Antoine Regnault

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.

Background and purpose: Guillain-Barré syndrome (GBS) is an autoimmune neurological disorder characterized by muscle weakness. In clinical trials, treatment benefit and disease severity are typically measured using clinician-reported outcome measures like the Hughes Functional Grading Scale (HFGS). However, patient-reported outcome measures, such as the Rasch-built Overall Disability Scale (R-ODS) may provide additional insight into the patient experience during treatment. In this study, exploratory analyses of clinical trial data were performed to investigate how existing clinician-reported outcomes and patient-reported outcomes can help to assess disease progression by providing an accurate measurement of functional status.Methods: Data were collected as part of a phase 3 study to assess the safety and efficacy of eculizumab in patients in Japan with severe GBS. The association between HFGS score and R-ODS total centile score (linear measure of limitations; 0, most severe activity and social participation limitations and 100, no limitations) was assessed using the Spearman rank-order correlation coefficient. Threshold values of R-ODS total centile score that could differentiate between patients with an HFGS score of ≤ 1 and > 1 were determined using receiver-operating characteristic curve analyses and mapping (Rasch measurement theory). A triangulation approach was used to establish a proposed value for R-ODS total centile score equivalent to an HFGS score of ≤ 1 or > 1.Results: Overall, 57 patients were included in this analysis. These exploratory analyses revealed good correlation between R-ODS total centile and HFGS scores. Using the Rasch model, mapping of HFGS to R-ODS scores showed a good fit. Evaluation of the R-ODS threshold that could approximate the functional motor symptom categories based on HFGS (score of 0 or 1) revealed a range of values from 60 to 80. Based on a trial sample, a threshold of 60 was found to have 100% sensitivity and 87% specificity at week 4, and 93.8% sensitivity and 77.8% specificity at week 24.Conclusion: This study established thresholds for the R-ODS total centile score that could approximate classification of functional impairment in GBS based on the HFGS score. Given that the R-ODS reflects the patient perspective, it may be used to capture a more complete picture of GBS severity.

Background: Trials of disease-modifying therapies (DMTs) for multiple sclerosis (MS) often include patients with minimal disability. Patient-reported outcome instruments used in these trials have often not captured physical and psychological treatment effects concomitant with observed clinical benefits. Objective: To examine whether the Multiple Sclerosis Impact Scale-29 (MSIS-29) captures changes in the impact of MS in a sample of patients enrolled in the Phase 3 ASCLEPIOS studies (ofatumumab vs. teriflunomide). Methods: Measurement properties (i.e. item fit, reliability, and targeting) of the MSIS-29 were analyzed using Rasch measurement theory (RMT) in data from two phase 3 ofatumumab clinical trials including patients with relapsing-remitting or secondary progressive MS ( N = 1882). Targeting of the MSIS-29 items to the patient population was explored within groups categorized by Expanded Disability Status Scale (EDSS) scores. Results: Under RMT analyses, both the Physical and Psychological Impact scales of the MSIS-29 were not appropriately targeted to the overall sample of patients. In particular, 49% and 30% of patients with an EDSS score ≤ 2.5 had fewer physical and psychological impacts, respectively, than would typically be captured by these MSIS-29 items compared to patients with EDSS scores of ≥ 3. Conclusion: The MSIS-29 is commonly used to evaluate the patient-reported physical and psychological impact of MS. However, it may be limited in evaluating changes associated with DMTs in patients with minimal disability.

Introduction Accurate measurement of myasthenia gravis (MG) severity is required for appropriate clinical monitoring of patients with MG and assessment of the benefit of new treatments in clinical trials. Our objective was to explore how MG severity can be measured and to determine how the newly developed MG Symptoms Patient-Reported Outcome (PRO) instrument complements the available measures of MG severity. Methods The conceptual coverage of the Quantitative MG (QMG), MG Composite (MGC), MG-Activities of Daily Living (MG-ADL), and MG Symptoms PRO was scrutinized against core symptoms of MG: muscle weakness in three muscle groups (ocular, bulbar, and respiratory), muscle weakness fatigability, and physical fatigue. Post hoc analyses of the MG0002 study, a Phase 2a clinical trial of rozanolixizumab in adults with moderate to severe generalized MG, included correlation and Rasch model analyses. Results The qualitative appraisal highlighted that only the MG Symptoms PRO captured physical fatigue. Data from 541 assessments (43 unique patients) were used for the analyses. Correlations ranged between 0.56 and 0.74 for the MG-ADL, QMG, MGC, and MG Symptoms PRO Muscle Weakness Fatigability score, and between 0.20 and 0.71 for the MG Symptoms PRO scores focusing on independent muscle groups. Analyses with the Rasch model estimated a meaningful continuum of severity of MG, including all items, except ocular muscles, from the four instruments. The QMG and MG Symptoms PRO had the broadest coverage of the MG severity continuum. Muscle fatigability and physical fatigue were more characteristic of low severity while bulbar weakness indicated more severe MG. Conclusion The severity of MG can be reflected in a meaningful continuum underpinned by the MG-specific outcome measures. Only ocular muscle manifestations were shown to reflect a possibly different facet of MG severity. With its modular nature and comprehensive content, the MG Symptoms PRO provides complementary information to the outcome measures widely used in MG. Trial Registration ClinicalTrials.gov identifier: NCT03052751.

Purpose: Physical functioning and fatigue are key patient concerns in myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). The objective of this research was to generate supportive quantitative evidence for modular physical functioning and fatigue measures based on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) and a customized selection of 10 supplemental items from the EORTC Item Library. Methods: The 40 items were completed online cross-sectionally by 51 patients (higher risk [HR] MDS: 53%; CMML: 26%; AML: 10%). Psychometric analyses based on Rasch measurement theory (RMT) were conducted on the QLQ-C30 physical functioning and fatigue domains as well as measures combining QLQ-C30 and supplemental items. A measure of anemia-related symptoms composed of QLQ-C30 and supplemental items covering fatigue, dyspnea, and dizziness was also investigated. Results: The QLQ-C30 physical functioning and fatigue domains showed good targeting to the sample and adequate reliability, with few conceptual gaps identified. Combining the QLQ-C30 and supplemental physical functioning and fatigue items improved the conceptual coverage and the reliability of the measures. The patient-reported anemia-related symptom measure showed good measurement performance, underpinned by a clinically meaningful characterization of severity of these symptoms over a spectrum, starting with fatigue, then dyspnea, and finally dizziness (most severe). Conclusion: The modular measurement approach of combining EORTC QLQ-C30 and Item Library offers a promising pragmatic solution to the measurement of physical functioning and fatigue, as well as anemia-related symptoms in clinical trials conducted in HR MDS, CMML, and AML.

Objectives Given the lack of validated patient-reported outcomes (PRO) instruments assessing cold symptoms, a new pediatric PRO instrument was developed to assess multiple cold symptoms: the Child Cold Symptom Questionnaire (CCSQ). The objective of this research was to evaluate the measurement properties of the CCSQ. Methods This observational study involved daily completion of the self-report CCSQ by children aged 6–11 years in their home for 7 days. These data were used to develop a scoring algorithm and item-scale structure and evaluate the psychometric properties of the resulting scores. Analyses included evaluation of item and dimensionality performance (item response distributions and confirmatory factor analysis) and assessment of test–retest reliability in stable patients, construct validity (convergent and known groups validity), and preliminary responsiveness. Qualitative exit interviews in a subgroup of the children with colds and their parents were conducted. Results More than 90% of children had no missing data during the testing period, reflecting an excellent completion rate. For most items, responses were distributed across the options, with approximately normal distributions. Test–retest reliability was adequate, with intra-class correlation coefficients ranging from 0.63 to 0.83. A logical pattern of correlations with the validated Strep-PRO instrument provided evidence supporting convergent validity. Single- and multi-item symptom scores distinguished between children who differed in their cold severity based on global ratings, providing evidence of known groups validity. Preliminary evidence indicates the CCSQ is responsive to changes over time. Conclusions The findings demonstrate that the CCSQ items and multi-item scores provide valid and reliable patient-reported measures of cold symptoms in children aged 6–11 years. They provide strong evidence supporting the validity of these items and multi-item scores for inclusion as endpoints in clinical trials to evaluate the efficacy of cold medicines.

Introduction P-2001, a randomized phase 2 trial (NCT02610777), investigated the efficacy and safety of pevonedistat (P), the first small-molecule inhibitor of the NEDD8-activating enzyme, in combination with azacitidine (A) versus A alone in patients (pts) with higher-risk (Revised International Prognostic Scoring System risk >3, including intermediate [≥5% blasts], high, or very high risk) myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myeloid leukemia (LB AML) naïve to hypomethylating agents. The P-2001 trial recently demonstrated median event-free survival of 21.0 vs 16.6 months (HR=0.665; P = .076), and overall response rates (complete remission [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR] + hematologic improvement [HI]) of 71% (n=39/55) vs 60% (n=32/53) with P+A compared with A, respectively. Management of MDS can significantly impact quality of life, and measures of high-symptom burden have been associated with worse clinical outcomes. We set out to explore patient-reported outcomes (PRO) as an exploratory endpoint in the study. Methods The study randomized 120 pts (1:1) to receive P+A or A alone in 28-day treatment cycles. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire - core 30 items (QLQ-C30) was administered at the first day of each cycle, at the end of treatment (EOT) visit and post-EOT visits. Physical functioning (PF), fatigue (FA), dyspnea (DY) and global health status/quality of life (QL) were identified as key PRO concepts that deserved specific attention in this population. Analyses were carried out to explore the PRO data: description of available PRO data, longitudinal analyses of change in the key PRO scores with repeated measurement mixed models (RMMM), including comparison between treatment arms, and descriptive analysis of the key PRO scores after clinical response depending on the type of response (PR, CR, CRi, or HI), and before and after transformation to AML for pts with higher-risk MDS, independently from the treatment received. Results There were 112 pts in the PRO population (defined as all pts with a PRO assessment at baseline and at least 1 post-baseline); baseline demographics and disease characteristics are presented in Table 1. At least 90% of pts in the study had a PRO available at each cycle. As expected, the amount of available PRO data decreased over the study due to progression, death, or study discontinuations. The RMMMs of the PRO population did not show any statistically significant difference in the change over time in key QLQ-C30 scores (PF, QL, FA, and DY) between P+A versus A alone. Pts who experienced CR (P+A, 40%; A, 29%) showed a nonsignificant improvement in PF and QL, as well as a nonsignificant decrease of FA after CR than at baseline; no differences were noted in DY. Pts for whom best response was PR had less improvement in the key PROs than pts with CR, and those with HI did not show improvement compared with baseline. Among the 12 pts with higher-risk MDS/CMML progressing to AML during the study with available PRO data (P+A, n=4; A, n=8), 6 showed worsening in PF score (vs 2 improving), 6 showed worsening in QL score (vs 1 improving), 7 showed worsening in FA score (vs 1 improving), and 7 showed worsening in DY score (vs none improving). Conclusions Measurement of QL and symptom burden are integral clinical endpoints in assessing new treatments in higher-risk MDS/CMML and LB AML. There was no evidence to suggest that the addition of P to A led to change in the key PROs identified: QL, PF, FA and DY. Achievement of CR was associated with higher PRO scores compared with baseline independently of the treatment received, and progression to AML was associated with worsening QL scores. Additional analyses are planned with the P-2001 PRO data to further explore the impact of P on PROs by evaluating the impact of dropout during the study, comparing findings according to treatment arm, and better understanding the possible effect of adverse events on PROs. Disclosures: Zeidner: AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria; AROG: Research Funding; AsystBio Laboratories: Consultancy; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Genentech: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding. Mazerolle:Takeda Pharmaceutical Company: Other: Granted research funding to Modus Outcomes, my employer; Modus Outcomes: Current Employment. Bell:Millennium Pharmaceuticals, Inc.: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Faller:Phoenicia Biosciences: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracta Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment; Briacell Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Dalal:Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA: Current Employment, Current equity holder in private company. Regnault:Modus Outcomes: Current Employment. Fram:Teva: Current equity holder in publicly-traded company; Baxter: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Pfizer:...