Measurement properties of the Inclusion Body Myositis Functional Rating Scale.

OBJECTIVES: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS). METHODS: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using standardised response mean (SRM). A receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change. RESULTS: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (rs modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in at least two IBMFRS total score points was shown to represent a meaningful decline. CONCLUSIONS: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline. TRIAL REGISTRATION NUMBER: NCT02753530.

Comparisons and correlations of 1-month recall vs 24-hour recall in patient-reported outcomes of an exploratory, phase 2b, randomized, double-blind, placebo-controlled clinical trial of sildenafil cream, 3.6% for the treatment of female sexual arousal disorder.

BACKGROUND: Efficacy assessments in clinical trials of treatments for female sexual arousal disorder (FSAD) and other female sexual dysfunction (FSD) diagnoses rely on various patient-reported outcomes (PROs). AIMS: We sought to compare 1-month recall PRO measures among participants enrolled in a clinical trial who provided these data without (test population) vs with (control population) use of an at-home, 24-hour recall electronic diary (eDiary), capturing similar data. METHODS: Preplanned subset analysis as performed during a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD. Preliminary product efficacy was assessed via 1-month recall and 24-hour recall questionnaires. A subset of the participants, the Evaluation of Recall Subset [ERS] provided PROs via the 1-month recall instruments but did not provide data via the 24-hour recall eDiary. OUTCOMES: Responses to the 1-month recall instruments were compared among ERS (test) vs non-ERS (control) participants. Among the non-ERS population, correlations between 1-month and 24-hour recall endpoints were calculated. RESULTS: There were no significant differences in the study co-primary 1-month recall efficacy endpoints, the Arousal Sensation (AS) domain of the 28-item Sexual Function Questionnaire (SFQ28) and the Female Sexual Distress Scale - Desire, Arousal, Orgasm question 14, among ERS vs non-ERS participants during the initial 1-month no-drug run-in period or the 1-month single-blind placebo run-in period (P values > .47). Scores on these 1-month recall PROs continued to be similar after randomization for sildenafil cream (P values > .30) and placebo cream (P values > .20) assigned ERS and non-ERS participants during the 3-month double-blind dosing period. There were strong correlations between the SFQ28 AS and eDiary AS scores during the no-drug run-in (R = 0.79, P < .01) and the single-blind run-in (R = 0.73 P < .001). During the double-blind dosing period, the SFQ28 AS score continued to be highly correlated with the eDiary AS score among sildenafil cream users (R = 0.83; P < .001) and placebo cream users (R = 0.8; 2 P < .001). CLINICAL IMPLICATIONS: There was no evidence that 1-month recall PRO instruments introduce recall bias; assessing arousal sensations with 24-hour vs 1-month PRO instruments is similar and either method could be used to assess efficacy depending on study objectives. STRENGTHS AND LIMITATIONS: This preplanned subset analysis compared efficacy of PROs based on recall duration. While the subset was preplanned, the study was powered to detect significant differences in the primary efficacy objectives, not among this subset analyses. CONCLUSION: These data will be used in planning future efficacy assessments of sildenafil cream for FSAD. CLINICAL TRIAL REGISTRATION: This clinical trial was registered with ClinicalTrials.gov, NCT04948151.

Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Validation of the novel Eosinophilic Esophagitis Impact Questionnaire.

BACKGROUND: Eosinophilic esophagitis (EoE) has a detrimental effect on health-related quality of life (HRQOL). The Eosinophilic Esophagitis Impact Questionnaire (EoE-IQ) is a novel patient-reported outcome (PRO) measure assessing the impact of EoE on HRQOL. To assess suitability of the EoE-IQ, its measurement properties were evaluated. METHODS: Using baseline and week 24 data from the pivotal, randomized, placebo-controlled, multinational phase 3 R668-EE-1774 trial (NCT03633617) of dupilumab, we evaluated EoE-IQ's measurement properties (including reliability, construct and known-groups validity, and ability to detect change) and established the threshold for change in scores that can be considered clinically meaningful. RESULTS: The analysis population comprised 239 adults and adolescents with EoE. Mean age was 28.1 (standard deviation, 13.14) years; 63.6% were male, and 90.4% were White. Reliability estimates for the EoE-IQ average score exceeded acceptable thresholds for patients who were stable as indicated by ratings of Patient Global Impression of Severity (PGIS) and Change (PGIC) (intraclass correlation coefficients, 0.75 and 0.81). Construct validity correlations with other EoE-specific PRO scores were moderate at baseline (|r|= 0.44-0.60) and moderate to strong at week 24 (|r|= 0.61-0.72). In known-groups analysis, EoE-IQ average score discriminated among groups of patients at varying EoE severity levels defined by PGIS scores. A ≥ 0.6-point reduction in EoE-IQ average score (where scores range from 1 to 5, with higher scores indicating worse HRQOL) from baseline to week 24 can be considered clinically meaningful. CONCLUSIONS: The EoE-IQ's measurement properties are acceptable, making it a valid, reliable measure of the HRQOL impacts of EoE among adults and adolescents. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03633617. Registered August 14, 2018, https://clinicaltrials.gov/study/NCT03633617 .

An Updated Review of Food and Drug Administration Warning and Untitled Letters for Clinical Outcome Assessment Claims Between 2013 and 2021.

OBJECTIVES: We aimed to ascertain the frequency and types of Food and Drug Administration (FDA)-identified clinical outcome assessment (COA) violations in US pharmaceutical promotional materials from 2013 to 2021 by updating the review by Symonds et al (covering the period 2006-2012 for patient-reported outcomes [PRO] measures), expanding to infringements across all types of COAs, and grouping by efficacy or overall patient experience. METHODS: Warning letters (WLs) and untitled letters (ULs) issued by the FDA's Office of Prescription Drug Promotion were reviewed for COA violations and classified by their type: (1) COA measure not fit for purpose, (2) issue with study design or interpretation of results, and (3) inadequate statistical analysis. RESULTS: From 2013 to 2021, the FDA issued 22 WLs and 65 ULs. Year 2013 showed the highest number of letters issued (n = 24). Of the total 87 letters reviewed, 22 (25%) contained a COA violation, consisting of 6 WLs (27%) and 16 ULs (25%), including 20 (23%) with a PRO-related violation. The most common violations cited "study design or interpretation of results" (21 of 22 [95%]). CONCLUSIONS: Overall, the absolute number of WLs and ULs issued declined when comparing 2006 to 2012 with 2013 to 2021. Despite the overall reduction, this review still identified 25% of letters citing COA infringements (23% with PRO issues), which was similar to the prior review (19% PRO infringements). This may be due to increased FDA attention to patient-focused drug development.

Treatment preference and quality of life impact: ravulizumab vs eculizumab for atypical hemolytic uremic syndrome.

Aim: Ravulizumab and eculizumab are complement C5 inhibitors approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Ravulizumab requires less frequent infusions than eculizumab, which may reduce treatment burden. This study investigated patients' treatment preferences and the impact of both treatments on patient and caregiver quality of life. Materials & methods: Two surveys were conducted (one for adult patients with aHUS and one for caregivers of pediatric patients with aHUS) to quantitatively assess treatment preference and the patient- and caregiver-reported impact of ravulizumab and eculizumab on quality of life. Patients were required to have a diagnosis of aHUS, to be currently receiving treatment with ravulizumab and to have received prior treatment with eculizumab. Participants were recruited via various sources: the Alexion OneSource™ patient support program, the Rare Patient Voice recruitment agency, the aHUS Foundation and directly via a clinician involved in the study. Results: In total, 50 adult patients (mean age: 46.5 years) and 16 caregivers of pediatric patients (mean age: 10.1 years) completed the surveys. Most adult patients (94.0%) and all caregivers reported an overall preference for ravulizumab over eculizumab; infusion frequency was one of the main factors for patients when selecting their preferred treatment. Fewer patients reported disruption to daily life and the ability to go to work/school due to ravulizumab infusion frequency (4.0% and 5.7%, respectively) than eculizumab infusion frequency (72.0% and 60.0%), with similar results for caregivers. Conclusion: Adult patients and caregivers of pediatric patients indicated an overall preference for ravulizumab than eculizumab for the treatment of aHUS, driven primarily by infusion frequency. This study contributes to the emerging real-world evidence on the treatment impact and preference in patients with aHUS.

Study to Assess Content Validity and Interrater and Intrarater Reliability of the Inclusion Body Myositis Functional Rating Scale.

Background and Objectives: Sporadic inclusion body myositis (IBM) is a rare, muscle-wasting disease that negatively affects health-related quality of life. Although a measure that has been developed to assess the impact of IBM, the IBM Functional Rating Scale (IBMFRS) has limited evidence of content validity or reliability, and what constitutes a meaningful change threshold; this study was conducted to address these gaps. Methods: Adult patients with a clinical diagnosis of IBM from the United Kingdom and disease area expert health care professionals from the United States and United Kingdom took part in this study. This study consisted of 5 stages including phone interviews (physicians), face-to-face interviews (patients), face-to-face ratings, phone ratings, and ratings of videos using the IBMFRS. Results: The IBMFRS adequately captures all core functional impacts of IBM, which was corroborated by both patient participants and physicians when debriefing the measure. Physicians and patient participants all thought any change on the measure would be meaningful change for a patient, either improvement or worsening. The quantitative analysis demonstrated good interrater reliability for face-to-face ratings (intraclass correlation coefficient [ICC] >0.7) and for video ratings (ICC >0.9). Intrarater reliability was excellent for face-to-face and video ratings (ICC >0.9). Equivalence between the modes of administration, face-to-face vs phone, was also excellent (ICC >0.9). Discussion: The IBMFRS is content valid in assessing the key functional impacts of IBM, and any change would be meaningful. It is reliable both within and across raters, and there is equivalence between different modes of administration (face-to-face vs phone).

Developing Angelman syndrome-specific clinician-reported and caregiver-reported measures to support holistic, patient-centered drug development.

BACKGROUND: Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable measures reporting key symptoms and functional impairments of AS are required to support development of patient-centered therapies. We describe the development of clinician- and caregiver-reported, AS-specific Global Impression scales for incorporation into clinical trials. Best practice US Food and Drug Administration guidance for measure development was followed with input from expert clinicians, patient advocates, and caregivers during content generation and refinement. RESULTS: Initial measurement domains for the Symptoms of AS-Clinician Global Impression (SAS-CGI) and the Caregiver-reported AS Scale (CASS) were identified from a conceptual disease model of AS symptoms and impacts, derived from interviews with caregivers and clinicians. Two rounds of cognitive debriefing (CD) interviews were performed; clinicians debriefed the SAS-CGI, with patient advocates and caregivers debriefing the CASS to ensure relevance and comprehension. Feedback was used to refine items and ensure wording was age-appropriate and captured AS-specific symptoms, as well as associated impacts and functional impairments. The SAS-CGI and CASS capture global assessments of seizures, sleep, maladaptive behaviors, expressive communication, fine and gross motor skills, cognition, and self-care, which were determined by clinicians, patient advocates, and caregivers to be the most challenging aspects of AS. Additionally, the measures include items for assessing overall AS symptoms and the meaningfulness of any change. In addition to ratings for severity, impact, and change, a notes field was included in the SAS-CGI to provide the rationale for the chosen rating. CD interviews confirmed the measures covered key concepts of AS from the perspective of clinicians and caregivers, and demonstrated that the measures' instructions, items, and response options were clear and appropriate. Interview feedback informed adjustments to the wording of the instructions and the items. CONCLUSIONS: The SAS-CGI and CASS were designed to capture multiple AS symptoms, reflecting the heterogeneity and complexity of AS in children 1 to 12 years old. These clinical outcome assessments have been incorporated into AS clinical studies, which will allow for the evaluation of their psychometric properties and inform further refinements if needed.

Qualitative Patient Interviews to Characterize the Human Burden of Advanced Basal Cell Carcinoma Following Hedgehog Pathway Inhibitor Treatment.

INTRODUCTION: Evidence of patients' experiences of living with advanced basal cell carcinoma (aBCC) are limited, particularly after hedgehog pathway inhibitor (HHI) treatment. We explored the burden of aBCC on symptoms and patients' everyday lives post HHI treatment. METHODS: In-depth, semi-structured, approximately 1-h qualitative interviews of US patients with aBCC and prior HHI treatment were conducted. Data were assessed using thematic analysis with NVivo 1.0 software. Saturation analysis was performed to ensure all concepts were captured. RESULTS: Fifteen patients (median age, 63 years; locally advanced BCC, n = 9; metastatic BCC, n = 6) were interviewed. A patient-led conceptual model was developed from the responses using 10 symptoms and 15 impact categories (comprising emotional/psychological, physical, and social domains) identified as most commonly discussed and important to patients. Overall, reported impacts were discussed more commonly than reported symptoms. Impacts most commonly discussed were related to emotions (e.g., anxiety, worry, fear [n = 14; 93%]; low mood, depression [n = 12; 80%]) and physical function (e.g., hobbies or leisure activities [n = 13; 87%]). Symptoms most commonly discussed were fatigue and tiredness (n = 14; 93%) and itch (n = 13; 87%). Out of all reported impacts and symptoms, fatigue and tiredness (n = 7, 47%) and anxiety, worry, and fear (n = 6; 40%) were most bothersome to patients. As a descriptive exercise, participant responses were mapped to commonly used patient-reported outcome scales in aBCC clinical trials. Most expressed concepts were captured across two common measures in oncology/skin conditions (European Organization for Research and Treatment of Cancer Quality of Life-Core 30 [EORTC QLQ-C30] and Skindex-16 questionnaires), but sun avoidance and others' perception of skin cancer were not explicitly mentioned by these instruments. CONCLUSION: Patients with aBCC experienced a significant disease burden post first-line HHI therapy, including major emotional and lifestyle impacts. Accordingly, through this study, patients with aBCC highlighted a significant unmet need for second-line treatment options post HHI therapy.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

BACKGROUND: Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. AIM: To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. METHODS: In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. OUTCOMES: Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. RESULTS: The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. CLINICAL IMPLICATIONS: Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. STRENGTHS AND LIMITATIONS: This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. CONCLUSION: The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Exploring Disease Remission and Bowel Urgency Severity Among Adults with Moderate to Severe Ulcerative Colitis: A Qualitative Study.

Purpose: Achieving and maintaining symptom control is a key treatment goal in ulcerative colitis (UC). Bowel urgency is an important symptom of UC, thus measurement of urgency is critical. This research explored the patient experience of UC and "remission" in UC, with a focus on urgency, and cognitively debriefed the Urgency Numeric Rating Scale (NRS), including score interpretation and examination of meaningful improvement. Patients and Methods: Semi-structured hybrid concept elicitation and cognitive debriefing interviews with adults with moderately-severely active UC were conducted to explore experiences of UC and urgency, as well as examine meaningful improvement and score interpretation of the Urgency NRS. Purposive sampling was used to identify 20 eligible adult participants with UC. Concept elicitation data were analyzed using thematic analysis, and a deductive approach was used to analyze cognitive debriefing data. Thematic analysis was also applied to meaningful change-related data. Results: Twenty participants were interviewed (average age = 42.6 years old, 50% male); 14 with moderately active (70.0%) and 6 with severely active UC (30.0%). Disease remission was not consistently defined by participants and description varied in terms of definition (absence vs not complete absence of symptoms), duration (months vs days) and key symptoms to consider. Urgency was a prominent symptom for all participants, with 8 (40.0%) identifying it as the most bothersome aspect of UC. No issues were identified with the Urgency NRS. Participants were able to define different levels of urgency severity, describe how they relate to daily life impacts, and score them differently on the Urgency NRS. Participants were also able to reflect urgency improvement on the NRS and discuss how small changes in numeric ratings of urgency can reflect meaningful change in the symptom burden of their UC. Conclusion: The Urgency NRS is a content valid and interpretable measure to assess bowel urgency severity.

Comparability of a provisioned device versus bring your own device for completion of patient-reported outcome measures by participants with chronic obstructive pulmonary disease: quantitative study findings.

OBJECTIVE: To quantitatively compare equivalence and compliance of patient-reported outcome (PRO) data collected via provisioned device (PD) versus bring your own device (BYOD). METHODS: Participants with stable chronic obstructive pulmonary disease (COPD) completed the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT®) daily and COPD Assessment Test™ (CAT) and Patient Global Impression of Severity (PGIS) of COPD weekly on either PD or BYOD for 15 days, then switched device types for 15 days. EXACT was scored using the Evaluating Respiratory Symptoms in COPD (E-RS®: COPD) algorithm and equivalence assessed using intraclass correlation coefficients (ICCs) adjusting for cross-over sequence, period, and time. Two one-sided tests (TOSTs) used ICC adjusted means with 10%, 20%, and 40% of total score tested as equivalence margins. Compliance and comfort with technology were assessed. Equivalence across 3 device screen sizes was assessed following the second completion period. RESULTS: Participants (N = 64) reported high comfort with technology, with 79.7% reporting being "quite a bit" or "very" comfortable. Weekly compliance was high (BYOD = 89.7-100%; PD = 76.9-100%). CAT and E-RS: COPD scores correlated well with PGIS (r > 0.50) and demonstrated equivalence between PD and BYOD completion (ICC = 0.863-0.908). TOST equivalence was achieved within 10% of the total score (p > 0.05). PRO measure scores were equivalent across 3 different screen sizes (ICC = 0.972-0.989). CONCLUSIONS: Measure completion was high and scores equivalent between PD and BYOD, supporting use of BYOD in addition to PD for collecting PRO data in COPD studies and in demographically diverse patient populations.

Comparability of a provisioned device versus bring your own device for completion of patient-reported outcome measures by participants with chronic obstructive pulmonary disease: qualitative interview findings.

BACKGROUND: There is interest in participants using their own smartphones or tablets ("bring your own device"; BYOD) to complete patient-reported outcome (PRO) measures in clinical studies. Our study aimed to qualitatively evaluate participants' experience using a provisioned device (PD) versus their own smartphone (BYOD) for this purpose. METHODS: Participants with chronic obstructive pulmonary disease (COPD) were recruited for this observational, cross-over study and completed PRO measures daily on one device type for 15 days, then switched to the other device type to complete the same measures for another 15 days. After each 15-day period, semi-structured interviews were conducted about their experience with the device. RESULTS: Of 64 participants enrolled, the final qualitative analysis populations comprised those who participated in an interview without protocol violations. Thus, the qualitative longitudinal population (LP) included n = 57 (89%), while the qualitative cross-sectional population (CSP) included n = 60 (94%). CSP participants found both device types easy to use. Twenty CSP participants (33%) reported missing data entry on at least one day when using PD, and 24 (40%) reported missing at least one day when using BYOD. In the LP, preference for one of the device types was somewhat evenly split; 45.6% (n = 26) preferred PD and 50.9% (n = 29) preferred BYOD. The most common reason for preferring PD was that it was "dedicated" to the study; the "convenience" of carrying a single device was the main reason for preferring BYOD. CONCLUSION: The findings from the interviews demonstrated few differences in participants' experience completing PRO measures on a PD versus BYOD. Our study supports the use of BYOD as a potential addition to PD for collecting PRO data and contributes evidence that BYOD may be employed to collect PRO data in demographically diverse patient populations.

Content validity of a newly developed observer-reported measure for pediatric asthma in children aged 2-5 years.

BACKGROUND: An observer-reported outcome (ObsRO) measure assessing both symptom control and health-related quality of life (HRQoL) in children with asthma younger than 6 years is lacking. The objective of this study was to evaluate the content validity of the Pediatric Asthma Questionnaire (PAQ), a newly developed 6-item ObsRO measure for caregivers of children aged 2-5 years diagnosed with asthma. RESULTS: In-depth, qualitative interviews were conducted with 15 parents or caregivers. The first part of the interview was an open-ended discussion whereby participants were asked to describe their observations of their child's asthma symptoms and HRQoL impacts followed by a cognitive debriefing of a draft version of the PAQ. The most frequently reported symptoms were coughing (n = 15, 100%), wheezing (n = 14, 93%), and trouble breathing (n = 10, 67%). Overall, participants found the PAQ easy to complete and relevant to their child's experience with asthma, with most reporting the instructions, response scales, and recall period for the items to be appropriate. The majority of participants (93%) believed they could accurately report on the items included in the PAQ based on their observations of their child's asthma symptoms and impacts, or reliably get the information from the child's teacher, school, or caregiver when their child was not in their presence. One item was modified based on feedback about the phrase "oral steroids" to clarify modes of administration. A few other minor changes were incorporated into the PAQ following suggestions from participants, including replacing the phrase "how often" with "how many days" in one of the items to improve clarity and overall consistency with the response options. CONCLUSION: Qualitative data support the content validity of the PAQ as a fit-for-purpose and well-understood 6-item observer-reported outcome measure to evaluate both symptoms and asthma-specific HRQoL impacts experienced by pediatric asthma patients aged 2-5 years for use in clinical and real-world studies.

Impacts and Burden of Niemann pick Type-C: a patient and caregiver perspective.

BACKGROUND: Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients' and caregivers' quality of life (QOL) and reduces the patient's life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients' and caregivers' daily lives to understand the burden of disease. RESULTS: A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months-65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients' and caregivers' activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL. Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and the ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients' and caregivers' HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers). CONCLUSIONS: Ambulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.

A novel patient-reported outcome instrument assessing the symptoms of paroxysmal nocturnal hemoglobinuria, the PNH-SQ.

BACKGROUND: Patient-reported outcome measures (PROs) used to measure symptoms of patients with paroxysmal nocturnal hemoglobinuria (PNH) in trials do not measure PNH symptoms comprehensively and do not assess daily fluctuations in symptoms. Following a literature review and consultation with a PNH expert, we drafted the PNH Symptom Questionnaire (PNH-SQ) and a patient-centric conceptual model of PNH symptoms and impacts. We then interviewed 15 patients with PNH to assess comprehensiveness of symptom capture from the patient perspective and to cognitively debrief the PNH-SQ. Patient interview data were also used to finalize the PNH conceptual model. RESULTS: Participants mentioned 27 signs or symptoms of PNH spontaneously or after being probed; 93% reported experiencing ≥ 1 PNH symptom. Concept saturation was reached for all PNH symptoms. Further, interviews confirmed the instrument captured the most common PNH symptoms, including fatigue (87%), abdominal pain (60%), and difficulty swallowing (47%), with fatigue ranked as the most bothersome symptom. The interviews demonstrated that participants understood the items of the PNH-SQ (90-100%); considered the symptoms relevant (> 50- > 90%); the recall period appropriate (> 80-100%); and the response options suitable (> 80-100%). Participants also suggested changes regarding item redundancy and relevance; this feedback was used to finalize the instrument. CONCLUSIONS: The finalized PNH-SQ assesses the presence and severity of 10 symptoms-abdominal pain, chest discomfort, difficulty sleeping, difficulty swallowing, difficulty thinking clearly, fatigue, headache, muscle weakness, pain in the legs or back, and shortness of breath-over 24 h. The PNH-SQ is a content-valid questionnaire suitable for assessing daily symptom presence and severity in PNH clinical trials.

A qualitative study to explore symptoms and impacts of pediatric and adolescent Crohn's disease from patient and caregiver perspective.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract that affects people across the age spectrum but often starts in childhood or early adulthood. Despite this, almost all published research examining the symptomatic and health-related quality of life (HRQL) experiences of CD has been conducted in an adult population. Studies providing a comprehensive overview of the lived experience of pediatric and adolescent CD are virtually non-existent. The experiences of younger children aged 2-7 years are especially unknown. RESULTS: A total of 49 participants (31 children and 18 parents) were interviewed. This included 11 dyads (i.e., parents and children from the same family). Analyses were conducted based on reporter-type (patient self-report vs parent observer-report) and age subgroups (ages 2-4 vs 5-7 vs 8-11 vs 12-17). Key symptoms were identified across the age subgroups and reporter types. Abdominal/stomach pain, passing gas/feeling gassy, diarrhea/liquid stools, fatigue/tiredness, bowel urgency, blood in stools, stomach cramping, constipation, and incomplete evacuation were discussed most frequently. The most common HRQL impacts included impact on physical activity, school, social life, and mood (i.e., feeling sad/low), and were mostly consistent between reporter type and across age spectrum. Concept agreement between parents and children in the dyad analysis was > 60% for most symptoms and impacts. CONCLUSIONS: Qualitative interviews revealed the substantial symptom and HRQL burden of pediatric CD from the child and parent perspectives and that disease experiences were largely consistent across the age range and based on both reporter perspectives. This is an important first step towards implementing a robust measurement strategy for the assessment of symptoms and HRQL impacts in pediatric CD.

Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale.

BACKGROUND: Niemann-Pick disease type C (NPC) is an ultra-rare, progressive, genetic disease leading to impaired lysosomal function and neurodegeneration causing serious morbidity and shortened life expectancy. The Niemann-Pick type C Clinical Severity Scale (NPCCSS) is a 17 domain, disease-specific, clinician-reported outcome measure of disease severity and progression. An abbreviated 5-domain NPCCSS scale has been developed (measuring Ambulation, Swallow, Cognition, Speech, and Fine Motor Skills) and the scale reliability has been established. Additional psychometric properties and meaningful change of the scale need, however, to be assessed. METHODS: Mixed method studies were conducted to ascertain which NPCCSS domains were most important, as well as to explore meaningful change: 1) surveys in caregivers/patients (n = 49) and 2) interviews with clinicians (n = 5) as well as caregivers/patients (n = 28). Clinical trial data (n = 43) assessed construct validity and meaningful change through an anchor-based approach. RESULTS: Domains identified as most important by clinicians, caregivers, and patients (independent of current age, age of onset, and disease severity) were Ambulation, Swallow, Cognition, Speech, and Fine Motor Skills, indicating content validity of the 5-domain NPCCSS. Criterion validity was shown with the 5-domain NPCCSS being highly correlated with the 17-item NPCCSS total score (excluding hearing domains), r2 = 0.97. Convergent validity was demonstrated against the 9 Hole Peg Test, r2 = 0.65 (n = 31 patients), and the Scale for Assessment and Rating of Ataxia (SARA), r2 = 0.86 (n = 49 patients). Any change was seen as meaningful by patients/caregivers across domains. Meaningful change using trial data and interviews with NPC experts (n = 5) and patients/caregivers (n = 28) suggested that a 1-category change on a domain is equivalent to 1-point change or greater in the 5-domain NPCCSS total score. CONCLUSIONS: Qualitative and quantitative data support content and construct validity of the 5-domain NPCCSS score as a valid endpoint in NPC trials. A 1-category change on any domain is equivalent to 1-point change or greater in the 5 domain NPCCSS total score, representing a clinically meaningful transition and reflecting loss of complex function and increased disability. Trial registration NCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129.

Burden of illness of trigeminal neuralgia among patients managed in a specialist center in England.

BACKGROUND: Trigeminal neuralgia (TN) causes severe episodic, unilateral facial pain and is initially treated with antiepileptic medications. For patients not responding or intolerant to medications, surgery is an option. METHODS: In order to expand understanding of the pain-related burden of illness associated with TN, a cross-sectional survey was conducted of patients at a specialist center that utilizes a multidisciplinary care pathway. Participants provided information regarding their pain experience and treatment history, and completed several patient-reported outcome (PRO) measures. RESULTS: Of 129 respondents, 69/128 (54%; 1 missing) reported no pain in the past 4 weeks. However, 84 (65%) respondents were on medications, including 49 (38%) on monotherapy and 35 (27%) on polytherapy. A proportion of patients had discontinued at least one medication in the past, mostly due to lack of efficacy (n = 62, 48%) and side effects (n = 51, 40%). A total of 52 (40%) patients had undergone surgery, of whom 30 had microvascular decompression (MVD). Although surgery, especially MVD, provided satisfactory pain control in many patients, 29% of post-surgical patients reported complications, 19% had pain worsen or stay the same, 48% were still taking pain medications for TN, and 33% reported new and different facial pain. CONCLUSIONS: In most PRO measures, respondents with current pain interference had poorer scores than those without pain interference. In the Patient Global Impression of Change, 79% expressed improvement since beginning of treatment at this clinic. These results indicate that while the multidisciplinary approach can substantially alleviate the impact of TN, there remains an unmet medical need for additional treatment options.