Clinical trial NCT02944448: A Study Evaluating Pain Relief and Safety of Orally Administered CR845 in Patients With Osteoarthritis of Hip or Knee
Official title: A Randomized, Double-Blind, Placebo-Controlled, Titration-to-Effect Study of Orally Administered CR845 in Patients With Osteoarthritis of the Hip or Knee
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Osteoarthritis, Hip
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Keywords: Osteoarthritis
Hip
Knee
CR845
Analgesic
Kappa opioid
difelikefalin
Lead sponsor: Cara Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2016-10-25
Enrollment: 761
Sex: ALL
Minimum age (years): 25
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline at Week 8 With Respect to the Weekly Mean of the Daily 24-hour Pain Intensity for the Index Joint as Measured by the Numeric Rating Scale (NRS).
timeFrame: Baseline, Week 8
Secondary outcomes:
measure: Change From Baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) Index Total Score at Week 8
timeFrame: Baseline, Week 8
measure: Change From Baseline in the WOMAC Pain Intensity Sub-scale Score at Week 8
timeFrame: Baseline, Week 8
measure: Change From Baseline in the WOMAC Stiffness Sub-scale Score at Week 8
timeFrame: Baseline, Week 8
measure: Change From Baseline in the WOMAC Function Sub-scale Score at Week 8
timeFrame: Baseline, Week 8
measure: Proportion of Patients With at Least 30% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8
timeFrame: Week 8
measure: Proportion of Patients With at Least 50% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8
timeFrame: Week 8
measure: Proportion of Patients Whose OA Pain Was "Very Much Improved" or "Much Improved" as Indicated by Patient Global Impression of Change (PGIC) Score at Week 8
timeFrame: Week 8
measure: Average Daily Number of Acetaminophen Tablets Used During Entire Study
timeFrame: Week 8
measure: Proportion of Patients Withdrawing From Treatment Due to Lack of Analgesic Efficacy
timeFrame: Week 8
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Cara Therapeutics Study Site
state: Alabama
city: Peoria
country: United States
facility: Cara Therapeutics Study Site
state: Arizona
city: Phoenix
country: United States
facility: Cara Therapeutics Study Site
state: Arizona
city: Carmichael
country: United States
facility: Cara Therapeutics Study Site
state: California
city: San Diego
country: United States
facility: Cara Therapeutics Study Site
state: California
city: Tustin
country: United States
facility: Cara Therapeutics Study Site
state: California
city: Homestead
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Jupiter
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Lake Worth
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Miami
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Oldsmar
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Orlando
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Plantation
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: South Miami
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Tampa
country: United States
facility: Cara Therapeutics Study Site
state: Florida
city: Savannah
country: United States
facility: Cara Therapeutics Study Site
state: Georgia
city: Hazelwood
country: United States
facility: Cara Therapeutics Study Site
state: Missouri
city: Omaha
country: United States
facility: Cara Therapeutics Study Site
state: Nebraska
city: Las Vegas
country: United States
facility: Cara Therapeutics Study Site
state: Nevada
city: Berlin
country: United States
facility: Cara Therapeutics Study Site
state: New Jersey
city: Binghamton
country: United States
facility: Cara Therapeutics Study Site
state: New York
city: Rochester
country: United States
facility: Cara Therapeutics Study Site
state: New York
city: Cincinnati
country: United States
facility: Cara Therapeutics Study Site
state: Ohio
city: Cincinnati
country: United States
facility: Cara Therapeutics Study Site
state: Ohio
city: Oklahoma City
country: United States
facility: Cara Therapeutics Study Site
state: Oklahoma
city: Duncansville
country: United States
facility: Cara Therapeutics Study Site
state: Pennsylvania
city: Charleston
country: United States
facility: Cara Therapeutics Study Site
state: South Carolina
city: Charleston
country: United States
facility: Cara Therapeutics Study Site
state: South Carolina
city: Greenville
country: United States
facility: Cara Therapeutics Study Site
state: South Carolina
city: Austin
country: United States
facility: Cara Therapeutics Study Site
state: Texas
city: Dallas
country: United States
facility: Cara Therapeutics Study Site
state: Texas
city: Plano
country: United States
facility: Cara Therapeutics Study Site
state: Texas
city: Plano
country: United States
facility: Cara Therapeutics Study Site
state: Texas
city: San Antonio
country: United States
facility: Cara Therapeutics Study Site
state: Texas
city: Charlottesville
country: United States
facility: Cara Therapeutics Study Site
state: Virginia
Study officials:
affiliation: Cara Therapeutics
name: Joseph Stauffer, DO, MBA
role: STUDY_DIRECTOR
References: