Clinically meaningful change in itch intensity scores: An evaluation in patients with chronic kidney disease–associated pruritus
Authors: Margaret Vernon, Sonja Ständer, Catherine Munera, Robert H. Spencer, Frédérique Menzaghi
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Clinical trials to assess the antipruritic effect of a treatment commonly use a numerical rating scale (NRS) ranging from 0 (no itching) to 10 (worst imaginable itching) to evaluate the worst itch intensity. However, for the drug effect to be clinically relevant, the magnitude of the reduction in the NRS scores must represent a meaningful improvement to the patients. Clinically meaningful changes with respect to NRS scores have been characterized in dermatologic conditions,1Reich A. Riepe C. Anastasiadou Z. et al.Itch assessment with visual analogue scale and numerical rating scale: determination of minimal clinically important difference in chronic itch.Acta Derm Venereol. 2016; 96: 978-980Crossref PubMed Scopus (44) Google Scholar, 2Mamolo C.M. Bushmakin A.G. Cappelleri J.C. Application of the Itch Severity Score in patients with moderate-to-severe plaque psoriasis: clinically important difference and responder analyses.J Dermatolog Treat. 2015; 26: 121-123Crossref PubMed Scopus (21) Google Scholar, 3Ständer S. Luger T.A. Cappelleri J.C. et al.Validation of the itch severity item as a measurement tool for pruritus in patients with psoriasis: results from a phase 3 tofacitinib program.Acta Derm Venereol. 2018; 98: 340-345Crossref PubMed Scopus (12) Google Scholar, 4Yosipovitch G. Reaney M. Mastey V. et al.Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis.Br J Dermatol. 2019; 181: 761-769Crossref PubMed Scopus (69) Google Scholar but to our knowledge, the threshold for such changes among patients with systemic chronic kidney disease–associated pruritus (CKD-aP) has not been established. To address this knowledge gap, we conducted a secondary analysis of data pooled across treatment groups from a phase 2, multicenter, double-blind, randomized, placebo-controlled study (NCT02858726) to determine the magnitude of change required for a meaningful reduction in itch intensity on the Worst Itching Intensity-NRS (WI-NRS) (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/yjntdkbp9r.1) in hemodialysis patients with moderate to severe pruritus. The study was approved by the Quorum Review Institutional Review Board before commencement and was conducted in accordance with the principles of Good Clinical Practice, as described in International Council for Harmonisation Guideline E6 and in accordance with the general ethical principles outlined in the Declaration of Helsinki. Patients provided written, informed consent before any study-related assessments were performed. This study demonstrated the antipruritic effects of the selective κ-opioid receptor agonist, difelikefalin, with a significant reduction of itch intensity and an improvement of itch-related quality of life (QoL) over placebo.5Fishbane S. Mathur V. Germain M. et al.Randomized controlled trial of difelikefalin for chronic pruritus in hemodialysis patients.Kidney Int Rep. 2020; 5: 600-610Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Itch intensity and QoL scores were collected over an 8-week treatment period.5Fishbane S. Mathur V. Germain M. et al.Randomized controlled trial of difelikefalin for chronic pruritus in hemodialysis patients.Kidney Int Rep. 2020; 5: 600-610Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar The Patient Global Impression of Change (PGI-C), with 7 categories ranging from "very much improved" to "very much worse," Patient Global Impression of Worst Itch Severity (PGI-S), with values from 0 (none) to 4 (very severe), and the Skindex-10 and 5-D itch QoL questionnaires were selected as anchor variables in the present analysis (Supplemental Figs 2-5). The threshold for meaningful reduction of WI-NRS was estimated using anchor- and distribution-based methods consistent with United States Food and Drug Administration guidance, as described in Table I and Supplemental Table I.Table IThresholds for clinically meaningful change for Worst Itching Intensity Numerical Rating Scale (WI-NRS) using primary and secondary anchor-based methods∗Anchor-based methods were linked to patients' reports of perception of change in WI-NRS at week 8 and were selected a priori to most closely relate to the concept measured by the WI-NRS. The PGI-C was the primary anchor variable because it is commonly used to evaluate meaningful change, including within populations with pruritus, and is recommended by the United States Food and Drug Administration. "Minimally improved," "minimally and much improved," and "much improved" anchor categories were used to represent minimal to larger improvements. The use of these anchors was justified by the absence of approved therapies for moderate to severe chronic kidney disease–associated pruritus (CKD-aP). Secondary anchors included (1) a 1-point and at least 1-point categorical severity change on the PGI-S, which corresponded to a shift in itch severity category (eg, from severe to moderate). The clinical significance of single-category shifts for CKD-aP is reinforced by data indicating that greater itch severity is linked to higher mortality; (2) the 5-D direction and degree questions asking patients whether itching got better or worse on a scale of 1 (completely resolved) to 5 (getting worse) within the past 2 to 4 weeks and to rate the intensity of their itching on a scale of 1 (not present) to 5 (unbearable), respectively; and (3) the Skindex-10 item 1 asking how often patients were bothered by itching on a scale of 0 (never bothered) to 6 (always bothered) within the past week.CriteriaWI-NRS change score (week 8 − baseline), meanChange from baseline, mean, %Effect size (Cohen d)Primary anchor PGI-C minimally improved−2.26−33.561.29 PGI-C minimally and much improved−3.02−42.991.65 PGI-C much improved−3.41−47.811.83Secondary anchors PGI-S improved 1 point−2.49−37.101.40 PGI-S improved at least 1 point−3.45−49.611.75 5-D Itch Direction (Itch)A little better−1.94−26.371.19A little better or much better−3.32−49.611.80 5-D Itch Degree (Itch Intensity)Improved 1 point−3.02−45.231.82 Skindex-10 (item 1) Itch Bothersome improved 2 points−2.65−39.051.47Mean (secondary anchors)−2.81−41.16PGI-C, Patient Global Impression of Change; PGI-S, Patient Global Impression of Severity.∗ Anchor-based methods were linked to patients' reports of perception of change in WI-NRS at week 8 and were selected a priori to most closely relate to the concept measured by the WI-NRS. The PGI-C was the primary anchor variable because it is commonly used to evaluate meaningful change, including within populations with pruritus, and is recommended by the United States Food and Drug Administration. "Minimally improved," "minimally and much improved," and "much improved" anchor categories were used to represent minimal to larger improvements. The use of these anchors was justified by the absence of approved therapies for moderate to severe chronic kidney disease–associated pruritus (CKD-aP). Secondary anchors included (1) a 1-point and at least 1-point categorical severity change on the PGI-S, which corresponded to a shift in itch severity category (eg, from severe to moderate). The clinical significance of single-category shifts for CKD-aP is reinforced by data indicating that greater itch severity is linked to higher mortality; (2) the 5-D direction and degree questions asking patients whether itching got better or worse on a scale of 1 (completely resolved) to 5 (getting worse) within the past 2 to 4 weeks and to rate the intensity of their itching on a scale of 1 (not present) to 5 (unbearable), respectively; and (3) the Skindex-10 item 1 asking how often patients were bothered by itching on a scale of 0 (never bothered) to 6 (always bothered) within the past week. Open table in a new tab PGI-C, Patient Global Impression of Change; PGI-S, Patient Global Impression of Severity. The study included 174 hemodialysis patients, who were predominantly male (60%) and African American (59%), with a median age of 59 years (range, 26-84 years) and history of chronic itching for 4.4 years. Distribution-based estimates, considered to provide lower boundaries of meaningful change thresholds, ranged from −0.67 to −1.78 points relative to a baseline WI-NRS mean of 6.8 (Supplemental Tables I and II). In the primary anchor analysis, mean changes in WI-NRS ranged from −2.26 to −3.41 points with large effect sizes (Cohen d > 1.0) associated with a priori definitions of a clinically important improvement measured by the PGI-C. This analysis was supported by the analysis of multiple secondary anchors (Table I, Fig 1). The PGI-C was identified as a primary anchor because it specifically asks patients about the improvement of their condition, taking into consideration treatment effect and patient expectation. These analyses demonstrated that a reduction of ≥3 points on the WI-NRS marks an appropriate threshold for defining a clinically meaningful change in pruritus in patients with CKD-aP. CKD-aP significantly impacts the patient's QoL, is associated with a poor prognosis, and represents a significant unmet need due to lack of treatment options. The present evidence should facilitate the development of treatments for CKD-aP that could ultimately affect patient care and clinical practice.