A Study Evaluating Pain Relief and Safety of Orally Administered CR845 in Patients With Osteoarthritis of Hip or Knee
Condition: Osteoarthritis, Hip; Osteoarthritis, Knee; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases
MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Rheumatic Diseases; Joint Diseases; Musculoskeletal Diseases; Osteoarthritis, Hip; Collagen Diseases
Intervention: CR845 tablet 1 mg; CR845 tablet 2.5 mg; CR845 tablet 5 mg; Placebo tablet
Intervention description: 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.; 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.; 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.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 761.0
Sex: All
Minimum age: 25 Years
Healthy volunteers: No
Keywords: Osteoarthritis; Hip; Knee; CR845; Analgesic; Kappa opioid; difelikefalin

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.
    

Eligibility criteria:

        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.