Efficacy and Safety of Difelikefalin in Japanese Patients With Moderate to Severe Pruritus Receiving Hemodialysis: A Randomized Clinical Trial

Abstract

Importance: Patients with pruritus receiving hemodialysis frequently experience oppressive physical and psychiatric symptoms that directly affect their quality of life and increase mortality. However, treatment options are limited.

Objective: To determine the clinically recommended dose of difelikefalin, a κ-opioid receptor agonist, based on the efficacy, dose response, safety, and pharmacokinetics.

Design, setting, and participants: This randomized, double-blind, placebo-controlled, 4-arm phase 2 trial was conducted from February 1, 2019, to October 22, 2019, at 94 sites in Japan. Patients with moderate to severe pruritus receiving hemodialysis were enrolled.

Interventions: Difelikefalin (0.25, 0.5, and 1.0 μg/kg) and placebo were intravenously administered 3 times a week at the end of each hemodialysis session for 8 weeks.

Main outcome and measures: The primary end point was the change from baseline in the weekly mean Worst Itching Intensity Numerical Rating Scale (NRS) score at week 8. Secondary outcomes measured changes in itch-related quality-of-life score using the Skindex-16 and 5-D itch scale. Safety was assessed according to adverse events, laboratory tests, vital signs, body weight, and 12-lead electrocardiogram.

Results: A total of 247 Japanese patients (186 male [75%]; mean [SD] age, 64.5 [11.7] years) were randomized to placebo (n = 63), 0.25 μg/kg of difelikefalin (n = 61), 0.5 μg/kg of difelikefalin (n = 61), or 1.0 μg/kg of difelikefalin (n = 62). The changes from baseline in the adjusted mean (SE) of the 24-hour Worst Itching Intensity NRS score at week 8 were -2.86 (0.29) in the placebo group, -2.97 (0.29) in the 0.25 μg/kg of difelikefalin group, -3.65 (0.30) in the 0.5 μg/kg of difelikefalin group, and -3.64 (0.30) in the 1.0 μg/kg of difelikefalin group. Significant differences were found in the 0.5 μg/kg of difelikefalin group (adjusted mean difference, -0.80; 95% CI, -1.55 to -0.04; P = .04) and the 1.0 μg/kg of difelikefalin group (adjusted mean difference, -0.78; 95% CI, -1.54 to -0.03; P = .04) compared with placebo. The Skindex-16 overall score and 5-D itch scale total score indicated an improvement with treatment with 0.5 and 1.0 μg/kg of difelikefalin (adjusted weekly mean [SE] Skindex-16 overall score at week 8, -27.79 [2.05]; 95% CI, -31.83 to -23.74 for 0.5 μg/kg of difelikefalin and -22.69 [2.04]; 95% CI, -26.71 to -18.68 for 1.0 μg/kg of difelikefalin; adjusted weekly mean [SE] 5-D itch scale total score at week 8, -6.5 [0.4]; 95% CI, -7.2 to -5.8 for 0.5 μg/kg of difelikefalin and -6.8 [0.3]; 95% CI, -7.5 to -6.2 for 1.0 μg/kg of difelikefalin). The incidence of adverse events was 67% (42 of 63 patients) in the placebo group, 72% (44 of 61 patients) in the 0.25 μg/kg of difelikefalin group, 77% (47 of 61 patients) in the 0.5 μg/kg of difelikefalin group, and 85% (53 of 62 patients) in the 1.0 μg/kg of difelikefalin group. No dependency was reported.

Conclusions and relevance: The findings of this phase 2 randomized clinical trial of difelikefalin suggest that 0.5 μg/kg of difelikefalin should be the clinically recommended dose as a new option for treating moderate to severe pruritus in patients undergoing hemodialysis because of its efficacy, acceptable tolerability, and manageable safety profile.

Trial registration: ClinicalTrials.gov Identifier: NCT03802617.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Narita reported receiving personal fees for consulting from Kissei Pharmaceutical Co Ltd and Maruishi Pharmaceutical Co Ltd during the conduct of the study. Dr Tsubakihara reported receiving personal fees from Kissei Pharmaceutical Co Ltd and Maruishi Pharmaceutical Co Ltd during the conduct of the study. Mr Uchiyama reported being an employee of Kissei Pharmaceutical Co Ltd during the conduct of the study and having a patent for 2021-123323 issued. Mr Okamura reported being an employee of Kissei Pharmaceutical Co Ltd during the conduct of the study. Ms Oya reported being an employee of Maruishi Pharmaceutical Cot Ltd during the conduct of the study. Mr Takahashi reported being an employee of Maruishi Pharmaceutical Co Ltd during the conduct of the study. Dr Gejyo reported receiving personal fees for consulting from Kissei Pharmaceutical Co Ltd and Maruishi Pharmaceutical Co Ltd during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Enrollment, Randomization, and Treatment Assignment

FAS indicates full analysis set; PPS, per protocol set; SS, safety set.

Figure 2.. Course of the Primary Outcomes During 8-Week Treatment Period

A and B, A mixed-effects model for repeated measures was used to compare the difelikefalin (0.25, 0.5, and 1.0 μg/kg) and placebo groups. C, A comparison between the difelikefalin (0.25, 0.5, and 1.0 μg/kg) and placebo groups was performed using the Fisher exact test. Error bars indicate SEs. NRS indicates Numerical Rating Scale. aP < .05.

Figure 3.. Mean (SD) Plasma Concentrations of Difelikefalin

Plasma concentrations of difelikefalin (0.25, 0.5, and 1.0 μg/kg) were measured before the first dialysis session at weeks 1, 2, 4, 7, and 8 and before the second dialysis session at weeks 1, 4, and 7. Error bars indicate SDs.