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.

Burden of Atopic Dermatitis in Pediatric Patients: An International Cross-sectional Study.

BACKGROUND: Few large-scale international studies broadly characterized the burden of atopic dermatitis (AD) across age groups among children and adolescents. OBJECTIVE: To better characterize the AD burden in pediatric subjects by disease severity. METHODS: This cross-sectional, web-based survey of pediatric subjects (6 months to <18 years old) was conducted in 18 countries representing North America, Latin America, Europe, Middle East/Eurasia, and East Asia. Subjects with diagnosed AD were identified based on the International Study of Asthma and Allergies in Childhood criteria and self-/parent-report of ever being told by a physician that they/their child had eczema. AD severity was assessed using Patient Oriented Eczema Measure and Patient Global Assessment. Outcomes included measures of itch, skin pain, sleep, health-related quality-of-life (HRQoL), missed school days, and atopic comorbidities. RESULTS: The survey included 1489 children 6 months to < 6 years; 2898 children 6 to < 12 years; and 3078 adolescents 12 to < 18 years diagnosed with AD. Although the burden of mild AD was substantial, pediatric subjects with moderate or severe AD had more itch, skin pain, sleep problems, and impaired HRQoL, and missed more school days relative to those with mild AD; greater burden was observed among severe relative to moderate AD. At least one atopic comorbidity was present in 92·5% of all respondents. CONCLUSIONS: These results highlight the burden of AD in pediatric subjects especially those with moderate-to-severe disease, and suggest the need for assessments that include the impact of AD on function and daily life.

Experience of Daily Life with Generalized Myasthenia Gravis: A Qualitative Investigation and Assessment of Instrument Content Validity.

INTRODUCTION: Generalized myasthenia gravis (gMG) is a rare autoimmune disease. Symptoms of gMG are diverse, and understanding of their impact on patients is limited. This qualitative study aimed to provide an in-depth exploration of patients' daily experiences of gMG. METHODS: Published qualitative studies were reviewed to identify the most important signs, symptoms, and functional impacts related to the patient experience in gMG. Semi-structured hybrid concept elicitation interviews (allowing spontaneous generation of disease concepts) and cognitive debriefing interviews (assessing the validity of existing disease assessments) were conducted with clinicians and adult patients with gMG. Signs, symptoms, and impacts were reviewed to understand which were most salient (i.e., reported by at least 50% of patients, with disturbance rating 5 or higher [10-point numeric scale]); concept saturation was also assessed. The disease conceptual model was updated. Existing clinical outcomes assessments (COAs) that capture how patients feel, function, and survive were assessed. RESULTS: Interviews with patients (n = 24) identified seven new signs and symptoms and 37 new impacts compared with the literature. Concept saturation was reached. Signs and symptoms identified by patients as most important (salient) were shortness of breath, general fatigue, muscle weakness of arms, legs, and neck, dysphonia, dysarthria, trouble swallowing liquids, choking, and heat sensitivity. Patient-identified salient impacts were work life, depression, difficulty walking, grooming hair, showering, and brushing teeth, eating, personal relationships, family life, and participating in social activities. Clinicians considered ocular, respiratory, swallowing, speech/talking, and extremity function as key clinical manifestations of gMG. Patients and clinicians found clinical outcome assessments (COAs) to be conceptually relevant and comprehensive. CONCLUSION: This research provides a holistic understanding of gMG signs, symptoms, and impacts experienced by patients, as observed by patients and clinicians. The conceptual model of gMG highlights the range of signs, symptoms, and impacts that adult patients with gMG experience in their everyday lives, emphasizing the humanistic impact and unmet needs.

Development of a disease conceptual model of patient experience with metastatic colorectal cancer: identification of the most salient symptoms and impacts.

PURPOSE: Patients with metastatic colorectal cancer (mCRC) experience multiple symptoms and impacts affecting their health-related quality of life. However, there is limited data on self-reported experience of the most relevant and bothersome aspects of patients living with mCRC. METHODS: Semi-structured interviews were conducted in patients with mCRC to identify and understand the signs, symptoms and impacts experienced. Patients were also asked to rate the level of bothersomeness for each concept reported on a scale ranging from 0 ("not bothersome at all") to 10 ("extremely bothersome"). Verbatim transcripts were analysed following a thematic analysis approach. The most salient concepts were identified (i.e. reported by > 50% of patients with a bothersome rating ≥ 5 out of 10). RESULTS: Twenty-five patients (USA; age: 26 to 72 years old) were interviewed. Patients reported 58 signs and symptoms, amongst which 8 were considered salient: fatigue, nausea, neuropathy, diarrhoea, loss of appetite, constipation, weight loss, and abdominal pain; 35 impacts were identified, and 7 were considered salient: reduced ability to work, interference with daily activities, impact on cognitive functioning, financial impact, sleep changes, impact on social life and walking difficulties. The concepts identified helped refine a literature-based disease conceptual model of patient experience with mCRC. CONCLUSIONS: The interviews provided insights into the most bothersome and salient signs, symptoms and impacts affecting the HRQoL of patients living with mCRC. IMPLICATIONS FOR CANCER SURVIVORS: There is a need to improve clinical strategies for future clinical development and inform clinical practice decision-making for mCRC survivors.

Development, Psychometric Validation and Responder Definition of Worst Itch Scale in Children with Severe Atopic Dermatitis.

INTRODUCTION: Itch associated with atopic dermatitis (AD) has a profoundly negative effect on patients of all ages. Therefore, itch is a main target for AD therapeutic approaches, and treatments are perceived as beneficial when they achieve an itch reduction. In the absence of a validated scale for children aged 6-11 years that is suitable for assessing itch intensity in clinical trial settings, the Worst Itch Scale was developed. METHODS: Qualitative interviews, comprising concept elicitation and cognitive debriefing, were conducted to develop and evaluate the content validity of the Worst Itch Scale. Psychometric assessments used data from the LIBERTY AD PEDS phase 3 trial of dupilumab in patients aged 6-11 years with severe AD. These included test-retest reliability, construct validity, known-groups validity and responsiveness. Thresholds for clinically meaningful change were defined using anchor- and distribution-based methods. RESULTS: The Worst Itch Scale consisted of two items asking about 'worst itching' experienced 'last night' and 'today'. Worst Itch Scale scores showed large, positive correlations with existing patient-reported outcome (PRO) measures of itch, and weaker correlations with clinician-reported outcome (ClinRO) measures assessing objective signs of AD. Improvements in Worst Itch Scale scores were highly correlated with improvements in other itch PROs and moderately correlated with improvements in ClinROs. The responder definition based on the primary anchor, a 1-point improvement in the Patient Global Impression of Disease, was 2.84. Supportive anchors produced response estimates ranging from 2.43 to 4.80 points. CONCLUSIONS: The Worst Itch Scale is a fit-for-purpose (e.g. well-defined, reliable, responsive and valid) scale for evaluating worst itch intensity in children aged 6-11 years with severe AD. The within-patient threshold for defining a clinically meaningful response was a ≥ 3-4-point change in the Worst Itch Scale score. TRIAL REGISTRATION: NCT03345914. Video: How can we reliably assess itch intensity in children 6-11 years with severe atopic dermatitis in clinical trial settings?

The Family Impact of Atopic Dermatitis in the Pediatric Population: Results from an International Cross-sectional Study.

OBJECTIVE: To evaluate the impact of atopic dermatitis on families of pediatric patients. STUDY DESIGN: This cross-sectional, web-based survey of children/adolescents (6 months to <18 years old) with atopic dermatitis and their parents and caregivers was conducted in 18 countries encompassing North America, Latin America, Europe, Middle East/Eurasia, and East Asia. Children and adolescents with atopic dermatitis and their parents and caregivers were identified by the International Study of Asthma and Allergies in Childhood criteria and ever being told by a physician that they had "eczema". Atopic dermatitis severity was assessed using the Patient-Oriented Eczema Measure and the Patient Global Assessment. Atopic dermatitis impact on families' lives was evaluated using the Dermatitis Family Impact questionnaire and stand-alone questions on hours of atopic dermatitis-related care (past week) and missed work days (past 4 weeks) owing to their child's atopic dermatitis. RESULTS: A total of 7465 pairs of pediatric participants with atopic dermatitis and their parents or caregivers were surveyed. Across age groups, the Dermatitis Family Impact questionnaire total score for all regions ranged from 7.1 to 8.6, 13.2 to 14.9, and 17.0 to 17.2 for Patient-Oriented Eczema Measure mild, moderate, and severe atopic dermatitis, respectively. Subscale scores showed that greater atopic dermatitis severity had a greater impact on all family life domains, including sleep and tiredness. No specific patterns or trends were observed across age groups. Time spent on childcare and missed work days increased with atopic dermatitis severity. CONCLUSIONS: Across pediatric age groups and geographic regions, greater atopic dermatitis severity was associated with a greater negative impact on physical, emotional, social, and economic components of family life.

Novel Questionnaires for Assessing Signs and Symptoms of Eosinophilic Esophagitis in Children.

BACKGROUND: Pediatric patients with eosinophilic esophagitis (EoE) experience heterogeneous symptoms and the patient's age may preclude reliable self-report of symptoms. OBJECTIVE: The goal of this study was to develop a patient-reported outcome and an observer-reported outcome questionnaire to evaluate the signs and symptoms of EoE in pediatric patients (≥1 to <12 y of age) in a clinical trial setting. METHODS: A concept-focused literature review, expert advice meetings, and concept elicitation interviews with pediatric EoE patients and their caregivers were conducted to identify disease-related signs and symptoms. Instructions, items, and response options were drafted. Cognitive debriefing interviews were conducted to evaluate children's and caregivers' ability to understand and respond to the questionnaires and to evaluate the comprehensiveness of the concepts measured. RESULTS: Results from the literature review, expert advice meetings (n = 6), and concept elicitation interviews (n = 24) informed the development of the Pediatric Eosinophilic Esophagitis Sign/Symptom Questionnaire intended for use by patients (PESQ-P) with EoE 8 years or older to younger than 12 years and an observer-reported outcome questionnaire planned for use by caregivers of patients (PESQ-C) 1 year old or older to younger than 12 years. Both questionnaires measure the same concepts; the PESQ-P assesses the frequency, duration, and/or severity of symptoms and the PESQ-C assesses the presence/absence of the signs/symptoms. The cognitive debriefing interviews (n = 17) demonstrated that participants were able to comprehend and complete the questionnaires as intended. CONCLUSIONS: This study provides evidence of the content validity of 2 novel questionnaires, PESQ-P and PESQ-C, designed to evaluate the symptom experience of pediatric EoE patients in a clinical trial setting.

Dupilumab improves health related quality of life: Results from the phase 3 SINUS studies.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2-mediated inflammatory disease with high symptom burden and reduced health-related quality of life (HRQoL). This report aimed to comprehensively understand the effects of dupilumab on domains of HRQoL, their individual elements, and health status in patients with severe CRSwNP from phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) trials. METHODS: Patients were randomized to dupilumab (n = 438) or placebo (n = 286) for 24 weeks (SINUS-24), or 52 weeks (SINUS-52). Disease-specific HRQoL using 22-item sino-nasal outcome test (SNOT-22), and health status using EuroQoL-visual analog scale (EQ-VAS) was evaluated in the pooled intention-to-treat (ITT) population (Week 24), SINUS-52 ITT (Week 52) and in the subgroups with/without asthma; non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD); and prior sinus surgery. RESULTS: At baseline, patients had poor disease-specific HRQoL and general health status and identified "Decreased sense of smell/taste" and "Nasal blockage" as the most important symptoms. Dupilumab significantly improved SNOT-22 total, domain (Nasal, Sleep, Function, Emotion, and Ear/facial), and 22-item scores, and EQ-VAS, at Week 24 vs placebo (all p < .0001), with continued improvements to Week 52 in SINUS-52. Improvements occurred irrespective of comorbid asthma, NSAID-ERD, or prior surgery. A significantly greater proportion of dupilumab-treated patients exceeded clinically meaningful thresholds for SNOT-22 total score and EQ-VAS vs placebo (all subgroups p < .05 except patients without surgery at Week 24). CONCLUSIONS: Dupilumab treatment led to significant clinically meaningful improvements across all aspects of disease-specific HRQoL, and general health status in patients with severe CRSwNP.

Estimating Clinically Meaningful Change of Efficacy Outcomes in Inadequately Controlled Chronic Rhinosinusitis with Nasal Polyposis.

OBJECTIVES/HYPOTHESIS: Clinical trials of biologics to treat chronic rhinosinusitis with nasal polyposis (CRSwNP) have evaluated objective outcomes (e.g., University of Pennsylvania Smell Identification Test [UPSIT], nasal polyps score [NPS], and computed tomography Lund-Mackay score [CT-LMK]) and patient-reported symptoms (e.g., nasal congestion/obstruction [NC], loss of smell [LoS], and total symptom score [TSS]). We estimated anchor-based thresholds for clinically meaningful change in objective and patient-reported outcomes in patients with CRSwNP using data from LIBERTY NP SINUS-24 and SINUS-52 trials (NCT02912468; NCT02898454). METHODS: Target patient-reported outcomes were NC, LoS, and TSS; target objective outcomes were UPSIT, NPS, and CT-LMK. Anchor measures were the 22-item sinonasal outcome test (SNOT-22) rhinologic symptoms domain and total score and rhinosinusitis visual analog scale (VAS). The appropriateness of each anchor measure was evaluated by reviewing correlations between change in anchor measures and target outcomes and descriptive scores on target outcomes by levels of change in the anchor measure. Established thresholds for anchor measures (3.8 points for SNOT-22 rhinologic symptoms, 8.9 points for SNOT-22 total, 1-category improvement for rhinosinusitis VAS) were used to estimate clinically meaningful score changes for each target outcome. RESULTS: Based on correlations between change in anchor measures and target outcomes, SNOT-22 rhinologic symptoms domain was deemed the most appropriate anchor measure. Using this anchor measure, thresholds for clinically meaningful within-patient change were NC: 1 point; LoS: 1 point; TSS: 3 points; UPSIT: 8 points; NPS: 1 point; and CT-LMK: 5 points. CONCLUSION: These thresholds support interpretation of efficacy results for target outcomes in CRSwNP trials. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:265-271, 2022.

Development of Sinonasal Outcome Test (SNOT-22) Domains in Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES/HYPOTHESIS: The 22-item Sinonasal Outcome Test (SNOT-22) is a validated chronic rhinosinusitis health-related quality-of-life outcome (HRQoL) measure; however, SNOT-22 domains have not been validated specifically for chronic rhinosinusitis with nasal polyps (CRSwNP). STUDY DESIGN: Validation of SNOT-22 domain structure, using data from 3 randomized, placebo-controlled, double-blinded, multicenter clinical trials of dupilumab in adults with moderate-to-severe CRSwNP. METHODS: Preliminary dimensional structure was derived by exploratory factor analyses of SNOT-22 data from a phase 2 trial (NCT01920893) of dupilumab for the treatment of CRSwNP. Data from 2 phase 3 clinical trials (NCT02912468 and NCT02898454) were then used for confirmatory factor analysis, and evaluated for reliability, construct validity, and responsiveness. In all three trials, the SNOT-22 was administered electronically on a tablet and trial participants were required to answer all items. RESULTS: Factor analysis supported five domains: Nasal, Ear/Facial, Sleep, Function, and Emotion. Correlations between domains were moderate to high, ranging from 0.53 (Nasal-Emotion) to 0.88 (Function-Sleep). Construct validity was mostly supported; relationships with other measures were almost always in the intended direction and magnitude. Internal consistency reliability also confirmed questionnaire structure with strong Cronbach's alpha values (all >0.80). Moderate-to-high correlations were observed between change in SNOT-22 domain scores and other study patient-reported outcome measures, along with large effect-size estimates (≥0.7), demonstrating responsiveness of the Nasal, Sleep, and Function domains. Emotion and Ear/Facial domains had small-to-moderate effect sizes. CONCLUSIONS: Psychometric analyses support the validity, reliability, and responsiveness of five domains of SNOT-22 (Nasal, Ear/Facial, Sleep, Function, and Emotion) for assessing symptoms and impact on HRQoL in patients with CRSwNP. Laryngoscope, 132:933-941, 2022.

Dupilumab in CRSwNP: Responder Analysis Using Clinically Meaningful Efficacy Outcome Thresholds.

OBJECTIVES/HYPOTHESIS: Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, significantly improved outcomes for patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-24 and SINUS-52 studies. This post hoc analysis evaluated dupilumab's effect on patient-reported symptoms and objective outcome measures using thresholds of clinically meaningful within-patient change from baseline. METHODS: Patients with CRSwNP receiving subcutaneous dupilumab or placebo every 2 weeks in SINUS-24/SINUS-52 were analyzed. Patients recorded severity of nasal congestion (NC), loss of smell (LoS), and anterior/posterior rhinorrhea (each within range 0-3) daily. Total Symptom Score (TSS) was calculated as a composite severity score (0-9) for these symptoms. Objective measures included University of Pennsylvania Smell Identification Test (UPSIT; 0-40), nasal polyps score (NPS; 0-8), and Lund-Mackay computed tomography score (LMK-CT; 0-24). Thresholds of within-patient change in scores from baseline at weeks 24 and 52 considered clinically meaningful were ≥1.0 (NC, LoS), ≥3.0 (TSS), ≥8.0 (UPSIT), ≥1.0 (NPS), and ≥5.0 (LMK-CT). RESULTS: A total of 724 and 303 patients were included in the week 24 and 52 analyses, respectively. Responder rates were significantly higher with dupilumab versus placebo at week 24 for NC (64% vs. 24%), LoS (63% vs. 14%), TSS (62% vs. 15%), UPSIT (54% vs. 6%), NPS (63% vs. 14%), and LMK-CT (59% vs. 3%); all P < .0001. Results were consistent at week 52. CONCLUSION: Significantly greater proportions of dupilumab-treated patients with CRSwNP compared with placebo demonstrated clinically meaningful improvements in patient-reported sinonasal symptoms and objective outcomes. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:259-264, 2022.

Definition of Clinically Meaningful Within-Patient Changes in POEM and CDLQI in Children 6 to 11 Years of Age with Severe Atopic Dermatitis.

INTRODUCTION: The Patient-Oriented Eczema Measure (POEM) assesses patient-reported severity of atopic dermatitis (AD) symptoms, whereas the Children's Dermatology Life Quality Index (CDLQI) measures how AD affects health-related quality of life (HRQoL) in children. Although the POEM and CDLQI have established thresholds for clinically meaningful within-patient change in adolescents (aged 12-17 years), there are no defined within-patient responder thresholds for clinically meaningful change in children aged 6-11 years. METHODS: Data from the LIBERTY AD PEDS phase 3 randomized, double-blind, placebo-controlled trial of dupilumab in children aged 6-11 years with severe AD were used to define the threshold for within-patient meaningful change in POEM and CDLQI scores. Anchor-based methods were applied to estimate mean change in POEM and CDLQI scores from baseline to week 16, with anchors of a 1-point improvement in the Patient Global Impression of Disease (PGID) scale and an improvement in score of ''A little better'' on the Patient Global Impression of Change (PGIC) scale. The distribution-based methods, a one-half standard deviation (SD) at baseline and a standard error mean (SEM) were also used. RESULTS: The mean POEM change scores associated with the anchors were a change of - 8.40 with the PGID anchor and - 6.30 with the PGIC anchor. Distribution-based estimates for POEM were one-half SD at baseline of 2.76, with a SEM of 3.32. Mean CDLQI change scores corresponding to the PGID and PGIC anchors were - 7.30 and - 6.80, respectively, while distribution-based estimates for CDLQI were a one-half SD at baseline of 3.69, with a SEM of 3.52. CONCLUSIONS: In children with severe AD, an appropriate minimum threshold of clinically meaningful within-patient change was estimated as 6 points for both the POEM and CDLQI scores. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03345914. What is the clinically meaningful within-person change in Patient-Oriented Eczema Measure and Children's Dermatology Life Quality Index scores in children 6 to 11 years old with severe atopic dermatitis? (MP4 289443 KB).

Atopic dermatitis in the pediatric population: A cross-sectional, international epidemiologic study.

BACKGROUND: Little is known on the current global prevalence of atopic dermatitis (AD) in the pediatric population. OBJECTIVE: To estimate the real-world global prevalence of AD in the pediatric population and by disease severity. METHODS: This international, cross-sectional, web-based survey of children and adolescents (6 months to <18 years old) was conducted in the following 18 countries: North America (Canada, United States), Latin America (Argentina, Brazil, Columbia, Mexico), Europe (France, Germany, Italy, Spain, United Kingdom), Middle East and Eurasia (Israel, Saudi Arabia, Turkey, United Arab Emirates, Russia), and East Asia (Japan, Taiwan). Prevalence was determined using the following 2 definitions: (1) diagnosed as having AD according to the International Study of Asthma and Allergies in Childhood (ISAAC) criteria and self- or parent-report of ever being told by a physician that they or their child child had AD (eczema); and (2) reported AD based on the ISAAC criteria only. Severity was assessed using the Patient Global Assessment (PtGA) and Patient-Oriented Eczema Measure (POEM). RESULTS: Among 65,661 responders, the 12-month diagnosed AD prevalence (ISAAC plus self-reported diagnosis) ranged from 2.7% to 20.1% across countries; reported AD (ISAAC only) was 13.5% to 41.9%. Severe AD evaluated with both PtGA and POEM was generally less than 15%; more subjects rated AD as mild on PtGA than suggested by POEM. No trends in prevalence were observed based on age or sex; prevalence was generally lower in rural residential settings than urban or suburban. CONCLUSION: This global survey in 18 countries revealed that AD affects a substantial proportion of the pediatric population. Although prevalence and severity varied across age groups and countries, less than 15% had severe AD.

Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS.

BACKGROUND: Pruritus (itch) is a cardinal symptom in atopic dermatitis (AD). OBJECTIVE: To evaluate the timing and effect of dupilumab on itch. METHODS: Analysis of data from 1505 patients with moderate to severe AD included in 4 randomized controlled studies, treated for up to 52 weeks. Adults received dupilumab 300 mg every 2 weeks or placebo monotherapy (SOLO 1: NCT02277743; SOLO 2: NCT02277769), with concomitant topical corticosteroids (CHRONOS: NCT02260986); adolescents (≥12 to <18 y) were treated with dupilumab monotherapy every 2 weeks (200 mg for baseline weight of <60 kg; 300 mg for baseline weight of ≥60 kg) or placebo (AD ADOL: NCT03054428). RESULTS: Dupilumab showed significant rapid improvements from baseline in daily Peak Pruritus Numerical Rating Scale scores versus placebo, by day 2 in adults and day 5 in adolescents. At treatment end, dupilumab vs placebo/control had greater least-squares mean percent change from baseline in the weekly average of Peak Pruritus Numerical Rating Scale scores: SOLO -47.5% vs -20.5%; AD-ADOL -47.9% vs -19.0%; CHRONOS -57.3% vs -30.9% (P < .0001 for all). LIMITATIONS: Short duration of monotherapy trials (16 weeks). CONCLUSION: Across 4 randomized trials, dupilumab treatment showed rapid and sustained improvements in the magnitude of itch, starting with first dose; responses progressively increased and were sustained through to the end of treatment, up to 1 year.

Evaluating patient-perceived control of atopic dermatitis: design, validation, and scoring of the Atopic Dermatitis Control Tool (ADCT).

Objectives: The Atopic Dermatitis Control Tool (ADCT) was designed to evaluate patient-perceived AD control and facilitate patient-physician discussion on long-term disease control.Methods: The study was performed in adult patients with AD. Development of the ADCT followed US Food and Drug Administration (FDA) guidelines on patient-reported outcome measures (PROMs). Qualitative research, including targeted literature review, interviews with clinical experts, and combined concept elicitation/cognitive debriefing with patients with AD, was conducted to provide a list of comprehensive concepts capturing AD control per physician and patient perspectives. Quantitative methods assessed psychometric properties of the instrument and defined the threshold for AD control.Results: The resulting pilot six-item ADCT, reflecting key concepts related to AD control, had 7-day recall and assessed symptoms and impacts on patients' everyday lives by severity and/or frequency. The ADCT showed good content validity (well understood by adult patients with AD), and quick completion time (<2 min). Psychometric analysis indicated no floor/ceiling effects for response distributions, particularly strong (r ≥ 0.80) inter-item correlations for the six ADCT items, robust construct validity (r > 0.50), and item-level discriminating ability (p < .03); this supported the derivation of a total score based on responses to all items. ADCT total score showed evidence of strong internal consistency reliability (Cronbach's alpha >0.80). A score ≥7 points was identified as an optimum threshold to identify patients whose AD is "not in control."Conclusions: No single validated instrument has been available to holistically evaluate patient-perceived AD control. The newly developed ADCT displays good-to-excellent content validity, construct validity, internal consistency, reliability, and discriminating ability.

Validation of the Atopic Dermatitis Control Tool (ADCT©) using a longitudinal survey of biologic-treated patients with atopic dermatitis.

BACKGROUND: The Atopic Dermatitis Control Tool (ADCT©) is a brief patient self-administered instrument designed and validated to assess atopic dermatitis (AD) control; six AD symptoms and impacts are evaluated over the past week, including overall severity of symptoms, days with intense episodes of itching, intensity of bother, problem with sleep, impact on daily activities, and impact on mood or emotions. This study assessed the reliability, validity, and responsiveness of the ADCT in a longitudinal context, and provided thresholds to identify meaningful within-person change. METHODS: Data were from a prospective, longitudinal patient survey study of real-world effectiveness of dupilumab in patients with AD. Eligible patients completed a baseline survey before starting dupilumab and were followed at Months 1, 2, 3, and 6 post-initiation as they became eligible. RESULTS: Psychometric analyses confirmed internal consistency; Cronbach's α coefficients were consistently above the threshold of 0.70 across each follow-up; item-to-total correlations were above the threshold of r ≥ 0.50. High correlations between the ADCT and the Dermatology Life Quality Index (DLQI) and skin pain supported construct validity, while known-group validity was shown on Patient Global Assessment of Disease (PGAD) overall well-being subgroups with worse AD-related overall well-being having higher mean ADCT total scores at all time points. The ability of the ADCT to detect change was confirmed; the threshold for meaningful within-person change was estimated to be 5 points. Finally, test-retest reliability was confirmed in subgroups of patients with stable PGAD responses. CONCLUSIONS: Our findings confirm that the ADCT is a valid and reliable tool for assessing AD control.

Responder Threshold for Patient-Oriented Eczema Measure (POEM) and Children's Dermatology Life Quality Index (CDLQI) in Adolescents with Atopic Dermatitis.

INTRODUCTION: The Patient-Oriented Eczema Measure (POEM) assesses patient-reported frequency of atopic dermatitis (AD) symptoms, while the Children's Dermatology Life Quality Index (CDLQI) measures the impact of skin disease on health-related quality of life (HRQoL) in children. There is currently no threshold for clinically meaningful within-person change in POEM or CDLQI scores in adolescents. Here we empirically derive within-person thresholds of meaningful within-person change in POEM and CDLQI scores in adolescents with moderate-to-severe AD. METHODS: Data were used from a phase 3, randomized, double-blind, placebo-controlled trial of dupilumab in adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD. Anchor-based methods were employed using the mean change in POEM and CDLQI scores from baseline to week 16 linked with a 1-point improvement in Patient Global Assessment of Disease (PGAD), a score of "a little better" on the Patient Global Assessment of Treatment effect (PGAT), a 50-74% improvement from baseline in the Eczema Area and Severity Index (EASI-50-74), and a 1-point improvement in Investigator's Global Assessment (IGA) score. RESULTS: A mean change of - 7.8 and - 5.6 in the POEM score was associated with PGAD and PGAT anchors, respectively. EASI-50-74 was associated with a mean change in POEM score of - 8.2, while the IGA anchor was associated with a mean change of - 7.9 in POEM score. The mean changes in CDLQI score associated with PGAD and PGAT anchors were - 6.4 and - 6.6, respectively, while CDLQI mean scores changed by - 8.3 and - 8.0 for the EASI and IGA anchors, respectively. CONCLUSION: In adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD, a within-person change of 6-8 points in POEM and CDLQI scores, independently, can be considered a reasonable responder threshold for clinically meaningful change in each of the two scales, respectively. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03054428. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc.

How to address the challenges of evaluating treatment benefits-risks in rare diseases? A convergent mixed methods approach applied within a Merkel cell carcinoma phase 2 clinical trial.

BACKGROUND: Demonstrating treatment benefits within clinical trials in the context of rare diseases is often methodologically and practically challenging. Mixed methods research offers an approach to overcome these challenges by combining quantitative and qualitative data, thus providing a better understanding of the research question. A convergent mixed methods design in the context of Merkel cell carcinoma, a rare skin cancer, was used during the JAVELIN Merkel 200 trial (NCT02155647). METHODS: Nine patients receiving avelumab in the JAVELIN Merkel 200 trial were interviewed at baseline prior to receiving study treatment, and at 13 weeks and 25 weeks after first avelumab administration. Key concepts of interest identified from the baseline interviews were physical functioning, fatigue/energy, and pain. Patient perceptions of the overall change in their cancer-related health status since starting study treatment were also recorded. During qualitative analysis, at each time-point, each concept of interest was assigned a category describing the trend in change (e.g. newly emerged, no change/stable, improved, worsened, ceased/disappeared). In parallel, patients' tumour status was determined by the clinical overall response status as per the clinical trial protocol. RESULTS: A high concordance between patient-reported qualitative data and assessed tumour response was observed. All eight patients who clinically improved had perceived a subjective improvement in their disease since the beginning of the study; the single patient whose disease worsened had a perceived deterioration. Patient perceived benefit in physical functioning, fatigue/energy and pain was subsequent to the measured change in clinical status as assessed by tumour response. This suggests that patient-reported assessment should be examined over the long term in order to optimally capture meaningful treatment effect. CONCLUSION: Embedding qualitative research in clinical trials to complement the quantitative data is an innovative approach to characterise meaningful treatment effect. This application of mixed methods research has the potential to overcome the hurdles associated with clinical outcomes assessment in rare diseases.

Living with Merkel Cell Carcinoma (MCC): Development of a Conceptual Model of MCC Based on Patient Experiences.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with limited treatment options at advanced stages. There is a paucity of data available regarding the impact of MCC and its management on patients' lives. This study aimed to address this gap by interviewing patients with metastatic MCC entering a trial of an immunotherapy (avelumab). METHODS: In a single-arm, open-label, international, phase 2 trial in patients with stage IV, chemotherapy-refractory, histologically confirmed MCC, patients were invited to participate in semi-structured phone interviews. These were conducted before avelumab administration. Interview transcripts were analysed qualitatively to identify concepts important to patients relating to their experience of metastatic MCC and its management. RESULTS: Nineteen patients were interviewed. Most reported MCC to be painless and asymptomatic. They reported being often misdiagnosed and described a long process before receiving the correct diagnosis. They also reported a feeling of "shock" after being informed of the severity and seriousness of their cancer. Overall, patients did not report impaired physical and cognitive capacities or impact on daily lives, either before or after diagnosis. However, patients and their relatives reported feelings of "worry" and "fear" about the unknown outcome of the disease. Chemotherapy and radiotherapy negatively affected patients physically and psychologically in their everyday lives. CONCLUSIONS: MCC disease was not perceived by the interviewed patients to result in severe functional limitations or to severely impact everyday activities, but was associated with substantial negative psychological impact. In contrast, chemotherapy and radiotherapy for MCC are highly debilitating and disrupt patients' lives. CLINICALTRIALS. GOV IDENTIFIER: NCT02155647.