Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria.

This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: -3.0, 21.5). The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated.

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study.

PURPOSE: This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. METHODS: Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0-10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. RESULTS: Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. CONCLUSION: Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.

Content Validity of HIT-6 as a Measure of Headache Impact in People With Migraine: A Narrative Review.

BACKGROUND: The short-form Headache Impact Test (HIT-6) is a widely used patient-reported outcome measure that assesses the negative effects of headaches on normal activity. It was developed using the general headache population and prior to the establishment of the now well-accepted FDA patient-reported guidance. OBJECTIVE: The objective of this narrative review was to examine existing qualitative research in patients with migraine and headache, providing insight into the relevance and meaningfulness of HIT-6 items to the lives of migraine patients. METHODS: Articles were identified through database searches (National Library of Medicine and Google Scholar) and review of reference lists of candidate articles. RESULTS: A total of 3227 articles were identified through database and hand searching. Of these, 12 contained patient- or expert-generated qualitative information regarding headache patients' experience (8 specific to migraine [episodic and chronic] patients and 4 citing general headache patients). The combined publications described a total of 283 patient interviews. Overarching themes and specific information were identified that provide support of the relevance of content for each HIT-6 item to migraine patients' lives. Identified effects of headaches on patients with migraine included limitations in daily activities, needing to lie down during headaches, feeling tired, being irritated by headaches, difficulty concentrating, and the experience of pain. Further, previous research specific to the HIT-6 indicated that patients understood the instructions, items, and response scales as intended by the instrument authors. CONCLUSIONS: This narrative literature review demonstrates qualitative research support for the relevance of the items of the HIT-6 in migraine patients, supporting its ongoing use in clinical migraine research and practice.

Affective and Situational Precipitants of Smoking Lapses Among Adolescents.

INTRODUCTION: Most adolescent smokers report a desire to quit, and many have made several unsuccessful quit attempts; however, when adolescents attempt to quit, they often resume smoking quickly. This ecological study aimed to (1) characterize affective and situational precipitants of smoking lapses among adolescents and (2) explore the moderating influence of nicotine dependence severity on lapse precipitants. METHODS: Adolescent daily smokers (n = 166; ages 14-18 years) completed electronic diaries of cigarettes smoked, craving and affective states, and situational variables on handheld computers in their natural environment for 2 weeks following an unassisted quit attempt. On average, adolescents were moderately nicotine dependent (Modified Fagerström Tolerance Questionnaire [mFTQ] score = 4.9; SD = 1.6). RESULTS: Craving was a significant episodic cue for lapse and stable influence on lapse, relating to 44% and 15% increased odds of lapse, respectively. High-arousal affective states-regardless of valence-were associated with 12%-13% increased odds of lapse. Low-arousal positive affective states were associated with 17% decreased odds of lapse. A 1-unit difference in a teen's mFTQ score related to 27% increased odds of lapse, but dependence severity did not moderate proximal lapse influences. CONCLUSIONS: This report provides some of the first ecological data characterizing adolescent smoking lapses following a quit attempt. As in prior work with teens, lapses were nearly universal and quickly followed the quit attempt. Specific situational and affective contexts of smoking lapses for adolescents were implicated, indicating the need for cessation interventions to address craving and high-arousal affective states as precipitators of lapse in this high-risk group. IMPLICATIONS: This report provides some of the first ecological data characterizing smoking lapses among teens attempting to quit smoking on their own. Like adults, adolescents face many barriers when making quit attempts. The present work provides ecological data to suggest that the experience of heightened arousal in teens' daily lives interferes with their efforts to quit smoking. Thus, this work highlights the importance of affective dysregulation, or amplitude of emotional feelings, for teen smoking lapses. Moment-to-moment fluctuation in craving was also implicated as a dynamic precipitator of smoking lapse in this high-risk group.

Psychometric properties of the Japanese version of the Kansas City Cardiomyopathy Questionnaire in Japanese patients with chronic heart failure.

BACKGROUND: Heart failure is a worldwide health problem that significantly affects patients' physical function and health state. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcome measure commonly used for the assessment of health states of patients with heart failure. This study aimed to evaluate the psychometric properties of the Japanese version of the KCCQ. METHODS: Using pooled data of 141 Japanese patients with chronic heart failure from three clinical trials, the Japanese version of the KCCQ was evaluated for validity and reliability, with a focus on the clinical summary score (CSS) and its component domains. For construct validity, the associations of baseline KCCQ scores with New York Heart Association (NYHA) class and the EuroQol five-dimension, three-level (EQ-5D-3L) scores at baseline were analyzed. For reliability, internal consistency was assessed using Cronbach's α, and test-retest reliability (reproducibility) was assessed among stable patients. Responsiveness to changes in patients' clinical status was assessed by analyzing score changes between two timepoints among patients whose health states improved. RESULTS: Among 141 patients (mean age, 73.7 ± 10.9 years), 76.6% were NYHA class II at baseline. For CSS and its component domains (physical limitations, symptom frequency, and symptom severity), baseline scores were all significantly lower in patients with a higher NYHA class (p <  0.001 for all, Jonckheere-Terpstra test). The physical limitations domain and CSS showed a moderate correlation (Spearman's ρ = - 0.40 to - 0.54) with three functional status-related EQ-5D dimensions (mobility, self-care, and usual activities). The Cronbach's standardized α was high (> 0.70) for all KCCQ domain/summary scores. In the test-retest analysis among 58 stable patients, all domain/summary scores minimally changed by 0.3-4.2 points with intraclass correlation coefficients of 0.65-0.84, demonstrating moderate to good reproducibility, except for the symptom stability domain. Among 44 patients with improved health states, all domain/summary scores except for the symptom stability and self-efficacy domains substantially improved from baseline with a medium to large effect size of 0.62-0.88. CONCLUSIONS: The Japanese version of the KCCQ was demonstrated to be a valid and reliable tool for the assessment of symptoms and physical function of Japanese patients with chronic heart failure.

Validation of a patient-reported outcomes symptom measure for patients with nontransfusion-dependent thalassemia (NTDT-PRO© ).

This study demonstrates the quantitative characteristics of the first patient-reported outcome (PRO) tool developed for patients with nontransfusion-dependent ß-thalassemia (NTDT), the NTDT-PRO© . A multicenter validation study was performed over 24 weeks, involving 48 patients from Italy, Lebanon, Greece, and Thailand. Most patients were female (68.8%), with a median age of 34.5 years (range, 18-52); 66.7% were diagnosed with ß-thalassemia intermedia, and median time since diagnosis was 22 years (range, 0-43). The NTDT-PRO comprises 6 items across 2 domains (Tiredness/Weakness and Shortness of Breath [SoB]), and was valid and reliable, with good consistency. At baseline, most patients reported symptoms as present via the NTDT-PRO, and were highly compliant, ≥90% completing the NTDT-PRO tool. In a pairwise correlation analysis, all items were positively correlated. Correlations between NTDT-PRO and existing tools-36-Item Short Form Health Survey version 2 (SF-36v2) and Functional Assessment of Cancer Therapy-Anemia (FACT-An)-were assessed at weeks 1, 3, and 12; robust correlations were seen between SoB and SF-36v2-Vitality (rs = -0.53), and between SoB and Fact-An-Fatigue Experience (rs = -0.66) at week 1. Internal consistency was high for both Tiredness/Weakness (Cronbach alpha, 0.91) and SoB (Spearman-Brown coefficient, 0.78); intraclass correlation coefficients were high (Tiredness/Weakness, 0.88 and 0.97; SoB, 0.92 and 0.98), demonstrating stability. Further studies are required to fully support the validity of this tool, this study demonstrated the usefulness of the NTDT-PRO in the clinical setting and for longitudinal clinical research, particularly in trials where patient health-related quality of life is expected to change.

Development of a patient-reported outcomes symptom measure for patients with nontransfusion-dependent thalassemia (NTDT-PRO© ).

ß-Thalassemia, a hereditary blood disorder caused by reduced or absent synthesis of the ß-globin chain of hemoglobin, is characterized by ineffective erythropoiesis, and can manifest as nontransfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT). Many patients with NTDT develop a wide range of serious complications that affect survival and quality of life (QoL). Patient-reported outcomes (PRO), including health-related QoL (HRQoL), are important tools for determining patient health impairment and selecting appropriate treatment. However, there are currently no disease-specific PRO tools available to assess symptoms related to chronic anemia experienced by patients with NTDT. This study aimed to develop a new, US Food and Drug Administration (FDA)-compliant PRO of chronic anemia symptoms, the NTDT-PRO© tool, for use in patients with NTDT. Participants had a median age of 36 years (range, 18-47) and 60% were female. The initial development of the NTDT-PRO tool involved concept-elicitation interviews with 25 patients from 3 centers (in Lebanon, Greece, and Canada); subsequent interview discussions and clinical input resulted in the generation of 9 items for inclusion in the draft NTDT-PRO. Following a round of cognitive interviews involving 21 patients from 2 centers (in Lebanon and Greece), 4 items (Pain, Headaches, Ability to Concentrate, and Paleness) were removed from the draft NTDT-PRO. The final NTDT-PRO comprises 6 items that measure Tiredness, Weakness, and Shortness of Breath, with or without Physical Activity. The NTDT-PRO is a new disease-specific HRQoL tool for patients with NTDT, developed using a thorough methodology based on FDA 2009 PRO development guidelines.

Topiramate and motivational enhancement therapy for cannabis use among youth: a randomized placebo-controlled pilot study.

Cannabis misuse accounts for nearly all of the substance abuse treatment admissions among youth in the United States. Most youth do not experience sustained benefit from existing psychosocial treatments; however, medication development research for treating adolescent cannabis misuse is almost nonexistent. We conducted a double-blind, placebo-controlled, pilot study to test the potential efficacy of topiramate plus motivational enhancement therapy (MET) for treating cannabis use among adolescents. Sixty-six heavy cannabis users, ages 15 to 24 years, were randomized to one of two 6-week treatment conditions: topiramate plus MET or placebo plus MET. Topiramate was titrated over 4 weeks then stabilized at 200 mg/day for 2 weeks. MET was delivered biweekly for a total of three sessions. Only 48 percent of youths randomized to topiramate completed the 6-week trial (n = 19), compared with 77 percent of youths in the placebo condition (n = 20). Adverse medication side effects were the most common reason for withdrawal among participants in the topiramate group. Latent growth models showed that topiramate was superior to placebo for reducing the number of grams smoked per use day, but it did not improve abstinence rates. The same pattern of results was found when values for missing outcomes were imputed. We show that topiramate combined with MET demonstrated efficacy for reducing how much cannabis adolescents smoked when they used but did not affect abstinence rates. The magnitude of this effect was modest, however, and topiramate was poorly tolerated by youths, which calls into question the clinical importance of these findings.

Self-Paced Exercise, Affective Response, and Exercise Adherence: A Preliminary Investigation Using Ecological Momentary Assessment.

Affective response to exercise may mediate the effects of self-paced exercise on exercise adherence. Fiftynine low-active (exercise <60 min/week), overweight (body mass index: 25.0-39.9) adults (ages 18-65) were randomly assigned to self-paced (but not to exceed 76% maximum heart rate) or prescribed moderate intensity exercise (64-76% maximum heart rate) in the context of otherwise identical 6-month print-based exercise promotion programs. Frequency and duration of exercise sessions and affective responses (good/bad) to exercise were assessed via ecological momentary assessment throughout the 6-month program. A regression-based mediation model was used to estimate (a) effects of experimental condition on affective response to exercise (path a = 0.20, SE = 0.28, f2 = 0.02); (b) effects of affective response on duration/latency of the next exercise session (path b = 0.47, SE = 0.25, f2 = 0.04); and (c) indirect effects of experimental condition on exercise outcomes via affective response (path ab = 0.11, SE = 0.06, f2 = 0.10). Results provide modest preliminary support for a mediational pathway linking self-paced exercise, affective response, and exercise adherence.

Recommending self-paced exercise among overweight and obese adults: a randomized pilot study.

BACKGROUND: National guidelines call for exercise of at least moderate intensity; however, recommending self-paced exercise may lead to better adherence, particularly among overweight and obese adults. PURPOSE: The purpose of this study was to test proof-of-concept for recommending self-paced exercise among overweight adults. METHODS: Fifty-nine healthy, low-active (exercise <60 min/week), overweight (body mass index 25.0-39.9) adults (18-65) received a 6-month print-based exercise promotion program with the goal of walking 30-60 min/day. Participants were surreptitiously randomly assigned to receive a recommendation for either self-paced (n = 30) or moderate (64-76 % maximum heart rate; n = 29) intensity exercise. All participants used electronic diaries and heart rate monitors to track exercise frequency, duration, and intensity. RESULTS: The self-paced condition reported more minutes/week of walking (f (2) = 0.17, p = 0.045) and a trend toward greater exercise-related energy expenditure/week (f (2) = 0.12, p = 0.243), corresponding to approximately 26 additional minutes/week and 83 additional kilocalories/week over 6 months. CONCLUSIONS: Explicit recommendation for self-paced exercise may improve adherence to exercise programs among overweight and obese adults.

Effects of naltrexone on adolescent alcohol cue reactivity and sensitivity: an initial randomized trial.

Adolescent alcohol use is associated with myriad adverse consequences and contributes to the leading causes of mortality among youth. Despite the magnitude of this public health problem, evidenced-based treatment initiatives for alcohol use disorders in youth remain inadequate. Identifying promising pharmacological approaches may improve treatment options. Naltrexone is an opiate receptor antagonist that is efficacious for reducing drinking in adults by attenuating craving and the rewarding effects of alcohol. Implications of these findings for adolescents are unclear; however, given that randomized trials of naltrexone with youth are non-existent. We conducted a randomized, double-blinded, placebo-controlled cross-over study, comparing naltrexone (50 mg/daily) and placebo in 22 adolescent problem drinkers aged 15-19 years (M = 18.36, standard deviation = 0.95; 12 women). The primary outcome measures were alcohol use, subjective responses to alcohol consumption, and alcohol-cue-elicited craving assessed in the natural environment using ecological momentary assessment methods, and craving and physiological reactivity assessed using standard alcohol cue reactivity procedures. Results showed that naltrexone reduced the likelihood of drinking and heavy drinking (P's ≤ 0.03), blunted craving in the laboratory and in the natural environment (P's ≤ 0.04), and altered subjective responses to alcohol consumption (P's ≤ 0.01). Naltrexone was generally well tolerated by participants. This study provides the first experimentally controlled evidence that naltrexone reduces drinking and craving, and alters subjective responses to alcohol in a sample of adolescent problem drinkers, and suggests larger clinical trials with long-term follow-ups are warranted.

Leveraging sensor-based functional outcomes to enhance understanding of the patient experience: challenges and opportunities.

INTRODUCTION: Sensor-based digital health technology (DHT) has emerged as a promising means to assess patient functioning within and outside clinical trials. Sensor-based functional outcomes (SBFOs) provide valuable insights that complement other measures of how a patient feels or functions to enhance understanding of the patient experience to inform medical product development. AREAS COVERED: This perspective paper provides recommendations for defining SBFOs, discusses the core evidence required to support SBFOs to inform decision-making, and considers future directions for the field. EXPERT COMMENTARY: The clinical outcome assessment (COA) development process provides an important starting point for developing patient-centered SBFOs; however, given the infancy of the field, SBFO development may benefit from a hybrid approach to evidence generation by merging exploratory data analysis with patient engagement in measure development. Effective SBFO development requires combining unique expertise in patient engagement, measurement and regulatory science, and digital health and analytics. Challenges specific to SBFO development include identifying concepts of interest, ensuring measurement of meaningful aspects of health, and identifying thresholds for meaningful change. SBFOs are complementary to other COAs and, as part of an integrated evidence strategy, offer great promise in fostering a holistic understanding of patient experience and treatment benefits, particularly in real-world settings.

Qualitative Study of the Patient Experience with Venglustat for Gaucher Disease Type 3 in a Phase 2 Open-Label, Multicenter, Multinational Study (LEAP).

INTRODUCTION: Gaucher disease type 3 (GD3) is a genetic, progressive lysosomal storage disorder characterized by visceral manifestations and chronic neurologic symptoms (e.g., horizontal ophthalmoplegia/supranuclear gaze palsy, ataxia, dystonia). The investigational agent venglustat is being studied in combination with imiglucerase as potential treatment for systemic and neuronopathic manifestations of GD3 in a single-arm, open-label, phase 2 trial (LEAP; N = 11). To understand perceived changes in GD3 symptoms from the perspectives of patients, caregivers, and clinicians, we conducted a qualitative case study of selected LEAP participants. METHODS: Four patients in LEAP (age range, 20-28 years), four of their caregivers, and three clinicians involved in LEAP were interviewed individually by moderators using semi-structured guides. Clinicians' perceptions were based on observation of interviewed patients and those in LEAP who were not interviewed, as well as information provided by other staff involved in LEAP, patients, and caregivers. RESULTS: Reported changes in GD3 symptoms varied among patients and among reporters. Only eye movement was spontaneously mentioned as improved by at least one patient, caregiver, and clinical expert. Symptom improvement also varied in terms of time to improvement. Within the first weeks, improvements were seen in understanding new information or complex instructions, remembering the weekday, eye movement, tremor, and seizures. Changes in alertness, engagement and responsiveness, memory, and concentration appeared after months or a year. Most caregivers and all clinical experts reported greater patient independence (e.g., increased ability to perform activities of daily living or travel independently during the trial) as a perceived treatment effect on a GD3 impact. For one patient who perceived benefits from venglustat therapy, pharmacokinetic analyses during LEAP found low to undetectable venglustat levels in their plasma and cerebrospinal fluid. CONCLUSION: Outcomes from this study provide insights into GD3 symptoms and the early signaling of changes reported during venglustat therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02843035.

Support for incentive-sensitization theory in adolescent ad libitum smokers using ecological momentary assessment.

The incentive-sensitization theory (IST) has emerged as a potentially useful theory in explaining substance addiction. IST postulates that the prolonged use of a substance can alter neural systems that are often involved in incentive motivation and reward processes, leading to an increased "sensitization" to the substance and associated stimuli. However, this increased sensitization is thought to mediate only the individual's craving of the substance (e.g., their "wanting"), not their enjoyment of the substance (e.g., their "liking"), a process that may involve unconscious implicit changes in cognitive networks linked to specific substances. Consequently, IST may better explain the real-world dissonance reported for individuals who want to accomplish long-term substance cessation but fail to do so, a phenomenon that is common in adolescent smokers. Thus, the present study aimed to examine the principles of IST in a sample of 154 adolescent ad libitum smokers (Mage = 16.57, SDage = 1.12, 61.14% male) utilizing ecological momentary assessment. Data were analyzed utilizing a multilevel structural equation model examining changes in positive affect (PA), negative affect (NA), and stress from Time 1 (T1) and Time 2 (T2) as a function of smoking and tested the influence of implicit cognition (specifically, implicit attitudes about smoking [Implicit Association Test (IAT)]) on these associations. Consistent with the principles of IST, results found a modest significant negative association between smoking status at T1 and PA at T2 (B = -0.11, p = .047). This association was further moderated by IAT (B = -0.19, p = .029) and was particularly potentiated at high levels of IAT (B = -0.44, p < .001), compared to low (B = -0.05, p = .663) or mean levels of IAT (B = -0.25, p = .004). Findings from this study provide additional support to the principles underlying IST and indicate that, in adolescents, smoking may result in thwarted PA indicative of a transition from "liking" toward "wanting," and this is especially pronounced among those with stronger implicit smoking cognitions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Item-level psychometric properties for a new patient-reported psoriasis symptom diary.

OBJECTIVES: This research evaluated the psychometric properties of a new Psoriasis Symptom Diary, identified diary responder definitions for use in determining whether a patient has experienced clinically meaningful change, and refined diary item content for use in future clinical trials. METHODS: The Psoriasis Symptom Diary was administered in a phase 2 clinical trial of AIN457 to US adult outpatients (N = 172) with physician-diagnosed moderate to severe chronic plaque-type psoriasis. Participant compliance with daily diary administration and item score variability, reliability, construct and discriminant validity, sensitivity to change, and interpretation were all evaluated. RESULTS: Participants completed 94% of scheduled diary assessments across 12 study weeks. Diary items were generally normally distributed, and no floor or ceiling effects were observed. Item reliability (reproducibility) was acceptable (intraclass correlation coefficients > 0.80), with an exception for one item (skin color). At week 12, items significantly related to criterion measures as predicted (Psoriasis Area and Severity Index r = 0.27-0.57; Investigator's Global Assessment r = 0.25-0.59), with the exception of items that measured skin color and difficulty using hands. Most items generated change scores that were synchronous to changes as measured by the Psoriasis Area and Severity Index, Investigator's Global Assessment, Dermatology Life Quality Index (r > 0.37), as well as the Patient Global Impression of Change. Responders experienced a 2- to 3-point and 3- to 5-point change in item scores for minimal and large improvements, respectively. Four items that did not perform well were dropped from the diary. CONCLUSIONS: The 16-item Psoriasis Symptom Diary demonstrated favorable psychometric properties and is a brief, useful tool for measuring patient-based symptoms and the impact of chronic plaque psoriasis.

Measurement Properties of 2 Novel PROs, the Pompe Disease Symptom Scale and Pompe Disease Impact Scale, in the COMET Study.

Background and Objectives: The Pompe Disease Symptom Scale (PDSS) and Impact Scale (PDIS) were created to measure the severity of symptoms and functional limitations experienced by patients with late-onset Pompe disease (LOPD). The objectives of this analysis were to establish a scoring algorithm and to examine the reliability, validity, and responsiveness of the measures using data from the COMET clinical trial. Methods: The COMET trial was a randomized, double-blind study comparing the efficacy and safety of avalglucosidase alfa and alglucosidase alfa in patients with LOPD aged 16-78 years at baseline. Adult participants (18 years or older) completed the PDSS and PDIS daily for 14 days at baseline and for 2 weeks before quarterly clinic visits for 1 year after randomization using an electronic diary. Data were pooled across treatment groups for the current analyses. Factor analysis and inter-item correlations were used to derive a scoring algorithm. Test-retest and internal consistency analyses examined the reliability of the measures. Correlations with criterion measures were used to evaluate validity and sensitivity to change. Anchor and distribution-based analyses were conducted to estimate thresholds for meaningful change. Results: Five multi-item domain scores were derived from the PDSS (Shortness of Breath, Overall Fatigue, Fatigue/Pain, Upper Extremity Weakness, Pain) and 2 from the PDIS (Mood, Difficulty Performing Activities). Internal consistency (Cronbach α > 0.90) and test-retest reliability (intraclass correlation >0.60) of the scores were supported. Cross-sectional and longitudinal correlations with the criterion measures generally supported the validity of the scores (r > 0.40). Within-patient meaningful change estimates ranging from 1.0 to 1.5 points were generated for the PDSS and PDIS domain scores. Discussion: The PDSS and PDIS are reliable and valid measures of LOPD symptoms and functional impacts. The measures can be used to evaluate burden of LOPD and effects of treatments in clinical trials, observational research, and clinical practice. Trial Registration Information: ClinicalTrials.gov identifier: NCT02782741.

High Hostility Among Smokers Predicts Slower Recognition of Positive Facial Emotion.

High levels of trait hostility are associated with wide-ranging interpersonal deficits and heightened physiological response to social stressors. These deficits may be attributable in part to individual differences in the perception of social cues. The present study evaluated the ability to recognize facial emotion among 48 high hostile (HH) and 48 low hostile (LH) smokers and whether experimentally-manipulated acute nicotine deprivation moderated relations between hostility and facial emotion recognition. A computer program presented series of pictures of faces that morphed from a neutral emotion into increasing intensities of happiness, sadness, fear, or anger, and participants were asked to identify the emotion displayed as quickly as possible. Results indicated that HH smokers, relative to LH smokers, required a significantly greater intensity of emotion expression to recognize happiness. No differences were found for other emotions across HH and LH individuals, nor did nicotine deprivation moderate relations between hostility and emotion recognition. This is the first study to show that HH individuals are slower to recognize happy facial expressions and that this occurs regardless of recent tobacco abstinence. Difficulty recognizing happiness in others may impact the degree to which HH individuals are able to identify social approach signals and to receive social reinforcement.

Regulatory Acceptance of Patient-Reported Outcome (PRO) Data from Bring-Your-Own-Device (BYOD) Solutions to Support Medical Product Labeling Claims : Let's Share the Success Stories to Move the Industry Forward.

Bring-your-own-device (BYOD) methods for collecting patient-reported outcome (PRO) data in clinical trials can decrease patient burden and improve data quality. However, adoption of BYOD in clinical trials is limited by the absence of publicly available case studies where BYOD PRO data supported regulatory medical product approvals. Anecdotally, we are aware of multiple examples where efficacy and safety label claims were based on BYOD PRO data; however-except for one-these examples have not been made public. The absence of these case studies can lead sponsors to be hesitant to use BYOD for capturing primary and secondary PRO-based endpoints in their trials. This commentary outlines the context of the issue faced and concludes with a call for sponsor transparency with regard to BYOD use through publicizing where approved labeling claims were based on BYOD data. We suggest how this data could be systematically captured going forward. Sharing this information will benefit the clinical trials enterprise by increasing confidence in the utilization of BYOD and provide opportunities to enhance patient-centricity.

Development of an Item Bank to Assess Patient-Reported Outcomes: Signs, Symptoms, and Impacts of COVID-19.

BACKGROUND AND OBJECTIVE: Patients experience a wide range of signs, symptoms, and impacts related to coronavirus disease 2019 (COVID-19). A patient-reported outcome (PRO) item bank that measures the most relevant patient experiences is needed to fully evaluate treatment benefit in COVID-19 clinical trials. METHODS: A review of the literature and social media informed a novel PRO item bank of COVID-19 signs, symptoms, and impacts and general pandemic impacts. Twenty 1:1 concept elicitation and cognitive debriefing interviews were conducted with adults in the US who had symptomatic COVID-19. A conceptual model was developed and the PRO item bank refined following interviews. RESULTS: A heterogenous set of signs, symptoms, and impacts of COVID-19, as well as impacts associated with the pandemic overall, was identified. Fifty-five short-term and long-term signs and symptom items, 26 items assessing disease-related impacts, and seven items evaluating pandemic-related impacts are included in the item bank. CONCLUSIONS: The novel and preliminarily content-valid IQVIA COVID-19 Daily Diary Item Bank© and the IQVIA COVID-19 Weekly Diary Item Bank© were developed to measure signs and symptoms, their associated severity, and disease-related and pandemic-related impacts. The items are arranged in seven groups and can be individually selected based on research needs.

Living with heart failure: patient experiences and implications for physical activity and daily living.

AIMS: Heart failure (HF) substantially limits the ability of patients to engage in physical activities. A detailed understanding of how patients experience these limitations is required to develop valid and sensitive measures for use in clinical research. This qualitative study was designed to provide a thorough description of how HF patients experience physical activity limitations in their daily lives. METHODS AND RESULTS: Semi-structured interviews were conducted with 40 HF patients. Interview transcripts were coded with the aim of identifying key aspects of physical activity. Patients were divided between HF with preserved ejection fraction (n = 21, 52.5%) and HF with reduced ejection fraction (n = 19, 47.5%); the majority of patients were New York Heart Association Class II (n = 22, 52.5%) or Class III (n = 16, 40.0%). Relevant physical activity themes, including mobility and broader daily function areas, were identified. The most frequently reported mobility limitations involved difficulty walking (up a steep incline, up steps, and long distances), limited walking speed, difficulty standing for long periods of time, and difficulty carrying and lifting objects. These limitations were principally related to three HF symptoms: dyspnoea, tiredness/fatigue, and peripheral oedema. Patients adapted to their symptoms and related mobility limitations in several ways, including taking rests during an activity, doing an activity more slowly, and avoiding/refraining from an activity altogether. The broader daily function areas most commonly impacted by the mobility limitations were housework, exercising or playing sports, and going shopping. CONCLUSIONS: Heart failure patients report numerous physical activity limitations. These specific mobility and daily function areas can be measured using clinical outcome assessments (e.g. patient-reported outcomes and performance outcomes) in clinical trials and observational research. Accelerometry can be used to contribute to a holistic picture of patient functioning by passively collecting this type of data.