Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies

Abstract

Rationale & objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics.

Study design: In KALM-1 and KALM-2, participants were randomized (1:1) to receive intravenous difelikefalin or placebo 3 times/wk for 12 weeks, followed by a 52-week open-label extension.

Setting & participants: Adults with moderate to severe CKD-aP treated by HD in North America, Europe, and the Asia-Pacific region.

Intervention: Intravenous difelikefalin at 0.5 mcg/kg or placebo.

Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch-related QoL (Skindex-10 and 5-D Itch questionnaires).

Results: 851 participants were randomized (difelikefalin, n = 426; placebo, n = 425). This pooled analysis demonstrated early (week 1), sustained difelikefalin efficacy, with significantly greater achievement of ≥3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; P < 0.001). Achievement of a ≥4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; P < 0.001). Difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of ≥15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; P < 0.001) and ≥5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; P = 0.01), with sustained 5-D Itch effects up to 64 weeks.

Limitations: Subgroup samples were small. The WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin.

Conclusions: Difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD.

Funding: Cara Therapeutics, Inc.

Trial registration: The KALM-1 trial is registered as NCT03422653 and the KALM-2 trial is registered as NCT03636269.

Keywords: Chronic kidney disease; difelikefalin; efficacy; pruritus; κ-opioid receptor.

Graphical abstract

Figure 1

Participant dispositions in the pooled KALM-1 and KALM-2 studies. There were 2 participants in the placebo group and 3 participants in the difelikefalin group who discontinued due to a lack of eligibility after randomization.

Figure 2

Proportions of participants with (A) A ≥3-point reduction in the weekly mean of the daily Worst Itching Intensity Numerical Rating Scale (WI-NRS) scores over 12 weeks, (B) A ≥4-point reduction in the weekly mean of the daily WI-NRS scores over 12 weeks, and (C) ≥3-point and ≥4-point reductions in weekly mean WI-NRS scores at week 12. ∗P < 0.05 and ∗∗P < 0.001 difelikefalin versus placebo. Differences between placebo and difelikefalin with respect to proportions were analyzed using a logistic regression model with terms for the treatment group, baseline WI-NRS score, use of an anti-itch medication during the week before randomization, presence of specific medical conditions, and geographic region. Missing weekly WI-NRS scores were imputed by multiple imputation under a missing-at-random assumption. Abbreviations: CI, confidence interval; LS, least squares; WI-NRS, Worst Itching Intensity Numerical Rating Scale.

Figure 3

Achievement of complete response on the Worst Itching Intensity Numerical Rating Scale (WI-NRS) over 12 weeks. ∗P < 0.05 and ∗∗P < 0.001 difelikefalin versus placebo. A complete response was defined as ≥80% of daily WI-NRS scores being equal to 0 or 1 for the preceding week. Differences between placebo and difelikefalin with respect to proportions were analyzed using a logistic regression model containing terms for the treatment group, baseline WI-NRS score, use of an anti-itch medication during the week before randomization, presence of specific medical conditions, and geographic region. Missing weekly WI-NRS scores were imputed by multiple imputation under a missing-at-random assumption. Abbreviations: CI, confidence interval; LS, least squares; WI-NRS, Worst Itching Intensity Numerical Rating Scale.

Figure 4

Achievement of clinically meaningful improvements in (A) Skindex-10 and (B) 5-D Itch total scores over 12 weeks. ∗P ≤ 0.05 and ∗∗P ≤ 0.001 difelikefalin versus placebo. Differences between placebo and difelikefalin with respect to proportions were analyzed using a logistic regression model containing terms for the treatment group, baseline score, use of an anti-itch medication during the week before randomization, presence of specific medical conditions, and geographic region. Missing values were not imputed. Clinically meaningful thresholds were determined as ≥15-point reductions in Skindex-10 and ≥5-point reductions in 5-D Itch total scores (unpublished data). Abbreviations: CI, confidence interval; LS, least squares.

Figure 5

Achievement of a ≥5-point improvement in 5-D Itch total score in the pooled KALM-1 and KALM-2 studies. Data given as n and N indicate the number of participants who achieved a ≥5-point improvement in the 5-D Itch total score and the total number of participants assessed at each time point, respectively. Data as observed. ∗Week 12 of the double-blind period and week 1 of the open-label extension period, during which participants taking placebo during the double-blind period switched to active treatment with difelikefalin. In KALM-2, in addition to the participants who discontinued from the open-label extension period, 313 of 399 (78.4%) participants could not complete the 52-week open-label extension period because of the sponsor’s decision to stop the study for reasons unrelated to safety or a lack of drug effects. A 2-week discontinuation following the end of the double-blind period of KALM-1 is not pictured in the figure. Abbreviation: OLE, open-label extension.

Figure 6

Subgroup analyses for ≥3-point Worst Itching Intensity Numerical Rating Scale (WI-NRS) responses at week 12. ∗Prior gabapentinoid use values include participants who used gabapentin or pregabalin for any condition, including itch. Differences between placebo and difelikefalin with respect to proportions were analyzed using a logistic regression model containing terms for the treatment group, baseline WI-NRS score, use of an anti-itch medication during the week before randomization, presence of specific medical conditions, and geographic region. Missing weekly WI-NRS scores were imputed by multiple imputation under a missing-at-random assumption. Abbreviations: CI, confidence interval; OR, odds ratio; WI-NRS, Worst Itching Intensity Numerical Rating Scale.