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The 32-item Motor Function Measure (MFM32) is an assessment of motor function, and its measurement properties were established in a broad neuromuscular disease population. This study sought to investigate the reliability, validity, and ability to detect change of MFM32 in individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA). Data were used from the Phase 2 study assessing the efficacy and safety of olesoxime. A total of 110 individuals with Type 2 or 3 SMA were included in the analyses. Test-retest reliability (intraclass-correlation coefficient in global impression-defined stable individuals), internal consistency (Cronbach's alpha), convergent validity (Spearman rank order correlations with other measures), known-groups validity (analysis of covariance comparing Hammersmith Functional Motor Scale -defined groups), and ability to detect change (analysis of covariance comparing global impression-defined groups) were calculated. Strong evidence of test-retest reliability (intraclass-correlation coefficient = 0.93-0.95), internal consistency (Cronbach's alpha = 0.89), convergent validity (Hammersmith Functional Motor Scale: rho = 0.87; forced vital capacity: rho = 0.61), known-groups validity (all p<0.0001), and ability to detect change (all p<0.001) were demonstrated. These results provide evidence of the MFM32's measurement properties, supporting its use in longitudinal research in individuals with Type 2 and non-ambulant Type 3 SMA.

Background Anemia is a common and debilitating manifestation of chronic kidney disease (CKD). Data from two clinical trials in patients with anemia of CKD were used to assess the measurement properties of the Medical Outcomes Survey Short Form-36 version 2 (hereafter SF-36) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An). The Vitality and Physical functioning domains of the SF-36 and the FACT-An Total, Fatigue and Anemia subscales were identified as domains relevant to CKD-associated anemia. Methods A total of 204 patients aged 18–80 years were included in the analyses that included internal consistency (Cronbach’s alpha), test-retest reliability (intraclass correlation coefficients [ICCs]), convergent and known-groups validity, responsiveness, and estimates of important change. Results Both the SF-36 and the FACT-An had strong psychometric properties with high internal consistency (Cronbach’s alpha: 0.69–0.93 and 0.79–0.95), and test-retest reliability (ICCs: 0.64–0.83 and 0.72–0.88). Convergent validity, measured by correlation coefficients between similar concepts in SF-36 and FACT-An, ranged from 0.52 to 0.77. Correlations with hemoglobin (Hb) levels were modest at baseline; by Week 9, the correlations with Hb were somewhat higher, r =  0.23 ( p  < 0.05) for SF-36 Vitality, r  = 0.22 ( p  < 0.05) for FACT-An Total, r  = 0.26 ( p  < 0.001) for FACT-Fatigue and r =  0.22 ( p  < 0.01) for Anemia. Correlations with Hb at Week 13/17 were r  = 0.28 ( p  < 0.001) for SF-36 Vitality and r  = 0.25 ( p  < 0.05) for Role Physical; FACT-An Total correlation was r  = 0.33 ( p  < 0.0001), Anemia was r  = 0.28 (p < 0.001), and Fatigue was r  = 0.30 ( p  < 0.001). The SF-36 domains and Component Summary scores ( p  < 0.05– p  < 0.0001) demonstrated ability to detect change. For the FACT-An, significant differences ( p  < 0.05– p  < 0.0001) were observed between responder and non-responder change scores: important change score estimates ranged from 2 to 4 for Vitality and 2–3 for Physical functioning. Important change scores were also estimated for the FACT-An Total score (6–9), the Anemia (3–5), and Fatigue subscale (2–4). Conclusions Both the SF-36 Vitality and Physical function scales and the FACT-An Total, Fatigue and Anemia scales, are reliable and valid measures for assessing health-related quality of life in anemia associated with CKD.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson’s disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab’s potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic–rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson’s disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings. An exploratory analysis of the 1-year clinical trial PASADENA in individuals with early-stage Parkinson’s disease suggests that prasinezumab might reduce motor signs progression to a greater extent in those with more rapidly progressing disease.

Background. The Self-Assessment of Treatment version II (SAT II) measures treatment-related improvements in pain and impacts and impressions of treatment in neuropathic pain patients. The measure has baseline and follow-up versions. This study assesses the measurement properties of the SAT II. Methods. Data from 369 painful diabetic peripheral neuropathy (PDPN) patients from a phase III trial assessing capsaicin 8% patch (Qutenza®) efficacy and safety were used in these analyses. Reliability, convergent validity, known-groups validity, and responsiveness (using the Brief Pain Inventory-Diabetic Neuropathy [BPI-DN] and Patient Global Impression of Change [PGIC]) analyses were conducted, and minimally important differences (MID) were estimated. Results. Exploratory factor analysis supported a one-factor solution for the six impact items. The SAT II has good internal consistency (Cronbach’s alpha: 0.96) and test-retest reliability (intraclass correlation coefficients: 0.62–0.88). Assessment of convergent validity showed moderate to strong correlations with change in other study endpoints. Scores varied significantly by level of pain intensity and sleep interference (p<0.05) defined by the BPI-DN. Responsiveness was shown based on the PGIC. MID estimates ranged from 1.2 to 2.4 (pain improvement) and 1.0 to 2.0 (impact scores). Conclusions. The SAT II is a reliable and valid measure for assessing treatment improvement in PDPN patients.

Tominersen and Huntington’s DiseaseA trial of tominersen, designed to slow Huntington’s disease progression by lowering levels of huntingtin protein, was stopped prematurely, and an ad hoc analysis of the results at week 69 was carried out.

The composite Unified Huntington’s Disease Rating Scale (cUHDRS) is a scoring algorithm that combines Total Functional Capacity (TFC), Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading measures. Our aim was to enhance understanding of cUHDRS scoring by linking to established measures of meaningful daily function and independence in individuals with early-to-moderate-manifest Hunting- ton’s disease (HD).Data from Enroll-HD were evaluated. For patients meeting the reference population for the cUHDRS (manifest HD, TFC 5–13, ≥20 years; N=3,490), cUHDRS score ranges were calculated. Patients were divided into groups around each integer score; for each grouping, the mean HD stage, Independence Scale (IS) score, mean Functional Assessment (FA) score and number of FA items that ≥50% of individuals achieved were calculated.cUHDRS score groupings ranged 3–18 (N=3,484). For patients in the 14–18 cUHDRS score groupings, ≥50% achieved 25 FA items and had a mean IS=95. For patients in the lowest cUHDRS score group, cUHDRS=3, only 12 FA items were achievable by ≥50% and mean IS=65.cUHDRS scores reflect the differing levels of function in individuals with early-to-moderate-manifest HD. The cUHDRS can better differentiate between individuals with Stage 1 HD than commonly used measures of function.rachel.blair@roche.com

BackgroundThe composite Unified Huntington’s Disease Ratings Scale (cUHDRS) is a combined score of measures of motor function (TMS), cognition (SDMT and SWR) and overall functional capacity (TFC). The cUHDRS was developed to assess multi-domain clinical progression in Huntington’s disease (HD), and was shown to be a sensitive, reliable, and valid. To support its use in clinical studies, further evidence is required. This includes estimates of clinically meaningful change of the cUHDRS and its individual measures.AimsTo assess the reliability, validity and ability to detect change of the cUHDRS and to estimate minimal clinically meaningful within-patient cUHDRS change.MethodsData from an early manifest HD population (TFC≥5) from two multi-national registries (ENROLL-HD and REGISTRY) were used. Test-retest reliability was assessed by calculating the intraclass correlation coefficient (ICC) in a subset of patients with no change in Clinical Global Impression of Severity (CGI-S) score. Convergent validity was assessed by Spearman rank order correlations. Known-groups validity was assessed by analysis of covariance (ANCOVA) between groups defined by CGI-S. Ability to detect change was assessed by ANCOVA comparing groups based on CGI-S score change. Regression analyses were conducted to estimate meaningful change, using CGI-S and Independence Scale (IS) as anchors.ResultsStrong evidence of test-retest reliability, known-groups validity and ability to detect change was demonstrated. Convergent validity was supported by stronger correlations with measures that are more similar. Meaningful within-patient change was estimated.ConclusionscUHDRS is valid, reliable and able to detect change in patients with early manifest HD. Analyses anchored against CGI-S and IS support that a decline on the cUHDRS is clinically meaningful.AcknowledgementsFunded by F. Hoffmann-La Roche.

BackgroundRG6042 (formerly IONIS-HTTRx) is a non-allele-specific, huntingtin mRNA-targeting antisense oligonucleotide which reversibly suppresses production of all forms of Huntingtin protein (HTT). In a first-in-human test of this approach, RG6042 safely lowered the pathogenic mutant HTT (mHTT) in early Huntington’s disease (HD) patients, prompting Roche to begin a Global Development Program. Questions to be answered in the next phase of development include: what is the ultimate sustained magnitude of lowering of mHTT that can be achieved over long-term dosing; will lowering of mHTT be associated with clinical benefit and what are the best ways to measure such benefit; and will the approach prove to be safe and well tolerated over longer-term dosing?Method/resultsThis Global Development Program includes a single, pivotal, 24-month efficacy study designed to demonstrate clinical efficacy and safety of RG6042 in early manifest HD patients, and examine the effects on slowing or stopping clinical progression of HD. The program also includes an ongoing, open-label extension study of the completed Phase I/IIa study (NCT03342053), and an observational natural history study, both being conducted in a limited number of sites. The rationale for the target population, pivotal study design, endpoints and digital monitoring tools will be discussed.ConclusionThe Roche Global Development Program will provide valuable information on the clinical benefit and safety of the huntingtin lowering treatment RG6042 for patients with HD, as well as further longitudinal evidence of the causal role of mHTT in disease progression.

Anemia is a common and debilitating manifestation of chronic kidney disease (CKD). Data from two clinical trials in patients with anemia of CKD were used to assess the measurement properties of the Medical Outcomes Survey Short Form-36 version 2 (hereafter SF-36) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An). The Vitality and Physical functioning domains of the SF-36 and the FACT-An Total, Fatigue and Anemia subscales were identified as domains relevant to CKD-associated anemia. A total of 204 patients aged 18-80 years were included in the analyses that included internal consistency (Cronbach's alpha), test-retest reliability (intraclass correlation coefficients [ICCs]), convergent and known-groups validity, responsiveness, and estimates of important change. Both the SF-36 and the FACT-An had strong psychometric properties with high internal consistency (Cronbach's alpha: 0.69-0.93 and 0.79-0.95), and test-retest reliability (ICCs: 0.64-0.83 and 0.72-0.88). Convergent validity, measured by correlation coefficients between similar concepts in SF-36 and FACT-An, ranged from 0.52 to 0.77. Correlations with hemoglobin (Hb) levels were modest at baseline; by Week 9, the correlations with Hb were somewhat higher, r = 0.23 (p < 0.05) for SF-36 Vitality, r = 0.22 (p < 0.05) for FACT-An Total, r = 0.26 (p < 0.001) for FACT-Fatigue and r = 0.22 (p < 0.01) for Anemia. Correlations with Hb at Week 13/17 were r = 0.28 (p < 0.001) for SF-36 Vitality and r = 0.25 (p < 0.05) for Role Physical; FACT-An Total correlation was r = 0.33 (p < 0.0001), Anemia was r = 0.28 (p < 0.001), and Fatigue was r = 0.30 (p < 0.001). Both the SF-36 Vitality and Physical function scales and the FACT-An Total, Fatigue and Anemia scales, are reliable and valid measures for assessing health-related quality of life in anemia associated with CKD.

Nighttime symptoms can negatively impact the quality of life of patients with chronic obstructive pulmonary disease (COPD). The Nighttime Symptoms of COPD Instrument (NiSCI) was designed to measure the occurrence and severity of nighttime symptoms in patients with COPD, the impact of symptoms on nighttime awakenings, and rescue medication use. The objective of this study was to explore item reduction, inform scoring recommendations, and evaluate the psychometric properties of the NiSCI. COPD patients participating in a Phase III clinical trial completed the NiSCI daily. Item analyses were conducted using weekly mean and single day scores. Descriptive statistics (including percentage of respondents at floor/ceiling and inter-item correlations), factor analyses, and Rasch model analyses were conducted to examine item performance and scoring. Test-retest reliability was assessed for the final instrument using the intraclass correlation coefficient (ICC). Correlations with assessments conducted during study visits were used to evaluate convergent and known-groups validity. Data from 1,663 COPD patients aged 40-93 years were analyzed. Item analyses supported the generation of four scores. A one-factor structure was confirmed with factor analysis and Rasch analysis for the symptom severity score. Test-retest reliability was confirmed for the six-item symptom severity (ICC, 0.85), number of nighttime awakenings (ICC, 0.82), and rescue medication (ICC, 0.68) scores. Convergent validity was supported by significant correlations between the NiSCI, St George's Respiratory Questionnaire, and Exacerbations of Chronic Obstructive Pulmonary Disease Tool-Respiratory Symptoms scores. The results suggest that the NiSCI can be used to determine the severity of nighttime COPD symptoms, the number of nighttime awakenings due to COPD symptoms, and the nighttime use of rescue medication. The NiSCI is a reliable and valid instrument to evaluate these concepts in COPD patients in clinical trials and clinical practice. Scoring recommendations and steps for further research are discussed.