Uremic Pruritus
Conditions
Keywords
Hemodialysis, difelikefalin, CR845, Pruritus, Chronic Itch, Itch, Itching, Uremic Pruritus, Dialysis, CKD, CKD-associated pruritus, CKD-aP, ESRD (end stage renal disease), KALM, Chronic Kidney Disease, Kidney failure, chronic, Kidney dysfunction, Generalized pruritus
Brief summary
This is a multicenter, international study to evaluate the safety and efficacy of intravenous (IV) CR845 at a dose of 0.5 mcg/kg administered after each dialysis session. The study includes a 12-week randomized, double-blind, placebo-controlled Phase and a 52-week Open-label Extension Phase.
Detailed description
Double-blind Phase: The Double-blind Phase of the study will consist of a Screening Visit, a 7-day Run-in Period, and a 12-week Double-blind Treatment Period. Informed consent will be obtained prior to performing any study-specific procedures. The Screening Visit will occur within 7 to 28 days prior to randomization to assess eligibility. Open-label Extension Phase: Patients who received at least 30 doses of study drug (either active or placebo) during the 12-week Double-blind Treatment Period and continue to meet other eligibility criteria will have the option to receive open label CR845 for an additional 52 weeks. The last dose of open-label study drug will be administered at the last dialysis visit on Week 52, or Early Termination. Follow-up Period: A final safety Follow up Visit will be conducted 7-10 days after the End of Treatment/Early Termination Visit.
Interventions
DRUGCR845 0.5 mcg/kg
IV CR845 0.5 mcg/kg administered three times/week
DRUGPlacebo
IV placebo administered three times/week
Sponsors
Cara Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: To be eligible for inclusion into the Double-blind Phase of the study, a patient must meet the following criteria: * Has end-stage renal disease (ESRD) and has been on hemodialysis 3 times per week for at least 3 months prior to the start of screening; * Has at least 2 single-pool Kt/V measurements ≥1.2, or at least 2 urea reduction ratio measurements ≥65%, or 1 single pool Kt/V measurement ≥1.2 and 1 urea reduction ratio measurement ≥65% on different dialysis days during the 3 months period prior to screening; * Prior to randomization: * Has completed Worst Itching Intensity NRS worksheets up to 8 days prior to 1st dose; * Has a mean baseline Worst Itching Intensity NRS indicative of moderate to severe uremic pruritus. * To be eligible for inclusion into the Open-label Extension Phase of the study, each patient will have to fulfill the additional key following criteria at the time of entry into the Open-label Extension Phase: * Has received at least 30 doses of the planned 36 doses of study drug during the Double-blind Phase of this study; * Continues to meet inclusion criteria. Key
Exclusion criteria
A patient will be excluded from the Double-blind Phase of the study if any of the following criteria are met: * Known noncompliance with dialysis treatment that in the opinion of the investigator would impede completion or validity of the study; * Scheduled to receive a kidney transplant during the study; * New or change of treatment received for itch including antihistamines and corticosteroids (oral, 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; * Has pruritus only during the dialysis session (by patient report); * Is receiving ongoing ultraviolet B and anticipates receiving such treatment during the study; * Participated in a previous clinical study with CR845. * A patient will be excluded from the Open-label Extension Phase of the study if any of the additional key following criteria are met at the time of entry into the Open-label Extension Phase: * Completed the Double-blind Phase of this study but exhibited adverse events during the course of the Treatment Period that may preclude continued exposure to the study drug; * Was noncompliant with protocol procedures during the Double-blind Phase of this study which is indicative of an inability to follow protocol procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score at Week 12 | 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. LS means estimated percent, odds ratio and P value used a logistic regression model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥4 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 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. LS means estimated percent, odds ratio and P value used a logistic regression model. |
| Improvement in Itch-related Quality of Life as Assessed by the 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. |
| Improvement in Itch-related Quality of Life as Assessed by the 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. |
Countries
Australia, Canada, Czechia, Germany, Hungary, New Zealand, Poland, South Korea, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
The ITT Population consisted of 473 subjects randomized to study treatment, 237 to difelikefalin and 236 to placebo. The Double-blind Safety Population consisted of 471 randomized subjects who received at least 1 dose of double-blind study drug during the Double-blind Treatment Period; 235 of these subjects were treated with difelikefalin, and 236 were treated with placebo. Two subjects were randomized to difelikefalin but did not receive any study drug.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind CR845 0.5mcg/kg IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)
CR845 0.5 mcg/kg: IV CR845 0.5 mcg/kg administered three times/week | 235 |
| Double-blind Placebo IV Placebo administered after each dialysis session (3 times/week)
Placebo: IV placebo administered three times/week | 236 |
| Total | 471 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1: Double-blind Phase | Adverse Event | 13 | 7 | 0 |
| Period 1: Double-blind Phase | Eligibility (inclusion/exclusion criteria) | 2 | 0 | 0 |
| Period 1: Double-blind Phase | Lack of Efficacy | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Lost to Follow-up | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Other | 6 | 3 | 0 |
| Period 1: Double-blind Phase | Subject non-compliance | 1 | 2 | 0 |
| Period 1: Double-blind Phase | Withdrawal by Subject | 5 | 1 | 0 |
| Period 2: Open-label Phase | Administrative | 0 | 0 | 36 |
| Period 2: Open-label Phase | Adverse Event | 0 | 0 | 21 |
| Period 2: Open-label Phase | Eligibility (inclusion/exclusion criteria) | 0 | 0 | 2 |
| Period 2: Open-label Phase | Lack of Efficacy | 0 | 0 | 2 |
| Period 2: Open-label Phase | Other | 0 | 0 | 9 |
| Period 2: Open-label Phase | Sponsor stopping study | 0 | 0 | 313 |
| Period 2: Open-label Phase | Withdrawal by Subject | 0 | 0 | 11 |
Baseline characteristics
| Characteristic | Double-blind Placebo | Total | Double-blind CR845 0.5mcg/kg |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 13.07 | 59.6 years STANDARD_DEVIATION 13.08 | 59.7 years STANDARD_DEVIATION 13.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 32 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 38 Participants | 91 Participants | 53 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 169 Participants | 331 Participants | 162 Participants |
| Sex: Female, Male Female | 97 Participants | 197 Participants | 100 Participants |
| Sex: Female, Male Male | 139 Participants | 274 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 235 | 2 / 236 | 15 / 399 |
| other Total, other adverse events | 56 / 235 | 43 / 236 | 204 / 399 |
| serious Total, serious adverse events | 58 / 235 | 51 / 236 | 130 / 399 |
Outcome results
Primary
Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score at 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. LS means estimated percent, odds ratio and P value used a logistic regression model.
Time frame: Week 12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 0.5mcg/kg | Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score at Week 12 | 54.0 percentage of subjects |
| Placebo | Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score at Week 12 | 42.2 percentage of subjects |
p-value: 0.0295% CI: [1.08, 2.41]Cui, Hung, Wang
Secondary
Improvement in Itch-related Quality of Life as Assessed by the 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 0.5mcg/kg | Improvement in Itch-related Quality of Life as Assessed by the Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | -4.9 score on a scale |
| Placebo | Improvement in Itch-related Quality of Life as Assessed by the Change From Baseline in 5-D Itch Scale Score at the End of Week 12 | -3.8 score on a scale |
p-value: 0.00295% CI: [-1.7, -0.4]ANCOVA
Secondary
Improvement in Itch-related Quality of Life as Assessed by the 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 0.5mcg/kg | Improvement in Itch-related Quality of Life as Assessed by the Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | -16.6 score on a scale |
| Placebo | Improvement in Itch-related Quality of Life as Assessed by the Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12 | -14.8 score on a scale |
p-value: 0.17195% CI: [-4.3, 0.8]ANCOVA
Secondary
Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥4 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at 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. LS means estimated percent, odds ratio and P value used a logistic regression model.
Time frame: Week 12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CR845 0.5mcg/kg | Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥4 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 41.2 percentage of subjects |
| Placebo | Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥4 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12 | 28.4 percentage of subjects |
p-value: 0.0195% CI: [1.14, 2.74]Cui, Hung, Wang