TY - JOUR
T1 - Safety and Effectiveness of Difelikefalin in Patients With Moderate-to-Severe Pruritus Undergoing Hemodialysis
T2 - An Open-Label, Multicenter Study
AU - Weiner, Daniel E.
AU - Vervloet, Marc G.
AU - Walpen, Sebastian
AU - Schaufler, Thilo
AU - Munera, Catherine
AU - Menzaghi, Frédérique
AU - Wen, Warren
AU - Bhaduri, Sarbani
AU - trial investigators
AU - Germain, Michael J.
N1 - Funding Information: This trial was funded by Cara Therapeutics. Funding Information: Medical writing support was provided by AXON Communications (London, United Kingdom) and funded by Vifor Pharma. The authors are grateful to all the investigators and the patients who participated in this study. Funding Information: A complete list of the trial investigators is provided in Item S1. Daniel E. Weiner, MD, MS, Marc G. Vervloet, MD, PhD, Sebastian Walpen, PhD, Thilo Schaufler, PhD, Catherine Munera, PhD, Frédérique Menzaghi, PhD, Warren Wen, PhD, Sarbani Bhaduri, MD, Michael J. Germain, MD; on behalf of the trial investigators. Research idea and study design: FM, CM, WW; data acquisition: DEW, MGV, MJG, SB; data analysis and interpretation: DEW, FM, CM, WW, SW, TS. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This trial was funded by Cara Therapeutics. Dr Weiner is a Medical Director of Clinical Research for Dialysis Clinic, Inc, served on advisory boards for Akebia representing Dialysis Clinic, Inc and Cara Therapeutics (2020) and on the adjudications committee for VALOR Trial (Tricida), and is a Site PI for Ardelyx, AstraZeneca, Cara Therapeutics, CSL Behring, and Goldfinch Bio. Dr Germain is a consultant and investigator for Cara Therapeutics. Drs Menzaghi, Munera, and Wen are employees and shareholders of Cara Therapeutics. Dr Vervloet received research support and consultancy fees from Vifor Pharma. Dr Bhaduri is a medical consultant for Cara Therapeutics. Drs Walpen and Schaufler are employees and shareholders of Vifor Pharma. Medical writing support was provided by AXON Communications (London, United Kingdom) and funded by Vifor Pharma. The authors are grateful to all the investigators and the patients who participated in this study. Received January 13, 2022 as a submission to the expedited consideration track with 2 external peer reviews. Direct editorial input from 2 external statistical reviewers and an Acting Editor-in-Chief (Editorial Board Member Manfred Hecking, MD). Accepted in revised form August 17, 2022. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with Kidney Medicine's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. Publisher Copyright: © 2022
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kidney disease-associated pruritus (CKD-aP), impacting sleep quality and quality of life (QoL) and increasing the likelihood of depression. Difelikefalin is a kappa-opioid receptor agonist recently approved in the United States for the treatment of moderate-to-severe CKD-aP in hemodialysis patients. Study 3105 was conducted to further assess the safety of difelikefalin and the effects on pruritus and QoL. Study Design: Open-label, multicenter, single-arm intervention trial. Setting & Participants: Maintenance hemodialysis patients with moderate-to-severe CKD-aP at enrollment. Intervention: Intravenous difelikefalin 0.5 μg/kg after each hemodialysis session for 12 weeks. Outcomes: The primary outcome was safety of difelikefalin. Secondary outcomes included: effectiveness of reducing itch intensity, assessed by the Worst Itching Intensity Numerical Rating Scale (WI-NRS); improving itch-related QoL, assessed with 5-D itch and Skindex-10 scales; and improvement of sleep, assessed with the Sleep Quality Numerial Rating Scale. Clinically meaningful thresholds for improvement in itch and QoL were previously established in this population. Results: Among 222 participants with baseline WI-NRS ≥5, mean [standard deviation] WI-NRS was 7.6 [1.3], mean age 58 years, 55% were male, and mean dialysis duration was 5.9 years; 197 participants (89%) completed treatment. Treatment-related treatment-emergent adverse events were reported in 16 participants (7.2%); those most commonly reported were somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%), and dizziness (0.9%). No deaths or serious treatment-emergent adverse events were considered treatment-related. Clinically meaningful reduction in itch intensity (≥3-point improvement) was reported by 74% of participants, with 70% and 63% also reporting a clinically relevant improvement in QoL as measured by 5-D itch and Skindex-10. Sleep quality improvement (≥3-point reduction on the Numerical Rating Scale) was reported in 66% of participants. Limitations: No placebo control group. Conclusions: Difelikefalin was well tolerated, and treatment was associated with clinically meaningful improvements in itch intensity and itch-related QoL measures as well as improvements in sleep quality among individuals receiving hemodialysis who had moderate-to-severe CKD-aP, providing important insights into expected real-world effectiveness. Funding: Cara Therapeutics. Trial Registration: NCT03998163.
AB - Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kidney disease-associated pruritus (CKD-aP), impacting sleep quality and quality of life (QoL) and increasing the likelihood of depression. Difelikefalin is a kappa-opioid receptor agonist recently approved in the United States for the treatment of moderate-to-severe CKD-aP in hemodialysis patients. Study 3105 was conducted to further assess the safety of difelikefalin and the effects on pruritus and QoL. Study Design: Open-label, multicenter, single-arm intervention trial. Setting & Participants: Maintenance hemodialysis patients with moderate-to-severe CKD-aP at enrollment. Intervention: Intravenous difelikefalin 0.5 μg/kg after each hemodialysis session for 12 weeks. Outcomes: The primary outcome was safety of difelikefalin. Secondary outcomes included: effectiveness of reducing itch intensity, assessed by the Worst Itching Intensity Numerical Rating Scale (WI-NRS); improving itch-related QoL, assessed with 5-D itch and Skindex-10 scales; and improvement of sleep, assessed with the Sleep Quality Numerial Rating Scale. Clinically meaningful thresholds for improvement in itch and QoL were previously established in this population. Results: Among 222 participants with baseline WI-NRS ≥5, mean [standard deviation] WI-NRS was 7.6 [1.3], mean age 58 years, 55% were male, and mean dialysis duration was 5.9 years; 197 participants (89%) completed treatment. Treatment-related treatment-emergent adverse events were reported in 16 participants (7.2%); those most commonly reported were somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%), and dizziness (0.9%). No deaths or serious treatment-emergent adverse events were considered treatment-related. Clinically meaningful reduction in itch intensity (≥3-point improvement) was reported by 74% of participants, with 70% and 63% also reporting a clinically relevant improvement in QoL as measured by 5-D itch and Skindex-10. Sleep quality improvement (≥3-point reduction on the Numerical Rating Scale) was reported in 66% of participants. Limitations: No placebo control group. Conclusions: Difelikefalin was well tolerated, and treatment was associated with clinically meaningful improvements in itch intensity and itch-related QoL measures as well as improvements in sleep quality among individuals receiving hemodialysis who had moderate-to-severe CKD-aP, providing important insights into expected real-world effectiveness. Funding: Cara Therapeutics. Trial Registration: NCT03998163.
KW - Chronic kidney disease-associated pruritus
KW - difelikefalin
KW - open-label clinical trial
KW - quality of life
KW - real-world efficacy
KW - safety
UR - http://www.scopus.com/inward/record.url?scp=85138286894&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.xkme.2022.100542
DO - https://doi.org/10.1016/j.xkme.2022.100542
M3 - Article
C2 - 36185706
SN - 2590-0595
VL - 4
JO - Kidney medicine
JF - Kidney medicine
IS - 10
M1 - 100542
ER -