A Study Evaluating Pain Relief and Safety of Orally Administered CR845 in Patients With Osteoarthritis of Hip or Knee

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.

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.

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 currently used pain medications beginning 5 days prior to the
Baseline Visit and throughout the study. Acetaminophen use is allowed. (Section 8.8)

9. If female:

1. 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.

2. 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 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

Exclusion Criteria:

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 currently used pain medications beginning 5 days prior to the
Baseline Visit and throughout the study. Acetaminophen use is allowed. (Section 8.8)

9. If female:

1. 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.

2. 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 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

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 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 (for weight loss).

12. Has a corrected QT interval of >450 msec in males, >470 msec in females, or clinically
significant abnormality on screening ECG.

13. Has a serum sodium level > 143 mmol/L at Screening.

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
drugs [NSAIDs] such as naproxen or cyclooxygenase-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.