CKD-Associated Pruritus and Clinical Outcomes in Nondialysis CKD.

Rationale & Objective: Itching is a frequent symptom experienced by people with chronic kidney disease (CKD). We investigated the associations of CKD-associated pruritus (CKD-aP) with clinical outcomes. Study Design: This was a longitudinal cohort study. Setting & Participants: Patients from Brazil, France, and the United States enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) from 2013 to 2021, an international prospective cohort study of adults with nondialysis dependent CKD, and an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 were included. Exposure: CKD-aP was self-reported by response to the question: "During the past 4 weeks, to what extent were you bothered by itchy skin?" Outcomes: The outcomes were as follows: CKD progression, kidney replacement therapy (KRT) initiation, mortality, hospitalization, cardiovascular events, infection events. Analytical Approach: Associations with time-to-event outcomes were investigated using Cox proportional hazards models adjusted for potential confounders. Results: There were 4,410 patients from 91 clinics with a median age of 69 years and a median eGFR at patient questionnaire completion of 29 (21-38) mL/min/1.73 m2. The proportion of patients not at all, somewhat, moderately, very much, and extremely bothered by itchy skin was 49%, 27%, 13%, 7%, and 3%, respectively. Patients with more advanced stages of CKD, older age, and greater comorbidities reported to be more likely bothered by itchy skin. Among patients at least moderately bothered, 23% were prescribed at least 1 pharmacotherapy (35% in the United States, 19% in France, 4% in Brazil), including antihistamine (10%), gabapentin (6%), topical corticosteroids (4%), pregabalin (3%), or sedating antihistamine (3%). The HR (95% CI) for patients extremely (vs not at all) bothered was 1.74 (1.11-2.73) for all-cause mortality, 1.56 (1.11-2.18) for all-cause hospitalization, and 1.84 (1.22-2.75) for cardiovascular events. As CKD-aP severity increased, patients also had higher rates of infection events (P = 0.04); CKD-aP severity was not associated with KRT initiation (P = 0.20) or CKD progression (P = 0.87). Limitations: The limitations were 25% nonresponse rate, recall bias, and residual confounding factors. Conclusions: These results demonstrate a strong association between severe itch and clinical outcomes, providing the nephrology community new insights into the possible adverse consequences of CKD-aP in individuals with nondialysis CKD, and warrant further exploration. Plain-Language Summary: Chronic kidney disease-associated pruritus (CKD-aP) is a common disturbing symptom of chronic kidney disease (CKD). This article analyzes longitudinal data from the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) to describe prevalence of CKD-aP in 4,410 individuals with nondialysis CKD, and its association with clinical outcomes. We found that 51% of the surveyed population were bothered by pruritus. CKD-aP was more prevalent in those with more advanced stages of CKD, older age, and with more comorbid conditions. Compared to those not at all bothered by pruritus, those who were extremely bothered had a higher risk of all-cause mortality, hospitalizations, and cardiovascular events. Severity of CKD-aP was not associated with CKD progression or initiation of kidney replacement therapy.

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post hoc Analysis of KALM-1 and KALM-2.

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 Skindex­10. 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 improves itch-related sleep disruption in patients undergoing haemodialysis.

BACKGROUND: Poor sleep quality is associated with increased mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis. This post hoc analysis of Phase 3 studies (3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in CKD-aP improved sleep quality. METHODS: Itch intensity was assessed in patients undergoing haemodialysis, who had moderate-to-severe CKD-aP treated with intravenous difelikefalin (0.5 µg/kg, three times weekly) (N = 222, Study 3105; N = 426, KALM-1/-2) or placebo (N = 425, KALM-1/-2) for 12 weeks, using the Worst Itch Intensity Numerical Rating Scale (WI-NRS). Sleep quality was assessed using the sleep disability question of the 5-D itch scale (5­D SDQ) in all studies and, in Study 3105, with the Sleep Quality Numeric Rating Scale (SQ-NRS). RESULTS: Greater improvements in sleep quality were observed in patients with ≥ 3-point, versus < 3-point WI-NRS improvement using SQ-NRS in Study 3105 (mean [95% confidence interval]: -5.2 [-5.6, -4.8] vs -1.5 [-2.0, -1.0]) and 5-D SDQ in KALM-1/-2 (-1.8 [-2.1, -1.6] vs -0.8 [-1.1, -0.4]). SQ-NRS and WI-NRS scores correlated strongly at baseline and Week 12 in Study 3105 (Spearman correlation coefficient: 0.77 and 0.84, respectively). Correlations were also observed between 5-D SDQ and WI-NRS scores in Study 3105 and KALM­1/­2. CONCLUSIONS: In patients undergoing haemodialysis with moderate-to-severe CKD-aP, itch reduction with intravenous difelikefalin was associated with improved sleep quality. As disturbed sleep may contribute to mortality and morbidity in CKD-aP, difelikefalin may help to address a major clinical burden by improving sleep quality, secondary to itch relief.

The Burden of Pruritus Associated With CKD: A Mixed Methods Analysis Among Patients Undergoing Dialysis.

Rationale & Objective: Despite its prevalence and distress to patients, chronic kidney disease-associated pruritus (CKD-aP) is poorly characterized, which may contribute to the condition's underdiagnosis and inadequate management. This study aimed to understand the symptom experience of patients with CKD-aP and the extent to which pruritus impacts their lives. Study Design: Mixed methods study including one-on-one qualitative interviews and completion of the Skindex-10 Questionnaire (measuring itch-related quality of life). Setting & Participants: A total of 23 patients undergoing hemodialysis and reporting pruritus at 4 dialysis centers in the United States. Analytical Approach: Interviews followed a semistructured guide that included targeted and follow-up questions to elicit discussion of patients' symptoms of pruritus, including frequency and variability, impact on activities of daily living, and emotional and social functioning. Interviews were digitally audio-recorded. A coding dictionary was developed from transcripts to analyze themes and concepts. Results: Participants described their itch with various terms, including "numbness," "pain," and "tingling" on their skin. Itch affected multiple areas but especially the back, usually occurred daily, and was often worse at night. For some, itching was a constant experience. Patients relieved their itch through scratching and various off-label treatments; some reported skin damage from excessive scratching and most indicated treatments provided limited relief. Pruritus considerably disrupted physical function, including sleep, daily activities, social functioning and relationships, and emotional and psychological wellbeing. All participants reported being bothered by their itching during the past week on the Skindex-10 Questionnaire. Limitations: All participants were from the United States, so the findings may not be generalizable to other countries. Conclusions: Although symptom experience varies considerably, CKD-aP causes severe distress for many patients undergoing hemodialysis and can profoundly impair their quality of life. The results of this study show the impact of itch from patients' perspectives and highlight the need for greater awareness and better management of this condition. Plain-Language Summary: Patients with chronic kidney disease often experience itching, or pruritus, but its importance to patients is regularly overlooked. This study used one-on-one interviews to investigate patients' experiences of chronic kidney disease-associated pruritus and how it impacts their lives. We found that participants experienced itch on various body areas and used different words to describe their itch (eg, "numbness" and "pain"). Some reported skin damage from excessive scratching, and many used off-label treatments and other interventions (eg, rubbing alcohol and multiple showers daily), which provided limited relief. For many, itching was experienced daily and severely disrupted sleep, daily activities, interactions with others, and mental wellbeing. These findings reveal chronic kidney disease-associated pruritus severely impacts patients and highlights the need for improved management of this condition.

Pharmacokinetics, Metabolism, and Excretion of Intravenous [14C]Difelikefalin in Healthy Subjects and Subjects on Hemodialysis.

BACKGROUND AND OBJECTIVE: Difelikefalin, a selective kappa-opioid receptor agonist, is the first approved treatment for moderate-to-severe pruritus in patients with end-stage renal disease (ESRD) on hemodialysis (HD) in the USA and Europe. The purpose of this open-label study was to investigate the pharmacokinetics and disposition of [14C]difelikefalin following a single intravenous dose in subjects with normal renal function and subjects on HD. METHODS: Twelve adult males (n = 6 healthy subjects; n = 6 subjects on HD) received single intravenous doses of [14C]difelikefalin containing 100 µCi (total doses of 1.7-3.0 µg/kg difelikefalin). Blood, urine, feces, and dialysate samples (when applicable) were collected after dosing. RESULTS: The median time to maximum concentration was similar for HD and healthy subjects, occurring at 5 min post-dose. The mean area under the concentration-time curve (AUC) was approximately 11-fold higher in HD versus healthy subjects; mean plasma half-life was 38.0 h and 2.6 h, respectively. In healthy subjects, 80.5% of the dose was recovered in urine, and 11.3% was recovered in feces. In subjects on HD, 58.8% of the dose was recovered in feces, and 19.5% was recovered in dialysate [for subjects on HD with residual kidney function (n = 3), 11.2% was recovered in urine]. Based on plasma AUClast, parent [14C]difelikefalin was the most abundant analyte in systemic circulation (> 99% of total exposure) for both cohorts. Metabolite profiles in urine and feces suggested minimal metabolism of the parent compound. CONCLUSION: In subjects on HD, difelikefalin total exposure was higher and plasma half-life was longer compared with subjects with intact renal function. Metabolism was low in both healthy subjects and subjects on HD, with unchanged drug representing > 99% of systemic circulation; however, the route of excretion was primarily into urine versus feces in healthy subjects, and feces versus dialysate in subjects on HD. REGISTRATION: ClinicalTrials.gov NCT03947970.

Assessment of the physical dependence potential of difelikefalin: Randomized placebo-controlled study in patients receiving hemodialysis.

Difelikefalin is a selective kappa opioid receptor agonist approved for treating moderate-to-severe pruritus in adults undergoing hemodialysis (HD). Difelikefalin is not a controlled substance under the Controlled Substances Act. This study assessed the potential for developing physical dependence on difelikefalin in patients undergoing HD. Eligible patients received open-label difelikefalin after each dialysis session for 3 weeks before entering a 2-week double-blind phase, when they were randomized to either continue difelikefalin or to switch to receiving placebo. Signs of physical withdrawal were assessed using the Clinical Opiate Withdrawal Scale (COWS), several patient-reported scales, and physiological measures. The primary end point was the between-group difference in mean maximum COWS total scores during the double-blind phase; the mean difference (placebo - difelikefalin) was compared against a predefined noninferiority limit (+4). Thirty-five patients (57.1% male; 91.4% Black or African American; median [range] age 58 [28-77] years) were included, of which 30 were randomized (placebo, n = 14; difelikefalin, n = 16). The least squares mean difference in maximum COWS total scores was 0.52 (95% confidence interval [CI]: -0.56, 1.59). The upper CI limit (1.59) was below +4, indicating that patients who discontinued difelikefalin (placebo group) had similar withdrawal scores to patients who continued difelikefalin. Additional assessments supported the COWS results, showing no meaningful differences between groups in physiological measures or in patient-reported measures of sleep or physical withdrawal. These results demonstrate that abruptly discontinuing chronic difelikefalin treatment in patients undergoing HD does not produce signs or symptoms of physical withdrawal.

A phase 2 study of oral difelikefalin in subjects with chronic kidney disease and moderate-to-severe pruritus.

INTRODUCTION/BACKGROUND: Chronic pruritus is burdensome for patients with chronic kidney disease (CKD). OBJECTIVE: We evaluated difelikefalin efficacy and safety in reducing itch in subjects with non-dialysis-dependent CKD and those undergoing hemodialysis (HD). METHODS: This phase 2, double-blind, randomized, placebo-controlled, dose-finding study enrolled non-dialysis-dependent CKD (stage 3-5) and HD subjects with moderate-to-severe pruritus. Subjects were equally randomized to oral difelikefalin (0.25, 0.5, or 1.0 mg) or placebo once daily for 12 weeks. The primary end point was the change in the weekly mean Worst Itching Intensity Numeric Rating Scale (WI-NRS) score at week 12. RESULTS: Two hundred sixty-nine subjects were randomized (mean [SD] baseline WI-NRS: 7.1 [1.2]). Difelikefalin 1.0 mg significantly reduced weekly mean WI-NRS scores versus placebo at week 12 (P = .018), with numerical reductions observed with difelikefalin 0.25 and 0.5 mg. At week 12, 38.6% of subjects receiving difelikefalin 1.0 mg achieved a complete response (WI-NRS 0-1) versus 14.4% receiving placebo. Difelikefalin resulted in ∼20% improvement in itch-related quality-of-life measures. The most common treatment-emergent adverse events were dizziness, fall, constipation, diarrhea, gastroesophageal reflux disease, fatigue, hyperkalemia, hypertension, and urinary tract infection. LIMITATIONS: Study duration was 12 weeks. CONCLUSIONS: Oral difelikefalin significantly reduced itch intensity in stage 3-5 CKD subjects with moderate-to-severe pruritus, supporting continued development for this condition.

Safety and Effectiveness of Difelikefalin in Patients With Moderate-to-Severe Pruritus Undergoing Hemodialysis: An Open-Label, Multicenter Study.

Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kidney disease-associated pruritus (CKD-aP), impacting sleep quality and quality of life (QoL) and increasing the likelihood of depression. Difelikefalin is a kappa-opioid receptor agonist recently approved in the United States for the treatment of moderate-to-severe CKD-aP in hemodialysis patients. Study 3105 was conducted to further assess the safety of difelikefalin and the effects on pruritus and QoL. Study Design: Open-label, multicenter, single-arm intervention trial. Setting & Participants: Maintenance hemodialysis patients with moderate-to-severe CKD-aP at enrollment. Intervention: Intravenous difelikefalin 0.5 µg/kg after each hemodialysis session for 12 weeks. Outcomes: The primary outcome was safety of difelikefalin. Secondary outcomes included: effectiveness of reducing itch intensity, assessed by the Worst Itching Intensity Numerical Rating Scale (WI-NRS); improving itch-related QoL, assessed with 5-D itch and Skindex-10 scales; and improvement of sleep, assessed with the Sleep Quality Numerial Rating Scale. Clinically meaningful thresholds for improvement in itch and QoL were previously established in this population. Results: Among 222 participants with baseline WI-NRS ≥5, mean [standard deviation] WI-NRS was 7.6 [1.3], mean age 58 years, 55% were male, and mean dialysis duration was 5.9 years; 197 participants (89%) completed treatment. Treatment-related treatment-emergent adverse events were reported in 16 participants (7.2%); those most commonly reported were somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%), and dizziness (0.9%). No deaths or serious treatment-emergent adverse events were considered treatment-related. Clinically meaningful reduction in itch intensity (≥3-point improvement) was reported by 74% of participants, with 70% and 63% also reporting a clinically relevant improvement in QoL as measured by 5-D itch and Skindex-10. Sleep quality improvement (≥3-point reduction on the Numerical Rating Scale) was reported in 66% of participants. Limitations: No placebo control group. Conclusions: Difelikefalin was well tolerated, and treatment was associated with clinically meaningful improvements in itch intensity and itch-related QoL measures as well as improvements in sleep quality among individuals receiving hemodialysis who had moderate-to-severe CKD-aP, providing important insights into expected real-world effectiveness. Funding: Cara Therapeutics. Trial Registration: NCT03998163.

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.

Rationale & Objective: We report a pooled safety analysis of intravenous difelikefalin in participants with moderate to severe chronic kidney disease-associated pruritus (CKD-aP) treated by hemodialysis in 4 phase 3 clinical studies. Study Design: KALM-1 and KALM-2 were randomized, double-blind, placebo-controlled, pivotal phase 3 studies; CLIN3101 (52 weeks) and CLIN3105 (12 weeks) were open-label studies. Setting & Participants: Adults with moderate to severe CKD-aP treated by hemodialysis in North America, Europe, and the Asia-Pacific region. Intervention: At least 1 intravenous placebo or difelikefalin dose of 0.5 mcg/kg for up to 64 weeks. Outcomes: Safety. Results: Safety analyses were conducted with 848 participants in the placebo-controlled cohort (424 participants each in the difelikefalin and placebo groups) and in 1,306 participants in the all-difelikefalin-exposure cohort. In the placebo-controlled cohort, the most commonly reported treatment-emergent adverse events (TEAEs), occurring in ≥2% of participants receiving difelikefalin and with a ≥1% higher incidence than placebo, were diarrhea (9.0% and 5.7%, respectively); dizziness (6.8% and 3.8%, respectively); nausea (6.6% and 4.5%, respectively); gait disturbances, including falls (6.6% and 5.4%, respectively), hyperkalemia (4.7% and 3.5%, respectively); headache (4.5% and 2.6%, respectively); somnolence (4.2% and 2.4%, respectively); and mental status changes (3.3% and 1.4%, respectively). These were mostly mild or moderate, with few leading to discontinuation. Incidence rates of TEAEs, serious TEAEs, and discontinuations because of TEAEs did not increase with long-term exposure. Three participants (0.7%) in the difelikefalin group and 5 participants (1.2%) in the placebo group died during the study. Limitations: Pooled data from studies with different designs. Conclusions: Intravenous difelikefalin demonstrated an acceptable safety profile, was generally well tolerated with long-term use, and may address the unmet treatment need for patients with CKD-aP treated by hemodialysis. Funding: Cara Therapeutics, Inc. Trial Registration: KALM-1 is registered as NCT03422653, KALM-2 as NCT03636269, CLIN3101 as NCT03281538, and CLIN3105 as NCT03998163.

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.

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.

Utility of a Single Itch-Related Question and the Skindex-10 Questionnaire for Assessing Pruritus and Predicting Health-Related Quality of Life in Patients Receiving Hemodialysis.

Rationale & Objective: Chronic kidney disease-associated pruritus has been linked with poorer mental and physical health-related quality of life (HR-QOL) in patients receiving hemodialysis. We used the Skindex-10 questionnaire and a single itch-related question to evaluate their prediction of HR-QOL. Study Design: Prospective, international cohort. Setting & Participants: We analyzed data from 4,940 patients receiving hemodialysis from 17 countries enrolled in phase 5 (2013) of the Dialysis Outcomes and Practice Patterns Study. Predictors: The responses to the 10 questions of Skindex-10 (0-6 scale) pertaining to itchiness in the past week were summed to create a summary score (range, 0-60). Concurrently, a single question from the Kidney Disease Quality of Life 36-item survey asked "during the past 4 weeks, to what extent were you bothered by itchy skin?" with 5 responses, ranging from "not at all" to "extremely" bothered. Outcomes: Physical component summary (PCS) and mental component summary (MCS) scores of HR-QOL. Analytical Approach: We used separate linear regression models to evaluate the predictive power, based on R2 values, for 3 models: 1 for each predictor and 1 with both predictors. Results: The correlation between the single itch-related question and the Skindex-10 score was 0.72. A 10-point higher Skindex-10 score was associated with a 1.2-point lower PCS score (95% CI, -1.4 to -0.9) and a 1.5-point lower MCS score (95% CI, -1.7 to -1.3) . The R2 value for PCS was 0.065 when the single question was used and only 0.033 when Skindex-10 was used as the predictor; the R2 value for MCS was 0.056 for the single question versus 0.052 for Skindex-10. Limitations: Measurement bias and translation issues in the questionnaires. Conclusions: The single question about the extent to which the patients were bothered by itchy skin was highly correlated with the Skindex-10 score and at least as predictive of key HR-QOL measures. In daily clinical practice, using 1 simple question about the extent to which patients are bothered by itchy skin can be a feasible and efficient method for the routine assessment of pruritus.

Evaluation of the abuse potential of difelikefalin, a selective kappa-opioid receptor agonist, in recreational polydrug users.

Difelikefalin, a selective kappa-opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double-blind, active- and placebo-controlled, four-way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.v.) injections of difelikefalin at supratherapeutic doses (5 and 15 mcg/kg); pentazocine (0.5 mg/kg), a schedule IV mu-opioid partial agonist and kappa-opioid receptor agonist; and placebo. The abuse potential of difelikefalin was compared with pentazocine and placebo using the maximal score (maximum effect [Emax ]) of the Drug Liking visual analog scale (VAS; primary end point), along with multiple secondary end points of subject-rated measures and pupillometry. Difelikefalin produced significantly lower Drug Liking VAS Emax , and lower peak positive, sedative, and perceptual effects compared with pentazocine. These effects of difelikefalin were small, brief, and not dose-dependent, although marginally greater than those observed with placebo. Neither dose of difelikefalin elicited significant negative or hallucinogenic effects. On end-of-session measures of overall drug liking and willingness to take the drug again, difelikefalin did not differ from placebo, indicating subjects neither liked nor disliked the effects overall and did not feel motivated to take the drug again. Consistent with its lack of mu agonist activity, difelikefalin did not induce miosis compared with pentazocine. All treatments were generally well-tolerated. This study indicates that difelikefalin presents a low potential for abuse.

Psychometric validation and meaningful change thresholds of the Worst Itching Intensity Numerical Rating Scale for assessing itch in patients with chronic kidney disease-associated pruritus.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP) is characterized by persistent itch that often leads to substantially impaired quality of life. The Worst Itching Intensity Numerical Rating Scale (WI-NRS) is a single-item patient-reported outcome measure in which patients indicate the intensity of the worst itching they experienced over the past 24 h. Here, we evaluated the content validity and psychometric properties of the WI-NRS and confirmed the threshold of meaningful change in hemodialysis patients with moderate-to-severe CKD-aP. METHODS: Content validity interviews were conducted in 23 patients. Psychometric properties of the WI-NRS were assessed using data from one phase 2 (N = 174) and two phase 3 (N = 848) clinical trials investigating an anti-pruritic treatment. Anchor-based methods were used to confirm meaningful within-patient change score thresholds in the phase 3 trial patients and mixed-method exit interviews (N = 70) contributed further insight. RESULTS: Content validity interviews indicated patients considered the WI-NRS to be straightforward, comprehensive, and relevant. Test-retest reliability was strong in both trial cohorts (intraclass correlation coefficients > 0.75). Construct validity analyses indicated high correlation between the WI-NRS and other measures of itch. Anchor-based analyses showed a reduction of ≥ 3 points from baseline score represented an appropriate clinically meaningful within-patient change on the WI-NRS. In the exit interviews, all patients with a reduction ≥ 3 points considered the change meaningful. CONCLUSIONS: The WI-NRS is a reliable, valid, and responsive measure of itch intensity for patients with moderate-to-severe CKD-aP. These results support its use to assess treatment efficacy and in clinical evaluation and management of pruritus in hemodialysis patients.

Itching is a distressing medical condition common in patients with chronic kidney disease, especially those undergoing hemodialysis. The itch often leads to skin damage due to a continuous and uncontrollable urge to scratch. It affects about 60% of hemodialysis patients and can be severe enough to seriously affect quality of life. At present, there are no approved therapies. To evaluate whether new treatments for itch are effective, clinicians need to assess if the intensity of itch decreases over time. However, because itch intensity can only be measured accurately by the person experiencing it, a measure is required that can be easily understood and used by patients. This study evaluated a scale in which patients mark a number between '0' (corresponding to no itch) and '10' (the worst itching imaginable), to describe the worst itch intensity they experienced over the last 24 hours. Using data from three clinical trials of a novel treatment for itch in patients undergoing hemodialysis with moderate-to-severe pruritus, we found that the scale was reliable in repeat-testing experiments, and mirrored other methods of measuring changes in itch. In interviews, patients said they found the scale straightforward and easy to complete. Our analysis and patients' opinions showed a 3-point reduction in itch intensity on the scale represented a meaningful improvement. These findings support the use of this scale to assess the efficacy of new treatments and in clinical evaluation and management of pruritus in patients with chronic kidney disease.

Self-reported Pruritus and Clinical, Dialysis-Related, and Patient-Reported Outcomes in Hemodialysis Patients.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD)-associated pruritus, generalized itching related to CKD, affects many aspects of hemodialysis patients' lives. However, information regarding the relationship between pruritus and several key outcomes in hemodialysis patients remains limited. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 23,264 hemodialysis patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018). EXPOSURE: Pruritus severity, based on self-reported degree to which patients were bothered by itchy skin (5-category ordinal scale from "not at all" to "extremely"). OUTCOMES: Clinical, dialysis-related, and patient-reported outcomes. ANALYTICAL APPROACH: Cox regression for time-to-event outcomes and modified Poisson regression for binary outcomes, adjusted for potential confounders. RESULTS: The proportion of patients at least moderately bothered by pruritus was 37%, and 7% were extremely bothered. Compared with the reference group ("not at all"), the adjusted mortality HR for patients extremely bothered by pruritus was 1.24 (95% CI, 1.08-1.41). Rates of cardiovascular and infection-related deaths and hospitalizations were also higher for patients extremely versus not at all bothered by pruritus (HR range, 1.17-1.44). Patients extremely bothered by pruritus were also more likely to withdraw from dialysis and miss hemodialysis sessions and were less likely to be employed. Strong monotonic associations were observed between pruritus severity and longer recovery time from a hemodialysis session, lower physical and mental quality of life, increased depressive symptoms, and poorer sleep quality. LIMITATIONS: Residual confounding, recall bias, nonresponse bias. CONCLUSIONS: Our findings demonstrate how diverse and far-reaching poor outcomes are for patients who experience CKD-associated pruritus, specifically those with more severe pruritus. There is need for change in practice patterns internationally to effectively identify and treat patients with pruritus to reduce symptom burden and improve quality of life and possibly even survival.

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients.

INTRODUCTION: There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus. METHODS: In this study, 174 hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive difelikefalin (0.5, 1.0, or 1.5 µg/kg) or placebo intravenously thrice weekly after each hemodialysis session for 8 weeks in a double-blind, controlled trial. The primary endpoint was the change from baseline at week 8 in the weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale score. The secondary efficacy endpoint was the change in itch-related quality of life measured by the Skindex-10 questionnaire. Other endpoints included safety, sleep quality, and additional measures including the 5-D itch scale. RESULTS: A significant reduction from baseline in itch intensity scores at week 8 favored all difelikefalin doses combined versus placebo (P = 0.002). Difelikefalin also showed improvement over placebo in Skindex-10, 5-D itch, and sleep disturbance scores (P ≤ 0.005). Overall, 78% of patients receiving difelikefalin reported treatment-emergent adverse events versus 42% of patients given placebo, with diarrhea, dizziness, nausea, somnolence, and fall being the most frequent (≥5%). CONCLUSION: In this trial, difelikefalin effectively reduced itching intensity and improved sleep and itch-related quality of life.

A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus.

BACKGROUND: Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients undergoing hemodialysis who had moderate-to-severe pruritus to receive either intravenous difelikefalin (at a dose of 0.5 µg per kilogram of body weight) or placebo three times per week for 12 weeks. The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). The secondary outcomes included the change from baseline in itch-related quality-of-life measures, the percentage of patients with an improvement of at least 4 points in the WI-NRS score at week 12, and safety. RESULTS: A total of 378 patients underwent randomization. A total of 82 of 158 patients (51.9%) in the difelikefalin group had a decrease of at least 3 points in the WI-NRS score (primary outcome), as compared with 51 of 165 (30.9%) in the placebo group. The imputed percentage of patients with a decrease of at least 3 points in the WI-NRS score was 49.1% in the difelikefalin group, as compared with 27.9% in the placebo group (P<0.001). Difelikefalin also resulted in a significant improvement from baseline to week 12 in itch-related quality of life as measured by the 5-D itch scale and the Skindex-10 scale. The imputed percentage of patients with a decrease of at least 4 points in the WI-NRS score at week 12 was significantly greater in the difelikefalin group than in the placebo group (37.1% [observed data: 64 of 158 patients] vs. 17.9% [observed data: 35 of 165 patients], P<0.001). Diarrhea, dizziness, and vomiting were more common in the difelikefalin group than in the placebo group. CONCLUSIONS: Patients treated with difelikefalin had a significant reduction in itch intensity and improved itch-related quality of life as compared with those who received placebo. (Funded by Cara Therapeutics; KALM-1 ClinicalTrials.gov number, NCT03422653.).

Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain.

BACKGROUND: Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). METHODS: The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. RESULTS: Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). CONCLUSION: CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization.

5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.

Novel D-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors.

Kappa-(kappa) opioid receptors are widely distributed in the periphery and activation results in antinociception; however supraspinal acting kappa-agonists result in unwanted side effects. Two novel, all d-amino acid, tetrapeptide kappa-opioid receptor agonists, FE 200665 and FE 200666, were identified and compared to brain penetrating (enadoline) and peripherally selective (asimadoline) kappa-agonists as potential analgesics lacking unwanted central nervous system (CNS) side effects. In vitro characterization was performed using radioligand binding and GTP gamma S binding. Antinociception was evaluated in both mice and rats. Rotarod tests were performed to determine motor impairment effects of the kappa-agonists. FE 200665 and FE 200666 showed high affinity for human kappa-opioid receptor 1 (Ki of 0.24 nM and 0.08 nM, respectively) and selectivity for human kappa-opioid receptor 1 (human kappa-opioid receptor 1/human mu-opioid receptor/human delta-opioid receptor selectivity ratios of 1/16,900/84,600 and 1/88,600/>1,250,000, respectively). Both compounds demonstrated agonist activity in the human kappa-opioid receptor 1 [35S]GTP gamma S binding assay (EC50 of 0.08 nM and 0.03 nM) and resulted in dose-related antinociception in the mouse writhing test (A50: 0.007 and 0.013 mg/kg, i.v., respectively). Markedly higher doses of FE 200665 and FE 200666 were required to induce centrally-mediated effects in the rotarod assay (548- and 182-fold higher doses, respectively), and antinociception determined in the mouse tail-flick assay (>1429- and 430-fold fold higher doses, respectively) after peripheral administration supporting a peripheral site of action. The potency ratios between central and peripheral activity suggest a therapeutic window significantly higher than previous kappa-agonists. Furthermore, FE 200665 has entered into clinical trials with great promise as a novel analgesic lacking unwanted side effects seen with current therapeutics.