Efficacy and Safety of Difelikefalin in Japanese Patients With Moderate to Severe Pruritus Receiving Hemodialysis
Authors: Ichiei Narita, Yoshiharu Tsubakihara, Takuma Uchiyama, Shota Okamura, Nobuyo Oya, Naoki Takahashi, Fumitake Gejyo, Akikazu Yamamoto, Akiko Ichikawa, Akira Ohishi, Atsunori Ishimura, Haruki Fuse, Hideaki Yoshida, Hidetoshi Yoshinaga, Hirokazu Okada, Hiromi Sanematsu, Hiroshi Mizuno, Hiroshi Seshita, Hiroyuki Kinuno, Hiroyuki Shimizu, Hisakazu Degawa, Hisaki Shimada, Isoji Sasagawa, Jong II Kim, Katsumi Takemura, Kazue Matsuoka, Keiichi Yoshimoto, Keiya Miki, Kenji Yaginuma, Kitagawa Kiyoki, Kunihiro Shimoji, Kuniko Takayama, Machiko Oka, Makoto Tsuchida, Mamoru Oki, Manabu Ogura, Masahiro Kakihara, Masahiro Yanase, Masakazu Otsuka, Masami Hashimoto, Masanori Matsukawa, Masaru Mori, Masataka Fukue, Masatsugu Sato, Mayumi Yoshihara, Megumu Fukunaga, Morikuni Nishihira, Naofumi Ikeda, Naokazu Ueda, Naoyuki Odaguchi, Nobuyuki Aizawa, Norisato Ikebe, Noritomo Itami, Noriyuki Degawa, Noriyuki Okada, Sakae Ishii, Sakae Miyazato, Satoshi Funakoshi, Sawako Fukazawa, Shigeki Ando, Shigeki Toma, Shinji Hayashi, Shinji Kageyama, Shintaro Yano, Shoji Fujisawa, Taihei Yanagida, Takahiro Yajima, Takashi Udagawa, Takayuki Toyoyama, Takeshi Nakanishi, Taro Misaki, Tetsuya Makiishi, Toko Endo, Tomio Suzuki, Toru Hasegawa, Toru Kawai, Toru Shiratori, Toshiki Nishio, Toshiro Shibata, Toshiya Ishida, Toshiyuki Takahashi, Toyonori Saiki, Tsutomu Shikano, Yasufumi Takahashi, Yasuhiro Onodera, Yasuyuki Ushiogi, Yorihiro Akamatsu, Yoshihiko Otsubo, Yoshimi Shoji, Yosuke Saka
Journal: JAMA Network Open (2022)

<h3>Importance</h3> 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. <h3>Objective</h3> To determine the clinically recommended dose of difelikefalin, a κ-opioid receptor agonist, based on the efficacy, dose response, safety, and pharmacokinetics. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> 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. <h3>Main Outcome and Measures</h3> 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. <h3>Results</h3> 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;<i>P</i> = .04) and the 1.0 μg/kg of difelikefalin group (adjusted mean difference, −0.78; 95% CI, −1.54 to −0.03;<i>P</i> = .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. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03802617