Chronic Kidney Diseases, Pruritus
Conditions
Keywords
difelikefalin, CR845, Pruritus, Chronic Itch, Itch, Itching, uremic pruritus, CKD, CKD-aP, CKD-associated pruritus, Chronic Kidney Disease, Kidney dysfunction, Generalized pruritus, Hemodialysis, Dialysis, ESRD (end stage renal disease), Kidney failure, chronic
Brief summary
This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of 3 dose levels of oral CR845 compared to placebo in reducing the intensity of itch in chronic kidney disease (CKD) patients with moderate-to-severe pruritus. This study will consist of a Screening Period, a 7-day Run-in Period, a 12 week Treatment Period, and a Follow-up Visit (approximately 7 days after the last dose of study drug).
Detailed description
This study will consist of a Screening Period, a 7-day Run-in Period, a 12 week Treatment Period, and a Follow-up Visit (approximately 7 to 10 days after the last dose of study drug). Informed consent will be obtained prior to performing any study-specific procedures. Screening will occur within 7 to 28 days prior to randomization to assess eligibility. If patients continue to meet all inclusion and no exclusion criteria at the end of the 7-day Run-in Period, they will be randomized in a 1:1:1:1 ratio to receive orally once daily either placebo or CR845 tablets at doses of 0.25, 0.5 or 1 mg. Randomization will be stratified according to the patient's renal disease status: moderate CKD; severe CKD non-dialysis; severe CKD on dialysis (ie, 3 categories). A final safety Follow-up Visit will be conducted 7 to 10 days after the last dose of study drug.
Interventions
DRUGCR845 0.25 mg Oral Tablet
CR845 0.25 mg medication taken orally 1 time/day
DRUGCR845 0.5 mg Oral Tablet
CR845 0.5 mg medication taken orally 1 time/day
DRUGCR845 1 mg Oral Tablet
CR845 1 mg medication taken orally 1 time/day
DRUGPlacebo Oral Tablet
Placebo tablet taken orally 1 time/day
Sponsors
Cara Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
CR845 will be provided as enteric-coated tablets. All tablets are white in color with no markings and are identical in appearance, regardless of dose. CR845 tablets will be provided at doses of 0.25, 0.5, and 1 mg.
Intervention model description
Randomized, double-blind, placebo controlled study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible for inclusion into the study, a patient must meet the following criteria: * CKD patients with stage III, IV, or V (ie, moderate renal impairment with estimated glomerular filtration rate (GFR) ≥30 and \<60 mL/min/1.73 m2 or severe renal impairment with estimated GFR \<30 mL/min/1.73 m2). * For severe CKD patients on hemodialysis, they must be receiving hemodialysis 3 times per week for at least 3 months prior to the start of screening; * Prior to randomization: 1. Has completed at least 4 Worst Itching Intensity NRS worksheets from the start of the 7-day Run-in Period; 2. Has a mean baseline Worst Itching Intensity NRS score ≥5, defined as the average of all non-missing scores reported from the start of the 7-day Run-in Period.
Exclusion criteria
A patient will be excluded from the study if any of the following criteria are met: * Patients not currently on dialysis who are likely to initiate routine dialysis during study participation; * Scheduled to receive a kidney transplant during the study; * New or change of treatment received for itch including antihistamines and corticosteroids (oral, intravenous \[IV\], or topical) within 14 days prior to screening; * Received another investigational drug within 30 days prior to the start of screening or is planning to participate in another clinical study while enrolled in this study; * Received ultraviolet B treatment within 30 days prior to the start of screening or anticipates receiving such treatment during the study; * Participated in a previous clinical study with CR845.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score During Week 12 | Baseline, Week 12 | Intensity of itch will be measured using an NRS used to indicate the intensity of the worst itching over the past 24 hours using a 0 to 10 numeric rating scale, where 0 represents no itching and 10 represents worst itching imaginable. Higher scores meant worse itch intensity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | Baseline, Week 12 | The 5-D Itch Scale is a multidimensional questionnaire which assesses itch-related quality of life over the past 2 weeks. The questions cover five dimensions of itch including the degree, duration of itch/day, direction (improvement/worsening), disability (impact on activities such as work), and body distribution of itch. The 5-D Itch Scale has 5 questions; the total 5-D Itch Scale score ranges from 5 to 25, with higher scores indicating worse responses. |
| Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | Baseline, Week 12 | The Skindex-10 Scale is a multidimensional questionnaire which assesses itch-related quality of life over the past week. The questions cover 3 domains: disease, mood/emotional distress, and social functioning domain. The Skindex-10 has 10 questions; the total Skindex-10 score ranges from 0 to 60. A lower total score represents better quality of life. |
| Reduction of Itch Intensity as Assessed by the Proportion of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | Week 12 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CR845 0.25 mg Oral Tablet Oral CR845 0.25 mg to be taken orally once daily for 12 weeks
CR845 0.25 mg Oral Tablet: CR845 0.25 mg medication taken orally 1 time/day | 69 |
| CR845 0.5 mg Oral Tablet Oral CR845 0.5 mg to be taken orally once daily for 12 weeks
CR845 0.5 mg Oral Tablet: CR845 0.5 mg medication taken orally 1 time/day | 66 |
| CR845 1 mg Oral Tablet Oral CR845 1 mg to be taken orally once daily for 12 weeks
CR845 1 mg Oral Tablet: CR845 1 mg medication taken orally 1 time/day | 67 |
| Placebo Oral Tablet Oral Placebo to be taken orally once daily
Placebo Oral Tablet: Placebo tablet taken orally 1 time/day | 67 |
| Total | 269 |
Baseline characteristics
| Characteristic | Total | Placebo Oral Tablet | CR845 1 mg Oral Tablet | CR845 0.5 mg Oral Tablet | CR845 0.25 mg Oral Tablet |
|---|---|---|---|---|---|
| Age, Continuous | 66.9 years STANDARD_DEVIATION 11.5 | 65.6 years STANDARD_DEVIATION 12.1 | 67.5 years STANDARD_DEVIATION 10.7 | 69.0 years STANDARD_DEVIATION 12 | 65.7 years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 2 Participants | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 17 Participants | 15 Participants | 12 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 193 Participants | 47 Participants | 48 Participants | 49 Participants | 49 Participants |
| Sex: Female, Male Female | 130 Participants | 30 Participants | 32 Participants | 33 Participants | 35 Participants |
| Sex: Female, Male Male | 139 Participants | 37 Participants | 35 Participants | 33 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 0 / 66 | 1 / 67 | 3 / 67 |
| other Total, other adverse events | 12 / 69 | 10 / 66 | 15 / 67 | 8 / 67 |
| serious Total, serious adverse events | 9 / 69 | 9 / 66 | 9 / 67 | 5 / 67 |
Outcome results
Primary
Change From Baseline in Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score During Week 12
Intensity of itch will be measured using an NRS used to indicate the intensity of the worst itching over the past 24 hours using a 0 to 10 numeric rating scale, where 0 represents no itching and 10 represents worst itching imaginable. Higher scores meant worse itch intensity.
Time frame: Baseline, Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CR845 0.25 mg Oral Tablet | Change From Baseline in Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score During Week 12 | -3.99 score on a scale |
| CR845 0.5 mg Oral Tablet | Change From Baseline in Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score During Week 12 | -3.84 score on a scale |
| CR845 1 mg Oral Tablet | Change From Baseline in Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score During Week 12 | -4.42 score on a scale |
| Placebo Oral Tablet | Change From Baseline in Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score During Week 12 | -3.32 score on a scale |
Secondary
Change From Baseline in 5-D Itch Scale Score at the End of Week 12
The 5-D Itch Scale is a multidimensional questionnaire which assesses itch-related quality of life over the past 2 weeks. The questions cover five dimensions of itch including the degree, duration of itch/day, direction (improvement/worsening), disability (impact on activities such as work), and body distribution of itch. The 5-D Itch Scale has 5 questions; the total 5-D Itch Scale score ranges from 5 to 25, with higher scores indicating worse responses.
Time frame: Baseline, Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CR845 0.25 mg Oral Tablet | Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | -6.17 score on a scale |
| CR845 0.5 mg Oral Tablet | Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | -6.84 score on a scale |
| CR845 1 mg Oral Tablet | Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | -6.97 score on a scale |
| Placebo Oral Tablet | Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | -5.74 score on a scale |
Secondary
Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12
The Skindex-10 Scale is a multidimensional questionnaire which assesses itch-related quality of life over the past week. The questions cover 3 domains: disease, mood/emotional distress, and social functioning domain. The Skindex-10 has 10 questions; the total Skindex-10 score ranges from 0 to 60. A lower total score represents better quality of life.
Time frame: Baseline, Week 12
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CR845 0.25 mg Oral Tablet | Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | -21.19 score on a scale |
| CR845 0.5 mg Oral Tablet | Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | -22.13 score on a scale |
| CR845 1 mg Oral Tablet | Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | -23.57 score on a scale |
| Placebo Oral Tablet | Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | -19.95 score on a scale |
Secondary
Reduction of Itch Intensity as Assessed by the Proportion of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12
Time frame: Week 12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 0.25 mg Oral Tablet | Reduction of Itch Intensity as Assessed by the Proportion of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 66.2 percentage of subjects |
| CR845 0.5 mg Oral Tablet | Reduction of Itch Intensity as Assessed by the Proportion of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 64.8 percentage of subjects |
| CR845 1 mg Oral Tablet | Reduction of Itch Intensity as Assessed by the Proportion of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 72.1 percentage of subjects |
| Placebo Oral Tablet | Reduction of Itch Intensity as Assessed by the Proportion of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 57.9 percentage of subjects |