Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Self-Report versus Clinician Examination in Early Parkinson's Disease.

BACKGROUND: Evaluating the discrepancies between patient-reported measures and clinician examination has implications for formulating individual treatment regimens. OBJECTIVE: This study investigated the association between health outcomes and level of self-reported motor-related function impairment relative to clinician-examined motor signs. METHODS: Recently diagnosed PD patients were evaluated using the Parkinson's Progression Marker Initiative (PPMI, N = 420) and the PASADENA phase II clinical trial (N = 316). We calculated the average normalized difference between each participant's part II and III MDS-UPDRS (Movement Disorder Society Unified Parkinson's Disease Rating Scale) scores. Individuals with score differences <25th or >75th percentiles were labeled as low- and high-self-reporters, respectively (those between ranges were labeled intermediate-self-reporters). We compared a wide range of clinical/biomarker readouts among these three groups, using Kruskal-Wallis nonparametric and Pearson's χ2 tests. Spearman's correlations were tested for associations between MDS-UPDRS subscales. RESULTS: In both cohorts, high-self-reporters reported the largest impairment/symptom experience for most motor and nonmotor patient-reported variables. By contrast, these high-self-reporters were similar to or less impaired on clinician-examined and biomarker measures. Patient-reported nonmotor symptoms on MDS-UPDRS part IB showed the strongest positive correlation with self-reported motor-related impairment (PPMI rs  = 0.54, PASADENA rs  = 0.52). This correlation was numerically stronger than the part II and clinician-examined MDS-UPDRS part III correlation (PPMI rs  = 0.38, PASADENA rs  = 0.28). CONCLUSION: Self-reported motor-related impairments reflect not only motor signs/symptoms but also other self-reported nonmotor measures. This may indicate (1) a direct impact of nonmotor symptoms on motor-related functioning and/or (2) the existence of general response tendencies in how patients self-rate symptoms. Our findings suggest further investigation into the suitability of MDS-UPDRS II to assess motor-related impairments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Measurement properties of the Short Form-36 (SF-36) and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) in patients with anemia associated with chronic kidney disease.

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 slows motor progression in rapidly progressing early-stage Parkinson's disease.

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.

Development of the SMA independence scale-upper limb module (SMAIS-ULM): A novel scale for individuals with Type 2 and non-ambulant Type 3 SMA.

BACKGROUND: The amount of assistance required to perform daily activities for individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) is often cited as meaningful for quality of life, and important to routinely assess. METHODS: The SMA Independence Scale (SMAIS), a patient-reported outcome measure for individuals with SMA aged ≥12 years, and an observer-reported outcome measure for caregivers of individuals aged ≥2 years, was developed and evaluated in two phases. In Phase 1, 30 draft items were developed following review of the literature. Semi-structured interviews were then conducted with individuals with SMA and caregivers to establish content validity, resulting in a 29-item measure. In Phase 2, classical test theory and Rasch measurement theory methods were used to examine the cross-sectional and longitudinal measurement performance of the SMAIS in two independent datasets. RESULTS: Phase 1 qualitative findings supported the relevance, acceptability, and comprehensibility of 29 items. In Phase 2, psychometric analyses indicated that the five response options were poorly discriminated and were thus collapsed to three options for subsequent analyses. Items showed statistical misfit, implying that the SMAIS was not assessing a single underlying construct. Based on conceptual evaluation of the items, and assessment of item performance, a more targeted 22-item upper limb score was derived. Reliability and validity analyses confirmed acceptable measurement properties of this score. CONCLUSIONS: Qualitative and quantitative analyses support the use of the 22-item SMAIS-Upper Limb Module in individuals with Type 2 and non-ambulant Type 3 SMA, aged ≥2 years.

Validity and Reliability of the 32-Item Motor Function Measure in 2- to 5-Year-Olds with Neuromuscular Disorders and 2- to 25-Year-Olds with Spinal Muscular Atrophy.

INTRODUCTION: To investigate the validity and reliability of the 32-item Motor Function Measure (MFM32) in individuals with neuromuscular disorders (NMD), including spinal muscular atrophy (SMA), aged 2-5 years, and in non-ambulant individuals with Types 2 or 3 SMA, aged 2-25 years. METHODS: Test-retest reliability (intraclass correlation coefficient [ICC]), internal consistency (Cronbach's alpha [α]), convergent validity (Spearman rank-order correlations), and known-groups validity (analysis of covariance comparing groups defined by the Clinical Global Impression of Severity [CGI-S] scale and Vignos grade) were calculated. The analysis was performed on a dataset provided by Hospices Civils De Lyon, extracted from the multinational MFM32 database. A total of 165 individuals were included in the analyses, of whom 84 were in the NMD group (aged 2-5 years) and 81 were in the SMA group (aged 2-25 years). RESULTS: Strong evidence of test-retest reliability (ICC: 2- to 5-years' population = 0.94-0.95; 2- to 25-years' population = 0.97), internal consistency (Cronbach's α: 2- to 5-years' population = 0.96; 2- to 25-years' population = 0.95), convergent validity (2- to 5-years' population: CGI-S rho = - 0.84, Vignos grade rho = - 0.79; 2- to 25-years' population: CGI-S rho = - 0.49), and known-groups validity (all P < 0.001) were demonstrated. CONCLUSIONS: These analyses provide supportive evidence of the validity and reliability of the MFM32 in younger individuals with NMDs, aged 2-5 years, and in non-ambulant individuals with Types 2 or 3 SMA, aged 2-25 years, supporting the use of the MFM32 across a wide age range.

Assessment of the validity and reliability of the 32-item Motor Function Measure in individuals with Type 2 or non-ambulant Type 3 spinal muscular atrophy.

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.

Evaluating the Measurement Properties of the Self-Assessment of Treatment Version II, Follow-Up Version, in Patients with Painful Diabetic Peripheral Neuropathy.

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.

Motor, cognitive, and functional declines contribute to a single progressive factor in early HD.

OBJECTIVE: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. METHODS: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. RESULTS: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. CONCLUSIONS: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.

Deriving health utility values from a randomized, double-blind, placebo-controlled trial of siltuximab in subjects with multicentric Castleman's disease.

PURPOSE: To estimate health utility values, explore predictors of utility values, and estimate the quality-adjusted life years (Q.A.L.Y.s) gained by treatment in multicentric Castleman's disease (M.C.D.). METHODS: The SF-36 was administered to 79 patients enrolled in a randomized, double-blind, placebo-controlled, multi-national study to determine the safety and efficacy of siltuximab plus best supportive care (B.S.C.) compared with B.S.C., in subjects with symptomatic M.C.D. Utility (SF-6D) scores were derived from the SF-36. Sensitivity analyses using utilities obtained by mapping the SF-36 to the EQ-5D were also conducted. Repeated measures, mixed effects models were conducted to estimate effects of treatment, responder status and ≥ Grade 3 adverse events (A.E.s) on changes in utility values over time, controlling for baseline utility value. Additionally, differential Q.A.L.Y. gain was assessed in the trial using multiple regression. RESULTS: Patients on siltuximab and those who experienced a complete or partial response had higher mean utility values over time than those on placebo or those with stable disease. After an initial response to treatment, the mean utility remained relatively stable for patients on siltuximab and those who experienced a complete or partial response during the period when most patients were on study. A significantly different Q.A.L.Y. gain was found for patients on siltuximab (versus placebo) as calculated by SF-6D (0.070 Q.A.L.Y.s, p < .05) scores at 6 months (EQ-5D 0.096 Q.A.L.Y.s, p < 0.05). CONCLUSIONS: Siltuximab demonstrated improved, durable health utility gains in this rare disease over B.S.C. The main SF-6D results were supported by EQ-5D sensitivity analysis. These findings are limited by the small study sample size and substantial missing data caused predominantly by crossover. A longitudinal, multisite international observational study capturing clinical, safety and health-related quality of life (H.R.Q.L.) endpoints are needed to confirm these findings.

Evaluation of the psychometric properties of the Nighttime Symptoms of COPD Instrument.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.