Validation and Meaningful Change Thresholds for an Objective Cough Frequency Measurement in Chronic Cough.

PURPOSE: Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. METHODS: Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. RESULTS: Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength (ρ = 0.30-0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1-3. CONCLUSION: Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Enabling patient-reported outcome measures in clinical trials, exemplified by cardiovascular trials.

OBJECTIVES: There has been limited success in achieving integration of patient-reported outcomes (PROs) in clinical trials. We describe how stakeholders envision a solution to this challenge. METHODS: Stakeholders from academia, industry, non-profits, insurers, clinicians, and the Food and Drug Administration convened at a Think Tank meeting funded by the Duke Clinical Research Institute to discuss the challenges of incorporating PROs into clinical trials and how to address those challenges. Using examples from cardiovascular trials, this article describes a potential path forward with a focus on applications in the United States. RESULTS: Think Tank members identified one key challenge: a common understanding of the level of evidence that is necessary to support patient-reported outcome measures (PROMs) in trials. Think Tank participants discussed the possibility of creating general evidentiary standards depending upon contextual factors, but such guidelines could not be feasibly developed because many contextual factors are at play. The attendees posited that a more informative approach to PROM evidentiary standards would be to develop validity arguments akin to courtroom briefs, which would emphasize a compelling rationale (interpretation/use argument) to support a PROM within a specific context. Participants envisioned a future in which validity arguments would be publicly available via a repository, which would be indexed by contextual factors, clinical populations, and types of claims. CONCLUSIONS: A publicly available repository would help stakeholders better understand what a community believes constitutes compelling support for a specific PROM in a trial. Our proposed strategy is expected to facilitate the incorporation of PROMs into cardiovascular clinical trials and trials in general.

Validation of the shortened Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS).

BACKGROUND: The rare disease, Hunter Syndrome (mucopolysaccharidosis type II; MPS II), characterized by iduronate-2-sulfatase deficiency, has heterogeneous symptoms often including cognitive impairment (CI). To evaluate physical functioning and daily activity limitations of patients with MPS II, the multidomain shortened Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire was previously developed and preliminarily validated. Here we gather data in a dedicated prospective longitudinal observational study using direct responses to the shortened instrument and assess its psychometric properties further. METHODS: Interview data were collected from eligible self-reporting patients (≥ 12 years of age) or caregivers of patients using respective versions of the instrument at baseline and 2-4 weeks later. Internal consistency, test-retest reliability, convergent and discriminant validity, and validity of known groups were assessed. Participants also completed Child Health Questionnaire (CHQ), Health Utilities Index Mark 3, and Global Impression of Severity (GIS) questionnaires. RESULTS: All patients were male, consisting of 31 caregiver-reported patients (aged 3-26 years) and 20 self-reported patients (aged 12-58 years). Most (77.4%) caregiver-reported patients had CI. Both questionnaire versions demonstrated good internal consistency and test-retest reliability; Cronbach's alpha and intra-class correlation coefficients were > 0.70. Spearman's correlations demonstrated good convergent validity with moderate (> 0.3) to high (> 0.6) correlations of the HS-FOCUS total score with physical functioning, role/social-physical, and bodily pain domains of CHQ. The tool also differentiated between MPS II severity levels based on GIS scores. CONCLUSIONS: The shortened HS-FOCUS questionnaire was found to be a valid and reliable tool to assess the physical functioning impact of MPS II.

Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report.

BACKGROUND: Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. OBJECTIVE: To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. GOOD PRACTICES FOR OUTCOMES RESEARCH: This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. CONCLUSIONS: This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

The multidisciplinary fetal center: clinical expertise is only part of the experience.

AIM: Multidisciplinary foetal centres have recently emerged in partnership with children's hospitals throughout the United States. The aim of this investigation was to describe the patient experience of pregnant women who were referred to our foetal centres for the evaluation of foetal congenital anomalies. METHODS: A qualitative interview study of women referred to our foetal centres was conducted using semi-structured telephone interviews. The data were coded and analysed using thematic networks analysis. RESULTS: Six themes were identified (i) foetal centre evaluations had a far-reaching impact on participants' lives, (ii) participants appreciated both expertise and support from providers, (iii) participants recognised the need to cope with uncertainty, (iv) participants sought additional support from multiple arenas, (v) participants specifically looked to the Internet for both information and support and (vi) participants had pre-established views about pregnancy termination. CONCLUSION: Multidisciplinary foetal centres can provide a unified source of clinical expertise to women who are carrying a foetus with a suspected or identified congenital anomaly. Despite this diagnostic acumen, uncertainty is pervasive and patients seek support and additional information from a variety of other sources. This investigation is an important initial step in the evaluation of this emerging model of care.

Outcomes and Predictors of Perinatal Mortality in Fetuses With Ebstein Anomaly or Tricuspid Valve Dysplasia in the Current Era: A Multicenter Study.

BACKGROUND: Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era. METHODS AND RESULTS: Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27±6 weeks, there were 11 lost to follow-up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001). CONCLUSION: In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival.

Utility of novel fetal echocardiographic morphometric measures of the aortic arch in the diagnosis of neonatal coarctation of the aorta.

OBJECTIVES: Prenatal diagnosis of neonatal coarctation of the aorta (CoA) is challenging; there is a high false-positive rate, yet 60-80% are not identified prenatally. We aimed to identify novel fetal echocardiographic measures to improve prenatal identification of CoA. METHODS: A retrospective review was conducted of subjects seen from 1/2007-1/2014 with prenatal suspicion for CoA and postnatal follow-up. The last fetal echocardiogram prior to delivery was evaluated for right/left ventricular dimensions, ascending (AAo), transverse (TAo), descending aorta (DAo), aortic isthmus (AoI), ductus arteriosus (DA), and main pulmonary artery diameters, and AoI and DA spectral Doppler. Three novel fetal measurements were performed: left common carotid-to-left subclavian artery distance (LCSA), AAo-DAo angle, and TAo-DAo angle. Postnatal data included diagnosis, surgical approach, and timing. RESULTS: Forty subjects were identified (mean gestational age at fetal echo 32.8 ± 4.2 weeks) with prenatal suspicion for CoA. Comparing subjects with (n = 20) and without CoA (n = 20), significant differences were detected for LCSA, AAo-DAo angle, and TAo-DAo angle (p < 0.0001). An LCSA >4.5 mm (sensitivity 80%,specificity 95%), AAo-DAo angle ≤20.31° (sensitivity 95%,specificity 100%) and TAo-DAo angle ≥96.15°(sensitivity 90%,specificity 100%) identified CoA. CONCLUSIONS: Fetal LCSA, AAo-DAo angle, and TAo-DAo angles are novel measures that can differentiate between subjects with and without CoA.

The Burden of Pruritus Associated With CKD: A Mixed Methods Analysis Among Patients Undergoing Dialysis.

Rationale & Objective: Despite its prevalence and distress to patients, chronic kidney disease-associated pruritus (CKD-aP) is poorly characterized, which may contribute to the condition's underdiagnosis and inadequate management. This study aimed to understand the symptom experience of patients with CKD-aP and the extent to which pruritus impacts their lives. Study Design: Mixed methods study including one-on-one qualitative interviews and completion of the Skindex-10 Questionnaire (measuring itch-related quality of life). Setting & Participants: A total of 23 patients undergoing hemodialysis and reporting pruritus at 4 dialysis centers in the United States. Analytical Approach: Interviews followed a semistructured guide that included targeted and follow-up questions to elicit discussion of patients' symptoms of pruritus, including frequency and variability, impact on activities of daily living, and emotional and social functioning. Interviews were digitally audio-recorded. A coding dictionary was developed from transcripts to analyze themes and concepts. Results: Participants described their itch with various terms, including "numbness," "pain," and "tingling" on their skin. Itch affected multiple areas but especially the back, usually occurred daily, and was often worse at night. For some, itching was a constant experience. Patients relieved their itch through scratching and various off-label treatments; some reported skin damage from excessive scratching and most indicated treatments provided limited relief. Pruritus considerably disrupted physical function, including sleep, daily activities, social functioning and relationships, and emotional and psychological wellbeing. All participants reported being bothered by their itching during the past week on the Skindex-10 Questionnaire. Limitations: All participants were from the United States, so the findings may not be generalizable to other countries. Conclusions: Although symptom experience varies considerably, CKD-aP causes severe distress for many patients undergoing hemodialysis and can profoundly impair their quality of life. The results of this study show the impact of itch from patients' perspectives and highlight the need for greater awareness and better management of this condition. Plain-Language Summary: Patients with chronic kidney disease often experience itching, or pruritus, but its importance to patients is regularly overlooked. This study used one-on-one interviews to investigate patients' experiences of chronic kidney disease-associated pruritus and how it impacts their lives. We found that participants experienced itch on various body areas and used different words to describe their itch (eg, "numbness" and "pain"). Some reported skin damage from excessive scratching, and many used off-label treatments and other interventions (eg, rubbing alcohol and multiple showers daily), which provided limited relief. For many, itching was experienced daily and severely disrupted sleep, daily activities, interactions with others, and mental wellbeing. These findings reveal chronic kidney disease-associated pruritus severely impacts patients and highlights the need for improved management of this condition.

Validation of the Peak Pruritus Numerical Rating Scale as a Patient-Reported Outcome Measure in Prurigo Nodularis.

INTRODUCTION: Validated patient report tools for quantifying patient experiences of itch in prurigo nodularis (PN) are limited. This study aimed to evaluate the validity of the 11-point peak pruritus numerical rating scale (PP NRS) as a single-item patient-reported outcome (PRO) measure for assessing itch severity in PN. METHODS: Content validity of the PP NRS was evaluated through qualitative interviews with adults with PN. The PP NRS was then psychometrically evaluated using data from a placebo-controlled trial of nemolizumab in adults with PN, during which patients completed the PP NRS daily. Meaningful within-patient change was estimated from the qualitative interviews and by anchor- and distribution-based analyses of trial data. RESULTS: The interview participants (N = 21) all understood the PP NRS and reported itch as their worst symptom overall. The PP NRS showed good test-retest reliability and demonstrated convergent validity and known-groups validity. PP NRS scores improved more in patients classified as "improved" on other clinical outcome measures than in those classified as "worsened/unchanged". Triangulation of the different estimates identified a 2- to 5-point decrease in PP NRS score as a meaningful within-patient change threshold. CONCLUSION: The PP NRS is a content-valid and reliable PRO measure for quantifying itch severity in adults with PN in clinical trials. TRIAL REGISTRATION NUMBER: NCT03181503.

Prurigo nodularis is a skin disease where the skin becomes inflamed and very itchy. Itching and scratching can ruin the lives of people with prurigo nodularis. For doctors to know how well treatments for prurigo nodularis are working, they need to be able measure how bad their patients' itching is. Here we tested whether a tool called the peak pruritus numeric rating scale (PP NRS) can be used to reliably measure itching in patients with prurigo nodularis. The PP NRS asks patients to rate their itch "at the worst moment during the previous 24 h" on a scale from 0 ("no itch") to 10 ("worst itch imaginable"). We interviewed 21 patients with prurigo nodularis. Overall, itch was their worst symptom. They were able to use the PP NRS with few or no problems. To further explore whether the PP NRS can be used by patients with prurigo nodularis, we also obtained data from a clinical study. In this clinical study, patients with prurigo nodularis received a drug that might one day be used to treat their disease. They completed the PP NRS daily during the time they received the drug. When we analyzed the data from the clinical study, we found that the PP NRS has the properties a tool like this needs to be useful. We also concluded that a decrease of 2­5 points on the PP NRS scale would be a meaningful improvement in itching for patients with prurigo nodularis.

The Sleep Disturbance Numerical Rating Scale: Content Validity, Psychometric Validation, and Meaningful Within-Patient Change in Prurigo Nodularis.

INTRODUCTION: Sleep is often disturbed in patients with prurigo nodularis (PN). To address the lack of validated patient-reported outcome (PRO) measures for quantifying sleep disturbance in PN, we evaluated the Sleep Disturbance Numerical Rating Scale (SD NRS) as a single-item PRO measure for quantifying sleep disturbance in PN. METHODS: Adults with PN participated in qualitative interviews, which included concept elicitation and cognitive debriefing of the SD NRS. The SD NRS was evaluated psychometrically using data from a phase 2 randomized trial in adults with PN (NCT03181503). Other PRO assessments included the Average Pruritus (AP) NRS, AP Verbal Rating Scale (VRS), peak pruritus (PP) NRS, PP VRS, and Dermatology Life Quality Index (DLQI). Reliability, validity, and responsiveness of the SD NRS were evaluated, and meaningful within-patient change was estimated from qualitative interview responses and quantitative trial data. RESULTS: All interview participants (N = 21) experienced sleep disturbance and most (95%) understood the SD NRS as intended. The SD NRS demonstrated test-retest reliability based on intra-class correlation coefficients for itch-stable participants of 0.87 for the AP VRS and 0.76 for the PP VRS. At baseline, Spearman's rank-order correlation coefficients were moderate to strong (0.3-0.8) between the SD NRS and the AP NRS, AP VRS, PP NRS, PP VRS, and DLQI. Known-groups validity was demonstrated by higher (worse) SD NRS scores in participants with worse scores on the AP NRS, AP VRS, PP VRS, and DLQI. Improvements in SD NRS scores were greater in participants classified as "improved" versus "worsened/unchanged" on the anchor PROs. A 2- to 4-point decrease on the 11-point SD NRS scale was identified as a meaningful within-patient change. CONCLUSION: The SD NRS is a well-defined, reliable, and valid PRO measure that can be used in daily practice and clinical trials to capture sleep disturbance in adults with PN.

Patients with the skin disease prurigo nodularis often sleep badly because their skin is very itchy in the evening and at night. In assessing the effectiveness of new treatments for prurigo nodularis, it is useful to know whether patients sleep better when taking them. Here, we tested whether the "Sleep Disturbance Numerical Rating Scale" (SD NRS), a tool for measuring sleep, can be used by patients with prurigo nodularis. The SD NRS asks patients to score their sleep loss during the previous night on a scale of 0 ("no sleep loss") to 10 ("I did not sleep at all"). When we interviewed 21 patients with prurigo nodularis, 19 of them had problems falling asleep and 18 of them woke up every night. Most of the patients found the SD NRS easy to use. To further explore whether the SD NRS is suitable for patients with prurigo nodularis, we also analyzed data from a European clinical study in which patients with prurigo nodularis received nemolizumab, a new treatment being developed for the disease. Patients completed the SD NRS each morning during the clinical study. We found that the SD NRS has the necessary properties to be useful for assessing sleep on a daily basis. We also determined that a 2- to 4-point decrease on the SD NRS scale would represent a meaningful improvement in sleep for patients with prurigo nodularis. We conclude that the SD NRS is a useful tool for assessing sleep in prurigo nodularis patients participating in clinical studies.

Patient-reported outcomes to assess the efficacy of extended-release guaifenesin for the treatment of acute respiratory tract infection symptoms.

BACKGROUND: Guaifenesin is a component of medicines used to improve symptoms associated with upper respiratory tract infections. Patient-reported outcome instruments are valuable for evaluating symptom improvements; however, a validated tool to assess efficacy of mucoactive drugs does not exist. We compared the efficacy of extended-release guaifenesin with placebo for treatment of symptoms of upper respiratory tract infection using subjective efficacy assessments in a pilot study and confirmed precision of assessments in a validation study. METHODS: The pilot study was a randomized, double-blind study where patients were dosed with either 1200 mg extended-release guaifenesin (n = 188) or placebo (n = 190), every 12 hours for 7 days. Efficacy was assessed using subjective measures including the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and the Wisconsin Upper Respiratory Symptom Survey. End-of-study assessments were completed by patients and investigator. The validation study consisted of two phases. In Phase I, subjects completed interviews to gather evidence to support the content validity of the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and Patient's End-of-Treatment Assessment. Phase II examined the psychometric properties of assessments evaluated in Phase I of the validation study using data from the pilot study. RESULTS: Subjective measures of efficacy at Day 4 showed the most prominent difference between treatment groups, in favor of guaifenesin. The 8-symptom related questions (SUM8) in the Daily Cough and Phlegm Diary, analyzed as a composite score appeared to be the strongest candidate endpoint for further evaluation. Results from the interviews in Phase I supported the content of the assessments which were validated during Phase II. Treatments were well tolerated. CONCLUSIONS: Results from the clinical pilot and validation studies showed that the SUM8 diary scores were robust and reliable for use as efficacy endpoints in studies of mucoactive drugs. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT01046136).

What do we know about asthma triggers? a review of the literature.

OBJECTIVE: For patients with asthma, exacerbations and poor control can result from exposure to environmental triggers, such as allergens and air particulates. This study reviewed the international literature to determine whether a global checklist of common asthma triggers might be feasible for use as a research or management tool in clinical practice. METHODS: Literature published from 2002 to 2012 was identified through PubMed and EMBASE using the following search terms: asthma, asthma triggers, prevalence, among others. A total of 1046 abstracts were found; 85 articles were reviewed covering six continents (number of articles): Africa (1), Asia (22), Australia (1), Europe (27), North America (22), and South America (4). RESULTS: The literature consistently pointed to asthma triggers as one contributor to poor asthma control. Frequently cited triggers were similar across countries/regions and included allergens (particularly pollens, molds, dust, and pet dander), tobacco smoke, exercise, air pollutants/particulates, weather patterns/changes, and respiratory infections. Definitions of asthma triggers, how triggers are taken into account in definitions of asthma control, and scientific inquiry into optimal management techniques for triggers were inconsistent and sparse. CONCLUSIONS: Given the apparent importance of triggers in attaining and maintaining asthma control, empirical research concerning optimal trigger management is needed. Results demonstrate that asthma triggers are similar across continents, suggesting a global checklist of triggers for use in research and clinical practice would be feasible.

Assessing the effect of darbepoetin alfa on patient-reported fatigue in chemotherapy-induced anemia in four randomized, placebo-controlled clinical trials.

PURPOSE: This analysis examined the effects of darbepoetin alfa on hemoglobin and fatigue outcomes in patients with cancer using latent growth curve modeling (LGM). METHODS: Data from 4 clinical trials of darbepoetin alfa in lung cancer (2 studies; n = 547; n = 288), lymphoproliferative malignancies (n = 339), and non-myeloid malignancies (n = 320) were analyzed separately. Fatigue was assessed using the FACT-Fatigue (FACT-F) scale. Effects of darbepoetin alfa on changes in hemoglobin and FACT-F scores were evaluated using LGM, controlling for age, gender, Eastern Cooperative Oncology Group performance status, health status, and total transfusions. RESULTS: Patients receiving darbepoetin alfa had higher rates of change in hemoglobin (standardized regression coefficient [[Formula: see text]] = 0.30 to 0.53, all P < 0.05) than placebo. Patients with greater rates of change in hemoglobin reported improvements in fatigue outcomes ([Formula: see text] = 0.28 to 0.59, all P < 0.05). The total standardized effect of darbepoetin alfa on fatigue outcomes corresponded to a mean change of 0.9 to 3.5 points in FACT-F scores, with one trial demonstrating changes exceeding the minimal important difference of 3 points. CONCLUSIONS: Darbepoetin alfa improved hemoglobin which was associated with improved fatigue across the 4 trials. Clinically, meaningful improvement in fatigue was seen in 2 trials. More complex statistical analysis models of treatment may assist in understanding the effects of erythropoiesis-stimulating agents on patient-reported outcomes.

Leicester Cough Questionnaire validation and clinically important thresholds for change in refractory or unexplained chronic cough.

INTRODUCTION: The Leicester Cough Questionnaire (LCQ), a cough-specific quality-of-life measure, evaluates the impact of cough across physical, psychological, and social domains in patients with chronic cough (CC). This study assessed the psychometric properties of the LCQ. METHODS: Data from a phase IIb, randomized controlled trial of the P2X3-receptor antagonist gefapixant were analyzed (NCT02612610). Subjective [Cough Severity Diary, cough severity visual analogue scale, and patient global impression of change (PGIC)] and objective (awake and 24-h cough frequency) data were used to validate the LCQ for use in patients with refractory or unexplained CC (RCC and UCC, respectively). Psychometric analyses included confirmatory factor analyses, internal consistency and test-retest reliability, validity, responsiveness, and estimated within-patient thresholds for clinically meaningful change. RESULTS: Model-fit values for the proposed three-factor LCQ domains and most individual items were acceptable. Analyses suggest that a mean improvement ranging from 1.3 to 2.3 points for the LCQ total and ⩾0.8, ⩾0.9, and ⩾0.8 points for physical, psychological, and social domain scores, respectively, had the best sensitivity and/or specificity for predicting patient ratings of improvement on the PGIC. CONCLUSIONS: The LCQ is a valid and reliable measure to evaluate cough-specific quality of life and is a fit-for-purpose measure for use in patients with RCC or UCC. Although a single threshold for defining clinically meaningful change depends on the context of use, the results can help guide both treatment decisions and drug development. Therefore, clinicians may consider a ⩾1.3-point increase in the LCQ total score as clinically meaningful.

Validation of a visual analog scale for assessing cough severity in patients with chronic cough.

INTRODUCTION: Patients with chronic cough experience considerable burden. The cough severity visual analog scale (VAS) records patients' assessment of cough severity on a 100-mm linear scale ranging from "no cough" (0 mm) to "worst cough" (100 mm). Although cough severity scales are widely used in clinical practice and research, their use in patients with refractory or unexplained chronic cough has not been formally validated. METHODS: This analysis includes data from a phase 2b randomized controlled trial of the P2X3-receptor antagonist gefapixant for treatment of refractory or unexplained chronic cough (NCT02612610). Cough severity VAS scores were assessed at baseline and Weeks 4, 8, and 12. The cough severity VAS was validated using several outcomes, including the Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), patient global impression of change (PGIC) scale, and objective cough frequency. Validation metrics included test-retest reliability, convergent and known-groups validity, responsiveness, and score interpretation (i.e., clinically meaningful change threshold). RESULTS: The analysis included 253 patients (median age, 61.0 years; females, 76%). Test-retest reliability of the cough severity VAS was moderate (intraclass correlation coefficient, 0.51). The cough severity VAS had acceptable convergent validity with other related measures (Pearson r of 0.53 and -0.41 for CSD and LCQ total scores, respectively; p < 0.0001 for each). Known-groups validity was supported by significant differences in mean cough severity VAS scores across severity groups defined using CSD, LCQ, and cough frequency tertiles. A large effect size was observed in patients with the greatest improvements in PGIC (Cohen d = -1.8). A ⩾ 30-mm reduction in the cough severity VAS was estimated as a clinically meaningful change threshold for clinical trials in chronic cough. CONCLUSIONS: The cough severity VAS is a valid and responsive measure. A cough severity VAS reduction of ⩾ 30 mm can discriminate clinically meaningful changes in chronic cough severity in clinical studies.

Psychometric validation and meaningful change thresholds of the Worst Itching Intensity Numerical Rating Scale for assessing itch in patients with chronic kidney disease-associated pruritus.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP) is characterized by persistent itch that often leads to substantially impaired quality of life. The Worst Itching Intensity Numerical Rating Scale (WI-NRS) is a single-item patient-reported outcome measure in which patients indicate the intensity of the worst itching they experienced over the past 24 h. Here, we evaluated the content validity and psychometric properties of the WI-NRS and confirmed the threshold of meaningful change in hemodialysis patients with moderate-to-severe CKD-aP. METHODS: Content validity interviews were conducted in 23 patients. Psychometric properties of the WI-NRS were assessed using data from one phase 2 (N = 174) and two phase 3 (N = 848) clinical trials investigating an anti-pruritic treatment. Anchor-based methods were used to confirm meaningful within-patient change score thresholds in the phase 3 trial patients and mixed-method exit interviews (N = 70) contributed further insight. RESULTS: Content validity interviews indicated patients considered the WI-NRS to be straightforward, comprehensive, and relevant. Test-retest reliability was strong in both trial cohorts (intraclass correlation coefficients > 0.75). Construct validity analyses indicated high correlation between the WI-NRS and other measures of itch. Anchor-based analyses showed a reduction of ≥ 3 points from baseline score represented an appropriate clinically meaningful within-patient change on the WI-NRS. In the exit interviews, all patients with a reduction ≥ 3 points considered the change meaningful. CONCLUSIONS: The WI-NRS is a reliable, valid, and responsive measure of itch intensity for patients with moderate-to-severe CKD-aP. These results support its use to assess treatment efficacy and in clinical evaluation and management of pruritus in hemodialysis patients.

Itching is a distressing medical condition common in patients with chronic kidney disease, especially those undergoing hemodialysis. The itch often leads to skin damage due to a continuous and uncontrollable urge to scratch. It affects about 60% of hemodialysis patients and can be severe enough to seriously affect quality of life. At present, there are no approved therapies. To evaluate whether new treatments for itch are effective, clinicians need to assess if the intensity of itch decreases over time. However, because itch intensity can only be measured accurately by the person experiencing it, a measure is required that can be easily understood and used by patients. This study evaluated a scale in which patients mark a number between '0' (corresponding to no itch) and '10' (the worst itching imaginable), to describe the worst itch intensity they experienced over the last 24 hours. Using data from three clinical trials of a novel treatment for itch in patients undergoing hemodialysis with moderate-to-severe pruritus, we found that the scale was reliable in repeat-testing experiments, and mirrored other methods of measuring changes in itch. In interviews, patients said they found the scale straightforward and easy to complete. Our analysis and patients' opinions showed a 3-point reduction in itch intensity on the scale represented a meaningful improvement. These findings support the use of this scale to assess the efficacy of new treatments and in clinical evaluation and management of pruritus in patients with chronic kidney disease.

Contemporary Outcomes in Tetralogy of Fallot With Absent Pulmonary Valve After Fetal Diagnosis.

Background Tetralogy of Fallot with absent pulmonary valve is associated with high mortality, but it remains difficult to predict outcomes prenatally. We aimed to identify risk factors for mortality in a large multicenter cohort. Methods and Results Fetal echocardiograms and clinical data from 19 centers over a 10-year period were collected. Primary outcome measures included fetal demise and overall mortality. Of 100 fetuses, pregnancy termination/postnatal nonintervention was elected in 22. Of 78 with intention to treat, 7 (9%) died in utero and 21 (27%) died postnatally. With median follow-up of 32.9 months, no deaths occurred after 13 months. Of 80 fetuses with genetic testing, 46% had chromosomal abnormalities, with 22q11.2 deletion in 35%. On last fetal echocardiogram, at a median of 34.6 weeks, left ventricular dysfunction independently predicted fetal demise (odds ratio [OR], 7.4; 95% CI 1.3, 43.0; P=0.026). Right ventricular dysfunction independently predicted overall mortality in multivariate analysis (OR, 7.9; 95% CI 2.1-30.0; P=0.002). Earlier gestational age at delivery, mediastinal shift, left ventricular/right ventricular dilation, left ventricular dysfunction, tricuspid regurgitation, and Doppler abnormalities were associated with fetal and postnatal mortality, although few tended to progress throughout gestation on serial evaluation. Pulmonary artery diameters did not correlate with outcomes. Conclusions Perinatal mortality in tetralogy of Fallot with absent pulmonary valve remains high, with overall survival of 64% in fetuses with intention to treat. Right ventricular dysfunction independently predicts overall mortality. Left ventricular dysfunction predicts fetal mortality and may influence prenatal management and delivery planning. Mediastinal shift may reflect secondary effects of airway obstruction and abnormal lung development and is associated with increased mortality.