A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus

Fishbane, Steven; Jamal, Aamir; Munera, Catherine; Wen, Warren; Menzaghi, Frédérique

doi:10.1056/nejmoa1912770

Cited by 251 publications

(239 citation statements)

References 27 publications

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“…The safety profile of difelikefalin was consistent with findings across the development program including a recent phase 3 trial, 27 and reflects this patient population that presents with significant comorbidities. The most frequently ($5%) reported TEAEs across all difelikefalin combined doses were diarrhea, dizziness, nausea, somnolence, and fall, and serious adverse events and discontinuations due to TEAEs were most prevalent in the 1.5 mg/kg group.…”

Section: Discussionsupporting

confidence: 76%

“…This dose of difelikefalin was recently evaluated in a phase 3 trial in hemodialysis patients with pruritus over a 12-week treatment period. 27 In conclusion, difelikefalin was effective at reducing the severity and duration of pruritus in hemodialysis patients with chronic moderate-to-severe CKD-aP, and improving sleep, mood, and social functioning. These data provide support for further investigation of the antipruritic effect of difelikefalin in larger and longerterm studies of the same population.…”

Section: Discussionmentioning

confidence: 82%

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Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients

Fishbane

Mathur²,

Germain

et al. 2020

Kidney International Reports

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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 mg/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 ¼ 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 itchrelated quality of life.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 82%

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients

Fishbane

Mathur²,

Germain

et al. 2020

Kidney International Reports

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“…17 A shorter version has been used in studies of CKD-aP outcomes. 4,18,19 Prevalence One of the first studies to measure CKD-aP in dialysis patients was published almost 50 years ago. 20 At that time, the prevalence in 36 hemodialysis (HD) patients was 86%.…”

Section: Qol Scalesmentioning

confidence: 99%

CKD-Associated Pruritus: New Insights Into Diagnosis, Pathogenesis, and Management

Verduzco

Shirazian

2020

Kidney International Reports

102

113

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Chronic kidney disease-associated pruritus (CKD-aP) is a common, troubling and in some cases debilitating problem for patients with CKD and end-stage renal disease. Despite a prevalence rate of approximately 20% in CKD and 40% in end-stage renal disease, and a clear association with poorer psychosocial and medical outcomes, this condition is often underreported by patients and overlooked by health care providers. This is likely due, in part, to uncertainty regarding its pathogenesis and treatment. Most commonly, CKD-aP is attributed to toxin build-up, peripheral neuropathy, immune system dysregulation, or opioid dysregulation. Prior treatment studies of CKD-aP have targeted these potential etiologies but have been limited by noncontrolled design, small sample size, and non-uniform definitions of CKD-aP. Recently, several large, randomized controlled trials targeting opioid dysregulation have yielded promising results. These trials have spurred new hope for understanding and treating this condition.

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“…Pain-activated spinal interneurons inhibit itch through the release of dynorphin, a kappa opioid receptor agonist, suggesting that this class of molecules could treat itch conditions [ 97 ]. Indeed, kappa opioid agonists such as nalfurafine and difelikefalin have shown clinical promise for treatment of a variety of chronic pruritic conditions and similar treatments could also benefit neuropathic itch associated with peripheral nerve injury [ 98 ].…”

Section: Future Therapeutic Directions For Neuropathic Itchmentioning

confidence: 99%

Neuropathic Itch

Meixiong

Dong

Weng

2020

Cells

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Neurologic insults as varied as inflammation, stroke, and fibromyalgia elicit neuropathic pain and itch. Noxious sensation results when aberrantly increased afferent signaling reaches percept-forming cortical neurons and can occur due to increased sensory signaling, decreased inhibitory signaling, or a combination of both processes. To treat these symptoms, detailed knowledge of sensory transmission, from innervated end organ to cortex, is required. Molecular, genetic, and behavioral dissection of itch in animals and patients has improved understanding of the receptors, cells, and circuits involved. In this review, we will discuss neuropathic itch with a focus on the itch-specific circuit.

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A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus

Cited by 251 publications

References 27 publications

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients

CKD-Associated Pruritus: New Insights Into Diagnosis, Pathogenesis, and Management

Neuropathic Itch

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