From the Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Great Neck, NY (S.F.); North America Research Institute, San Dimas, CA (A.J.); and Cara Therapeutics, Stamford, CT (C.M., W.W., F.M.).
N Engl J Med. 2020 Jan 16;382(3):222-232. doi: 10.1056/NEJMoa1912770. Epub 2019 Nov 8.
Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease.
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients undergoing hemodialysis who had moderate-to-severe pruritus to receive either intravenous difelikefalin (at a dose of 0.5 μg per kilogram of body weight) or placebo three times per week for 12 weeks. The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). The secondary outcomes included the change from baseline in itch-related quality-of-life measures, the percentage of patients with an improvement of at least 4 points in the WI-NRS score at week 12, and safety.
A total of 378 patients underwent randomization. A total of 82 of 158 patients (51.9%) in the difelikefalin group had a decrease of at least 3 points in the WI-NRS score (primary outcome), as compared with 51 of 165 (30.9%) in the placebo group. The imputed percentage of patients with a decrease of at least 3 points in the WI-NRS score was 49.1% in the difelikefalin group, as compared with 27.9% in the placebo group (P<0.001). Difelikefalin also resulted in a significant improvement from baseline to week 12 in itch-related quality of life as measured by the 5-D itch scale and the Skindex-10 scale. The imputed percentage of patients with a decrease of at least 4 points in the WI-NRS score at week 12 was significantly greater in the difelikefalin group than in the placebo group (37.1% [observed data: 64 of 158 patients] vs. 17.9% [observed data: 35 of 165 patients], P<0.001). Diarrhea, dizziness, and vomiting were more common in the difelikefalin group than in the placebo group.
Patients treated with difelikefalin had a significant reduction in itch intensity and improved itch-related quality of life as compared with those who received placebo. (Funded by Cara Therapeutics; KALM-1 ClinicalTrials.gov number, NCT03422653.).
地氟烷是一种外周受限且选择性的κ阿片受体激动剂，被认为在调节慢性肾脏病等疾病的瘙痒中起重要作用。
在这项双盲、安慰剂对照、3 期试验中，我们将接受血液透析且有中重度瘙痒的患者随机分配，接受每周 3 次静脉注射地氟烷（剂量为 0.5μg/千克体重）或安慰剂，治疗 12 周。主要结局是在第 12 周时，每周平均 24 小时最严重瘙痒强度数字评定量表（WI-NRS；评分范围为 0 至 10，评分越高表示瘙痒强度越大）的基线下降至少 3 分的患者比例。次要结局包括瘙痒相关生活质量测量的基线变化、第 12 周时 WI-NRS 评分至少改善 4 分的患者比例以及安全性。
共有 378 名患者接受了随机分组。与安慰剂组（51.9%，165 例中有 82 例）相比，地氟烷组（51.9%，158 例中有 158 例）中至少有 3 分 WI-NRS 评分下降的患者比例更高（主要结局）。地氟烷组 WI-NRS 评分至少下降 3 分的患者比例为 49.1%，而安慰剂组为 27.9%（P<0.001）。地氟烷还显著改善了瘙痒相关的生活质量，这是通过 5-D 瘙痒量表和 Skindex-10 量表来衡量的。第 12 周时，地氟烷组 WI-NRS 评分至少下降 4 分的患者比例明显高于安慰剂组（37.1%[观察数据：158 例患者中 64 例]与 17.9%[观察数据：165 例患者中 35 例]，P<0.001）。地氟烷组腹泻、头晕和呕吐的发生率高于安慰剂组。
与接受安慰剂治疗的患者相比，接受地氟烷治疗的患者瘙痒强度显著降低，瘙痒相关的生活质量得到改善。（由 Cara Therapeutics 资助；KALM-1 ClinicalTrials.gov 编号，NCT03422653。）
