Safety and Effectiveness of Difelikefalin in Patients With Moderate-to-Severe Pruritus Undergoing Hemodialysis: An Open-Label, Multicenter Study

Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kid-ney 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 mu g/kg after each hemodialysis session for 12 weeks.Outcomes: The primary outcome was safety of difelikefalin. Secondary outcomes included: effec-tiveness of reducing itch intensity, assessed by the Worst Itching Intensity Numerical Rating Scale (WI-NR S); 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-NR S 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.