Efficacy and safety of anrikefon in patients with pruritus undergoing haemodialysis: multicentre, double blind, randomised placebo controlled phase 3 trial

Abstract

Objective: To evaluate the efficacy and safety of anrikefon (formerly known as HSK21542), a novel selective peripherally restricted kappa opioid receptor agonist, in patients with chronic kidney disease associated pruritus.

Design: Multicentre, double blind, randomised placebo controlled phase 3 trial.

Setting: 50 centres in China, June 2022 to June 2024.

Participants: 652 patients with moderate to severe CKD associated pruritus undergoing haemodialysis were screened: 545 were randomly assigned (1:1 ratio) to receive either anrikefon (n=275) or placebo (n=270).

Interventions: Intravenous anrikefon (0.3 μg/kg body weight) or placebo three times weekly for 12 weeks, followed by an optional open label extension phase with anrikefon treatment for 40 weeks.

Main outcome measures: The primary endpoint was the percentage of patients achieving at least a 4 point reduction in weekly mean 24 hour worst itching intensity numerical rating scale (WI-NRS) score from baseline to week 12. Secondary outcomes were the percentage of patients achieving at least a 3 point reduction in weekly mean WI-NRS score from baseline to week 12, as well as changes in itch related quality of life from baseline using the Skindex-10 and 5-D itch scales. The change in itch related quality of life from baseline to week 40 of open label treatment was also reported using the 5-D itch scale. The safety of anrikefon was evaluated throughout the trial.

Results: 243/275 (88%) patients in the anrikefon group and 254/270 (94%) in the placebo group completed the 12 week double blind treatment. 443 subsequently entered the 40 week open label extension phase. 37% of patients in the anrikefon group showed at least a 4 point reduction in WI-NRS score at week 12 compared with 15% in the placebo group (P<0.001). The percentage of patients with at least a 3 point reduction in WI-NRS score from baseline to week 12 was 51% in the anrikefon group compared with 24% in the placebo group (P<0.001). The anrikefon group showed significant improvements in itch related quality of life (mean change from baseline in 5-D itch scale -5.3 v -3.1, P<0.001 and in Skindex-10 scale -15.2 v -9.3, P<0.001). Anrikefon also showed sustained long term efficacy during the open label extension phase at week 40, with persistent improvement in quality of life scores on the 5-D itch scale. Mild to moderate dizziness was more common in the anrikefon group than placebo group but without evident clinical consequences.

Conclusions: In patients with moderate to severe pruritus undergoing haemodialysis, anrikefon was found to be safe and resulted in a noticeable reduction in itch intensity and an improvement in itch related quality of life.

Trial registration: ClinicalTrials.gov NCT05135390.

Fig 1

Overall study design of phase 3 clinical trial of anrikefon in patients with moderate to severe pruritus undergoing haemodialysis. *Visit dates coincided with patients’ regular dialysis days, with at least one day between each of the planned visits. WI-NRS=worst itching intensity numerical rating scale

Fig 2

Patient flow chart. *Patients could have multiple reasons for being excluded during screening. †Participants missed three consecutive doses of study drug in either week 11 or week 12 or missed six consecutive doses of study drug throughout the entire treatment period. ‡Deaths due to disease progression during treatment period

Fig 3

Proportion of patients in anrikefon and placebo groups at week 12 with at least a 4 point reduction from baseline in weekly mean 24 hour WI-NRS score (A) and at least a 3 point reduction from baseline in weekly mean WI-NRS score (B). Mean change from baseline in Skindex-10 scale (C) and 5-D itch scale (D) total score at 12 weeks. The Skindex-10 scale is a validated instrument designed to measure the impact of skin disease on patients’ quality of life. The 5-D itch scale measures five dimensions of itch: degree, duration, direction, disability, and distribution. Whiskers represent standard errors. P values were calculated using χ² test (A and B) and analysis of covariance (C and D). WI-NRS=worst itching intensity numerical rating scale

Fig 4

Mean change from baseline in 24 hour WI-NRS score over 12 weeks in anrikefon and placebo groups. Whiskers represent 95% confidence intervals. WI-NRS=worst itching intensity numerical rating scale

Fig 5

Mean change from baseline in Skindex-10 total score over 12 weeks in anrikefon and placebo groups. Whiskers represent 95% confidence intervals

Fig 6

Mean change from baseline in 5-D itch total score over 52 weeks. Whiskers represent 95% confidence intervals