Pruritus Severity and Serum Phosphate in CKD: A Post Hoc Analysis of Difelikefalin Studies

Abstract

Key Points:

1. No correlation was observed between pruritus severity and serum phosphate or response to placebo or difelikefalin in patients with CKD-associated pruritus undergoing hemodialysis.

2. Difelikefalin improved itch versus placebo irrespective of baseline serum phosphate.

Background: CKD-associated pruritus (CKD-aP) has historically been associated with elevated serum phosphate (sP). Difelikefalin is a novel antipruritic agent approved for the treatment of moderate-to-severe CKD-aP in adults undergoing hemodialysis. This post hoc analysis used data from phase 3 difelikefalin studies (KALM-1, KALM-2, and open-label Study 3105) to assess the role of sP in the pathogenesis of CKD-aP and whether difelikefalin ameliorates CKD-aP in patients with and without elevated sP.

Methods: Patients with moderate-to-severe CKD-aP undergoing hemodialysis with baseline sP data were included in the analysis (KALM-1 and KALM-2, n=845; Study 3105, n=220). Assessments included correlation between 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) score and sP.

Results: In KALM-1 and KALM-2, baseline characteristics in the overall population were similar between patients with sP ≤5.5 and >5.5 mg/dl; no significant correlation was observed between WI-NRS and sP at baseline or in week 12. In patients receiving placebo, no correlation was observed between WI-NRS and sP at baseline or between their change from baseline to week 12 (all P < 0.05). Clinically meaningful (≥3-point) reductions from baseline to week 12 in WI-NRS scores were reported by more patients receiving placebo with baseline sP ≤5.5 mg/dl than >5.5 mg/dl (least squares mean 37.2% versus 27.4%; odds ratio [95% confidence interval], 0.63 [0.41 to 0.97]; P = 0.04). A greater proportion of patients treated with difelikefalin achieved a ≥3-point WI-NRS reduction from baseline to week 12 versus placebo and was similar between sP ≤5.5 and >5.5 mg/dl subgroups (least squares means 51.1% versus 57.6% [P = 0.20]). No significant relationships between sP and WI-NRS in patients receiving difelikefalin were identified in Study 3105 at any time point.

Conclusions: No correlation was observed between pruritus severity and sP or response to placebo or difelikefalin in patients with CKD-aP undergoing hemodialysis. Difelikefalin improved itch versus placebo irrespective of baseline sP.

Trial registration: ClinicalTrials.gov NCT03422653 NCT03636269 NCT03998163.

Graphical abstract

Figure 1

Correlation between WI-NRS and sP at baseline at various time points from KALM-1 and KALM-2 (overall population, including difelikefalin and placebo arms). (A) Baseline WI-NRS score by baseline sP, (B) week 12 WI-NRS score by baseline sP, and (C) week 12 WI-NRS score by week 12 sP. Correlation shows the Pearson correlation coefficient. sP, serum phosphate; WI-NRS, 24-hour Worst Itching Intensity Numerical Rating Scale.

Figure 2

Correlation between WI-NRS by change in sP from baseline to week 12 across different populations from KALM-1 and KALM-2. Change in WI-NRS by change in sP from baseline to week 12 in the (A) overall population (placebo and difelikefalin arms), (B) difelikefalin, or (C) placebo arms. Correlation shows the Pearson correlation coefficient.

Figure 3

KALM-1 and KALM-2: proportion of patients achieving a clinically meaningful (≥3- or ≥4-point) reduction from baseline to week 12 in WI-NRS score by treatment arm and baseline sP subgroup. A logistic regression model was used to calculate estimated percentages, ORs, and P values. This model considered terms for baseline phosphate group, baseline WI-NRS score, use of anti-itch medication during the week before randomization, the presence of specific medical conditions, and region/study-combined variables. For the pooled data analysis, the treatment group was also included in the model. CI, confidence interval; LS, least squares; OR, odds ratio.

Figure 4

Correlation between WI-NRS and sP at baseline at various time points from Study 3105 (difelikefalin only [open-label trial]). (A) baseline WI-NRS score by baseline sP, (B) week 12 WI-NRS score by baseline sP, (C) week 12 WI-NRS score by week 12 sP, and (D) change in WI-NRS and change in sP from baseline to week 12.