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

Abstract

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.

Keywords: Chronic kidney disease-associated pruritus; difelikefalin; open-label clinical trial; quality of life; real-world efficacy; safety.

© 2022 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.

Figures

Graphical abstract

Figure 1

Study disposition flow diagram. ∗The screen failures patient count for the category “Exclusion criteria” excluded 1 patient, who was rescreened and enrolled. #Patients could be recreened if they failed the inclusion/exclusion criteria at their initial screening visit. Rescreening was considered on an individual patient basis and must first have been approved by the Sponsor or designee. However, rescreening was not permitted if a patient missed the entry criteria for itch intensity, ie, mean Worst Itching Intensity NRS score >5. Additionally, a patient could only be rescreened once, and rescreening could only occur at least 2 weeks after the original screening visit. Seven of the 14 patients who failed initial screening were included upon rescreening. For patients who screen-failed more than once, the reason for failure was the final screen failure. Abbreviation: AE, adverse event.

Figure 2

WI-NRS and Sleep Quality NRS scores at baseline and week 12. The Worst Itching Intensity Numerical Rating Scale, an 11-point scale (range 0 to 10; higher scores indicate greater itch intensity), which has been validated in patients with CKD-aP., , Reduction of ≥3 points on the WI-NRS has been shown to be associated with a clinically meaningful change in itch intensity for patients with moderate-to-severe pruritus undergoing HD. Sleep Quality Numerical Rating Scale (NRS) indicates how much itch interfered with sleep over the preceding 24 hours, with responses ranging from 0 (“did not interfere”) to 10 (“completely interfered”). Abbreviations: CI, confidence interval; WI-NRS: Worst Itching Intensity Numerical Rating Scale.

Figure 3

WI-NRS and Sleep Quality NRS response rate at Week 12. Data as observed at Week 12, N = 194. The Worst Itching Intensity Numerical Rating Scale, an 11-point scale (range 0 to 10; higher scores indicate greater itch intensity), which has been validated in patients with CKD-aP., , Reduction of ≥3 points on the WI-NRS has been shown to be associated with a clinically meaningful change in itch intensity for patients with moderate-to-severe pruritus undergoing HD. Sleep Quality Numerical Rating Scale (NRS) indicates how much itch interfered with sleep over the preceding 24 hours, with responses ranging from 0 (“did not interfere”) to 10 (“completely interfered”). ∗Complete resolution defined as ≥75% of weekly mean WI-NRS scores equal to 0 or 1 or all Sleep Quality NRS scores equal to 0. During the run-in period and at baseline, only 2.7% of patients had Sleep Quality NRS scores equal to 0 and scores for WI-NRS were ≥5. Abbreviations: CI, confidence interval; WI-NRS, Worst Itching Intensity Numerical Rating Scale.

Figure 4

Mean change from baseline in total and domain scores at Week 12 for (A) 5-D itch scale and (B) Skindex-10 scale. Error bar represents standard deviation. (A) The 5D-itch scale, a multidimensional tool that assesses itch-related quality of life and itch intensity across 5 separate itch-related domains (duration, degree, direction, disability, and distribution). The scores for each domain are added separately and then summed together to obtain a total 5-D score. 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus). A clinically meaningful improvement has been reported for a reduction from baseline of ≥5-point in the total 5-D itch score. (B) Skindex-10 scale: Score: 0 (never bothered) to 6 (always bothered). The total score is the sum of the numeric value of each answered question. The domain scores are the sum of the following: disease domain (questions 1- 3); mood/emotional distress domain (questions 4-6); social functioning domain (questions 7-10). A clinically meaningful improvement has been reported for a reduction from baseline of ≥15-points.