Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis.

OBJECTIVES: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS. METHODS: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated. RESULTS: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30th-], 2.11 [20th-], and 2.8 [10th percentile], P = 0.007, 0.012 and 0.005, respectively). CONCLUSIONS: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback.

Qualitative Exploration in Exit Interviews of Changes Observed in Clinical Trials for Individuals with Autism Spectrum Disorder Without Intellectual Disability.

Purpose: To explore, from the perspective of Study Partners (SPs; eg, caregivers) of clinical trial participants with autism spectrum disorder (ASD), any changes experienced in socialization and communication over the clinical trial, how these changes manifested, and the impact these changes had on the autistic individual, the SP, and family. This helps interpret whether changes in trial outcomes were meaningful. Patients and Methods: Interviews were conducted with the SPs of individuals with ASD, without intellectual disability, from 2 clinical trials: 86 children (aged 5-12 years) or adolescents (aged 13-17 years) who took part in the aV1ation trial (83.7% male), and 41 adults (aged 18+ years) who took part in the V1aduct trial (80.5% male). The primary endpoint for both trials was change from baseline in the VinelandTM-II two-domain composite, consisting of the mean of the Socialization and Communication domains. In these interviews the participants verbally indicated level of change for each of these key domains on 7-point change scales. Results: Improvements in the Socialization domain enabled greater awareness of the feelings of others and allowed for stronger empathy and kindness. Improvements in the Communication domain allowed for the autistic individual to be better at listening and better at self-expression. Together, changes in these two domains, which were considered most important, allowed for richer, deeper relationships. Study Partners noted that improvements in these domains allowed for better integration within the family unit, decreased stress, and increased optimism about the autistic individual's future. Conclusions: The impacts of changes in either domain were synergistic, combining together to create positive experiences which in turn led to further positive impacts in other skills. These qualitative insights provide context to the changes that were observed during the clinical trial and captured using the VinelandTM-II, illustrating the meaning of these changes to the individuals with ASD without intellectual disability and their families, and the impact that they have on people's everyday lives and overall health-related quality of life.

Quantitative and Qualitative Exploration of Meaningful Change on the Vineland Adaptive Behavior Scales (Vineland™-II) in Children and Adolescents with Autism Without Intellectual Disability Following Participation in a Clinical Trial.

Purpose: The VinelandTM Adaptive Behavior Scale is often used in autism spectrum disorder (ASD) trials. The Adaptive Behavior Composite Score (VABS-ABC) is the standardized overall score (the average of the Socialization, Communication and Daily Living skills domains), and the standardized 2-Domain Composite Score (VABS-2DC) is a novel outcome measure (average of the Socialization and Communication domains). A within-person meaningful change threshold (MCT) has not been established for the VABS-2DC. This paper presents a quantitative and qualitative interpretation of what constitutes a meaningful change in these scores to individuals with ASD without Intellectual Disability (ID; IQ≥70) and their families, as reported by their study partners (SPs). Participants and Methods: Data were obtained from the aV1ation clinical trial in children and adolescents with ASD and associated exit interviews. The intent-to-treat (ITT) clinical trial population included 308 individuals with autism (85.4% male; average age: 12.4 years [standard deviation (SD)=2.97]); 124 in the child cohort (aged 5 to 12 years; average age: 9.4 years [SD=1.86]), and 184 in the adolescent cohort (aged 13 to 17 years; average age: 14.5 years [SD=1.39]). Study partners of 86 trial participants were included in the Exit Interview Population (EIP): participants represented were 83.7% male, average age: 12.3 years [SD=2.98]). Anchor and distribution-based methods were used to estimate within-person change to support a responder definition, to aid interpretation of the clinical trial data; qualitative data were used to contextualize the meaning of changes observed. Results: A within-person MCT range of 4 to 8 points was proposed for both VABS-ABC and VABS-2DC, which was associated with at least a 1-point improvement on 4 different anchors. Evidence for this within-person MCT was further supported by qualitative data, which suggested any change was considered meaningful to the individual with ASD, as reported by their SP, no matter what the magnitude. Conclusion: A change in standardized score of 4 to 8 points constitutes a within-person MCT on both VABS-ABC and novel VABS-2DC in those with ASD and no ID. A change of this, or more, was reported by the SPs in this trial to be meaningful and highly impactful upon the individuals with ASD and their family.

Developing Angelman syndrome-specific clinician-reported and caregiver-reported measures to support holistic, patient-centered drug development.

BACKGROUND: Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable measures reporting key symptoms and functional impairments of AS are required to support development of patient-centered therapies. We describe the development of clinician- and caregiver-reported, AS-specific Global Impression scales for incorporation into clinical trials. Best practice US Food and Drug Administration guidance for measure development was followed with input from expert clinicians, patient advocates, and caregivers during content generation and refinement. RESULTS: Initial measurement domains for the Symptoms of AS-Clinician Global Impression (SAS-CGI) and the Caregiver-reported AS Scale (CASS) were identified from a conceptual disease model of AS symptoms and impacts, derived from interviews with caregivers and clinicians. Two rounds of cognitive debriefing (CD) interviews were performed; clinicians debriefed the SAS-CGI, with patient advocates and caregivers debriefing the CASS to ensure relevance and comprehension. Feedback was used to refine items and ensure wording was age-appropriate and captured AS-specific symptoms, as well as associated impacts and functional impairments. The SAS-CGI and CASS capture global assessments of seizures, sleep, maladaptive behaviors, expressive communication, fine and gross motor skills, cognition, and self-care, which were determined by clinicians, patient advocates, and caregivers to be the most challenging aspects of AS. Additionally, the measures include items for assessing overall AS symptoms and the meaningfulness of any change. In addition to ratings for severity, impact, and change, a notes field was included in the SAS-CGI to provide the rationale for the chosen rating. CD interviews confirmed the measures covered key concepts of AS from the perspective of clinicians and caregivers, and demonstrated that the measures' instructions, items, and response options were clear and appropriate. Interview feedback informed adjustments to the wording of the instructions and the items. CONCLUSIONS: The SAS-CGI and CASS were designed to capture multiple AS symptoms, reflecting the heterogeneity and complexity of AS in children 1 to 12 years old. These clinical outcome assessments have been incorporated into AS clinical studies, which will allow for the evaluation of their psychometric properties and inform further refinements if needed.

Effect of Children's Autism Spectrum Disorder Severity on Family Strain and Sleep Quality: A Cross-Sectional Online Survey in the U.S.

To better understand the impact of children's autism spectrum disorder (ASD) severity on families, we evaluated pathways through which ASD severity affected child sleep quality, caregiver strain, and caregiver sleep quality. In a cross-sectional analysis through the U.S.-wide Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. Participants were caregivers of dependents with ASD aged 3-17 years (N = 3150). We found that increased severity strongly affects caregiver strain and child sleep quality. Child sleep quality was a minor mediator of increasing caregiver strain. Caregiver sleep quality depended on ASD severity only through child sleep quality and caregiver strain. Interventions aimed at improving child sleep quality or reducing caregiver strain could positively impact families of children with ASD.

The Autism Impact Measure (AIM): Meaningful Change Thresholds and Core Symptom Changes Over One Year from an Online Survey in the U.S.

Validated outcome measures with the capacity to reflect meaningful change are key to assessing potential interventions for autism spectrum disorder (ASD). We derive clinically meaningful change thresholds (MCTs) of the Autism Impact Measure (AIM) and identify factors associated with meaningful change. Baseline and 12-months follow-up survey of caregivers of 2,761 children with ASD aged 3-17 years from the U.S. Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort were analyzed. Using caregiver-reported anchors for change, the 12-month change in estimated AIM MCT (95% confidence interval) for symptom improvement was -4.5 (-7.61, -1.37) points and 9.9 (5.12, 14.59) points for symptom deterioration. These anchor-based MCTs will facilitate future assessments of caregiver-reported change in AIM scores.

Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program.

BACKGROUND: Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials. DISCUSSION POINTS: The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results. CONCLUSION: Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

Objectively characterizing Huntington's disease using a novel upper limb dexterity test.

BACKGROUND: The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington's, that is not reliant on clinical expertise for administration. METHODS: One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington's disease completed the Unified Huntington's Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman's R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures. RESULTS: Baseline C3t scores predicted baseline clinical scores to within 9-13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ([Formula: see text] ≤ 0.15) and mirrored the change in clinical scores. CONCLUSION: The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington's disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington's disease.

Rethinking Functional Outcome Measures: The Development of a Novel Upper Limb Token Transfer Test to Assess Basal Ganglia Dysfunction.

The basal ganglia are implicated in a wide range of motor, cognitive and behavioral activities required for normal function. This region is predominantly affected in Huntington's disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n = 64) and healthy controls (n = 21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behavior, and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson's correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behavior, and function. The MBT provides a valid, sensitive, and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials.

Rehabilitation training in neural restitution.

Over the last decade, neural transplantation has emerged as one of the more promising, albeit highly experimental, potential therapeutics in neurodegenerative disease. Preclinical studies in rat lesion models of Huntington's disease (HD) and Parkinson's disease (PD) have shown that transplanted precursor neuronal tissue from a fetus into the lesioned striatum can survive, integrate, and reconnect circuitry. Importantly, specific training on behavioral tasks that target striatal function is required to encourage functional integration of the graft to the host tissue. Indeed, "learning to use the graft" is a concept recently adopted in preclinical studies to account for unpredicted profiles of recovery posttransplantation and is an emerging strategy for improving graft functionality. Clinical transplant studies in HD and PD have resulted in mixed outcomes. Small sample sizes and nonstandardized experimental procedures from trial to trial may explain some of this variability. However, it is becoming increasingly apparent that simply replacing the lost neurons may not be sufficient to ensure the optimal graft effects. The knowledge gained from preclinical grafting and training studies suggests that lifestyle factors, including physical activity and specific cognitive and/or motor training, may be required to drive the functional integration of grafted cells and to facilitate the development of compensatory neural networks. The clear implications of preclinical studies are that physical activity and cognitive training strategies are likely to be crucial components of clinical cell replacement therapies in the future. In this chapter, we evaluate the role of general activity in mediating the physical ability of cells to survive, sprout, and extend processes following transplantation in the adult mammalian brain, and we consider the impact of general and specific activity at the behavioral level on functional integration at the cellular and physiological level. We then highlight specific research questions related to timing, intensity, and specificity of training in preclinical models and synthesize the current state of knowledge in clinical populations to inform the development of a strategy for neural transplantation rehabilitation training.

Direct Comparison of Rat- and Human-Derived Ganglionic Eminence Tissue Grafts on Motor Function.

Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.

Novel Application of Behavioral Assays Allows Dissociation of Joint Pathology from Systemic Extra-Articular Alterations Induced by Inflammatory Arthritis.

Introduction: Although rheumatoid arthritis (RA) is a disease of articular joints, patients often suffer from co-morbid neuropsychiatric changes, such as anxiety, that may reflect links between heightened systemic inflammation and abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we apply behavioral neuroscience methods to assess the impact of antigen-induced arthritis (AIA) on behavioral performance in wild type (WT) and interleukin-10 deficient (Il10-/-) mice. Our aim was to identify limb-specific motor impairments, as well as neuropsychological responses to inflammatory arthritis. Methods: Behavioral testing was performed longitudinally in WT and Il10-/- mice before and after the induction of arthritic joint pathology. Footprint analysis, beam walking and open field assessment determined a range of motor, exploratory and anxiety-related parameters. Specific gene changes in HPA axis tissues were analyzed using qPCR. Results: Behavioral assessment revealed transient motor and exploratory impairments in mice receiving AIA, coinciding with joint swelling. Hind limb coordination deficits were independent of joint pathology. Behavioral impairments returned to baseline by 10 days post-AIA in WT mice. Il10-/- mice demonstrated comparable levels of swelling and joint pathology as WT mice up to 15 days post-AIA, but systemic differences were evident in mRNA expression in HPA axis tissues from Il10-/- mice post-AIA. Interestingly, the behavioral profile of Il10-/- mice revealed a significantly longer time post-AIA for activity and anxiety-related behaviors to recover. Conclusions: The novel application of sensitive behavioral tasks has enabled dissociation between behaviors that occur due to transient joint-specific pathology and those generated by more subtle systemic alterations that manifest post-AIA.