Thomas Morel

Cognitive dysfunction is a prevalent and impactful feature of Parkinson's disease (PD), with substantial heterogeneity in onset, severity, and progression, and a high lifetime risk of dementia. Despite its clinical importance, effective treatments and fit-for-purpose outcome measures remain limited. This article reports outcomes from a multi-stakeholder roundtable convened by The Michael J. Fox Foundation for Parkinson's Research, outlining priorities to advance patient-focused endpoints and improve clinical trial design to accelerate therapeutic development for cognitive dysfunction. In the context of the current understanding of cognitive impairment across the PD/dementia with Lewy bodies (DLB) spectrum and existing neuropsychological assessment approaches, recommendations are made regarding necessary literature reviews, including qualitative data and related conceptual models, disease models including pathophysiology and neuropsychological profile, and clinical outcome assessment (COA) reviews, including content validity, psychometrics, and fitness-for-purpose. Additionally, novel conceptual models of cognitive impairment across the normal, mild cognitive impairment (MCI) and dementia spectrum are needed and may require further qualitative evidence.

Introduction: Developers of disease-modifying therapies (DMTs) for early-stage Parkinson's are in dialogue with regulators to identify the relative merits of the Movement Disorder Society – Unified Parkinson's Disease Rating Scale (MDS-UPDRS) for detecting clinically meaningful changes in patients’ daily functioning during early-stage disease. We report the first qualitative assessment of MDS-UPDRS part III items’ clinical meaningfulness for use in DMT pivotal trials. Methods: Semi-structured interviews were conducted with 40 patients and 20 movement disorder neurologists. Evidence was synthesized using an interpretation framework to evaluate items according to four appraisal components. Results: Based on synthesized evidence for each appraisal component: Patient feedback indicated all items were at least somewhat meaningful to patients ; 12/18 items were classified as “highly meaningful” given their linkage to motor/daily activities functioning. See Interactive Supplement . 4/18 items were endorsed by >90% of neurologists as clinically relevant in early-stage Parkinson's (“highly relevant”). Evidence from neurologists was supportive of 6/18 items in terms of their usefulness for capturing disease progression (“highly useful”). Neurologist feedback suggested response option distinction/assessment specificity is inconsistent across items. Together, qualitative evidence endorsed the value of items 3.3 Rigidity, 3.4 Finger tapping, 3.5 Hand movements, 3.6 Pronation-supination, 3.7 Toe tapping, and 3.8 Leg agility across all four appraisal components. Conclusions: A subset of limb-related rigidity/bradykinesia items may be most clinically meaningful for detecting changes in early-stage Parkinson's. Consolidation of quantitative data with evidence from this large qualitative sample will inform final decision-making for a primary efficacy outcome measure in DMT pivotal trials.

Objective: Fatigue is a common, multifaceted symptom in SLE which is difficult to treat. There has been a lack of broadly accepted SLE-specific assessment tools for fatigue. This study assessed the psychometric properties of the FATIGUE-PRO, a new patient-reported outcome measure, in patients with SLE in real-world clinical outpatient settings (Birmingham, UK, and Düsseldorf, Germany). Methods: Patients with SLE aged ≥18 years from cross-sectional, observational studies in Birmingham and Düsseldorf completed the three FATIGUE-PRO domains (physical fatigue, mental and cognitive fatigue and susceptibility to fatigue). Psychometric evaluation was completed using Rasch Measurement Theory and classical test theory methods. Association between the FATIGUE-PRO and other clinical outcome assessments was evaluated using Spearman’s rank order correlations. Results: Overall, 200 patients were recruited from Birmingham and 234 from Düsseldorf. The FATIGUE-PRO demonstrated consistently adequate measurement properties. Items demonstrated high levels of targeting (82–95%) and the response scale functioned as intended for most items across all domains (82−100% ordered thresholds). Domains were cohesive overall, with minimal item misfit, and demonstrated little local dependency. Principal component analysis of residuals was supportive of unidimensionality of all three domains. All domain scores were reliable and demonstrated high internal consistency reliability (0.90−0.97). Moderate-to-high correlations, supportive of construct validity, were observed between the FATIGUE-PRO scores and other patient-reported outcomes, including Lupus Quality of Life. Low correlations were seen with outcome measures such as Brief Index of Lupus Damage and clinician-reported SLE Disease Activity Index-2000. Conclusions: The FATIGUE-PRO was demonstrated to be fit-for-purpose in real-world clinical outpatient settings, with strong measurement properties, supporting its use in the assessment of fatigue in SLE.

The MDS-UPDRS was not specifically developed for early-stage Parkinson’s disease (PD). This study investigated a sub-score of MDS-UPDRS Part III to assess bradykinesia and rigidity, which would be more targeted and clinically meaningful to assess disease progression in early-stage PD. A cross-sectional Rasch model was applied to the Parkinson’s Progression Markers Initiative (PPMI) untreated PD cohort data ( N = 423) to define an adequate item set. Additionally, we evaluated how the daily life items from MDS-UPDRS Part II relate to bradykinesia and rigidity severity. A sub-score of 15 MDS-UPDRS Part III items focusing on limb-related bradykinesia and rigidity demonstrated good measurement properties in early-stage PD. Items adequately targeted to the study sample, and a meaningful hierarchy supported the validity of the scale. The scale was invariant to symptomatic treatment intake. Onset of clinical signs was represented as a milestone in the emergence of impairment in patients’ daily functioning.

Introduction Parkinson’s disease (PD) is a progressive neurodegenerative condition, characterized by motor symptoms (MS) and non-motor symptoms (NMS). Currently, there is no global definition of advanced PD, but those in advanced stages experience diverse and severe symptomatology, and significant impacts to their health-related quality of life (HRQoL). This qualitative interview study aimed to explore the experience of symptoms and HRQoL impacts of advanced PD from the patient and clinician perspective and identify key concepts for assessment in PD clinical trials. Methods A targeted review of literature and qualitative concept elicitation interviews conducted with people with advanced PD (N = 20) and expert clinicians (N = 3) in the US aimed to identify symptoms of advanced PD and their impact on HRQoL. People with advanced PD (PwP) were defined as those diagnosed ≥ 5 years, experiencing ON/OFF motor fluctuations despite levodopa therapy, and classified as modified Hoehn and Yahr stages 2–4. Results In total, 65 symptoms (48 NMS, 17 MS) were identified across the reviewed literature and qualitative interviews. The most frequently reported MS included tremor, rigidity, balance issues, and slowness of movement. Several NMS were also frequently reported by participants, including fatigue, cognitive dysfunction (e.g., difficulty thinking), neuropsychiatric symptoms (e.g., apathy), pain, sleep problems, urinary dysfunction, autonomic dysfunction, excessive daytime sleepiness, gastrointestinal dysfunction, and sensory dysfunction. Participants reported these to impact HRQoL, including daily activities, emotional functioning, physical functioning, social functioning, work/study, and financial well-being. Conclusion The study provides in-depth insights into the symptoms and HRQoL impacts experienced by those with advanced PD. A comprehensive conceptual model of the patient experience of advanced PD was developed to support the identification of relevant concepts for assessment in PD clinical trials.

A comprehensive, patient-centered conceptual model of early Parkinson’s is lacking and is greatly needed. A systematic review and meta-synthesis of qualitative and quantitative research was conducted by a multi-stakeholder taskforce using JBI Mixed Methods Review criteria and GRADE-CERQual standards for assessment of evidence. Over 340 symptoms and impacts were identified across ten symptom domains (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) and two impact domains (Physical and Psychosocial functioning). A wide range of motor and non-motor symptoms were present in early disease, with strongest support for tremor, dexterity, gait, stiffness, slow movements, cognitive, mood, and sleep alterations, urinary dysfunction, constipation, pain, and fatigue. These affected mobility, self-concept, coping, effort of living, interactions and important activities, with evidence of many understudied concepts. This model offers the most comprehensive catalogue of symptoms and impacts in Parkinson’s to date and will support clinical practice and endpoint selection for therapeutic trials.

Objectives: The objective of this research was to generate psychometric evidence supporting the myasthenia gravis (MG) symptoms patient-reported outcome (PRO) scales as a fit-for-purpose measure of severity of core symptoms of MG and provide information allowing their meaningful interpretation using data from a phase 3 study in MG.Methods: Data from the MycarinG study, a phase 3 study of rozanolixizumab in patients with generalized MG who experience moderate to severe symptoms (ClinicalTrials.gov Identifier: NCT03971422) were analyzed with both classical test theory (CTT) and Rasch measurement theory (RMT). Meaningful within-individual change and group-level meaningful change were estimated for three MG Symptoms PRO scales using anchor- and distribution-based methods. Anchor-based methods used patient global impression of severity (PGIS) and change (PGIC) in MG symptoms as anchors.Results: Good measurement properties of the MG Symptoms PRO scales were shown in the sample of 200 participants: good to excellent reliability (test–retest and internal consistency reliability) and validity (associations between items and scores within the MG Symptoms PRO scales and between the MG Symptoms PRO scores and other clinical outcomes—MG ADL, QMG score, MGC score, and MGFA classes—were as expected); and the items showed good coverage of the continuum and fit to the Rasch model. Triangulation of the anchor- and distribution-based method results led to the definition of clinically meaningful within-patient improvement in scores for Muscle Weakness Fatigability (−16.67), Physical Fatigue (−20.00), and Bulbar Muscle Weakness (−20.00), with associated ranges. Benchmarks are also proposed for the interpretation of group-level results.Conclusion: The strong psychometric performance of the MG Symptoms PRO scales and the information generated to guide its interpretation supports its use in clinical trials for demonstrating the clinical benefits of new treatments targeting core symptoms of MG (muscle weakness fatigability, physical fatigue, bulbar muscle weakness, respiratory muscle weakness, and ocular muscle weakness).

Background: In support of UCB pharmaceutical research programs, the aim of this research was to implement a novel process for patient involvement in a multidisciplinary research group to co-create a clinical outcome assessment strategy to accurately reflect the experience of people living with early-stage Parkinson’s. Patient experts were an integral part of the decision-making process for patient-reported outcome (PRO) research and instrument development. Methods: In partnership with two patient organizations (Parkinson’s UK and the Parkinson’s Foundation), 6 patient experts were recruited into a multidisciplinary research group alongside clinical, patient engagement and involvement, regulatory science, and outcome measurement experts. The group was involved across two phases of research; the first phase identified what symptoms are cardinal to the experience of living with early-stage Parkinson’s and the second phase involved the development of PRO instruments to better assess the symptoms that are important to people living with early-stage Parkinson’s. Patient experts were important in performing a variety of roles, in particular, qualitative study protocol design, conceptual model development, and subsequent co-creation of two PRO instruments. Results: Involving people with Parkinson’s in PRO research ensured that the expertise of these representatives from the Parkinson’s community shaped and drove the research; as such, PRO instruments were being developed with the patient at the forefront. Working with patient experts required considerable resource and time allocation for planning, communication, document development, and organizing meetings; however, their input enriched the development of PRO instruments and was vital in developing PRO instruments that are more meaningful for people with Parkinson’s and clinicians. Conclusions: Conducting PRO research, in the context of clinical development involving pharmaceutical companies, requires balancing regulatory and scientific rigor with tight time constraints. Incorporating a multi-stakeholder perspective, which included patient experts as joint investigators, had a strong positive impact on our research, despite the logistical complexities of their involvement. Due to the input of patient experts, the innovative clinical outcome assessment strategy and the co-created novel PRO instruments were more relevant and holistic to the patient experience of early-stage Parkinson’s. Graphical