Conditions: Osteoarthritis, Hip Osteoarthritis, Knee Arthritis Joint Diseases Musculoskeletal Diseases Rheumatic Diseases
Keywords: Osteoarthritis Hip Knee CR845 Analgesic Kappa opioid difelikefalin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 761
Healthy volunteers: no

Brief summary:
The study schedule consists of a Screening Period (up to 14 days), a blinded 4- week Titration-to-Effect Period with weekly visits, a blinded 4-week Maintenance Treatment Period at the optimal dose level determined for each patient, and a 1-week Follow-up Period.

Eligible patients will be randomized to receive either CR845 or placebo in a 2:1 ratio. Every patient will be started on a 1-mg dose of CR845 or matching placebo. During the post-randomization Titration-to-Effect period, the dose of study drug may be increased to 2.5 mg or 5 mg in a double-blind fashion. Patients may know their dose is being changed but will not know whether they were randomization to active study drug or placebo. Approximately 330 patients will be enrolled in this study.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled, titration-to-effect study of orally administered CR845 in patients with osteoarthritis of the hip or knee.

The study schedule consists of a Screening Period (up to 14 days), a blinded 4- week Titration-to-Effect Period with weekly visits, a blinded 4-week Maintenance Treatment Period at the optimal dose level determined for each patient, and a 1-week Follow-up Period.

Eligible patients will be randomized to receive either CR845 or placebo in a 2:1 ratio. Randomization will be stratified based on a patient's primary OA joint (knee vs. hip). Every patient will be started on a 1-mg dose of CR845 or matching placebo. During the post-randomization Titration-to-Effect period, the dose of study drug may be increased to 2.5 mg or 5 mg in a double-blind fashion.

Patients may know their dose is being changed but will not know whether they were randomized to active study drug or placebo. Approximately 330 patients will be enrolled in this study.

During the Screening, Titration-to-Effect and Follow-up Period, pain intensity scores will be obtained at specified time points. Blood sampling and safety assessments will be conducted during this period as well.

The use of rescue medication for the treatment of any pain (including but not limited to headache, menstrual cramps, or non-target joint pain) during the study will be discussed with the patients at the Screening Visit. Acetaminophen is the only allowable rescue medication for pain beginning from Day -5 until the end of the Maintenance Treatment Period. Starting at the Screening Visit Acetaminophen will be provided as 325-mg tablets and its use (number of tablets taken in the previous 24 hours) will be reported each evening in the patient diary.

Arms:
arm 1: Dosing twice a day (BID) for a total of 8 weeks, with each dose administered at least 2 hours prior to or after a meal. arm 2: Dosing twice a day (BID) for a total of 8 weeks, with each dose administered at least 2 hours prior to or after a meal. arm 3: Dosing twice a day (BID) for a total of 8 weeks, with each dose administered at least 2 hours prior to or after a meal. arm 4: Dosing twice a day (BID) for a total of 8 weeks, with each dose administered at least 2 hours prior to or after a meal.

Interventions: intervention 1: CR845 tablet 1 mg intervention 2: CR845 tablet 2.5 mg intervention 3: CR845 tablet 5 mg intervention 4: Placebo tablet
Intervention descriptions: intervention 1: CR845 tablets will be provided as 1 mg enteric-coated tablets. All tablets are white in color with no markings and are identical in appearance, regardless of dose and treatment. intervention 2: CR845 tablets will be provided as 2.5 mg enteric-coated tablets. All tablets are white in color with no markings and are identical in appearance, regardless of dose and treatment. intervention 3: CR845 tablets will be provided as 5 mg enteric-coated tablets. All tablets are white in color with no markings and are identical in appearance, regardless of dose and treatment. intervention 4: Placebo tablets will be provided as enteric-coated tablets. All tablets are white in color with no markings and are identical in appearance, regardless of dose and treatment.

Protocol document:
Prot_000.pdf: 
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A Randomized, Double-Blind, Placebo-Controlled, Titration-to-Effect Study of Orally 
Administered CR845 in Patients with Osteoarthritis of the Hip or Knee  
PROTOCOL NUMBER: 
CR845-CLIN2002-PO 
IND NUMBER: 
113,440 
DEVELOPMENT PHASE: 
Phase 2 
PROTOCOL TITLE: 
A Randomized, Double-Blind, Placebo-Controlled, 
Titration-to-Effect Study of Orally Administered CR845 in 
Patients with Osteoarthritis of the Hip or Knee 
PROTOCOL VERSION: 
DATE: 
Version 3.0 
04 November 2016 
SPONSORED BY: 
CARA Therapeutics, Inc. 
Four Stamford Plaza 
Stamford, CT 09602 
(203) 567-1500
CONTRACT RESEARCH 
ORGANIZATION: 
INC Research, LLC 
MEDICAL MONITOR: 
 
 
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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2. TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................................. 3 
2. 
TABLE OF CONTENTS ............................................................................................................. 14 
3. 
LIST OF ABBREVIATIONS ........................................................................................................ 18 
4. 
INTRODUCTION ...................................................................................................................... 20 
4.1 
Background and Rationale ........................................................................................... 20 
4.2 
Clinical Experience ....................................................................................................... 20 
4.2.1 Previous Studies with the Oral Formulation .................................................... 21 
4.3 
Summary of Potential Risks and Benefits .................................................................... 22 
5. 
STUDY OBJECTIVES ................................................................................................................ 24 
5.1 
Primary Objective ......................................................................................................... 24 
5.2 
Secondary Objectives ................................................................................................... 24 
6. 
INVESTIGATIONAL PLAN ........................................................................................................ 25 
6.1 
Study Design ................................................................................................................. 25 
6.2 
Number of Patients and Sites ...................................................................................... 28 
6.3 
Duration of Treatment ................................................................................................. 28 
6.4 
Stopping Rules .............................................................................................................. 29 
6.5 
Safety Monitoring Team (SMT) .................................................................................... 29 
7. 
PATIENT POPULATION ........................................................................................................... 30 
7.1 
Inclusion Criteria .......................................................................................................... 30 
7.2 
Exclusion Criteria .......................................................................................................... 31 
7.3 
Clinical Surveillance Team (CST) Eligibility Assessment ............................................... 32 
7.4 
Premature Patient Withdrawal .................................................................................... 32 
7.5 
Patient Replacement Criteria ....................................................................................... 33 
7.6 
Counseling Women of Childbearing Potential ............................................................. 33 
8. 
STUDY TREATMENTS .............................................................................................................. 34 
8.1 
Investigational Product ................................................................................................ 34 
8.1.1 Labeling ............................................................................................................ 34 
8.2 
Dispensing and Storage ................................................................................................ 34 
8.3 
Method of Assigning Patients to Treatment Groups ................................................... 35 
8.4 
Emergency Unblinding ................................................................................................. 35 
8.5 
Selection of Doses in the Study .................................................................................... 35 
8.6 
Selection of Timing of Dose for Each Patient ............................................................... 35 
8.7 
Dosing Regimen............................................................................................................ 36 
8.8 
Analgesic Rescue Medication ....................................................................................... 36 


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8.9 
Drug Accountability ...................................................................................................... 36 
8.10 Treatment Compliance................................................................................................. 37 
8.11 Prior and Concomitant Medications ............................................................................ 37 
8.12 Prohibited Medications ................................................................................................ 37 
9. 
STUDY PROCEDURES .............................................................................................................. 39 
9.1 
Study Periods and Visits ............................................................................................... 39 
9.1.1 Screening and Washout ................................................................................... 39 
9.1.2 Baseline (Visit 2) ............................................................................................... 40 
9.1.3 Titration Period................................................................................................. 41 
9.1.3.1 
Day 8 (Visit 3) ....................................................................................... 41 
9.1.3.2 
Days 15 and 22 (Visits 4 and 5) ............................................................ 41 
9.1.3.3 
Day 29 (Visit 6) ..................................................................................... 42 
9.1.4 Maintenance Treatment Period ....................................................................... 42 
9.1.4.1 
Day 43 (Visit 7) ..................................................................................... 42 
9.1.4.2 
Day 57 (Visit 8) or Early Termination ................................................... 43 
9.1.5 Follow-Up Evaluation (Visit 9) .......................................................................... 43 
9.1.6 Unscheduled Visits ........................................................................................... 44 
9.2 
Assessments ................................................................................................................. 44 
9.2.1 Efficacy Evaluations .......................................................................................... 44 
9.2.1.1 
Pain Intensity Numerical Rating Scale.................................................. 44 
9.2.1.2 
Western Ontario and McMaster Universities Osteoarthritis Index..... 44 
9.2.1.3 
Patient Global Impression of Change ................................................... 44 
9.2.2 Safety Evaluations ............................................................................................ 45 
9.2.2.1 
Physical Examination ............................................................................ 45 
9.2.2.2 
Vital Signs ............................................................................................. 45 
9.2.2.3 
Electrocardiogram ................................................................................ 45 
9.2.2.4 
Clinical Laboratory Assessments .......................................................... 45 
9.2.3 Management of Fluid Balance.......................................................................... 46 
10. SAFETY DEFINITIONS, REPORTING AND MONITORING ......................................................... 47 
10.1 Definition of Adverse Events ........................................................................................ 47 
10.1.1 Recording and Reporting Adverse Events ........................................................ 48 
10.1.2 Deaths ............................................................................................................... 48 
10.1.3 Pregnancy and Other Events that Require Accelerated Reporting .................. 48 
10.2 Adverse Event Identification and Assessment ............................................................. 49 
10.2.1 Evaluation of Severity ....................................................................................... 50 


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10.2.2 Evaluation of Causality ..................................................................................... 50 
10.3 Adverse Event Follow-up and Reporting ..................................................................... 50 
10.3.1 Investigator Alert Notification .......................................................................... 50 
10.3.2 Adverse Event Follow-up .................................................................................. 50 
10.3.3 Adverse Event Documentation ........................................................................ 51 
10.3.4 Serious Adverse Event Reporting ..................................................................... 51 
10.3.4.1 Notification and Documentation from the Investigator to the Sponsor51 
10.3.4.2 Reporting to Regulatory Authorities .................................................... 52 
11. STATISTICAL METHODS .......................................................................................................... 53 
11.1 General Considerations ................................................................................................ 53 
11.2 Determination of Sample Size ...................................................................................... 53 
11.3 Interim Assessment ...................................................................................................... 54 
11.4 Analysis Populations .................................................................................................... 54 
11.5 Patient Accounting and Study Disposition ................................................................... 54 
11.5.1 Patient Disposition ........................................................................................... 54 
11.5.2 Protocol Deviations .......................................................................................... 54 
11.6 Baseline Patient Data ................................................................................................... 55 
11.6.1 Demographic and Other Baseline Characteristics ............................................ 55 
11.7 Study Drug Accountability ............................................................................................ 55 
11.8 Efficacy Analyses .......................................................................................................... 55 
11.7.1 Primary Efficacy Variable .................................................................................. 55 
11.8.1 Secondary Efficacy Variables ............................................................................ 58 
11.9 Safety 
60 
11.9.1 Adverse Events ................................................................................................. 60 
11.9.2 Prior and Concomitant Medications ................................................................ 61 
11.9.3 Clinical Safety Laboratory Evaluations ............................................................. 61 
11.9.4 Vital Signs ......................................................................................................... 61 
11.9.5 ECGs .................................................................................................................. 62 
12. STUDY CONDUCT ................................................................................................................... 63 
12.1 Sponsor and Investigator Responsibilities ................................................................... 63 
12.1.1 Sponsor Responsibilities ................................................................................... 63 
12.1.2 Investigator Responsibilities ............................................................................. 63 
12.2 Quality Control and Quality Assurance ........................................................................ 63 
12.2.1 Audits and Inspections ..................................................................................... 64 
12.2.1.1 Source Documents and Access to Source Data/Documents ............... 64 


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12.3 Data Collection, Validation and Analysis...................................................................... 64 
12.4 Study Monitoring Plan ................................................................................................. 64 
12.5 Safety Monitoring Plan ................................................................................................ 64 
12.6 Data Management and Record Keeping ...................................................................... 65 
12.6.1 Case Report Form Completion ......................................................................... 65 
12.6.2 Data Management Responsibilities.................................................................. 65 
12.7 Administrative Procedures ........................................................................................... 65 
12.7.1 Study Records Retention .................................................................................. 65 
12.7.2 Protocol Adherence .......................................................................................... 65 
12.8 Changes to the Protocol ............................................................................................... 66 
12.9 Publication of Study Findings ....................................................................................... 66 
13. ETHICS/PROTECTION OF HUMAN PATIENTS ......................................................................... 67 
13.1 Ethics 
67 
13.2 Good Clinical Practices ................................................................................................. 67 
13.3 Institutional Review Board ........................................................................................... 67 
13.4 Informed Consent Process ........................................................................................... 68 
13.5 Patient Confidentiality ................................................................................................. 68 
13.6 Study Discontinuation .................................................................................................. 69 
14. REFERENCES ........................................................................................................................... 70 
15. SCHEDULE OF EVENTS ........................................................................................................... 71 
16. APPENDICES ........................................................................................................................... 74 
Appendix 1 
Regulations and Guidelines........................................................................... 75 
Appendix 2 
Numerical Rating Scale ................................................................................. 76 
Appendix 3 
Western Ontario and McMaster Osteoarthritis Index ................................. 77 
Appendix 4 
Patient Global Impression of Change ........................................................... 79 
Appendix 5 
Investigator Approval Statement .................................................................. 80 
 


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3. LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice a day 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CARA 
Cara Therapeutics, Inc. 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CV 
coefficient of variation 
DIBD 
development international birth date 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAP 
Full Analysis population 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LOCF 
last observation carried forward 
LOTE 
lack of therapeutic efficacy 
MCH 
mean corpuscular hemoglobin 


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MCHC 
mean corpuscular hemoglobin concentration 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFMC 
medium-fat, medium-calorie 
MMRM 
mixed effect model with repeated measures 
NRS 
numerical rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OA 
osteoarthritis 
PCP 
phencyclidine 
PGIC 
Patient Global Impression of Change 
PNS 
peripheral nervous system 
PO 
oral (per os) 
PP 
Per-Protocol 
PT 
preferred term 
RBC 
red blood cell 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
WOMAC 
Western Ontario and McMaster Osteoarthritis Index 
 


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4. INTRODUCTION 
4.1 
Background and Rationale 
CR845 is a selective kappa-opioid receptor agonist with a peripheral mechanism of action that 
is currently being developed by Cara Therapeutics, Inc. (CARA) as a novel therapeutic agent for 
the treatment of acute and chronic pain. 
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. 
Morphine, the most widely used opioid analgesic, acts primarily via activation of the mu opioid 
receptor located in the CNS and PNS. Mu opioid receptor activation is associated with a wide 
array of undesirable side effects, including sedation, respiratory depression, abuse liability, 
itching, 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 pain and 
inflammatory signals without producing the side effects reported after 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 with no known activity at other non-opioid receptors, 
ion channels, or transporters. Its unique peptidic structure significantly differs from that of 
small molecule kappa opioid agonists developed to date, which, for the most part, are active 
within the CNS. 
Due to its hydrophilic tetrapeptide structure, CR845 has limited membrane permeability by 
passive diffusion that limits its access to the CNS. Thus, the compound preferentially activates 
kappa opioid receptors located outside the CNS (e.g., in peripheral sensory nerves and ganglia). 
Findings from nonclinical pharmacological studies in rodents have indicated that CR845 can 
decrease pain related to activation of nociceptors and/or nerve injury, decrease itch caused by 
different pruritogens, and reduce the production and release of pro-inflammatory mediators.  
Intravenous (IV) and oral formulations of CR845 are being developed as treatments for 
postoperative and chronic pain, respectively, with the potential for reduced side effects and 
improved tolerability compared with currently available opioid medications. CR845 (IV) is also 
being evaluated for the treatment of uremic pruritus.  
4.2 
Clinical Experience 
CR845 has been tested as oral capsules, oral tablets, and IV formulations.  
To date, 818 subjects across 15 US studies and 2 Japanese studies have received CR845 
treatment, 577 have been treated with an IV formulation and 241 have been treated with an 
oral formulation (capsules or tablets).  
Subjects/patients were treated with single IV doses of CR845 ranging from 1 to 40 mcg/kg, or 
repeated IV dosing for up to a 48-hour period for a total dose up to 160 mcg/kg (i.e., 11 mg 


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over a 24-hour period). Studies using the IV formulation evaluated patients with postoperative 
pain (abdominal surgery and bunionectomy) and uremic pruritus.  
Subjects/patients treated with the oral formulation were exposed to doses ranging from 
0.25 mg to 10 mg in both fasted and fed conditions. Outpatients with OA of the hip or knee 
were treated in a small Phase 2a study evaluating doses up to 5 mg twice a day (BID). 
Overall, CR845 has been shown to be safe and well tolerated when administered as both single 
and multiple IV or oral doses. A total of 650 patients/subjects have experienced treatment-
emergent adverse events (TEAEs) have been reported in the program across active- and 
placebo-treated patients. There have been no deaths reported. 
A cumulative total of 33 serious adverse events (SAEs) have been reported in patients exposed 
to CR845 in the both IV and PO studies from the time of the DIBD to March 2016, of which 9 
SAEs were classified by the Investigators as being related to study drug. These events include 
hypernatremia/blood sodium increased (2 cases), sinus tachycardia (1 case), sedation (1 case), 
somnolence and drowsiness (2 cases), hypertension (1 case) and mental status changes (2 
cases). All 9 of these events occurred in CR845-treated patients/subjects, with 7 of the 9 events 
occurring in the highest CR845 dose group (> 5mcg/kg IV). The other 2 SAEs were associated 
with lower doses of CR845 and occurred in the same hemodialysis patient.  
While there is no apparent dose-relationship for CR845 in the reported adverse events (AEs) in 
any system organ class (SOC), it is clear that there are more AEs reported in each SOC for the 
highest CR845 dose groups (20 to 40 mcg/kg, IV). To mitigate the risks associated with the 
higher dose range, the highest dose to be evaluated in this study is 5 mg. 
CR845 also produces a transient increase in urine output (on average, 0 to 12 hours after 
dosing) without a corresponding increase in electrolyte loss (i.e., increased excretion of free 
water only). This aquaretic activity, which is to be distinguished from the non–
electrolyte-sparing action of diuretics, is a well-known pharmacological effect of kappa opioid 
agonists. This aquaretic effect may be related to reports of tachycardia and elevations in serum 
sodium that have been reported in CR845 clinical studies.  
In contrast to the classical side effects reported with mu opioid agonists like morphine, 
respiratory depression related to the use of CR845 has not been reported. The relative abuse 
potential of CR845, compared to placebo or pentazocine (a schedule IV CNS-acting mixed 
mu-kappa partial agonist analgesic) has also been evaluated in recreational poly-drug users 
experienced with the use of opioids and hallucinogenic agents. In these patients/subjects, it 
was demonstrated that CR845 may present a low risk for abuse potential in humans in 
comparison to clinically used opioids. This observation is consistent with the absence of miosis 
after administration of CR845, a classical indicator of mu opioid CNS bioactivity, in contrast to 
the robust miosis observed in the same patients/subjects who are administered pentazocine. 
4.2.1  Previous Studies with the Oral Formulation 
Phase 1 Study in Healthy Volunteers:  A phase 1 trial (CR845-CLIN1001-PO) testing 
enteric-coated capsules of CR845 (0.5 mg, 1 mg, 3 mg, or 10 mg) or matched placebo was 
completed December 2011 with 50 healthy volunteers and established the preliminary oral 


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bioavailability and safety parameters of CR845. Oral bioavailability was estimated to be 
approximately 16%, with maximal plasma concentration and overall exposure increasing in a 
linear fashion at ascending doses, and a time to maximal concentration of approximately 3 
hours. Although variability was observed in systemic exposure (i.e., inter-individual 
bioavailability ranged from 1% to 43% with a coefficient of variation of 61.5%), the level of 
exposure at all doses was sufficient to activate peripheral kappa receptors, as indicated by an 
increase in serum prolactin, a known biomarker of kappa receptor activation (with prolactin 
levels comparable to those seen after administration of commonly used mu opioids). Oral 
CR845 was well tolerated and considered safe across all doses tested. There were no SAEs 
during the study, no severe AEs, no discontinuation of the study drug, and no subjects 
withdrew from the study due to AEs.  
The most common TEAEs were increased orthostatic heart rate, abdominal discomfort and 
paresthesia. With the exception of abdominal discomfort, this TEAE profile is consistent with 
previous studies in humans with the IV formulation of CR845. Clinical laboratory results were 
generally stable throughout the study and no significant changes in electrocardiogram (ECG) 
measurements were reported.  
The consumption of a high-fat meal decreased the exposure of CR845 and delayed its oral 
absorption relative to fasting subjects (tmax ~ 12 hours) and mean estimate of oral bioavailability 
of 3%), suggesting that this formulation should not be taken at the time of a high-fat meal. 
Phase 2 Study in Patients with Osteoarthritis:  A Phase 2a multiple ascending-dose pilot study 
(CR845-CLIN2001-PO) in patients with osteoarthritis (OA) of the hip and knee was completed in 
October 2015. Four different doses of CR845 were evaluated over a 2-week treatment period in 
a single-blinded study (0.25-, 0.5-, 1- and 5-mg tablets BID; n=20 per treatment group). 
Safety and Tolerability: CR845 was well tolerated in the first 3 treatment groups (0.25- 0.5- and 
1-mg tablets BID). An increase in AEs was noted in the 5-mg dose group (4 patients 
discontinued secondary to dizziness). In addition, although no patients were symptomatic, 
there was a dose-related increase in the number of slightly elevated serum sodium levels 
observed during the study. The majority of cases were between 146 to 147 mmol/L (normal 
range: 135 to 145 mmol/L). No patients exceeded a serum sodium level of 150 mmol/L.  
Efficacy:  All treatment groups showed a continued improvement over time in numerical rating 
scale (NRS) pain scores (index joint) with a percent improvement on Day 15 ranging from 25 to 
31% (last observation carried forward [LOCF]) and 25 to 26% (mixed imputation). 
 
 
4.3 
Summary of Potential Risks and Benefits 
CR845 is a novel analgesic medication that could provide benefit to patients with acute or 
chronic pain. 
Treatment with CR845 has not generally been associated with the AEs often experienced with 
mu-opioid receptor agonists such as constipation, nausea and vomiting, respiratory depression, 


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itching, cognitive impairment or abuse liability, nor does it appear to have the gastrointestinal 
or cardiovascular risks associated with nonsteroidal anti-inflammatory drug (NSAID) use. 
The incidences of nausea and vomiting observed in the Phase 2a OA study were 6% and 2% 
respectively, lower than rates reported for mu-opioid receptor agonists. 
A fully detailed summary of the potential risks and benefits of CR845 is provided in the 
Investigator’s Brochure (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. STUDY OBJECTIVES 
5.1 
Primary Objective 
• To characterize the analgesic efficacy of orally administered CR845 in patients with OA 
of the hip or knee. 
5.2 
Secondary Objectives 
 To compare the treatment effect on patient function, pain and stiffness between 
CR845- and placebo-treated patients as measured by the Western Ontario and 
McMaster Osteoarthritis Index (WOMAC). 
 To compare the treatment effect on Patient Global Impression of Change between 
CR845- and placebo-treated patients.  
 To compare the use of analgesic rescue medications between CR845- and 
placebo-treated patients. 
 To characterize the safety and tolerability of titration-to-effect administration of oral 
CR845. 


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6. INVESTIGATIONAL PLAN 
6.1 
Study Design  
This is a multicenter, randomized, double-blind, placebo-controlled, titration-to-effect study of 
orally administered CR845 in patients with OA of the hip or knee. 
Eligible patients will be randomized to receive either CR845 (1 mg-, 2.5 mg- or 5-mg tablets) or 
placebo in a 2:1 ratio. Approximately 405 patients will be enrolled in this study.  
The study schedule consists of a Screening Period (up to 14 days), a blinded 4-week 
Titration-to-Effect Period with weekly visits, a blinded 4-week Maintenance Treatment Period 
at the optimal dose level determined for each patient, and a Follow-Up Period.  
Screening Period (Visit 1/Day -14 to Day -1):  Screening for this study must be conducted 
within 2 weeks of the Baseline visit. 
Screening will consist of the following assessments: informed consent, review of enrollment 
criteria, medical history and demographics, prior medications, height, weight, physical 
examination, vital signs (supine and standing), 12-lead ECG, pregnancy test (if required), drug 
screening test, and clinical laboratory evaluations including serum sodium level that must be 
≤ 143 mmol/L at screening. During this period, patients will also be instructed on how to assess 
and accurately report their pain intensity. 
Patients will keep a diary of their pain scores for the 7 days prior to their scheduled Baseline 
Visit. Final eligibility for study enrollment will be based upon diary pain scores for the 7 days 
prior to the Baseline visit. Only patients who report a daily pain intensity in the index joint ≥ 5 
during 4 or more of the last 7 days prior to randomization, with 2 consecutive days ≥ 5 
occurring just prior to randomization, and continue to satisfy all other inclusion/exclusion 
criteria (Section 7.1 and Section 7.2) will be randomized into the Titration-to-Effect period. 
Titration-to-Effect Period (Days 1-28/Weeks 1-4): 
CR845 is a highly charged peptide with limited bioavailability when administered orally. Based 
upon previous studies with oral CR845, a significant inter-patient variability in plasma 
concentrations of CR845 has been observed that is likely due to differences in the absorption of 
CR845 from the gastrointestinal tract. It is presumed that patients who absorb CR845 well will 
not need higher doses to achieve an adequate analgesic response and patients who absorb the 
drug poorly will need to be titrated up to a higher dose to achieve a similar effect. 
The purpose of this Titration-to-Effect Period is to identify the optimal dose level of CR845 for 
each patient, based upon tolerability and efficacy, prior to the beginning of the 4-week 
Maintenance Treatment Period. Once patients enter into the Maintenance Treatment Period, 
the dose level can no longer be changed. 
The Titration-to-Effect Period is 4 weeks in duration, with a clinic visit at the end of each 7-day 
period. Patients will be treated at each dose level for 1 week (7 days) prior to determining 
whether or not they should be moved to the next higher/lower dose level or stay at their 
current dose level (see Figure 1). 


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Figure 1:  Titration-to-Effect Scheme 
 
On Day 1 of the study (Visit 2/Baseline), patients will be randomized to receive active treatment 
or placebo in a 2:1 ratio if serum sodium level is ≤ 143 mmol/L. Randomization will be stratified 
according to primary OA joint (knee versus hip). Patients who are randomized to active 
treatment will receive blinded 1-mg tablets of CR845 BID for 7 days. Patients who are 
randomized to placebo will receive blinded matching placebo tablets BID for 7 days. 
At the end of this first week of treatment, patients will return to the clinical site for an 
evaluation (Visit 3/Day 8). This evaluation will consist of a review of the daily pain diary, the 
amount of rescue medication taken, any adverse events (AEs) or other safety event 
experienced during the prior week, and a serum sodium measurement.  
a. The decision by the clinical team to titrate up to the next dose level should be based 
primarily on tolerability. If the patient is tolerating the drug well with a limited analgesic 
response, he/she should be titrated up to the next dose level. 
b. If the patient has a good analgesic response after a single week of treatment (reduction 
from baseline in NRS pain score > 2) and reports an average daily use of rescue 
medication < 1 g, then the patient should remain at the current dose, assuming the 
patient is tolerating the current dose.  If the reduction from baseline in NRS pain scores 
is ≥ 2 and the patient desires to uptitrate, an increase in dose is allowed if deemed 
suitable by the Investigator based on clinical and tolerability assessments. 
c. If the patient has experienced AEs during the first week of treatment that, in the opinion 
of the treating physician, may resolve spontaneously (e.g. headache, low back pain, 
upper respiratory infection, the clinical team (in conjunction with the patient) should 
determine if the patient should stay at the current dose level or be discontinued from 
the study. 
For the second week of treatment, patients whose dose was titrated from dose level 1 (1 mg) to 
the next dose level will receive either 2.5-mg tablets of CR845 or matching placebo BID for 
7 days. Patients whose dose was maintained will continue to receive blinded 1-mg tablets of 
CR845 or matching placebo BID. 


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At the end of this second week of treatment, patients will again return to the clinical site for an 
evaluation (Visit 4/Day 15). This evaluation will consist of a review of the daily pain diary, the 
amount of rescue medication taken, and any adverse events or other safety event experienced 
during that week.  
The decision process at this visit is similar to the one followed at the end of Week 1, but with 
the additional option of down-titrating to the previous dose level: 
a. The decision by the clinical team to titrate up to the next dose level should be based 
primarily on tolerability. If the patient is tolerating the drug well with a limited analgesic 
response, he/she should be titrated up to the next dose level. 
b. If the patient has a good analgesic response after an additional week of treatment 
(reduction from baseline in NRS pain score ≥ 2) and reports an average daily use of 
rescue medication < 1 g, then the patient should remain at the current dose, assuming 
the patient is tolerating the current dose. If the reduction from baseline in NRS pain 
scores is ≥ 2 and the patient desires to uptitrate, an increase in dose is allowed if 
deemed suitable by the Investigator based on clinical and tolerability assessments. 
c. If the patient has experienced AEs during the week of treatment that, in the opinion of 
the treating physician, may resolve spontaneously (e.g., headache, low back pain, upper 
respiratory infection), the clinical team (in conjunction with the patient) should 
determine if the patient should stay at the current dose level, return to the previous 
dose level, or be discontinued from the study.  
For the third week of treatment, patients whose dose was titrated from dose level 2 (2.5 mg) to 
dose level 3 (5.0 mg) will receive either 5.0-mg tablets of CR845 or matching placebo BID for 
7 days. Patients whose dose was maintained will continue to receive blinded 2.5-mg tablets of 
CR845 or matching placebo BID. Patients whose dose was decreased will receive blinded 
1.0-mg tablets of CR845 or matching placebo BID. 
At the end of the third week of treatment (Visit 5/Day 22), patients will again return to the 
clinical site for evaluation consisting of a review of the daily pain diary, the amount of rescue 
medication taken, any AEs or other safety event experienced during the prior week, and a 
serum sodium measurement. The decision to modify dosing or to continue on the current dose 
will be made using the same criteria as defined above. Patients can only be up-titrated or 
down-titrated one dose level at a time. Therefore, at the end of Week 3, patients on dose level 
3 (5.0 mg) can only be down-titrated to dose level 2 (2.5 mg). Patients receiving 2.5 mg of 
CR845 or matching placebo (dose level 2) can be up-titrated to dose level 3 (5 mg) or down-
titrated to dose level 1 (1 mg). Finally, patients still receiving 1.0 mg of CR845 or matching 
placebo (dose level 1) can only be up-titrated to dose level 2 (2.5 mg). 
Visit 5, occurring at the end of Week 3/Day 22, is the last visit where patients will have the 
option of titrating up to a higher dose (2.5 mg or 5 mg).  
At the end of Week 4 (Visit 6/Day 29), patients will again return to the clinical site for an 
evaluation consisting of a review of the daily pain diary, the amount of rescue medication 
taken, and any adverse events (AEs) or other safety event experienced during the prior week. 


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At the end of Week 4, patients will only have the option of staying at their current dose or 
titrating down to a lower dose.  
During the Titration-to-Effect Period, patients are permitted to return to the clinical site for an 
unscheduled visit and have a dose decrease between 2 scheduled visits if deemed necessary. 
If at any time during the Titration-to-Effect Period, the patient’s serum sodium level is 
> 150 mmol/L, dosing should be paused for patient assessment (i.e., retesting of sodium in 
approximately 1 hour after the patient is given a glass of water, and clinical evaluation). Based 
upon the outcome of the clinical evaluation of the patient by the clinical staff, the dosing of 
study medication will either be: a) continued or b) terminated. 
Maintenance Treatment Period (Days 29-57/Weeks 4-8): 
Following completion of the Titration-to-Effect Period at the end of Week 4 (Visit 6/Day 29), 
patients will begin 4 weeks of treatment at their optimal dose as long as their sodium level is 
≤ 150 mmol/L. A full description of the activities to be conducted during the Maintenance 
Treatment Period can be found in Section 9.1.4. 
Two weeks of study medication and analgesic rescue medication will be dispensed to the 
patients at this visit. Patients will return to the clinic at the end of Week 6 (Visit 7/Day 43) to 
complete safety and efficacy assessments, including serum sodium, and study and rescue 
medication for the remaining 2 weeks of treatment will be dispensed at that time. Patients will 
return to the clinic for their final study visit at the end of Week 8 (Visit 8/Day 57). 
If at any time during the Maintenance Treatment Period, the patient’s serum sodium level is 
> 150 mmol/L, dosing should be paused for patient assessment (i.e., retesting of sodium in 
approximately 1 hour after the patient is given a glass of water and clinical evaluation). Based 
upon the outcome of the clinical evaluation of the patient by the clinical staff, the dosing of 
study medication will either be: a) continued or b) terminated. 
Follow-Up Period (1-week post treatment): 
Seven to 10 days after the last dose of study medication, patients will return to the study site 
for a follow-up safety evaluation. 
6.2 
Number of Patients and Sites 
The study is planned to enroll approximately 405 patients and will be randomized using a 2:1 
(active: placebo) ratio.  
The study will be conducted at up to 40 sites in the United States.  
6.3 
Duration of Treatment  
The duration of treatment in this study is 8 weeks (56 days). The total duration of the study 
(including the Screening Period and the Follow-Up Period) is a maximum of 12 weeks (84 days). 


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6.4 
Stopping Rules  
Elevations of serum sodium have been associated with the PO administration of CR845. Based 
upon this potential risk, dosing for an individual patient should be paused and the patient 
should be evaluated if serum sodium levels are observed to be > 150 mmol/L at any time during 
the study. The patient should be assessed (i.e., retesting of sodium in approximately 1 hour 
after the patient is given a glass of water) and clinically evaluated. Based upon the outcome of 
the clinical evaluation of the patient by the clinical staff, the dosing of study medication will 
either be: a) continued or b) terminated. 
6.5 
Safety Monitoring Team (SMT) 
A safety monitoring team at Cara Therapeutics, Inc. will meet periodically to review all blinded 
safety data as the study progresses. These data will include, but are not limited to: 
 Treatment-emergent AEs that result in an early study withdrawal 
 Serious AEs 
 Serum sodium levels 
Appropriate action will be taken based upon this review. All events will be managed and 
reported in compliance with all applicable regulations and included in the final clinical study 
report. 


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7.
PATIENT POPULATION
The study population will consist of male and female patients aged ≥ 25 years with moderate to 
severe pain associated with OA of the hip or knee. All inclusion/exclusion criteria must be met 
before the patient is enrolled.  
A Screening log of potential study candidates and an enrollment log of patients must be 
maintained at each study site. 
No medical waivers for enrollment will be provided during this study. 
7.1 
Inclusion Criteria 
A patient will be eligible for enrollment if the following criteria are met: 
1. Voluntarily provides written informed consent to participate in the study prior to any study
procedures.
2. Is able to speak, read, and communicate clearly in English or Spanish; is able to understand
the study procedures.
3. Male or female ≥ 25 years of age.
4. Body mass index (BMI) ≤ 40 kg/m2.
5. Has OA of the hip or knee according to American College of Rheumatology (ACR) criteria.
6. Reports an average pain intensity level ≥ 5 in the index joint at Screening on a 0-10 NRS
scale.
7. Is either opioid-naïve (defined as taking < 10 mg a day of morphine equivalent 14 days prior
to screening) or opioid-experienced. If receiving opioid analgesic medication for OA,
patients must be on a stable dose ≤ 40 mg of morphine equivalents for 14 days prior to
screening.
8. Willing to discontinue all currently used pain medication beginning 5 days prior to the
Baseline Visit and throughout the study. Acetaminophen use is allowed. (Section 8.8).
9. If female:
a. Of childbearing potential – the patient must be willing to practice an acceptable form of
birth control (defined as the use of an intrauterine device, a barrier method with
spermicide, condoms, any form of hormonal contraceptives, or abstinence from sexual
intercourse) for the duration of treatment and for at least 3 days following the last dose
of study drug.
b. Of non-childbearing potential – the patient must be surgically or biologically sterile
(hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or postmenopausal for
at least 1 year).
10. If male, the patient must be surgically or biologically sterile. If not sterile, the patient must
agree to use an acceptable form of birth control with a heterosexual partner (as described
in inclusion criterion #9) or abstain from sexual relations during the treatment period and
for 3 days following the last dose of study drug.


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11. Is free of other physical, mental, or medical conditions that, in the opinion of the 
Investigator, would make study participation inadvisable. 
12. Reports a daily pain intensity score in the index joint ≥ 5 (on a 0-10 NRS scale) during 4 or 
more of the last 7 days prior to randomization, with 2 consecutive days ≥ 5 occurring just 
prior to randomization.  
7.2 
Exclusion Criteria 
A patient will be excluded from enrollment if the patient meets any of the following criteria: 
1. Has had a joint replacement in the index joint. 
2. Has received an intra-articular injection of corticosteroids or hyaluronic acid in any  joint(s) 
within 3 months prior to the Screening Visit. 
3. Has started a new medication for chronic illness within 30 days prior to the Screening Visit. 
4. Is receiving opioid analgesic treatment for OA of the hip or knee at a dose > 40 mg of 
morphine equivalent.  
5. Uses antipsychotics, antiepileptics, sedatives, hypnotics, or antianxiety agents, selective 
serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants with a dose change < 30 days 
prior to day 1 of the study. 
6. Has a history or current diagnosis of substance dependence (except caffeine or nicotine) or 
alcohol abuse, according to the criteria of the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5). 
7. Has a positive urine drug screen for drugs of abuse at Screening. 
8. Has been diagnosed with a condition of hyperhidrosis (excessive sweating) or primary 
hypodipsia (a reduced sense of thirst).  
9. Has a history (within 6 months) of clinically meaningful orthostatic changes in vital signs OR, 
at Screening, has a decrease in systolic blood pressure by > 20 mm Hg or a decrease in 
diastolic blood pressure by 10 mm Hg together with an increase in heart rate of > 30 beats 
per minute when transitioning from supine to standing measurements. 
10. Has a medical condition (e.g., a cardiovascular, pulmonary, hepatic, renal, hematologic, 
gastrointestinal, endocrine [adrenal hyperplasia], immunologic, dermatologic, neurologic, 
oncologic, or psychiatric) or a significant laboratory abnormality that, in the Investigator’s 
opinion, would jeopardize the safety of the patient or is likely to confound the study 
measurements.  
11. Has had any gastric bypass surgery, sleeve, or lap-band (for weight loss).  
12. Has a corrected QT interval > 450 msec in males, or > 470 msec in females or clinically 
significant abnormality on screening ECG.  
13. Has a serum sodium level > 143 mmol/L at Screening or Baseline (i.e., Visit 2 prior to 
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14. Has impaired renal function indicated by serum creatinine > 2 × the reference upper limit of 
normal (ULN). 
15. Has a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × the 
reference ULN, or total bilirubin > 2 × the ULN at Screening. 
16. Has, in the opinion of the Investigator, any clinical signs of dehydration or hypovolemia 
(e.g., symptomatic hypotension) or associated laboratory abnormalities (e.g., elevated 
hematocrit or elevated blood urea nitrogen [BUN] > 1.5 × the reference ULN) at Screening. 
17. Has taken opioid or non-opioid pain medication (e.g., NSAIDs such as naproxen or 
cyclo-oxygenase-2 inhibitors) within 5 days prior to study drug administration. 
Acetaminophen use is allowed. (Section 8.8) 
18. Has received another investigational drug within 30 days prior to Baseline or has planned to 
participate in another clinical trial while enrolled in this study. 
7.3 
Clinical Surveillance Team (CST) Eligibility Assessment 
The Clinical Surveillance Team (CST) is a division of INC Research CNS Clinical Development.  The 
CST eligibility assessment will be reviewed by the CST, along with the Sponsor, based on 
protocol-specified inclusion and exclusion criteria to promote appropriate patient enrollment 
and data quality. Sites will complete the CST Eligibility Packet at screening and submit the data 
to the CST for review.  This submission and review should be completed as soon as possible 
after screening and prior to baseline.  Decisions regarding inclusion of patients and assessment 
of patient safety throughout the trial primarily remain at the discretion of the Investigator; 
however, the Medical Monitor or Sponsor may request exclusion or discontinuation of a patient 
based on entry criteria or patient safety.  
 
7.4 
Premature Patient Withdrawal 
All patients will be advised at the time of informed consent that they are free to withdraw from 
participation in this study at any time, for any reason, and without prejudice. Every reasonable 
attempt should be made by the Investigator to keep patients in the study; however, patients 
must be withdrawn from the study if they withdraw their consent to participate. Investigators 
must attempt to contact patients who fail to attend scheduled visits by telephone or other 
means to exclude the possibility of an AE being the cause of withdrawal. Should this be the 
cause, the AE must be documented, reported, and followed as described in Section 10. 
The Sponsor reserves the right to request the withdrawal of a patient due to protocol violations 
or other reasons. 
The Investigator also has the right to withdraw patients from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the patient, for intolerable 
or unacceptable AEs, noncompliance with study procedures, administrative reasons, or in the 
Investigator’s opinion, to protect the patient’s best interest. 


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If a patient is withdrawn before completing the study, the reason for the withdrawal and the 
date of study discontinuation will be recorded on the appropriate electronic case report form 
(eCRF). Whenever possible and reasonable, the evaluations that were to be conducted at the 
completion of the study should be performed at the time of premature discontinuation. 
7.5 
Patient Replacement Criteria 
Withdrawn patients who have received study drug will not be replaced. If a substantial number 
of patients withdraw from the study, then the Sponsor will evaluate the need for developing 
replacement criteria. 
Enrolled patients withdrawn from the study may not re-enter. The patient number for a 
withdrawn patient will not be reassigned to another patient. 
7.6 
Counseling Women of Childbearing Potential 
All women are considered to be of childbearing potential unless they are surgically or 
biologically sterile (e.g., hysterectomy, bilateral oophorectomy, bilateral tubal ligation or 
postmenopausal for at least 1 year). 
All women of childbearing potential should be counseled on the need to practice adequate 
birth control during the use of study drug and on the importance of avoiding pregnancy. 
Medically acceptable methods of birth control include any form of a hormonal contraceptive, a 
barrier method with spermicide, condoms, intrauterine device, vasectomized partner 
(vasectomy 6 months prior to Screening), or abstinence from heterosexual intercourse starting 
after informed consent, for the duration of the study, and continuing for 3 days after the last 
dose of study drug. Women should be told to contact the Investigator or his/her staff 
immediately if pregnancy is suspected. 


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8. STUDY TREATMENTS 
8.1 
Investigational Product 
CR845 will be provided as enteric-coated tablets at doses of 1 mg, 2.5 mg and 5 mg with 
matching placebo tablets. All tablets are white in color with no markings and are identical in 
appearance, regardless of dose.  
Study medication should be stored refrigerated but may be brought to room temperature prior 
to dosing. CR845 tablets can be maintained at room temperature for several hours without any 
impact on drug stability. This would include the time required for patients to transport the 
tablets to and from home for clinic visits. 
The tablets are manufactured and packaged in high-density polyethylene bottles of 15 tablets 
by Enteris BioPharma (Boonton, NJ). Labeling of CR845 tablets will be conducted at Sherpa 
Clinical Packaging (San Diego CA).  
8.1.1 Labeling 
Each bottle of CR845 tablets will be labeled and placed into secondary packaging.  
The study drug will be provided in identical kits and numbered so that treatment cannot be 
identified.  
Each bottle of tablets will be labeled to include the following information: 
 Study Protocol number 
 Patient ID Number 
 Temperature storage instructions  
 Retest date 
 Name and location of Sponsor 
 The following statements: 
i. 
Administration according to study protocol 
ii. 
Caution: New Drug – Limited by Federal (or United States) Law to Investigational Use 
8.2 
Dispensing and Storage 
The study medication is to be used exclusively in the clinical study according to the instructions 
of this protocol. The Investigator is responsible for dispensing the study medication according 
to the dosage scheme and for ensuring proper storage of the study medication. 
The Investigator must confirm receipt of the study medication with his/her signature. A copy of 
this receipt must be kept by the Investigator and another copy will be stored at CARA and/or 
INC Research.  Until the medication is dispensed to the patients, it must be stored at 2° to 8°C 
in a securely locked area that is not generally accessible. 


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The key to the storage area is to be kept by the Investigator or designee responsible for the 
study medication. The storage area will be accessible only to those persons authorized by the 
Investigator to dispense the study medication. 
8.3 
Method of Assigning Patients to Treatment Groups 
This is a multicenter, randomized, double-blind, placebo-controlled, titration-to-effect study of 
orally administered CR845 in patients with osteoarthritis of the hip or knee.  
Eligible patients will be randomized to receive either CR845 or placebo in a 2:1 ratio, and will be 
stratified according to their primary joint affected by OA (knee vs. hip). Randomization will be 
performed using an Interactive Web Response System (IWRS). Approximately 405 patients will 
be enrolled in this study.  
Because of the known titration scheme during the Titration-to-Effect Period, the clinical staff 
may be aware of the dose being administered, but all attempts should be made to keep the 
patients blinded as to the study dose being administered during both titration and treatment.  
8.4 
Emergency Unblinding 
Emergency unblinding (via IWRS) of treatment assignment for a patient may be necessary due 
to a medical emergency, such as an SAE that is unexpected and for which a causal relationship 
to study drug cannot be ruled out or any other significant medical event (e.g., pregnancy).  
If emergency unblinding is required for a medical emergency: 
o Only the Investigator will make the decision to unblind the treatment assignment. 
o Only the patient with the medical emergency will be unblinded. 
The Investigator should notify the INC Medical Director and/or designee prior to breaking the 
blind, whenever possible. In all cases, the INC Medical Director and/or designee must be 
notified within 24 hours of the blind being broken. 
8.5 
Selection of Doses in the Study 
The doses of CR845 to be evaluated in this study were selected based upon the results of the 
multiple-dose Phase 1 study of oral tablets in healthy volunteers (CLIN1002-PO) and a Phase 2a 
study in patients with OA of the hip or knee.  
8.6 
Selection of Timing of Dose for Each Patient 
In the Phase 1 study of oral tablets in healthy volunteers (CLIN1002-PO), the effect of meal 
timing on the oral absorption of CR845 tablets was evaluated by dosing the drug at either 
fasted conditions or at 1 hour before, 2 hours before, or 2 hours after a medium-fat, 
medium-calorie (MFMC) meal.  
In general, the mean concentration-time profiles for tablets administered 2 hours prior to 
meals were similar to the profiles observed following fasted conditions. However, when tablets 
were administered 1 hour prior or 2 hours after a meal, the overall plasma exposure of CR845 


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was reduced by ~ 50%. These data suggest that the optimal time for the oral dosing of CR845 is 
at least 2 hours prior to meals. 
8.7 
Dosing Regimen 
Study medication will be taken BID. It is recommended that the medication be taken 2 hours 
before a meal or about 4 hours after a meal.  The first dose should be taken at mid-morning 
(9:30-10 am) assuming breakfast is between 6 and 7 am and lunch is after 12 pm and the 
second dose should be taken just before going to bed at night, 4 hours post the last meal. 
Study medication should be taken with a full glass of water (250 mL).  
8.8 
Analgesic Rescue Medication 
The use of rescue medication for the treatment of any pain (including but not limited to 
headache, menstrual cramps, or non-target joint pain) during the study will be discussed with 
the patients at the Screening Visit. Acetaminophen is the only allowable rescue medication for 
pain beginning from Day -5 until the end of the Maintenance Treatment Period. 
Acetaminophen will be provided as 325-mg tablets and its use (number of tablets taken in the 
previous 24 hours) will be reported each evening in the patient diary. Drug accountability will 
also be conducted at each clinic visit starting at the Screening Visit and continuing through the 
End-of-Study Visit (Visit 8).  
Acetaminophen should be taken as directed for pain, with a maximum allowable dose of 
8 tablets per day (given 1 to 2 tablets every 4 to 6 hours as needed). However, the use of 
acetaminophen is not allowed for the 12 hours prior to a scheduled office visit until after the 
efficacy assessments have been completed, in order to minimize the confounding effects of 
rescue medication on these measures. 
8.9 
Drug Accountability 
The Investigator must maintain adequate records showing the receipt, dispensing, return, or 
other disposition of the study medication including the date, quantity, batch or code number, 
and identification of patients (patient number and initials) who received the study medication. 
The Investigator will not supply the study medication to any person except those named as 
sub-investigators on the Form Food and Drug Administration (FDA) 1572, designated study 
personnel, and patients in this study. The Investigator will not dispense the study medication 
from any study sites other than those listed on the Form FDA 1572. The study medication may 
not be relabeled or reassigned for use by other patients. If any of the study medication is not 
dispensed or is lost, stolen, spilled, unusable, or received in a damaged container, this 
information must be documented and reported to CARA and appropriate regulatory agencies, 
as required. 
Upon completion of the study, the study medication (partly used, unused, and empty bottles) 
must be left in the original packaging and destroyed at the site or returned to the Sponsor or 
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8.10 Treatment Compliance 
All patients will receive the first dose of study medication at the study site under the 
surveillance of appropriate study personnel. The dosing time will be recorded in the patient’s 
eCRF. 
A visit window of plus or minus one day will be allowed.  
Treatment compliance with study medication regimens will be assessed by study personnel via 
tablet counts of returned medication and by questioning the patient, if necessary, at every 
posttreatment visit.  
Patients will be considered noncompliant if they miss more than one dose during the 
Titration-to-Effect period and will be discontinued from the study. 
Patients will be considered noncompliant if their overall study drug use is not within 80% to 
110% (inclusive) of the expected drug use during the Maintenance Treatment period. A patient 
who is not compliant (took < 80% or > 110% of study medication) will be discontinued from the 
study.  
In addition, for each 7-day administration period, patients will be asked to record their daily 
intake of study medication on a diary card. These diaries will be reviewed by study personnel at 
each visit and will be collected as source documents. Information from the patient diary will be 
transcribed onto the appropriate eCRF pages for documentation of patient compliance with 
study medication. 
8.11 Prior and Concomitant Medications 
Prior medications are defined as those that the patient has taken at any time during the 30 days 
prior to the Screening Visit up until administration of the first dose of study drug. Concomitant 
medications are defined as medications that are taken at any time from after the 
administration of the first dose of study drug through the end of the study. 
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 
study visit, and recorded on the appropriate page of the eCRF. 
Patients taking antianxiety agents, selective serotonin reuptake inhibitors (SSRIs), or other 
medications to treat a chronic condition (e.g., hypothyroidism, hypertension) for more than 
1 month prior to the study and who expect to remain on stable doses throughout the duration 
of the study will be eligible to participate if their conditions are well controlled in the opinion of 
the Investigator. 
Low-dose aspirin (acetylsalicylic acid), defined as up to 81 mg daily, taken for cardio-protection 
is allowed.  
8.12 Prohibited Medications 
Patients who meet the initial eligibility criteria at the Screening Visit will be asked to 
discontinue their current NSAID and opioid analgesic medications beginning 5 days prior to 
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Intra-articular injections of either corticosteroids or hyaluronic acid in any joint within 3 months 
prior to Screening and for the duration of the study are prohibited.  


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9. STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
initiated. 
For the timing of assessments and procedures throughout the study, refer to the schedule of 
events (Section 15). Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the schedule of events for 
each patient. If a patient misses a study visit for any reason, the visit should be rescheduled as 
soon as possible. Patients are permitted to return to the clinical site for an unscheduled visit 
and have a dose decrease between 2 scheduled visits if deemed necessary only during the 
Titration-to-Effect Period of the study. 
9.1 
Study Periods and Visits 
Screening occurs within 14 days before enrollment in the study; during the week prior to 
randomization (Day -5 to -1), patients will discontinue all current pain medications. 
Acetaminophen use is allowed (reference Section 8.8). The duration of treatment for this study 
is approximately 57 consecutive days. Clinic visits will take place on Days 1 (Baseline, Visit 2), 8, 
15, 22, 29, 43, and 57 (Visit 8). Titration to the optimum dose will take place during the first 4 
weeks of treatment (ending at Day 29 – Visit 6). A Follow-Up Visit will be performed 7 to 10 
days after the last dose of study drug. 
9.1.1 Screening and Washout 
Each patient must be screened within 14 days before randomization in the study. The following 
procedures will be performed at Screening: 
1. Obtain written informed consent. 
2. Review inclusion/exclusion criteria. 
3. Collect demographic information. 
4. Record medical history (including duration of OA symptoms), and prior and current 
therapies (e.g., prescription and non-prescription medications). 
5. Identify the index joint for the study. 
6. Review how to complete assessment of pain intensity for the identified joint using the NRS. 
7. Obtain a pain intensity score for the index joint using the NRS. 
8. Review with the patient how to complete the WOMAC and Patient Global Impression of 
Change (PGIC). 
9. Perform a physical examination including weight and height. 
10. Collect vital signs (including body temperature). 
11. Perform a 12-lead ECG. 
12. Obtain blood and urine samples for drug screening, serum pregnancy (women of 
childbearing potential only), and clinical laboratory evaluations (including serum sodium 
measurement where sodium level must be ≤ 143 mmol/L).  If sodium level is > 143 mmol/L, 


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then the patient can be retested in approximately 1 hour after being given a glass of water 
to drink. 
13. If patient is eligible:  
a. Instruct patient to discontinue current pain medications 5 days prior to the Baseline 
Visit (Washout is Days -5 to -1). Instruct patients how to assess and record in the 
Patient Diary their pain intensity score and number of rescue medication tablets 
taken each evening for the 7 days prior to the Baseline Visit. 
b. Dispense rescue medication (acetaminophen). 
c. On Day -7, contact the patient to remind him or her about the washout week and 
the collection of daily pain scores. 
d. Schedule Visit 2 (Baseline; Day 1). 
9.1.2 Baseline (Visit 2) 
Baseline is defined as Day 1 (Visit 2). The following procedures will be performed at baseline: 
1. Obtain a blood sample for serum sodium (sodium level must be ≤ 143 mmol/L) prior to 
dispensing study medication). If sodium level is > 143 mmol/L, then the patient can be 
retested in approximately 1 hour after being given a glass of water to drink. 
2. Perform urine pregnancy test for female patients of childbearing potential. 
3. Record any changes in prior and current therapies (e.g., prescription and non-prescription 
medications). 
4. Assess vital signs. 
5. Assess and record any AEs that have occurred since the last evaluation. Those will be 
recorded as medical history. 
6. Perform drug accountability and, if necessary, counsel on compliance. 
7. Review NRS data in the patient diary (Day -7 to Day -1) to calculate the Baseline NRS score 
and determine study eligibility. (The patient must have 4 pain scores at the index joint ≥ 5 
for 4 or more of the last 7 days, with 2 consecutive days ≥ 5 immediately prior to 
randomization). 
8. Review inclusion/exclusion criteria. 
9. If patient is eligible:  
a. Assign the next patient number. 
b. Obtain blood samples for clinical laboratory evaluations including serum sodium. 
c. Have the patient complete the WOMAC.  
d. Dispense study medication and administer the first dose. 
e. Instruct patient on the use of rescue medication and fluid replacement. 
f. Review the PRO assessments and the recording of information in the patient diary. 
g. Schedule Visit 3 (Day 8) and instruct the patient to discontinue acetaminophen at 
least 12 hours prior to the clinic visit. 


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9.1.3 Titration Period 
Patients will return to the clinic on Days 8, 15, 22, and 29 (±1 day), during which dose of CR845 
will be titrated to the optimal level for each patient, based on tolerability and efficacy.  
9.1.3.1 Day 8 (Visit 3) 
Patients will return to the clinic on Day 8 (±1 day). The following procedures will be performed: 
1. Perform drug accountability and, if necessary, counsel on compliance. 
2. Record any changes in current therapies (e.g., prescription and non-prescription 
medications). 
3. Assess vital signs. 
4. Assess and record AEs occurring since the last evaluation. 
5. Administer WOMAC.  
6. Collect daily diaries (average pain intensity NRS scores, use of study drug and rescue 
medication). 
7. Obtain a blood sample for serum sodium. 
8. Review all outcome scores, use of rescue medication, and any AEs experienced during the 
prior week and determine if patient should remain at current dose level or be escalated to 
the next higher dose level. Enter this into the IVRS/IWRS to obtain the dosing kit number 
corresponding to the appropriate dose. 
9. Schedule the next visit and instruct the patient to discontinue acetaminophen at least 
12 hours prior to the clinic visit. 
10. Dispense study and rescue medication for the next week.  
9.1.3.2 Days 15 and 22 (Visits 4 and 5) 
Patients will return to the clinic on Days 15 and 22 (±1 day). The following procedures will be 
performed: 
1. Perform drug accountability and, if necessary, counsel on compliance. 
2. Record any changes in current therapies (e.g., prescription and non-prescription 
medications). 
3. Assess vital signs. 
4. Assess and record AEs occurring since the last evaluation. 
5. Administer WOMAC.  
6. Collect daily diaries (average pain intensity NRS scores, use of study drug and rescue 
medication). 
7. Obtain a blood sample for serum sodium (Days 15 and 22). 
8. Review all outcome scores, use of rescue medication, and any adverse events experienced 
during the prior week and determine if patient should:  
a. Remain at the current dose level   
b. Be escalated to the next higher dose level 


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c. Be decreased to the previous dose level. 
9. Enter dose level into the IWRS. 
10. Schedule the next visit and instruct the patient to discontinue acetaminophen at least 
12 hours prior to the clinic visit. 
11. Dispense study and rescue medication for the next week 
9.1.3.3 Day 29 (Visit 6) 
Patients will return to the clinic on Day 29 (±1 day). The following procedures will be 
performed: 
1. Perform drug accountability and, if necessary, counsel on compliance. 
2. Record any changes in current therapies (e.g., prescription and non-prescription 
medications). 
3. Assess vital signs. 
4. Assess and record AEs occurring since the last evaluation. 
5. Administer WOMAC.  
6. Collect daily diaries (average pain intensity NRS scores, use of study drug and rescue 
medication). 
7. Obtain a blood sample for serum sodium. 
8. Review all outcome scores, use of rescue medication, and any adverse events experienced 
during the prior week and determine if patient should:  
a. Remain at the current dose level   
b. Be decreased to the previous dose level. 
9. Enter this into the IWRS. Please note that this is the final titration point. The dose level 
determined here will be used during the 4-week Maintenance Treatment Period. 
10. Schedule the next visit and instruct the patient to discontinue acetaminophen at least 
12 hours prior to the clinic visit. 
11. Dispense study and rescue medication for the next 2 weeks. 
9.1.4 Maintenance Treatment Period 
9.1.4.1 Day 43 (Visit 7) 
Patients will return to the clinic on Day 43 (± 2 days). The following procedures will be 
performed: 
1. Perform drug accountability and, if necessary, counsel on compliance. 
2. Record any changes in current therapies (e.g., prescription and non-prescription 
medications). 
3. Assess vital signs. 
4. Assess and record AEs occurring since the last evaluation. 


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5. Administer WOMAC.  
6. Collect daily diary (average pain intensity NRS scores, use of study drug and rescue 
medication). 
7. Obtain a blood sample for serum sodium. 
8. Schedule the next visit and instruct the patient to discontinue acetaminophen at least 
12 hours prior to the clinic visit. 
9. Dispense study and rescue medication for the next 2 weeks. 
9.1.4.2 Day 57 (Visit 8) or Early Termination 
Patients will return to the clinic on Day 57 (± 2 days) (Visit 8) or upon early termination from the 
study. The following procedures will be performed: 
1. Collect the bottle of study medication, whether partly used, unused, or empty. 
2. Perform drug accountability. 
3. Record any changes in current therapies (e.g., prescription and non-prescription 
medications). 
4. Assess vital signs (including body temperature). 
5. Perform physical examination and record any changes from Screening. 
6. Perform a 12-lead ECG. 
7. Assess and record AEs occurring since the last evaluation. 
8. Perform WOMAC. 
9. Perform the PGIC. 
10. Collect daily diary (average pain intensity NRS scores, use of study drug and rescue 
medication). 
11. Obtain a blood sample for clinical laboratory evaluations and serum sodium measurement. 
12. Schedule Visit 9 (Follow-up Visit; 7 to 10 days after last dose) and instruct the patient to 
resume pain medications as needed. 
9.1.5 Follow-Up Evaluation (Visit 9) 
At 7 to 10 days after the last dose of study medication, the following procedures will be 
performed: 
1. Measure vital signs (blood pressure and heart rate). 
2. Assess and record AEs occurring since the last evaluation. If any AEs are ongoing at 
this visit, telephone the patient 30 days after the last dose to assess and record 
additional updates to these AEs. 
3. If not collected at Visit 8, collect the bottle of study medication, whether partly used, 
unused, or empty. 


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9.1.6 Unscheduled Visits  
Unscheduled visits may be necessary for outstanding, unresolved TEAEs. Additional safety 
laboratory or clinical evaluations will be at the discretion of the Investigator. 
9.2 
Assessments 
9.2.1 Efficacy Evaluations 
9.2.1.1 Pain Intensity Numerical Rating Scale  
Joint pain intensity will be assessed daily using an 11-point NRS2 (see Appendix 2). The patient 
will rate his or her index joint pain intensity using the following question: “On a scale from 0 to 
10, where ‘zero’ represents ‘no pain’ and ‘10’ represents ‘the worst possible pain,’ how would 
you rate the average pain that you experienced in the last 24 hours?”  
Daily assessment and recording of joint pain should be performed at the same time each day at 
approximately 6:00 pm, when possible. Patients will review their joint pain/diary data with the 
appropriate study site personnel during their clinic visits. 
9.2.1.2  Western Ontario and McMaster Universities Osteoarthritis Index 
The WOMAC Index is a self-administered assessment used to measure pain, stiffness, and 
physical function in patients with osteoarthritis (Appendix 3). It is considered to be a reliable 
and valid instrument.3 4 
The WOMAC Index contains 24 questions across 3 different sub-scales (pain, stiffness, and 
function). Patients will complete the WOMAC at each clinic visit starting with the Baseline Visit. 
9.2.1.3 Patient Global Impression of Change 
The PGIC is a self-administered instrument that measures the patient’s overall impression of 
his/her OA on a 7-point scale where 1 = “Very much improved” and 7 = “Very much worse” (see 
Appendix 4). 
Patients will be asked the complete the following statement: “Since the start of the study, my 
osteoarthritis is:” using one of the following response options: 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
The PGIC will be completed by the patient during the clinic visit on Day 57 (or early 
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10. SAFETY DEFINITIONS, REPORTING AND MONITORING 
10.1 Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product, 
and does not necessarily have a causal relationship with the treatment. An AE 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.  
An AE 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 Definition 
of Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
 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 that 
hypothetically might have caused death had it occurred in a more severe form 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered AEs 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) 
 Results in persistent or significant disability/incapacity, defined as a substantial 
disruption of a patient's 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 vs. Serious AEs: The term “severe” is 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 upon 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. 


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10.1.1 Recording and Reporting Adverse Events 
All AEs and SAEs must be recorded on the eCRF and in the patient’s source documents. 
Laboratory evaluations, fluid imbalance, outcome of a physical examination, vital signs, or ECG 
abnormalities are to be recorded as AEs only if they are clinically relevant. 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
Sponsor (or designee) as follows: 
 Telephone the Sponsor (or designee) at the contact information provided in the SAE 
completion guidelines, within 24 hours of learning of the event. 
 Fax the completed SAE form to the Sponsor (or designee) at the contact information 
provided in the SAE completion guidelines, within 24 hours of learning of the event.  
CARA will provide the Investigators with blank SAE forms that are to be completed when 
reporting an initial or follow-up SAE. Information not available at the time of the initial report 
must be documented on a follow-up SAE form. Substantiating data such as relevant hospital or 
medical records and diagnostic test reports may also be requested. 
The Investigator must promptly report to the Institutional Review Board (IRB) all unanticipated 
problems involving risks to patients. This includes death from any cause and all SAEs related to 
the use of the study drug. It is recommended that all SAEs be reported to the IRB, regardless of 
assessed causality. Further details will be given in the Safety Management Plan. 
10.1.2 Deaths 
Any AE that results in death is considered an SAE. Deaths that occur from the time the patient 
signs the informed consent form (ICF) until 30 days after the completion of dosing must be 
reported to the appropriate IRB and to the Medical Monitor at CARA (or designee) within 
24 hours of learning of the death. The reporting procedures detailed in Section 10.1.1 should be 
followed. 
Any available autopsy reports and relevant medical reports must be sent to the Sponsor (or 
designee) as soon as possible. 
10.1.3 Pregnancy and Other Events that Require Accelerated Reporting 
The following events also require reporting to the Sponsor (or designee) within 24 hours of 
learning of the event: 
 Overdose: Accidental or intentional overdose of at least 2 times the 
study/recommended dose of study drug/concomitant medication, if associated with an 
AE. Accidental or intentional administration of the study drug at a frequency higher 
than that allowed by the study protocol, if associated with an AE. 
 Malignancy: Any diagnosis (excluding non-melanoma skin cancer) during the study. 
 Pregnancy: Although it is not considered an AE, it is the responsibility of the 
Investigator to report to the Sponsor (or designee), by telephone within 24 hours, any 
pregnancy occurring in a female patient or female partner of a male patient, during the 


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study or within 85 days following the last dose of study drug. The Sponsor will provide 
the Investigator with a Pregnancy Tracking Form that is to be completed by the study 
site on a monthly basis and faxed to the Sponsor (or designee). The Investigator will 
follow the pregnancy until delivery or longer. If the pregnancy continues to term 
(delivery), the health of the infant must also be reported to the Sponsor (or designee). 
10.2 Adverse Event Identification and Assessment 
Adverse events are illnesses or signs/symptoms that appear or worsen during the testing of a 
drug any time after the first dose is administered, whether or not considered related to the 
investigational product, including side effects, injury, toxicity, or hypersensitivity reactions. 
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, AEs 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 an inclusive 
term (e.g., gastroenteritis in lieu of abdominal pain, nausea, vomiting, and diarrhea). 
A pre-existing condition is a condition that is present prior to signing informed consent. For 
instance, this would include in this definition the discovery of an unexpected cancer following a 
laparoscopic hysterectomy. A worsening of a pre-existing condition should be captured as an AE 
if the frequency, intensity, or character of the condition worsens during the study period. 
Adverse events occurring after signing of the ICF but prior to the first administration of the 
study drug should be reported as medical history. 
During the Screening process, any physical examination abnormalities deemed to be clinically 
significant by the Investigator should be recorded as Baseline conditions and recorded as the 
medical history. These will not be captured as AEs. After the first dose of study drug, any 
physical examination change deemed to be clinically significant by the Investigator that meets 
the definition of an AE must be recorded and documented as a TEAE. 
Abnormal laboratory tests at Screening or Baseline assessed as clinically significant should not 
be reported as AEs but as medical history. 
All abnormal laboratory test results that are clinically significant (including those reported as 
chronically typical for the patient) must comply with exclusionary criteria; otherwise, the 
Medical Monitor must be contacted to decide whether to continue the participation of the 
patient in the study. A laboratory abnormality should be documented as an AE if it is considered 
by the Investigator to be a clinically significant adverse change from Baseline. 
Any AE that results in hospitalization or prolonged hospitalization should be reported as an SAE. 
An abnormal result of a diagnostic procedure should be captured as an AE if the abnormality: 
 Results in study withdrawal 
 Is associated with signs or symptoms 
 Is considered by the Investigator to be of clinical significance. 


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The underlying diagnosis will be captured as the AE, not the procedure itself. 
Overdose is defined as an accidental or intentional exposure to study drug at a dose higher than 
specified in the protocol or higher than the known therapeutic dose. An overdose of study drug 
must be reported as a protocol deviation. If the overdose is associated with clinical signs or 
symptoms, then these should be captured as AEs. An overdose is not expected to occur in this 
study based on the protocol design. 
10.2.1 Evaluation of Severity 
Adverse events will be graded according to the following scale: 
 Mild: Transient or mild discomfort (< 48 hours); no medical intervention/therapy 
required. Does not interfere in a significant manner with the patient’s normal 
functioning level.  
 Moderate: Mild to moderate limitation in activity – some assistance may be needed; 
minimal medical intervention/therapy may be required. Produces some impairment of 
functioning but is not hazardous to health.  
 Severe: Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If the intensity of an AE changes, the maximum severity for the event should be listed. If the 
intensity category changes over a number of days, these mini-events or changes should be 
recorded separately (i.e., having distinct onset dates). 
10.2.2  Evaluation of Causality 
The relationship to treatment will be determined by the Investigator and reported on the eCRF 
and/or SAE form, as appropriate. The following terms will be used: 
 Not Related: likely or clearly due to causes other than the study drug 
 Related: possibly, probably, or definitely related to the study drug 
10.3 Adverse Event Follow-up and Reporting 
10.3.1 Investigator Alert Notification 
CARA or its designee will inform all Investigators participating in this clinical trial, as well as in 
any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the 
Investigator’s Brochure, and has a reasonable suspected causal relationship to the 
medicinal/investigational product). 
10.3.2 Adverse Event Follow-up 
All patients with documented AEs (including SAEs) will be followed by the Investigator until the 
AE resolves, resolves with sequelae, decreases in severity to a clinically insignificant level, is 
otherwise explained by a medical condition, or is not possible to follow-up (document) due to 
loss of follow-up or the death of the patient. 


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10.3.3 Adverse Event Documentation 
All AEs, including observed, elicited, or volunteered problems, complaints, or symptoms, are to 
be recorded on the AE page in the patient’s eCRF. 
The need to capture this information is not dependent upon whether AEs are associated with 
use of investigational product. 
Each AE is to be evaluated for date/time of onset, duration, intensity, and causal relationship 
with the study drug or other factors. 
At every study visit, the Investigator or designee must document new AEs and the outcome of 
ongoing AEs. 
All SAEs will be documented on the SAE form. 
10.3.4 Serious Adverse Event Reporting 
10.3.4.1 Notification and Documentation from the Investigator to the Sponsor 
The Investigator will immediately, and in no case later than 24 hours of awareness, notify CARA 
by telephone if a death or life-threatening event occurs, whether related or unrelated to the 
study drug. In this instance, an SAE report form will also be completed by the Investigator 
immediately (and in no case later than 24 hours of site awareness). Serious AEs other than 
death and immediately life-threatening events, regardless of relationship to study drug, will be 
reported to CARA by telephone and email within 24 hours (and in no case later than 72 hours 
[in case of weekends]) of Investigator awareness, and the SAE form will be completed within 
48 hours of becoming aware of the event. 
The Investigator will forward details of SAE(s) to the Sponsor within 2 working days for an 
expedited report and 3 working days for a non-expedited report. 
The Sponsor may contact the Investigator to obtain more information or clarification on the 
SAE reported. Other supporting documentation of the SAE requested by the Sponsor should be 
provided as soon as possible. The Sponsor contact person is:  
Heidi Schecodnic, M.D., Medical Director, Medical Affairs 
INC Research, LLC 
3201 Beechleaf Ct., Suite 600  
Raleigh, North Carolina 27604 
Office: 919-745-2785   Mobile: 984-242-6534 
heidi.schecodnic@incresearch.com 
The initial telephone report from the Investigator to the Sponsor of the SAE will include all 
available information in order to assist the Sponsor in submitting SAEs (e.g., “Investigational 
New Drug [IND] Safety Report”) to the appropriate regulatory agencies as defined by 
country-specific regulations. Initial minimal information required will include: 
 An identifiable patient 
 An identifiable reporter 


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 A suspect drug/product 
 An adverse drug reaction 
An SAE eCRF page must be completed in the electronic database and supporting 
documentation given to the Sponsor. 
Follow-up information to a safety report shall be submitted as soon as the relevant information 
(e.g., discharge summary) is available. A Follow-up SAE report must be completed and 
transmitted via facsimile to the Sponsor or designee as soon as the information is available for 
relevant follow-up information only. For non-relevant additional information, the Investigator 
should send information in a timely manner via facsimile to the Sponsor. The Sponsor’s Medical 
Monitors or designee will contact the Investigator to obtain more information or clarification 
on the SAE reported. 
10.3.4.2 Reporting to Regulatory Authorities 
All expedited SAEs will be reported to the regulatory authorities per regulatory requirements. 
Adverse events that are serious and related to the study drug and unexpected must be 
reported to the regulatory authorities on an expedited basis as an IND Safety Report. Of these 
IND safety reports, those with the outcome of death or life threatening will be reported by the 
Sponsor to the regulatory authorities within 7 calendar days (from the date of SAE notification); 
and all the other expedited IND safety reports will be reported to the regulatory authorities 
within 15 calendar days (from the date of SAE notification). 
The Sponsor will also notify the participating Investigator 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. 
Per regulatory requirement, the Investigator should promptly report all SAEs, in addition to all 
changes in research activity, protocol violations, and unanticipated problems involving risk to 
human patients or others, to their IRB. 
All other SAEs that do not fulfill the expedited reporting criteria are to be included in the IND 
Annual Report.  


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11. STATISTICAL METHODS 
11.1 General Considerations  
The following section summarizes the statistical methods that will be used in the analysis of the 
clinical data from this study. A statistical analysis plan (SAP) with further detail will be 
developed and finalized prior to unblinding of the study. If differences occur between analyses 
described in the final SAP and the current protocol, those found in the SAP will assume primacy.  
Unless otherwise noted, continuous variables will be summarized using the 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. 
Statistical significance will be declared for all hypothesis testing if the unadjusted 2-sided 
probability value is < 0.05. Tests for interaction among the sites will be performed at the 
0.1 alpha level. All computations will be performed using SAS® (Version 9.2 or higher).  
11.2 Determination of Sample Size 
Approximately 405 patients with OA of the hip and knee will be randomized in a 2:1 ratio (270 
to CR845 and 135 to placebo) at approximately 40 sites in the United States.  
 
 
 
 
 
 
 
 
 


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11.4 Analysis Populations 
Three patient analysis populations are defined as follows: 
•
Safety Population: All randomized patients who received at least 1 dose of double-blind
study drug will be included in the safety evaluation.
•
Full Analysis Population (FAP):  All randomized patients who received at least 1 dose of
double-blind study drug will be included in the safety evaluation. The FAP and the Safety
populations are identical.
•
Per Protocol (PP):  All randomized patients in the FAP without any major protocol
violations that could affect the efficacy analyses. The criteria for determining what
constitutes a major protocol violation will be defined prior to database lock and the
breaking of the blinded treatment assignment code.
Membership in the analysis populations will be determined prior to unblinding the data and will 
be detailed in the SAP.  
11.5 Patient Accounting and Study Disposition 
11.5.1 Patient Disposition 
A complete accounting of patient participation in the study will display the number of patients 
that were enrolled and the number and percentage of patients that: 
•
Were screen failures
•
Were randomized
•
Are included in each analysis population
•
Have completed or discontinued study drug early
In addition, the reason for early study termination will be summarized separately and 
presented using counts and percentages.  
11.5.2 Protocol Deviations 
Protocol deviations or violations will be identified in several ways: through programmatic 
checks, through medical reviews, and by clinical research associates during site monitoring. 
They will be classified as minor or major prior to the database lock and included in the SAP. 


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Major protocol deviations/violations will be summarized by treatment group. All protocol 
deviations will be listed.  
Patients with major protocol violations that affect efficacy will be excluded from analysis for the 
PP population.  
11.6 Baseline Patient Data 
11.6.1  Demographic and Other Baseline Characteristics 
The following demographic variables will be summarized by treatment group and overall: age, 
sex, race, ethnicity, height, weight, BMI, and duration of time with OA.  
11.7 Study Drug Accountability 
A data listing of the study drug dispensed and returned will be provided. 
Patients will be considered noncompliant if they miss 2 or more doses during the Titration-to-
Effect period. 
Patients will be considered noncompliant if their overall study drug use is not within 80% to 
110% (inclusive) of the expected drug use during the Maintenance Treatment period.  
The expected number of tablets to be taken will be calculated based on the duration of 
treatment. The count and percentage of patients compliant with study drug will be summarized 
by treatment group (CR845 vs. placebo).  
The number of patients who titrated to Level 1 (CR845 1 mg or matching placebo), Level 2 
(CR845 2.5 mg or matching placebo) or Level 3 (CR845 5 mg or matching placebo) will be 
summarized. In addition, the average dose of each patient during the study will be calculated 
and presented for each treatment group.  
The number and percentage of patients exposed to double-blind study drug for overlapping 
time intervals (e.g., any exposure, ≥ 1 week, ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks) will be calculated 
by treatment group. Descriptive statistics (mean, standard deviation (SD), median, minimum, 
maximum) will be provided to summarize the length of exposure (in days) to each treatment.  
Dosing details and any deviations from the planned dose will be listed. 
11.8 Efficacy Analyses 
All efficacy analyses will be conducted on the FAP. An analysis of the primary efficacy variable 
using the PP population may be performed if a significant number (≥ 20%) of the patients in the 
FAP are regarded as major protocol violators that would affect the evaluation of efficacy and 
are excluded from the PP population. The need for a PP population analysis will be examined 
prior to database unblinding. All hypothesis tests will be 2-sided at the α=0.05 level.  
11.7.1 Primary Efficacy Variable 
The primary efficacy variable is the weekly mean pain intensity score calculated using the 
‘average pain over the last 24 hours’ scores collected in the daily diaries using an 11-point scale 
where 0 = no pain, and 10= pain as bad as you can imagine. The weekly mean pain intensity 


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score will be defined as the sum of non-missing daily "average pain over the last 24 hours" 
scores reported during that week (Days 1-7, Days 8-14, Days 15-21, … , Days 50-56) divided by 
the number of days with non-missing scores for that week. If a patient reports less than 3 days 
of pain scores during a week, the weekly mean pain intensity score will be set to missing. 
The primary efficacy endpoint is defined as the change from baseline at Week 8 with respect to 
the weekly mean of the daily 24-hour pain intensity in at the index joint.  
The primary efficacy variable will be analyzed using a mixed effect model with repeated 
measures (MMRM). The model will contain treatment (placebo vs CR845), treatment-by-week 
interaction as fixed effects, baseline value and OA joint (hip vs knee) as covariates, and patient 
as a random effect. The baseline score will be calculated as the average of the 4 pain scores 
collected during the Screening period that qualified the patient for randomization (inclusion 
criteria 12). The treatment difference between CR845 (across all doses) and placebo at Week 8 
(the primary efficacy endpoint) will be estimated as the simple contrast in the treatment effect. 
The 2-sided 95% confidence interval, based on the difference in the least squares means 
between the 2 treatment groups (CR845 vs placebo) will be presented. 
The MMRM model will be implemented using SAS PROC MIXED. A restricted maximum 
likelihood (REML) method will be used . 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 Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom and adjust 
standard errors.  
For the primary efficacy analysis, the treatment of missing data will be addressed using pattern 
mixture model methodology. Within each treatment, 4 data patterns will be defined as follows:   
 Pattern 1: will include patients who completed treatment on study drug  
 Pattern 2: will include patients who discontinue treatment early due to AEs  
 Pattern 3: will include patients who discontinue treatment early due to lack of 
therapeutic efficacy (LOTE)  
 Pattern 4: will include patients who discontinue treatment early due to reasons other 
than AE event or LOTE.  
The pattern mixture model methodology will be implemented using SAS procedures MI and 
MIANALYZE. Specifically, the following steps will be followed: 
 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 for patients who discontinue early will be multiply imputed using multiple calls of 
the SAS MI procedure. 


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o 
If the patient discontinues due to AE (pattern 2) or LOTE (pattern 3), then 
missing data will be assumed to follow a distribution similar to the baseline 
values observed in the patient’s randomized treatment.  
o 
If the patient discontinues due to reasons other than AE or LOTE (pattern 4), at 
each time point, missing data will be assumed to follow a distribution similar to 
scores for patients who are still in the study and randomized to the same 
treatment group.  
 Results of the MMRM on the multiply imputed data will be summarized using the SAS 
MIANALYZE procedure. 
Three sensitivity analyses (described below) will be conducted to assess the impact of the 
treatment of missing data on the study results. These sensitivity analyses may not necessarily 
reach statistical significance at the 5% level. However, a consistency of treatment effect (similar 
estimate of CR845 mean relative to placebo) is expected across the primary and all sensitivity 
analyses.  
Sensitivity analysis 1 (Multiple Imputation Missing at Random ) 
This sensitivity analysis assumes that patients with missing data follow the same trajectory as 
other patients in their respective treatment arm that have complete data. 
 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 then be multiply imputed 
with the SAS MI procedure using a method appropriate for monotone missingness (e.g., 
regression statement). At each time point, missing data will be assumed to follow a 
distribution similar to scores for patients who are still in the study and randomized to 
the same treatment group.  
 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, Placebo-based 
Imputation) 
This sensitivity analysis assumes that patients in the active treatment group who discontinue 
early will have the same evolution, after treatment is stopped, as patients in the placebo group 
(who are not exposed to 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. 


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Sensitivity analysis 3 (Multiple Imputation, MNAR, Hybrid BOCF /LOCF): 
This sensitivity analysis makes different assumptions about the pain trajectory of patients who 
discontinue study drug early depending on the reason for discontinuation. For patients who 
discontinue due to AE or reasons other than AE or LOTE, assumptions are similar to the ones 
made for the primary efficacy analysis. It is plausible that patients who discontinue due to LOTE 
experience worsening pain scores after randomization; in this case, their last observed pain 
scores would be higher (worse) that their baseline pain scores. This sensitivity analysis assumes 
that missing data for these patients is similar to observed pain scores for patients who 
discontinue due to LOTE but are still 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 for patients who discontinue early will be multiply imputed using multiple calls of 
the SAS MI procedure. 
o 
If the patient discontinues due to AE (pattern 2), missing data will be assumed to 
follow a distribution similar to the baseline values observed in the patient’s 
randomized treatment.  
o 
If the patient discontinues due to LOTE (pattern 3), at each time point, missing 
data will be assumed to follow a distribution similar to scores for patients who 
are still in the study and randomized to the same treatment group.  
o 
If the patient discontinue due to reasons other than AE or LOTE (pattern 4), at 
each time point, missing data will be assumed to follow a distribution similar to 
scores for patients who are still in the study and randomized to the same 
treatment group.  
 Results of the MMRM on the multiply imputed data will be summarized using the SAS 
MIANALYZE procedure. 
Finally, an MMRM analysis using observed data only will be provided as a reference.  
11.8.1 Secondary Efficacy Variables 
Western Ontario & McMaster Osteoarthritis (WOMAC) Index 
The change from baseline in the WOMAC Index total score will be analyzed using an MMRM 
with treatment (placebo vs CR845) and treatment-by-week interaction as fixed effects, baseline 
value and OA joint (hip vs knee) as covariates, and patient as a random effect. The primary 
comparison between groups will be based on estimates and contrasts for the weeks 4, 6, and 8 
means. The comparison at week 8 will be viewed as secondary. A 95% CI will be constructed for 
the weeks 4, 6 and 8 mean differences between CR845 and placebo based on the MMRM. 
The MMRM model will be implemented using SAS PROC MIXED. REML will be used. 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 


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examined. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom and adjust standard errors.  
Data missing after early discontinuation will be treated using the same pattern mixture 
methodology as the one implemented for the primary efficacy analysis. In addition, an MMRM 
analysis using observed data only (i.e., no imputation) will be presented. 
WOMAC Pain Intensity, Stiffness, and Function Sub-scales 
The change from baseline in the WOMAC sub-scales for pain intensity, stiffness and function 
will be analyzed using an MMRM model similar to the one presented above for the WOMAC 
index total score. Data missing after early discontinuation will be treated using the same 
pattern mixture methodology as the one implemented for the primary efficacy analysis. In 
addition, an MMRM analysis using observed data only (i.e., no imputation) will be presented. 
Treatment Pain Response 
A patient’s pain response to treatment is defined as the percent improvement from baseline 
with respect to the weekly mean of “average pain in the last 24 hours” pain score during the 
last week of the Maintenance Treatment Period (Week 8)  
If a patient’s mean weekly pain score during the last week of the Maintenance Treatment 
Period is greater than the baseline score (i.e., the patient has an increase in pain compared to 
baseline), his/her response to treatment will be assigned a value of 0. Patients who discontinue 
study drug early will be considered non-responders to treatment and will be assigned a pain 
response of 0.  
A graph of percentage of patients who have a treatment pain 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 ≥ 30% will be analyzed using logistic 
regression, including treatment, baseline pain score, and OA joint as independent variables. The 
cutoff of 30% was chosen as it has been shown to represent a clinically important improvement 
in pain. This analysis will be repeated for patients who have a response to treatment ≥ 50%. 
Patient Global Impression of Change (PGIC) 
The PGIC score collected at Week 8, or at the End of Treatment visit (for patients who 
discontinue treatment early) ranges from 1 (Very Much Improved) to 7 (Very Much Worse). The 
count and proportion of patients in each response category will be displayed for each 
treatment group. In addition, summary statistics (n, mean, standard error, median, minimum, 
and maximum) and 95% CI for the mean treatment response will be tabulated. 
The proportion of patients with PGIC scores of “Very Much Improved” and “Much Improved” 
will be analyzed using logistic regression with treatment as a main effect, and OA joint as a 
covariate.  
Supplemental Analgesic Medication Used 
Acetaminophen is the only allowable rescue medication for pain beginning from Day -5 until the 
end of the Maintenance Treatment Period. Acetaminophen will be provided as 325-mg tablets 
with a maximum allowable dose of 8 tablets per day (given every 4 to 6 hours as needed). 


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However, the use of acetaminophen is not allowed for the 12 hours prior to a scheduled office 
visit until after the efficacy assessments have been completed, in order to minimize the 
confounding effects of rescue medication on these measures. 
The average daily number of acetaminophen tablets used during the study will be calculated 
using data recorded in the patient diary as the sum of the total number of tablets used divided 
by the length of exposure (in days). The average daily number of acetaminophen tablets used 
during the Maintenance Treatment Period will be calculated using a similar algorithm. 
Descriptive statistics for each of these 2 variables (n, mean, SD, median, minimum, maximum) 
will be presented by treatment group.  
Due to the nature of the data, the average daily number of analgesic rescue doses used (in this 
case acetaminophen) tends to have a large portion of zeroes (contributed by patients not 
taking any supplemental pain medication) followed by continuous distribution of non-zero 
values. Therefore, the supplemental pain medication for OA will be summarized categorically 
into the following classes: (1) no supplemental acetaminophen tablets, (2) 0 to ≤ 0.5 tablets, (3) 
> 0.5 to ≤ 1.0 tablets, (4) > 1.0 to ≤ 2.0 tablets, and (5) > 2.0 tablets. Upon review of the blinded 
data prior to database lock, the classes will be reviewed and if any adjustments are deemed 
necessary, the rationale and new categories will be documented in the final SAP. 
The number and percentage of patients who withdraw from the study due to lack of analgesic 
efficacy will be tabulated for each treatment group and compared using a generalized linear 
model; the distribution of the data will be specified as binomial.  
11.9 Safety 
Analysis of all safety data will be performed on the safety population and will be presented 
based on the treatment received.  
11.9.1 Adverse Events  
All reported adverse events will be coded using the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Verbatim descriptions of the adverse event in addition to 
the SOC and the preferred term (PT) will be included in the patients’ data listings. 
Data for AEs will be analyzed using the treatment-emergent signs and symptoms philosophy. A 
TEAE is defined as an AE where: 
 onset occurs during exposure to study medication or within 7 days after the last dose of 
study medication, having been absent prior to receiving study medication, or 
 onset reoccurs during exposure to study medication or within 7 days after the last dose 
of study medication, having been present but stopping prior to receiving study 
medication, or 
 worsening in severity occurs during exposure to study medication relative to the 
pre-treatment state, when the AE is continuous. 
All reported AEs (whether treatment-emergent or not) will be included in a by-patient AE 
listing. Only TEAEs will be included in summary tables. Adverse events that occur up to the 
follow-up visit will be counted as TEAEs. The incidence of TEAEs will be presented by the counts 


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and percentages of patients with AEs. A patient will be counted only once in the incidence 
count for a MedDRA PT, although a patient may have multiple occurrences (start and stop) of 
an event associated with a specific MedDRA PT. 
Serious adverse events, AEs that lead to study drug or to study discontinuation, and AEs related 
to treatment will also be summarized. In addition, a table of TEAEs by severity and of TEAEs 
occurring in ≥ 5% of the patients in at least one treatment group will be presented.  
If the severity or relationship to the study drug is missing, a worst-case scenario will be 
assumed (i.e., it will be set to severe or definitely related relationship). All SAEs will be 
tabulated overall and by severity and relationship to the study drug.  
11.9.2 Prior and Concomitant Medications  
Concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary (WHO-DD). The number and percent of patients taking 
concomitant medications will be tabulated for each treatment group by appropriate WHO-DD 
classifications. Prior medications will be presented in a listing.  
11.9.3 Clinical Safety Laboratory Evaluations  
Mean changes from baseline to Day 57 will be presented for each of the laboratory parameters. 
Shift tables from baseline to Day 57 will be provided and abnormalities will be flagged (i.e., 
values above or below the reference ranges). The incidence of markedly abnormal laboratory 
results may be calculated. Additional analyses of liver function test will be completed to 
address the FDA guidance on the assessment of drug-induced liver injuries. Specifically, 
additional shift tables for AST, ALT and Total Bilirubin will be generated using the categories 
presented in Table 2 below. 
Table 2 
Categories for Shift Analysis of AST, ALT, and Total Bilirubin 
AST/ALT 
Total Bilirubin 
≤ 1 x ULN 
1 x ULN 
> 1 - ≤ 3 x ULN 
> 1 – 1.5 x ULN 
> 3 - ≤ 5 x ULN 
> 1.5 – 2.0 x ULN 
> 5 - ≤ 10 x ULN 
> 2.0 x ULN 
> 10 - ≤ 20 x ULN 
 
> 20 x ULN 
 
 
For each time point, the proportion of patients who have a serum sodium value > 146 mmol/L 
in each treatment group will be tabulated. In addition, a listing including all patients who had at 
least one serum sodium measurement post treatment > 146 mmol/L will be prepared. 
11.9.4 Vital Signs  
Summary statistics will be presented for vital signs and mean changes from baseline to each of 
the time points. An analysis of abnormal and clinically notable vital sign changes will also be 


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conducted. Details of these analyses, in particular the definition of abnormal and clinically 
notable vital signs, will be included in the SAP.  
11.9.5 ECGs  
Electrocardiogram results at Baseline will be summarized as normal or abnormal. If a result is 
abnormal, the abnormality will be assessed as either clinically significant or not clinically 
significant.  


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12. STUDY CONDUCT 
12.1 Sponsor and Investigator Responsibilities 
12.1.1 Sponsor Responsibilities 
The Sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 13). The Sponsor reserves the right to withdraw a patient from the study (Section 7.4) 
to terminate participation of a study site at any time, and/or to discontinue the study 
(Section 13.6). 
CARA agrees to provide the Investigator with sufficient material and support to permit the 
Investigator to conduct the study according to the study protocol. 
12.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Appendix 5), the Investigator indicates that he/she has 
carefully read the protocol, fully understands the requirements, and agrees to conduct the 
study in accordance with the procedures and requirements described in this protocol. 
The Investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the 
April 1996 International Conference on Harmonisation (ICH) Guidance for Industry E6 Good 
Clinical Practices (GCP), and in agreement with the 1996 version of the Declaration of Helsinki. 
While delegation of certain aspects of the study to subinvestigators and study coordinators is 
appropriate, the Investigator will remain personally accountable for closely overseeing the 
study and for ensuring compliance with the protocol and all applicable regulations and 
guidelines. The Investigator is responsible for maintaining a list of all persons that have been 
delegated study-related responsibilities (e.g., subinvestigators and study coordinators) and 
their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, the study 
medication, and their specific duties within the context of the study. Investigators are 
responsible for providing CARA with documentation of the qualifications, GCP training, and 
research experience for themselves and their staff as required by the Sponsor and the relevant 
governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. 
The Investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
12.2 Quality Control and Quality Assurance 
The clinical monitors will follow written standard operating procedures as agreed to between 
the contract research organization (CRO) and the Sponsor. The monitors 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. 


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12.2.1 Audits and Inspections 
12.2.1.1 Source Documents and Access to Source Data/Documents 
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH-GCP and 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 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. 
The investigational site will provide direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor and 
inspection by regulatory authorities. 
12.3 Data Collection, Validation and Analysis 
The data management coordinator 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. 
12.4 Study Monitoring Plan 
Monitoring and auditing procedures that comply with current GCP guidelines will be followed. 
On-site review of the eCRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 
The study will be monitored by CARA or its designee. Monitoring will be done by personal visits 
from a representative of the Sponsor (site monitor) who will review patient enrollment, eCRFs, 
source documents, drug accountability records, and reporting and recording of AEs. 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). 
12.5 Safety Monitoring Plan 
Due to the controlled nature of this study and the limited exposure to study drug in this study, 
the safety risks to patients participating in this study should be minimal. The Investigators, as 
well as the CRO and the Sponsor’s Medical Monitor, will closely monitor and assess the clinical 
safety and safety data from patients participating in the study. In addition, safety data will be 
reviewed periodically by an external independent data monitoring committee (IDMC). 


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12.6 Data Management and Record Keeping 
12.6.1 Case Report Form Completion 
Electronic case report forms (eCRFs) 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, AEs, 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. 
12.6.2 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the site clinical team and 
data-entry 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. 
12.7 Administrative Procedures 
12.7.1 Study Records Retention 
The Investigator will retain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained until notified by CARA 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, 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 must be notified in writing. 
12.7.2 Protocol Adherence 
It is vital to the success of the study that the Investigator adheres to the details of the protocol, 
and keeps 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 


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necessary to depart from the protocol, then that protocol deviation will pertain to that 
individual patient only.  
Protocol deviations due to lack of patient compliance must also be documented. All protocol 
deviations will be summarized in the final clinical study report. 
The Clinical Monitor will review protocol deviations 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. 
12.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, 
which requires the written approval of Cara. The protocol amendment must be signed by the 
Investigator and approved by the IRB or IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency having jurisdiction over the 
conduct of the study.  
12.9 Publication of Study Findings 
All information regarding CR845 provided by CARA to the Investigator is privileged and 
confidential. By conducting this study, the Investigator affirms to the Sponsor that he/she will 
maintain, in strict confidence, information furnished by the Sponsor, including data generated 
from this study and preliminary laboratory results, except as exempted for regulatory purposes.  
All data generated during the conduct of this study are owned by CARA. The Investigator agrees 
to use the information to accomplish the study and will not use it for other purposes without 
written permission from CARA. Partial or full data or results from this study cannot be 
published without express written consent from CARA. It is understood that there is an 
obligation to provide CARA with complete data obtained during the study. The information 
obtained from the clinical study will be used toward the development of CR845 and may be 
disclosed to regulatory authority, other Investigators, corporate partners or consultants as 
required. 


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13. ETHICS/PROTECTION OF HUMAN PATIENTS 
This study will be conducted in compliance with the Declaration of Helsinki and its 
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. 
13.1 Ethics 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki and all accepted amendments. The IRB will review all appropriate study documentation 
in order to safeguard the rights, safety, and well-being of the patients. The study will only be 
conducted at a site where IRB approval has been obtained. The protocol, Investigator’s 
Brochure (IB), informed consent, 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. 
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 or its designee copies of all IRB 
approval notices, correspondence, annual reports, and final study progress reports. 
13.2 Good Clinical Practices  
The study will be conducted in accordance with the ICH - GCP 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 IB. Essential clinical documents will be maintained 
to demonstrate the validity of the study and the integrity of the data collected. Master files will 
be established at the beginning of the study, maintained for the duration of the study, and 
retained according to the appropriate regulations. 
13.3 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. 


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13.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. The Investigator or 
designee will discuss extensively with the participant patient the study risks and possible 
benefits of this therapy. Copies of the ICF detailing the risks and benefits of study participation 
will be provided to the participants and their families. 
Informed 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 study agent/intervention. Informed 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 trial. A 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. 
Informed consent is required for all patients participating in this study. In obtaining and 
documenting informed consent, the Investigator should comply with applicable regulatory 
requirements and should adhere to GCP guidelines. Prior to the beginning of the trial, the 
Investigator should have the IRB written approval/favorable opinion 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 a signed ICF is obtained from the patient before any activity or 
procedure is undertaken that is not part of routine care. 
13.5 Patient Confidentiality 
In order to maintain patient privacy, all eCRFs, 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 designee and regulatory 
authority access to the patient’s original medical records for verification of data gathered on 
the eCRFs and to audit the data-collection process. The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
Participant confidentiality is strictly held in trust by the participating Investigators, their staff, 
and the Sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participating patients. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the Sponsor. 


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The Clinical 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. 
13.6 Study Discontinuation 
This study may be prematurely terminated if, in the opinion of the Investigator or CARA, there 
is reasonable cause. Written notification documenting the reason for study termination will be 
provided to the Investigator or CARA by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient data and/or data that cannot be evaluated 
 Plans to modify, suspend, or discontinue the development of the study drug 
Should the study be closed prematurely, all study materials (completed, partially completed, 
and blank eCRFs, study drug, etc.) must be returned to CARA. Study drug must be destroyed at 
the site authorized by CARA or returned to the Sponsor. 


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14. REFERENCES 
1. Investigator’s Brochure for CR845. Edition No. 2, Release date: 11 April 2014, Cara 
Therapeutics, Inc. 
2. Farrar JT, Young JP, La Moreaux L, Werth JL, and Poole MR: Clinical importance of changes 
in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. (2001); 
94:149-158. 
3. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: 
a health status instrument for measuring clinically important patient relevant outcomes to 
anti-rheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 
1988; 15:1833-1840. 
4. Bellamy N. Pain assessment in osteoarthritis: experience with the WOMAC osteoarthritis 
index. Semin Arthritis Rheum. 1989; 18:14-17. 
5. Smith, HS, Smith JM, Seidner.  Opioid-induced nausea and vomiting.  Annals of Palliative 
Medicine. July 2012. 
6. Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. September 1999; 55:853-857. 
 
 






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5.
Discontinuation of Pain Medication: Patients will be instructed to discontinue their current nonsteroidal anti-inflammatory drugs and opioid analgesic
medications starting on Day -5 and continuing for the duration of the study (through Day 57).
6.
Treatment Assignment: Patients will be enrolled and assigned to treatment following successful completion of the Baseline assessments.
7.
Dispensing of Study Medication: Study medication will be dispensed to patients in bottles of 15 tablets at the Baseline Visit. The patients will take their first
dose of study medication at the clinic.
8.
Concomitant Medications: Concomitant medications are defined as medications taken at any time from post-dose on Day 1 until the end of the study (i.e.,
at the Follow-up Visit). Any new concomitant medication added during the Titration-to-Effect and Maintenance Treatment Periods must also have the
reason for taking the new concomitant medication recorded in the case report form. Any concomitant medication administered due to an adverse event
must also be recorded on the adverse event case report form page.
9.
Physical Exam: A physical examination will be performed at Screening and on Day 57 (or early termination). On Day 57, any changes from the previous
physical exam conducted at Screening will be noted.
10. Vital Signs: Vital signs will be measured at each clinic visit. Vital signs (blood pressure and heart rate) at the Screening visit will be conducted in both the
supine and standing positions. For the purpose of these assessments, patients should be assessed in the supine position first and then, after sitting up for
at least 1 minute, should be standing for at least 3 minutes prior to measuring blood pressure or heart rate. For the remainder of the study, vital signs will
be assessed in the sitting position. Body temperature will be measured at screening and at Day 57 (or early termination).
11. Pregnancy Testing: For female patients of childbearing potential, a serum pregnancy test will be conducted at Screening and a urine pregnancy test will be
conducted at the Baseline Visit prior to the administration of study drug. “Childbearing potential” is defined in Section 7.6.
12. Laboratory Evaluations: Clinical laboratory evaluations will consist of hematology and blood chemistry and will be conducted at Screening, at Baseline
(prior to drug administration), and on Day 57 (or early termination).
13. Serum Sodium Measurement: Blood samples to measure serum sodium levels will be taken at all visits (or early termination).  If at any time during the
study, the patient’s serum sodium level is > 150 mmol/L, dosing should be paused for patient assessment (i.e., retesting of sodium in approximately 1 hour
after the patient is given a glass of water and clinical evaluation). Based upon the outcome of the clinical evaluation by the clinical staff, the dosing of study
medication will either be: a) continued or b) terminated.
14. Daily Joint Pain: The average daily index joint pain intensity will be assessed using the numeric rating scale. The numeric rating scale score will be recorded
into the electronic case report form by the site at the Screening Visit and by the patient each day (at approximately 6:00 PM) in their patient diary. The
patient should make all attempts to assess their joint pain at the same time each day. During the Screening Period, assessments will be conducted for
5 days prior to the Baseline Visit.
15. The Western Ontario will be completed at each clinic visit from Baseline to Day 57 (or early termination).
16. The Patient Global Impression of Change will be completed on Day 57 (or early termination).
A visit window of +/- 1 day will be allowed


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16. APPENDICES 


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Appendix 1 
Regulations and Guidelines 
a) Declaration of Helsinki 
This Policy of the World Medical Association is available at URL:  
http://www.wma.net/en/30publications/10policies/b3/index.html 
Approval by an Institutional Review Board 
For IND studies, the minimum standards of conduct and requirements for informed consent are 
defined in the FDA regulations. 
This protocol must be reviewed and approved by a valid IRB before initiation of the study. 
Written notification of approval is to be submitted by the Investigator to the CARA, Inc. monitor 
before shipment of investigational drug supplies, and will include the date of the committee's 
approval and the chairperson's signature. This written approval must consist of a completed 
CARA, Inc. IRB Approval form or written documentation from the IRB containing the same 
information. 
Until written approval by the IRB has been received by the Investigator, no patient may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from 
the IRB, or a designee, must be received by CARA, Inc., before implementation. This written 
approval will consist of a completed IRB Approval form or written documentation from the IRB 
containing the same information. 
b) FDA Regulations 
Refer to the following United States Code of Federal Regulations (CFR):  
 FDA Regulations 21 CFR 
Parts 50.20 - 50.27 
Subpart B - Informed Consent of Human Patients 
 FDA Regulations 21 CFR Parts 56.107 - 56.115 
Part 56-Institutional Review Boards  
Subpart B - Organization and Personnel 
Subpart C – IRB Functions and Operations  
Subpart D – Records and Reports 
 FDA Regulations 21 CFR Parts 312.50 - 312.70 
Subpart D - Responsibilities of Sponsors and Investigators 


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Appendix 2 
Numerical Rating Scale 
This is a sample of the Numerical Rating Scale.  
Instructions: Show the pain scale to the patient and explain that on the 0 to 10 pain rating 
scale, 0 means no pain and 10 means the worst possible pain. A value in the middle of the scale 
(around 5) would be moderate pain; a value of 2 or 3 would be mild pain, and a value of 7 or 
higher is considered severe pain. 
Ask the patient the following question: “On a scale of 0 – 10, with 0 being ‘no pain’ and 10 
being the ‘worst possible pain’, how would you rate your average pain in the last 24 hours?” 
The intent of the question is to gain an understanding of the intensity of the patient’s index 
joint pain. 
 
 
 
 
 
No Pain 
 
 
 
 
                      Worst Possible Pain 
 
 
 
 
 
 
Adapted from: Farrar JT, Young JP, La Moreaux L, Werth JL, and Poole MR: Clinical importance 
of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 
94 (2001) 149–158. 


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Appendix 3 
Western Ontario and McMaster Osteoarthritis Index 
This is a sample questionnaire. The actual questionnaire will be provided in the eCRF. 
Patients will be provided with the Western Ontario and McMaster Osteoarthritis Index 
(WOMAC) scale and instruction sheet at each clinic visit at which the patient is scheduled to be 
assessed using the WOMAC questionnaire. 
The WOMAC index is used to assess patients with osteoarthritis of the hip or knee using 
24 parameters. It can be used to monitor the course of the disease or to determine the 
effectiveness of anti-rheumatic medications. Additional information regarding this scale can be 
found in the WOMAC Osteoarthritis Index Guide that will be provided to the sites. 
Patients will be asked to score the impact of their index joint OA on each of the parameters for 
pain, stiffness and activities (function) using the 11-point numerical scales shown below. 
Patients should put an “X” in the box that best represents their score for that item. The time 
frame of assessment is the past 48 hours. 
 
Pain: 
1. Walking on a flat surface 
2. Stair climbing 
3. Nocturnal (at night, lying in bed) 
4. Rest (sitting or lying down) 
5. Weight bearing (standing upright) 
 
 
Stiffness: 
1. Morning stiffness 
2. Stiffness occurring later in the day 
 
 
 
 


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Function 
1. Difficulty descending stairs
2. Difficulty ascending stairs
3. Rising from sitting
4. Standing
5. Bending to floor (to pick something up)
6. Walking on a flat surface
7. Getting in or out of car
8. Going shopping
9. Putting on socks
10. Rising from bed
11. Taking off socks
12. Lying in bed
13. Getting in and out of the bathtub
14. Difficulty sitting (for a period of time)
15. Getting on or off the toilet
16. Heavy domestic duties
17. Light domestic duties


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Appendix 4 
Patient Global Impression of Change 
This is a sample questionnaire.  
The patients will provide their overall impression of the status of their OA in the index joint 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 
osteoarthritis 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


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Appendix 5 
Investigator Approval Statement 
A Randomized, Double-Blind, Placebo-Controlled, Titration-to-Effect Study of Orally 
Administered CR845 in Patients with Osteoarthritis of the Hip or Knee 
Protocol: CR845-CLIN2002-PO 
I 
have 
read 
and 
understand 
the 
protocol 
(CR845-CLIN2002-PO) 
and 
the Investigator's Brochure and I agree that these documents contain all the 
information necessary to conduct this study. I will conduct the study as outlined in 
the protocol and any amendment(s) to the protocol. 
In my formal capacity as Investigator, I understand the study protocol and will conduct this 
study according to the principles of Good Clinical Practice (in compliance with the 
International Conference on Harmonisation Harmonized Tripartite Guideline for Good Clinical 
Practice E6 dated 10 June 1996) and all applicable federal and local regulations.  
I will ensure that all individuals assisting with the study are adequately trained and informed 
about the protocol, investigational product(s), procedures and they study-related duties and 
functions. 
I agree not to deviate from the protocol without prior agreement from the Sponsor except to 
avoid an immediate safety hazard to the study subjects.  
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.  
Printed Name: Principal 
Investigator  
_________________________________________________ 
Signature: 
_________________________________________________ 
Title: 
_________________________________________________ 
Study Site/Site 
Number: 
_________________________________________________ 
Date: 
_________________________________________________ 

SAP_001.pdf: 
CARA Therapeutics, LP
Statistical Analysis Plan
Protocol: CLIN2002-PO
Version 1.0
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Page 1 of 56
Version Date:  18JAN2017
DOCUMENT:
STATISTICAL ANALYSIS PLAN
PROTOCOL
Number:
CLIN2002-PO
Title:
A Randomized, Double-Blind, Placebo-Controlled, 
Titration-to-Effect Study of Orally Administered CR845 
in Patients with Osteoarthritis of the Hip or Knee 
Date:
04NOV2016, Version 3.0
STUDY PHASE
Phase 2
SAP STATUS
SAP Version 1.0
SAP VERSION DATE
18JAN2017
SPONSOR:
CARA Therapeutics, LP
Four Stamford Plaza
Stamford CT 06902
(203) 406 3700




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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................... 7 
2. INTRODUCTION ................................................................................................... 9 
3. STUDY OBJECTIVES........................................................................................... 9 
4. STUDY DESIGN.................................................................................................. 10 
4.1. General Study Design and Plan..................................................................... 10 
4.2. STUDY POPULATION ............................................................................................ 12 
4.2.1. Inclusion criteria............................................................................................. 12 
4.2.2. Exclusion criteria............................................................................................ 13 
4.3. RANDOMIZATION AND BLINDING............................................................................ 14 
4.4. STUDY ASSESSMENTS ......................................................................................... 15 
5. STUDY VARIABLES AND DEFINITIONS........................................................... 18 
5.1. EFFICACY VARIABLES.......................................................................................... 18 
5.1.1. Primary Efficacy Variable............................................................................... 18 
5.1.2. Secondary Efficacy Variables ........................................................................ 18 
5.2. SAFETY VARIABLES............................................................................................. 20 
5.2.1. Adverse Events.............................................................................................. 20 
5.2.2. Clinical Laboratory Evaluations...................................................................... 20 


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5.2.3. Vital Signs...................................................................................................... 21 
5.2.4. ECGs ............................................................................................................. 22 
6. SAMPLE SIZE DETERMINATION ...................................................................... 23 
7. ANALYSIS POPULATIONS................................................................................ 24 
7.1. ENROLLED POPULATION ...................................................................................... 24 
7.2. EFFICACY POPULATIONS...................................................................................... 24 
7.2.1. Full Analysis Population (FAP)....................................................................... 24 
7.2.2. Per Protocol (PP) Population ......................................................................... 24 
7.3. SAFETY POPULATION........................................................................................... 24 
7.4. PROTOCOL DEVIATIONS....................................................................................... 24 
8. GENERAL STATISTICAL CONSIDERATIONS.................................................. 26 
8.1. ADJUSTMENTS FOR COVARIATES.......................................................................... 26 
8.2. HANDLING OF INCOMPLETE OR MISSING DATA....................................................... 27 
8.3. INTERIM ANALYSES AND DATA MONITORING.......................................................... 28 
8.4. MULTI-CENTER STUDIES ...................................................................................... 28 
8.5. MULTIPLE COMPARISONS / MULTIPLICITY.............................................................. 28 
8.6. EXAMINATION OF SUBGROUPS ............................................................................. 28 


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9. STUDY POPULATION CHARACTERISTICS ..................................................... 29 
9.1. SUBJECT DISPOSITION......................................................................................... 29 
9.2. PROTOCOL DEVIATIONS....................................................................................... 29 
9.3. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................... 29 
9.4. MEDICAL HISTORY ............................................................................................... 30 
9.5. DOSING AND EXTENT OF EXPOSURE ..................................................................... 30 
9.6. PRIOR AND CONCOMITANT MEDICATION AND THERAPIES ......................................... 31 
10. EFFICACY ANALYSES .................................................................................... 33 
10.1. PRIMARY EFFICACY VARIABLE ........................................................................... 33 
10.2. SECONDARY EFFICACY VARIABLE(S).................................................................. 36 
11. SAFETY ANALYSES ........................................................................................ 37 
11.1. ADVERSE EVENTS ............................................................................................. 37 
11.2. CLINICAL LABORATORY EVALUATIONS................................................................ 39 
11.3. VITAL SIGNS ..................................................................................................... 42 
11.4. ECGS .............................................................................................................. 43 


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12. SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ...... 44 
13. REPORTING CONVENTIONS .......................................................................... 44 
14. REFERENCES .................................................................................................. 46 
15. TOCS FOR TABLES, FIGURES, LISTINGS AND OUTPUT ............................ 47 
15.1. TABLES ............................................................................................................ 47 
15.2. DATA LISTINGS FOR APPENDIX 16.2 ................................................................... 52 
16. ATTACHMENTS................................................................................................ 53 
16.1. PRIMARY ANALYSIS PROGRAMMING PLAN .......................................................... 53 


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1.  LIST F ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical-Therapeutic-Chemical
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
DB
Double-blind
ECG
Electrocardiogram
FAP
Full Analysis Population
FDA
US Food and Drug Administration
ICH
International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human 
Use
IV
Intravenous
IWRS
Interactive Web Response System
LNH
Low/Normal/High
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities


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MMRM
Mixed Models with Repeated Measures
NRS
Numerical Rating Scale
OA
Osteoarthritis
PP
Per Protocol
PR
ECG PR Interval
QRS
ECG QRS Duration
QT
ECG QT Interval
QTcF
ECG QT Interval, Fridericias Correction
RR
ECG RR Duration
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SAF
Safety Population
SD
Standard Deviation
SE
Standard Error
SI
Système International
SOC
MedDRA System Organ Class
TEAE
Treatment-emergent Adverse Event
WBC
White Blood Cell
WOMAC
Western Ontario and McMaster Osteoarthritis Index
WHO DD
World Health Organization Drug Dictionary


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2.  INTRODUCTION
This statistical analysis plan (SAP) summarizes the planned presentation and analyses of the 
clinical data from CARA Therapeutics Protocol CLIN2002-PO (version 3.0 dated 04 November 
2016), This is a multicenter, randomized, double-blind, placebo-controlled, titration-to-effect 
study of orally administered CR845 in patients with osteoarthritis (OA) of the hip or knee. 
CR845 is a selective kappa-opioid receptor agonist with a peripheral mechanism of action as a 
novel therapeutic agent for the treatment of acute and chronic pain.  CR845 is a potent and 
selective kappa receptor agonist with more than 30,000-fold selectivity over mu and delta opioid 
receptors and with no known activity at other non-opioid receptors, ion channels, or 
transporters. Its unique peptidic structure significantly differs from that of small molecule kappa 
opioid agonists developed to date, which, for the most part, are active within the Central 
Nervous System. Intravenous (IV) and oral formulations of CR845 are being developed as 
novel treatments for post-operative and chronic pain, respectively, with the potential for reduced 
side effects and improved tolerability compared with currently available opioid medications.  
The planned analyses identified in this SAP may be included in regulatory submissions and/or 
future manuscripts. Additional exploratory analyses, not identified in this SAP, may be 
performed to support the clinical development program.  Unplanned, analyses that are 
performed but not identified in this SAP will be clearly identified in the clinical study report 
(CSR).  The structure and content of this SAP provides sufficient detail to meet the 
requirements identified by the US Food and Drug Administration (FDA) and International 
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use (ICH): Guidance on Statistical Principles in Clinical Trials.
3.  STUDY BJECTIVES
The primary objective of this study is to characterize the analgesic efficacy of orally 
administered CR845 in patients with OA of the hip or knee.
There are 4 secondary objectives:
x
To compare the treatment effect on patient function, pain and stiffness between CR845-
and placebo-treated patients as measured by the Western Ontario and McMaster 
Osteoarthritis Index (WOMAC). 
x
To compare the treatment effect on Patient Global Impression of Change between 
CR845- and placebo-treated patients. 
x
To compare the use of analgesic rescue medications between CR845- and placebo-
treated patients. 


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x
To characterize the safety and tolerability of titration-to-effect administration of oral 
CR845.  
4.  STUDY DESIGN
4.1.  General tudy esign and lan
This is a multicenter, randomized, double-blind, placebo-controlled, titration-to-effect study of 
orally administered CR845 in patients with OA of the hip or knee. 
CR845 is a highly charged peptide with limited bioavailability when administered orally. Based 
upon previous studies with oral CR845, a significant inter-patient variability in plasma
concentrations of CR845 has been observed that is likely due to differences in the absorption of 
CR845 from the gastrointestinal tract. It is presumed that patients who absorb CR845 well will 
not need higher doses to achieve an adequate analgesic response and patients who absorb the 
drug poorly will need to be titrated up to a higher dose to achieve a similar effect. The purpose 
of this Titration-to-Effect Period is to identify the optimal dose level of CR845 for each patient, 
based upon tolerability and efficacy, prior to the beginning of the 4-week Maintenance 
Treatment Period. Once patients enter into the Maintenance Treatment Period, the dose level 
can no longer be changed. 
The study schedule is comprised of the following:
x
Screening period (Visit 1/Day -14 to Day -1)
o
Patients will keep a diary of their pain scores for the 7 days prior to baseline (Day 
1) 2QO\ SDWLHQWV ZKR UHSRUW D GDLO\ SDLQ LQWHQVLW\ LQ WKH LQGH[ MRLQW   GXULQJ  RU
more of the last 7 days prior to randomization, with 2 consecutive GD\V  
occurring just prior to randomization, and continue to satisfy all other 
inclusion/exclusion criteria will be entered into the Titration-to-Effect period and
will be randomized to receive either CR845 or placebo in a 2:1 ratio stratified by 
primary OA joint (knee versus hip).
x
Blinded 4-week Titration-to-Effect Period (Days 1-28 / Weeks 1-4):
o
Patients will receive either CR845 1mg or matching placebo twice daily (BID) for 
1 week (7 days). Placebo patients will continue to take matching placebo 
throughout the study, regardless of the decisions described below which will be 
made for all patients.
o
At the end of each week, there will be a clinic visit to review the patient diary, 
rescue medication use, Adverse Events, any other safety related events and


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serum sodium levels. The clinical team will decide on the next dose level to give 
the patient for the following week.
o
At the end of each week for the first 3 weeks, the clinical team will decide 
whether or not the patient should stay at their current dose level BID, move to the 
next higher dose level BID (if not currently taking 5mg), move to the next lower 
dose level BID (if not currently taking 1mg) or discontinue from the study.
o
At the end of the 4th week, the clinical team will decide whether or not the patient
should stay at their current dose level BID or move to the next lower dose level
BID (if not currently taking 1mg) for the maintenance treatment period or whether 
they should be discontinued from the study.
x
Blinded 4-week Maintenance Treatment Period (Days 29-57/Weeks 5-8):
o
4 weeks of treatment at the optimal dose of CR845 (or matching placebo) 
following the Titration-to-Effect period.
o
Patients will return to the clinic at the end of Week 6 (Day 43) and Week 8 (Day 
57) to complete safety and efficacy assessments.
x
Follow-Up Period (1-week post treatment)
o
7-10 days after the last dose of study medication, patients will return to the study 
site for a follow-up safety evaluation
If at any time during the Titration-to-Effect or Maintenance Treatment Period, the patients 
serum sodium level is > 150 mmol/L, dosing should be paused for patient assessment (i.e.,
retesting of sodium approximately 1 hour after the patient is given a glass of water, and clinical 
evaluation). Based upon the outcome of the clinical evaluation by the clinical staff, the dosing of 
study medication will either be continued or terminated. 
 
Study medication will be taken BID with a full glass of water (250 mL). It is recommended that 
the medication be taken in the morning (at least 2 hours before or 4 hours after breakfast) and 
on a night (at least 4 hours after the last meal). 
Acetaminophen is the only allowable rescue medication for pain beginning from Day -5 until the 
end of the Maintenance Treatment Period and will be provided as 325-mg tablets and its use 
(number of tablets taken in the previous 24 hours) will be reported each evening in the patient 
diary.  Acetaminophen should be taken as directed for pain, with a maximum allowable dose of 
8 tablets per day (given 1 to 2 tablets every 4 to 6 hours as needed). However, the use of 
acetaminophen is not allowed for the 12 hours prior to a scheduled office visit until after the 
efficacy assessments have been completed, in order to minimize the confounding effects of 
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Patients will record their pain intensity score (all days), the number of rescue medication tablets 
taken for target or other pain (Day -5 onwards) and AM/PM dosing of study drug (Day 1 
onwards) in a patient diary.
4.2.  STUDY POPULATION
7KH VWXG\ SRSXODWLRQ ZLOO FRQVLVW RI PDOH DQG IHPDOH SDWLHQWV DJHG   \HDUV ZLWK PRGHUDWH WR
severe pain associated with OA of the hip or knee. All inclusion/exclusion criteria below must be 
met before the patient is enrolled.
4.2.1.  Inclusion criteria
1. Voluntarily provides written informed consent to participate in the study prior to any study 
procedures. 
2. Is able to speak, read, and communicate clearly in English or Spanish; is able to understand 
the study procedures. 
 0DOH RU IHPDOH   \HDUV RI DJH
4. %RG\ PDVV LQGH[ %0,   NJP2
5. Has OA of the hip or knee according to American College of Rheumatology (ACR) criteria. 
 5HSRUWV DQ DYHUDJH SDLQ LQWHQVLW\ OHYHO   LQ WKH LQGH[ MRLQW DW 6FUHHQLQJ RQ D -10 NRS 
scale. 
7. Is either opioid-naïve (defined as taking < 10 mg a day of morphine equivalent 14 days prior 
to screening) or opioid-experienced. If receiving opioid analgesic medication for OA, patients 
PXVW EH RQ D VWDEOH GRVH   PJ RI PRUSKLQH HTXLYDOHQWV IRU  GD\V SULRU WR VFUHHQLQJ
8. Willing to discontinue all currently used pain medication beginning 5 days prior to the 
Baseline Visit and throughout the study. Acetaminophen use is allowed. 
9. If female: 
a. Of childbearing potential  the patient must be willing to practice an acceptable form of birth 
control (defined as the use of an intrauterine device, a barrier method with spermicide, 
condoms, any form of hormonal contraceptives, or abstinence from sexual intercourse) for the 
duration of treatment and for at least 3 days following the last dose of study drug. 


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b. Of non-childbearing potential  the patient must be surgically or biologically sterile 
(hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or postmenopausal for at least 1 
year). 
10. If male, the patient must be surgically or biologically sterile. If not sterile, the patient must
agree to use an acceptable form of birth control with a heterosexual partner (as described
in inclusion criterion #9) or abstain from sexual relations during the treatment period and
for 3 days following the last dose of study drug.
11. Is free of other physical, mental, or medical conditions that, in the opinion of the Investigator, 
would make study participation inadvisable. 
12. Reports a daily pain intensity score in the index jRLQW   RQ D -10 NRS scale) during 4 or 
PRUH RI WKH ODVW  GD\V SULRU WR UDQGRPL]DWLRQ ZLWK  FRQVHFXWLYH GD\V   RFFXUULQJ MXVW SULRU WR
randomization. 
4.2.2.  Exclusion criteria
1. Has had a joint replacement in the index joint. 
2. Has received an intra-articular injection of corticosteroids or hyaluronic acid in the index 
joint(s) within 3 months prior to the Screening Visit. 
3. Has started a new medication for chronic illness within 30 days prior to the Screening Visit. 
4. Is receiving opioid analgesic treatment for OA of the hip or knee at a dose > 40 mg of 
morphine equivalent. 
5. Uses antipsychotics, antiepileptics, sedatives, hypnotics, or antianxiety agents, selective 
serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants with a dose change <30 days 
prior to day 1 of the study. 
6. Has a history or current diagnosis of substance dependence (except caffeine or nicotine) or 
alcohol abuse, according to the criteria of the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5). 
7. Has a positive urine drug screen for drugs of abuse at Screening. 
8. Has been diagnosed with a condition of hyperhidrosis (excessive sweating) or primary 
hypodipsia (a reduced sense of thirst). 
9. Has a history (within 6 months) of clinically meaningful orthostatic changes in vital signs OR, 
at Screening, has a decrease in systolic blood pressure by > 20 mm Hg or a decrease in 
diastolic blood pressure by 10 mm Hg together with an increase in heart rate of > 30 beats per 
minute when transitioning from supine to standing measurements. 


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10. Has a medical condition (e.g., a cardiovascular, pulmonary, hepatic, renal, hematologic, 
gastrointestinal, endocrine [adrenal hyperplasia], immunologic, dermatologic, neurologic, 
oncologic, or psychiatric) or a significant laboratory abnormality that, in the Investigators 
opinion, would jeopardize the safety of the patient or is likely to confound the study 
measurements. 
11. Has had any gastric bypass surgery, sleeve, or lap-band (for weight loss). 
12. Has a corrected QT interval > 450 msec in males, or > 470 msec in females or clinically 
significant abnormality on screening ECG. 
13. Has a serum sodium level > 143 mmol/L at Screening or Baseline (i.e., Visit 2 prior to 
initiating study drug).
14. Has impaired renal function indicated by serum creatinine > 2 × the reference upper limit of 
normal (ULN). 
15. Has a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 ×
the reference ULN, or total bilirubin > 2 × the ULN at Screening. 
16. Has, in the opinion of the Investigator, any clinical signs of dehydration or hypovolemia (e.g., 
symptomatic hypotension) or associated laboratory abnormalities (e.g., elevated hematocrit or 
elevated blood urea nitrogen [BUN] > 1.5 × the reference ULN) at Screening. 
17. Has taken opioid or non-opioid pain medication (e.g., Nonsteroidal anti-inflammatory drug
such as naproxen or cyclo-oxygenase-2 inhibitors) within 5 days prior to study drug 
administration. Acetaminophen use is allowed. 
18. Has received another investigational drug within 30 days prior to Baseline or has planned to 
participate in another clinical trial while enrolled in this study. 
4.3.  RANDOMIZATION ND BLINDING
Randomization
Subjects will be assigned unique subject numbers upon enrollment into the screening period.  
Subject numbers will be recorded on all clinical investigation documentation (ie, CRFs, clinical 
drug supply labels, laboratory kits, ECGs, etc.).  
Eligible patients will be randomized to receive either CR845 or placebo in a 2:1 ratio, and will be 
stratified according to their primary joint affected by OA (knee vs. hip). Unique randomization 
numbers, generated according to the randomization specifications approved by CARA 
Therapeutics and INC Research, LLC, will be assigned through Medidata Balance and will 
determine the drug supply given to each subject.


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Blinding
CR845 will be provided as enteric-coated tablets at doses of 1 mg, 2.5 mg and 5 mg with 
matching placebo tablets. All tablets are white in color with no markings and are identical in 
appearance, regardless of dose. 
Because of the known titration scheme during the Titration-to-Effect Period, the clinical staff 
may be aware of the dose being administered, but all attempts should be made to keep the 
patients blinded as to the study dose being administered during both titration and treatment. 
Emergency unblinding (via IWRS) of treatment assignment for a patient may be necessary due 
to a medical emergency, such as an Serious Adverse Event (SAE) that is unexpected and for 
which a causal relationship to study drug cannot be ruled out or any other significant medical 
event (e.g. pregnancy). 
If emergency unblinding is required for a medical emergency: 
x
Only the Investigator will make the decision to unblind the treatment assignment. 
x
Only the patient with the medical emergency will be unblinded. 
The Investigator should notify the INC Medical Director and/or designee prior to breaking the 
blind, whenever possible. In all cases, the INC Medical Director and/or designee must be 
notified within 24 hours of the blind being broken.
4.4.  STUDY ASSESSMENTS
The schedule of study visits and measurements is shown in Table 1. A visit window of +/- 1 day 
will be allowed.


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Table 1
Schedule of Visits and Procedures
1. Prior Medications: Prior medications are defined as medications taken at any time during the 30 days prior to Screening until the 
time of dosing on Day 1, whether continuing or not. Any changes to prior medications (dose, regimen, etc.) during the course of the 
study must be considered as a new concomitant medication.
2. Patient-reported Outcome Training: A member of the clinical staff will review the patient-reported outcome assessments for this 
study with each patient during the Screening and Baseline Visits. Patient-reported outcome assessments for this study are the 
Numeric Rating Scale, the Western Ontario and McMaster Osteoarthritis Index, and the Patient Global Impression of Change.
3. Patient Diary: Patients will be shown how to capture their daily pain scores and the number of rescue medication tablets taken 
each day (the preceding 24 hours) in their diaries beginning 7 days before their scheduled Baseline Visit and continuing for the 
duration of the Titration-to-Effect and Maintenance Treatment Periods.
4. Rescue Medication: A bottle of analgesic rescue medication (acetaminophen, 325 mg) will be provided at the Screening Visit to 
be used (if needed) throughout the study. Patients will be instructed to take acetaminophen as needed for pain (up to 2 tablets of 
325mg per administration for a maximum of 8 tablets per day). Patients will also be instructed to bring the bottle of medication back 
with them for each clinic visit for drug accountability and dispensation of another bottle of rescue medication if needed. Patients 
should also be instructed not to take any analgesic rescue medication within 12 hours of a scheduled clinic visit to prevent 
confounding of the pain assessments during the visit.
5. Discontinuation of Pain Medication: Patients will be instructed to discontinue their current nonsteroidal anti-inflammatory drugs 
and opioid analgesic medications starting on Day -5 and continuing for the duration of the study (through Day 57).
6. Treatment Assignment: Patients will be enrolled and assigned to treatment following successful completion of the Baseline 
assessments.
7. Dispensing of Study Medication: Study medication will be dispensed to patients in bottles of 15 tablets at the Baseline Visit. The 
patients will take their first dose of study medication at the clinic.
8. Concomitant Medications: Concomitant medications are defined as medications taken at any time from post-dose on Day 1 until 
the end of the study (i.e., at the Follow-up Visit). Any new concomitant medication added during the Titration-to-Effect and 
Maintenance Treatment Periods must also have the reason for taking the new concomitant medication recorded in the case report 
form. Any concomitant medication administered due to an adverse event must also be recorded on the adverse event case report 
form page.


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Table 1
Schedule of Visits and Procedures (continued)
9. Physical Exam: A physical examination will be performed at Screening and on Day 57 (or early termination). On Day 57, any 
changes from the previous physical exam conducted at Screening will be noted.
10. Vital Signs: Vital signs will be measured at each clinic visit. Vital signs (blood pressure and heart rate) at the Screening visit will 
be conducted in both the supine and standing positions. For the purpose of these assessments, patients should be assessed in the 
supine position first and then, after sitting up for at least 1 minute, should be standing for at least 3 minutes prior to measuring blood 
pressure or heart rate. For the remainder of the study, vital signs will be assessed in the sitting position. Body temperature will be 
measured at screening and at Day 57 (or early termination).
11. Pregnancy Testing: For female patients of childbearing potential, a serum pregnancy test will be conducted at Screening and a
urine pregnancy test will be conducted at the Baseline Visit prior to the administration of study drug. 
12. Laboratory Evaluations: Clinical laboratory evaluations will consist of hematology and blood chemistry and will be conducted at 
Screening, at Baseline (prior to drug administration), and on Day 57 (or early termination).
13. Serum Sodium Measurement: Blood samples to measure serum sodium levels will be taken at all visits (or early termination). If 
at any time during the study, the patients serum sodium level is > 150 mmol/L, dosing should be paused for patient assessment 
(i.e., retesting of sodium in approximately 1 hour after the patient is given a glass of water and clinical evaluation). Based upon the 
outcome of the clinical evaluation by the clinical staff, the dosing of study medication will either be: a) continued or b) terminated.
14. Daily Joint Pain: The average daily index joint pain intensity will be assessed using the numeric rating scale. The numeric rating
scale score will be recorded into the electronic case report form by the site at the Screening Visit and by the patient each day (at 
approximately 6:00 PM) in their patient diary. The patient should make all attempts to assess their joint pain at the same time each 
day. During the Screening Period, assessments will be conducted for 5 days prior to the Baseline Visit.
15. The Western Ontario will be completed at each clinic visit from Baseline to Day 57 (or early termination).
16. The Patient Global Impression of Change will be completed on Day 57 (or early termination).
A visit window of +/- 1 day will be allowed


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5.  STUDY VARIABLES AND DEFINITIONS
5.1.  EFFICACY VARIABLES
5.1.1.  Primary Efficacy ariable
The primary efficacy variable is the weekly mean pain intensity score calculated using the 
average pain over the last 24 hours scores collected in the daily diaries using an 11-point scale 
where 0 = no pain, and 10= pain as bad as you can imagine. The weekly mean pain intensity 
score will be defined as the sum of non-missing daily "average pain over the last 24 hours" 
scores reported during that week (Days -7 to -1 [Baseline], Days 1-7 [Week 1], Days 8-14
[Week 2], Days 15-21 [Week 3],  , Days 50-56 [Week 8]) divided by the number of days with 
non-missing scores for that week. If a subject reports less than 3 days of pain scores during a 
week, the weekly mean pain intensity score will be set to missing.
The primary efficacy endpoint is defined as the change from baseline at Week 8 with respect to 
the weekly mean of the daily 24-hour pain intensity for the index joint. This will be compared 
between the CR845 and placebo group.
5.1.2.  Secondary Efficacy Variables
The following will be secondary efficacy variables/endpoints and will be compared between the 
CR845 and placebo group:
x
Change from baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) 
Index Total Score at each week
x
Change from baseline in the WOMAC Pain Intensity, Stiffness and Function Sub-scale 
Scores at each week
x
Treatment Pain Response: Proportion of patients with at least 30% and 50%
improvement from baseline in the weekly mean pain intensity at week 8
x
Patient Global Impression of Change (PGIC) at Week 8 or End of Treatment visit
x
Supplemental Analgesic Medication Used: Average daily number of acetaminophen 
tablets used over the study and during the Maintenance Treatment Period
x
Proportion of patients withdrawing from treatment due to lack of analgesic efficacy


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Western Ontario & McMaster Osteoarthritis (WOMAC) Index
The WOMAC Index is a self-administered assessment used to measure pain, stiffness, and 
physical function in patients with osteoarthritis.  The WOMAC Index contains 24 questions 
across 3 different sub-scales (pain, stiffness, and function) all with scoring 0-10 (0 = No 
Pain/Stiffness/Difficulty, 10 = Extreme Pain/Stiffness/Difficulty). The WOMAC Index Total Score 
is calculated as the sum of all 24 scores. Each WOMAC Index Subscale score 
(Pain/Stiffness/Function) is calculated as the sum of all scores within that subscale. Patients will 
complete the WOMAC at each clinic visit starting with the Baseline Visit.
Treatment Pain Response
A patients pain response to treatment is defined as the percent improvement from baseline with 
respect to the weekly mean of average pain in the last 24 hours pain score during the last 
week of the Maintenance Treatment Period (Week 8) . If a patients mean weekly pain score 
during the last week of the Maintenance Treatment Period is greater than the baseline score 
(i.e., the patient has an increase in pain compared to baseline), his/her response to treatment 
will be assigned a value of 0 (i.e. the patient will be considered a non-responder). Patients who 
discontinue study drug early will be considered non-responders to treatment and will be 
assigned a pain response of 0.
The percentage of subjects achieving levels of treatment response 10% to 100% by 10% 
increments as defined above will be calculated with 30% of key interest as it has been shown 
to represent a clinically important improvement in pain. 
Patient Global Impression of Change (PGIC)
The PGIC score collected at Week 8, or at the End of Treatment visit (for patients who 
discontinue treatment early) ranges from 1 (Very Much Improved) to 7 (Very Much Worse).
Supplemental Analgesic Medication Used
The average daily number of acetaminophen tablets used during the study will be calculated 
using data recorded in the patient diary as the sum of the total number of tablets used divided 
by the length of exposure (in days). A similar algorithm will be used to derive the average daily 
number of acetaminophen tablets used during each week (baseline will be study day -5 to study 
day -1), the Titration-to-Effect Period, the Maintenance Treatment Period, Study Day 1 to 56 
Period and the End of Treatment week 
Due to the nature of the data, the average daily number of analgesic rescue use (in this 
case acetaminophen) tend to have a large portion of zeroes (contributed by subjects not 
taking any supplemental pain medication) followed by continuous distribution of non-zero 
values. Therefore, the supplemental pain medication for OA will be grouped categorically 
into the following classHV  QR VXSSOHPHQWDO DFHWDPLQRSKHQ WDEOHWV   WR   WDEOHWV
 !  WR   WDEOHWV  !  WR   WDEOHWV DQG  !  WDEOHWV


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Withdrawal Due to Lack of Analgesic Efficacy
This will be obtained from the treatment completion form of the eCRF.
5.2.  SAFETY VARIABLES
The safety variables are:
x
Adverse events
x
Clinical laboratory evaluations (including serum sodium levels)
x
Vital signs : systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate 
and body temperature
x
ECGs: heart rate, PR interval, QRS duration, QT interval, RR duration, QTcF, and 
clinical interpretation of ECG test results
5.2.1.  Adverse vents
Adverse events that occur after the signing of the informed consent up to study completion, 
including the Follow-up visit 7-10 days after the last dose of study medication, will be recorded 
on CRFs for all subjects who enter the study. An additional follow-up telephone call may be 
performed up to 30 days after the last dose as a final assessment of treatment-emergent 
adverse events unresolved at the final clinic visit attended. Information gathered by telephone 
related to status of adverse events will be documented in the patient case report form. 
5.2.2.  Clinical aboratory Evaluations
The following clinical laboratory tests will be performed at Screening, Day 1 (Baseline prior to 
drug administration) and at Day 57 (or early termination), with additional blood sampling for the 
valuation of serum sodium as follows:




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5.2.4.  ECGs
An ECG will be performed at Screening and Day 57 (or early termination) and will consist of 
heart rate, PR duration, QRS duration, QT interval, RR interval, uncorrected QT interval and 
corrected Fridericias QT interval. The investigator will interpret the ECG as Normal, Abnormal 
Not Clinically Significant or Abnormal  Clinically Significant.


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6.  SAMPLE IZE ETERMINATION
Approximately 405 patients with OA of the hip and knee will be randomized in a 2:1 ratio (270 to 
CR845 and 135 to placebo) at approximately 40 sites in the United States.
A sample size re-estimation will be made after approximately 50% of the planned 405 patients 
have been randomized and have either completed the 8-week treatment period or have 
discontinued from treatment early (see Section 8.3). 
The sample size will be calculated to ensure 90% conditional power such that: 
 
where t1 and t2 are the t-statistics from separately performing the primary analysis for stage 1 
(interim) and stage 2 (post interim) patients respectively (see Section 8). Maintaining a 2:1 ratio, 
the required total sample size (n2) to achieve the above criteria will be calculated using the 
difference between least square means and the corresponding standard error divided by 
sqrt(1/n11 + 1/n12) from stage 1 analysis (where n11 and n12 are the sample size in each 
treatment group from stage 1).
A maximum total sample size of 480 randomized patients will be allowed for the study 
regardless of the sample size re-estimation at the interim analysis.


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7.  ANALYSIS POPULATIONS
Several analysis populations are described below.  The analysis of the Full Analysis and Per 
Protocol populations will be based on planned (randomized) treatment, the analysis of the 
Safety population will be based on actual treatment received.
7.1.  ENROLLED POPULATION
The enrolled population consists of all individuals who signed the informed consent form.
7.2.  EFFICACY POPULATIONS
7.2.1.  Full Analysis opulation FAP)
The Full Analysis population (FAP) consists of all randomized patients who received at least 1 
dose of double-blind study drug will be included in the efficacy evaluation. 
7.2.2.  Per rotocol PP) Population
The Per Protocol population (PP) consists of all randomized patients in the FAP without any 
major protocol violations that could affect the efficacy analyses. The criteria for determining 
what constitutes a major protocol violation will be defined prior to database lock and the 
breaking of the blinded treatment assignment code. 
The requirement for a PP population and exclusion of subjects from it will be decided at a 
blinded data review meeting (BDRM) and decisions will be documented in a separate BDRM 
document approved and signed by all authors of this SAP (or equivalents) prior to database lock 
and unblinding of the data.
7.3.  SAFETY POPULATION
The Safety population (SAF) is the group of subjects who were randomized and received at 
least one dose of double-blind study drug. The FAP and the Safety populations are identical.
7.4.  PROTOCOL DEVIATIONS
Protocol deviations will be identified in several ways: through programmatic checks, through 
medical reviews, and by clinical research associates during site monitoring. The protocol 
deviations include but are not limited to: 


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1.) Exclusionary medical history at screening
2.) Violation of sodium criteria at screening or at admission to surgery
3.) Prior, concomitant, or supplemental medication deviations
4.) Violation of inclusion/exclusion criteria related to the pain intensity scores 
5.) Other known violation of inclusion/exclusion criteria
6.) Deviations with respect to concomitant analgesic rescue medication 
At the BDRM, protocol deviations will be classified as minor or major and whether they would 
affect efficacy sufficiently to exclude the patient from the PP population. 


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8.  GENERAL TATISTICAL ONSIDERATIONS
This SAP contains a detailed description of the analytical variables and the statistical 
methods/procedures that will be presented in support of this clinical study (CLIN2002-PO).  Any 
modification to the proposed analyses will be documented in the integrated statistical/clinical 
report.  Additionally, any exploratory analyses not described in the Statistical Analysis Plan will 
be documented in the integrated statistical/clinical report.
The overall objectives of this study will be achieved through descriptive and/or inferential 
analyses involving the efficacy and safety variables collected in this study. All variables 
specified in the protocol will be reported in listing format. All such variables (other than those 
used purely for screening purposes) and resulting change from baseline values will be 
summarized using descriptive statistics for each treatment group. Selected change from 
baseline values will be compared between the treatment groups statistically. Within this general 
framework, attention is called to variables that will be used to evaluate the primary hypothesis, 
pre-specified secondary hypotheses, and additional hypotheses of special interest.
The primary population for efficacy analysis will be the FAP population. Sensitivity analyses 
based on the PP population will be conducted for the primary efficacy variable if greater than or 
equal to 20% of FAP patients are excluded from the PP population. The primary population for 
safety analysis will be the safety population (see Section 7.0 for definitions)
All hypothesis tests comparing CR845 and placebo will be two-sided and conducted at the 5% 
significance level, unless otherwise specified.
All summary tables will be presented by treatment group (if applicable) and over all patients in 
the analysis population being summarized. Continuous variables will be summarized using the 
following descriptive statistics: n, mean, SD, median, minimum, and maximum.  Categorical 
variables will be summarized using counts and percentages.  Unless specified otherwise, 
percentages presented will be calculated using all patients in the analysis population being 
summarized (with randomized or received treatment as/if appropriate) as the denominator.
SAS® Version 9.2 or later will be used to produce all statistical tables, listings and figures to be
contained in Section 14 of the integrated statistical/clinical report.
8.1.  ADJUSTMENTS OR COVARIATES
All statistical analyses of efficacy variables comparing CR845 versus placebo will be adjusted 
by the location of the primary OA joint (hip vs knee) unless otherwise specified.
Statistical models without repeated measures which compare the change from baseline 
endpoints will additionally be adjusted for the value observed at baseline prior to first dose of 
treatment and effect of the study center.


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Mixed Models with Repeated Measures (MMRM) comparing results which are included across 
all time-points will additionally be adjusted for the baseline value, week, treatment by week 
interaction and the effect of the patient. 
8.2.  HANDLING OF NCOMPLETE OR MISSING DATA
No missing or incomplete safety data will be imputed. 
Weekly Mean Pain Intensity Scores
If a patient reports at least 3 days with non-missing pain intensity scores within a particular 
week, the weekly mean pain intensity score will be derived using the non-missing scores only. 
This is identical to imputing the missing scores as the mean of the non-missing scores. If the 
patient reports less than 3 days with non-missing pain intensity scores within a particular week, 
the weekly mean pain intensity score will be treated as missing data.
Missing weekly mean pain intensity scores will be imputed using multiple missing data and
pattern mixture methodology as detailed in Section 10.1. Sensitivity analyses will be conducted 
exploring different patterns for missing data. An MMRM will be performed using only observed 
data without multiple imputation and an analysis using the change from baseline to the last non-
missing weekly mean pain intensity score will also be provided.
 
WOMAC Index Total Score and WOMAC Pain Intensity, Stiffness and Function Sub-Scale 
Scores
If at least 50% of items within a subscale are non-missing, the missing items of the WOMAC 
score at a weekly visit will be imputed using the mean of non-missing items within the same 
subscale. Otherwise, the item, the subscale score and the total score will all remain missing. 
The total and subscale scores will be derived as the sum of all respective observed and imputed 
scores. If all values of a particular subscale are missing at a particular week then the total and 
corresponding subscale score will be treated as missing.  
An MMRM will be performed using only observed data for WOMAC related endpoints.
Treatment Pain Response
Patients with a missing weekly mean pain intensity score for Week 8 will be assumed to be a 
non-responder and assigned a pain response of 0%.
Rescue Medication
If the patient recorded that they did not confirm rescue medication was taken on a particular 
day, yet the number of tablets was recorded, it will be assumed rescue medication was taken.
All other efficacy endpoints
Missing data will not be imputed.


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8.4.  MULTI-CENTER STUDIES
There is no plan to include study center in the primary analysis because the MMRM will already 
include a random effect for patient. A model with random patient effects nested within study 
center would be unwieldy due to expected small numbers of patients per study center and large 
number of centers.
However, to satisfy ICH guidance (E9 Section 3.2), the difference between treatment means in 
the change from baseline with respect to the weekly mean of the daily 24-hour pain intensity for 
the index joint for each center will be plotted by week (observed data only). Only centers with at 
least 2 patients per treatment group will be included in this plot.
8.5.  MULTIPLE COMPARISONS / MULTIPLICITY
One primary efficacy endpoint has been specified in the protocol and the study has been 
powered sufficiently to show statistical significance in this endpoint. However, as this study is a
Phase 2 study, there will be no adjustment for multiplicity for secondary endpoints. The results 
for the primary efficacy analysis will be the key result to aid planning of future Phase 3 studies. 
Results from other endpoints may be used to aid the generation of future hypothesis to be 
explored and/or warrant inclusion of such endpoints in future studies.
8.6.  EXAMINATION F SUBGROUPS
Summaries relating to the Pain Intensity and WOMAC endpoints will be presented by location of 
the primary OA joint.


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9.  STUDY POPULATION CHARACTERISTICS
Unless specified otherwise, all summaries of study population characteristics will be 
summarized for the FAP. Since the SAF and FAP are equivalent populations, an additional 
summary table for patients in the SAP will only be produced if any patients are mis-randomized.
9.1.  SUBJECT DISPOSITION
A complete accounting of patient participation in the study will display the number of patients 
that were enrolled (i.e. signed informed consent) and the number and percentage of patients 
that were:
x
Screen failures (Enrolled population)
x
Randomized (Enrolled population)
x
Randomized following re-screening (Enrolled population)
x
Dosed with study drug (Enrolled population)
x
Included in each population (FAP, SAF, PP)
x
Completed the 8-week treatment with study drug
x
Discontinued the study drug early with reasons
x
Completed the follow-up visit
In addition, the number and percentage of patients completing each week of the Titration to 
Effect Period and completing the Maintenance Treatment periods, as well as the assigned 
doses across each week/period will be summarized.
Listings including the patient disposition, status with respect to inclusion and exclusion criteria, 
and population eligibility will be presented.
9.2.  PROTOCOL DEVIATIONS
Major protocol deviations and deviations that may affect the analysis of efficacy will be 
summarized for all patients. All protocol deviations will be listed, and sorted by patient number 
and date of deviation (if available). This by-patient listing will identify whether a specific protocol 
deviation is major or minor, and whether it is considered to potentially affect the analysis of 
efficacy.
9.3.  DEMOGRAPHICS ND BASELINE CHARACTERISTICS
Demographic and baseline characteristics will be summarized based on the information 
provided during the screening visit. The demographic characteristics to be summarized are 


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listed below with details of whether they will be summarized as a categorical (with categories if 
not direct from the eCRF) or continuous variable:
x
Age at study entry  continuous
x
Age at study entry  categorical
o
25 to 44; 45 to 64; 65 to 74; 75+
x
Gender  categorical
x
Race  categorical
x
Ethnicity - categorical
x
Weight (kg)  continuous
x
Height (cm)  continuous
x
Body Mass Index (BMI) (kg/m2)  continuous
x
Duration of time with OA  continuous
x
Location of primary OA - categorical
Age at study entry will be calculated as (date the informed consent was signed  date of birth) / 
365.25 rounded down to the nearest integer.
The supportive data for the summary of demographic and baseline characterisitcs will be listed, 
and sorted by patient number. 
9.4.  MEDICAL ISTORY
The medical history reported on the eCRF will be coded to Medical Dictionary for Regulatory 
Activities Terminology (MedDRA) terminology. Coded medical history terms will be summarized 
by SOC and Preferred Term. Medical history data will be listed including the verbatim 
investigator description of the relevant history, the coded terms, the start/stop dates, and 
whether the history is ongoing, if not stop date is provided.
A separate listing will be created with all the distinct levels of SOC, Preferred Terms and the 
verbatim investigator description reported in the study. Sorting will be alphatically by SOC, 
Preferred Term and then verbatim description. 
9.5.  DOSING AND EXTENT F EXPOSURE
Treatment compliance (%) will be calculated as follows:
100 * Number of doses actually taken 
         Expected number of doses to have been taken


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During the Titration to Effect and Maintenance Treatment periods as well as over the study, it is 
most likely the first dose will be a PM dose (following a clinic visit) and the last dose will be an 
AM dose (prior to a clinic visit). Therefore, the expected number of doses over a particular 
period will be calculated as [end date start date] * 2.
The number of doses actually taken will be compared to the expected number of doses to 
derive the number of missed doses. There will be monitoring by the clinic staff to ensure that the 
diary dosing coincides with the drug accountability at each visit.
The number of missed doses (0, 1,  2) and treatment compliance (continuous and as 
categories <80%, 80% to 110%, >110%) will be summarized for the Titration to Effect, 
Maintenance Treatment and overall study period. Additionally, the length of exposure to study 
drug (continuous and as overlapping categories: any exposure,  1 week,  2 weeks,  4
weeks,  8 weeks), maximum titration level (1mg, 2,5mg and 5mg) and average dose taken 
over the study will be summarized.
9.6.  PRIOR ND ONCOMITANT MEDICATION ND HERAPIES
Prior medications are defined as medications taken at any time during the 30 days prior to 
Screening until the time of dosing on Day 1, whether continuing or not. Any changes to prior 
medications (dose, regimen, etc.) during the study will be considered a new Concomitant 
Medication.
Concomitant medications are defined as any medications taken following the administration of 
the first dose of study drug on Day 1 through the end of the study (i.e., at the Follow-up Visit). 
These will be categorized into two groups, 1) During treatment with study drug and 2) Following 
end of treatment with study drug.
Whether a medication is prior, concomitant or both will be assessed by comparing the start date 
of the medication to the date of the first dose. If the medication start and/or end date is fully 
missing or sufficiently partially missing such that it cannot be determined whether it was taken 
prior to the first dose of study drug, then the medication will be considered concomitant.
Similarly, if the medication start and/or end date is fully missing or sufficiently partially missing 
such that it cannot be determined whether it was taken following the last dose of study drug 
then it will be classed as being concomitant during treatment with study drug.
Prior and Concomitant medications (during and after treatment) will be coded using the 
Anatomical-Therapeutic-Chemical (ATC) classification text from the World Health Organization
Drug Dictionary (WHO DD) and summarized seperately.  The number and percentage of 
patients taking a medication will be displayed by ATC Class 1 and Preferred Term. Patients will 
only be counted one time in each unique ATC Class 1 and Preferred Term.
All prior and concomitant medications will be listed and will include both the medication name as 
reported by the investigator as well as the coded information. 


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A separate listing will be created with all the distinct levels of ATC Class 1, Preferred Terms and 
the verbatim investigator description reported in the study. Sorting will be by ATC Class 1,
Preferred Term and then verbatim description. 


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10.  EFFICACY ANALYSES
All efficacy analyses will be conducted on the FAP and PP population if neccesary (see Section 
8).
In addition to the statistical analyses described in the sections below, descriptive summaries (as 
per Section 8) and data listings sorted by unique patient number will be presented for all efficacy 
variables.
10.1.  PRIMARY EFFICACY VARIABLE
To account for the interim unblinded sample size re-assessment, the analyses relating to the 
primary efficacy variable will employ weighted test statistics as proposed by Cui, Hung and 
Wang in order to maintain the 5% two-sided type 1 error rate. As there is no potential for early 
stopping of the study, no adjustments need to be made to the significance levels for the 
combined final analysis. The primary analysis and sensitivity analyses described in this section 
will be performed on each stage (pre and post interim patients) seperately and test statistics (t1
and t-2) from each stage will be combined to obtain the CHW Z statistic as follows:
ZCHW =
from which the two-sided p-value will be obtained using the normal 
distribution.
Point estimates and 95% CI will be obtained using methodology suggested by Hung and 
Lawrence2:
Point estimate: 
where 
t1 = 0.5
t* = (Re-estimated total sample size)/405
95% CI = 
The primary analysis and each sensitivity analysis will also be performed using the full 
combined dataset with no CHW adjustment. Presentation of results will start with these 
analyses (additionally including the CHW results) and then follow with the results of the analysis 
from each individual stage.


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The primary efficacy variable will be analyzed using a mixed effect model with repeated 
measures (MMRM). The model will contain treatment (placebo vs CR845), treatment-by-week 
interaction as fixed effects, baseline value and OA joint (hip vs knee) as covariates, and patient 
as a random effect. 
The treatment difference between CR845 (across all doses) and placebo at Week 8 (the
primary efficacy endpoint) will be estimated as the simple contrast in the treatment effect. The 2-
sided 95% confidence interval (CI), based on the difference in the least squares (LS) means 
between the 2 treatment groups (CR845 vs placebo) will be presented. The LS means (and 
95% CI) will be additionally be presented for each treatment for each week.
The MMRM model will be implemented using SAS PROC MIXED. A restricted maximum 
likelihood (REML) will be used. The Kenward-Roger3 approximation will be used to estimate the 
denominator degrees of freedom and adjust standard errors. An appropriate covariance matrix 
will be used to model the within patient errors until there are no convergence issues in the 
following order: 1) unstructured, 2) Toeplitz, 3) autoregressive [1], 4) compound symmetry, 5) 
variance components. For analyses of multiple imputed datasets, this selection will continue 
until analyses for all imputations converge.
The treatment of missing data will be addressed using pattern mixture model methodology. 
Within each treatment, 4 data patterns will be defined as follows: 
x
Pattern 1: will include patients who completed treatment on study drug 
x
Pattern 2: will include patients who discontinue treatment early due to AEs 
x
Pattern 3: will include patients who discontinue treatment early due to lack of therapeutic 
efficacy (LOTE) 
x
Pattern 4: will include patients who discontinue treatment early due to reasons other 
than AE event or LOTE. 
The pattern mixture model methodology will be implemented using SAS procedures MI and 
MIANALYZE. Specifically, the following steps will be followed: 
x
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. 
x
Data for patients who discontinues early will be multiply imputed as follows:
o
If the patient discontinues due to AE (pattern 2) or LOTE (pattern 3), then 
missing data will be assumed to follow a distribution similar to the baseline 
values observed in the patients randomized treatment. 
o
If the patient discontinues due to reasons other than AE or LOTE (pattern 4), at 
each time point, missing data will be assumed to follow a distribution similar to 
scores for patients that are still in the study and randomized to the same 
treatment group.
x
Results of the MMRM on the multiply imputed data will be summarized using the SAS 
MIANALYZE procedure using Rubins rule.


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A detailed plan of the above procedure is included as an attachment in Section 16.1.
Three sensitivity analyses (described below) will be conducted to assess the impact of the 
treatment of missing data on the study results. These sensitivity analyses may not necessarily 
reach statistical significance at the 5% level. However, a consistency of treatment effect (similar 
estimate of CR845 mean relative to placebo) is expected across the primary and all sensitivity 
analyses.
The MMRM analysis will be applied using observed data only to provide a reference in addition 
to the following sensitivity analyses:
Sensitivity analysis 1 (Multiple Imputation Missing at Random4)
This sensitivity analysis assumes that patients with missing data follow the same trajectory as 
other patients in their respective treatment arm that have complete data. 
x
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. 
x
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). At each time point, missing data will be assumed to follow a 
distribution similar to scores for patients who are still in the study and randomized to the 
same treatment group. 
x
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, placebo-based
imputation4)
This sensitivity analysis assumes that patients in the active treatment group who discontinue 
early will have the same evolution, after treatment is stopped, as patients in the placebo group 
(who are not exposed to 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. 
x
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. 
x
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. 
x
Results of the MMRM on the multiply imputed data sets will be summarized by the SAS 
MIANALYZE procedure. 
Sensitivity analysis 3 (Single Imputation, MNAR, Hybrid BOCF /LOCF): 
This sensitivity analysis makes different assumptions about the pain trajectory of patients who 
discontinue study drug early depending on the reason for discontinuation. For patients who 


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discontinue due to AE, Baseline Observation Carried Forward (BOCF) will be used. For patients 
who discontinue due to reasons other than AE, Last Observation Carried Forward (LOCF) will 
be used. It is plausible that patients who discontinue due to LOTE experience worsening pain 
scores after randomization; in this case, their last observed pain scores would be higher (worse) 
than their baseline pain scores. This sensitivity analysis assumes that missing data for these 
patients is similar to observed pain scores for patients who discontinue due to LOTE but are still 
in the study. 
10.2.  SECONDARY EFFICACY VARIABLE(S)
Change from baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) Index 
Total Score at each week
The change from baseline in the WOMAC Index total score will be analyzed using an MMRM 
with treatment (placebo vs CR845) and treatment-by-week interaction as fixed effects, baseline 
value and OA joint (hip vs knee) as covariates, and patient as a random effect. The primary 
comparison between groups will be based on estimates and contrasts for the weeks 4, 6, and 8 
means. The comparison at week 8 will be viewed as secondary. A 95% CI will be constructed 
for the weeks 4, 6 and 8 mean differences between CR845 and placebo based on the MMRM.
The MMRM model (based on observed data) will be implemented using SAS PROC MIXED. 
REML will be used. An appropriate covariance matrix will be used to model the within patient 
errors. An appropriate covariance matrix will be used to model the within patient errors until 
there are no convergence issues in the following order: 1) unstructured, 2) Toeplitz, 3) 
autoregressive [1], 4) compound symmetry, 5) variance components. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom and adjust standard 
errors. 
Change from baseline in the WOMAC Pain Intensity, Stiffness and Function Sub-scale 
Scores at each week
The change from baseline in the WOMAC sub-scales for pain intensity, stiffness and 
function will be analyzed using an MMRM model similar to the one presented above for the 
WOMAC index total score. 
Treatment Pain Response: Proportion of patients with a X0% improvement from
baseline in the weekly mean pain intensity at week 8
The proportion of patients with a respRQVH WR WUHDWPHQW WKDW LV   ZLOO EH DQDO\]HG XVLQJ
logistic regression, including treatment, baseline weekly pain score, and OA joint as 
independent variables. Site will be included as a random effect. Additionally, the proportions will 
be compared using a Cochran-Mantel-Haenzel test stratified by OA joint (hip or knee) and 


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dichotomized baseline weekly pain score (<6.7, 6.7). These analyses will be repeated for 
SDWLHQWV ZKR KDYH D UHVSRQVH WR WUHDWPHQW  
The cumulative proportion of patients that achieve at least 10%, 20%, 30%, 40%, 50%, 60%, 
70%, 80%, 90% and 100% response to treatment will be summarized and plotted for each 
treatment.
Patient Global Impression of Change (PGIC) at Week 8 or End of Treatment visit
The PGIC will be summarized as both a categorical and continuous variable (including 95% CI 
for the mean). The proportion of patients with PGIC scores of Very Much Improved and Much 
Improved will also be summarized and compared between treatments using a logistic 
regression with treatment as a main effect and OA joint as a covariate. Additionally, this 
proportion will be compared using a Cochran-Mantel-Haenzel test stratified by OA joint (hip 
or knee) and dichotomized baseline pain score (<6.7, 6.7).
Supplemental Analgesic Medication Used: Average daily number of acetaminophen 
tablets used over the study and during the Maintenance Treatment Period
The average daily number of acetaminophen tablets used during the study and during the 
Maintenance Treatment Period will be compared between treatments using a Wilcoxon Rank 
Sum Test stratified by Primary OA Joint (Hip or Knee) and dichotomized baseline pain score 
(<6.7, 6.7) (van Elteren test4). The categorized groupings will also be summarized.
Proportion of patients withdrawing from treatment due to lack of analgesic efficacy
The proportion of patients withdrawing from treatment due to lack of analgesic efficacy will be
analyzed using logistic regression, including treatment, baseline pain score, and OA joint as 
independent variables. Additionally, the proportions will be compared using a Cochran-Mantel-
Haenzel test stratified by OA joint (hip or knee) and dichotomized baseline pain score (<6.7, 
6.7). 
11.  SAFETY ANALYSES
Evaluation of safety will be performed for all patients in the SAF population. 
11.1.  ADVERSE EVENTS
Adverse events will be coded using MedDRA.  Verbatim description of the adverse events and 
the MedDRA System Organ Class (SOC) and Preferred Term (PT) for all AEs will be contained 
in the patient data listings. A separate listing sorted by MedDRA SOC and PT will include all 
verbatim descriptions associated with each SOC/PT category.


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Treatment emergent AEs (TEAEs) will be defined as AEs where onset occurs from the day of 
first dose of study medication up to and including the 2nd day following the day of last dose of 
study medication.
All reported AEs (whether treatment-emergent or not) will be included in by-subject AE listings.
A separate listing will be created with all the distinct levels of SOC, Preferred Terms and the 
verbatim investigator description reported in the study. Sorting will be alphabetically by SOC, 
Preferred Term and then verbatim description. 
If the adverse event start date is completely/partially missing, the AE will be considered a TEAE 
unless the following can be determined:
o The partial AE start date is sufficient to show that the AE started prior to the day 
of first dose of study drug.
o The AE stop date shows that the AE ended prior to the day of first dose of study 
drug.
o The partial AE start date is sufficient to show that the AE started after the 2 days 
following the day of last dose of study drug.
The incidence of TEAEs will be presented using counts and percentages of patients with AEs
and tabulated by SOC and PT. SOC will be sorted alphabetically and PT within SOC will be 
sorted by descending frequency based on the incidence across subjects overall. If a patient has
multiple occurrences (start and stop) of an event associated with a specific SOC or PT within a 
SOC, a patient will only be counted once in the incidence count for the SOC or PT within SOC 
respectively.
The following specific summary tables will be generated:
x
Overall incidence of adverse events
x
Incidence of TEAEs by SOC overall and by PT within each SOC
x
Incidence of TEAEs related to Treatment by SOC overall and by PT within each SOC
o
If a patient reports two or more adverse events that code to the same PT, the 
event with the maximum relationship will be included in the table. TEAEs with a 
missing relationship will be assumed to be treatment related.
x
Incidence of TEAEs by Maximum Severity, SOC overall and by PT within each SOC
o
If a patient reports two or more adverse events that code to the same PT, the 
event with the maximum severity will be included in the table. TEAEs with a 
missing severity will be assumed to be severe.


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x
Incidence of TEAEs occurring in  5% of patients in at least one treatment group by 
SOC overall and by PT within each SOC
x
Incidence of treatment-related TEAEs occurring in  5% of patients in at least one 
treatment group by SOC overall and by PT within each SOC
x
Incidence of Serious TEAEs by SOC overall and by PT within each SOC
x
Incidence of TEAEs leading to treatment discontinuation by SOC overall and by PT
within each SOC
x
Incidence of non TEAEs following last dose of study drug for patients taking opioids by 
SOC overall and by PT within each SOC
Deaths, other SAEs, and AEs leading to treatment discontinuation, dose interruption, or dose 
reduction will be listed including the treatment group and dosing information (if applicable), start 
and stop dates/times of the AE, and days on study relative to the day of first dose of study drug.
The following listings will be provided:
x
Listing of subjects who died
x
Listing of subjects with Serious TEAEs
x
Listing of subjects with non treatment-emergent SAEs
x
Listing of subjects with TEAEs leading to study drug discontinuation, dose reduction, or 
dose interruption
11.2.  CLINICAL LABORATORY EVALUATIONS
Chemistry and Hematology Laboratory Data
Laboratory tests from unscheduled study assessments outside planned protocol windows will 
not be included in the summary tables, except in the derivation of the laboratory test value at 
Baseline. If multiple assessments are recorded within a planned protocol window, the closest 
assessment to the planned time point will be used. If there are two assessments within equal 
proximity either side of the planned time point the earlier assessment will be used.
All laboratory tests results, whether scheduled or unscheduled, will be included in the by-subject
listings.  Laboratory values will be reported in standard Système International (SI) units
For all laboratory listings and summaries described in this section, the following definitions will 
be applied to each laboratory test:


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x
Screening value = the last scheduled or unscheduled (repeat) test result obtained prior 
to, but not including Day 1
x
Baseline value = the last scheduled or unscheduled (repeat) test result obtained prior to 
the first dose of study drug
x
End of treatment = the last scheduled test result (Day 57 or early termination) obtained 
within 48 hours from the last dose of study drug.
Chemistry and Hematology laboratory results at Day 57 (or early termination), and the 
corresponding change from baseline will be summarized for the safety population by presenting 
summary statistics (n, mean, SD, median, and range).
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 each 
treatment arm, a 3 by 3 tables shift tables will compare the Baseline LNH classification of each 
laboratory test to the LNH classification at Day 57 (or early termination).    
Selected laboratory test results will be flagged as markedly abnormal based on the ranges 
defined in Table 4 below.  A summary table of the incidence of markedly abnormally low and 
markedly abnormally high laboratory tests results will be presented by treatment arm for all 
patients in the safety population. For these calculations, each subject may be counted once in 
the laboratory parameter value high and in the laboratory parameter low categories as 
applicable.  


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Table 4. aboratory anges Used to dentify Markedly Abnormal aboratory Values
Units
Laboratory Parameter
Lower Limita
Upper Limita
Hematology
Hemoglobin
10 g/dL or <100 g/L

Platelets
75.0 u 109/L or 75000/mm3

Leukocytes
3.0 u 109/L or 3000/mm3

Leukocytes - infants, young children
75% LLN b

Lymphocytes
LLN

Lymphocytes - infants, young children
75% LLN

Neutrophils
1500 u 106/L or 1500/mm3

Clinical Chemistry
Electrolytes
Potassium
 LLN
!5.5 mmol/L
Bicarbonate (CO2)
d15 mEq/dL or d15 mmol/L

Liver Function Tests 
Alkaline phosphatase

!3 u ULN b,c
AST

!3 u ULN c
ALT

!3 u ULN c
Total bilirubin

!1.5 u ULN
Renal Function Tests
Creatinine

!1.5 u ULN
Other Chemistry
Calcium
8 mg/dL or 2.0 mmol/L
!11.5 mg/dL or !2.9 mmol/L
Phosphorous
2.5 mg/dL or 0.8 mmol/L

Glucose
55 mg/dL or 3.0 mmol/L
!160 mg/dL or !8.9 mmol/L
Uric acid

! ULN
Cholesterol

!300 mg/dL or !7.75 mmol/L
Triglycerides

!2.5 u ULN
Albumin
3 g/dL or <30 g/L

a
National Cancer Institute Common Toxicity Criteria, Version 2, Grade 2 limits (Grade 1 limit if Grade 2 limit missing).
b
LLN = lower limit of the laboratory reference (normal) range; ULN = upper limit of the laboratory reference (normal) range.
c
Modified Version 2 of the National Cancer Institute Common Toxicity Criteria.


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A patient listing, sorted by patient identifier, will present all laboratory results (scheduled or
unscheduled) and will include flags to identify whether a result is outside of the normal range 
and whether it is markedly abnormal. 
A listing of all subjects with at least one markedly abnormal laboratory value will be prepared; 
for a given patient, this listing will not only include the laboratory results flagged as markedly 
abnormal, but will also present the results from all other scheduled and unscheduled 
evaluations of the same laboratory parameter, whether or not they are markedly abnormal.
A separate listing of patients that have liver function test results for AST or ALT > 3 ULN or total 
bilirubin  1.5 ULN will be presented.
Additional analyses of liver function tests (AST, ALT, and total bilirubin) will be conducted by 
generating shifts tables from baseline to Day 57 (or early termination) using the categories 
presented in Table 5 below.
Table 5. ategories or hift Analysis of AST, ALT, nd Total ilirubin
AST/ALT
Total Bilirubin
  x ULN
1 x ULN
> 1 -   x ULN
> 1   1.5 x ULN
>3 -   x ULN
> 1.5   2 x ULN
>5 -   x ULN
> 2 x ULN
>10 -   x ULN
> 20 x ULN
Sodium Laboratory Tests
Sodium values (absolute and change from baseline as appropriate) will be summarized at each 
timepoint (Screening, Baseline [Day 1], Week 1 [Day 8], Week 2 [Day 15], Week 3 [Day 22],
Week 4 [Day 29], Week 6 [Day 43], Week 8 [Day 57] and at Day 57 [or early termination]).
The number of patients who meet the important sodium levels (> 146 mmol/L or > 150 mmol/L) 
anytime between first dose and within 72 hours of final dose of study drug) will be summarized.
A patient listing including all sodium test results will be programmed, flagging values that are > 
146 mmol/L and > 150 mmol/L. In addition, a listing of patients with at least one sodium result > 
150 mmol/L (whether during or after treatment with study drug) will be prepared; this listing will 
include all sodium test results for the selected patients.
11.3.  VITAL SIGNS 
Vital sign measurements of Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate and 
Respiratory Rate (absolute and change from baseline as appropriate) will be summarized at 


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each timepoint (Screening [supine], Baseline [Day 1], Week 1 [Day 8], Week 2 [Day 15], Week 3 
[Day 22], Week 4 [Day 29], Week 6 [Day 43], Week 8 [Day 57] and at Day 57 [or early 
termination]). Temperature will be summarized in similar fashion at Screening and Day 57 (or 
early termination).
For vital signs, abnormal values will be identified as those outside (above or below) the 
reference ranges that are defined in Table 6.
Table . eference Range or Vital ign Values
Vital Sign Parameter
Range
Systolic blood pressure
100140 mmHg
Diastolic blood pressure
6090 mmHg
Respiratory rate
1220 breaths per minute
Heart rate
60-100 beats per minute
Temperature
36.8°C38.3°C
All vital sign values collected after the Baseline dose of study drug will be evaluated for clinically 
notable results using the criteria presented in Table 7. A listing of all subjects with at least one 
clinically notable vital sign value will be prepared; for a given subject, this listing will not only 
include flagged vital sign parameters, but will present the results of all scheduled and 
unscheduled vital sign evaluations for the patient.  A summary table of the incidence of clinically 
notable vital signs may be presented. 
Table . riteria sed o Identify linically otable Vital Sign Abnormalities
Vital Sign Parameter
Value
Change From Baselinea
Systolic blood pressure
t180 mm Hg
Increase of t20 mm Hg
d90 mm Hg
Decrease of t20 mm Hg
Diastolic blood pressure
t105 mm Hg
Increase of t15 mm Hg
d50 mm Hg
Decrease of t15 mm Hg
Heart rate
t120 bpm
Increase of t15 bpm
d50 bpm
Decrease of t15 bpm
Respiratory rate
<12 breaths per minute

> 20 breaths per minute

a Both value and change from baseline criteria must be met to qualify as a clinically notable abnormality.
11.4.  ECGS
Continuous ECG parameters (absolute and change from baseline as appropriate) will be 
summarized at screening and Day 57 (or early termination). A by-patient listing will also be 


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prepared, with a separate listing for those patients with a clinically significant abnormal 
investigator interpretation of ECG results.
12.  SUMMARY OF HANGES ROM ROTOCOL-SPECIFIED ANALYSES
At the time of finalizing this SAP, only the following update has been made in this SAP 
compared to the Study Protocol V3.0 4th November 2016:
Update 1
Protocol Section 11.7.1 Text:
The baseline score will be calculated as the average of the 4 pain scores
collected during the Screening period that qualified the patient for randomization
SAP Section 5.1.1 Text:
The weekly mean pain intensity score will be defined as the sum of non-missing daily "average 
pain over the last 24 hours" scores reported during that week (Days -7 to -1 [Baseline].
divided by the number of days with non-missing scores for that week.
Reason for update 
To ensure the derived baseline derivation of the weekly pain score was equivalent in terms of 
number of days assessed (i.e. 7 day period using any day with a recorded pain score).  
13.  REPORTING ONVENTIONS
P-values will be reported to four decimal places; p-values less than 0.0001 will be reported as 
p<0.0001. The mean and median will be displayed to one decimal place greater than the 
original value and the measure of variability will be displayed to two decimal places greater than 
the original value. All statistical programming and analyses will be performed using SAS® (SAS 
institute, Cary, NC 27513).
The following standards will be used in the data presentation:
x
In text tables should be in portrait format, font type would be Arial and font size 9 and RTF 
format.  Section 14 tables and figures, and Appendix 16.2 listings should be in landscape 
format.  Output should adhere to US / ICH margins and should not require changes for 
European page size.  For section 14 tables, a blank row will separate the header from the 
content of the table listing.  For tables that have n (%) only, the placement should be 
centered below N=xx in the column header.  Frequency tables will be center justified, and 
descriptive statistics decimal justified.  ICH margins are Top=0.75, Bottom=0.75, Left=1, 
Right=0.75, Gutter=0, Header=0.6, Footer=0.6, Width=8.27 and Height=11.
x
Percentages presented in the in-text tables should be rounded to whole numbers using the 
SAS rounding function.  Percentages presented in Section 14 tables should be rounded to a


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single decimal point (xx.x%) using the SAS rounding function.  Percentages for values in 
tables that are <1 should be represented as <1.  If % is part of the column heading, do 
not repeat the % sign in the body of the table.  Unless specified otherwise, % should 
reflect the total population of the treatment group(s).  Any deviation from that should be part 
of the footnote.  For 0 counts, leave the corresponding percentage blank.
x
The format for minimum and maximum should be Min, Max.  Standard deviation should be 
the default for representing scale for demographic and baseline characteristics. For tables 
presenting statistical analyses, the SD will be used unless the standard error has been 
specified.  Standard deviation should be abbreviated as SD, and presented within 
parenthesis next to the mean value, without any +/- sign.  The standard deviation should 
have one additional decimal place beyond that of the mean (eg, mean has one decimal 
place, SD should have two).
x
N will represent the entire treatment group, while n will represent a subset of the 
treatment group.  For tables with population designated as a row heading, N should be
used (ie, tables where all participant data is not available for every variable within a 
treatment group).  As a guideline, if the number is used in a denominator it should be 
presented as N.  If the number is used in the numerator, it should be presented as an n.
x
The heading should consist of at least 3 lines.  Line 1:  Table/Appendix number.  Line 2:  
Protocol identifier / Table Title  Adjunct Description of Table Title (optional).  Line 3: 
Population.  The title for in-text tables should begin with the Table/Appendix number.
x
A solid line should appear both above and below the column headings of a table.  A solid 
line should appear at the end of the table or at the bottom of each page if the table extends 
to more than one page.  Footnotes should start after the bottom solid line.
x
Footnotes should be left-justified at the bottom of the page.  Footnotes must be present on 
the page where they are first referenced.  If more than four footnote lines are planned then a 
cover page may be used to display footnotes.
x
The maximum length of a title is 255 characters (including spaces).
x
Legends will be used for all figures with more than one variable or tiem displayed. 
x
Figures should be generated in black and white. Lines should be wide enough to see the 
line after the figure has been fotocopied.
x
All tables, figures, and data listings will have the name of the program and date/time stamp 
on the bottom of each output.
All statistics will be validated with two independent programming codes.  All tables, figures and
listings will be validated by a two-person review of the output.


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14.  REFERENCES
1. Cui L, Hung HM, Wang SJ. (1999), Modification of sample size in group sequential 
clinical trials. Biometrics. 55:853-857.
2. Lawrence J, Hung H.M. (2003), Estimation and Confidence after Adjusting the 
Maximum Information. Biometrical Journal 45, 143152
3. Kenward, M. G. and Roger, J. H. (1997), Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood, Biometrics, 53, 983997.
4. Ratitch B., and OKelly M., Implementation of pattern-mixture models using standard 
SAS/STAT procedures, SUGI 2011.


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15.  TOCS OR ABLES, IGURES, ISTINGS ND UTPUT
15.1.  TABLES  
Mock tables are presented in a separate document. The current version based on this SAP are 
detailed in CLIN2002-PO SAP Table Shells V1_0 18JAN17 and detailed below:
Table 14.1.1.1 Patient Disposition  Screening and Randomization Enrolled Population 
Table 14.1.1.2 Patient Disposition Full Analysis Population (FAP) 
Table 14.1.1.3 Patient Disposition  Weekly Dose Full Analysis Population (FAP) 
Table 14.1.1.4 Patient Disposition  Analysis Populations  Full Analysis Population (FAP) 
Table 14.1.1.5 Major Protocol Deviations  Full Analysis Population (FAP) 
Table 14.1.2 Demographic and Baseline Characteristics Full Analysis Population (FAP) 
Table 14.1.3 Medical History Full Analysis Population (FAP) 
Table 14.1.4 Extent of Exposure to Study Drug Full Analysis Population (FAP) 
Table 14.1.5 Treatment Compliance Full Analysis Population (FAP) 
Table 14.1.6.1 Prior Medication Full Analysis Population (FAP) 
Table 14.1.6.2 Concomitant Medication During Treatment with Study Drug Full Analysis Population (FAP) 
Table 14.1.6.3 Concomitant Medication Following End of Treatment with Study Drug Full Analysis 
Population (FAP) 
Table 14.2.1.1.1.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) 
Scores over time 
 Descriptive Statistics Over All Patients Full Analysis Population (FAP) 
Table 14.2.1.1.1.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) 
Scores over time 
 Descriptive Statistics for Stage 1 Full Analysis Population (FAP) 
Table 14.2.1.1.1.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) 
Scores over time 
 Descriptive Statistics for Stage 2 Full Analysis Population (FAP) 
Table 14.2.1.1.2.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Primary Efficacy Analysis (MMRM with MNAR Pattern Mixture Modeling) Over All Patients Full 
Analysis Population (FAP) 
Table 14.2.1.1.2.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Primary Efficacy Analysis (MMRM with MNAR Pattern Mixture Modeling) for Stage 1 Full 
Analysis Population (FAP) 
Table 14.2.1.1.2.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Primary Efficacy Analysis (MMRM with MNAR Pattern Mixture Modeling) for Stage 2 Full 
Analysis Population (FAP) 


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Table 14.2.1.1.3.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Primary Efficacy Analysis (MMRM with MNAR Pattern Mixture Modeling) Over All Patients Per-
Protocol Population (PP) 
Table 14.2.1.1.3.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Primary Efficacy Analysis (MMRM with MNAR Pattern Mixture Modeling) for Stage 1 Per-
Protocol Population (PP) 
Table 14.2.1.1.3.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Primary Efficacy Analysis (MMRM with MNAR Pattern Mixture Modeling) for Stage 2 Per-
Protocol Population (PP) 
Table 14.2.1.1.4.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8  MMRM Analysis on Observed Data Over All Patients Full Analysis Population (FAP) 
Table 14.2.1.1.4.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8  MMRM Analysis on Observed Data For Stage 1 Full Analysis Population (FAP) 
Table 14.2.1.1.4.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8  MMRM Analysis on Observed Data For Stage 2 Full Analysis Population (FAP) 
Table 14.2.1.1.5.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 1: MMRM with MAR Pattern Mixture Modeling Over All Patients Full 
Analysis Population (FAP) 
Table 14.2.1.1.5.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 1: MMRM with MAR Pattern Mixture Modeling for Stage 1 Full Analysis 
Population (FAP) 
Table 14.2.1.1.5.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 1: MMRM with MAR Pattern Mixture Modeling for Stage 2 Full Analysis 
Population (FAP) 
Table 14.2.1.1.6.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 2: MMRM with MNAR Placebo Based Pattern Mixture Modeling Over All 
Patients Full Analysis Population (FAP) 
Table 14.2.1.1.6.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 2: MMRM with MNAR Placebo Based Pattern Mixture Modeling For Stage 1 
Full Analysis Population (FAP) 
Table 14.2.1.1.6.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 2: MMRM with MNAR Placebo Based Pattern Mixture Modeling For Stage 2 
Full Analysis Population (FAP) 
Table 14.2.1.1.7.1 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 3: Single Imputation BOCF/LOCF Over All Patients Full Analysis Population 
(FAP) 
Table 14.2.1.1.7.2 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 3: Single Imputation BOCF/LOCF For Stage 1 Full Analysis Population (FAP) 
Table 14.2.1.1.7.3 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS) at 
Week 8 - Sensitivity Analysis 3: Single Imputation BOCF/LOCF For Stage 2 Full Analysis Population (FAP) 


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Table 14.2.1.1.8 Change from Baseline in the Weekly Mean of the Daily 24 Hour Pain Intensity (NRS)  
Descriptive Statistics by Primary OA Joint  Full Analysis Population (FAP) 
Table 14.2.1.2.1 Responder Analysis of Percentage Improvement from Baseline in the Weekly Mean of 
the Daily 24 Hour Pain Intensity (NRS) Scores at Week 8 Full Analysis Population (FAP) 
Table 14.2.1.2.2 Responder Analysis of Percentage Improvement from Baseline in the Weekly Mean of 
the Daily 24 Hour Pain Intensity (NRS) Scores at Week 8 by Primary OA Joint Full Analysis Population 
(FAP) 
Table 14.2.2.1.1 Change from Baseline in the WOMAC Index Score Over Time  Descriptive Statistics Full 
Analysis Population (FAP) 
Table 14.2.2.1.2 Change from Baseline in the WOMAC Index Total Score  MMRM Analysis Full Analysis 
Population (FAP) 
Table 14.2.2.1.3 Change from Baseline in the WOMAC Index Total Score Over Time by Primary OA Joint 
Full Analysis Population (FAP) 
Table 14.2.2.2.1 Change from Baseline in the WOMAC Index Pain Intensity Subscale Score Over Time  
Descriptive Statistics Full Analysis Population (FAP) 
Table 14.2.2.2.2 Change from Baseline in the WOMAC Index Pain Intensity Subscale Score  MMRM 
Analysis Full Analysis Population (FAP) 
Table 14.2.2.2.3 Change from Baseline in the WOMAC Index Total Score Over Time by Primary OA Joint 
Full Analysis Population (FAP) 
Table 14.2.2.3.1 Change from Baseline in the WOMAC Index Stiffness Intensity Subscale Score Over Time 
 Descriptive Statistics Full Analysis Population (FAP) 
Table 14.2.2.3.2 Change from Baseline in the WOMAC Index Stiffness Intensity Subscale Score  MMRM 
Analysis Full Analysis Population (FAP) 
Table 14.2.2.3.3 Change from Baseline in the WOMAC Index Stiffness Intensity Subscale Score Over Time 
by Primary OA Joint Full Analysis Population (FAP) 
Table 14.2.2.4.1 Change from Baseline in the WOMAC Index Function Intensity Subscale Score Over 
Time  Descriptive Statistics Full Analysis Population (FAP) 
Table 14.2.2.4.2 Change from Baseline in the WOMAC Index Function Intensity Subscale Score  MMRM 
Analysis Full Analysis Population (FAP) 
Table 14.2.2.4.3 Change from Baseline in the WOMAC Index Function Intensity Subscale Score Over 
Time by Primary OA Joint Full Analysis Population (FAP) 
Table 14.2.3 Patient Global Impression of Change (PGIC) at Day 57/ET Full Analysis Population (FAP) 
Table 14.2.4 Average Daily Use of Rescue Medication for Target Joint Pain  Full Analysis Population (FAP) 
Table 14.2.5 Proportion of patients withdrawing from treatment due to lack of analgesic efficacy Full 
Analysis Population (FAP) 
Table 14.3.1.1 Overall Summary of Adverse events 
Safety Population (SAF) 
Table 14.3.1.2 Summary of Treatment Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term Safety Population (SAF) 


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Table 14.3.1.3 Summary of Treatment-Related Treatment Emergent Adverse Events (TEAEs) by System 
Organ Class and Preferred Term Safety Population (SAF) 
Table 14.3.1.4 Summary of Treatment Emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term and Maximum Severity Safety Population (SAF) 
Table 14.3.1.5 Summary of Treatment Emergent Adverse Events (TEAEs) occurring in >= 5% of patients 
in at least one treatment group by System Organ Class and Preferred Term Safety Population (SAF) 
Table 14.3.1.6 Summary of Treatment-Related Treatment Emergent Adverse Events (TEAEs) occurring in 
>= 5% of patients in at least one treatment group by System Organ Class and Preferred Term Safety 
Population (SAF) 
Table 14.3.1.7 Summary of Serious Treatment Emergent Adverse Events (TEAEs) by System Organ Class 
and Preferred Term Safety Population (SAF) 
Table 14.3.1.8 Summary of Treatment Emergent Adverse Events (TEAEs) leading to treatment 
discontinuation by System Organ Class and Preferred Term Safety Population (SAF) 
Table 14.3.1.9 Summary of Non-Treatment Emergent Adverse Events (NTEAEs) Following Last Dose of 
Study Drug by System Organ Class and Preferred Term Safety Population (SAF) 
Table 14.3.2.1 Listing of Deaths Safety Population (SAF) 
Table 14.3.2.2 Listing of Treatment-Emergent Serious Adverse Events (SAEs) Safety Population (SAF) 
Table 14.3.2.3 Listing of Non Treatment-Emergent Serious Adverse Events (SAEs)  Safety Population 
(SAF) 
Table 14.3.2.4 Listing of Treatment-Emergent Adverse Events (TEAEs) leading to study drug 
discontinuation, dose reduction or dose interruption Safety Population (SAF) 
Table 14.3.4.1.1 Summary of Hematology Quantitative Laboratory Parameters Safety Population (SAF) 
Table 14.3.4.1.2 Shift Table of L/N/H Classification for Hematology Laboratory Parameters Safety 
Population (SAF) 
Table 14.3.4.1.3 Shift Table of Incidence of Markedly Abnormal Results for Hematology Laboratory 
Parameters Safety Population (SAF) 
Table 14.3.4.1.4 Listing of Patients with at Least One Markedly Abnormal Hematology Laboratory 
Parameter Safety Population (SAF) 
Table 14.3.4.2.1 Summary of Sodium Laboratory Tests Safety Population (SAF) 
Table 14.3.4.2.2  Categorical Summary of Sodium Laboratory Tests Safety Population (SAF) 
Table 14.3.4.2.3 Listing of Patients with at Least One Sodium Result > 146 mmol/L or > 150 mmol/L 
Safety Population (SAF) 
Table 14.3.4.3.1 Summary of Liver Function Tests Safety Population (SAF) 
Table 14.3.4.3.2 Shift Tables of Categorical Classification for Liver Function Tests  AST Safety Population 
(SAF) 
Table 14.3.4.3.3 Shift Tables of Categorical Classification for Liver Function Tests  ALT Safety Population 
(SAF) 
Table 14.3.4.3.4 Shift Tables of Categorical Classification for Liver Function Tests  Total Bilirubin Safety 
Population (SAF) 


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Table 14.3.4.3.5 Listing of Patients with at AST > 3 ULN, ALT > 3 ULN or Total Bilirubin > 1.5 ULN Safety 
Population (SAF) 
Table 14.3.4.4.1 Summary of Other Quantitative Serum Chemistry Laboratory Parameters Safety 
Population (SAF) 
Table 14.3.4.4.2 Shift Table of L/N/H Classification for Other Serum Chemistry Laboratory Parameters 
Safety Population (SAF) 
Table 14.3.4.4.3 Shift Table of Incidence of Markedly Abnormal Results for Other Serum Chemistry 
Laboratory Parameters Safety Population (SAF) 
Table 14.3.4.4.4 Listing of Patients with at Least One Markedly Abnormal Other Serum Chemistry 
Parameter Safety Population (SAF) 
Table 14.3.4.5.1 Summary of Systolic Blood Pressure During the Study Safety Population (SAF) 
Table 14.3.4.5.2 Shift Table of Maximum L/N/H Classification for Systolic Blood Pressure During the 
Study Safety Population (SAF) 
Table 14.3.4.5.3 Shift Table of Minimum L/N/H Classification for Systolic Blood Pressure During the Study 
Safety Population (SAF) 
Table 14.3.4.6.1 Summary of Diastolic Blood Pressure During the Study Safety Population (SAF) 
Table 14.3.4.6.2 Shift Table of Maximum L/N/H Classification for Diastolic Blood Pressure During the 
Study Safety Population (SAF) 
Table 14.3.4.6.3 Shift Table of Minimum L/N/H Classification for Diastolic Blood Pressure During the 
Study Safety Population (SAF) 
Table 14.3.4.7.1 Summary of Heart Rate During the Study Safety Population (SAF) 
Table 14.3.4.7.2 Shift Table of Maximum L/N/H Classification for Heart Rate During the Study Safety 
Population (SAF) 
Table 14.3.4.7.3 Shift Table of Minimum L/N/H Classification for Heart Rate During the Study Safety 
Population (SAF) 
Table 14.3.4.8.1 Summary of Temperature During the Study Safety Population (SAF) 
Table 14.3.4.8.2 Shift Table of Maximum L/N/H Classification for Temperature During the Study Safety 
Population (SAF) 
Table 14.3.4.8.3 Shift Table of Minimum L/N/H Classification for Temperature During the Study Safety 
Population (SAF) 
Table 14.3.4.9.1  Incidence of Clinically Notable Vital Sign Abnormalites for SBP, DBP, Respiratory Rate 
and Heart Rate  Safety Population (SAF) 
Table 14.3.4.9.2 Listing of Patients with Clincally Notable Vital Sign Abnormalities for SBP, DBP, 
Respiratory Rate or Heart Rate Safety Population (SAF) 
Table 14.3.4.10.1  ECG Results  Safety Population (SAF) 
Table 14.3.4.10.2 Shift Table of Investigator Interpretation of ECG Results over the study Safety 
Population (SAF) 
Table 14.3.4.10.3 Listing of Clinically Significant Abnormal ECG Results over the study Safety Population 
(SAF) 
 


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15.2.  DATA LISTINGS FOR APPENDIX 16.2
Mock listings are presented in a separate document. The current version based on this SAP are 
detailed in CLIN2002-PO SAP Listing Shells V1_0 18JAN17 and detailed below:
Listing 16.2.1.1 Patient Disposition  Screen Failures 
Listing 16.2.1.2 Patient Disposition over the study  All Randomized Patients 
Listing 16.2.2 Protocol Deviations  All Randomized Patients 
Listing 16.2.3 Treatment and NRS Completion and Analysis Populations  All Randomized Patients 
Listing 16.2.4.1 Demographics and Informed Consent All Randomized Patients 
Listing 16.2.4.2 Other Baseline Characteristics All Randomized Patients 
Listing 16.2.4.3.1 Medical History All Randomized Patients 
Listing 16.2.4.3.2 MedDRA Classification of Medical History All Randomized Patients 
Listing 16.2.4.4.1 Prior and Concomitant Medication All Randomized Patients 
Listing 16.2.4.4.2 ATC Classification of Medications All Randomized Patients 
Listing 16.2.5.1 Randomization and treatment administration All Randomized Patients 
Listing 16.2.5.2 Dosing, Extent of Exposure and Accountability of Study Drug All Randomized Patients 
Listing 16.2.5.3 Treatment Compliance All Randomized Patients 
Listing 16.2.5.4 Exposure to and Compliance With Rescue Medication All Randomized Patients 
Listing 16.2.6.1 Pain NRS  All Randomized Patients 
Listing 16.2.6.2 WOMAC Index All Randomized Patients 
Listing 16.2.6.3 Patient Global Impression of Change All Randomized Patients 
Listing 16.2.6.4 Usage of Acetaminophen Rescue Medication for Target Joint Pain All Randomized 
Patients 
Listing 16.2.6.5 Scheduled Efficacy Assessments Not Conducted/Recorded SAF Population 
Listing 16.2.7.1 Adverse Events (AEs) SAF Population 
Listing 16.2.7.2 MedDRA Classification of Adverse Events All Randomized Patients 
Listing 16.2.8.1 Hematology Laboratory Parameters SAF Population 
Listing 16.2.8.2 Serum Sodium Results SAF Population 
Listing 16.2.8.3 AST, ALT and Total Bilirubin Results SAF Population 
Listing 16.2.8.4 Other Serum Chemistry Laboratory Parameters SAF Population 
Listing 16.2.8.5 Urine Drug Tests at Screening SAF Population 
Listing 16.2.8.6 Pregnancy Tests SAF Population 
Listing 16.2.8.7 Vital Signs  SAF Population 
Listing 16.2.8.8 ECG  All Randomized Patients 
Listing 16.2.8.9 Scheduled Safety Assessments Not Conducted SAF Population 


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16.   ATTACHMENTS
16.1.  PRIMARY ANALYSIS PROGRAMMING PLAN  
The primary efficacy endpoint is defined as the change from baseline at Week 8 with respect to 
the weekly mean of the daily 24-hour pain intensity in at the index joint. 
 
Step 1  Change data structure from ADaM dataset 
Manipulate data into dataset (DATAIN) with multivariate structure with one record per subject 
and separate variables for treatment (TRTP), OA joint (STRATA) and each weekly NRS mean 
daily score (NRSWEEK1 to NRSWEEK8) including baseline week (BASE). Keep the reason for 
treatment discontinuation variable (DCTREAS). Set any imputed data (where DTYPE not missing) 
to missing. 
 
Step 2  Impute intermittent missing data 
Impute intermittent missing data using the Markov Chain Monte Carlo (MCMC) method 
implemented with the SAS MI procedure with treatment, baseline value and OA joint (hip vs 
knee) included as follows (need to create numeric 0/1 variables TRTPN and STRATAN based on 
TRTP [CR845=1, Placebo=0] and STRATA [HIP=1, KNEE=0]): 
 
proc mi data=DATAIN nimpute=100 seed=543571857 out=MONOTONIC;
var TRTPN STRATAN BASE NRSWEEK1-NRSWEEK8;
mcmc chain=multiple impute=monotone;
run; 
 
This will create 100 records per subject with only monotonic missing data in the dataset 
MONOTONIC. 
 
Set any imputed values <0 or >10 to 0 and 10 respectively. 
 
Step 3  Impute missing data due to AE or Lack of Therapeutic Effect (LOTE) 
If the patient discontinues treatment due to AE or LOTE then missing data will be assumed to 
follow a distribution similar to the baseline values observed in the patients randomized 
treatment. 
o
To impute missing data, the following will be performed: 

Obtain the mean (1dp) and standard deviation (2dp) across all the 
patients in the treatment group at baseline (use DATAIN dataset to do 
this). 


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Split the MONOTONIC data into 3 datasets 
1) Non-missing or missing and discontinued treatment not due 
to AE/LOTE (Both groups)  discard data 
2) Missing and discontinued treatment due to AE/LOTE (Placebo) 
3) Missing and discontinued treatment due to AE/LOTE (CR845) 

Sort the missing datasets (2 and 3) by imputation and then subject 
number 
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Within each of the missing datasets (2 and 3), create a variable using the 
RANNOR function in SAS, seed=543571857, with mean and standard 
deviation as found above 
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Impute any missing values of NRSWEEKx with the value of the created 
variable. 
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Set any imputed values <0 or >10 to 0 and 10 respectively. 
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Combine datasets from 2 and 3 with all data imputed and keep for Step 
5. 
 
Step 4 - Impute missing data due to reasons other than AE or LOTE 
If the patient discontinues due to reasons other than AE or Lack of Efficacy, at 
each time point, missing data will be assumed to follow a distribution similar to 
scores for patients who are still in the study and randomized to the same 
treatment group. 
o
To impute missing data at the first week x with any missing data not due to 
AE/LOTE, the following will be performed to the MONTONIC dataset:  
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Split the MONOTONIC data into 2 datasets 
1) Non-missing at Week x or missing at Week x and discontinued 
treatment not due to AE/LOTE 
2) Missing at Week x and discontinued treatment due to 
AE/LOTE  discard data 
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Sort dataset (1) by imputation and subject number 
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Impute the missing data at week x in dataset (1) as follows: 
proc mi data=DATA1 out=WEEKx seed=543571857 nimpute=1;
by
Imputation ;
var TRTPN STRATAN BASE NRSWEEK1-NRSWEEKx;
monotone regression;
run; 
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Set any imputed values <0 or >10 to 0 and 10 respectively. 
 
o
To impute missing data at the next week y with any missing data not due to 
AE/LOTE, the following will be performed to the WEEKx dataset:  
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Split the WEEKx data into 2 datasets 


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Statistical Analysis Plan
Protocol: CLIN2002-PO
Version 1.0
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3) Non-missing at Week y or missing at Week y and discontinued 
treatment not due to AE/LOTE  
4) Missing at Week y and discontinued treatment due to 
AE/LOTE  discard data 
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Sort dataset (3) by imputation and subject number 
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Impute the missing data at week y in dataset (3) as follows: 
proc mi data=DATA3 out=WEEKy seed=543571857 nimpute=1;
by _Imputation_;
var TRTPN STRATAN BASE NRSWEEK1-NRSWEEKx;
monotone regression;
run; 

Set any imputed values <0 or >10 to 0 and 10 respectively. 
 
o
Continue in similar fashion until no missing data with dataset including either 
completers or those that discontinued treatment not due to AE/LOTE.   
 
Step 5  Combine datasets back together and re-structure back as per ADaM 
Combine final datasets from Steps 3 and 4. Sort by imputation and subject number. Re-
structure dataset to be univariate with a Week (AVISITN = 1, 2,3 ,4 ,5 ,6 7, 8) and AVAL  (using 
NRSWEEK1 to NRSWEEK8) and CHG (AVAL-BASE) variable. (MMRMDATA) 
 
 
Step 6  Perform MMRM on each imputed dataset 
The primary efficacy variable will be analyzed using a mixed effect model with repeated 
measures (MMRM). The model will contain treatment (placebo vs CR845), treatment-by-week 
interaction as fixed effects, baseline value and OA joint (hip vs knee) as covariates, and patient 
as a random effect. 
proc mixed data=MMRMDATA;
by _Imputation_;
class TRTP AVISITN STRATA SUBJID;
model CHG = TRTP|AVISITN STRATA BASE /ddfm=kr;
repeated AVISITN/SUBJECT=SUBJID type=un;
lsmeans TRTP*AVISITN/diff;
ods output Diffs=DIFF_MI LSMeans=LSM_MI;
run;
Check log to ensure that there are no convergence problems across all 100 analyses. If so then 
use different covariance structures in the following order until this is achieved: 
type=toep


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Statistical Analysis Plan
Protocol: CLIN2002-PO
Version 1.0
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type=ar(1)
type=cs
type=vc
Extract 2 separate datasets from DIFF_MI and LSM_MI selecting the LS means (and standard 
errors) and difference between LS means (and standard errors) at Week 8 only. (DIFF_MI8 and 
LSM_MI8). 
 
Step 7  Combine MMRM results using Proc MIANALYZE 
Use PROC MIANALYZE to obtain estimates of LS means and differences and 95% CIs. 
proc mianalyze data=DIFF_MI8;
modeleffects estimate;
stderr sdterr;
ods output ParameterEstimates=DIFF_MIAN8;
run;
proc mianalyze data=LSM_MI8;
modeleffects estimate;
by TRTP;
ods output ParameterEstimates=LSM_MIAN8;
run;