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 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.