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.

Development and testing of an alternative responder definition for EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI).

OBJECTIVES: Dryness, fatigue and joint/muscle pain are typically assessed in Sjögren's trials using European Alliance of Associations for Rheumatology Sjögren's Syndrome Patient Reported Index (ESSPRI). A Patient Acceptable Symptom State of <5 and a Minimal Clinically Important Improvement (MCII)/responder definition (RD) of ≥1 point or 15% on ESSPRI have previously been defined. This study explored alternative RDs to better discriminate between active treatment and placebo in trials. METHODS: Anchor-based and distribution-based methods were used to derive RD thresholds in blinded phase IIb trial data (N=190) and confirm these in blinded data pooled from three early phase II trials (N=126). The populations consisted of individuals with moderate-to-severe systemic primary Sjögren's. Anchors were prioritised by ESSPRI correlations and used in similar conditions. Triangulated estimates were discussed with experts (N=3). The revised RD was compared with the original using unblinded data to assess placebo and treatment responder rates. RESULTS: Patients were predominantly female (>90%), white (90%), with mean age of 50 years. Receiver operating characteristic estimates supported an MCII threshold of 1.5-1.6 in the phase II data, whereas correlation-weighted mean change estimates supported a low/minimal symptom severity threshold of ≥2. A low/minimal symptom severity of ≤3 showed the greatest sensitivity/specificity balance. Analyses in the pooled data supported these thresholds (MCII: 1.5-2.1; low/minimal symptom severity: 2.7-3.7). Unblinded analyses confirmed the revised RD reduced placebo rates. CONCLUSIONS: Completing a trial with an improvement of ≥1.5 points compared with baseline and an ESSPRI score of ≤3 points is a relevant RD for moderate-to-severe systemic Sjögren's and reduces placebo rates.

A qualitative study to explore the symptoms and impacts of Crohn's disease and to develop the Crohn's Disease Diary.

PURPOSE: To explore symptoms and disease impacts of Crohn's disease and to develop a new patient-reported outcomes (PRO) measure according to industry best practices. METHODS: A conceptual model of relevant symptoms experienced by patients with Crohn's disease was developed following a literature review. Three rounds of combined qualitative semi-structured concept elicitation and cognitive debriefing interviews with 36 patients (≥ 16 years) with Crohn's disease and 4 clinicians were conducted to further explore the most commonly reported and most bothersome symptoms to patients. Interview results were used to update the conceptual model as well as items and response options included in The Crohn's Disease Diary, a new PRO measure. RESULTS: All patients (N = 36) reported abdominal pain, loose or liquid bowel movements, and high or increased frequency of bowel movements, with most reporting these symptoms spontaneously (100%, 92%, and 75%, respectively). All patients reported bowel movement urgency, but 61% reported this symptom only when probed. Most also reported that symptoms impacted activities of daily living, work/school, and emotional, social, and physical functioning (overall, 78%-100%; spontaneously, 79% - 92%). Data regarding core symptoms of Crohn's disease from clinician concept elicitation interviews supported patient data. The 17-item Crohn's Disease Diary assesses core symptoms and impacts of Crohn's disease over 24 h, and extraintestinal manifestations over 7 days. The content validity of the diary was confirmed during cognitive debriefing interviews. CONCLUSION: The Crohn's Disease Diary is a new PRO measure for the assessment of Crohn's disease symptoms and impacts, developed according to industry best practices.

Qualitative Research with Patients and Physicians to Assess Content Validity and Meaningful Change on ESSDAI and ESSPRI in Sjögren's.

INTRODUCTION: European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) is a clinician-reported outcome (ClinRO) instrument, assessing Sjögren's disease activity from the physician perspective. EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is a patient-reported outcome (PRO) instrument, assessing patient-defined Sjögren's symptom severity. Both instruments are commonly used as clinical trial endpoints and have been psychometrically validated. However, qualitative evidence supporting content validity and what constitutes a meaningful change is limited. Qualitative evidence supporting Physician/Patient Global Assessment of disease activity and symptom severity (PhGA/PaGA) items used within anchor-based analyses for ESSDAI/ESSPRI is also lacking. METHODS: Qualitative, semi-structured, telephone/video interviews were conducted with patients with Sjögren's (n = 12) and physicians who specialise in Sjögren's (n = 10). Interviews explored: appropriateness of ESSDAI domain weights and meaningful improvements on domain/total scores from the physician perspective, appropriateness of ESSPRI's 2-week recall period from the patient/physician perspective, patients' perspectives on meaningful improvements in ESSPRI total scores, and patients'/physicians' interpretation of PhGA/PaGA items. RESULTS: Most ESSDAI domain weights were considered clinically appropriate. Generally, a one-category improvement in domain-level scores and a 3-point improvement in total ESSDAI scores were considered clinically meaningful. Most patients/physicians considered ESSPRI's 2-week recall period appropriate, and patients considered a 1-to-2-point ESSPRI total score improvement meaningful. PhGA/PaGA items developed for use as ESSDAI/ESSPRI anchors were consistently interpreted. CONCLUSIONS: The findings support use of ESSDAI and ESSPRI as Sjögren's clinical trials endpoints, as well as in clinical practice and other research settings. Qualitative data exploring meaningful change supports existing minimal clinically important improvement (MCII) thresholds.

European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) is an assessment used by physicians to measure how active Sjögren's is in individuals with the condition. EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is a questionnaire completed by individuals with Sjögren's to assess the severity of their symptoms. It is important to show that ESSDAI and ESSPRI are considered appropriate by physicians and individuals with Sjögren's, respectively, and that ESSPRI is well understood by individuals with Sjögren's completing the questionnaire. Therefore, interviews were conducted with physicians who specialise in Sjögren's to explore the appropriateness of ESSDAI, the level of improvement on the assessment that would be important to individuals with Sjögren's, and the appropriateness of the ESSPRI recall period (i.e. whether it is acceptable to ask individuals to remember their symptoms over the past 2 weeks). Interviews were also conducted with individuals with Sjögren's to explore their understanding and relevance of ESSPRI (including the 2-week recall period) and the level of improvement on the questionnaire that would be important to them. Most physicians and patients considered ESSDAI and ESSPRI appropriate, supporting their use in a range of settings including Sjögren's clinical trials, clinical practice and other research settings. Most physicians reported that a 3-point improvement in ESSDAI total score would be meaningful to individuals with Sjögren's. Individuals with Sjögren's reported that a 1-to-2-point improvement in ESSPRI total score would be meaningful.

Content Validity of Sjögren's Syndrome Symptom Diary and Functional Assessment of Chronic Illness Therapy-Fatigue in Patients with Sjögren's.

INTRODUCTION: Sjögren's Syndrome Symptom Diary (SSSD) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) are patient-reported outcome (PRO) instruments assessing Sjögren's symptoms. Original SSSD items have demonstrated content validity, however qualitative evidence supporting the updated 'tiredness' item and two new supplementary items is lacking. Although well established and validated in other rheumatic diseases, there is no qualitative evidence supporting content validity of FACIT-F in Sjögren's. This study addressed these evidence gaps to support use of SSSD and FACIT-F as clinical trial endpoints, in clinical practice and in other research settings. METHODS: Qualitative, semi-structured telephone interviews were conducted with patients with Sjögren's (n = 12) and expert Sjögren's physicians (n = 10). Patient interviews explored content validity (e.g., understanding and relevance) of the new and updated SSSD items, perceptions of item and total score meaningful change on SSSD, and understanding and relevance of FACIT-F items. Physician interviews explored opinions on various SSSD scoring approaches. RESULTS: The new and updated SSSD items and FACIT-F demonstrated good content validity. Most patients considered a two-point improvement on most SSSD items meaningful, as well as a one- or two-point total score improvement. Most physicians reported tracking changes in patient responses to individual items as the most appropriate SSSD scoring approach. CONCLUSIONS: SSSD and FACIT-F are content valid in a Sjögren's population, meeting an important criterion to support their use as clinical trial endpoints, but also their use in clinical practice and other research settings. Qualitative data exploring meaningful change will be valuable in supporting psychometrically derived responder definitions.

Sjögren's Syndrome Symptom Diary (SSSD) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) are questionnaires completed by individuals with Sjögren's to assess the severity of their symptoms. It is important to show that these questionnaires are well understood and relevant to the individuals who complete them. Therefore, interviews were conducted with individuals with Sjögren's to explore their understanding and relevance of new and updated SSSD questions. Similarly, the interviews explored whether the FACIT-F questionnaire was well understood and relevant to individuals with Sjögren's, as this has not been explored before. Interviews were also conducted with expert Sjögren's physicians to explore the best approach to scoring SSSD (e.g., calculating a total score or looking at scores on individual items). The new and updated SSSD questions and the FACIT-F questionnaire were well understood and considered relevant by most individuals with Sjögren's. This suggests these questionnaires are appropriate for use in Sjögren's clinical trials, clinical practice, and other research settings. Most individuals with Sjögren's considered an improvement of two points on individual SSSD questions to be important, as well as a one- or two-point improvement in their total SSSD score. Most physicians agreed on the best approach to scoring SSSD.

The endometriosis daily diary: qualitative research to explore the patient experience of endometriosis and inform the development of a patient-reported outcome (PRO) for endometriosis-related pain.

PURPOSE: Endometriosis is a chronic disorder of the female reproductive system characterized by debilitating symptoms, particularly endometriosis-related pain (ERP). Patient-reported outcome (PRO) measures of symptoms and impacts are required to assess disease severity in ERP clinical studies and clinical practice. A content-valid instrument was developed by modifying the Dysmenorrhea Daily Diary (DysDD) to form the Endometriosis Daily Diary (EDD), an electronic PRO administered via handheld device. METHODS: Qualitative research with US females with ERP was conducted in three stages: (1) Development of an endometriosis conceptual model based on qualitative literature and conduct of concept elicitation (CE) interviews (N = 30). (2) Cognitive debriefing (CD) interviews (N = 30) conducted across two rounds to assess relevance and understanding of the EDD, with modifications between interview rounds. (3) Pilot testing to assess usability/feasibility of administrating the EDD daily on an electronic handheld device (N = 15). Clinical experts provided guidance throughout the study. RESULTS: The conceptual model provided a comprehensive summary of endometriosis to inform modifications to the DysDD, forming the EDD. CD results demonstrated that EDD items were relevant for most participants. Instructions, items, response scales, and recall period were well-understood. The resulting daily diary assesses severity of cyclic and non-cyclic pelvic pain, dyspareunia, impact of ERP on functioning and daily life, symptoms associated with ERP, and bowel symptoms. Participants were able to complete the diary daily and found the device easy to use. CONCLUSION: The EDD demonstrated good content validity in females experiencing ERP. The next step is to perform psychometric validation in an ERP sample.

Perceptions of gendered and ungendered pain relief norms and stereotypes using Q-methodology.

Pain is ubiquitous, but effective pain relief eludes many. Research has shown that some pain behaviours are perceived as gendered, and this may influence the way men and women express and cope with pain, but such enquiries have not extended to specific methods of pain relief. Our aim was to explore perceptions of the most socially acceptable ways for men and women to relieve pain. Across 2 studies, 60 participants (50% men) aged 18 to 78 years completed a Q-sort task, sorting different pain relief strategies by the social acceptability for either women (study 1; N = 30) or men (study 2; N = 30). Analyses revealed 2 stereotypes for each sex. The overarching stereotype for women suggested it is most acceptable for them to use pain relief strategies considered conventional and effective. However, a second stereotype suggested it is most acceptable for women to use strategies that generally conform to feminine gender norms and stereotypes. The overarching male stereotype suggested it is most acceptable for men to use pain relief aligned with stereotypical masculinity; however, a second stereotype also emerged, characterised by conventional and effective responses to pain, much like the overarching stereotype for women. These differing viewpoints seem to depend on whether gender norm conformity or perceived analgesic efficacy is believed to determine social acceptability. These studies provide initial evidence of both a gendered and ungendered lens through which pain relief can be viewed, which may influence how men and women use pain relief.