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 μg/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 = 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 itch-related quality of life.

Keywords: CKD-aP; CR845; chronic kidney disease; hemodialysis; kappa opioid receptor agonist; uremic pruritus.

Graphical abstract

Figure 1

Patient disposition.

Figure 2

(a) Change from baseline at week 8 in the weekly mean of the daily 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) scores for difelikefalin versus placebo. (b) Weekly mean of daily 24-hour WI-NRS scores over 8 weeks for difelikefalin versus placebo. The shaded areas indicate the itch severity category based on the WI-NRS classification. (c) Changes from baseline at week 8 in the weekly mean of the daily 24-hour WI-NRS score for difelikefalin (all difelikefalin doses combined) versus placebo according to baseline use or nonuse of antipruritic medications. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 versus placebo (mixed effects model with repeated measures; see Statistical Analysis section), (n = 41–45/group). LS, least-squares.

Figure 3

(a) Changes from baseline at week 8 in quality-of-life (QoL) measures for difelikefalin versus placebo as per Skindex-10 total score (left) and 5-D itch total score (right). (b) Correlation between changes from baseline for QoL measures and Worst Itching Intensity Numerical Rating Scale (WI-NRS) at week 8. ∗P < 0.05, ∗∗∗P < 0.001 versus placebo based on a mixed effects model with repeated measures analysis, (n = 41–45/group). LS, least-squares; r, Pearson’s correlation coefficient.

Figure 4

Percentage of patients per Patient Global Impression of Change categories on 8 weeks of exposure to all difelikefalin combined or placebo. For graphic representation, percentages were rounded to the nearest whole number.