Arthritis, Joint Diseases, Musculoskeletal Diseases, Osteoarthritis, Hip, Osteoarthritis, Knee, Rheumatic Diseases
Conditions
Keywords
Osteoarthritis, Hip, Knee, CR845, Analgesic, Kappa opioid, difelikefalin
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.
Interventions
DRUGCR845 tablet 1 mg
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.
DRUGCR845 tablet 2.5 mg
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.
DRUGCR845 tablet 5 mg
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.
DRUGPlacebo tablet
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.
Sponsors
Cara Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). | Baseline, Week 8 | 11-point NRS scale where 0 = no pain, and 10= pain as bad as you can imagine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the WOMAC Pain Intensity Sub-scale Score at Week 8 | Baseline, Week 8 | The pain subscale consists of five scores from 0-10, 0 is no pain 10 is extreme pain possible for a range of 0 - 50 points. |
| Change From Baseline in the WOMAC Stiffness Sub-scale Score at Week 8 | Baseline, Week 8 | The stiffness subscale consists of two scores from 0-10, 0 is no stiffness 10 is extreme stiffness possible for a range of 0 - 20 points. |
| Change From Baseline in the WOMAC Function Sub-scale Score at Week 8 | Baseline, Week 8 | The function subscale consists of 17 scores from 0-10, 0 is no difficulty and 10 is extreme difficulty, for a range of 0 - 170 points. |
| Proportion of Patients With at Least 30% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8 | Week 8 | 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. |
| Change From Baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) Index Total Score at Week 8 | Baseline, Week 8 | 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). Each WOMAC Index Subscale score (Pain/Stiffness/Function) is calculated as the sum of all scores within that subscale. The pain subscale consists of five scores from 0-10, 0 is no pain 10 is extreme pain possible for a range of 0 - 50 points. The stiffness subscale consists of two scores from 0-10, 0 is no stiffness 10 is extreme stiffness possible for a range of 0 - 20 points. The function subscale consists of 17 scores from 0-10, 0 is no difficulty and 10 is extreme difficulty, for a range of 0 - 170 points. The WOMAC Index Total Score is calculated as the sum of all 24 scores (range of 0-240). |
| 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 | Week 8 | 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. |
| Average Daily Number of Acetaminophen Tablets Used During Entire Study | Week 8 | 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 supplemental pain medication for OA will be grouped 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. |
| Proportion of Patients Withdrawing From Treatment Due to Lack of Analgesic Efficacy | Week 8 | — |
| Proportion of Patients With at Least 50% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8 | Week 8 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CR845 Tablet Every patient was started on a twice daily (BID) 1 mg dose of CR845. During the post-randomization Titration-to-Effect Period, the dose of study drug may have been increased to 2.5 mg BID or 5 mg BID in a double-blind fashion. | 316 |
| Placebo Tablet Twice daily dosing (BID) | 160 |
| Total | 476 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory values | 1 | 0 |
| Overall Study | Adverse Event | 37 | 6 |
| Overall Study | Lack of Efficacy | 8 | 5 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Noncompliant with dosing | 1 | 0 |
| Overall Study | Protocol Violation | 25 | 7 |
| Overall Study | Sponsor did not supply drug in time | 0 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 4 |
Baseline characteristics
| Characteristic | Placebo Tablet | Total | CR845 Tablet |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 10.26 | 60.5 years STANDARD_DEVIATION 10.25 | 60.4 years STANDARD_DEVIATION 10.26 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 7 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 94 Participants | 61 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) White | 122 Participants | 367 Participants | 245 Participants |
| Sex: Female, Male Female | 89 Participants | 299 Participants | 210 Participants |
| Sex: Female, Male Male | 71 Participants | 177 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 316 | 0 / 160 |
| other Total, other adverse events | 82 / 316 | 17 / 160 |
| serious Total, serious adverse events | 9 / 316 | 1 / 160 |
Outcome results
Primary
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).
11-point NRS scale where 0 = no pain, and 10= pain as bad as you can imagine
Time frame: Baseline, Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR845 Tablet | 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). | -2.3 score on a scale | Standard Error 0.14 |
| Placebo Tablet | 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). | -2.4 score on a scale | Standard Error 0.19 |
p-value: 0.709395% CI: [-0.4, 0.5]Mixed Models Analysis
Secondary
Average Daily Number of Acetaminophen Tablets Used During Entire Study
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 supplemental pain medication for OA will be grouped 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.
Time frame: Week 8
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| CR845 Tablet | Average Daily Number of Acetaminophen Tablets Used During Entire Study | 0.5 Tablets | Standard Deviation 2.27 |
| Placebo Tablet | Average Daily Number of Acetaminophen Tablets Used During Entire Study | 0.4 Tablets | Standard Deviation 1.75 |
p-value: 0.2858Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) Index Total Score at Week 8
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). Each WOMAC Index Subscale score (Pain/Stiffness/Function) is calculated as the sum of all scores within that subscale. The pain subscale consists of five scores from 0-10, 0 is no pain 10 is extreme pain possible for a range of 0 - 50 points. The stiffness subscale consists of two scores from 0-10, 0 is no stiffness 10 is extreme stiffness possible for a range of 0 - 20 points. The function subscale consists of 17 scores from 0-10, 0 is no difficulty and 10 is extreme difficulty, for a range of 0 - 170 points. The WOMAC Index Total Score is calculated as the sum of all 24 scores (range of 0-240).
Time frame: Baseline, Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR845 Tablet | Change From Baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) Index Total Score at Week 8 | -62.4 score on a scale | Standard Error 3.28 |
| Placebo Tablet | Change From Baseline in the Western Ontario & McMaster Osteoarthritis (WOMAC) Index Total Score at Week 8 | -59.7 score on a scale | Standard Error 4.34 |
p-value: 0.600795% CI: [-13.1, 7.6]Mixed Models Analysis
Secondary
Change From Baseline in the WOMAC Function Sub-scale Score at Week 8
The function subscale consists of 17 scores from 0-10, 0 is no difficulty and 10 is extreme difficulty, for a range of 0 - 170 points.
Time frame: Baseline, Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR845 Tablet | Change From Baseline in the WOMAC Function Sub-scale Score at Week 8 | -43.1 score on a scale | Standard Error 2.34 |
| Placebo Tablet | Change From Baseline in the WOMAC Function Sub-scale Score at Week 8 | -41.5 score on a scale | Standard Error 3.1 |
p-value: 0.651695% CI: [-9.1, 5.7]Mixed Models Analysis
Secondary
Change From Baseline in the WOMAC Pain Intensity Sub-scale Score at Week 8
The pain subscale consists of five scores from 0-10, 0 is no pain 10 is extreme pain possible for a range of 0 - 50 points.
Time frame: Baseline, Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR845 Tablet | Change From Baseline in the WOMAC Pain Intensity Sub-scale Score at Week 8 | -13.5 score on a scale | Standard Error 0.7 |
| Placebo Tablet | Change From Baseline in the WOMAC Pain Intensity Sub-scale Score at Week 8 | -12.7 score on a scale | Standard Error 0.92 |
p-value: 0.456395% CI: [-3, 1.4]Mixed Models Analysis
Secondary
Change From Baseline in the WOMAC Stiffness Sub-scale Score at Week 8
The stiffness subscale consists of two scores from 0-10, 0 is no stiffness 10 is extreme stiffness possible for a range of 0 - 20 points.
Time frame: Baseline, Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR845 Tablet | Change From Baseline in the WOMAC Stiffness Sub-scale Score at Week 8 | -5.7 score on a scale | Standard Error 0.29 |
| Placebo Tablet | Change From Baseline in the WOMAC Stiffness Sub-scale Score at Week 8 | -5.6 score on a scale | Standard Error 0.38 |
p-value: 0.869395% CI: [-1, 0.8]Mixed Models Analysis
Secondary
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
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.
Time frame: Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 Tablet | 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 | 44.3 percentage of patients |
| Placebo Tablet | 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 | 40.0 percentage of patients |
p-value: 0.195995% CI: [0.9, 2]Regression, Logistic
Secondary
Proportion of Patients With at Least 30% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8
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.
Time frame: Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 Tablet | Proportion of Patients With at Least 30% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8 | 41.5 percentage of patients |
| Placebo Tablet | Proportion of Patients With at Least 30% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8 | 50.6 percentage of patients |
p-value: 0.103395% CI: [0.5, 1.1]Regression, Logistic
Secondary
Proportion of Patients With at Least 50% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8
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.
Time frame: Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 Tablet | Proportion of Patients With at Least 50% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8 | 25.6 percentage of patients |
| Placebo Tablet | Proportion of Patients With at Least 50% Improvement From Baseline in the Weekly Mean Pain Intensity at Week 8 | 31.3 percentage of patients |
p-value: 0.283195% CI: [0.5, 1.2]Regression, Logistic
Secondary
Proportion of Patients Withdrawing From Treatment Due to Lack of Analgesic Efficacy
Time frame: Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 Tablet | Proportion of Patients Withdrawing From Treatment Due to Lack of Analgesic Efficacy | 2.5 percentage of patients |
| Placebo Tablet | Proportion of Patients Withdrawing From Treatment Due to Lack of Analgesic Efficacy | 3.1 percentage of patients |
p-value: 0.800295% CI: [0.3, 2.7]Regression, Logistic