Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients

Abstract

Introduction: There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus. Methods: In this study, 174 hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive difelikefalin (0.5, 1.0, or 1.5 mg/kg) or placebo intravenously thrice weekly after each hemodialysis session for 8 weeks in a double-blind, controlled trial. The primary endpoint was the change from baseline at week 8 in the weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale score. The secondary efficacy endpoint was the change in itch-related quality of life measured by the Skindex-10 questionnaire. Other endpoints included safety, sleep quality, and additional measures including the 5-D itch scale. Results: A significant reduction from baseline in itch intensity scores at week 8 favored all difelikefalin doses combined versus placebo (P ¼ 0.002). Difelikefalin also showed improvement over placebo in Skindex-10, 5-D itch, and sleep disturbance scores (P # 0.005). Overall, 78% of patients receiving difelikefalin reported treatment-emergent adverse events versus 42% of patients given placebo, with diarrhea, dizziness, nausea, somnolence, and fall being the most frequent ($5%). Conclusion: In this trial, difelikefalin effectively reduced itching intensity and improved sleep and itchrelated quality of life.

Effect of difelikefalin, a selective kappa opioid receptor agonist, on respiratory depression: A randomized, double‐blind, placebo‐controlled trial

“…The 2 doses of difelikefalin in the current study are 2 to 10 times higher than the doses assessed in the phase 3 study of difelikefalin in patients with CKD-aP. 18,19 In previous clinical studies, bolus IV doses of Accepted Article difelikefalin 0.5 to 40.0 mcg/kg have been administered to healthy volunteers (unpublished data) or patients with chronic kidney disease without any indication of compromised respiratory safety compared with placebo. 18,19 SpO 2 is less sensitive to changes in acute respiratory events than the ETCO 2 parameter.…”

Clinically meaningful change in itch intensity scores: An evaluation in patients with chronic kidney disease–associated pruritus

“…This study demonstrated the antipruritic effects of the selective -opioid receptor agonist, difelikefalin, with a significant reduction of itch intensity and an improvement of itch-related quality of life (QoL) over placebo. 5 Itch intensity and QoL scores were collected over an 8-week treatment period. 5 The Patient Global Impression of Change (PGI-C), with 7 categories ranging from ''very much improved'' to ''very much worse,'' Patient Global Impression of Worst Itch Severity (PGI-S), with values from 0 (none) to 4 (very severe), and the Skindex-10 and 5-D itch QoL questionnaires were selected as anchor variables in the present analysis (Supplemental Figs 2-5).…”

Emerging Therapeutic Options for Chronic Pruritus

“…Another compound currently receiving growing interest, difelikefalin (CR845), is selective towards peripheral kappa-opioid receptors in the skin as it is not able to cross the blood-brain barrier [45]. In a phase II randomized trial among subjects with UP, difelikefalin was administered intravenously (after a [46,47]. Notably, the beneficial WI-NRS response of difelikefalin started to unveil after 1 week of treatment.…”

“…Another compound currently receiving growing interest, difelikefalin (CR845), is selective towards peripheral kappa-opioid receptors in the skin as it is not able to cross the blood–brain barrier [ 45 ]. In a phase II randomized trial among subjects with UP, difelikefalin was administered intravenously (after a hemodialysis session) thrice weekly for 8 weeks in doses of 0.5, 1.0 or 1.5 mg/kg to 44, 42 and 44 patients, respectively, while 45 patients received placebo [ 46 ]. At week 8, patients receiving difelikefalin were significantly more prone to experience alleviation of pruritus (at least − 3 points in the WI-NRS) when compared with placebo (59% vs. 29%; p = 0.001), as well as significant improvement in itch-related QoL.…”

“…Significantly more patients receiving difelikefalin experienced at least 3 points of improvement in pruritus at week 12, as measured by the WI-NRS (49.1% vs. 27.9%; p < 0.001). The most common AEs were diarrhea, dizziness and nausea/vomiting [ 46 , 47 ]. Notably, the beneficial WI-NRS response of difelikefalin started to unveil after 1 week of treatment.…”