Chad Gwaltney’s research while affiliated with Brown University and other places

Background Gaucher disease type 3 (GD3) is a lysosomal storage disease characterized by diverse neurological and systemic manifestations. Symptoms of ataxia, cognitive impairment, and other systemic symptoms profoundly impact daily activities and the quality of life for individuals living with the disease. Development of a conceptual model of disease for persons living with GD3 from birth to adulthood would enable objective monitoring of disease progression and assessment of treatment benefits. Methods A targeted literature review, interviews with clinical experts, and interviews with individuals and their caregivers living in the UK and the US were carried out to understand the patient experience. Interviews were transcribed and de-identified data were analyzed to identify signs, symptoms, and impacts of ataxia, cognitive impairment, and other systemic impairments. A conceptual model was developed by integrating relevant signs, symptoms, and impacts experienced from birth through adulthood. Results Review of symptoms and impacts of GD3 from three published scientific articles, and interviews with six clinical experts, 12 individuals living with GD3, and 12 caregivers, identified 58 patient experience concepts associated with GD3. Signs and symptoms associated with ataxia appear during the first 3 years of life and persist beyond 5 years of age, while signs and symptoms related to neurocognition appear later in life. Difficulty in shifting gaze and/or tracking objects, ataxia, tremors, memory problems, difficulty in processing new information, fatigue, and bone pain are most salient concepts for GD3. In patients aged ≤ 5 years, motor manifestations and symptoms were far more prevalent than neurocognitive signs and symptoms. Inability to work or perform at school, limited social and family engagements, restricted mobility (walking, driving, public transportation), and declining independence were the most important impacts on individuals with GD3. Conclusions Heterogeneity exists in GD3 manifestations, especially neuromuscular and neurocognitive signs, symptoms, and impacts, across all age ranges of individuals living with GD3. The conceptual model developed in the study provided a comprehensive understanding of the disease in individuals with GD3.

Purpose The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) comprises 7 common MF symptom items (fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, bone pain) and is the first patient-reported outcome (PRO) instrument designed to assess MF symptom burden. Given that information on the psychometric properties of this instrument has been limited, we sought to evaluate its measurement properties and validate its use in the phase 3 MOMENTUM trial. Methods Data were pooled to assess MFSAF item distribution, structural validity, reliability (test-retest and internal consistency), construct validity (convergent, divergent, and known-groups), and sensitivity to change. Other PRO measures included Patient Global Impression of Severity/Change (PGIS/PGIC), EORTC QLQ-C30, PROMIS Physical Function Short Form 10b, and ECOG performance status. Results Participants (N = 195) showed high completion rates (> 93%) across 24 weeks. Moderate to strong Spearman correlation coefficients among items were mostly observed at baseline (range, 0.289–0.772) and week 24 (range, 0.391–0.829), which supported combining items into a multi-item scale and total score. Internal consistency (Cronbach’s α, 0.877 at baseline and 0.903 at week 24) and test-retest reliability (intraclass correlation coefficient, > 0.829) were satisfactory across selected time intervals. Reliability was also supported by McDonald’s omega (ω) coefficient (> 0.875). MFSAF moderately correlated with PRO measures of similar content, differentiated between PGIS and ECOG groups (P < .001), and was able to detect change over time. Conclusions The MFSAF v4.0 is a valid tool to assess MF symptom burden, supporting its use in future trials in similar populations.

Background There are limited tools to measure the burden of disease and effectiveness of medical/surgical interventions in patients with cryptoglandular fistulas. The aim of this study was to explore concepts that are relevant and important to patients with complex cryptoglandular fistulas (CCF) and to develop a patient-centred, disease-specific, patient-reported outcome measure (PROM) to assess symptom burden and impacts of CCF. Methods A targeted literature review was conducted, followed by one-to-one telephone interviews with five colorectal surgeons (USA, n = 3; UK, n = 1; Spain, n = 1) and 20 US adult patients with CCF to inform the development of a conceptual model and a CCF-specific PROM. The targeted literature review informed the development of the preliminary conceptual model and identified a PROM in the literature that was used as a reference to generate the draft CCF-specific PROM. The colorectal surgeon interviews provided insights on the experience of patients with CCF to refine the conceptual model, formulate probing questions for use in patient interviews, and to develop the draft CCF-specific PROM. Patients’ descriptions of their experiences with symptoms and the impacts on their lives and evaluation of the draft CCF-specific PROM in concept elicitation and cognitive interviews were used to develop the final conceptual model and final CCF-specific PROM. Results Ten symptoms (odour, pain during bowel movement, abscess, post-operative pain, discharge/drainage/leakage, anal/perianal pain, inflammation/swelling, skin irritation, bleeding and itchiness) and 11 impacts (discomfort, inability to exercise, embarrassment, difficulty sitting, worry about disease, adapted life to maintain hygiene, negatively impacted social life/isolation, inability to perform daily activities, reduced interest in sex, negatively impacted intimate relationships and negatively impacted mood) were reported as most salient by patients. The patient experience, clinician perspective, and literature review provided input to item generation. Evaluation of relevance and patient understanding through cognitive interviews with patients provided evidence for the content validity of the new patient-reported outcome measure: the 20-item Complex Cryptoglandular Fistula Questionnaire ™ (CCFQ-20 ™ ). Conclusion The CCFQ-20 ™ is a new clinician-guided, patient-validated, disease-specific patient-reported outcome measure that measures disease impact and quality of life in patients with CCF.

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.

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. 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. 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. Outcomes from this study provide insights into GD3 symptoms and the early signaling of changes reported during venglustat therapy. ClinicalTrials.gov identifier, NCT02843035.

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