) will be allowed to complete the end of study visit if they 
return to the site within 3 days of the scheduled visit.  The end of study visit will 
correspond to a dialysis day.   
Blood samples for inflammatory biomarkers will be collected for all randomized patients 
prior to dialysis on Day 1 and prior to the last dialysis of the Treatment Period.  
For Part A, blood samples for evaluating the PK of CR845 will be collected in up to 
40 patients (approximately 10 patients per treatment group) who have consented for this 
purpose, and will be collected prior to dosing on Day 1, and at pre-specified time points 
after the first dose of study drug.  For Part B, blood samples for evaluating the PK of 
CR845 will be collected by sparse-sampling, using a more limited set of time points than 
in Part A. 
Vital signs and clinical laboratory tests will be monitored periodically, and adverse 
events and concomitant medications will be continuously recorded during the study 
starting at the Screening Visit until the end of the Follow-up Period.  
A final safety Follow-Up Visit will be conducted 7 days (+3) after the last dose of study 
drug. 
A review of the safety data for each part of this study will be conducted on an ongoing 
basis by the Sponsor and an independent Data Monitoring Committee (DMC). 
 


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7.2 
Number of Patients and Sites 
The planned sample size for this clinical investigation is approximately 400 male and 
female hemodialysis patients with persistent moderate-to-severe pruritus (mean baseline 
Worst Itching Intensity NRS score > 4).  
Part A: Approximately 160 male and female hemodialysis patients with 
moderate-to-severe pruritus will be randomized at approximately 40 clinical sites.  For 
Part A, a subset of up to 40 patients (10 per treatment group) will be consented for the 
collection of blood samples for evaluating the PK profile of CR845. 
Part B: Approximately 240 male and female hemodialysis patients with 
moderate-to-severe pruritus will be randomized at approximately 60 clinical sites. 
7.3 
Randomization  
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).  For Part A, patients will be randomized in a 1:1:1:1 ratio to 
receive CR845 1.5 mcg/kg, CR845 1.0 mcg/kg, CR845 0.5 mcg/kg, or placebo.  Patients 
will be stratified according to their use or non-use (i.e., 2 strata will be defined) of 
concomitant medications to treat their itch and their inclusion in the PK sample of 
approximately 10 patients per treatment arm.  For Part B, patients will be randomized in a 
1:1 ratio to receive either CR845 or placebo, with the dose of CR845 determined based 
on safety and efficacy determined in Part A.  Patients enrolled in Part B will also be 
stratified according to their use or non-use of concomitant medications to treat their itch. 
For both Part A and B, patients will be categorized as “using anti-pruritic medications” if 
they have used >1 dose of potentially anti-pruritic medications used to treat their uremic 
pruritus during the week prior to Randomization (e.g. antihistamine (H1), pregabalin, 
gabapentin, nalbuphine, naltrexone, corticosteroids, or buprenorphine).  
7.4 
Blinding 
Patients, Investigators, study staff, and the Sponsor will be blinded to treatment 
assignment.  


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For medically urgent or emergent situations that necessitate knowledge of treatment 
assignment for patient management, the blind may be broken via the IVRS/IWRS.  The 
Medical Monitor must be contacted prior to breaking the blind, whenever possible; 
however, in all cases, the Medical Monitor must be notified within 24 hours of the blind 
being broken.  
7.5 
Endpoints 
7.5.1 
Safety Endpoints 
The safety assessments used to evaluate the overall safety of CR845 include the 
frequency and severity of adverse events by treatment group, physical examination, 
12-lead ECG, vital signs, and clinical safety laboratory evaluations.  
7.5.2 
Pharmacokinetic Endpoints 
For Part A, the PK profile of CR845 will be determined between Week 1 and Week 8, 
and calculation of the accumulation ratio between the first and last doses with respect to 
Cmax and AUC will be reported.  The PK profile from Part A will be used to determine the 
sparse sampling schedule for Part B of the study. 
Details of the PK analysis will be provided in a separate PK analysis plan. 
7.5.3 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be change from baseline with respect to the weekly 
mean of the daily 24-hour Worst Itching Intensity NRS score during Week 8 (Part A) or 
Week 12 (Part B) of the Treatment Period.  
7.5.4 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint will be change from baseline in itch-related 
quality-of-life at the end of Week 8 (Part A) or Week 12 (Part B) as assessed by the total 
Skindex-10 Scale score. 
7.5.5 
Other Efficacy Endpoints 
Itch-related and quality-of-life endpoints include the following: 
Itch intensity: 


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 Change from baseline with respect to the weekly mean of the daily Worst Itching 
Intensity NRS score from Week 2 through the end of the Treatment Period 
(Week 8 for Part A or Week 12 for Part B) 
 Treatment Response, defined as the percent improvement from baseline with 
respect to the weekly mean of the daily Worst Itching Intensity NRS score during 
the last week of the Treatment Period (Week 8 for Part A or Week 12 for Part B) 
Itch-related quality-of-life: 
 Change from baseline in itch-related quality-of-life from Week 2 through the last 
week of the Treatment Period (Week 8 for Part A or Week 12 for Part B) as 
assessed by the total Skindex-10 Scale score 
 Change from baseline in itch-related quality-of-life at the end of the last week of 
the Treatment Period (Week 8 for Part A or Week 12 for Part B), and over each 
week of the Treatment Period within each of the 3 domains of the Skindex-10 
Scale 
 Change from baseline to the end of Week 8 (Part A) or Week 12 (Part B) in 
itch-related quality-of-life, as measured by the 5-D Itch Scale 
 Change from baseline to the end of Week 8 (Part A) or Week 12 (Part B) in 
itch-related sleep disturbance, as measured by the Sleep Disturbance Subscale of 
the MOS Sleep Scale 
 Proportion of patients who rate their itch condition as “Very much improved” or 
“Much Improved”, as measured by the Patient Global Impression of Change at 
the end of the Treatment Period (Week 8 for Part A or Week 12 for Part B) 
 Proportion of patients who have a 1-point improvement or more at Week 2, 4, 8, 
and Week 12 (Part B only), as measured by the Patient Global Impression of 
Worst Itch Severity 
Missed dialysis visits and incidence of infection include the following: 
 Missed dialysis visits based on percentage of patients who missed 1 or more visits 
at the dialysis unit and total number of missed dialysis visits during the Treatment 
Period 
 Incidence of infection based on adverse events, hospitalizations, and/or use of 
antibiotics for treatment of infection related to uremic pruritus 
Inflammatory biomarkers include: 


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 Changes in blood levels of  inflammatory biomarkers, including but not limited to 
hepcidin, interleukin [IL]-2, IL-6, IL-31, pre-albumin and C-reactive protein from 
pre-dose to the end of the Treatment Period (Week 8 for Part A or Week 12 for 
Part B) 
Iron Status and use of Erythropoiesis-stimulating agents and IV iron include: 
 Changes in ferritin and transferrin saturation from pre-dose to the end of the 
Treatment Period (Week 8 for Part A or Week 12 for Part B) 
 Changes in ESAs and/or IV iron dose, and erythropoiesis resistive index from 
pre-dose to the end of the Treatment Period (Week 8 for Part A or Week 12 for 
Part B) 
The baseline value of the primary efficacy endpoint will be calculated using all the 
24-hour Worst Itching Intensity NRS scores reported during the last 7 days prior to 
randomization, including Day 1 scores collected prior to the administration of the first 
dose of double-blind study drug.  The baselines for other PRO measures are the pre-dose 
assessments collected on Day 1.   
7.6 
Duration of Treatment 
For Part A, the duration of treatment for each individual patient is expected to be 
8 weeks, for a total of approximately 24 doses of study drug (3 doses per week) 
administered immediately following each dialysis session.  The overall study duration for 
each individual patient is expected to be up to 11.5 weeks.  
For Part B, the duration of treatment for each individual patient is expected to be 
12 weeks, for a total of approximately 36 doses of study drug (3 doses per week) 
administered immediately following each dialysis session.  The overall study duration for 
each individual patient is expected to be up to 15.5 weeks.  
7.7 
Selection of the Patient Population 
A screening log of potential study candidates will be maintained at each study site. 
Patients will be screened for inclusion in the study before enrollment, randomization, and 
dosing.  All inclusion/exclusion criteria must be met before a patient is enrolled. 


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Rescreening will be considered on an individual subject basis and must first be approved 
by the Sponsor or Medical Monitor. 
The Sponsor reserves the right to grant waivers for certain subjects who may not meet all 
inclusion and exclusion criteria.  Waivers granted must first be approved by the Medical 
Monitor. Documentation of all waivers and rationale will be included in the clinical study 
report. 
7.7.1 
Inclusion Criteria 
To be eligible for inclusion into either Part A or Part B of the study, each patient will 
have to fulfill 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 read, 
complete questionnaires, and understand the study procedures; 
3. 
Males or females 18 years of age or older; 
4. 
ESRD patients who have 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. 
Female patients who are surgically sterile; or amenorrheic for at least 1 year and 
over the age of 55 years; or amenorrheic for at least 1 year, between the ages of 
45 and 55 years, and have a serum follicle-stimulating hormone (FSH) level in 
the post-menopausal range at Screening; or have a negative serum pregnancy 
test at Screening and agree to use acceptable contraceptive measures 
(e.g., hormonal contraceptives, barrier with spermicide, intrauterine device, 
vasectomized partner, or abstinence) from the time of informed consent until the 
safety Follow-Up Visit or at least 7 days after the last dose, whichever is later. 
(Note: If the result from serum pregnancy testing at Screening is indeterminate 
because of possible human chorionic gonadotropin elevation secondary to 
ESRD unrelated to pregnancy, 1 or more serum pregnancy re-tests will be 
performed and reported to the Investigator prior to first dosing with the study 
drug to establish if a negative test result for pregnancy can be confirmed);  
6. 
If male, agrees not to donate sperm after the first dose of study drug until 7 days 
after the last dose, and agrees to use a condom with spermicide or abstain from 
heterosexual intercourse during the study until 7 days after study drug 


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administration. (Note: No restrictions are required for a vasectomized male 
provided his vasectomy has been performed ≥ 4 months prior to dosing); 
7. 
Has a body weight of between 40.0 kg and 135.0 kg, inclusive (dry body 
weight); 
8. 
Patient who self-reports experiencing pruritus during the month prior to 
Screening;  
9. 
If currently using antihistamines (oral, IV, or topical), topical non-drug 
treatments (e.g., emollients, creams, oils), or oral or intravenous corticosteroids 
for itch, the current regimen (i.e., same drug, same dose, same route of 
administration, and same frequency) has been stable for 14 days prior to 
Screening and no change to the regimen is anticipated from Screening through 
the end of the Treatment Period; 
10. If currently using opioids, gabapentin or pregabalin, the current regimen (i.e., 
same drug, same dose, same route of administration, and same frequency) has 
been stable for at least 14 days prior to Screening and no change to the regimen 
is anticipated from Screening through the end of the Treatment Period; 
11. 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; 
12. Patient who self-categorizes on the Patient Self-categorization of Pruritus 
Disease Severity questionnaire as a B or C profile at Screening;  
13. At the end of the Screening Period prior to randomization; 
a. Patient has completed at least 4 Worst Itching Intensity NRS scores out of 
7 possible daily assessments during the last 7 days prior to randomization 
(0-10 NRS scale where 0 = “No itch at all” and 10 = “Worst itching 
imaginable”);  
b. Patient has a mean baseline Worst Itching Intensity NRS score > 4, defined 
as the average of all non-missing scores reported during the last 7 days prior 
to randomization (including scores collected on Day 1, prior to 
randomization). 
7.7.2 
Exclusion Criteria 
A patient will be excluded from either Part A or Part B of the study if any of the 
following criteria are met: 
1. 
Known to be non-compliant with dialysis treatment (i.e., has missed more than 
2 dialysis sessions in the past 2 months because of non-compliance); 
2. 
Anticipated 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 
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4. 
Known or suspected history of Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition-diagnosed alcohol, narcotic, or other drug abuse or 
dependence within 12 months prior to Screening; 
5. 
Patient has any clinically relevant acute or chronic medical or neuropsychiatric 
condition including, but not limited to, severe co-morbid condition such as 
congestive heart failure (New York Heart Association class IV), severe mental 
illness, or cognitive impairment which, in the opinion of the Investigator, would 
pose undue risk to the patient, would impede completion of the study 
procedures, or would compromise the validity of the study measurements; 
6. 
Serum alanine aminotransferase or aspartate aminotransferase greater than 
2.5 times the reference upper limit of normal (ULN), or total bilirubin greater 
than 2 times ULN at Screening; 
7. 
Received another investigational drug within 30 days prior to the start of 
Screening or has planned to participate in another clinical trial while enrolled in 
this study; 
8. 
Has pruritus probably or definitely attributed to a cause other than ESRD or its 
complications (e.g., patients with concomitant pruritic dermatological disease or 
cholestatic liver disease would be excluded).  (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. Anticipated to receive opioid antagonists (e.g., naloxone, naltrexone), or opioid 
mixed agonist-antagonist (e.g., buprenorphine, nalbuphine) from the start of 
Screening through the end of the Treatment Period; 
12. Used Salvia divinorum or Salvinorin A within 30 days prior to the start of 
Screening or is anticipated to use it during the study; 
13. Received ultraviolet B treatment within 30 days prior to the start of Screening 
or anticipated to receive such treatment during the study;  
14. Participated in a previous clinical trial with CR845. 
 
7.8 
Withdrawal of Patients from Therapy or Assessment 
A patient may voluntarily withdraw from the study at any time for any reason without 
prejudice to their future medical care by the physician or at the institution.  The 
Investigator or Sponsor may withdraw the patient at any time for any reason (e.g., in the 
interest of patient safety).  Additional reasons for premature discontinuation of study drug 
may include adverse events and major non-compliance with study procedures as 
described below.  The withdrawal of a patient from study drug by the Investigator should 


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be discussed with the Medical Monitor before the patient stops study drug, whenever 
possible.  
If study drug is discontinued, regardless of the reason, an Early Termination Visit should 
be completed immediately or within no more than 2 to 3 days after the last dose of study 
drug or, if not feasible during that timeframe, then as soon as feasible afterwards.  The 
reason(s) for termination and date of stopping study drug must be recorded on the case 
report form (CRF) and source documents.  Patients prematurely discontinuing study drug 
are required to undergo the final safety Follow-Up Visit, if possible.  Even if this visit is 
missed, adverse events starting within 7 days following the last dose of study drug must 
be reported.  
Although a patient will not be obliged to give a reason for withdrawing prematurely, the 
Investigator is asked to make a reasonable effort to obtain the reason while fully 
respecting the patient’s rights.  The reason for premature discontinuation from the study 
must be recorded in the patient’s source document and on the CRF whenever possible.  
Reasons for patient discontinuation from the study may include but are not limited to: 
 Major protocol violation 
 Adverse event 
 Lack of therapeutic efficacy 
 Patient non-compliance 
 Withdrawal of consent by patient for any or all study procedures 
 Sponsor decision to terminate the study early. 
If a patient withdraws or is withdrawn for more than 1 reason, each reason should be 
documented in the source document.  However, only the primary reason will be captured 
on the CRF. 
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. 
Patients who discontinue after the administration of the first dose of study drug will not 
be replaced. 
7.9 
Contraception, Pregnancy, and Sperm Donation 


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All females are considered to be of childbearing potential unless they are  
 surgically sterile (i.e., 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 or  
 between 45 and 55 years of age and have not had a menstrual period in at least 
1 year and have serum FSH level in the post-menopausal range.  
All women of childbearing potential should be counseled on the need to practice 
adequate birth control once they have consented to participate in the study for the 
duration of the study, from Screening until 7 days after the last treatment, and on the 
importance of avoiding pregnancy. 
Medically acceptable methods of birth control are methods with a low failure rate of less 
than 1% per year, which include hormonal contraceptives for at least 1 cycle of treatment 
before trial enrollment or an intra-uterine device, or double barrier method (male or 
female condom, diaphragm).  
Women should be counseled to contact the Investigator or his/her staff immediately if 
pregnancy is suspected.  Males will be instructed that if their partner becomes pregnant 
during the study this should be reported to the Investigator. 
If a patient becomes pregnant during or after exposure to a study drug received in this 
study within 7 days, 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 pregnancy exposures in the clinical trial.  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 is 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 notification form will be completed. 
Male patients must agree not to donate sperm from study drug administration on Day 1 
until 7 days after dosing, and must agree to use a condom with spermicide or abstain 
from heterosexual intercourse during the study until 7 days after study drug 


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administration.  No restrictions are required for a vasectomized male provided his 
vasectomy has been performed 4 months or more prior to dosing. 
7.10 
Data Monitoring Committee 
An ongoing review of the cumulative safety data for this study will be conducted by an 
external DMC for both Part A and Part B of this study. The DMC will be comprised of 
approximately 3 to 5 voting members with expertise in areas relevant to the clinical 
program. 
This DMC will meet periodically to review safety data as the study progresses and, based 
upon the findings, will make recommendations about the conduct of the study. 
The operation of the DMC will be governed by a charter that will describe the groups’ 
frequency of meeting, procedures (including, but not limited to, periodic safety 
monitoring) and requirements for reporting its observations to the Sponsor. 




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Give patient NRS worksheets 
to take home and collect NRS 
worksheets completed at home 
at each dialysis session for 7 
days. In addition have patient 
complete NRS worksheet at the 
dialysis unit on the day of their 
dialysis (prior or during 
dialysis) until the day the of 
randomization. 
In order to establish a baseline itch intensity, NRS 
worksheets will be completed by the patient daily at home 
on non-dialysis days, and at the dialysis center on dialysis 
days for 7 days prior to randomization and after patient’s 
eligibility to the study has been confirmed.  For consistency, 
patients will be requested to complete the NRS worksheets 
(either at home or in the dialysis unit) at a similar time of 
day around the normal start time of their dialysis.  The 
patient will be instructed to bring the completed worksheets 
from home to the dialysis unit at each dialysis session for 
collection.  It is imperative that worksheets be collected 
from the patients and reviewed by the study staff on the days 
indicated, both to help remind the patients to complete them 
and to provide additional training, if initial returned 
worksheets were not completed according to instructions. 
 
8.2 
Treatment Period 
All questionnaires must be completed in strict adherence to the Patient Reported 
Outcomes Instructions (as per Study Reference Manual).  














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 Obtain blood for central laboratory tests (chemistry and hematology) prior to 
starting dialysis  
 Obtain blood for serum pregnancy test (females of childbearing potential only) 
 Obtain blood for inflammatory biomarker analysis prior to starting dialysis 
 Perform 12-lead ECG prior to dialysis 
 Have the patient complete the last Skindex-10 Scale, MOS Sleep Scale, 5-D Itch 
Scale, and Patient Global Impression of Worst Itch Severity 
 Have the patient complete the Patient Global Impression of Change 
 Record procedural data for dialysis, including ESA and IV iron usage 
 Record adverse events and concomitant medications 
 Measure post-dialysis body weight and record estimated dry weight 
 Record reason for early termination, if applicable. 
 
8.4 
Follow-Up Visit 
The Follow-Up Visit will occur on Day 64 (+3 days) for Part A and Day 92 (+3 days) for 
Part B.  The following procedures/assessments will be performed. 
 Measure vital signs (blood pressure, heart rate, and body temperature) prior to 
starting dialysis  
 Record adverse events and concomitant medications. 
 
8.5 
Unscheduled Visits 
Unscheduled visits may be necessary for outstanding, unresolved adverse events (e.g., 
additional safety laboratory or clinical evaluations).  At minimum, for any unscheduled 
visit, record the reason for the visit, any adverse events reported, and changes to 
concomitant medications.  Additional testing (e.g., laboratory tests, vital signs, ECG, etc.) 
should be performed as clinically indicated.  An unscheduled visit should be used to 
conduct unscheduled procedures during the Follow-Up Visit to follow-up clinically 
significant ECG or laboratory tests observed at the End-of-Treatment Visit.  


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9.0 
Study Drug Administration 
9.1 
Identity of Investigational Product(s) 
Please see the study Pharmacy Manual for full details. 
9.1.1 
Formulation of CR845 and Placebo  
Study drug will be supplied by the Sponsor as a solution in 2 mL glass vials containing 
an extractable volume of 1.3 mL of CR845 at concentrations of 0.05 mg/mL, 
0.10 mg/mL, and 0.15 mg/mL in 0.04M isotonic acetate buffer, pH 4.5.  The composition 
of the CR845 solution contains 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 an 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 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. 
9.1.2 
Packaging, Labeling, and Storage Stability of CR845 and Placebo  
Study drug will be shipped at controlled room temperature (15°C to 30°C).  Temperature 
will be monitored during shipment and verified and recorded in pharmacy log by 
pharmacist upon arrival at the site.  The vials must be stored at controlled room 
temperature (15°C to 30°C) upon receipt. 
For Part A, vials will be packaged (blinded) in boxed kits (also blinded) containing 
27 vials per kit (3 extra vials for backup).  For Part B, vials will be packaged (blinded) in 
boxed kits (also blinded) containing 40 vials per kit (4 extra vials for backup).  Each 
patient will be assigned 1 kit upon randomization.  
Labeling of the vials will include the following: 
 Study protocol number 
 Blinded name of study drug (CR845 or placebo IV solution) 


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 Temperature storage instructions (store at 25◦ C) 
 Space for patient identification number  
 Space for patient initials 
 Extractable volume:  1.3 mL 
 Retest date 
 Name and location of Sponsor 
 Kit number 
 Vial number 
 Administer according to study protocol 
 Caution: New Drug – Limited by Federal Law (United States) to Investigational 
Use 
 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. 
9.2 
Preparation, Blinding, Administration, and Dosage of CR845 and 
Placebo 
Study drug will be administered as an IV bolus via IV push into dialysis venous line (e.g., 
into the venous port) within 15 minutes following the end of dialysis (i.e., return of blood 
to the patient) on scheduled drug administration days (see Schedule of Events, 
Section 18.0).  Following the bolus, the venous line will be flushed with at least 10 mL of 
normal saline.  The patient’s estimated dry weight (i.e., 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 Treatment Period.  
For Part A, the study drug doses (CR845 0.5 mcg/kg, 1 mcg/kg, and 1.5 mcg/kg or 
placebo) will be administered as a single IV bolus 3 times a week post-dialysis for 
8 weeks.  For Part B, CR845 or placebo will be administered as a single IV bolus 3 times 


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a week post-dialysis for 12 weeks, with the dose of study drug determined based on the 
safety and efficacy observed in Part A.  
If a patient misses a dialysis visit, the dose for that day should be withheld and dosing 
should resume at the next dialysis visit.  The Medical Monitor should be contacted if 
more than 2 consecutive doses are missed.  If a dose is missed, it cannot be administered 
on another day. 
The blinded study drug will be dispensed by staff members who have received training 
on study drug handling and administration.   
Information on the study drug preparation, administration, storage, supply, disposition 
and accountability of the study drug can be found in the Pharmacy Manual. 
9.2.1 
Individual Dose Labeling (CR845 and Placebo) 
One syringe will be prepared for each patient.  
Each syringe containing the individual dosing solution will be labeled to include the 
following information: 
 Cara Therapeutics study number 
 Blinded name of study drug (“CR845 or placebo”) 
 Randomization/Subject Number 
 Sponsor name and location 
 Date/time prepared 
 Expiration date/time 
 Caution: New Drug - Limited by Federal Law (United States) to Investigational 
Use 
 Administration according to protocol 
 For Clinical Trial Use Only 
 


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9.2.2 
Selection of Doses Used in the Study 
The combined safety and PK data from the studies CR845-CLIN1003 and 
CR845-CLIN2005 provided the basis for the selection of the doses and dose regimen of 
CR845 to be used in this study.   
In the Phase 2 trial CR845-CLIN2005, the dose of 1 mcg/kg was established as an 
effective anti-pruritic dose in hemodialysis patients with moderate-to-severe pruritus 
when administered after each dialysis over a 2-week period, but the effectiveness of a 
dose range of CR845 was not explored.  In the PK and safety studies CR845-CLIN1003 
and CR845-CLIN2005 Part A, Cara Therapeutics demonstrated that CR845 was safe and 
well-tolerated in hemodialysis patients at dose < 2.5 mcg/kg; therefore, the objective of 
the present study is to assess the efficacy of 2 additional doses of 0.5 and 1.5 mcg/kg of 
CR845, with the goal of comparing the effectiveness and safety of 2 doses bracketing the 
dose shown to be efficacious in the Phase 2 trial CLIN2005 (i.e., 1 mcg/kg).  These doses 
have been shown to be safe and well-tolerated across 2 previous trials in 70 hemodialysis 
patients (Studies CR845-CLIN1003 and CLIN2005) as summarized in the IB1.  
The 0.5 mcg/kg dose has been selected to determine if a dose 50% lower than the 
1 mcg/kg dose provides efficacy.  The intention of studying the 1.5 mcg/kg dose is to 
inform dosing guidance for patients who may not achieve sufficient response at the lower 
doses of CR845.  In hemodialysis patients, somnolence appears to be sporadically 
reported at dose ≥ 2.5 mcg/kg; therefore, a dose of 1.5 mcg/kg was chosen, which is 50% 
above the effective dose determined in the Study CR845-CLIN2005. 
9.3 
Drug Accountability 
All supplies will be maintained under adequate security by the pharmacist or approved 
staff at the investigator site.  At the end of each injection, the used vials will be stored 
until the study monitor performs accountability.  After accountability is performed at the 
end of the study, used vials and remaining unused materials (either CR845 vials or 
placebo vials) will be returned to the study drug distributor as per instruction to be 
provided by the Sponsor in the Pharmacy Manual, and certificates of destruction will be 
provided from the drug distributor to the Sponsor. 


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The site will maintain an adequate record of receipt and distribution of all trial supplies.  
The pharmacist (or qualified staff member), study coordinator and/or Investigator will 
agree not to dispense any trial medication to any person, except study patients. 
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. 
Retention samples of the study drug will be retained by the manufacturer(s) on behalf of 
the Sponsor for 2 years after completion of the study. 


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10.0 
Prior, Concomitant, and Prohibited Medications 
10.1 
Prior and Concomitant Medications 
Prior medications are defined as those that the patient has taken any time during the 
14 days prior to the start of Screening through prior to the first dose of study drug on 
Day 1.  The dose and type of ESAs and IV iron administered at each dialysis visit will 
also be recorded.  Concomitant medications are medications that are taken from after the 
start of the first dose of study drug on Day 1 through the end of the study (i.e., Follow-Up 
Visit).   
All prior and concomitant medications, including over-the-counter medications used by 
patients during this study, are to be recorded in the appropriate source documents at each 
scheduled visit and noted on the appropriate page of the CRF. 
If currently using antihistamines (oral, IV, or topical), topical non-drug treatments (e.g., 
emollients, creams, oils) or oral or intravenous corticosteroids for itch, the current 
regimen (i.e., same drug, same dose, same route of administration, and same frequency) 
has been stable for 14 days prior to Screening and no change to the regimen is anticipated 
from Screening through the end of the Treatment Period. 
If currently using opioids, gabapentin or pregabalin, the current regimen (i.e., same drug, 
same dose, same route of administration, and same frequency) has been stable for at least 
14 days prior to Screening and no change to the regimen is anticipated from Screening 
through the end of the Treatment Period. 
10.2 
Restricted and Prohibited Medications 
Restricted and prohibited medications are presented in the table below: 
 
 


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Drug, Drug Class, or Treatment 
Restrictions Prior to 
Screening Period 
Restrictions During 
Study 
Investigational drug (other than the 
study drug) 
Not allowed within 
30 days prior to the start 
of Screening  
Not allowed 
Ultraviolet light-B treatments 
Not allowed within 
30 days prior to the start 
of Screening  
Not allowed 
Salvia divinorum and Salvinorin A 
Not allowed within 
30 days prior to the start 
of Screening  
Not allowed 
Naloxone, naltrexone, or mixed 
agonist-antagonists (e.g., 
buprenorphine and nalbuphine) 
Allowed 
Not allowed from the 
start of Screening to the 
end of Treatment Period 
Antihistamines (oral, IV, or topical) 
Allowed 
Allowed, but changes to 
current regimen should 
be avoided (i.e., same 
drug, same dose, same 
route of administration, 
and same frequency) 
from Screening to the 
end of Treatment Period  
No new medication to 
treat itch should be 
initiated. 
Topical, non-drug treatments for 
pruritus (e.g., emollients, creams, 
oils) 
Opioids   
Gabapentin, pregabalin  
Not allowed if newly 
started within 14 days 
prior to Screening or if 
dose change anticipated 
from Screening through 
the end of Treatment 
Period 
Allowed, but changes to 
current regimen should 
be avoided (i.e., same 
drug, same dose, same 
route of administration, 
and same frequency) 
from Screening to the 
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11.0 
Assessments 
11.1 
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 
 MOS Sleep Scale 
 5-D Itch Scale  
 Patient Global Impression of Change 
 Patient Global Impression of Worst Itch Severity 
Patients will be trained on completion of the Worst Itching Intensity NRS scale at the 
first Screening Visit before the Worst Itching Intensity baseline NRS measurements for 
eligibility are collected, and will be trained on all other PRO measures during the week 
prior to randomization or prior to randomization on Day 1 of the Treatment Period. All 
questionnaires must be completed in strict adherence to the Patient Reported Outcomes 
Instructions (as per Study Reference Manual).  
11.1.1 
Worst Itching Intensity Numerical Rating Scale 
Intensity of itch will be measured using a NRS scale (Appendix III, Section 18.3) on a 
worksheet in 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 non-dialysis days.   
The Worst Itching Intensity NRS has been widely utilized for evaluation of chronic itch, 
including, uremic pruritus2,3,6,7. 
11.1.2 
Patient Self-categorization of Pruritus Disease Severity 
Patients will be asked to complete the Patient Self-categorization of Pruritus Disease 
Severity questionnaire (see Appendix IV, Section 18.4) at Screening only.  Using this 
questionnaire, patients will select 1 of 3 patient profiles (labeled A, B or C) that most 
closely resembles their own profile, with profile A being the least affected by itch and 


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profile C being the most affected by itch.  To qualify for inclusion in the study, patients 
must have classified themselves as having a Patient B or Patient C profile. 
The Patient Self-categorization of Pruritus Disease Severity questionnaire was tested 
previously in a longitudinal study of uremic pruritus and found to correlate with both itch 
intensity as well as instruments evaluating quality-of-life6.  
11.1.3 
Skindex-10 Scale 
Developed specifically for uremic pruritus, the Skindex-10 Scale (Appendix V, 
Section 18.5) is an instrument for measurement of quality-of-life6.  Patients are asked to 
fill in 1 of 7 circles numbered from 0 (labeled with the anchor phrase “never bothered”) 
to 6 (labeled as “always bothered”) for each of the 10 questions.  The total score is the 
sum of the numeric value of each answered question.  The total score is subdivided into 
3 domain scores, which are sums of the scores of the following questions: disease domain 
(questions 1 to 3), mood/emotional distress domain (questions 4 to 6), and social 
functioning domain (questions 7 to 10). 
The Skindex-10 Scale was found to correlate with both itch intensity as well as other 
instruments evaluating quality-of-life in patients with uremic pruritus6. 
11.1.4 
MOS Sleep Scale 
The MOS Sleep Scale (Appendix VI, Section 18.6) was developed by the Medical 
Outcomes Study sleep survey in order to measure sleep disturbance8.  For most questions, 
the scale instructs patients to circle 1 of 6 numbers, ranging from 1 (labeled with the 
anchor phrase “all of the time”) to 6 (labeled “none of the time”), indicating the 
frequency of various aspects of pruritus-related sleep disruption over the preceding week.  
Patients are also provided instructions to estimate the average amount of sleep per night 
during the past week.  The 9-item Sleep Problem Index II, the 6-item Sleep Problem 
Index-I, and the 4-item Sleep Disturbance subscales will be calculated. 
11.1.5 
5-D Itch Scale 
The 5-D Itch Scale was developed as a brief but multidimensional questionnaire designed 
to be useful as an outcome measure in clinical trials.  The 5 dimensions of itch being 
assessed are degree, duration, direction, disability and distribution (Appendix VII, 


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Section 18.7).  The scale has been validated in patients with chronic pruritus and has been 
shown to be sensitive to changes in pruritus over time9.   
11.1.6 
Patient Global Impression of Worst Itch Severity 
The Patient Global Impression of Worst Itch Severity is a PRO measure that assesses itch 
severity10.  The scale has only 1 item, with 5 possible values ranging from none to very 
severe (Appendix VIII, Section 18.8).   
11.1.7 
Patient Global Impression of Change 
The Patient Global Impression of Change is a global PRO measure that assesses the 
change (improvement or worsening) in overall status relative to the start of the study11.  
The scale has only 1 item, with values ranging from 1 (Very Much Improved) to 7 (Very 
Much Worse) (Appendix IX, Section 18.9).   
11.2 
Safety Assessments 
The safety assessments for each patient are the following: 
 Incidence and severity of adverse events  
 Physical examination 
 Vital signs  
 12-lead ECG 
 Clinical laboratory tests 
These safety assessments may be performed at time point(s) other than those listed below 
as described in Section 8.5, Unscheduled Visits.  
11.2.1 
Physical Examination 
Physical examinations will include, at minimum, an examination of the heart, lungs, 
abdomen, extremities, neurological system, and vascular system.  Clinically significant 
abnormalities prior to signature of the ICF will be reported as medical history and 
clinically significant new or worsening findings observed after the signature of the ICF 
will be reported as adverse events.  


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11.2.2 
Vital Signs 
Vital signs include sitting or semi-recumbent (for at least 3 minutes) body temperature, 
heart rate, and blood pressure.   
Measurements will be repeated if a value is out of the reference range due to a technical 
issue, considered abnormal for the patient, or for other medical concerns.  All values will 
then be recorded. 
In the event of a clinically significant change in blood pressure and/or heart rate, the 
Investigator and dialysis staff should evaluate and manage the patient per standard 
dialysis unit practices with knowledge of the patient’s typical blood pressure and heart 
rate excursions.   
11.2.3 
Electrocardiogram 
The 12-lead ECGs will be obtained and read locally by the Investigator or qualified 
physician designee.  Clinically significant abnormalities or worsening findings observed 
after the first dose of study drug will be reported as treatment-emergent adverse events 
(TEAEs).  
11.2.4 
Clinical Laboratory Tests 
The following clinical laboratory tests will be performed and will be analyzed by 1 of the 
central laboratories.  Processing and shipment of central laboratory samples will be 
described in the Laboratory Manual.  
Hematology: 
Hemoglobin, hematocrit, platelet count, white blood 
cell count (including differential) 
Serum chemistry: 
Total bilirubin, direct bilirubin (if total bilirubin is 
outside the ULN) and alkaline phosphatase, alanine 
transaminase, aspartate aminotransferase, glucose 
(non-fasting), blood urea nitrogen, creatinine, 
albumin, and electrolytes (sodium, potassium, 
chloride, calcium and phosphorus). Parathyroid 
hormone, pre-albumin, ferritin, and transferrin 
saturation on Day 1, 29, 43, and 57 for Part A, and 
Day 1, 29, 43, 57, and 85 for Part B.  
Serum pregnancy: 
Women of childbearing potential only 


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Follicle stimulating 
hormone: 
Women who have been amenorrheic for at least 1 year and 
are between 45 and 55 years of age to confirm that they are 
not of childbearing potential 
11.3 
Adverse Events 
11.3.1 
Definition of Adverse Events  
The period of adverse event reporting will start after the signing of the ICF through the 
study follow-up visit or early termination visit (or 7 days after the last dose if no early 
termination visit was conducted). 
All adverse events that occur during this reporting period will be collected for all 
patients, including patients who are deemed to be a screen failure (i.e., patient did not 
meet the eligibility criteria) and will not be randomized into the study after signing of the 
ICF. Adverse events will be classified as TEAE or non-TEAE based on the time of 
occurrence in relation to the first dose of study drug.  
A TEAE can be any unfavorable and unintended sign (e.g., including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study 
drug, whether or not it is considered to be study drug related.  A TEAE also includes any 
worsening (i.e., any clinically significant change in frequency and/or intensity) of a 
pre-existing condition that is temporally associated with the use of the study drug.  A 
pre-existing condition is a condition that is present prior to signing an ICF, which has 
been recorded as medical history.  A worsening of a pre-existing condition should be 
captured as an adverse event if the frequency, intensity, or character of the condition 
worsens after the use of study drug as judged by the Investigator (i.e., to a clinically 
significant extent).   
Treatment-emergent adverse events will be therefore defined as those events which 
 Start any time after the first dose of study drug up to the follow-up visit or early 
termination visit (or 7 days after the last dose if no early termination visit was 
conducted), whichever is later.  
 Increase in frequency or severity any time after the first dose of study drug up to 
the follow-up visit or early termination visit (or 7 days after the last dose if no 
early termination visit was conducted), whichever is later. 


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Clinically significant abnormalities prior to signing the ICF will be reported as medical 
history, unless they are expected findings from medical history that have already been 
reported.  Any new or significantly worsened clinically significant abnormalities 
occurring after the patient signs informed consent should be entered as adverse events.   
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states should also be 
recorded.  In order to avoid vague, ambiguous, or colloquial expressions, adverse events 
should be recorded in standard medical terminology rather than the patient’s own words.  
Signs and symptoms should be reported individually unless, in the judgment of the 
Investigator, they can be grouped under a widely accepted inclusive term (e.g., 
gastroenteritis in lieu of abdominal pain, nausea, vomiting, and diarrhea). 
Following signature of the ICF, any adverse event that results in hospitalization or 
prolonged hospitalization should be reported as an SAE as described below.  
Overdose is defined as an accidental or intentional exposure to study drug at a dose 
higher than specified in the protocol or higher than known therapeutic dose.  An overdose 
of study drug must be reported as a major protocol deviation.  If the overdose is 
associated with clinical signs or symptoms, then these should be captured as adverse 
events. 
11.3.2 
Adverse Event Intensity Assessment 
The Investigator will assess the intensity of each adverse event reported during the study.  
The assessment will be based on the Investigator’s clinical judgment.  The intensity of 
each adverse event should be assigned to 1 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 
 


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11.3.3 
Definition of Serious Adverse Events 
An SAE is any adverse event occurring at any dose and regardless of causality that: 
 Results in death 
 Is life-threatening.  Life-threatening means that the patient was at immediate risk 
of death from the reaction as it occurred (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form).  
For example, drug-induced hepatitis that resolved without evidence of hepatic 
failure would not be considered life-threatening even though drug-induced 
hepatitis can be fatal.   
 Requires in-patient hospitalization (hospital admission, not an emergency room 
visit) or prolongation of existing hospitalization.  Hospitalization admissions 
and/or surgical operations scheduled to occur during the study period, but planned 
prior to study entry (i.e., prior to signing of the informed consent) are not 
considered adverse events if the illness or disease existed before the patient was 
enrolled in the study, provided that it did not deteriorate in an unexpected manner 
during the study (e.g., surgery performed earlier than planned).  For example, for 
patients on the transplant waiting list prior to study entry, a renal transplant would 
not be considered an SAE.  If complications occur as a result of transplant 
surgery, these complications will need to be evaluated for SAE criteria.  
 Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a patients’ ability to conduct normal life functions 
 Is a congenital anomaly/birth defect 
 Is an important medical event.  An important medical event is an event that may 
not result in death, be life threatening, or require hospitalization but may be 
considered an SAE when, based upon appropriate medical judgment, it may 
jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions for SAEs. 
Severe versus serious adverse events: An adverse event that is assessed as severe should 
not be confused with an SAE.  Severity is a category utilized for rating the intensity of an 
event; and both adverse events and SAEs can be assessed as severe. The term “severe” is 


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often 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).  This 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. 
11.3.4 
Adverse Event Causality or Relatedness to the Study Drug 
Every effort should be made by the Investigator to try to explain each adverse event and 
assess its relationship, if any, to the study drug.  The temporal relationship of the event to 
study drug administration should be considered in the causality assessment (i.e., if the 
event starts soon after study drug administration and resolves when the study drug is 
stopped).  The Investigator should not assume that any adverse event is necessarily 
drug-related, but should complete a thorough and diligent medical workup to investigate 
any other possible medical causes of the adverse event. 
Adverse events will be classified by the Investigator as follows: 
Definitely Related 
There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out.  The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals.  The event resolves or improves upon 
withdrawal of drug (dechallenge).  The event would be considered as definitely related to 
the study drug upon results of a positive rechallenge procedure. 
Probably Related 
There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely.  The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time sequence to administration of the drug, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable 
response on withdrawal (dechallenge), if dechallenge was done.  


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Possibly Related 
There is some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of the trial medication).  However, the influence of 
other factors may have contributed to the event (e.g., the patient’s clinical condition, 
other concurrent disease, concomitant medications or events).  Although an adverse drug 
reaction may be classified only as “possible” soon after discovery, it can be flagged as 
requiring more information, and later be upgraded to “probably related” or “definitely 
related”, if appropriate. 
Unlikely Related 
A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) 
and in which other drugs or concurrent or underlying disease provide plausible 
explanations (e.g., the patient’s clinical condition, other concomitant treatments). 
Not related 
The adverse event is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology.  There must be an 
alternative, definitive etiology documented by the clinician. 
11.3.5 
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 CRF from the 
time the patient signs the ICF and until the Follow-Up Visit/early termination (or 7 days 
after the last dose if no early termination visit was conducted), whichever is later, 
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 associated with the use 
of study drug. 
Each adverse event is to be documented with verbatim term, start and stop date and time, 
intensity, causal relationship with the study drug, action taken with study drug and 
outcome (resolved, resolved with sequelae, resolving, fatal, unknown).  The Investigator 


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must review new adverse events and the outcome of ongoing adverse events frequently 
throughout the study.  
All SAEs will be documented on the SAE form.   
The reporting period for all adverse events begins with the signature of the ICF and ends 
at the study Follow-Up Visit or 7 days following the last dose of study drug, whichever is 
later.  All AEs should be followed until they resolve or the Investigator assesses them as 
stable or the subject’s participation in the trial ends, whichever comes first. .  In addition, 
all assessed by the Investigator as definitely or possibly or probably related to the study 
medication that are ongoing at the time of the patient’s last visit, should continue to be 
followed even after the subject's participation in the trial is over. Such events should be 
followed until they resolve or until the Investigator assesses them as “stable.” Resolution 
of such events is to be documented on the appropriate CRF. 
SAEs that occur after the Follow-Up Visit and up to 30 days thereafter should also be 
documented on an SAE form if they are deemed by the Investigator to be “definitely 
related”, “probably related”, or “possibly related” to the study drug.  SAEs that occur 
after the Follow-up Visit and up to 30 days thereafter do not need to be documented on 
an SAE form if they are deemed by the Investigator to be “unlikely related” or “not 
related” to study drug. 
11.3.6 
Serious Adverse Event Notification, Documentation, and 
Reporting 
The Investigator will immediately notify the Medical Monitor/Sponsor by telephone of 
any patient deaths or life-threatening events, whether related or unrelated to the study 
drug.  
The Investigator will notify the Medical Monitor/Sponsor within 24 hours regarding any 
SAEs other than death and immediately life-threatening events, regardless of relationship 
to study drug.  
The Investigator will also complete an SAE Report form (according to SAE and 
Pregnancy Report Form Completion Guidance) and will email or fax it within 24 hoursto 
Biorasi Drug Safety and Pharmacovigilance for case processing as defined in the Safety 
Management Plan: 


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E-mail: safety@biorasi.com 
Fax: +1 (786) 221-3531 
SAE report form will be completed regardless of relationship to the study drug.  
In the event of any SAE (other than death) occurring after the last treatment day 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 Investigator will not delay reporting anSAE (following the directions above) 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. 
The Medical Monitor or designee may contact Biorasi Drug Safety and 
Pharmacovigilance for further information or clarification on the reported SAE.  Biorasi 
Drug Safety and Pharmacovigilance will then contact the Investigator to obtain further 
information or clarification, or any other requested supporting documentation and will 
forward any information received to the Medical Monitor. In some instances, the Medical 
Monitor may contact the PI directly for further information. 
The name and contact information for the Medical Monitor is: 
Sarbani Bhaduri, MD 
Telephone: (415) 613-6514 
Email: sbhaduri@caratherapeutics.com 
 
Alternate contact will be provided in the Safety Management Plan.  
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 Institutional Review Board (IRB).   
It is the responsibility of Cara Therapeutics to send all regulatory reports to the FDA.  
Adverse events that are serious and related to the study drug and unexpected will be 
reported to the regulatory authorities 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. 


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For regulatory reporting purposes, Cara Therapeutics can upgrade the Investigator’s 
assessment (e.g., 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 the drug and the event, then the relationship should be considered drug related. 
If applicable, the Sponsor will also notify other participating Investigator(s) of all IND 
Safety Reports to ensure prompt notification of significant new adverse effects or risks 
with respect to the drug.  This notification will occur as soon as possible and in 
compliance with country-specific regulations. 
Further details about SAE reporting and processing will be provided in a Safety 
Management Plan. 
11.4 
Pharmacokinetic Evaluation 
For PK analysis, in the subset of patients who consented to participate in the PK analysis, 
blood samples will be collected from the predialyzer (arterial) line at the time points 
listed in the Pharmacokinetic Sampling Schedule (Appendix II, Section 18.2).  The actual 
time of collection will be recorded.  Plasma samples will be analyzed for CR845 using 
liquid chromatography with tandem mass spectrometric detection according to validated 
analytical methods.  Full details of the methodology and results for bioanalytical and PK 
analysis will be presented in separate reports, which will be appended to the clinical 
study report.  
Detailed instructions for PK sample collection and processing will be provided in the lab 
manual.  
11.5 
Inflammatory Biomarker Evaluation 
Inflammatory biomarkers will include hepcidin, IL-2, IL-6, IL-31, and C-reactive protein.  
Additional biomarkers of interest may be evaluated and will be identified in the 
Statistical Analysis Plan and laboratory manual, as applicable.  A blood sample of 
sufficient volume to provide for replicate assays of each biomarker, as specified by the 
laboratory performing the analysis, will be collected prior to dialysis on Day 1 and at the 
end of the Treatment Period.  If the patient misses the last visit of the Treatment Period, 


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the sample may be collected at their next dialysis visit for the same week.  The actual 
time of sample collection will be recorded. 
Detailed instructions for biomarker sample collection and processing will be provided in 
the lab manual.  


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12.0 
Statistical Methods 
12.1 
General Considerations 
A statistical analysis plan (SAP) will be developed based on the latest version of the 
clinical protocol and CRFs and finalized prior to unblinding of the study.  No database 
may be locked, or analyses completed until the SAP has been approved. 
The SAP will provide a detailed description for the handling of missing data, patient 
eligibility criteria for the analysis, and statistical methodology for the data summary and 
analysis of safety and efficacy variables.  This protocol describes key analyses as 
currently contemplated.  If differences occur between analyses described in the SAP and 
the current protocol, those found in the SAP will assume primacy. 
Unless otherwise noted, continuous variables will be summarized using number of 
non-missing observations, mean, standard deviation, median, minimum, and maximum; 
categorical variables will be summarized using the frequency count and the percentage of 
patients in each category.  In addition to the descriptive summaries, pertinent data listings 
will be provided to facilitate case studies.  
All analyses will be performed using SAS® version 9.2 or higher, unless otherwise 
specified. 
12.2 
Determination of Sample Size 
Part A: Approximately 160 male and female hemodialysis patients with 
moderate-to-severe pruritus will be randomized at approximately 40 clinical sites.  A 
subset of up to 40 patients (approximately 10 per treatment group) will be consented for 
the collection of blood samples for evaluating the PK profile of CR845.  No formal 
sample size calculation was performed to select this sample size.  However, a sample size 
of 40 patients per group is adequate to provide an appropriate estimate of the magnitude 
and variability of treatment effect at each dose, and select the appropriate dose to be 
further evaluated compared to placebo in Part B. 
Part B: Approximately 240 male and female hemodialysis patients with 
moderate-to-severe pruritus will be randomized at approximately 60 clinical sites. 


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12.5 
Statistical Summary and Analysis 
12.5.1 
Patient Disposition 
The number of patients randomized, completed, or discontinued from the study, along 
with the reason for discontinuation, will be presented overall and by treatment group.  
Patient count by analysis population will also be tabulated. 
12.5.2 
Protocol Deviations 
Protocol deviations or violations will be identified in several ways: through 
programmatic checks, through medical reviews, and by CRAs during site monitoring.  
They will be classified as minor or major prior to the database lock.  Major protocol 
deviations/violations will be summarized by treatment group.  All protocol deviations 
will be listed.   
12.5.3 
Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by treatment group. 
12.6 
Efficacy Analysis 
12.6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the change from baseline to the last week of 
the Treatment Period (Week 8 for Part A, and Week 12 for Part B) with respect to the 
weekly mean of the daily 24-hour Worst Itching Intensity NRS score.  The weekly mean 
of the 24-hour Worst Itching Intensity NRS score will be defined as the sum of the daily 
Worst Itching Intensity NRS score reported during a specific week (Days 2-8; 
Days  9-15; Days 16–22; etc.) divided by the number of days with non-missing scores for 
that week.  If the daily worst itching score is missing for > 3 days during a specific week, 
the corresponding weekly mean worst itching score will be set to missing.  The baseline 
score will be defined as the average of the daily worst itching scores over the last 7 days 
prior to randomization, including pre-treatment assessments collected on Day 1.  
The primary efficacy variable will be analyzed using a mixed effects model with repeated 
measures (MMRM).  The model will contain treatment, week, and treatment-by-week 
interaction as fixed effects; baseline as a covariate, and patient as a random effect.  The 
baseline score will be defined as the mean of the 24-hour worst itching score over the last 


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7 days prior to randomization, including pre-treatment assessments collected on Day 1.  
For each dose group (Part A) or for the selected dose of CR845 (Part B), the treatment 
group difference versus placebo will be estimated as the simple contrast in the treatment 
effect on the last week of treatment.   
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 
autoregressive [1], or compound symmetry) will be examined.  The Akaike information 
criterion will be used to determine the appropriate covariance matrix for the MMRM 
model.  The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom.  
In the primary efficacy analysis (both Part A and Part B), missing daily worst itching 
scores will not be imputed.  Assuming that the data are missing at random (MAR), the 
estimates of the treatment differences calculated from the MMRM model described 
above are unbiased.  
Sensitivity analyses will be conducted to evaluate the effect of the MAR assumption on 
the study results for Part B as described below.  Depending on the pattern and the amount 
of early treatment discontinuations in Part A, similar sensitivity analyses may also be 
performed for Part A in order to provide estimates of treatment effect under different 
imputation algorithms and help refine the sample size for Part B. 
Sensitivity analysis 1 (Multiple Imputation; MAR): 
This sensitivity analysis assumes that patients with missing data follow the same model 
as other patients in their respective treatment arm that have complete data. 
 Intermittent missing data 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.   
 Data missing after patients discontinue treatment early will then be multiply 
imputed with the SAS MI procedure using a method appropriate for monotone 
missingness (e.g., regression statement).  


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 Results of the MMRM on the multiply imputed data sets will be summarized by 
the SAS MIANALYZE procedure.  
Sensitivity analysis 2 (Multiple Imputation; Missing Not at Random): 
This sensitivity analysis is an implementation of a pattern mixture model that uses control 
data for pattern imputation12.  The authors also provide appropriate SAS code.  It assumes 
that patients who discontinue early in any of the 3 active treatment groups will have the 
same evolution, after treatment is stopped, as patients in the placebo group (who are not 
exposed to active treatment, by definition).  Patients who discontinue treatment early in 
the placebo group are assumed to behave as the placebo patients that remain in the study.  
 Intermittent missing data will first be imputed using the MCMC method 
implemented with the SAS MI procedure, which is appropriate for non-monotonic 
missing data.   
 Data missing after patients discontinue treatment early will be multiply imputed 
using multiple calls of the SAS MI procedure.  At each time point, missing data 
will be imputed using data from patients in the placebo group that have complete 
data at that time.  
 Results of the MMRM on the multiply imputed data sets will be summarized by 
the SAS MIANALYZE procedure. 
Sensitivity Analysis 3 (Single Imputation; Hybrid Baseline Observation Carried 
Forward/Last Observation Carried Forward): 
 Intermittent missing data will not be imputed. 
 For patients who discontinued study drug due to adverse events, data missing 
after discontinuation will be imputed using the baseline value of the daily worst 
itching score. 
 For patients who discontinue due to reasons other than adverse event, missing 
data will be imputed using the last observation carried forward. 


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12.6.2 
Secondary Efficacy Endpoint 
The secondary efficacy variable is the change from baseline in the (total) Skindex-10 
Scale score.  An MMRM, similar to that used for the primary efficacy analysis, will be 
fitted to the data.  The baseline value will be defined as the value of the Skindex-10 Scale 
score collected on Day 1, prior to randomization.  For each dose group, the treatment 
group difference versus placebo will be estimated as the simple contrast in the treatment 
effect at Week 8 (Part A) or Week 12 (Part B). 
Missing Skindex-10 Scale scores will not be imputed.  Assuming that the data are MAR, 
the estimates of the treatment differences calculated from the MMRM models above are 
unbiased. 
12.6.3 
Hypothesis Testing Strategy 
PART A 
The primary goal for Part A of this clinical investigation is to evaluate the efficacy of 
different dose levels of IV CR845 administered after each dialysis session in reducing the 
intensity of itch over an 8-week Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus.  Three doses will be studied (1.5 mcg/kg, 1.0 mcg/kg, and 
0.5 mcg/kg), and each will be compared against placebo.  One of these doses will be 
selected for further evaluation compared to placebo in Part B.  Although a hypothesis test 
of each CR845 dose against placebo will be performed for each of the primary, secondary 
and exploratory variables, these hypothesis tests are not expected to be statistically 
significant based on the planned sample size of approximately 40 patients per treatment 
group and effect size data from previous studies of CR845 in the same population.  
Nevertheless, the estimates of treatment effect and p-values resulting from these 
hypothesis tests will be used, in addition to a review of safety data, to select the most 
appropriate dose for Part B.  A sample size of 40 patients per group is adequate to 
provide an appropriate estimate of the magnitude and variability of treatment effect at 
each dose. 
PART B 
Each hypothesis test will be 2-sided and conducted at the 5% significance level.  The 
study will be considered positive if the null hypothesis of no treatment difference is 
rejected in favor of the alternative that patients randomized to CR845 experience 


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significantly less itching as measured by the change from baseline to Week 12 of the 
Treatment Period with respect to the weekly mean of the 24-hour Worst Itching Intensity 
NRS score.   
12.6.4 
Other Efficacy Endpoints 
12.6.4.1 
Itch Intensity Measures 
 Change from baseline with respect to the weekly mean of the 24-hour Worst 
Itching Intensity NRS score from Week 2 through the end of the Treatment Period 
(Week 8 for Part A or Week 12 for Part B).  Treatment differences with respect to 
this variable will be evaluated using the same MMRM model fitted for the 
primary efficacy analysis. 
 Treatment Response defined as the percent improvement from baseline with 
respect to the weekly mean of the 24-hour Worst Itching Intensity NRS score 
during the last week of the Treatment Period (Week 8 for Part A or Week 12 for 
Part B):  
If a patient’s mean daily itch score during the last week of the Treatment Period is 
greater than their baseline score (i.e., the patient has an increase in itch compared 
to baseline), his/her response to treatment will be assigned a value of 0.  The 
treatment response for patients who discontinue treatment early will be estimated 
depending on the reason for discontinuation.  For patients who discontinue due to 
their underlying condition (i.e., non-treatment related adverse event), the 
treatment response will be estimated by carrying forward the last non-missing 
weekly mean worst itch score.  Patients who discontinue due to any other reason 
will be considered non-responders and will be assigned a treatment response 
value of 0.   
A graph of percentage of patients who have a treatment response  10%,  20%, 
 30%,  40%,  50%,  60%,  70%,  80%,  90%, and  100% will be 
presented.  In addition, the proportion of patients with a response to treatment that 
is ≥ 20% will be analyzed using logistic regression, including treatment and 
baseline itch score as independent variables.  The cutoff of 20% was shown to be 
clinically significant in a longitudinal study of uremic pruritus in hemodialysis 
patients6 .  This analysis may be repeated for other cutoffs. 


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12.6.4.2 
Itch-Related Quality-of-Life Measures 
 Change from baseline in itch-related quality-of-life from Week 2 through the last 
week of the Treatment Period (Week 8 for Part A or Week 12 for Part B) as 
assessed by the total Skindex-10 Scale scores.  Treatment differences will be 
evaluated using the same MMRM model fitted for the analysis of the change from 
baseline in the overall Skindex-10 Scale score (secondary efficacy endpoint). 
 Change from baseline in itch-related quality-of-life at the end of the last week of 
the Treatment Period (Week 8 for Part A or Week 12 for Part B), and over each 
week of the Treatment Period within each of the 3 domains of the Skindex-10 
Scale.  Treatment differences with respect to each domain will be evaluated using 
the same MMRM model fitted for the analysis of the change from baseline in the 
overall Skindex-10 Scale score (secondary efficacy endpoint). 
 Change from baseline to the end of Week 8 (Part A) or Week 12 (Part B) in itch 
related quality-of-life, as measured by the 5-D Itch Scale.  An MMRM, similar to 
the one used for the primary efficacy analysis, will be fitted to the data.  In Part A, 
the model will contain treatment (4 levels: 0.5 mcg/kg; 1.0 mcg/kg; 1.5 mcg/kg or 
placebo), week, and treatment by week interaction as fixed effects; baseline as a 
covariate; and patient as a random effect.  The baseline value will be defined as 
the value of the 5-D Itch Scale score collected on Day 1, prior to randomization.  
In Part B, the model will be similar except that there will only be 2 levels for 
treatment (CR845 and placebo).  For each dose group, the treatment group 
difference versus placebo will be estimated as the simple contrast in the treatment 
effect at Week 8 (Part A) or Week 12 (Part B). 
 Change from baseline to the end of Week 8 (Part A) or Week 12 (Part B) in itch 
related sleep disturbance, as measured by the Sleep Disturbance Subscale of the 
MOS Sleep Scale.  An MMRM, similar to the one used for the primary efficacy 
analysis, will be fitted to the data.  In Part A, the model will contain treatment 
(4 levels: 0.5 mcg/kg; 1.0 mcg/kg; 1.5 mcg/kg or placebo), week, and treatment 
by week interaction as fixed effects; baseline as a covariate; and patient as a 
random effect.  The baseline value will be defined as the value of the Sleep 
Disturbance Subscale score collected on Day 1, prior to randomization.  In Part B, 
the model will be similar except that there will only be 2 levels for treatment 


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(CR845 and placebo).  For each pairwise comparison against placebo, the 
treatment group difference will be estimated as the simple contrast at Week 8 
(Part A) or Week 12 (Part B). 
 Proportion of patients who rate their itch condition as “Very Much Improved” or 
“Much Improved”, as measured by the Patient Global Impression of Change at 
the end of the Treatment Period (Week 8 for Part A or Week 12 for Part B): 
Pairwise treatment differences with respect to this variable will be tested using the 
Fisher’s exact test.  
 The number and percentage of patients in each of the 5 categories of the Patient 
Global Impression of Worst Itch Severity at baseline, Weeks 2, 4, and 8 (Part A), 
or baseline, Weeks 2, 4, 8, and 12 (Part B), will be tabulated.  In addition, the 
proportion of patients who have a 1-point improvement or more at Week 2, 4, 8, 
and Week 12 (Part B only), as measured by the Patient Global Impression of 
Worst Itch Severity.  Pairwise treatment differences with respect to this variable 
will be tested using the Fisher’s exact test.   
12.6.4.3 
Missed Dialysis Visits and Incidence of Infection  
 Missed dialysis visits based on percentage of patients who missed 1 or more visits 
at the dialysis unit and total number of missed dialysis visits during the Treatment 
Period.  Statistical analyses will be defined in the SAP. 
 Incidence of infections based on adverse events, hospitalizations, and/or use of 
antibiotics for treatment of infection related to uremic pruritus.  The rate of 
infections will be analyzed using logistic regression.  Baseline factors known to 
be correlated to the risk of infection in hemodialysis patients may be included in 
the analysis.   
12.6.4.4 
Inflammatory Biomarkers, ESA, and IV Iron Use 
 Changes in inflammatory biomarkers (e.g., hepcidin, IL-2, IL-6, IL-31, C-reactive 
protein) from pre-dose to the end of the Treatment Period.  Statistical analyses 
will be defined in the SAP. 


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 Changes in ESAs, IV iron dose, and erythropoiesis resistive index from pre-dose 
to the end of the Treatment Period.  Statistical analyses will be defined in the 
SAP. 
12.6.5 
Additional Statistical Considerations 
Part A: 
For each analysis variable (primary, secondary, exploratory), all pairwise comparisons 
against placebo will be evaluated.  Pairwise comparisons between each dose will be 
conducted but will be considered secondary.  There will be no adjustments for 
multiplicity.   
A dose-response analysis of the primary and secondary variable will also be conducted.  
In this case, the null hypothesis of no dose response will be tested against the 1-sided 
alternative that the treatment effect increases linearly with dose.  A dose-response 
analysis of the exploratory variables may be considered.  Further details will be included 
in the SAP.   
In addition, an analysis of all CR845 doses combined against placebo will be performed 
with respect to the primary and secondary variables.  An analysis of all CR845 doses 
combined versus placebo with respect to the exploratory variables may be considered. 
Further details will be included in the SAP.   
Part B: 
In Part B, only 1 dose will be evaluated against placebo.  As defined in the previous 
section, Part B will be considered positive if the primary efficacy analysis rejects the null 
hypothesis of no treatment difference.  There will be no adjustment for multiplicity for 
the secondary variables.  
12.7 
Pharmacokinetic Analysis  
Plasma concentrations will be summarized descriptively and graphically by nominal 
time.  Pharmacokinetic parameters (Cmax, time to Cmax, AUC, clearance, steady state 
volume of distribution, and accumulation factors) will be calculated based on the actual 
time of blood sampling, listed and summarized.  Accumulation ratios for Cmax (RCmax) and 
AUC (RAUC) will also be calculated.  Individual plasma CR845 concentrations will be listed 


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and plotted by patient.  Details of the PK analyses and PK tables, listings and figures will 
be provided in a separate PK analysis plan. 
12.8 
Safety Analysis  
Analysis of all safety data will be performed on the Safety Population and will be 
summarized by the treatment received.  The SAP will detail the analyses that will be 
applied to each safety parameter.  
The objective of the evaluation of the safety variables is to investigate the data for any 
effects on clinical tolerability, vital signs, ECG, and laboratory tests.  All safety variables 
will be summarized by treatment group (and time point as appropriate).  The general 
strategy of the safety analysis will be to examine the data summaries for any differences 
from placebo and any trends among the dose levels.  No formal hypothesis testing will be 
carried out and no formal statistical analysis of the safety parameters will be performed. 
Summaries of the data for use of prior and concomitant medications; vital signs; 12-lead 
ECGs; clinical safety laboratory evaluations; adverse events (including SAEs); and other 
relevant safety parameters will be presented in addition to by-patient listings of all safety 
data.   
12.8.1 
Adverse Events  
All adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  The MedDRA treatment dictionary will be used to map adverse events 
verbatim to system organ class (SOC) and MedDRA preferred term for standardization 
and summary purposes. 
All reported adverse events (regardless of treatment-emergent or not) will be included in 
a by-subject adverse event listing.  Only TEAEs will be included in summary tables.  
TEAES will be defined as any AEs occurring starting after the first dosing of the study 
drug. The number and percentage of patients experiencing TEAEs will be summarized 
for each treatment group.  The incidence of TEAEs will be presented by the counts and 
percentages of patients with adverse events.  A patient will be counted only once in the 
incidence count for a MedDRA preferred term, although a patient may have multiple 
occurrences (start and stop) of an event associated with a specific MedDRA preferred 
term.  The most frequent TEAEs (greater than 5% per group) will also be tabulated for 
each treatment group by SOC and preferred term.   


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The incidence and percentage of patients experiencing treatment-emergent SAEs and 
TEAEs leading to study discontinuation will be presented for each treatment group by 
appropriate MedDRA SOC and preferred term.   
Tabulations of TEAEs will include summaries by: 
 by SOC, preferred term, and severity and 
 by SOC, preferred term, and relationship to study drug (not related versus 
related). 
Treatment-emergent adverse events considered by the Investigator to be “definitely 
related,” “probably related,” or “possibly related” to the study drug will be characterized 
as “related” to the study drug.  Treatment-emergent adverse events considered by the 
Investigator to be “unlikely related” or “not related” to the study drug based on the 
definitions below will be characterized as “not related” to the study drug. 
If the severity and/or relationship to the study drug of an adverse event is missing, a 
worst-case scenario will be assumed (i.e., the adverse event will be defined as “severe” 
and/or “definitely related” to the study drug). 
Deaths, non-fatal SAEs, and adverse events leading to treatment discontinuation or dose 
interruption will be listed including the treatment group, start and stop dates of the 
adverse event, and days on study relative to the start of adverse event (if applicable).   
No statistical tests will be performed on adverse event data. 
12.8.2 
Other Safety Analyses 
Summary statistics for each scheduled time point measured and mean changes from 
baseline to each time point (when applicable) will be presented.  This will apply to the 
assessment of vital signs and clinical safety laboratory evaluation.  Clinically significant 
new or worsening findings on physical examinations and ECGs will be collected as 
adverse events.  The baseline value will be defined as the last value obtained prior to the 
first dose of study drug and includes both scheduled and repeat (unscheduled) 
observations.   
Laboratory values will be reported in both standard and Système International units.   


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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.  
Within treatment comparisons will be based on 3 by 3 tables (shift tables) that, for a 
particular laboratory test, compare the baseline LNH classification to the LNH 
classification at the end of double-blind treatment. 
12.8.3 
Prior and Concomitant Medications  
Medications will be coded using the World Health Organization Drug Dictionary.   
All prior medications will be summarized by treatment group using the 
Anatomical-Therapeutic-Chemical code and preferred term.  Similar summaries will be 
produced for all concomitant medications.  In addition, a summary of all prior and 
concomitant medications used to treat the patient’s chronic pruritus may be produced.   


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13.0 
Quality Control and Quality Assurance 
13.1 
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 CRFs 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 by personal visits from a representative of the Sponsor or its 
designee (site monitor) who will review patient enrollment, CRFs, 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 trial 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. 
13.2 
Audits and Inspections 
The investigational site will maintain appropriate medical and research records for this 
trial, in compliance with International Conference on Harmonisation (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 trial necessary for the 
reconstruction and evaluation of the trial.  Examples of these original documents and data 
records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, participants’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 


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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 
trial, as applicable.  
The investigational site will provide access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, 
and inspection by local and regulatory authorities. 
13.3 
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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14.0 
Ethics and Regulatory Compliance 
14.1 
Ethics 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki (Edinburgh 2000) 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. 
A properly constituted, valid IRB or Independent Ethics Committee (IEC) must review 
and approve the protocol, the Investigator’s informed consent document, and related 
patient information and recruitment materials 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.  
No amendments to the study protocol should be made without the prior written 
agreement of the Investigator, the Sponsor, and the IRB.  
The Investigator will maintain documentation of the composition of the IRB as well as all 
correspondence with the IRB.  The Investigator 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 prepare a final study report and submit it to the 
IRB no later than 3 months after study completion.  The Investigator will provide Cara 
Therapeutics or its designee copies of all IRB approval notices, correspondence, annual 
reports, and final study progress reports. 
14.2 
Good Clinical Practices 
The study will be conducted in accordance with the ICH for GCP and the appropriate 
regulatory requirement(s).  The Investigator will be thoroughly familiar with the 


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appropriate use of the study drug as described in the protocol, IB, 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 trial master file will be 
established at the beginning of the study, maintained for the duration of the study, and 
retained according to the appropriate regulations. 
14.3 
Institutional Review Board 
Each participating IRB will be constituted and function per GCP guidelines to provide for 
the review and approval of this protocol and the associated informed consent documents.  
Any amendments to the protocol or consent materials must also be approved before they 
are placed into use. 
A properly constituted, valid IRB must review and approve the protocol, ICF, and related 
patient information and recruitment materials before the start of the study. 
14.4 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and which continues throughout the individual’s study 
participation.  The Investigator or designee will discuss extensively with the participant 
patient the study risks.  Copies of the 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.  Consent forms will be IRB approved and the participant will 
be asked to read and review the document.  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.  
The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to 
participate in this study or withdraw during the course of the study. 


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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 guidelines.  Prior to the beginning of the trial, the 
Investigator must have written approval/favorable opinion from the IRB of the written 
ICFs and any other written information to be provided to the participants.  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. 
14.5 
Patient Confidentiality 
In order to maintain patient privacy, all CRFs, study drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient 
number.  The Investigator will grant monitor(s) and auditor(s) from the Sponsor, or its 
designee, and regulatory authority access to the patient’s original medical records for 
verification of data gathered on the CRFs and to audit the data collection process.  The 
patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Participant confidentiality is strictly held in trust by the participating Investigators, their 
staff, and the Sponsor(s) and their agents.  This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information 
relating to participating patients. 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence.  No information concerning the study or the data will be released to 
any unauthorized third party, without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but not 
limited to, medical records (office, clinic or hospital) and pharmacy records for the 
participants in this study. 
14.6 
Study Suspension, Termination and Completion 
The Sponsor may suspend or terminate the study or part of the study at any time for any 
reason.  If the study is suspended or terminated, the Sponsor will ensure that applicable 
regulatory agencies and IRBs/IECs are notified as appropriate.  


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Should the study be closed prematurely, all study materials (completed, partially 
completed, and blank CRFs, study drug, etc.) must be returned to Cara Therapeutics or 
destroyed at the site if authorized by Cara Therapeutics. 


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15.0 
Data Handling and Record Keeping 
15.1 
Case Report Form Completion 
Electronic case report forms (eCRF) will be completed for each study patient.  It is the 
Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the patient’s eCRF.  Source documentation supporting the eCRF data 
should indicate the patient’s participation in the study and should document the dates and 
details of study procedures, adverse events, and patient status. 
The Investigator or designated representative will complete the eCRF pages as soon as 
possible after information is collected, preferably on the same day that a study patient is 
seen for an examination, treatment, or any other study procedure.  Any outstanding 
entries must be completed immediately after the final examination.  An explanation 
should be given in the source document for all missing data. 
The Investigator must sign and date the Investigator’s Statement on the appropriate page 
of the eCRF to endorse the recorded data. 
15.2 
Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and 
data management staff, who will ensure that they are accurate and complete.  Adverse 
events must be graded, assessed for severity and causality, and reviewed by the 
Investigator or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the Investigator.  During the study, the Investigator must maintain 
complete and accurate documentation for the study. 


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16.0 
Administrative Procedures 
16.1 
Study Records Retention 
The Investigator will retain all study records according to ICH-GCP and applicable 
regulatory requirement(s) (generally 2 years after discontinuing clinical development or 
after the marketing approval of the study drug).  The Investigator agrees to adhere to the 
document retention procedures by signing the study protocol.  Records will be retained 
until notified by Cara Therapeutics in writing that the records may be destroyed.  The 
Investigator shall take responsibility for maintaining adequate and accurate hard copy 
source documents of all observations and data generated during this study, including any 
data clarification forms received from the Sponsor.  Such documentation is subject to 
inspection by Cara Therapeutics, its representatives, and regulatory authorities.  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. 
16.2 
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.  Major 
protocol deviations will be summarized in the final clinical study report and all protocol 
deviations will be presented in a listing. 
The site monitor will review protocol deviations/violations throughout the course of 
monitoring visits and document new findings of violations and deviations.  The monitor 
will notify the Investigators of violations and deviations verbally or in writing.  The IRB 
should be notified of all protocol violations and deviations in a timely manner according 
to IRB requirements. 
16.3 
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 


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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 is 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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17.0 
References 
1. Investigator’s Brochure for CR845. Edition No. 7, Cara Therapeutics, Inc. 
2. 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. 2009; Apr;25(4):1251-7. 
3. Pisoni RL, Wikstrom B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al. Pruritus in 
haemodialysis patients: international results from the Dialysis Outcomes and Practice 
Patterns Study (DOPPS). NDT. 2006; 21: 3495–505. 
4. Narita I, Omori K, Gejyo F, et al. Etiology and prognostic significance of severe 
uremic pruritus in chronic hemodialysis patients. Kidney Int. 2006;69:1626–32. 
5. Wikström B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K, et al.  Kappa-opioid 
system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled 
clinical studies. J Am Soc Nephrol. 2005;16(12):3742-7.  
6. Mathur VS, Lindberg J, Germain M, Block G, Tumlin J, Smith M, et al. A 
longitudinal study of uremic pruritus in hemodialysis patients. Clin J Am Soc 
Nephrol. 2010; 5:1410-9. 
7. Ständer S, Richter L, Osada N, Metze D. Hydroxyethyl Starch-induced Pruritus: 
Clinical Characteristics and Influence of Dose, Molecular Weight and Substitution. 
Acta Derm Venereol. 2013 Sep 16. 
8. Stewart AL, Ware JE, eds. Measuring Functioning and Well-Being: The Medical 
Outcomes Study Approach, Durham, N.C.: Duke University Press, 1992. 
9. Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D Itch Scale: a new measure of 
pruritus.  University of Wisconsin School of Medicine, Madison, WI. 
10. Guy W: Clinical Global Impressions (CGI) Scale. Modified From: Rush J, et al.: 
Psychiatric Measures, APA, Washington DC, 2000. 
11. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain 
clinical trials: IMMPACT recommendations. Pain. 2005;130:9–19 


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12. Ratitch B, O’Kelly M. (2011), “Implementation of Pattern-Mixture Models Using 
Standard SAS/STAT Procedures,” in Proceedings of PharmaSUG 2011 
(Pharmaceutical Industry SAS Users Group), SP04, Nashville. 


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18.0 
Appendices 
 






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EOT=end of treatment; ESA= erythropoiesis-stimulating agent; F=Friday; FSH=follicle-stimulating hormone; IV=intravenous; M=Monday; 
MOS=Medical Outcomes Study; NRS=numerical rating scale; PRO=patient reported outcome; Sa=Saturday; Th=Thursday; Tu=Tuesday; 
W=Wednesday; 
See footnotes as well as Section 8 and 11 for additional procedural details. 
a  Each visit during the Treatment Period will coincide with the patient’s normal dialysis treatments. 
b  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. 
c Electrocardiogram must be performed prior to dialysis at Screening, Day 1, Day 29, and Day 57 (or early termination). 
d Vital signs will be obtained in a sitting or semi-recumbent position (for at least 3 min) and will include body temperature, heart rate, and blood 
pressure. 
e  On Day 15 and 29 only, pre-dialysis vital signs should be recorded  
f  On Day 1, 15, 29, 43, and 57 only. Serum chemistry should include parathyroid hormone, pre-albumin, ferritin and transferrin saturation. 
g  Obtain on women who have been amenorrheic for at least 1 year and are between 45 and 55 years of age. 
h  Training on Worst Itching Intensity NRS only 
i  Training on Skindex-10 Scale, MOS Sleep Scale, 5-D Itch Scale and Patient Global Impression of Worst Itch Severity scales may be performed 
at any time during the week prior to randomization. 
j  To be performed prior to or during dialysis, but must be completed prior to dosing.   
k Skindex-10 Scale and 5-D Itch Scale completed on the first visit of Week 3, 5, and 7 (Day 15, 29, and 43, respectively).  MOS Sleep Scale 
completed on the first visit of Week 4 and 8 (Day 22 and 50, respectively).  Patient Global Impression of Worst Itch Severity completed on the 
first visit of Week 2, 4, and 8 (Day 8, 22, and 50, respectively).  If the first visit of the week is missed, the patient may complete the procedures 
at their next visit for the same week. Questionnaires will be completed in strict adherence to the Patient Reported Outcomes Instructions (as per 
Study Reference Manual). 
l Biomarker samples must be collected prior to the start of dialysis. 
m Concomitant medications will be updated on a weekly basis at the beginning of each week. Prior medications will be recorded until the time of 
first dosing. 








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f  On Day 1, 15, 29, 43, 57, and 85 only. Serum chemistry should include parathyroid hormone, pre-albumin, ferritin and transferrin saturation. 
g  Obtain on women who have been amenorrheic for at least 1 year and are between 45 and 55 years of age. 
h  Training on Worst Itching Intensity NRS only 
i  Training on Skindex-10 Scale, MOS Sleep Scale, 5-D Itch Scale, and Patient Global Impression of Worst Itch Severity scales may be performed 
at any time during the week prior to randomization. 
j  To be performed prior to or during dialysis, but must be completed prior to dosing.   
k Skindex-10 Scale and 5-D Itch Scale completed on the first visit of Week 3, 5, 7, 9, and 11 (Day 15, 29, 53, 57, and 71, respectively).  MOS 
Sleep Scale completed on the first visit of Week 4, 8, and 12 (Day 22, 50, and 78, respectively).  Patient Global Impression of Worst Itch 
Severity completed on the first visit of Week 2, 4, 8, and 12 (Day 8, 22, 50, and 78, respectively).  If the first visit of the week is missed, the 
patient may complete the procedures at their next visit for the same week. 
l Biomarker samples must be collected prior to the start of dialysis. 
m Concomitant medications will be updated on a weekly basis at the beginning of each week. 


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18.2 
APPENDIX II 
Pharmacokinetic Blood Sampling Schedule   
A subset of up to 40 patients (10 patients per treatment group) who consent to have blood 
samples taken for determining the PK profile of CR845 will be evaluated in the study.  A 
total of 25 samples are to be collected from each patient.  The timing for the collection of 
these samples will be according to the following schedule: 
 
 
Pharmacokinetic Samples 
Treatment  
Time After Study Drug Administration (Post-dialysis)a 
Week Day Pre-dialysisb Post-dialysisc 5 minutes 30 minutes 1 hour 2 hours 4 hours 24 hours 
1 
1 
X 
X 
X 
X 
X 
X 
X 
 
2 
 
 
 
 
 
 
 
X 
3 
X 
 
X 
 
 
 
 
 
2 
8 
X 
 
X 
 
 
 
 
 
4 
22 
X 
 
X 
 
 
 
 
 
6 
36 
X 
 
X 
 
 
 
 
 
8 
50 
X 
X 
X 
X 
X 
X 
X 
 
51 
 
 
 
 
 
 
 
X 
52 
X 
 
 
 
 
 
 
 
a 
Time relative to injection of study drug (i.e., t = 0).  Sample taken at 5 minutes will have a window of 
± 1 minute, the 30-minute sample will have a window of ± 5 minutes, the 1-hour, 2-hour, 4-hour samples will 
have a window of ± 10 minutes, and the 24-hour sample will have a window of ± 1 hour. 
b 
Sample to be collected within 30 minutes prior to start of dialysis. 
c 
Sample to be collected within 15 minutes following the end of dialysis and prior to study drug administration. 
 
 




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18.4 
APPENDIX IV Patient Self-Categorization of Pruritus Disease 
Severity 
This is a representation of the content of the instrument to be used, but is not the actual 
instrument.  Please refer to the Study Reference Manual for the instrument to be administered to 
patients and instructions. 
 
Patient A: 
I do not generally have scratch marks on my skin. 
I do not generally have a problem sleeping because of itching.  
My itching does not generally make me feel agitated or sad. 
 
Patient B: 
I sometimes have scratch marks on my skin.  
I sometimes have problems sleeping because of itching. 
My itching can sometimes make me feel agitated or sad.  
 
Patient C: 
I often have scratch marks on my skin that may or may not bleed or 
get infected.  
I often have a problem sleeping because of itching.  
My itching often makes me feel agitated or sad.  
 
Which of these patients are you most like? (Mark one) 
o Patient A 
o Patient B 
o Patient C 
 
 
 
Mathur VS et al. CJASN 2010; 5 :1410-1419 
 
 


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18.5 
APPENDIX V 
Skindex-10 Scale 
This is a representation of the content of the instrument to be used, but is not the actual 
instrument.  Please refer to the Study Reference Manual for the instrument to be administered to 
patients and instructions. 
 
 
 
Mathur VS et al. CJASN 2010; 5 :1410-1419 
 
 


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18.6 
APPENDIX VI Medical Outcomes Study (MOS) Sleep Scale 
This is a representation of the content of the instrument to be used, but is not the actual 
instrument.  Please refer to the Study Reference Manual for the instrument to be administered to 
patients and instructions. 
 
 
 


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18.7 
APPENDIX VII 5-D Itch Scale 
This is a representation of the content of the instrument to be used, but is not the actual 
instrument.  Please refer to the Study Reference Manual for the instrument to be administered to 
patients and instructions. 
 


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18.8 
APPENDIX VIII Patient Global Impression of Worst Itch Severity 
This is a representation of the content of the instrument to be used, but is not the actual 
instrument.  Please refer to the Study Reference Manual for the instrument to be 
administered to patients and instructions. 
Please choose from the following options the one that best describes your worst 
itch in the last 24 hours.  
 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 
 


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18.9 
APPENDIX IX Patient Global Impression of Change 
This is a representation of the content of the instrument to be used, but is not the actual 
instrument.  Please refer to the Study Reference Manual for the instrument to be 
administered to patients and instructions. 
 
The patient will provide their overall impression of the status of the itch related to their 
uremic pruritus on a 7-point scale where 1 = “Very much improved” and 7 = “Very much 
worse.”  
 
Patients will be asked to complete the following statement: “Since the start of the study, 
my itch is?” The response options are as follows: 
 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
 

SAP_001.pdf: 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
STATISTICAL ANALYSIS PLAN 
22 February 2017 FINAL 
 
 
 
 
 
 A TWO-PART, MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND 
EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS WITH 
MODERATE-TO-SEVERE PRURITUS 
 
 
 
 
PROTOCOL NUMBER CR845-CLIN2101 
 
 
 
 
 
 
 
SPONSORED BY 
 
Cara Therapeutics, Inc. 
4 Stamford Plaza 
Stamford, CT 06902 
(203) 406-3700 
 
 
PREPARED BY 
 
Rho, Inc. 
6330 Quadrangle Drive, Suite 500 
Chapel Hill, NC  27517 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
This document is confidential and proprietary to Cara Therapeutics.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Cara Therapeutics, 
except that this document may be disclosed to appropriate Institutional Review Boards under the condition 
that they keep the information confidential. 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
Page 2 of
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
DRAFT 
22 NOV 2016 
 
FINAL 
22FEB 2017 
Clarifications and updates to 
model specifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
Page 3 of
APPROVALS 
Approved: 
 
Date: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
  
 
 








Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
Page 4 of
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 6 
LIST OF IN-TEXT TABLES ............................................................................................. 7 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 8 
2. 
PROTOCOL SUMMARY .......................................................................................... 9 
2.1 
Study Objectives ........................................................................................... 9 
2.1.1 
Part A .................................................................................................. 9 
2.1.2 
Part B .................................................................................................. 9 
2.2 
Overall Study Design and Plan ..................................................................... 9 
2.3 
Study Population ......................................................................................... 10 
2.4 
Treatment Regimens................................................................................... 10 
2.5 
Treatment Group Assignments or Randomization ....................................... 11 
2.6 
Sample Size Determination ......................................................................... 11 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1 
Full Analysis (FAP) Population .................................................................... 14 
4.2 
Per Protocol Population .............................................................................. 14 
4.3 
Safety Analysis Population .......................................................................... 15 
4.4 
Pharmacokinetic Evaluable Population ....................................................... 15 
5. 
STUDY PATIENTS ................................................................................................. 16 
5.1 
Disposition of Patients ................................................................................. 16 
5.2 
Protocol Deviations ..................................................................................... 16 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 17 
6.1 
Demographic Characteristics ...................................................................... 17 
6.2 
Baseline characteristics .............................................................................. 17 
6.3 
et................................................................................................................. 18 
6.4 
Prior and Concomitant Medications ............................................................. 18 
6.4.1 
Prior Medication ................................................................................. 18 
6.4.2 
Concomitant Medication .................................................................... 18 
6.4.3 
Anti-Itch Medication ........................................................................... 19 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 20 
8. 
EFFICACY EVALUATION ..................................................................................... 21 
8.1 
Overview of Efficacy Analysis Issues .......................................................... 21 
8.1.1 
Handling of Dropouts or Missing Data ................................................ 21 
8.1.2 
Multicenter Studies ............................................................................ 21 
8.1.3 
Assessment Time Windows ............................................................... 21 
8.2 
Efficacy Variables ....................................................................................... 21 
8.2.1 
Efficacy Variables .............................................................................. 23 
8.2.1.1 
Worst Itching Intensity Numerical Rating Scale (NRS) .......... 23 
8.2.1.2 
Skindex-10 Scale score ........................................................ 24 
8.2.1.3 
5-D Itch Scale ....................................................................... 24 
8.2.1.4 
Medical Outcomes Study (MOS) Sleep Scale ....................... 25 
8.2.1.5 
Patient Global Impression of Worst Itch Severity ................... 25 
8.2.1.6 
Patient Global Impression of Change .................................... 26 
8.2.1.7 
Missed Dialysis Visits and Incidence of Infection ................... 26 


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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
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8.2.1.8 
Iron Status and use of Erythropoiesis-stimulating agents 
(ESA) and IV iron .................................................................. 26 
8.2.1.9 
Inflammatory biomarkers ....................................................... 26 
8.3 
Analysis Methods ........................................................................................ 27 
8.3.1 
Primary Efficacy Analyses ................................................................. 27 
8.3.2 
Secondary Efficacy Analyses ............................................................. 30 
8.3.3 
Other Efficacy Analyses ..................................................................... 30 
8.3.3.1 
Itch Intensity Measures ......................................................... 30 
8.3.3.2 
Itch-Related Quality-of-Life Measures ................................... 31 
8.3.3.3 
Missed Dialysis Visits and the Incidence of Infection ............. 32 
8.3.3.4 
Iron Status and use of Erythropoiesis-stimulating agents 
(ESA) and IV iron .................................................................. 32 
8.3.3.5 
Change in inflammatory biomarkers ...................................... 33 
8.4 
Examination of Subgroups .......................................................................... 33 
9. 
SAFETY EVALUATION ......................................................................................... 34 
9.1 
Overview of Safety Analysis Methods ......................................................... 34 
9.2 
Adverse Events ........................................................................................... 34 
9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 36 
9.4 
Clinical Laboratory Evaluation ..................................................................... 36 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 37 
9.5.1 
Vital Signs .......................................................................................... 37 
9.5.2 
12-Lead ECGs ................................................................................... 39 
10. PHARMACOKINETIC EVALUATION .................................................................... 40 
10.1 
Plasma Concentration Data ........................................................................ 40 
10.2 
Pharmacokinetic Parameters in Plasma ......... Error! Bookmark not defined. 
10.2.1 
Pharmacokinetic Endpoints Estimation . Error! Bookmark not defined. 
11. OTHER ANALYSES .............................................................................................. 42 
12. INTERIM ANALYSES AND DATA MONITORING ................................................. 43 
13. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 44 
14. REFERENCES ....................................................................................................... 46 
15. APPENDICES ........................................................................................................ 47 
15.1 
Schedule of Events ..................................................................................... 47 
 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
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LIST OF ABBREVIATIONS 
Abbreviation  
Definition  
AUC 
area under the curve 
Cmax 
maximum concentration 
CRF 
case report form 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
H 
above laboratory reference range 
ICF 
Informed consent form 
IV 
intraveneous 
IVRS/IWRS 
Interactive voice response system/interactive web response system 
L 
below laboratory reference range 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed effects model with repeated measures 
MOS 
Medical Outcomes Study 
N 
within laboratory reference range 
NRS 
numerical rating scale 
PK 
pharmacokinetic(s) 
PNS 
Peripheral nervous system 
PRO 
patient reported outcome 
Rauc 
accumulation ratio for AUC 
Rcmax 
accumulation ratio for Cmax 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
Upper limit of normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
Page 7 of
LIST OF IN-TEXT TABLES 
Table 8-1 
Efficacy Variables and Analysis Methods ...................................... 21 
 
 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
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1. 
PURPOSE OF THE ANALYSES 
CR845-CLIN2101 is a two-part, multicenter, double-blind, randomized, placebo-
controlled study to evaluate the safety and efficacy of CR845 in hemodialysis patients 
with moderate-to-severe pruritus.  This study is sponsored by Cara Therapeutics, Inc. 
This statistical analysis plan (SAP) provides a detailed description of the strategy and 
statistical methodology to be used for analysis of data in Part A of the CR845-CLIN2101 
protocol.  
The purpose of the SAP is to ensure the credibility of the study findings by pre-
specifying the statistical approaches to the analysis of study data prior to data base lock 
for Part A.  This analysis plan is meant to supplement the study protocol.  If differences 
occur between analyses described in the SAP and the current protocol, those found in this 
SAP will assume primacy.  Any deviations from this plan will be described in the 
Clinical Study Report (CSR). 
 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
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2. 
PROTOCOL SUMMARY 
 
2.1 
Study Objectives 
2.1.1 
Part A 
Primary Objective  
The primary objective is to evaluate the efficacy of 3 dose levels of IV CR845 
administered after each dialysis session, compared to placebo, in reducing the 
intensity of itch as assessed by the change from baseline to the last week of the 8-
week Treatment Period with respect to the Worst Itching Intensity Numerical Rating 
Scale (NRS) score in hemodialysis patients with moderate-to-severe pruritus.  
 
Secondary Objectives  
The secondary objectives are:  
• To evaluate the efficacy of 3 dose levels of IV CR845 administered after each 
dialysis session, compared to placebo, in improving itch-related quality-of-life 
measures as assessed by the Skindex-10 Scale over an 8-week Treatment 
Period in hemodialysis patients with moderate-to-severe pruritus.  
• To evaluate the safety of 3 dose levels of IV CR845 administered after each 
dialysis session over an 8-week Treatment Period in hemodialysis patients 
with moderate-to-severe pruritus.  
• To evaluate the Pharmacokinetic (PK) of 3 dose levels of IV CR845 
administered after each dialysis session over an 8-week Treatment Period in 
hemodialysis patients with moderate-to-severe pruritus.  
 
2.1.2 
Part B 
One dose level will be tested in Part B after selection from the doses tested in part A 
and which will be the dose which represents best efficacy and safety. Part B analyses 
are outside the scope of this document.  
 
2.2 
Overall Study Design and Plan 
This is a two-part, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety and efficacy of IV CR845 administered after each dialysis session. In 
Part A, 3 dose levels of CR845 will be evaluated relative to placebo over an 8-week 
Treatment Period in hemodialysis patients with moderate-to-severe pruritus. A subset of 
patients (approximately 10 patients per treatment group) will also be consented for the 
collection of blood samples for evaluating the PK profile of CR845. Based on the overall 
safety and efficacy profile from Part A, 1 dose of CR845 will be selected for Part B and 


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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
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evaluated relative to placebo over a 12-week Treatment Period in hemodialysis patients 
with moderate-to-severe pruritus.  
Part A consists of a Screening Period, an 8-week Treatment Period, an End-of-Treatment 
Visit (approximately 3 days after the last dose), and a Follow-Up Visit (approximately 1 
week after the last dose).  
Part B consists of a Screening Period, a 12-week Treatment Period, an End-of-Treatment 
Visit (approximately 3 days after the last dose), and a Follow-Up Visit (approximately 1 
week after the last dose). Part B will not be initiated until an unblinded review of the 
safety and efficacy data from Part A has been completed.  
The Screening Period will occur between 8 and 14 days prior to randomization following 
the signing of the informed consent form.  
Eligible patients will then be trained on completion of the 24-hour Worst Itching 
Intensity NRS scale and required to record their Worst Itching Intensity NRS score each 
day for at least 7 days prior to randomization. For consistency, patients will be requested 
to 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 (+/- 2 hours). During the 
week prior to randomization up to the first day of study drug (Day 1), patients will be 
trained on other PRO measures, including quality-of-life measurements. Day 1 of the 
Treatment Period will be defined as the day of the first dose of administration of study 
drug.  
All study visits (scheduled and unscheduled) will be conducted on dialysis days, 
including the end of study visit.  
A final safety Follow-Up Visit will be conducted 7 days (+3) after the last dose of study 
drug.  
 
2.3 
Study Population 
For both Parts A and B of the study, male and female hemodialysis patients aged 18 years 
of age or older with end stage renal disease who have been on hemodialysis 3 times per 
week for at least 3 months prior to start of Screening, who have moderate-to-severe 
pruritus (mean baseline Worst Itching Intensity NRS score > 4), and who meet additional 
eligibility criteria are included. A full list of the inclusion and exclusion criteria can be 
found in the CR845 protocol. 
 
2.4 
Treatment Regimens 
Part A: Four groups with a sample size of approximately 40 patients each will be 
administered CR845 0.5, 1, or 1.5 mcg/kg, or placebo as a single IV bolus 3 times a week 
immediately after each dialysis session for 8 weeks.  
Part B: Two groups with a sample size of approximately 120 patients each will be 
administered CR845 or placebo as a single IV bolus 3 times a week immediately after 


Cara Therapeutics 
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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
Page 11 o
each dialysis session for 12 weeks. The dose of CR845 and the total sample size will be 
confirmed based on an unblinded review of the safety and efficacy data collected in Part 
A.  
2.5 
Treatment Group Assignments or Randomization 
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).  
For Part A, patients will be randomized in a 1:1:1:1 ratio to receive CR845 1.5 mcg/kg, 
CR845 1.0 mcg/kg, CR845 0.5 mcg/kg, or placebo. Patients will be stratified according 
to their use or non-use (i.e., 2 strata will be defined) of concomitant medications to treat 
their itch and their inclusion in the PK sample of approximately 10 patients per treatment 
arm.  
For Part B, patients will be randomized in a 1:1 ratio to receive either CR845 or placebo, 
with the dose of CR845 determined based on safety and efficacy determined in Part A. 
Patients enrolled in Part B will also be stratified according to their use or non-use of 
concomitant medications to treat their itch. For both Part A and B, patients will be 
categorized as “using anti-pruritic medications” if they have used >1 dose of potentially 
anti-pruritic medications used to treat their uremic pruritus during the week prior to 
randomization (e.g. antihistamine (H1), pregabalin, gabapentin, nalbuphine, naltrexone, 
corticosteroids, or buprenorphine). 
2.6 
Sample Size Determination 
The planned sample size for this clinical investigation is approximately 400 male and 
female hemodialysis patients with persistent moderate-to-severe pruritus (mean baseline 
Worst Itching Intensity NRS score > 4). 
Part A: Approximately 160 male and female hemodialysis patients with moderate-to-
severe pruritus will be randomized at approximately 40 clinical sites. A subset of up to 40 
patients (approximately 10 per treatment group) will be consented for the collection of 
blood samples for evaluating the PK profile of CR845. No formal sample size calculation 
was performed to select this sample size. However, a sample size of 40 patients per group 
is adequate to provide an appropriate estimate of the magnitude and variability of 
treatment effect at each dose, and select the appropriate dose to be further evaluated 
compared to placebo in Part B. 
Part B: Approximately 240 male and female hemodialysis patients with moderate-to-
severe pruritus will be randomized at approximately 60 clinical sites. Details of the 
assumptions and the calculations for sample size determination can be found in Section 
12.2 of the protocol. 


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Statistical Analysis Plan 
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22 February 2017 
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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the 
data from the study.  Departures from these general policies may be given in the specific 
detailed sections of this SAP.  When this situation occurs, the rules set forth in the 
specific section take precedence over the general policies. 
For categorical variables, summary statistics will consist of the number and percentage of 
patients in each category. All percentages will be rounded to one decimal point.  The 
number and percentage of patients will always be presented in the form XX (XX.X%) 
where the percentage is in parentheses. To ensure completeness, all summaries for 
categorical and discrete variables will include all categories, even if none of the patients 
had a response in a particular category. Unless otherwise noted, for all percentages, the 
number of patients in the analysis population for the treatment group will be the 
denominator. 
 
For continuous variables, summary statistics will consist of the number of patients with 
data, mean, median, standard deviation, minimum, and maximum values. The summary 
statistic n will be the number of patients with non-missing values. All means and medians 
will be reported to one more significant digit than the values being analyzed.  Standard 
errors will be reported to two more significant digits than the values being analyzed.  The 
minimum and maximum will be reported to the same number of significant digits as the 
values being analyzed. 
 
For tests of hypothesis of treatment group differences, the associated p-value will be 
reported.  All p-values will be rounded to three decimal places; p-values that round to 
0.000 will be presented as “< 0.001”. 
In general, the baseline value will be considered the last non-missing measurement 
observed prior to the first dose of study treatment. 
For efficacy, patients will be analyzed according to randomized treatment.  For safety 
analyses, patients will be analyzed according to the actual treatment received.  Data from 
all sites will be pooled for the purpose of analysis.   
 
Aside from the primary analysis, P-values are considered descriptive in nature; there are 
no adjustments for multiple comparisons. 
Data will be listed by treatment and patient. In general, listings will be sorted in the order 
that columns are displayed, starting with the first column on the left (treatment). Patient 
listings of data will be presented for all randomized patients unless specified otherwise. 


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Statistical Analysis Plan 
Protocol No. CR845-CLIN2101 
 
22 February 2017 
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Unless otherwise specified, summaries will include the following treatment groups for 
Part A:  
• CR-845 1.5 mcg/kg 
• CR-845 1.0 mcg/kg 
• CR-845 0.5 mcg/kg 
• CR-845 (All Doses Combined), used for primary and secondary analysis only 
• Placebo 
 
SAS statistical software, version 9.4 will be used for all analyses.    


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22 February 2017 
Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
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4. 
ANALYSIS POPULATIONS 
Four analysis populations will be used for this study: the Full Analysis (FAP) population, 
the Per Protocol (PP) population, the Safety population (same as FAP population), and 
the Pharmacokinetic (PK) Evaluable population. 
The analysis of the primary efficacy and secondary endpoints will be performed using the 
FAP population. Sensitivity analyses of the primary and secondary efficacy endpoints 
will also be performed on the PP population (if the criteria are met). For exploratory 
efficacy endpoints, analyses will be performed on the FAP population only.  All safety 
analyses will be performed using the Safety Population. Pharmacokinetics analyses will 
be performed using the PK Evaluable population. 
 
4.1 
Full Analysis (FAP) Population 
The Full Analysis Population is defined as the group of all randomized patients who 
received at least 1 dose of double-blind study drug. Following the intent-to-treat 
principle, patients in the Full Analysis Population will be analyzed according to their 
randomized treatment, regardless of the actual treatment received.  
 
The Full Analysis Population will be used to analyze all efficacy endpoints.  
 
 
4.2 
Per Protocol Population 
The Per-Protocol Population is defined as the subset of patients in the Full Analysis 
Population who do not have any major protocol deviations that could affect the efficacy 
analyses.  
The Per Protocol Population is defined as patients who: 
• Received at least 80% of the planned study drug doses 
• Had a mean baseline Worst Itching Intensity score > 4.0 
• Had a non-missing average 24-hour weekly Worst Itching NRS score available 
for at least 75% of study weeks (weeks with >3 missing daily values are missing) 
• Did not have significant amounts of restricted and prohibited medications listed in 
protocol Section 10.2 based on medical review. 
• Did not have major protocol violations that would impact efficacy outcomes  
Prior to unblinding, the protocol violations and medications will be reviewed in a blinded 
manner and the per-protocol population will be determined.  Patients will be analyzed in 
the treatment arm to which they were randomly assigned regardless of which treatment 
they received. Patients receiving different treatment than the treatment to which they 
were randomized will be considered major protocol deviations and will not be included in 
the Per-Protocol Population. 


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22 February 2017 
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An analysis of the primary and secondary efficacy variables for the Per-Protocol 
Population may be performed if more than 20% of the patients in the Full Analysis 
Population are excluded.  
 
 
4.3 
Safety Analysis Population 
The Safety Analysis Population is identical to the Full Analysis Population.  However, 
patients in the Safety Population will be analyzed according to their actual treatment. 
 
The Safety Population will be used to analyze all safety endpoints. 
 
4.4 
Pharmacokinetic Evaluable Population 
The Pharmacokinetic Evaluable Population is defined as all patients who received CR845 
and had sufficient plasma concentrations for PK analysis. 
 


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5. 
STUDY PATIENTS 
 
5.1 
Disposition of Patients 
The number of patients screened, randomized, treated, completed, or discontinued from 
the study, along with the reason for discontinuation, will be presented overall and by 
treatment group. Patient count by analysis population will also be tabulated. 
The following provides the definitions of the aforementioned groups: 
• Screened patients have a date of informed consent.  
• Randomized patients consist of all screened patients who have met the eligibility 
criteria (based on Inclusion/Exclusion Summary CRF) or were waived and have a 
date of randomization, regardless of whether treatment was subsequently 
received. 
• Treated patients are all patients were randomized and who received at least one 
dose of study treatment. 
• Completers are randomized patients with ‘Yes’ noted for the question ‘Did the 
patient complete the 8 week treatment period’ on the End of Treatment (Study 
Completion Status) CRF.  
• Patients who discontinued the study are randomized patients with ‘No’ noted for 
the question ‘Did the patient complete the 8 week treatment period’ on the End of 
Treatment (Study Completion Status) CRF.  Reasons for study discontinuation are 
also collected on this CRF. 
 
For all categories of patients (except for the screened patients and enrolled patients) 
percentages will be calculated using the number of randomized patients as the 
denominator.  
 
Additionally, the analysis populations will be summarized in a table by patient counts, as 
well as in a patient listing, for the randomized population.  
• Full Analysis population; 
• Per Protocol population; 
• Safety population; 
• PK Evaluable population 
 
5.2 
Protocol Deviations 
Protocol deviations will be identified in several ways: through programmatic checks, 
through medical reviews, and by CRAs during site monitoring. Deviations will be 
classified as minor or major prior to the database lock. Major protocol 
deviations/violations will be summarized by treatment group. All protocol deviations will 
be listed. 


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22 February 2017 
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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics were collected during the screening visit. 
 
Descriptive statistics will be provided for all demographic and baseline characteristics 
based on the Safety population.  For categorical variables, the number and percentages of 
patients in each category will be presented.  For continuous variables, summaries will 
include the number of patients with data, mean, median, standard deviation, minimum, 
and maximum.   
 
All demographic and other baseline characteristics will be provided in a listing. 
 
6.1 Demographic Characteristics 
Demographic and baseline variables will be summarized by treatment group and include 
the following: 
 
• Age at screening (years) 
• Age category at screening (<45, 45-<65, 65-<75, ≥75) 
• Gender 
• Ethnicity  
• Race  
• Height (cm) 
• Target Dry Body Weight (kg) 
 
Age will be calculated using the following formula: 
Age = (Date of the screening visit – the date of birth + 1)/365.25. 
 
 
6.2 Baseline characteristics 
Baseline characteristics of the disease will also be summarized by treatment group and 
include the following: 
 
• Duration of pruritus (years) 
• Patient self-characterization of disease severity 
• Localized itch (Palms of Hands) (Yes/No) 
• Pruritus during dialysis session only (Yes/No) 
• Years since ESRD 
• Months on chronic hemodialysis 
• Baseline single pool Kt/V (spKt/V) 
• Baseline urea reduction ratio (URR) 


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• Etiology of chronic kidney disease 
 
Duration of pruritus (years) will be calculated as: 
(Date of the screening visit – the start date of the pruritus+ 1)/365.25.   
 
Similarly, years since ESRD will be calculated as: 
 (Date of the screening visit – first date of ESRD+ 1)/365.25.  
 
Months on chronic hemodialysis will be calculated as: 
(Date of the screening visit – date of first chronic hemodialysis + 1)/30.4. 
 
6.3 
Medical History 
Medical history data will be coded using MedDRA version 19.0 available at the time of 
reporting.  A summary table by treatment group will be presented by MedDRA system 
organ class and preferred term.   The data will also be listed including whether or not the 
patient reported any medical history (yes/no), if yes, system organ class, preferred term, 
recorded medical condition, start date, end date, and whether or not the condition is 
ongoing.  
 
6.4 
Prior and Concomitant Medications 
All medications, including any itch medications, must be recorded within 14 
days prior to the start of Screening through the Follow Up Visit.  These will be coded 
using the March 2016 WHO Drug Dictionary. All prior and concomitant medications will 
be listed.   Additionally, a listing unique medications and their corresponding coding will 
be presented. 
 
 
6.4.1 
Prior Medication 
Prior medications are defined as medications collected on the Previous or Concomitant 
Medications CRF page that the patient has taken any time during the 14 days prior to the 
start of Screening through to the first dose of study drug on Day 1. Prior medications  will 
be summarized in a table using the Safety Population by treatment group.  Medications 
will be reported by drug class (ATC3) and preferred term; a patient will be counted only 
once for each of these.   
 
 
6.4.2 
Concomitant Medication  
Concomitant medications are defined as medications collected on the Previous or 
Concomitant Medications CRF page that are taken from after the start of the first dose of 
study drug on Day 1 through the end of the study (i.e., Follow-Up Visit). Concomitant 


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medications will be summarized for the Safety Population by treatment group.  
Medications will be reported by drug class (ATC3) and preferred term; a patient will be 
counted only once for each of these.   
6.4.3 
Anti-Itch Medication 
Prescribed anti-itch medications are identified as medications where ‘Yes’ is checked on 
the Previous or Concomitant Medications CRF page to the question ‘Was this medication 
used to treat pruritus?’.   
The prior and concomitant medication summaries described in Sections 6.4.1 and 6.4.2 
will be repeated for the prescribed anti-itch medications 
In addition, the number of patients using anti-itch medications and the number of days of 
anti-itch medication use as recorded on the Anti-Itch Medications CRF page will be 
summarized by week in the study.   The mean number of days will also be plotted by 
treatment group.  
 


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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
For Part A, the duration of treatment for each individual patient is expected to be 8 weeks, for 
a total of approximately 24 doses of study drug (3 doses per week) administered immediately 
following each dialysis session. The overall study duration for each individual patient is 
expected to be up to 11.5 weeks.  
The following variables will be summarized by treatment group.  
• Duration of treatment (days) 
• Duration of study (days) 
• Total number of doses actually received (1-3, 4-6, 7-9, etc) 
• Number of missed doses 
Duration of treatment (days) = (Date of first dialysis after last dose) – (Date of first dose) 
+ 1. 
 
Duration of study (days) = (End of participation date) – (Date of first dose) + 1. 
Note that per protocol patients receiving a 4th dialysis treatment during a given week (e.g., 
for fluid overload) should receive an extra dose of CR845 following dialysis after this 
treatment.  The number of patients getting such an extra treatment will be summarized. 
Missed and extra doses will be determined as follows: 
1) Individual weeks for each patient are examined 
2) Apart from the last week, each patient should have 3 doses per week.  Anything more 
would count as extra doses; anything less is counted as missed doses 
3) Patients that complete at or after day 54 should also have 3 doses for their last week 
(and anything going beyond week 8 is included in week 8) 
4) Patients that do not complete through day 54, will be checked for how far they were 
into the week that they discontinued: 1,2 days means that they should have 1 dose; 3,4=2 
doses; 5+=3 doses.  This is compared to actual doses for that week to get determine 
missed/extra 
5) The missed and extra doses are then summed across each patient’s weeks to get the 
total missed and extra. 
 
 
 
 


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8. 
EFFICACY EVALUATION 
8.1 
Overview of Efficacy Analysis Issues 
8.1.1 
Handling of Dropouts or Missing Data 
For the primary efficacy analysis (Part A), missing daily worst itching scores will not be 
imputed. Assuming that the data are missing at random (MAR), the estimates of the 
treatment differences calculated from the MMRM model described above are unbiased. 
Depending on the pattern and the amount of early treatment discontinuations in Part A, 
sensitivity analyses may be performed for Part A in order to provide estimates of 
treatment effect under different imputation algorithms and help refine the sample size for 
Part B. These sensitivity analyses are described in section 8.3.1. 
8.1.2 
Multicenter Studies 
The primary efficacy outcome analysis will be repeated with summary statistics by 
site, but otherwise data from all sites will be pooled for the purpose of analyses.  
8.1.3 
Assessment Time Windows 
For the primary analysis variable, assessment time windows are not needed since the 
NRS Itch Intensity Assessments Log collects the individual scores and average NRS 
score for screening and each post-baseline visit week.  Similarly, the assessments for 
other PROs are collected by visit week on the CRF. 
8.2 
Efficacy Variables 
Table 8-1 
Efficacy Variables and Analysis Methods 


Version:  CARA_CR845-CLIN2101_Draft_SAP_PartA_Final.doc 
 
 
Efficacy Variables  (Part A) 
 
 
MMRM 
 
Logistic 
Regression 
Fisher’s 
Exact  
Test 
Descriptive 
Summary  
Table 
Primary 
Change from baseline to Week 8 in weekly mean of daily 24-hour Worst Itching Intensity NRS  
 
X 
 
 
 
 
 
 
 
 
Secondary 
Change from baseline to Week 8 in total Skindex-10 Scale score 
 
X 
 
 
 
 
 
 
 
 
Other Efficacy Variables 
 
 
 
 
Itch-intensity Variables 
 
 
 
 
Change from baseline in weekly mean of daily 24-hour Worst Itching Intensity NRS score,  
 
 
 
 
  Week 1 to Week 8 
X 
 
 
 
Treatment Response at Week 8 
 
 
 
X 
Proportion of Patient that have a ≥20% Treatment Response 
 
X 
 
 
Itch-related quality of life Variables: 
 
 
 
 
Change from baseline in total Skindex-10 Scale score, Week 2 to Week 8 
X 
 
 
 
Change from baseline to Week 8 in each of the 3 Skindex-10 Scale Scores 
X 
 
 
 
Change from baseline to Week 8 in the total 5-D Itch Scale 
X 
 
 
 
Change from baseline to Week 8 in the total Sleep Disturbance Subscale of the MOS Sleep 
Scale 
X 
 
 
 
Proportion of patients with ‘Very Much Improved’ or ‘Much Improved’ on Patient Global 
 
 
 
 
  Impression of Change at  Week 8 
 
 
X 
 
Proportion of patients with 1pt. improvement in Patient Global Impression of Worst Itch 
Severity 
 
 
X 
 
Changes in ESA from pre-dose to the end of the Treatment Period. 
X 
 
 
 
Missed Dialysis Visits and Incidence of Infection 
 
 
 
 
Total number of missed dialysis visits during treatment period 
 
 
 
X 
Proportion of patients who missed 1 or more visits 
 
 
 
X 
Rate of infections 
 
X 
 
 


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8.2.1 
Efficacy Variables 
The baseline value of the primary efficacy endpoint will be calculated using all the 24-
hour Worst Itching Intensity NRS scores reported during the last 7 days prior to 
randomization, including Day 1 scores collected prior to the administration of the first 
dose of double-blind study drug. The baselines for other PRO measures are the pre-dose 
assessments collected on Day 1. 
8.2.1.1 
Worst Itching Intensity Numerical Rating Scale (NRS) 
Intensity of itch will be measured using the Worst Itching Intensity NRS (see protocol 
Appendix III, Section 18.3) on a worksheet in 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 non-dialysis days.  
 
The Worst Itching Intensity NRS is collected daily during Screening and during the entire 
treatment period. 
8.2.1.1.1 Weekly mean of daily 24-hour Worst Itching Intensity NRS 
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 
(Week 1: Days 2-8; Week 2: Days 9-15; Week 3: Days 16–22; etc.) divided by the 
number of days with non-missing scores for that week. If the daily worst itching score is 
missing for > 3 days during a specific week, the corresponding weekly mean worst 
itching score will be set to missing. The baseline score will be defined as the mean of the 
24-hour worst itching score over the last 7 days prior to randomization (Day -7 to Day -
1), including pre-treatment assessments collected on Day 1 (Day 1). 
Weekly averages are calculated within the EDC system on all available data; these will 
be retained in the analysis datasets, but analyses will be performed on the weekly 
averages with weekly mean values set to missing when more than 3 days in a week are 
missing. 
8.2.1.1.2 Treatment Response 
Treatment Response is defined as the percent improvement from baseline with 
respect to the weekly mean of the 24-hour Worst Itching Intensity NRS score during 
the last week of the Treatment Period (Week 8 for Part A). 
 
If a patient’s mean daily itch score during the last week of the Treatment Period is 
greater than their baseline score (i.e., the patient has an increase in itch compared to 
baseline), his/her response to treatment will be assigned a value of 0. The treatment 
response for patients who discontinue treatment early will be estimated depending on 
the reason for discontinuation. For patients who discontinue due to their underlying 
condition (i.e., non-treatment related adverse event), the treatment response will be 


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estimated by carrying forward the last non-missing weekly mean worst itch score. 
Patients who discontinue due to any other reason will be considered non-responders 
and will be assigned a treatment response value of 0. 
 
8.2.1.1.3 Proportion of patients who have a ≥20% treatment response 
 
This is defined as the number of patients with a treatment response ≥20% based on 
the percent improvement in weekly mean of the 24-hour Worst Itching Intensity 
NRS.  The denominator is the number of patients in the Full Analysis Population. 
8.2.1.2 
Skindex-10 Scale score 
Developed specifically for uremic pruritus, the Skindex-10 Scale (see protocol Appendix 
V, Section 18.5) is an instrument for measurement of quality-of-life. Patients are asked 
the question ‘During the past week, how often have you been bothered by’ and fill in 1 of 
7 circles numbered from 0 (labeled with the anchor phrase “never bothered”) to 6 
(labeled as “always bothered”) for each of the 10 questions.  
The Skindex-10 scale is collected prior to dosing on Week 3, 5,  7 and 8 (Day 15, 29, 43, 
and 57). 
8.2.1.2.1 Average Total Skindex-10 Scale Score 
The total score is the sum of the numeric value of each answered question.  
8.2.1.2.2 Skindex-10 Scale Domain Scores 
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).  
8.2.1.3 
5-D Itch Scale 
The 5-D Itch Scale was developed as a brief but multidimensional questionnaire designed 
to be useful as an outcome measure in clinical trials. The 5 dimensions of itch being 
assessed are degree, duration, direction, disability and distribution (see protocol 
Appendix VII, Section 18.7).  
 
The duration, degree and direction domains each include one item, while the disability 
domain has four items. All items of the first four domains were measured on a five-point 
Likert scale.  The distribution domain included 16 potential locations of itch, including 
15 body part items and one point of contact with clothing or bandages.  
 
Single-item domain scores (duration, degree and direction) are equal to the value 
indicated below the response choice (range 1–5).   The disability domain includes four 
items that assess the impact of itching on daily activities: sleep, leisure ⁄ social activities, 
housework ⁄errands and work ⁄ school. The score for the disability domain is achieved by 


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taking the highest score on any of the four items. For the distribution domain, the number 
of affected body parts is tallied (potential sum 0–16) and the sum is sorted into five 
scoring bins: sum of 0–2 = score of 1, sum of 3–5 = score of 2, sum of 6–10 = score of 3, 
sum of 11–13 = score of 4, and sum of 14–16 = score of 5. 
 
The scores of each of the five domains are achieved separately and then summed together 
to obtain a total 5-D score. 5-D scores can potentially range between 5 (no pruritus) and 
25 (most severe pruritus).  
 
Total 5-D Itch score = duration score (single item) + degree score (single item) + duration 
score (single item) + maximum (4 disability items) + category score based on sum of 
affected body parts. 
 
The 5-D Itch Scale is collected prior to dosing on Weeks 3, 5,  7 and 8 (Day 15, 29 and 43, 
50). 
 
 
8.2.1.4 
Medical Outcomes Study (MOS) Sleep Scale 
The MOS Sleep Scale (see protocol Appendix VI, Section 18.6) was developed by the 
Medical Outcomes Study sleep survey in order to measure sleep disturbance. For most 
questions, the scale instructs patients to circle 1 of 6 numbers, ranging from 1 (labeled 
with the anchor phrase “all of the time”) to 6 (labeled “none of the time”), indicating the 
frequency of various aspects of sleep disruption over the preceding week. Patients are 
also provided instructions to estimate the average amount of sleep per night during the 
past week.  
Ten of the scale’s 12 items are scored using a 6-point response scale, 1 using a 5-point 
scale, and sleep quantity is an open-ended question recording the actual number of hours 
slept.  High score of sleep disturbance, somnolence, sleep indices or low score of sleep 
quantity, adequacy indicates relatively worse sleep problem, whereas lower scores for 
sleep quantity and sleep adequacy indicate worse sleep problems.  The recall period for 
the MOS Sleep Scale is over the past week. 
The original survey items except item 2 will be converted to a 0 to 100 range. For the 5-
point scale (1 to 0, 2 to 25, …, and 5 to 100). For the 6-point scales (1 to 0, 2 to 20, …, 
and 6 to 100). Items in each sleep scale are averaged together to create the score for the 
scale. The scoring method follows MOS Sleep Scale User’s Manual.  
8.2.1.5 
Patient Global Impression of Worst Itch Severity 
The Patient Global Impression of Worst Itch Severity is a PRO measure that assesses 
itch severity. The scale has only 1 item, with 5 possible values ranging from none to 
very severe (see Protocol Appendix VIII, Section 18.8). 


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8.2.1.6 
Patient Global Impression of Change 
The Patient Global Impression of Change is a global PRO measure that assesses the 
change (improvement or worsening) in overall status relative to the start of the study. 
The scale has only 1 item, with values ranging from 1 (Very Much Improved) to 7 
(Very Much Worse) (see protocol Appendix IX, Section 18.9). 
8.2.1.7 
Missed Dialysis Visits and Incidence of Infection 
Missed dialysis visits will be examined by the percentage of patients who missed 
1 or more visits at the dialysis unit and the total number of missed dialysis visits 
during the Treatment Period; this will be derived in a manner identical to the 
missed doses in section 7, but counting dialysis instead of dialysis and dosing.  
 
Incidence of infection is defined based on adverse events, hospitalizations, and/or 
use of antibiotics for treatment of infection related to uremic pruritus.  
 
8.2.1.8 
Iron Status and use of Erythropoiesis-stimulating agents 
(ESA) and IV iron  
The dose and type of ESAs and IV iron administered at each dialysis visit and at the 
End of Treatment will be recorded on the ESA log CRF and Parenteral (IV or 
dialysate) Iron Log CRF respectively.  
The baseline ESA (mcg) will be defined as the average ESA dose for each patient 
during the 4 weeks prior to randomization.  The average ESA dose across dialysis 
visits during each week and each month will also be calculated.    Change from 
baseline will be defined as the difference between the average ESA dose during 
month 1 and month 2 and the baseline average ESA. A similar definition applies to 
change from baseline in IV iron dose (mcg). 
Serum chemistry will include ferritin and transferrin saturation at baseline and on 
Days 1, 15, 29, 43, and 57 only. Change from baseline in ferritin and similarly in 
transferrin saturation will be defined as the difference between the value at a specific 
visit and the baseline value. 
 
8.2.1.9 
Inflammatory biomarkers 
Inflammatory biomarkers will include hepcidin, IL-1, IL-2, IL-6, IL-8, IL-31, 
TNF, IFN, MCP and C-reactive protein. A blood sample of sufficient volume to 
provide for replicate assays of each biomarker, as specified by the laboratory 
performing the analysis, will be collected prior to dialysis on Day 1 and at the end 
of the Treatment Period (Week 8 for Part A).  


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8.3 
Analysis Methods 
The primary goal for Part A of this clinical investigation is to evaluate the efficacy of 
different dose levels of IV CR845 administered after each dialysis session in reducing the 
intensity of itch over an 8-week Treatment Period in hemodialysis patients with 
moderate-to-severe pruritus. Three doses will be studied (1.5 mcg/kg, 1.0 mcg/kg, and 
0.5 mcg/kg), and each will be compared against placebo. One of these doses will be 
selected for further evaluation compared to placebo in Part B. Although a hypothesis test 
of each CR845 dose against placebo will be performed for each of the primary, secondary 
and exploratory variables, these hypothesis tests are not expected to be statistically 
significant based on the planned sample size of approximately 40 patients per treatment 
group and effect size data from previous studies of CR845 in the same population. 
Nevertheless, the estimates of treatment effect and p-values resulting from these 
hypothesis tests will be used, in addition to a review of safety data, to select the most 
appropriate dose for Part B. A sample size of 40 patients per group is adequate to provide 
an appropriate estimate of the magnitude and variability of treatment effect at each dose. 
 
For each analysis variable (primary, secondary, exploratory), all pairwise comparisons 
against placebo will be evaluated. There will be no adjustments for multiplicity.  
 
In addition, an analysis combining the two highest doses of CR845 and analysis of all 
CR845 doses combined against placebo will be performed with respect to the primary 
and secondary variables. An analysis of all CR845 doses combined versus placebo with 
respect to the exploratory variables may be considered.  A dose response analysis will be 
performed with respect to the primary and secondary variables.  
 
8.3.1 
Primary Efficacy Analyses 
Part A 
 
The primary efficacy variable, change from baseline to Week 8 in weekly mean of daily 
24-hour Worst Itching Intensity NRS score, will be analyzed using a mixed effects model 
with repeated measures (MMRM)[1-3] using all visit weeks in the model. The model will 
contain treatment, week, and treatment-by-week interaction as fixed effects; baseline 
score and prior anti-itch medication usage as covariates, and patient as a random effect.  
 
The baseline score will be defined as the mean of the 24-hour worst itching score over the 
last 7 days prior to randomization (Day -7 to Day -1), including pre-treatment 
assessments collected on Day 1 (Day 1). 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 (Week 1: Days 2-8; Week 2: Days 9-15; Week 3: 
Days 16–22; etc.) divided by the number of days with non-missing scores for that week. 
If the daily worst itching score is missing for > 3 days during a specific week, the 


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corresponding weekly mean worst itching score will be set to missing.  The average NRS 
score at each week is also collected on the CRF. 
 
The mixed model can be written as: 
 
dNRSij = β0 + β1 treati + β2 weekj + β3 treat×weekij +  β4Anti-Itchk + bm patientm  + dNRS0 
+ εij 
 
where bm ~ N(0, σ2), 
dNRS – dNRS0 - dNRSj, change from baseline to Week 8 in weekly mean of daily 24 hr  
NRS score, 
dNRS0  : baseline Worst Itching NRS score 
treat : treatment, CR845 1.5 mcg/kg, CR845 1.0 mcg/kg, CR845 0.5 mcg/kg, Placebo 
week : visit week (Week 1, Week 2, Week 3,….. Week 8) 
patient : patient 
 
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 autoregressive, or compound 
symmetry) will be examined. The Akaike information criterion (AIC) will be used to 
determine the appropriate covariance matrix for the MMRM model. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom.  
 
In the primary efficacy analysis, missing daily worst itching scores will not be imputed. 
Assuming that the data are missing at random (MAR), the estimates of the treatment 
differences calculated from the MMRM model described above are unbiased.  
For Week 8, the adjusted Least Square Means and standard error from the model will be 
presented for each treatment group.  For each CR845 treatment group, the treatment group 
difference versus placebo will be estimated as the simple contrast in the treatment effect on 
the last week of treatment (Week 8). For each week, the Least Square Means estimate for the 
difference, standard error, 95% CI, and p-value will be presented. The primary analysis will 
be conducted using the Full Analysis Population. 
An additional supporting table will present descriptive statistics (n, mean, SD, median, min, 
max) for the observed value and change from baseline at each timepoint by treatment group. 
As an exploratory analysis, the primary analysis may be repeated separately using dialysis 
days only. Additionally, the largest sites will be presented individually, with identical 
statistics as sample size allows (if the mixed models do not converge, summary statistics only 
will be presented). 
For the analysis of the primary and secondary variables, the same MMRM model will be 
used to compare all CR845 doses combined vs. placebo by specifying appropriate contrasts 
in the model.  The aforementioned statistics will be presented for this comparison. 
For the primary analysis, the two higher doses will be combined and compared against 
placebo by specifying appropriate contrasts in the model.  A linear trend test across the doses 


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will also be presented for week 8 to explore the dose response curve.  These may also be 
added to other secondary analyses as needed to better understand the response curve. 
Depending on the pattern and the amount of early treatment discontinuations in Part A, 
sensitivity analyses may be performed in order to provide estimates of treatment effect 
under different imputation algorithms and help refine the sample size for Part B.  The 
following sensitivity analyses will be considered: 
1. Sensitivity analysis 1 (Multiple Imputation; MAR):  
This sensitivity analysis assumes that patients with missing data follow the same 
model as other patients in their respective treatment arm that have complete data.  
• Intermittent missing data 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.  
• Data missing after patients discontinue treatment early will then be multiply 
imputed with the SAS MI procedure using a method appropriate for monotone 
missingness (e.g., regression statement).  
• Results of the MMRM on the multiply imputed data sets will be summarized 
by the SAS MIANALYZE procedure.  
 
2. Sensitivity analysis 2 (Trimmed mean):  
This sensitivity analysis uses a trimmed mean approach that assumes that all dropouts 
are “bad” outcomes.   
• The percent change from baseline to week 8 for each outcome and treatment 
group will be determined and the worst 30% percent (or more) of patients will 
be trimmed from each group.  Patients with missing weekly data at Week 8 or 
a percent change from baseline at Week 8 that represents a worsening in 
symptoms are automatically considered to be in the set to be trimmed.  The 
choice of trimmed cut-off may be revised based on a blinded review of the 
data prior to DBL. 
• If this exceeds 30% in any treatment group, the percent trimmed from each 
group will be increased for both groups to cover the larger percentage.   
• Once the population of patients to be trimmed has been established, the mean 
change from baseline to week 8 for each group among the non-trimmed 
patients and the difference between groups will be calculated.   
• Confidence intervals and p-values will be calculated using an approximate 
permutation test:  treatments will be randomly assigned to the observed data 
for the full analysis population (including records for discontinued patients 
and those with missing values) and the above process repeated 10,000 times to 
establish the distribution of the outcome under the null, then the resulting CI 
and p-value will be reported. If the resulting p-value is in close proximity to 
0.05, the number of samples will be increased accordingly to firmly establish 
on which side of 0.05 the p-value falls. 
 
3. Sensitivity Analysis 3 (Multiple Imputation; Missing Not at Random):  


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This sensitivity analysis is an implementation of a pattern mixture model that 
draws from different populations based on the reason for withdrawal. 
• Intermittent missing data will first be imputed using the MCMC method 
implemented with the SAS MI procedure, which is appropriate for non-
monotonic missing data  
• For patients who discontinued study drug due to adverse events, data 
missing after discontinuation will be imputed using the distribution of the 
baseline value of all patients’ daily worst itching score assuming a 
trimmed normal (from 0 to 10).  
• For patients who discontinue due to reasons other than adverse event, 
missing data will after patients discontinue treatment early will be 
multiply imputed using multiple calls of the SAS MI procedure. At each 
time point, missing data will be imputed using data from patients in with 
in each group that have complete data at that time.  
 
8.3.2 
Secondary Efficacy Analyses 
 
The secondary efficacy variable, change from baseline to Week 8 in the average total 
Skindex-10 Scale score, will be analyzed using a MMRM similar to that used for the 
primary efficacy analysis described in Section 8.3.1.   
 
The baseline value will be defined as the value of the Skindex-10 Scale total score 
collected on Day 1, prior to randomization. Timepoints will include: Week 3, Week 5, 
and Week 7, and Week 8 (Day 57). For each dose group, the treatment group difference 
versus placebo will be estimated as the simple contrast in the treatment effect at Week 8 
(Part A).  
 
The total score is the sum of the numeric value of each of 10 questions.  Missing 
Skindex-10 Scale scores will not be imputed. Assuming that the data are MAR, the 
estimates of the treatment differences calculated from the MMRM models above are 
unbiased. 
 
8.3.3 
Other Efficacy Analyses 
8.3.3.1 
Itch Intensity Measures 
Change from baseline in weekly mean of the 24-hour Worst Itching Intensity NRS score 
from Week 2 through the end of the Treatment Period (Week 8) 
This analysis will focus on looking at treatment differences at each post-baseline 
timepoint with respect to this variable and will be evaluated using the same MMRM 
model fitted for the primary efficacy analysis.  
For each time point, the adjusted Least Square Means and standard error from the model 
will be presented for each treatment group.  For each CR845 treatment group, the 


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treatment group difference versus placebo will be estimated as the simple contrast in the 
treatment effect at each time point. The Least Square Means estimate for the difference, 
standard error, 95% CI, and p-value will be presented.  
Treatment Response 
Treatment Response is defined as the percent improvement from baseline with respect to 
the weekly mean of the 24-hour Worst Itching Intensity NRS score during the last week 
of the Treatment Period (Week 8 for Part A). 
  
If a patient’s mean daily itch score during the last week of the Treatment Period is greater 
than their baseline score (i.e., the patient has an increase in itch compared to baseline), 
his/her response to treatment will be assigned a value of 0. The treatment response for 
patients who discontinue treatment early will be estimated depending on the reason for 
discontinuation. For patients who discontinue due to their underlying condition (i.e., non-
treatment related adverse event), the treatment response will be estimated by carrying 
forward the last non-missing weekly mean worst itch score. Patients who discontinue due 
to any other reason will be considered non-responders and will be assigned a treatment 
response value of 0.  
The number and percentage of patients in each category of treatment response will be 
tabulated.  A continuous responder graph of percentage of patients who have a treatment 
response ≥ 10%, ≥ 20%, ≥ 30%, ≥ 40%, ≥ 50%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90%, and ≥ 
100% will be presented. 
 
Proportion of patients who have a ≥20% treatment response 
The proportion of patients who have a ≥20% treatment response will be tabulated and 
analyzed with a logistic regression model containing terms for treatment group, and 
additional covariates chosen using forward selection techniques.  Possible covariates for 
inclusion are age, gender, and Patient Self-Categorization of Pruritus Disease Severity at 
screening (B or C).  The cutoff of 20% was shown to be clinically significant in a 
longitudinal study of uremic pruritus in hemodialysis patients (Mathur, 2010). This 
analysis may be repeated for other cutoffs. 
 
8.3.3.2 
Itch-Related Quality-of-Life Measures 
The following endpoints will be analyzed using a MMRM similar to that used for the 
primary efficacy analysis described in Section 8.3.1: 
• Change from baseline in each of the 3 domains of the Skindex-10 score 
• Change from baseline in the total 5-D Itch Scale Score 
• Change from baseline in the total sleep disturbance subscale of the MOS Sleep 
Scale 
 
Patient Global Impression of Change 
The number and percentage of patients in each of the 7 categories of the Patient Global 
Impression of Change at the end of the Treatment Period (Week 8 for Part A) will be 
tabulated by treatment group.  


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The proportion of patients who rate their itch condition as “Very Much Improved” or 
“Much Improved” will be tabulated. Pairwise treatment differences with each CR845 
treatment group vs. placebo with respect to this variable will be tested using the Fisher’s 
exact test.  
 
Patient Global Impression of Worst Itch Severity 
The number and percentage of patients in each of the 5 categories of the Patient Global 
Impression of Worst Itch Severity at baseline, Weeks 2, 4, and 8 (Part A) will be 
tabulated. Pairwise treatment differences with each CR845 treatment group vs. placebo 
with respect to this variable will be tested using a CMH row means score differ test;  the 
number and percentage of patients with a 1 unit improvement will also be tabulated and 
tested using the Fisher’s exact test.  
 
 
8.3.3.3 
Missed Dialysis Visits and the Incidence of Infection 
The total number of missed dialysis days and the number of patients with at least 1 
missed day will be summarized descriptively. 
The incidence of infection will be tabulated and compared with a Fisher’s exact test. 
 
8.3.3.4 
Iron Status and use of Erythropoiesis-stimulating agents 
(ESA) and IV iron  
The dose and type of ESAs and IV iron administered at each dialysis visit and at the End 
of Treatment will be recorded on the ESA log CRF and Parenteral (IV or dialysate) Iron 
Log CRF respectively.  
The baseline ESA (mcg) will be defined as the average ESA dose for each patient during 
the 4 weeks prior to randomization.  The average ESA dose across dialysis visits during 
each week and each month will also be calculated.    Descriptive statistics will be 
presented for average ESA dose at each timepoint and change from baseline in average 
ESA.  ESA over time will also be plotted by treatment group. Similar analysis will be 
conducted for IV iron dose (mcg).   LS means and 95%CIs for each treatment groups and 
pairwise comparisons will be reported using a MMRM approach identical to that for the 
primary analysis (but with monthly values analyzed rather than weekly). 
Serum chemistry will include ferritin and transferrin saturation at baseline and on Days 1, 
15, 29, 43, and 57 only. Observed values and change from baseline in ferritin and 
transferrin saturation from pre-dose to the end of the Treatment Period (Week 8 for Part 
A) will be summarized. 
 
 


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8.3.3.5 
Change in inflammatory biomarkers 
Changes in blood levels of inflammatory biomarkers, including but not limited to 
hepcidin, interleukin [IL]-2, IL-6, IL-31, pre-albumin, C-reactive protein from pre-dose 
to the end of the Treatment Period (Week 8 for Part A) will be summarized descriptively. 
 
 
8.4 
Examination of Subgroups 
Given the small number of patients per treatment group in Part A, the MMRM employed 
as part of the primary and secondary efficacy analyses will not be repeated for subgroups.  
However, the descriptive summaries for the primary and secondary outcome measures 
will be provided for the following subgroups:  
1. Use of concomitant medication ‘anti-itch medication’ during the week prior to 
randomization (use or non-use). This is also a stratification factor. Patients 
will be categorized as “using anti-pruritic medications” if they have used >1 
dose of potentially anti-pruritic medications used to treat their uremic pruritus 
during the week prior to randomization (e.g. antihistamine (H1), pregabalin, 
gabapentin, nalbuphine, naltrexone, corticosteroids, or buprenorphine). 
2. Patient Self-Categorization of Pruritus Disease Severity at screening (B or C) 
• B profile  
o I sometimes have scratch marks on my skin.  
o I sometimes have problems sleeping because of itching.  
o My itching can sometimes make me feel agitated or sad. 
• C profile 
• I often have scratch marks on my skin that may or may not bleed 
or get infected.  
• I often have a problem sleeping because of itching.  
• My itching often makes me feel agitated or sad. 
 


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9. 
SAFETY EVALUATION 
 
9.1 
Overview of Safety Analysis Methods 
The following assessments will be used to evaluate the safety of CR845 in hemodialysis 
patients with moderate-to-severe pruritus: 
• Adverse Events (AEs) 
• Clinical Laboratory Parameters  
• Vital Signs 
• 12-lead ECG 
All safety analysis will be performed using the Safety Population based upon the 
treatment the patient actually received after randomization. All safety endpoints will be 
summarized by treatment group (and visit as appropriate). 
9.2 
Adverse Events 
The period of adverse event reporting will start after the signing of the ICF through the 
study follow-up visit or early termination visit (or 7 days after the last dose if no early 
termination visit was conducted). All adverse events that occur during this reporting 
period will be collected for all patients, including patients who are deemed to be a screen 
failure. 
All tabular AE summaries will be for treatment-emergent AEs (TEAEs).  Treatment-
emergent adverse events are defined as those events which: 
• Start any time after the first dose of study drug up to the follow-up visit or early 
termination visit (or 7 days after the last dose if no early termination visit was 
conducted), whichever is later.  
• Increase in severity any time after the first dose of study drug up to the follow-up 
visit or early termination visit (or 7 days after the last dose if no early termination 
visit was conducted), whichever is later.  
Given that worsening of a pre-existing condition should be captured as an adverse event 
if the frequency, intensity, or character of the condition worsens after the use of study drug as 
judged by the Investigator, for purposes of analysis, TEAEs are identified as any AE 
starting after the first dose of the study drug up to the study follow-up visit or early 
termination visit (or 7 days after the last dose if no early termination visit was 
conducted). 
For events with missing start dates, the following criteria will be used: 
• if the start date for a particular event is missing, then the event is considered 
treatment-emergent; 
• if the start time is missing and the start date is the same as the first dosing date, 
then the event is considered treatment-emergent. 


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If it cannot be determined whether or not an event is treatment emergent due to a missing 
or partial date, then the event will be assumed to be treatment emergent. 
 
All AEs will be coded to a system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 18.0.  The MedDRA 
treatment dictionary will be used to map adverse events verbatim to system organ class 
(SOC) and MedDRA preferred term for standardization and summary purposes. 
 
The incidence of TEAEs will be summarized by treatment group and overall.  If a patient 
experienced more than one episode of an adverse event, the patient is counted once for 
that Preferred Term. If a patient had more than one adverse event in a System Organ 
Class, the patient is counted only once in that System Organ Class.  The summary tables 
will include incidence estimates for overall system organ class as well as for preferred 
terms within each system organ class.  Incidence will be presented for system organ class 
by decreasing frequency overall and then alphabetically and by preferred term within 
each system organ class by decreasing frequency overall and then alphabetically. 
 
The investigator is to record the severity of each adverse event as mild, moderate, or 
severe. If the same TEAE occurs for a patient on multiple occasions, the TEAE will be 
categorized according to the highest severity rating for that TEAE in that patient.  If the 
severity of the TEAE is not reported, then the severity of the AE will be counted as 
severe. For each treatment group, the incidence within each category will be presented.   
 
The investigator is to record their opinion on the relationship of each adverse event to 
study drug (not related, unlikely related, possibly related, probably related and definitely 
related). If a patient experiences the same adverse event multiple times, the event with the 
strongest relationship to study drug will be counted. For each treatment group, the 
incidence within each category will be presented. For the summary of TEAEs by 
relationship to study drug, if the relationship is missing, it will be counted as related.  The 
incidence of drug-related events (those categorized as possibly related or related) will be 
summarized by treatment group and overall.   
 
The following summary tables will be presented for the Safety population: 
• An overall summary showing for each treatment group, the number and 
percentage of patients with a TEAE, serious TEAE, related TEAE, severe 
TEAE, TEAE leading to dose interruption, TEAE leading to dose reduction, 
TEAE leading to study drug discontinuation, TEAE leading to study 
discontinuation. This table will also include number of events. 
• TEAEs by SOC and preferred term 
• Serious TEAEs by SOC and preferred term  
• TEAEs by SOC, preferred term and maximum severity 
• Related TEAEs by SOC and preferred term 


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• TEAEs leading to study drug discontinuation by SOC and preferred term 
• Most common TEAEs (5% or more of patients in any treatment group) by 
preferred term  
 
In addition, all AEs will be listed in chronological order including patient identifier, age, 
race, gender, 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). Note: For the all AE listing 
only, any screen failure patient that has an adverse event after signing ICF will be 
included for completeness. Separate listings will be generated for SAEs, deaths, and AEs 
leading to treatment discontinuation.  Additionally, a coding list of preferred terms and 
the verbatim text associated with them will be produced. 
No statistical tests will be performed on adverse events. 
9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
A serious adverse event is defined as any AE occurring at any dose and regardless of 
causality that results in death, is life-threatening, requires in-patient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, or is an important medical 
event.   
 
SAEs will be collected from date the informed consent form is signed up to the Follow-
up visit or 7 days following the last dose of study drug, whichever is later.  SAEs that 
occur after the Follow-Up Visit and up to 30 days thereafter should also be documented 
on an SAE form if they are deemed by the Investigator to be “definitely related”, 
“probably related”, or “possibly related” to the study drug. SAEs that occur after the 
Follow-up Visit and up to 30 days thereafter do not need to be documented on an SAE 
form if they are deemed by the Investigator to be “unlikely related” or “not related” to 
study drug.  A more detailed definition of SAEs is provided in Protocol sections 11.3.5 
and 11.3.6.  The analysis of SAEs is similar to that of AEs described in Section 9.2.   
 
Patient deaths are captured on the Adverse Events eCRF page. Patient death listings will 
include all death data available including date of death and cause of death.  Additionally, 
SAEs and AEs resulting in discontinuation will be listed. 
 
9.4 
Clinical Laboratory Evaluation 
Blood and urinalysis samples will be collected during screening and day 1 before study 
drug administration, on days 15, 29 and 43 and day 57 (end of treatment). 
All clinical laboratory data will be reported in SI units.  Baseline will be defined as the 
last lab value obtained prior to treatment.  Note that the Day 1 assessment can be 


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included in the evaluation of baseline given that the assessment is performed prior to 
dosing.  
Summaries of actual values and change from baseline values by visit will be presented 
for quantitative laboratory parameters (e.g., WBC, lymphocytes). Only data from the 
central laboratory will be used.   
If two or more evaluations occur in the same visit window, the evaluation closest to the 
target visit day will be selected for inclusion in the analysis.  If multiple evaluations are 
equally close to the target visit day, then the latest evaluation will be selected for 
inclusion in the analysis.   
All clinical laboratory values will be presented in a listing; additionally, ALT, AST, 
bilirubin and ALP will be presented in a separate listing with 3x and 5x ULN flagged for 
ALT and AST; 2x ULN flagged for bilirubin; and 1.5x ULN flagged for ALP. 
Figures will be presented for a subset of laboratory values including Calcium, Ferritin, 
Transferritin Saturation, Intact Parathyroid Hormone, Serum Albumin and Phosphate. 
 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
 
9.5.1 
Vital Signs 
Vital signs (including body temperature, heart rate, systolic and diastolic blood 
pressure) will be collected during screening and on days 1, 15, 29, 57 (end of 
treatment visit), and 64 (follow-up visit).  Baseline is defined as the last measurement 
taken on or prior to the first day of dosing.  Note that the Day 1 assessment can be 
included in the evaluation of baseline given that the assessment is performed prior to 
dosing.  
Summary tables will include descriptive statistics (number of patients, mean, std, 
median, min, and max) for baseline and each post-baseline assessment. Descriptive 
statistics will be calculated on both the actual score and the change from baseline 
score.  If two or more evaluations occur in the same visit window, the evaluation 
closest to the target visit day will be selected for inclusion in the analysis.  If multiple 
evaluations are equally close to the target visit day, then the latest evaluation will be 
selected for inclusion in the analysis.   
All vital sign summaries will include the patients in the Safety Population who have 
at least a post-baseline assessment (for criteria based on post-baseline assessments) 
and with both a baseline and at least one post-baseline assessment (for criteria 
evaluating changes from baseline). 
 
A second summary will focus on the individual patient measures with the intent of 
identifying post-baseline abnormalities defined as clinically significant. Using the 


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clinically significant ranges specified below, descriptive statistics will summarize the 
post-baseline patient frequencies (percentages) that are outside the range defined for 
each vital sign measure.  All vital sign values will be considered when evaluating the 
criteria. 
 
The number and percent of patients meeting the criteria for each of the following 
categories during the study will also be presented: 
 
Body Temperature 
>38 degrees centigrade or <36 degrees centigrade 
Heart Rate 
>130 bpm or <55 bpm 
 
Change from baseline (increase or decrease) of ≥30 bpm 
Blood Pressure 
BP > 180/100 or BP < 90/60 
 
Change from baseline (increase or decrease) in SBP of ≥40 
mmHg 
 
 
Change from baseline (decrease) in SBP of ≥60 mmHg 
 
 
Change from baseline in DBP (increase or decrease) of ≥20 
mmHg 
 
 
Change from baseline in DBP (decrease) of ≥40 mmHg 
 
 
All vital signs will be listed in by patient listings including visit, collection date/time, and 
will be sorted by treatment group, patient ID, and date/time of assessment.   


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9.5.2 
12-Lead ECGs 
Standard 12-lead ECG readings with the patient in a supine position will be performed in 
triplicate during screening and day 1 prior to study drug administration, and on days 29 
and 57 (end of treatment).  
ECG results include an overall interpretation of ‘normal’, ‘abnormal but not clinically 
significant’ or ‘abnormal and clinically significant’.  These results will be tabulated by 
treatment group and overall at each time point. ECG values will also be listed by patient. 
Summaries of actual values and change from baseline by visit will be presented.    
 
If two or more evaluations occur in the same visit window, the evaluation closest to the 
target visit day will be selected for inclusion in the analysis.  If multiple evaluations are 
equally close to the target visit day, then the latest evaluation will be selected for 
inclusion in the analysis.   The worst post-baseline result across all visits will be flagged 
and reported separately; this may include measures that were not in the individual visit 
summaries.  
 
Clinically significant abnormalities at screening will be recorded as medical history.  
Clinically significant abnormalities or worsening of ECG findings observed after the first 
dose of study drug should be reported as Adverse Events. 
 
 
ECG 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 # or AE # if deemed a clinically significant 
abnormality. 
 


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10. 
PHARMACOKINETIC EVALUATION 
Plasma samples will be analyzed for CR845 using liquid chromatography with tandem 
mass spectrometric detection according to validated analytical methods.  All PK analyses 
will be performed using the PK Evaluable population.   
Missing data will not be imputed.  If any patients are noncompliant with the dosing 
schedule or have incomplete data, a decision will be made on a case-by-case basis as to 
their inclusion in the analysis prior to database lock. 
 
10.1 
Plasma Concentration Data 
Blood samples for PK analysis will be collected from the predialyzer (arterial) line at  
Week 1, Day 1,  Day 2, and Day 3; Week 2, Day 8; Week 4, Day 22; Week 6, Day 36; 
Week 8, Day 50, Day 51 and 52; at time points listed in the Pharmacokinetic Sampling 
Schedule (Protocol Appendix II, Section 18.2). 
Treatment 
Pharmacokinetic Samples 
  
Time After Study Drug Administration (Post-
dialysis) 
Week Day 
Pre-
dialysis 
Post-
dialysis 
5 
minutes 
30 
minutes 
1 
hour 
2 
hours 
4 
hours 
24 
hours 
1 
1 
X 
X 
X 
X 
X 
X 
X 
  
2 
  
  
  
  
  
  
  
X 
3 
X 
  
X 
  
  
  
  
  
2 
8 
X 
  
X 
  
  
  
  
  
4 
22 
X 
  
X 
  
  
  
  
  
6 
36 
X 
  
X 
  
  
  
  
  
8 
50 
X 
X 
X 
X 
X 
X 
X 
  
51 
  
  
  
  
  
  
  
X 
52 
X 
  
  
  
  
  
  
  
 
Plasma concentrations of CR845 will be summarized by dosing group and overall at each 
nominal sampling time point.  Descriptive statistics will include n, arithmetic mean, SD, 
median, minimum, maximum, and geometric mean with 95% CI.  
• Geometric mean = exp (mean of log-transformed concentration data).   
• Below quantitation limit (BQL) concentrations will be treated as 0.5 x the 
LOQ for descriptive statistics.  Mean concentrations that are BQL will be 
presented as BQL, and the SD will be reported as not applicable (N/A).  
In plasma concentration tables and plots of mean profiles, statistics will be calculated 
having set concentrations to missing if one of the following cases is true: 
1. A concentration has been collected as ND (i.e., not done) or NS (i.e., no sample), 


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2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Mean and individual patient plasma concentration-time profiles will be plotted by dose 
on linear and semi-logarithmic scales for CR845. 
All individual patient concentration data will be listed, including those being excluded 
from PK analyses. 


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11. 
OTHER ANALYSES 
Not applicable at this time. 
 
 


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12. 
INTERIM ANALYSES AND DATA MONITORING 
No formal interim analysis of efficacy data is planned for Part A or Part B.  
 
Following completion of Part A, there will be an unblinded analysis to determine the 
dose of CR845 to be used in Part B. This analysis will not affect the Type I error for Part 
B, as it will represent the final analysis for Part A.  
An ongoing review of the cumulative safety data for this study will be conducted by an 
external DMC for both Part A and Part B of this study. The operation of the DMC will be 
governed by a charter that will describe the groups’ frequency of meeting, procedures 
(including, but not limited to, periodic safety monitoring) and requirements for reporting 
its observations to the Sponsor. 
 


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13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Sensitivity analyses have been updated from those described in the protocol to reflect 
more current methods being applied by FDA. 


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14. 
STATISTICAL APPENDIX 
For the mixed model analyses, the code will be of the following form: 
The MMRM with maximum likelihood estimation will utilize the following SAS Proc 
Mixed code: 
proc mixed data = adweek; 
class trt01p avisitn usubjid antiitch; 
model aval = trt01p avisitn trt01p*avisitn treat*week base antiitch /ddfm=KR; 
repeated avisitn / type = <selected covariance matrix> patient = usubjid; 
run; 
 
Note that it is at the programmer’s discretion to use numeric vs character variables for treatment and use 
other parameterizations of an equivalent model. 
 
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. 


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15. 
REFERENCES 
 
1. Brown H., Prescott R. Applied Mixed Models in Medicine. John Wiley & Sons, 
2002. 
2. Verbeke G., Molenberghs G. Linear Mixed Models for Longitudinal Data. 
Springer-Verlag, New   York, 2002. 
3. Mallinckrodt C.H. et al. Assessing Response Profiles from Incomplete 
Longitudinal Clinical Trial Data Under Regulatory Considerations. Journal of 
Biopharmaceutical Statistics; Vol. 13, No. 2, pp. 179-190, 2003. 
4. Mathur VS, Lindberg J, Germain M, Block G, Tumlin J, Smith M, et al. A 
longitudinal study of uremic pruritus in hemodialysis patients. Clin J Am Soc 
Nephrol. 2010; 5:1410-9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16. 
APPENDICES 
 
16.1 
Schedule of Events 
 


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