Abstract
Key Points
No correlation was observed between pruritus severity and serum phosphate or response to placebo or difelikefalin in patients with CKD-associated pruritus undergoing hemodialysis.
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.
Keywords: CKD, hemodialysis, hyperphosphatemia, patient satisfaction, patient self-assessment, quality of life, randomized controlled trials
Visual Abstract
Introduction
CKD-associated pruritus (CKD-aP) is an important and common condition that is under-recognized and under-reported in patients with kidney failure, including in those undergoing hemodialysis.1,2 The prevalence of moderate-to-severe itching in patients undergoing hemodialysis varies, but it is estimated to affect 26%–48% of patients.1,3,4 CKD-aP has a substantial negative effect on sleep quality and quality of life (QoL) and is also associated with depression.1,3
Despite the prevalence and effect to patients, the pathophysiology of CKD-aP remains unknown but is believed to be multifactorial.5,6 Toxin accumulation and deposition, particularly inadequate serum phosphate (sP), have historically been identified as potential causes.6 As such, CKD-aP was originally being termed uremic pruritus because triggers were believed to include uremia-related abnormalities.6 Other potential contributors to CKD-aP etiology include peripheral neuropathy, immune system dysregulation, and opioid dysregulation,7 although the cause(s) remain unclear.8 While some studies have shown a link between calcium-phosphate product or sP and pruritus in patients on hemodialysis,9–11 other studies have reported little to no correlation between sP levels and pruritus.1,12–15
Initial data from a Disease Outcomes and Practice Patterns Study (DOPPS) in 2006 indicated strong associations between worse severity of itch and sP ≥5.5 mg/dl,16 as did a recent QoL study in 269 patients with CKD-aP, which reported a positive association between sP and pruritus severity measured by the 5D-itch scale.17 Lower sP, along with higher residual kidney function, has also been associated with a lower burden of CKD-aP 12 months after initiation of hemodialysis.18 By contrast, analyses from the 2012–2015 DOPPS data from 17 countries did not show an association between itch severity and sP ≥5.5 mg/dl,1 which is also supported by other recent studies.12–15 As such, further studies are required to understand the role of phosphate metabolism in the pathogenesis of CKD-aP, the potential relationship between elevated sP and CKD-aP, and the response to treatment.
Difelikefalin is a novel antipruritic agent approved for the treatment of moderate-to-severe CKD-aP in adults undergoing hemodialysis in territories including the United States and the European Union.19,20 Two placebo-controlled studies (KALM-1 and KALM-2) and one open-label study (Study 3105) were conducted to evaluate the efficacy and safety of intravenous difelikefalin for the treatment of CKD-aP in patients undergoing hemodialysis.21–24 In these studies, difelikefalin significantly reduced itch intensity and improved itch-related QoL versus placebo.21,23,24 The data from these studies provide an opportunity to assess the relationship between a validated patient-reported outcome, the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS), and sP levels in a multicenter, controlled clinical trial setting with collection of itch intensity at baseline and after 12 weeks. In addition, these data provide an opportunity to evaluate whether response to difelikefalin varies depending on sP.
Therefore, this post hoc analysis used data from phase 3 studies (KALM-1, KALM-2, and Study 3105) and aimed to assess the role of sP in the pathogenesis of CKD-aP and whether difelikefalin improves CKD-aP in patients undergoing hemodialysis with and without elevated sP.
Methods
Studies
This is a post hoc analysis of data collected in two randomized, placebo-controlled phase 3 studies (KALM-1 and -2) and one open-label, single-arm study (Study 3105). Detailed methods of the studies (NCT03422653, NCT03636269, and NCT03998163, respectively) have previously been described.21–24
In brief, KALM-1 and KALM-2 were multicenter, double-blind, placebo-controlled studies in patients with moderate-to-severe CKD-aP undergoing hemodialysis, randomized to receive 0.5 µg/kg difelikefalin (n=426) or placebo (n=425) three times per week (following each hemodialysis session) for 12 weeks, with an additional open-label extension of 52 weeks.21–23 Inclusion criteria were a weekly mean WI-NRS score of >4 (KALM-1) or ≥5 (KALM-2) during the 7-day run-in period (scores ranged from 0 to 10, with higher scores indicating greater itch intensity).23 The patients were from the United States in KALM-1 and from Australia, Canada, Europe, New Zealand, South Korea, Taiwan, and the United States in KALM-2.22
Study 3105 was a multicenter, open-label, single-arm study of patients with moderate-to-severe CKD-aP (WI-NRS weekly mean score ≥5) undergoing hemodialysis treated with intravenous difelikefalin 0.5 µg/kg, three times per week (following each hemodialysis session) for 12 weeks (N=222).24 Itch intensity was evaluated by the weekly mean WI-NRS score. Patients were from Czech Republic, Hungary, Poland, and the United States.24
All three phase 3 studies were conducted in accordance with the principles of the Declaration of Helsinki. Institutional review boards or independent ethics committees reviewed and approved the protocols before studies were commenced (approval numbers available on request).21–24
In all three studies, the proportion of patients reporting clinically meaningful reductions (≥3-point reduction) from baseline in WI-NRS or more (≥4-point reduction) was determined.21–24 While least squares (LS) mean is reported for KALM-1 and -2 data, mean is reported for Study 3105 owing to the stratification factors that were adjusted for in the statistical analysis of KALM-1 and -2 but not for the open-label Study 3105. Outcomes from these studies have been previously reported.21–24
Analysis by Baseline sP
In this analysis, patient-level data from the randomized, placebo-controlled KALM-1 and KALM-2 studies and the open-label study 3105 were used and results reported separately. Patients were divided on the basis of their individual baseline predialysis sP levels—with baseline defined as the last nonmissing measurement observed before the first dose of the study treatment—into either sP ≤5.5 mg/dl or sP >5.5 mg/dl. A cutoff of 5.5 mg/dl for sP was chosen on the basis of DOPPS findings, which indicated strong associations between worse severity of itch and sP >5.5 mg/dl.16 Correlations between WI-NRS score and sP at baseline and week 12 and change in WI-NRS by change in sP from baseline to week 12 were assessed for all studies using Pearson correlation analysis. For the KALM-1 and KALM-2 studies, the proportions of patients in each subgroup achieving a ≥3- or ≥4-point change from baseline in WI-NRS score were also assessed in each treatment group with a logistic regression model with terms for baseline sP subgroup, baseline WI-NRS score, use of anti-itch medication during the week before randomization, the presence of specific medical conditions, and a region/study-combined variable. Additional logistic regression analyses were performed for each sP subgroup including terms for treatment group, baseline WI-NRS score, use of anti-itch medication during the week before randomization, the presence of specific medical conditions, and a region/study-combined variable. Missing values were imputed using a multiple imputation under missing at random missing data assumption. Because this is a post hoc analysis, all P values are exploratory and should be interpreted descriptively.
Results
KALM-1 and KALM-2
Baseline Demographics and Characteristics
In total, 845 patients in the KALM-1 and -2 studies had a baseline phosphate measurement and were included in the analyses (Table 1). Approximately half (438 [51.8%]) of the patients in these studies had a baseline sP measurement ≤5.5 mg/dl; 407 patients (48.2%) had baseline sP >5.5 mg/dl. Demographics and characteristics were generally similar between sP subgroups in the overall population (including placebo and difelikefalin treatment arms) at baseline and were consistent across sP subgroups in the individual placebo and difelikefalin treatment arms (Table 1). However, in the overall population, patients with baseline sP ≤5.5 versus >5.5 mg/dl were older (mean [SD] 61.0 years [12.6], versus 56.2 years [12.8]), were more likely to be of Hispanic or Latino ethnicity (34.0% versus 29.2%) (Table 1), and were more likely to reside in the United States (79.2% versus 75.2%). Prescription dry body weight was also lower in patients with baseline sP ≤5.5 mg/dl than >5.5 mg/dl (80.78 versus 85.05 kg) (Table 1). In addition, the duration of pruritus, years since diagnosis of CKD and ESKD, and years undergoing chronic hemodialysis were all similar across sP subgroups. Patients in baseline sP ≤5.5 versus >5.5 mg/dl had similar use of anti-itch medications at baseline (37.9% versus 38.1%) (Table 1).
Table 1.
KALM-1 and KALM-2: patient demographics and characteristics by treatment arm and baseline serum phosphate subgroups
| Characteristic | Placebo | Difelikefalin | Overall | |||
|---|---|---|---|---|---|---|
| Baseline sP ≤5.5 mg/dl (n=213) | Baseline sP >5.5 mg/dl (n=209) | Baseline sP ≤5.5 mg/dl (n=225) | Baseline sP >5.5 mg/dl (n=198) | Baseline sP ≤5.5 mg/dl (n=438) | Baseline sP >5.5 mg/dl (n=407) | |
| Age, yr | ||||||
| Mean (SD) | 60.2 (13.4) | 56.5 (13.4) | 61.7 (11.7) | 55.9 (12.2) | 61.0 (12.6) | 56.2 (12.8) |
| Range (min–max) | (24–88) | (24–86) | (23–87) | (22–84) | (23–88) | (22–86) |
| Age group, n (%) | ||||||
| <75 | 183 (85.9) | 185 (88.5) | 195 (86.7) | 185 (93.4) | 378 (86.3) | 370 (90.9) |
| <65 | 134 (62.9) | 154 (73.7) | 127 (56.4) | 154 (77.8) | 261 (59.6) | 308 (75.7) |
| <45 | 28 (13.1) | 35 (16.7) | 13 (5.8) | 37 (18.7) | 41 (9.4) | 72 (17.7) |
| Sex, n (%) | ||||||
| Male | 126 (59.2) | 130 (62.2) | 126 (56.0) | 121 (61.1) | 252 (57.5) | 251 (61.7) |
| Ethnicity, n (%) | ||||||
| Hispanic or Latino | 70 (32.9) | 66 (31.6) | 79 (35.1) | 53 (26.8) | 149 (34.0) | 119 (29.2) |
| Not Hispanic or Latino | 142 (66.7) | 142 (67.9) | 143 (63.6) | 142 (71.7) | 285 (65.1) | 284 (69.8) |
| Not reported | 1 (0.5) | 1 (0.5) | 2 (0.9) | 0 | 3 (0.7) | 1 (0.2) |
| Unknown | 0 | 0 | 1 (0.4) | 3 (1.5) | 1 (0.2) | 3 (0.7) |
| Region, n (%) | ||||||
| United States | 164 (77.0) | 155 (74.2) | 183 (81.3) | 151 (76.3) | 347 (79.2) | 306 (75.2) |
| Rest of the world | 49 (23.0) | 54 (25.8) | 42 (18.7) | 47 (23.7) | 91 (20.8) | 101 (24.8) |
| Asia | 5 (2.3) | 7 (3.3) | 6 (2.7) | 2 (1.0) | 11 (2.5) | 9 (2.2) |
| Eastern Europe | 24 (11.3) | 36 (17.2) | 23 (10.2) | 30 (15.2) | 47 (10.7) | 66 (16.2) |
| Western Europe/European origin | 20 (9.4) | 11 (5.3) | 13 (5.8) | 15 (7.6) | 33 (7.5) | 26 (6.4) |
| Baseline WI-NRSa | ||||||
| Mean (SD) | 7.1 (1.5) | 7.2 (1.4) | 7.1 (1.3) | 7.2 (1.5) | 7.1 (1.4) | 7.2 (1.5) |
| Range (min–max) | (4.1–10.0) | (4.1–10.0) | (4.2–10.0) | (4.3–10.0) | (4.1–10.0) | (4.1–10) |
| Baseline anti-itch medication use?b, n (%) | ||||||
| Yes | 85 (39.9) | 78 (37.3) | 81 (36.0) | 77 (38.9) | 166 (37.9) | 155 (38.1) |
| Specific medical conditions?c, n (%) | ||||||
| Yes | 41 (19.2) | 24 (11.5) | 38 (16.9) | 28 (14.1) | 79 (18.0) | 52 (12.8) |
| Duration of pruritus, yr | ||||||
| Mean (SD) | 3.0 (3.3) | 3.6 (3.3) | 3.4 (4.8) | 3.0 (2.9) | 3.2 (4.1) | 3.3 (3.1) |
| Range (min–max) | (0.1–24.3) | (0.0–23.2) | (0.1–58.4) | (0.0–17.3) | (0.1–58.4) | (0.0–23.2) |
| Years since diagnosis of ESKD | ||||||
| Mean (SD) | 5.3 (4.6) | 5.8 (5.0) | 4.9 (4.5) | 5.1 (4.2) | 5.1 (4.5) | 5.5 (4.7) |
| Range (min–max) | (0.3–27.9) | (0.3–28.7) | (0.3–30.2) | (0.3–26.4) | (0.3–30.2) | (0.3–28.7) |
| Years since diagnosis of CKD | ||||||
| Mean (SD) | 8.1 (6.0) | 9.0 (7.2) | 7.9 (6.8) | 8.6 (7.2) | 8.0 (6.4) | 8.8 (7.2) |
| Range (min–max) | (0.3–29.5) | (0.6–48.3) | (0.3–46.3) | (0.8–40.2) | (0.3–46.3) | (0.6–48.3) |
| Years on chronic hemodialysis | ||||||
| Mean (SD) | 4.7 (4.2) | 5.1 (4.4) | 4.7 (4.5) | 4.6 (4.2) | 4.7 (4.3) | 4.9 (4.3) |
| Range (min–max) | (0.1–27.9) | (0.0–27.9) | (0.2–30.2) | (0.2–26.4) | (0.1–30.2) | (0.0–27.9) |
| Prescription dry body weight, kg | ||||||
| Mean (SD) | 79.1 (19.0) | 85.2 (21.2) | 82.4 (19.7) | 84.9 (20.4) | 80.8 (19.4) | 85.1 (20.8) |
| Range (min–max) | (42.0–135.0) | (50.0–135.0) | (46.0–130.0) | (42.0–135.0) | (42.0–135.0) | (42.0–135.0) |
| Etiology of CKD, n (%) | ||||||
| Cystic kidney | 6 (2.8) | 9 (4.3) | 5 (2.2) | 9 (4.5) | 11 (2.5) | 18 (4.4) |
| Diabetes only | 51 (23.9) | 30 (14.4) | 57 (25.3) | 36 (18.2) | 108 (24.7) | 66 (16.2) |
| Diabetes, hypertension | 54 (25.4) | 47 (22.5) | 66 (29.3) | 57 (28.8) | 120 (27.4) | 104 (25.6) |
| Diabetes, hypertension, other | 5 (2.3) | 9 (4.3) | 4 (1.8) | 4 (2.0) | 9 (2.1) | 13 (3.2) |
| Diabetes, other | 4 (1.9) | 5 (2.4) | 0 | 1 (0.5) | 4 (0.9) | 6 (1.5) |
| GN only | 3 (1.4) | 8 (3.8) | 6 (2.7) | 9 (4.5) | 9 (2.1) | 17 (4.2) |
| GN, other | 3 (1.4) | 2 (1.0) | 1 (0.4) | 2 (1.0) | 4 (0.9) | 4 (1.0) |
| Hypertension only | 56 (26.3) | 57 (27.3) | 53 (23.6) | 48 (24.2) | 109 (24.9) | 105 (25.8) |
| Hypertension, other | 10 (4.7) | 13 (6.2) | 9 (4.0) | 9 (4.5) | 19 (4.3) | 22 (5.4) |
| Other | 21 (9.9) | 29 (13.9) | 24 (10.7) | 23 (11.6) | 45 (10.3) | 52 (12.8) |
| Baseline weekly mean WI-NRS score, n (%) | ||||||
| Moderate (score 4–6) | 104 (48.8) | 88 (42.1) | 96 (42.7) | 87 (43.9) | 200 (45.7) | 175 (43.0) |
| Severe (score 7–10) | 109 (51.2) | 121 (57.9) | 129 (57.3) | 111 (56.1) | 238 (54.3) | 232 (57.0) |
| P valued | 0.17 | 0.79 | 0.44 | |||
GN, glomerulonephritis; sP, serum phosphate; WI-NRS, 24-hour Worst Itching Intensity Numerical Rating Scale.
Baseline WI-NRS was calculated as the average of the 24-hour Worst Itching Intensity Numerical Rating Scale scores collected over the run-in period, including assessments collected on day 1 before the first dose.
Observed stratum values.
Special medical conditions included any or all of the following: history of fall or fracture (related to fall), confusional state or mental status change or altered mental status or disorientation, gait disturbance, or movement disorder. More than 1 item may have been checked.
P value based on chi-squared test.
Itch Severity and sP Changes during the Study
The overall population (placebo and difelikefalin arms) had similar baseline mean (SD) WI-NRS scores in baseline sP ≤5.5 versus >5.5 mg/dl subgroups (7.13 [1.4] versus 7.23 [1.5], P = 0.307) (Table 1) and similar proportions of patients with severe itch (WI-NRS score ≥7) at baseline (54.3% versus 57.0%, P = 0.44) (Table 1).
In the overall population, there was no significant correlation observed between WI-NRS and sP at any time point: between baseline WI-NRS score and baseline sP (Pearson correlation 0.02, P = 0.54) (Figure 1A), between week 12 WI-NRS and baseline sP (Pearson correlation 0.04, P = 0.27) (Figure 1B), or between week 12 WI-NRS and week 12 sP (Pearson correlation −0.01, P = 0.79) (Figure 1C). There was a negligible correlation between change in WI-NRS and change in sP from baseline to week 12 in the overall population (Pearson correlation −0.07, P = 0.04) (Figure 2A).
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.
Difelikefalin Treatment and sP
There was no significant difference between the LS mean estimate of the percentage of patients reporting clinically meaningful reductions from baseline to week 12 in WI-NRS in either of the sP subgroups receiving difelikefalin (baseline sP ≤5.5 versus >5.5 mg/dl, 51.1% versus 57.6% (odds ratio [OR; 95% confidence interval (CI)], 1.3 [0.87 to 11.96]); P = 0.20) for ≥3-point reduction; 39.3% versus 40.2% (OR [95% CI], 1.0 [0.67 to 1.59]; P = 0.87) for ≥4-point reduction; Figure 3).
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.
Clinically meaningful reductions from baseline to week 12 in the WI-NRS score were reported by more patients receiving placebo who had a baseline sP ≤5.5 mg/dl than >5.5 mg/dl (LS mean 37.2% versus 27.4% (OR [95% CI], 0.63 [0.41 to 0.97]; P = 0.04) for ≥3-point reduction and LS mean 26.2% versus 18.6% (OR [95% CI], 0.64 [0.40 to 1.04]; P = 0.07) for ≥4-point reduction; Figure 3).
Significantly more patients reported a clinically meaningful ≥3-point reduction from baseline to week 12 in WI-NRS for the sP >5.5 mg/dl group with difelikefalin versus placebo (LS mean 56.0% versus 31.5%, OR [95% CI], 2.76 [1.81 to 4.22]; P < 0.001), whereas the difference between difelikefalin and placebo was NS for the sP ≤5.5 mg/dl group (LS mean 47.4% versus 38.8%, OR [95% CI], 1.42 [0.95 to 2.13]; P = 0.09). Significantly more patients reported a clinically meaningful ≥4-point reduction from baseline to week 12 in WI-NRS with difelikefalin than placebo in the baseline sP >5.5 mg/dl subgroup (LS mean 37.9% versus 18.4%, OR [95% CI], 2.71 [1.67 to 4.41]; P < 0.001) and in the <5.5 mg/dl subgroup (LS mean 38.9% versus 27.5% (OR [95% CI], 1.68 [1.10 to 2.58]; P = 0.02).
There was no significant correlation between change in WI-NRS and change in sP from baseline to week 12 in either the difelikefalin (Pearson correlation −0.04, P = 0.46) (Figure 2B) or placebo (Pearson correlation −0.1, P = 0.06) (Figure 2C) groups.
Study 3105
Baseline Demographics and Characteristics
Overall, 220 patients had a baseline phosphate measurement and were included in the analysis (Table 2). Baseline sP ≤5.5 mg/dl was measured for 102 patients (46.4%) while 118 patients (53.6%) had baseline sP >5.5 mg/dl (Table 2).
Table 2.
Study 3105: patient demographics and characteristics by baseline serum phosphate subgroups
| Characteristic | Baseline sP ≤5.5 mg/dl (n=102) | Baseline sP >5.5 mg/dl (n=118) | Overall (n=220) |
|---|---|---|---|
| Age, yr | |||
| Mean (SD) | 60.7 (12.9) | 56.1 (12.4) | 58.2 (12.8) |
| Range (min–max) | (28–85) | (22–82) | (22–85) |
| Age group, n (%) | |||
| <45 | 12 (11.8) | 19 (16.1) | 31 (14.1) |
| ≥45 to <65 | 48 (47.1) | 69 (58.5) | 117 (53.2) |
| ≥65 to <75 | 26 (25.5) | 22 (18.6) | 48 (21.8) |
| ≥75 | 16 (15.7) | 8 (6.8) | 24 (10.9) |
| Sex, n (%) | |||
| Male | 52 (51.0) | 67 (56.8) | 119 (54.1) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 26 (25.5) | 22 (18.6) | 48 (21.8) |
| Not Hispanic or Latino | 76 (74.5) | 95 (80.5) | 171 (77.7) |
| Not reported | 0 | 1 (0.8) | 1 (0.5) |
| Race, n (%) | |||
| American Indian or Alaska Native | 2 (2.0) | 0 | 2 (0.9) |
| Asian | 5 (4.9) | 2 (1.7) | 7 (3.2) |
| Black or African American | 52 (51.0) | 58 (49.2) | 110 (50.0) |
| Native Hawaiian or other Pacific Islander | 0 | 3 (2.5) | 3 (1.4) |
| White | 42 (41.2) | 54 (45.8) | 96 (43.6) |
| Other | 1 (1.0) | 1 (0.8) | 2 (0.9) |
| Region, n (%) | |||
| Eastern Europe | 11 (10.8) | 6 (5.1) | 17 (7.7) |
| United States | 91 (89.2) | 112 (94.9) | 203 (92.3) |
| Baseline WI-NRSa | |||
| Mean (SD) | 7.4 (1.3) | 7.7 (1.3) | 7.6 (1.3) |
| Range (min–max) | (5.0–10.0) | (5.0–10.0) | (5.0–10.0) |
| Baseline anti-itch medication use?, n (%) | |||
| Yes | 27 (26.5) | 43 (36.4) | 70 (31.8) |
| Duration of pruritus, yr | |||
| Mean (SD) | 3.9 (3.3) | 3.9 (3.3) | 3.9 (3.3) |
| Range (min–max) | (0.3–17.9) | (0.3–15.9) | (0.3–17.9) |
| Years since diagnosis of ESKD | |||
| Mean (SD) | 5.7 (4.0) | 6.0 (5.2) | 5.9 (4.7) |
| Range (min–max) | (0.5–19.7) | (0.6–33.3) | (0.5–33.3) |
| Years since diagnosis of CKD | |||
| Mean (SD) | 8.1 (6.3) | 8.9 (7.4) | 8.5 (6.9) |
| Range (min–max) | (0.6–43.8) | (0.7–38.5) | (0.6–43.8) |
| Years on chronic hemodialysis | |||
| Mean (SD) | 5.4 (4.1) | 5.5 (4.7) | 5.4 (4.4) |
| Range (min–max) | (0.4–19.4) | (0.6–26.7) | (0.4–26.7) |
| Prescription dry body weight, kg | |||
| Mean (SD) | 84.8 (19.8) | 87.7 (26.2) | 86.4 (23.5) |
| Range (min–max) | (42.5–149.0) | (44.0–178.0) | (42.5–178.0) |
| Etiology of CKD, n (%) | |||
| Hypertension | 66 (64.7) | 68 (57.6) | 134 (60.9) |
| Diabetes | 51 (50.0) | 58 (49.2) | 109 (49.5) |
| GN | 5 (4.9) | 6 (5.1) | 11 (5.0) |
| Large vessel disease | 2 (2.0) | 2 (1.7) | 4 (1.8) |
| Urologic | 3 (2.9) | 0 | 3 (1.4) |
| Cystic | 0 | 2 (1.7) | 2 (0.9) |
| Pyelonephritis | 2 (2.0) | 0 | 2 (0.9) |
| Interstitial nephritis | 1 (1.0) | 0 | 1 (0.5) |
| Nephrotic syndrome | 1 (1.0) | 0 | 1 (0.5) |
| Tumors | 1 (1.0) | 0 | 1 (0.5) |
| Vasculitis | 1 (1.0) | 0 | 1 (0.5) |
| Other | 11 (10.8) | 14 (11.9) | 25 (11.4) |
| Unknown | 1 (1.0) | 1 (0.8) | 2 (0.9) |
| Baseline WI-NRS severity category, n (%) | |||
| Moderate 4–6 | 36 (35.3) | 34 (28.8) | 70 (31.5) |
| Severe 7–10 | 66 (64.7) | 84 (71.2) | 152 (68.5) |
| P valueb | 0.30 | ||
sP, serum phosphate; WI-NRS, 24-hour Worst Itching Intensity Numerical Rating Scale.
Baseline 24-hour Worst Itching Intensity Numerical Rating Scale was calculated as the average of the 24-hour Worst Itching Intensity Numerical Rating Scale scores collected over the run-in period, including assessments collected on day 1 before the first dose.
P value based on chi-squared test.
Baseline characteristics were generally similar for patients in both sP subgroups. Consistent with the KALM-1 and -2 studies, patients with baseline sP ≤5.5 versus >5.5 mg/dl were older (mean [SD] 60.7 [12.9] versus 56.1 [12.4]) and were more likely to be of Hispanic or Latino ethnicity (25.5% versus 18.6%) (Table 2).
Patients with baseline sP ≤5.5 versus >5.5 mg/dl were less likely to be from the United States (89.2% versus 94.9%) and had a lower target dry body weight at baseline (84.83 versus 87.67 kg) (Table 2). Mean duration of pruritus (3.89 versus 3.91 years), time on chronic hemodialysis (5.41 versus 5.47 years), and years since diagnosis of ESKD (5.70 versus 6.02 years) were similar in sP ≤5.5 versus >5.5 mg/dl subgroups, despite patients with baseline sP ≤5.5 versus >5.5 mg/dl having a shorter mean time since diagnosis of CKD (8.05 versus 8.94 years). Notably, in contrast to the KALM-1 and -2 studies, patients with baseline sP ≤5.5 versus >5.5 mg/dl were less likely to be using other anti-itch medications at baseline (26.5% versus 36.4%).
Itch Severity and sP Changes during the Study
At baseline, mean [SD] WI-NRS scores were similar between the sP ≤5.5 and >5.5 mg/dl groups (7.41 [1.3] versus 7.70 [1.3]) (Table 2), with similar proportions of patients reporting severe itch (WI-NRS score ≥7) at baseline (64.7% versus 71.2%, P = 0.30) (Table 2).
There was no significant correlation observed between WI-NRS and sP at any time point: baseline WI-NRS score and baseline sP (Pearson correlation 0.03, P = 0.62) (Figure 4A), week 12 WI-NRS and baseline sP (Pearson correlation −0.06, P = 0.43) (Figure 4B), week 12 WI-NRS and week 12 sP (Pearson correlation −0.02, P = 0.74) (Figure 4C), or change in WI-NRS and change in sP from baseline to week 12 (Pearson correlation 0.07, P = 0.36) (Figure 4D).
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.
Discussion
This post hoc analysis of patients with CKD-aP undergoing hemodialysis from the phase 3 difelikefalin clinical trial program aimed to assess the role of sP in the pathogenesis of CKD-aP and whether difelikefalin improves CKD-aP in patients irrespective of baseline sP levels (≤5.5 or >5.5 mg/dl).
In KALM-1 and KALM-2 and Study 3105, there was no difference in baseline itch severity by baseline sP ≤5.5 versus >5.5 mg/dl, and there was no significant correlation observed between baseline or week 12 WI-NRS scores and sP or between their change from baseline to week 12 with difelikefalin or placebo. There was a negligible correlation between change in WI-NRS and change in sP from baseline to week 12 in the overall population of KALM-1 and KALM-2. Difelikefalin reduced itch severity at week 12 irrespective of baseline sP subgroup; there was no significant difference in the proportion of patients receiving difelikefalin who reported clinically meaningful reductions in itch severity from baseline to week 12 in the sP subgroups. Furthermore, a larger proportion of patients reported a clinically meaningful response (≥3- or ≥4-point reduction in WI-NRS) with difelikefalin than with placebo irrespective of baseline sP ≤5.5 or >5.5 mg/dl.
It has previously been suggested that uremic toxicity may cause or contribute to CKD-aP because increasing dialysis efficiency (with resulting increasing Kt/V) and reducing serum calcium, parathyroid hormone, or phosphate have been reported to potentially alleviate itching in a subset of patients.7,17 Historically, the pathogenesis of CKD-aP has been believed to be linked to phosphate, with sP >5.5 mg/dl associated with severe CKD-aP and, therefore, higher burden and poorer QoL compared with patients with <5.5 mg/dl sP.16–18,25 However, this viewpoint is contradicted by some published literature, which concurs with the findings of this analysis, that is, phosphate levels are not associated with increased severity of CKD-aP in patients undergoing hemodialysis.12–14,16
The etiology of CKD-aP is complex, with a variety of factors such as hypercalcemia, hypermagnesemia, hyperphosphatemia, elevated parathyroid hormone, and calcium phosphate all historically identified as independent risk factors for the development of severe itching in CKD-aP.25 However, these data are likely to be confounded by factors beyond metabolism; for example, patients reporting that they are extremely bothered by pruritus are also more likely to miss hemodialysis sessions, meaning any elevation in sP may be a result of poor dialysis adherence.3 While, despite the conflicting data,12–15 itching may be attributed to sP >5.5 mg/dl in patients undergoing hemodialysis and this relationship used as a rationale to justify only treating the elevated sP, there is no evidence to show that other interventions, such as gabapentin, should not be used to address CKD-aP in patients with sP >5.5 mg/dl. This post hoc analysis suggests that difelikefalin should be considered for CKD-aP regardless of baseline sP level. Furthermore, the assumption that itching is attributed to sP >5.5 mg/dl may mean that the true cause of itching is overlooked. Although sP did not correlate with CKD-aP in this analysis, control of sP is important for other, well-established clinical reasons. Elevated sP is an independent risk factor of both kidney failure and mortality in patients with CKD,26,27 with Kidney Disease Improving Global Outcomes guidelines recommending the reduction of elevated sP as a treatment strategy for the management of CKD and CKD mineral bone disease.28–30
Owing to factors listed above, such as unknown etiology of CKD-aP, the management of CKD-aP in patients undergoing hemodialysis remains complex. However, although the understanding of the pathogenesis of CKD-aP is unclear, effective management of pruritus with agents such as difelikefalin could lead to improvements in patients' status, including QoL, sleep, and mental health. Further research is required to broaden the understanding of potential causes and prevention and management strategies for CKD-aP with hemodialysis and the findings used to further affect updates to clinical guidelines.
There are limitations to this analysis. Notably, because it is a post hoc subgroup analysis, results should be interpreted with caution because findings are descriptive and, therefore, exploratory and hypothesis generating only.
In this post hoc analysis of the phase 3 difelikefalin clinical trial program, sP did not correlate with pruritus severity or response to placebo or difelikefalin in patients with CKD-aP undergoing hemodialysis. Difelikefalin can provide clinically meaningful reduction in itch severity in patients with CKD-aP undergoing hemodialysis, regardless of the presence of elevated sP.
Acknowledgments
Medical writing support was provided by Katherine Hardy, AXON Communications (London, United Kingdom), and funded by Vifor Fresenius Medical Care Renal Pharma Ltd.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/A588.
Funding
S.N. Fishbane: Vifor Pharma.
Author Contributions
Conceptualization: Jeffrey Budden, Frédérique Menzaghi, Isabelle Morin, Warren Wen.
Data curation: Isabelle Morin.
Formal analysis: Steven N. Fishbane, Isabelle Morin.
Methodology: Jeffrey Budden, Frédérique Menzaghi, Warren Wen.
Validation: Isabelle Morin.
Visualization: Frédérique Menzaghi, Warren Wen.
Writing – original draft: Steven N. Fishbane.
Writing – review & editing: Geoff A. Block, Jeffrey Budden, Pieter Evenepoel, Steven N. Fishbane, Edgar V. Lerma, Frédérique Menzaghi, Isabelle Morin, Warren Wen.
Data Sharing Statement
Previously published data were used for this study. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F, KALM-1 Trial Investigators. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. N Engl J Med. 2020;382(3):222–232. Fishbane S, Wen W, Munera C, et al. Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program. Kidney Med. 2022;4(8):100513. Topf J, Wooldridge T, McCafferty K, et al. 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. Kidney Med. 2022;4(8):100512.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Previously published data were used for this study. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F, KALM-1 Trial Investigators. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. N Engl J Med. 2020;382(3):222–232. Fishbane S, Wen W, Munera C, et al. Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program. Kidney Med. 2022;4(8):100513. Topf J, Wooldridge T, McCafferty K, et al. 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. Kidney Med. 2022;4(8):100512.