Introduction: Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. Methods: This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-h Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex‑10. Results: There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n = 135 difelikefalin; n = 114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (p < 0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs. 35.7%; p = 0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs. 28.9%; p = 0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). Conclusion: In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

Difelikefalin is approved in the USA and Europe for the treatment of moderate-to-severe CKD-aP in patients undergoing HD [1, 2]. Difelikefalin was well tolerated, reduced itch intensity, and improved itch-related quality of life (QoL) versus placebo in pooled Phase 3 (KALM-1 and -2) analyses [3, 4].

Black/AA people are over-represented in the US kidney failure population (34.1% of patients undergoing HD are Black/AA compared with 37.2% White patients, 20.4% Hispanic patients, and 4.9% Asian patients) [5]; therefore, it is important to evaluate the safety and efficacy of therapies in this population. Here, we report a pooled post hoc subgroup analysis of the KALM studies to evaluate the safety and efficacy of difelikefalin in Black/AA patients with CKD undergoing HD with moderate-to-severe pruritus.

KALM-1 and KALM-2 Study Designs

Details of the KALM-1 (NCT03422653) and KALM-2 (NCT03636269) studies have been previously reported [6, 7]. In both studies, patients completed a 7-day run-in to confirm they had moderate-to-severe pruritus (weekly average 24-h WI-NRS score ≥4 [KALM-1] or ≥5 [KALM-2]). Patients were then randomized (1:1; N = 851) to receive either IV difelikefalin 0.5 μg/kg or placebo post-dialysis for 12 weeks.

Study Endpoints and Assessments for Subgroup Analysis

This post hoc analysis of Black/AA and White patients was performed using pooled data from KALM-1 and -2 studies. The KALM efficacy outcome analyzed was the proportion of patients achieving a clinically meaningful ≥3-point improvement [8] from baseline in weekly mean of daily 24-h WI-NRS score at week 12. Key secondary efficacy endpoints were proportion of patients achieving a ≥4-point improvement in WI-NRS from baseline to week 12, and proportion achieving a clinically meaningful improvement in total 5-D itch scale score, and total Skindex-10 score (≥5- and ≥15-point reductions, respectively) [4].

Other efficacy endpoints analyzed included: mean change from baseline in WI-NRS score at each week of the double-blind treatment period; mean change from baseline in each of the 5-D itch domain scores and each of the Skindex-10 domain scores at week 12.

Safety endpoints analyzed were adverse events (AEs), clinical laboratory test results, and vital sign measurements. Details of the statistical analysis for subgroup analysis are described in the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000534227).

Patient Characteristics

In the Black/AA subgroup, 112 (83.0%; difelikefalin) and 106 (93.0%; placebo) patients completed the 12-week double-blind treatment period (online suppl. Fig. 1); the most common reason for study discontinuation was AEs (8.1% [n = 11] difelikefalin and 3.5% [n = 4] placebo). In the White subgroup, 92.4% (n = 242, difelikefalin) and 88.2% (n = 225, placebo) of patients completed the treatment period, with discontinuation due to AEs reported in 4.7% (n = 12 difelikefalin) and 3.8% (n = 10 placebo).

Baseline characteristics were generally balanced between the difelikefalin and placebo subgroups. Notable differences included higher mean body weight and use of anti-itch medication (diphenhydramine) in Black/AA patients, and higher hypertension, glomerulonephritis, and cystic disease CKD etiologies in White patients (online suppl. Table S1).

Efficacy

Worst Itch Numerical Rating Scale

The least squares (LS) mean percentage of Black/AA patients who achieved a ≥3-/≥4-point reduction in WI-NRS score at week 12 was 47.9% with difelikefalin versus 24.6% with placebo (odds ratio [OR]: 2.82, 95% confidence interval [CI]: 1.63, 4.87; p < 0.001) and 35.8% versus 17.0% (OR 2.72, 95% CI: 1.47, 5.01; p = 0.001), respectively. Similar results were found in the White subgroup (Fig. 1a and online suppl. Table S2). Treatment effect on WI-NRS was sustained from week 2 to week 12 in both subgroups (Fig. 1b).

Fig. 1.

a Proportion of patients achieving ≥3-point improvement and ≥4-point improvement in WI-NRS scores at week 12 (ITT).ab Mean change from baseline in weekly WI-NRS score over 12 weeks.bc Proportion of patients achieving clinically meaningful improvements in 5-D itch total scores.cd Proportion of patients achieving clinically meaningful improvements in Skindex-10 at week 12 (ITT population).c *p < 0.05; p < 0.01; p < 0.001 versus placebo. Missing data were imputed using multiple imputation under a missing at random assumption. aDifferences between difelikefalin and placebo were analyzed by a logistic regression model with terms for treatment group, baseline WI-NRS score, use of anti-itch medication during the week prior to randomization, presence of specific medical conditions, and region/study. bData represent least-squares mean ± SE. Differences between difelikefalin and placebo were analyzed using a mixed model with repeated measures with effects for treatment, visit, treatment-by-visit interaction, baseline WI-NRS score, use of anti-itch medication during the week prior to randomization, the presence of specific medical conditions, and region/study. The model was fit using an unstructured covariance structure. cDifferences between difelikefalin and placebo were analyzed by a logistic regression model with terms for treatment group, baseline score, use of anti-itch medication during the week prior to randomization, presence of specific medical conditions, and region/study. Missing values were not imputed. CI, confidence interval; ITT, intent-to-treat; LS, least squares; OR, odds ratio; SE, standard error; WI-NRS, Worst Itch Numeric Rating Scale.

Fig. 1.

a Proportion of patients achieving ≥3-point improvement and ≥4-point improvement in WI-NRS scores at week 12 (ITT).ab Mean change from baseline in weekly WI-NRS score over 12 weeks.bc Proportion of patients achieving clinically meaningful improvements in 5-D itch total scores.cd Proportion of patients achieving clinically meaningful improvements in Skindex-10 at week 12 (ITT population).c *p < 0.05; p < 0.01; p < 0.001 versus placebo. Missing data were imputed using multiple imputation under a missing at random assumption. aDifferences between difelikefalin and placebo were analyzed by a logistic regression model with terms for treatment group, baseline WI-NRS score, use of anti-itch medication during the week prior to randomization, presence of specific medical conditions, and region/study. bData represent least-squares mean ± SE. Differences between difelikefalin and placebo were analyzed using a mixed model with repeated measures with effects for treatment, visit, treatment-by-visit interaction, baseline WI-NRS score, use of anti-itch medication during the week prior to randomization, the presence of specific medical conditions, and region/study. The model was fit using an unstructured covariance structure. cDifferences between difelikefalin and placebo were analyzed by a logistic regression model with terms for treatment group, baseline score, use of anti-itch medication during the week prior to randomization, presence of specific medical conditions, and region/study. Missing values were not imputed. CI, confidence interval; ITT, intent-to-treat; LS, least squares; OR, odds ratio; SE, standard error; WI-NRS, Worst Itch Numeric Rating Scale.

Close modal

5-D Itch Scale

The proportion of patients who achieved a clinically meaningful improvement in 5-D itch total score at week 12 was greater in the Black/AA subgroup with difelikefalin versus placebo (54.9% vs. 35.7%; OR: 2.18 [95% CI: 1.18, 4.03], p = 0.013), compared with the White subgroup (39.1% vs. 49.4%; OR 1.52 [95% CI: 1.03, 2.25], p = 0.037) (Fig. 1c).

Black/AA patients reported improvements with difelikefalin versus placebo in 5-D itch total score at week 12, with LS mean (standard error [SE]) reductions from baseline to week 12 of −3.8 (0.7) versus −2.2 (0.7), respectively (LS mean treatment difference: −1.6 [95% CI: −2.5, −0.6]; p < 0.001) (online suppl. Table S2), with similar results in the White subgroup (LS mean treatment difference: −1.2 [95% CI –1.9, −0.6], p < 0.001).

Skindex-10 Scale

Clinically meaningful improvement from baseline in total Skindex-10 score at Week 12 with difelikefalin versus placebo was 49.0% versus 28.9% for the Black/AA subgroup (OR: 2.36 [95% CI: 1.28, 4.36]; p = 0.006) (Fig. 1d), 36.9% versus 52.6% for the White subgroup (OR: 1.90 [95% CI: 1.26, 2.86]; p = 0.002) (Fig. 1d).

In Black/AA patients, the LS mean (SE) change in Skindex-10 total score from baseline to week 12 was −11.3 (2.5) with difelikefalin versus −8.5 (2.5) with placebo (LS mean treatment difference −2.8 [95% CI: −6.2, 0.7]; p = 0.115). Similar results were found in the White subgroup (LS mean treatment difference: −4.0 [95% CI: −6.4, −1.6], p = 0.001) (online suppl. Table S2). Evaluation of the Skindex-10 itch-related domains showed numerically greater improvements with difelikefalin versus placebo for all three domains in both subgroups (online suppl. Table S2).

Safety

The overall incidence of TEAEs in both treatment groups was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%), compared with White patients (difelikefalin: 64.8%; placebo: 61.8%) (online suppl. Table S3).

The most frequent AEs (≥5% of the Black/AA population and ≥1% higher than placebo) reported with difelikefalin were similar between the Black/AA and White subgroups (online suppl. Table S3), with most AEs being mild–moderate in severity. Nonfatal serious AEs occurred in 32.6% (difelikefalin) and 27.4% (placebo) in the Black/AA subgroup (online suppl. Table S3); none were considered by the investigator to be related to difelikefalin treatment.

Among Black/AA patients, TEAEs leading to treatment discontinuation occurred in 9.6% (difelikefalin) and 3.5% (placebo) of patients (online suppl. Table S4). The most common AEs that led to treatment discontinuation with difelikefalin were dizziness (2/135) and mental status changes (2/135) (online suppl. Table S4). All AEs leading to treatment discontinuation were considered unrelated to study drug aside from dizziness and constipation (n = 2).

One Black/AA patient in each treatment group experienced sepsis during the 12-week treatment period, which led to death. No clinically relevant differences were observed between the difelikefalin and placebo treatment groups in laboratory parameters or vital signs in Black/AA patients.

This post hoc subgroup analysis of the pooled KALM-1 and -2 studies showed that treatment with difelikefalin reduced itch intensity and was well tolerated in both White and Black/AA patients with moderate-to-severe CKD-aP undergoing HD.

While a placebo response for WI-NRS was observed in both subgroups, higher WI-NRS response rates were reported in difelikefalin-treated patients. Additionally, more patients had clinically significant improvements in itch-related QoL (5-D itch and Skindex-10) in Black/AA patients treated with difelikefalin versus placebo. In both itch severity and QoL, the placebo response was lower in Black/AA than White patients, which may be a result of racial disparities in access to medical care and patient-physician communication [9].

Diphenhydramine use was more than twice as high in the Black/AA subgroup than in the White subgroup. Further investigation is required to elucidate why Black/AA patients are exposed to systemic antihistamines at double the prevalence of White patients.

The safety profile of difelikefalin in Black/AA patients was generally consistent with the White patient group; however, the AEs within the difelikefalin and placebo groups of the Black/AA patient subgroup were slightly higher than in the White population. The incidence of Black/AA patients who discontinued the study owing to AEs was higher (although still relatively low) with difelikefalin than placebo.

Black/AA patients were well-represented in the KALM studies overall. However, the number of patients (n = 249) meant this subgroup analysis was underpowered. This post hoc subgroup analysis of the pooled KALM-1 and -2 data indicated that difelikefalin treatment reduced itch intensity and provided clinically meaningful improvements in itch-related QoL among Black/AA populations undergoing HD with moderate-to-severe pruritus, consistent with the White patient population.

Medical writing support was provided by AXON Communications (London, United Kingdom) and funded by CSL Vifor.

KALM-1 and KALM-2 were both conducted in accordance with principles of the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice and applicable regulations of all countries with participating study sites. Study protocols were reviewed and approved by Institutional Review Boards before the studies commenced (KALM-1: Schulman IRB, approval number 201709004; KALM-2: WCB IRB, approval number 20181326). All patients provided written informed consent prior to participating in the study.

S.F. reports receipt of grants from Cara Therapeutics, Inc. D.J.C. has no conflicts of interest to declare. E.V.L. reports speaker/advisory board/steering committee involvements with Akebia, AstraZeneca, Bayer, GlaxoSmithKline, Otsuka, Travere Therapeutics, and CSL Vifor. A.R. reports advisory board participation and speakers bureau fees from AstraZeneca and Relypsa Inc, and research grants from AstraZeneca. J.B. reports that they are an employee and shareholder of CSL Vifor. I.M. reports that they are an employee and shareholder of CSL Vifor. W.W. reports that they are an employee and shareholder of Cara Therapeutics, Inc. F.M. reports that they are an employee and shareholder of Cara Therapeutics, Inc. J.T. reports advisory board membership for Cara Therapeutics, Inc.

This analysis was funded by CSL Vifor. The research and clinical trial studies were sponsored by Cara Therapeutics, Inc.

All authors participated in the data analysis and preparation of the manuscript and approved the final manuscript for publication. Research idea and study design: Frédérique Menzaghi, Jeffrey Budden, Steven Fishbane, Warren Wen; data acquisition: Jeffrey Budden, Joel Topf, Isabelle Morin, Steven Fishbane; data analysis and interpretation: Anjay Rastogi, Deborah J. Clegg, Edgar V. Lerma, Steven Fishbane, Frédérique Menzaghi, Jeffrey Budden, Warren Wen, and Isabelle Morin. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Additional Information

Trial Registration: KALM-1 (NCT03422653) and KALM-2 (NCT03636269).

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author [S.F.]. Further inquiries can be directed to the corresponding author [S.F.].

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