Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger containing (PIKfyve) inhibitor with favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis models. In this amyotrophic lateral sclerosis clinical trial, the safety, tolerability, CNS penetrance, and modulation of pharmacodynamic target engagement biomarkers were evaluated. This Phase 2a, randomized, double-blind, placebo-controlled, biomarker-endpoint clinical trial was conducted in four USA centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansion were randomly assigned (2:1) to receive twice-daily oral treatment of 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent adverse or serious adverse events attributable to study drug, and tolerability as trial completion on treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition (soluble glycoprotein nonmetastatic melanoma protein B [sGPNMB] upregulation) and disease-specific CNS target engagement (poly[GP]). Between Dec 16, 2021, and Jul 7, 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance (N=9 [90%] apilimod dimesylate; N=5 [100%] placebo). At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/mL (SD: 0.937). At Week 12, apilimod dimesylate increased plasma sGPNMB by > 2.5-fold (p < 0.001) indicating PIKfyve inhibition and lowered CSF poly(GP) protein levels by 73% (p < 0.001) indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker endpoints in this Phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to have the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Minimal clinically important difference in the World Health Organization Quality of Life Brief (WHOQOL-BREF) for adults with neurofibromatosis.

PURPOSE: This study aimed to estimate minimal clinically important difference (MCID) values for the World Health Organization Quality of Life Brief version (WHOQOL-BREF) among adults with neurofibromatosis (NF). An MCID is needed to demonstrate clinical meaningfulness of interventions for NF. METHODS: We estimated MCID for the WHOQOL-BREF: the quality of life (QoL) measure recommended by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration. We used data from 228 clinical trial participants with NF type 1, NF type 2-related schwannomatosis, or schwannomatosis (SCHWN) who completed 10 weeks of a virtual group mind-body program targeting resiliency or a time- and attention-matched control. Following established guidelines, we estimated MCIDs using both anchor-based and distribution-based methods for physical, psychological, social relationships, and environmental domains of the WHOQOL-BREF. RESULTS: MCID results varied across method and QoL domain. Three anchor-based methods, average change (AC), change difference (CD), and regression (REG), yielded the most consistent and comparable MCID across QoL domains. Based on these methods, we recommend ranges for each QoL domain: Physical QoL (3.9-7.3), Psychological QoL (4.7-8.1), Social QoL (2.6-5.9), and Environmental QoL (4.1-6.6). CONCLUSION: Establishing a rigorous MCID for QoL in NF is a critical step toward evaluating meaningful change in response to psychosocial interventions.

Intrinsic auricular muscle zone stimulation for Parkinson disease: The EARSTIM-PD Phase II multi-center pilot study results.

BACKGROUND: Studies have suggested that intrinsic auricular muscle zones (IAMZ) stimulation alleviates motor features of Parkinson disease (PD). METHODS: A randomized, blinded, active sham-controlled pilot trial was conducted to evaluate the safety and dose-response-time curve of Earstim using a 3-treatment, 3-period crossover design in PD patients experiencing OFF time on levodopa. Treatments were: short (20-min) IAMZ stimulation; long (60-min) IAMZ stimulation; and 20-min active sham stimulation of non-muscular areas. Assessment time points were: prior to treatment, and 20, 40, 60, 90, and 120 min after treatment onset. Primary safety endpoints were adverse events frequency and severity. Primary efficacy endpoint was the change in MDS-UPDRS motor score at 20 min after treatment onset in the IAMZ treatment groups versus sham. RESULTS: Forty-six individuals consented; 38 were randomized (average age 64 years, 65 % male, mean 8.2 years from diagnosis). No serious adverse events or significant device-related events occurred. At 20 min after treatment onset, motor improvements did not differ between IAMZ treatments versus sham. However, at 60 min after treatment onset, motor improvement peaked on IAMZ treatments compared to sham (difference: 3.1 [-5.9 to 0.3], p = 0.03). While the difference in 120-min AUC change between IAMZ treatments versus sham was not significant, the short-stimulation IAMZ treatment showed the largest aggregate motor score improvement (AUC = -456 points, 95 % CI -691 to -221) compared to sham. CONCLUSION: Earstim was well-tolerated. The greatest motor improvement occurred at 60 min after stimulation onset in the short-stimulation IAMZ treatment, and supports its further study to alleviate OFF periods.

Mindfulness-Based App to Reduce Stress in Caregivers of Persons With Alzheimer Disease and Related Dementias: Protocol for a Single-Blind Feasibility Proof-of-Concept Randomized Controlled Trial.

BACKGROUND: Informal caregivers (ie, individuals who provide assistance to a known person with health or functional needs, often unpaid) experience high levels of stress. Caregiver stress is associated with negative outcomes for both caregivers and care recipients. Mindfulness-based interventions (MBIs) show promise for improving stress, emotional distress, and sleep disturbance in caregivers of persons with Alzheimer disease and related dementias (ADRD). Commercially available mobile mindfulness apps can deliver MBIs to caregivers of persons with ADRD in a feasible and cost-effective manner. OBJECTIVE: We are conducting a single-blind feasibility proof-of-concept randomized controlled trial (RCT; National Institutes of Health [NIH] stage 1B) comparing 2 free mobile apps: the active intervention Healthy Minds Program (HMP) with within-app text tailored for addressing stress among caregivers of persons with ADRD, versus Wellness App (WA), a time- and dose-matched educational control also tailored for caregivers of persons with ADRD. METHODS: We aim to recruit 80 geographically diverse and stressed caregivers of persons with ADRD. Interested caregivers use a link or QR code on a recruitment flyer to complete a web-based eligibility screener. Research assistants conduct enrollment phone calls, during which participants provide informed consent digitally. After participants complete baseline surveys, we randomize them to the mindfulness-based intervention (HMP) or educational control podcast app (WA) and instruct them to listen to prescribed content for 10 minutes per day (70 minutes per week) for 12 weeks. Caregivers are blinded to intervention versus control. The study team checks adherence weekly and contacts participants to promote adherence as needed. Participants complete web-based self-report measures at baseline, posttest, and follow-up; weekly process measures are also completed. Primary outcomes are a priori set feasibility benchmarks. Secondary outcomes are stress, emotional distress, sleep disturbance, caregiver burden, mindfulness, awareness, connection, insight, and purpose. We will calculate 1-sided 95% CI to assess feasibility benchmarks. Effect sizes of change in outcomes will be used to examine the proof of concept. RESULTS: Recruitment started on February 20, 2023. We have enrolled 27 caregivers (HMP: n=14; WA: n=13) as of June 2023. Funding began in August 2022, and we plan to finish enrollment by December 2023. Data analysis is expected to begin in May 2024 when all follow-ups are complete; publication of findings will follow. CONCLUSIONS: Through this trial, we aim to establish feasibility benchmarks for HMP and WA, as well as establish a proof of concept that HMP improves stress (primary quantitative outcome), emotional distress, sleep, and mindfulness more than WA. Results will inform a future efficacy trial (NIH stage II). HMP has the potential to be a cost-effective solution to reduce stress in caregivers of persons with ADRD, benefiting caregiver health and quality of care as well as patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05732038; https://clinicaltrials.gov/study/NCT05732038. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50108.

Addressing the Chronic Pain-Early Cognitive Decline Comorbidity Among Older Adults: Protocol for the Active Brains Remote Efficacy Trial.

BACKGROUND: Chronic pain and early cognitive decline, which are costly to treat and highly prevalent among older adults, commonly co-occur, exacerbate one another over time, and can accelerate the development and progression of Alzheimer disease and related dementias. We developed the first mind-body activity program (Active Brains [AB]) tailored to the needs of older adults with chronic pain and early cognitive decline. Results from our previous study strongly supported the feasibility of conducting AB remotely and provided evidence for improvements in outcomes. OBJECTIVE: We are conducting a single-blinded, National Institutes of Health stage-2, randomized clinical trial to establish the efficacy of AB versus a time-matched and dose-matched education control (Health Enhancement Program [HEP]) in improving self-reported and objective outcomes of physical, cognitive, and emotional functions in 260 participants. The methodology described in this paper was informed by the lessons learned from the first year of the trial. METHODS: Participants are identified and recruited through multidisciplinary clinician-referred individuals (eg, pain psychologists and geriatricians), the Rally Research platform, social media, and community partnerships. Interested participants complete eligibility screening and electronic informed consent. Baseline assessments include self-report, performance-based measures (eg, 6-min walk test) and objective measures (eg, Repeatable Battery for the Assessment of Neuropsychological Status). Participants are mailed a wrist-worn ActiGraph device (ActiGraph LLC) to passively monitor objective function (eg, steps) during the week between the baseline assessment and the beginning of the programs, which they continue to wear throughout the programs. After baseline assessments, participants are randomized to either AB or HEP and complete 8 weekly, remote, group sessions with a Massachusetts General Hospital psychologist. The AB group receives a Fitbit (Fitbit Inc) to help reinforce increased activity. Assessments are repeated after the intervention and at the 6-month follow-up. Coprimary outcomes include multimodal physical function (self-report, performance based, and objective). Secondary outcomes are cognitive function (self-report and objective), emotional function, and pain. RESULTS: We began recruitment in July 2022 and recruited 37 participants across 4 cohorts. Of them, all (n=37, 100%) have completed the baseline assessment, 26 (70%) have completed the posttest assessment, and 9 (24%) are actively enrolled in the intervention (total dropout: n=2, 5%). In the three cohorts (26/37, 70%) that have completed the AB or HEP, 26 (100%) participants completed all 8 group sessions (including minimal makeups), and watch adherence (1937/2072, 93.48%, average across ActiGraph and Fitbit devices) has been excellent. The fourth cohort is ongoing (9/37, 24%), and we plan to complete enrollment by March 2026. CONCLUSIONS: We aim to establish the efficacy of the AB program over a time-matched and dose-matched control in a live video-based trial and test the mechanisms through theoretically driven mediators and moderators. Findings will inform the development of a future multisite effectiveness-implementation trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05373745; https://classic.clinicaltrials.gov/ct2/show/NCT05373745. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47319.

The STEPWISE study: study protocol for a smartphone-based exercise solution for people with Parkinson's Disease (randomized controlled trial).

BACKGROUND: Exercise has various health benefits for people with Parkinson's disease (PD). However, implementing exercise into daily life and long-term adherence remain challenging. To increase a sustainable engagement with physical activity of people with PD, interventions that are motivating, accessible, and scalable are needed. We primarily aim to investigate whether a smartphone app (STEPWISE app) can increase physical activity (i.e., step count) in people with PD over one year. Our second aim is to investigate the potential effects of the intervention on physical fitness, and motor- and non-motor function. Our third aim is to explore whether there is a dose-response relationship between volume of physical activity and our secondary endpoints. METHODS: STEPWISE is a double-blind, randomized controlled trial. We aim to include 452 Dutch people with PD who can walk independently (Hoehn & Yahr stages 1-3) and who do not take more than 7,000 steps per day prior to inclusion. Physical activity levels are measured as step counts on the participant's own smartphone and scaled as percentage of each participant's baseline. Participants are randomly assigned to an active control group with an increase of 5-20% (active controls) or any of the three intervention arms with increases of 25-100% (intermediate dose), 50-200% (large dose), or 100-400% (very large dose). The primary endpoint is change in step count as measured by the STEPWISE smartphone app from baseline to 52 weeks. For our primary aim, we will evaluate the between-group difference in average daily step count change from baseline to 52 weeks. For our second aim, measures of physical fitness, and motor- and non-motor function are included. For our third aim, we will associate 52-week changes in step count with 52-week changes in secondary outcomes. DISCUSSION: This trial evaluates the potential of a smartphone-based intervention to increase activity levels in people with PD. We envision that motivational apps will increase adherence to physical activity recommendations and could permit conduct of remote clinical trials of exercise for people with PD or those at risk of PD. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04848077; 19/04/2021. CLINICALTRIALS: gov/ct2/show/NCT04848077.

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial.

BACKGROUND: SYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms. OBJECTIVES: We evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD). METHODS: In a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI). RESULTS: Eighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028). CONCLUSIONS: SYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study. REGISTRATION: Clinicaltrials.gov as NCT02258152.

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal. RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Effect of Mind-Body Skills Training on Quality of Life for Geographically Diverse Adults With Neurofibromatosis: A Fully Remote Randomized Clinical Trial.

Importance: Neurofibromatoses (NF; NF1, NF2, and schwannomatosis) are hereditary tumor predisposition syndromes with a risk for poor quality of life (QOL) and no evidence-based treatments. Objective: To compare a mind-body skills training program, the Relaxation Response Resiliency Program for NF (3RP-NF), with a health education program (Health Enhancement Program for NF; HEP-NF) for improvement of quality of life among adults with NF. Design, Setting, and Participants: This single-blind, remote randomized clinical trial randomly assigned 228 English-speaking adults with NF from around the world on a 1:1 basis, stratified by NF type, between October 1, 2017, and January 31, 2021, with the last follow-up February 28, 2022. Interventions: Eight 90-minute group virtual sessions of 3RP-NF or HEP-NF. Main Outcomes and Measures: Outcomes were collected at baseline, after treatment, and at 6-month and 1-year follow-up. The primary outcomes were physical health and psychological domain scores of the World Health Organization Quality of Life Brief Version (WHOQOL-BREF). Secondary outcomes were the social relationships and environment domain scores of the WHOQOL-BREF. Scores are reported as transformed domain scores (range, 0-100, with higher scores indicating higher QOL). Analysis was performed on an intention-to-treat basis. Results: Of 371 participants who underwent screening, 228 were randomized (mean [SD] age, 42.7 [14.5] years; 170 women [75%]), and 217 attended 6 or more of 8 sessions and provided posttest data. Participants in both programs improved from baseline to after treatment in primary outcomes of physical health QOL score (3RP-NF, 5.1; 95% CI, 3.2-7.0; P < .001; HEP-NF, 6.4; 95% CI, 4.6-8.3; P < .001) and psychological QOL score (3RP-NF, 8.5; 95% CI, 6.4-10.7; P < .001; HEP-NF, 9.2; 95% CI, 7.1-11.2; P < .001). Participants in the 3RP-NF group showed sustained improvements after treatment to 12 months; posttreatment improvements for the HEP-NF group diminished (between-group difference for physical health QOL score, 4.9; 95% CI, 2.1-7.7; P = .001; effect size [ES] = 0.3; and psychological QOL score, 3.7; 95% CI, 0.2-7.6; P = .06; ES = 0.2). Results were similar for secondary outcomes of social relationships and environmental QOL. There were significant between-group differences from baseline to 12 months in favor of the 3RP-NF for physical health QOL score (3.6; 95% CI, 0.5-6.6; P = .02; ES = 0.2), social relationships QOL score (6.9; 95% CI, 1.2-12.7; P = .02; ES = 0.3), and environmental QOL score (3.5; 95% CI, 0.4-6.5; P = .02; ES = 0.2). Conclusions and Relevance: In this randomized clinical trial of 3RP-NF vs HEP-NF, benefits from 3RP-NF and HEP-NF were comparable after treatment, but at 12 months from baseline, 3RP-NF was superior to HEP-NF on all primary and secondary outcomes. Results support the implementation of 3RP-NF in routine care. Trial Registration: ClinicalTrials.gov Identifier: NCT03406208.

Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis.

Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.

Enrollment of Participants From Marginalized Racial and Ethnic Groups: A Comparative Assessment of the STEADY-PD III and SURE-PD3 Trials.

Background and Objectives: Representation of persons from marginalized racial and ethnic groups in Parkinson disease (PD) trials has been low, limiting the generalizability of therapeutic options for individuals with PD. Two large phase 3 randomized clinical trials sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), STEADY-PD III and SURE-PD3, screened participants from overlapping Parkinson Study Group clinical sites under similar eligibility criteria but differed in participation by underrepresented minorities. The goal of this research is to compare recruitment strategies of PD participants belonging to marginalized racial and ethnic groups. Methods: A total of 998 participants with identified race and ethnicity consented to STEADY-PD III and SURE-PD3 from 86 clinical sites. Demographics, clinical trial characteristics, and recruitment strategies were compared. NINDS imposed a minority recruitment mandate on STEADY-PD III but not SURE-PD3. Results: Ten percent of participants who consented to STEADY-PD III self-identified as belonging to marginalized racial and ethnic groups compared to 6.5% in SURE-PD3 (difference = 3.9%, 95% confidence interval [CI] 0.4%-7.5%, p value = 0.034). This difference persisted after screening (10.1% of patients in STEADY-PD III vs 5.4% in SURE-PD 3, difference = 4.7%, 95% CI 0.6%-8.8%, p value = 0.038). Discussion: Although both trials targeted similar participants, STEADY-PD III was able to consent and recruit a higher percentage of patients from racial and ethnic marginalized groups. Possible reasons include differential incentives for achieving minority recruitment goals. Trial Registration Information: This study used data from The Safety, Tolerability, and Efficacy Assessment of Isradipine for Parkinson Disease (STEADY-PD III; NCT02168842) and the Study of Urate Elevation in Parkinson's Disease (SURE-PD3; NCT02642393).

Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Higher urate levels are associated with improved ALS survival in retrospective studies, however whether raising urate levels confers a survival advantage is unknown. In the Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (SURE-ALS) trial, inosine raised serum urate and was safe and well-tolerated. The SURE-ALS2 trial was designed to assess longer term safety. Functional outcomes and a smartphone application were also explored. METHODS: Participants were randomized 2:1 to inosine (n = 14) or placebo (n = 9) for 20 weeks, titrated to serum urate of 7-8 mg/dL. Primary outcomes were safety and tolerability. Functional outcomes were measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Mobility and ALSFRS-R were also assessed by a smartphone application. RESULTS: During inosine treatment, mean urate ranged 5.68-6.82 mg/dL. Treatment-emergent adverse event (TEAE) incidence was similar between groups (p > .10). Renal TEAEs occurred in three (21%) and hypertension in one (7%) of participants randomized to inosine. Inosine was tolerated in 71% of participants versus placebo 67%. Two participants (14%) in the inosine group experienced TEAEs deemed related to treatment (nephrolithiasis); one was a severe adverse event. Mean ALSFRS-R decline did not differ between groups (p = .69). Change in measured home time was similar between groups. Digital and in-clinic ALSFRS-R correlated well. DISCUSSION: Inosine met pre-specified criteria for safety and tolerability. A functional benefit was not demonstrated in this trial designed for safety and tolerability. Findings suggested potential utility for a smartphone application in ALS clinical and research settings.

Validation of a predictive model for obstructive sleep apnea in people with Down syndrome.

Detecting obstructive sleep apnea (OSA) is important to both prevent significant comorbidities in people with Down syndrome (DS) and untangle contributions to other behavioral and mental health diagnoses. However, laboratory-based polysomnograms are often poorly tolerated, unavailable, or not covered by health insurance for this population. In previous work, our team developed a prediction model that seemed to hold promise in identifying which people with DS might not have significant apnea and, consequently, might be able to forgo a diagnostic polysomnogram. In this study, we sought to validate these findings in a novel set of participants with DS. We recruited an additional 64 participants with DS, ages 3-35 years. Caregivers completed the same validated questionnaires, and our study team collected vital signs, physical exam findings, and medical histories that were previously shown to be predictive. Patients then had a laboratory-based polysomnogram. The best modeling had a validated negative predictive value of 50% for an apnea-hypopnea index (AHI) > 1/hTST and 73.7% for AHI >5/hTST. The positive predictive values were 60% and 39.1%, respectively. As such, a clinically reliable screening tool for OSA in people with DS was not achieved. Patients with DS should continue to be monitored for OSA according to current healthcare guidelines.

Child Behavior Problems and Parenting Stress in Underserved Families of Children with ASD: Investigation of Family Resources and Parenting Self-efficacy.

Behavior problems in children with autism spectrum disorder (ASD) may exacerbate parenting stress. Parenting self-efficacy and family resources may influence this association. We examined cross-sectional statistical mediation effects of parenting self-efficacy on the relationship between child behavior problems and parenting stress and hypothesized that family-level resources moderated this indirect effect. Participants included 132 underserved (Medicaid-eligible) children with ASD (ages 3-13) with racial/ethnic diversity; many (63%) had intellectual disability. Greater externalizing problems were linked with lower parenting self-efficacy, which in turn was associated with increased parenting stress. A larger mediation effect was observed for families with fewer resources. A plausible alternative model (parenting stress mediating parenting self-efficacy) exhibited poorer fit. Implications for family supports and benefits of longitudinal follow-up are discussed.

Optimizing Parent Training to Improve Oral Health Behavior and Outcomes in Underserved Children with Autism Spectrum Disorder.

A randomized controlled trial established initial efficacy of a novel parent training (PT) intervention for improving oral hygiene and oral health in underserved children with ASD (Fenning et al., 2022), a population at risk for unmet dental needs. The present study describes our emic approach to PT development alongside treatment outcome data examining feasibility, acceptability, and engagement. Families with Medicaid-eligible children with ASD ages 3 to 13 years (85% male, 62% with intellectual disability) were assigned to receive PT (n = 60) or a psychoeducational toolkit (n = 59). Results indicate strong retention, fidelity, and adherence, with quantitative and qualitative metrics revealing high treatment satisfaction and utilization. Discussion focuses on implications for individualizing treatment to optimize engagement of underrepresented families.

The Recovering Together study protocol: A single-blind RCT to prevent chronic emotional distress in patient-cargiver dyads in the Neuro-ICU.

INTRODUCTION: Patients admitted to the Neuroscience Intensive Care Unit (Neuro-ICU) with acute neurological illnesses (ANI; e.g., stroke, tumor, TBI) and their informal caregivers experience high rates of anxiety, depression, and posttraumatic stress. To address this need, we previously developed the Recovering Together (RT) dyadic intervention to help prevent chronic emotional distress in both patients and caregivers. Currently, we are conducting a fully-powered, single-blind randomized clinical trial (RCT) to evaluate the efficacy of RT versus an attention matched health education control. Here, we describe the protocol and current status of this RCT. METHODS: We aim to recruit 194 at risk patient-caregiver dyads from the Neuro-ICU at MGH. Eligible dyads include patients diagnosed with ANI, cognitively intact, at least one partner endorses emotional distress (on Hospital Anxiety and Depression Scale), English speaking, age 18 or older. Dyads are randomized to the intervention (RT-1) or control condition (RT-2) (both six sessions). RT-1 teaches resiliency (e.g., coping, mindfulness) and interpersonal skills. RT-2 provides education on health-related topics (e.g., stress, self-care, adhering to medical recommendations). Blinded research assistants collect measures at baseline, post-intervention, and three months follow-up. We will conduct mixed linear, mediation, and actor-partner interdependence models to examine changes in dyads' outcomes across time. RESULTS: We have recruited 41 dyads and aim to recruit 194 total. DISCUSSION: If successful, we plan to test RT in a large-scale, multisite hybrid effectiveness-implementation study in Neuro-ICUs across the country. Enhancing psychosocial supports for patients and families could improve health outcomes, healthcare efficiency, and the culture of these units.

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial.

Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3-5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results. METHODS: Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 106 cells/kg) IV every 4 weeks and IL-2 (2 × 105 IU/m2) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 106 cells/kg and 3 × 106 cells/kg at 4-week intervals. RESULTS: The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of -2.7 points per the ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of -10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group. DISCUSSION: Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.

Statistical Considerations in the Design of Clinical Trials Targeting Prodromal Parkinson Disease.

Clinical trials testing interventions for prodromal Parkinson disease (PD) hold particular promise for preserving neuronal function and thereby slowing or even forestalling progression to overt PD. Selection of the appropriate target population and outcome measures presents challenges unique to prodromal PD. We propose 3 clinical trial designs, spanning phase 2a, phase 2b, and phase 3 development, that might serve as templates for prodromal PD trials. The proposed phase 2a trial is of a 3-arm design of short duration and focuses on proof of concept with respect to target engagement and change in a motor outcome in a subset of prodromal participants who already manifest asymptomatic but measurable motor dysfunction as an exploratory aim. The proposed phase 2b trial suggests progression of dopamine transporter imaging specific binding ratio as a primary outcome evaluated annually over 2 years with phenoconversion to PD as a key secondary outcome. The proposed phase 3 trial is a large, simple design of a nutraceutical or behavioral intervention with remote administration and phenoconversion as the primary outcome. We then consider what additional data are needed in the short term to better design prodromal PD trials and examine what longer-term goals would accelerate discovery of safe and effective therapies for individuals at risk of PD. Clear and potentially context-specific definitions of phenoconversion and validation of intermediate endpoints are needed in the short term. The use of adaptive trial designs, master protocols, and research registries would help accelerate therapy development in the long term.

Trial of Cinpanemab in Early Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).