A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1)

A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Intravenous CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus, With a 52-Week Open Label Extension

This is a multicenter, randomized, double-blind, placebo-controlled 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 Double-blind Phase and a 52-week Open-label Extension Phase.

Study Overview

• Status: Completed
• Conditions: Uremic Pruritus
• Intervention / Treatment: Drug: CR845 0.5 mcg/kg; Drug: Placebo

Detailed Description

Double-blind Phase The Double-blind Phase of the study will consist of a Screening Visit, a 7-day Run-in Period, a 12 week Double-blind Treatment Period, and a 2-week Discontinuation 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 Open-label Extension Phase will be comprised of the Open-label Treatment Period and the Follow-up Period.

The last dose of open-label study drug will be administered at the last dialysis visit on Week 52, or Early Termination. A final safety Follow up Visit will be conducted 7-10 days after the End of Treatment/Early Termination Visit.

• Study Type: Interventional
• Enrollment (Actual): 378
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Homewood, Alabama, United States, 35209
      • Cara Therapeutics Study Site
    • Huntsville, Alabama, United States, 35805
      • Cara Therapeutics Study Site
  • California
    • Bakersfield, California, United States, 93309-5030
      • Cara Therapeutics Study Site
    • Beverly Hills, California, United States, 90211
      • Cara Therapeutics Study Site 2
    • Beverly Hills, California, United States, 90211
      • Cara Therapeutics Study Site
    • Chula Vista, California, United States, 91910
      • Cara Therapeutics Study Site
    • Corona, California, United States, 92881
      • Cara Therapeutics Study Site
    • Escondido, California, United States, 92025
      • Cara Therapeutics Study Site
    • Fountain Valley, California, United States, 92708
      • Cara Therapeutics Study Site
    • La Mesa, California, United States, 91942
      • Cara Therapeutics
    • Long Beach, California, United States, 90807
      • Cara Therapeutics Study Site
    • Ontario, California, United States, 91762
      • Cara Therapeutics Study Site
    • Riverside, California, United States, 92505
      • Cara Therapeutics Study Site
    • Roseville, California, United States, 95661
      • Cara Therapeutics Study Site
    • San Diego, California, United States, 92111
      • Cara Therapeutics Study Site
    • San Dimas, California, United States, 91773
      • Cara Therapeutics Study Site
    • Tarzana, California, United States, 91356
      • Cara Therapeutics Study Site
  • Colorado
    • Denver, Colorado, United States, 80218
      • Cara Therapeutics Study Site
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
      • Cara Therapeutics Study Site
    • Hartford, Connecticut, United States, 06112
      • Cara Therapeutics Study Site
    • Middlebury, Connecticut, United States, 06762
      • Cara Therapeutics Study Site
  • Florida
    • Coral Springs, Florida, United States, 33071
      • Cara Therapeutics Study Site 1
    • Hialeah, Florida, United States, 33016
      • Cara Therapeutics Study Site
    • Miami, Florida, United States, 33125
      • Cara Therapeutics Study Site
    • Miami Gardens, Florida, United States, 33169
      • Cara Therapeutics Study Site
    • Tampa, Florida, United States, 33614
      • Cara Therapeutics Study Site
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Cara Therapeutics Study Site
    • Roseville, Michigan, United States, 48066
      • Cara Therapeutics Study Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Cara Therapeutics Study Site
  • Mississippi
    • Brookhaven, Mississippi, United States, 39601
      • Cara Therapeutics Study Site
    • McComb, Mississippi, United States, 39648
      • Cara Therapeutics Study Site
    • Tupelo, Mississippi, United States, 38801
      • Cara Therapeutics Study Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Cara Therapeutics Study Site
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Cara Therapeutics Study Site
    • Las Vegas, Nevada, United States, 89102
      • Cara Therapeutics Study Site
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Cara Therapeutics Study Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Cara Therapeutics Study Site
    • Gallup, New Mexico, United States, 87301
      • Cara Therapeutics Study Site
  • New York
    • Bronx, New York, United States, 10461
      • Cara Therapeutics Study Site
    • Fresh Meadows, New York, United States, 11365
      • Cara Therapeutics Study Site
    • Great Neck, New York, United States, 11021
      • Cara Therapeutics Study Site
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Cara Therapeutics Study Site
  • Ohio
    • Canton, Ohio, United States, 44718
      • Cara Therapeutics Study Site
  • Oregon
    • Roseburg, Oregon, United States, 97471
      • Cara Therapeutics Study Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37408
      • Cara Therapeutics Study Site
  • Texas
    • Dallas, Texas, United States, 75231
      • Cara Therapeutics Study Site
    • Duncanville, Texas, United States, 75137
      • Cara Therapeutics Study Site
    • Greenville, Texas, United States, 75402
      • Cara Therapeutics Study Site
    • Houston, Texas, United States, 77054
      • Cara Therapeutics Study Site
    • Lewisville, Texas, United States, 75057
      • Cara Therapeutics Study Site
    • McAllen, Texas, United States, 78503
      • Cara Therapeutics Study Site
    • Mesquite, Texas, United States, 75150
      • Cara Therapeutics Study Site
    • San Antonio, Texas, United States, 78207
      • Cara Therapeutics Study Site
    • Waxahachie, Texas, United States, 75165
      • Cara Therapeutics Study Site
  • Virginia
    • Chesapeake, Virginia, United States, 23320
      • Cara Therapeutics Study Site
    • Hampton, Virginia, United States, 23666
      • Cara Therapeutics Study Site
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226
      • Cara Therapeutics Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; IV Placebo administered after each dialysis session (3 times/week)	Drug: Placebo; IV medication delivered three times/week
Active Comparator: CR845 0.5mcg/kg; IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)	Drug: CR845 0.5 mcg/kg; IV medication delivered three times/week; Other Names: Difelikefalin; CR845

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 12
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.	Baseline, Week 12
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.	Week 12

Collaborators and Investigators

• Sponsor: Cara Therapeutics, Inc.

Publications and helpful links

General Publications

• Hercz D, Jiang SH, Webster AC. Interventions for itch in people with advanced chronic kidney disease. Cochrane Database Syst Rev. 2020 Dec 7;12(12):CD011393. doi: 10.1002/14651858.CD011393.pub2.
• Fishbane S, Wen W, Munera C, Lin R, Bagal S, McCafferty K, Menzaghi F, Goncalves J. Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program. Kidney Med. 2022 Jun 28;4(8):100513. doi: 10.1016/j.xkme.2022.100513. eCollection 2022 Aug.
• Topf J, Wooldridge T, McCafferty K, Schomig M, Csiky B, Zwiech R, Wen W, Bhaduri S, Munera C, Lin R, Jebara A, Cirulli J, Menzaghi F. Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies. Kidney Med. 2022 Jun 28;4(8):100512. doi: 10.1016/j.xkme.2022.100512. eCollection 2022 Aug.
• Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F; KALM-1 Trial Investigators. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. N Engl J Med. 2020 Jan 16;382(3):222-232. doi: 10.1056/NEJMoa1912770. Epub 2019 Nov 8.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2018
• Primary Completion (Actual): April 6, 2019
• Study Completion (Actual): March 26, 2020

Study Registration Dates

• First Submitted: January 25, 2018
• First Submitted That Met QC Criteria: January 30, 2018
• First Posted (Actual): February 6, 2018

Study Record Updates

• Last Update Posted (Actual): April 26, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Chronic Kidney Disease; CKD; Itch; Dialysis; Hemodialysis; Pruritus; Itching; CR845; ESRD (end stage renal disease); Kidney failure, chronic; Kidney dysfunction; Chronic Itch; difelikefalin; Generalized pruritus; Uremic Pruritus; CKD-associated pruritus; CKD-aP; KALM
• Additional Relevant MeSH Terms: Skin Diseases; Skin Manifestations; Pruritus
• Other Study ID Numbers: CR845-CLIN3102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No