Worst Itch Numeric Rating Scale for Prurigo Nodularis: A Secondary Analysis of 2 Randomized Clinical Trials.

Importance: Prurigo nodularis (PN) is a debilitating skin disease characterized by the hallmark symptom of chronic itch; the intensity of itch in PN was assessed using the Worst Itch Numeric Rating Scale (WI-NRS) to evaluate the primary efficacy end point of 2 recent phase 3 studies of dupilumab treatment for PN. Objective: To validate the psychometric properties and to determine the clinically meaningful improvement threshold for WI-NRS in patients with moderate to severe PN. Design, Setting, and Participants: In this secondary analysis of the PRIME and PRIME2 trials, content validity of WI-NRS was assessed through in-depth patient interviews. Psychometric assessments used pooled data from masked, intention-to-treat (ITT) patients with PN from randomized, double-masked, and placebo-controlled studies. Psychometric assessments included test-retest reliability, construct validity, known-groups validity, and sensitivity to change in adult patients with moderate-to-severe PN. Thresholds for meaningful within-patient improvement in the WI-NRS score were determined using anchor and distribution-based approaches. Data were analyzed after completion of each study, December 2019 to November 2021 for PRIME and January 2020 to August 2021 for PRIME2. Exposures: Dupilumab (300 mg) or placebo subcutaneously every 2 weeks for 24 weeks. Main outcomes and measures: WI-NRS score at specified time points up to 24 weeks after randomization. Results: A total of 20 patients were included across the 2 studies (mean [SD] age, 49.3 [17.2] years; 11 female [55%]); 311 patients were included in the pooled intention-to-treat analysis (mean [SD] age, 49.5 [16.1] years; 203 female [65.3%]). The WI-NRS questions (20 of 20 patients), recall period (19 of 20 patients), and response scale (20 of 20 patients) were easy to understand and relevant for patients with PN. Adequate test-retest reliability was observed between screening and baseline (intraclass correlation coefficient = 0.72, using Patient Global Impression of Severity [PGIS] to define stable patients). Convergent and discriminant validity was supported by moderate to strong correlations (absolute r range = 0.34-0.73) with other conceptually related measures and weaker correlations (absolute r range = 0.06-0.32) with less-related measures, respectively. WI-NRS was sensitive to change, as demonstrated by differences in change from baseline among groups (per PGIS change and PGI of Change [PGIC]). Using anchor-based approach with PGIS and PGIC, the clinically meaningful improvement threshold was 4 points (range, 3.0-4.5), which was also supported by distribution-based methods. Conclusion and Relevance: This study found that WI-NRS may be a fit-for-purpose instrument to support efficacy end points measuring the intensity of itching in adults with PN. Trial Registration: NCT04183335 (PRIME) and NCT04202679 (PRIME2).

Prevalence, Incidence and Treatment Patterns of Prurigo Nodularis in England: A Retrospective Database Analysis.

BACKGROUND: Prurigo nodularis (PN) is a pruritic skin disease characterised by multiple, intensely itchy skin nodules in symmetrically distributed areas of the extremities. There are very limited studies on the epidemiology and treatment pathways for PN, especially moderate-to-severe PN, from England. OBJECTIVES: To assess the epidemiology and treatment pathways of mild and moderate-to-severe PN in England. METHODS: This retrospective cohort study used data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) in England. Adult patients (≥18 years) with a PN specific diagnosis code any time between 1 April 2007 and 1 March 2019 (patient identification period) were selected. Patients were included if their first PN diagnostic code (index diagnosis date, IDD) was recorded during the identification period, with data available 6 months pre- and ≥12 months post-IDD. Patients were classified into moderate-to-severe PN (MSPN) or mild PN (MiPN) based on the presence or absence of a prescription record, post IDD, for either a systemic immunosuppressant or a gabapentinoid. Patients with MSPN and MiPN were matched 1:1 for age, gender and IDD. Prevalence and incidence were calculated for each year from 2007 to 2019. Drugs prescribed post IDD were analysed. RESULTS: A total of 8,933 patients (MSPN: 2,498 patients; MiPN: 6,539 patients) were included for the study; 2,462 patients each with MiPN and MSPN were included for the comparative analysis. Atopic dermatitis, asthma and eosinophilic oesophagitis were significantly higher (all p<0.001) in patients with MSPN (vs MiPN). The prevalence of overall PN cases increased during the study period. The incidence rate also showed a similar trend. The rates of prescription of potent and super potent topical corticosteroids (TCS), topical calcineurin inhibitors, first- and second- generation antihistamines, oral and injectable systemic corticosteroid, methotrexate, antidepressants and tacrolimus were significantly higher (all p <0.001) in patients with MSPN (vs MiPN). CONCLUSIONS: The epidemiology of PN was consistent with other European studies. Patients with MSPN received a significantly higher number of prescriptions for potent TCS and systemic drugs, as compared with milder patients.

Estimating the healthcare burden of Prurigo Nodularis in England: a CPRD database study.

Purpose: Prurigo nodularis (PN) is a skin disease characterized by intensely itchy skin nodules and is associated with a significant healthcare resource utilization (HCRU). This study aimed to estimate the HCRU of patients in England with PN overall and moderate-to-severe PN (MSPN) in particular.Methods: This retrospective cohort study used data from the Clinical Practice Research Datalink and Hospital Episode Statistics in England. Patients with Mild PN (MiPN) were matched to patients with MSPN by age and gender for the primary analysis. Patients were enrolled in the study between 1st April 2007 and 1st March 2019. All-cause HCRU was calculated, including primary and secondary care contacts and costs (cost-year 2022).Results: Of 23,522 identified patients, 8,933 met the inclusion criteria, with a primary matched cohort of 2,479 PN patients. During follow up, the matched cohort's primary care visits were 21.27 per patient year (PPY) for MSPN group and 11.35 PPY for MiPN group. Any outpatient visits were 10.72 PPY and 4.87 PPY in MSPN and MiPN groups, respectively. Outpatient dermatology visits were 1.96 PPY and 1.14 PPY in MSPN and MiPN groups, respectively.Conclusion: PN, especially MSPN, has a high HCRU burden in England, highlighting the need for new and improved disease management treatments.

Responder analysis using clinically meaningful thresholds: Post hoc analyses from randomized dupilumab clinical trials in patients with prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is an intensely pruritic disease characterized by itchy nodules on the trunk/extremities; it is often accompanied by skin pain and sleep disruption with negative impacts on the quality of life (QoL). The patient-reported outcome (PRO) instruments, Worst Itch-Numeric Rating Scale (WI-NRS), Skin Pain-NRS, Sleep-NRS and Dermatology Life Quality Index (DLQI) have been psychometrically validated and the clinically meaningful within-patient improvement thresholds (responder definition) have been established through data pooled from the two Phase-3 trials (PRIME, NCT04183335 and PRIME2, NCT04202679) of dupilumab in adults with PN uncontrolled on topical therapies. OBJECTIVES: To estimate the proportion of dupilumab-treated patients (vs. placebo) achieving clinically meaningful improvement in itch, skin pain, sleep and QoL, either alone or in combination, from the data pooled from PRIME and PRIME2 trials. METHODS: The patient-level data pooled from the two Phase-3 trials (N = 311) were used for this post hoc analysis. Thresholds of clinically meaningful within-patient improvement in PRO instrument scores from baseline at Week 24 used for defining responders were 4 (WI-NRS and Skin Pain-NRS), 2 (Sleep-NRS) and 9 points (DLQI). The proportion of dupilumab-treated patients, versus placebo, achieving the thresholds, and the time taken to achieve the thresholds were evaluated for the individual and combination of PROs. RESULTS: Responder rates were significantly higher with dupilumab, versus placebo at Week 24 for WI-NRS (58.8% vs. 19.0%, p < 0.0001), Skin Pain-NRS (49.7% vs. 20.9%, p < 0.0001), Sleep-NRS (42.5% vs. 23.4%, p < 0.0001) and DLQI (64.7% vs. 22.8%, p < 0.0001). Proportion of patients achieving simultaneous improvement in symptoms and QoL (24.8% vs. 6.3%, p < 0.0001) were significantly higher in dupilumab-treated patients versus placebo. The time needed for achieving clinically meaningful improvement in symptoms were significantly lower in dupilumab-treated patients, versus placebo. CONCLUSIONS: Significantly greater proportion of dupilumab-treated patients with PN, versus placebo, demonstrated clinically meaningful improvements in PRO measures of symptoms and QoL.

Validation of a scoring algorithm for the clinician-reported outcome tool 'prurigo activity and severity (PAS)' based on clinical studies of dupilumab in adults with prurigo Nodularis.

BACKGROUND: Prurigo nodularis (PN) also known as chronic prurigo, is a chronic inflammatory skin disease characterized by intensely itchy nodules/lesions which occur due to intensive scratching. PN management is, in part, based on clinician evaluations of PN lesions, which can be supported by clinician-reported outcomes (ClinRO) such as the Prurigo Activity and Severity (PAS) instrument. A 5-item version of PAS was included in recent phase-3 dupilumab PN trials (PRIME [NCT04183335]/PRIME2 [NCT04202679]). The PAS score was derived using the unweighted sum of 3-items of the 5-item PAS (range, 0-11; higher score indicates worse activity and severity): Item 2 (number of lesions), Item 5a (percentage of lesions with excoriations/crusts) and Item 5b (percentage of healed lesions) for use in clinical practice and for communication of treatment benefit to physicians. OBJECTIVES: To evaluate the measurement properties of PAS score and derive within-patient (responder definition) and between-group improvement thresholds for interpreting changes in PAS score in patients with PN. METHODS: The data source was the pooled treatment group, intention-to-treat (ITT) data from the phase-3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. PAS score reliability, validity and sensitivity to change were evaluated, and anchor- and distribution-based methods were applied to derive meaningful change thresholds. RESULTS: The pooled ITT population included 311 patients (mean age 49.5 years, 65.3% female). Adequate to good psychometric properties were demonstrated for PAS score. The within-patient meaningful improvement threshold was estimated as 3.0 points (absolute change) and 37% (per cent change). A 1.7-point (absolute change) and 20% (per cent change) improvement were estimated to reflect a between-group meaningful change in PAS score. CONCLUSIONS: PAS score is a simple, clinically relevant indicator of PN lesion activity and severity supported by suitable psychometric performance.