Clinical presentation and diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: a literature analysis of case studies.

Introduction: Because adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive, debilitating, and ultimately fatal neurodegenerative disease, a rapid and accurate diagnosis is critical. This analysis examined the frequency of initial misdiagnosis of ALSP via comprehensive review of peer-reviewed published cases. Methods: Data were extracted from a MEDLINE search via PubMed (January 1, 1980, through March 22, 2022) from eligible published case reports/series for patients with an ALSP diagnosis that had been confirmed by testing for the colony-stimulating factor-1 receptor gene (CSF1R) mutation. Patient demographics, clinical symptoms, brain imaging, and initial diagnosis data were summarized descriptively. Categorical data for patient demographics, symptoms, and brain imaging were stratified by initial diagnosis category to test for differences in initial diagnosis based on each variable. Results: Data were extracted from a cohort of 291 patients with ALSP from 93 published case reports and case series. Mean (standard deviation) age of symptom onset was 43.2 (11.6) years. A family history of ALSP was observed in 59.1% of patients. Cognitive impairment (47.1%) and behavioral and psychiatric abnormalities (26.8%) were the most frequently reported initial symptoms. Of 291 total cases, an accurate initial diagnosis of ALSP was made in 72 cases (24.7%) and the most frequent initial misdiagnosis categories were frontotemporal dementia (28 [9.6%]) and multiple sclerosis (21 [7.2%]). Of the 219 cases (75.3%) that were initially mis- or undiagnosed, 206 cases (94.1%) were later confirmed as ALSP by immunohistology, imaging, and/or genetic testing; for the remaining 13 cases, no final diagnosis was reported. Initial diagnosis category varied based on age, family history, geographic region, mode of inheritance, and presenting symptoms of pyramidal or extrapyramidal motor dysfunction, behavioral and psychiatric abnormalities, cognitive impairment, and speech difficulty. Brain imaging abnormalities were common, and initial diagnosis category was significantly associated with white matter hyperintensities, white matter calcifications, and ventricular enlargement. Discussion: In this literature analysis, ALSP was frequently misdiagnosed. Improving awareness of this condition and distinguishing it from other conditions with overlapping presenting symptoms is important for timely management of a rapidly progressive disease such as ALSP.

Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models.

This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, or 30 mg/kg once daily; each n = 12) for 4 weeks. Nerve conduction velocity (NCV), mechanical threshold, ß-tubulin polymerization, and intraepidermal nerve fiber (IENF) density were assessed. Proteasome inhibition was evaluated in peripheral blood mononuclear cells. Cytotoxicity was assessed in human multiple myeloma cell lines (MCLs) exposed to BTZ alone (IC50 concentration), BTZ+suvecaltamide (10, 30, 100, 300, or 1000 nM), suvecaltamide alone, or vehicle. Tumor volume was estimated in athymic nude mice bearing MCL xenografts receiving vehicle, BTZ alone (1 mg/kg twice weekly), or BTZ+suvecaltamide (30 mg/kg once daily) for 28 days, or no treatment (each n = 8). After 4 weeks, suvecaltamide 10 or 30 mg/kg reversed BTZ-induced reduction in NCV, and suvecaltamide 30 mg/kg reversed BTZ-induced reduction in IENF density. Proteasome inhibition and cytotoxicity were similar between BTZ alone and BTZ+suvecaltamide. BTZ alone and BTZ+suvecaltamide reduced tumor volume versus the control (day 18), and BTZ+suvecaltamide reduced tumor volume versus BTZ alone (day 28). Suvecaltamide reversed CIPN without affecting BTZ anti-cancer activity in preclinical models.

A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development.

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection.

Background: Essential tremor (ET) is a common, progressive neurological syndrome with bilateral upper-limb dysfunction of at least 3-year duration, with or without tremor in other body locations. This disorder has a negative impact on daily function and quality of life. A single oral therapy has been approved by FDA for ET. Off-label pharmacotherapies have inadequate efficacy and poor tolerability with high rates of patient dissatisfaction and discontinuation. Safe and efficacious pharmacotherapies are urgently needed to decrease tremor and improve daily living. T-CALM (Tremor-CAv3 modulation) protocol is designed to assess safety and efficacy of CX-8998, a selective modulator of the T-type calcium channel, for ET therapy. Methods/Design: T-CALM is a phase 2, proof of concept, randomized, double-blind, placebo-controlled trial. Titrated doses of CX-8998 to 10 mg BID or placebo will be administered for 28 days to moderate to severe ET patients who are inadequately treated with existing therapies. The primary endpoint will be change from baseline to day 28 of The Essential Tremor Rating Assessment Performance Subscale (TETRAS-PS). Secondary efficacy endpoints for clinician and patient perception of daily function will include TETRAS Activity of Daily Living (ADL), Quality of Life in Essential Tremor Questionnaire (QUEST), Clinical Global Impression-Improvement (CGI-I), Patient Global Impression of Change (PGIC), and Goal Attainment Scale (GAS). Kinesia One, Kinesia 360, and iMotor will biometrically evaluate motor function and tremor amplitude. Safety will be assessed by adverse events, physical and neurological exams and laboratory tests. Sample size of 43 patients per group is estimated to have 90% power to detect a 5.5-point difference between CX-8998 and placebo for TETRAS-PS. Efficacy analyses will be performed with covariance (ANCOVA) and 2-sided test at 0.05 significance level. Discussion: T-CALM has a unique design with physician rating scales, patient-focused questionnaires and scales and objective motor measurements to assess clinically meaningful and congruent efficacy. Patient perception of ET debilitation and therapy with CX-8998 will be key findings. Overall goal of T-CALM is generation of safety and efficacy data to support a go, no-go decision to further develop CX-8998 for ET. Design of T-CALM may guide future clinical studies of ET pharmacotherapies. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03101241.

Quantification of Motor Function in Huntington Disease Patients Using Wearable Sensor Devices.

Previous studies have demonstrated the feasibility and promise of wearable sensors as objective measures of motor impairment in Parkinson disease and essential tremor. However, there are few published studies that have examined such an application in Huntington disease (HD). This report provides an evaluation of the potential to objectively quantify chorea in HD patients using wearable sensor data. Data were derived from a substudy of the phase 2 Open-PRIDE-HD study, where 17 patients were screened and 15 patients enrolled in the substudy and ultimately 10 patients provided sufficient wearable sensor data. The substudy was designed to provide high-resolution data to inform design of predictive algorithms for chorea quantification. During the entire course of the 6-month study, in addition to chorea ratings from 18 in-clinic assessments, 890 home assessments, and 1,388 responses to daily reminders, 33,000 h of high-resolution accelerometer data were captured continuously from wearable smartwatches and smartphones. Despite its limited sample size, our study demonstrates that arm chorea can be characterized using accelerometer data during static assessments. Nonetheless, the small sample size limits the generalizability of the model. The sensor-based model can quantify the chorea level with high correlation to the chorea severity reported by both clinicians and patients. In addition, our analysis shows that the chorea digital signature varies between patients. This work suggests that digital wearable sensors have the potential to support clinical development of medications in patients with movement disorders, such as chorea. However, additional data would be needed from a larger number of HD patients with a full range of chorea severity (none to severe) with and without intervention to validate this potentially predictive technology.

Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques.

BACKGROUND: Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID). OBJECTIVE: This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. METHODS: The pharmacokinetic profile and effects of pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to σ1 and dopamine D2 receptors, in vivo PET imaging, and pharmacokinetic profiling across different species. RESULTS: Pridopidine produced a dose-dependent reduction in dyskinesia (up to 71%, 30 mg/kg) and decreased the duration of on-time with disabling dyskinesia evoked by l-dopa by 37% (20 mg/kg) and 60% (30 mg/kg). Pridopidine did not compromise the anti-parkinsonian benefit of l-dopa. Plasma exposures following the ineffective dose (15 mg/kg) were associated with full σ1 occupancy (>80%), suggesting that σ1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20-30 mg/kg), while providing full σ1 occupancy, provide only modest dopamine D2 occupancy (<40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic-α2C , dopamine-D3 , and serotoninergic-5-HT1A sites) to a higher degree than D2 and might contribute to the antidyskinetic actions. CONCLUSIONS: In MPTP macaques, pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of l-dopa. Although the actions of pridopidine were associated with full σ1 occupancy, effective exposures are more likely associated with occupancy of additional, non-sigma receptors. This complex pharmacology may underlie the effectiveness of pridopidine against LID. © 2018 International Parkinson and Movement Disorder Society.

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study.

BACKGROUND: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. METHODS: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). FINDINGS: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. INTERPRETATION: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. FUNDING: Teva Pharmaceutical Industries.

Characterizing patient compliance over six months in remote digital trials of Parkinson's and Huntington disease.

BACKGROUND: A growing number of clinical trials use various sensors and smartphone applications to collect data outside of the clinic or hospital, raising the question to what extent patients comply with the unique requirements of remote study protocols. Compliance is particularly important in conditions where patients are motorically and cognitively impaired. Here, we sought to understand patient compliance in digital trials of two such pathologies, Parkinson's disease (PD) and Huntington disease (HD). METHODS: Patient compliance was assessed in two remote, six-month clinical trials of PD (n = 51, Clinician Input Study funded by the Michael J. Fox Foundation for Parkinson's Research) and HD (n = 17, sponsored by Teva Pharmaceuticals). We monitored four compliance metrics specific to remote studies: smartphone app-based medication reporting, app-based symptoms reporting, the duration of smartwatch data streaming except while charging, and the performance of structured motor tasks at home. RESULTS: While compliance over time differed between the PD and HD studies, both studies maintained high compliance levels for their entire six month duration. None (- 1%) to a 30% reduction in compliance rate was registered for HD patients, and a reduction of 34 to 53% was registered for the PD study. Both studies exhibited marked changes in compliance rates during the initial days of enrollment. Interestingly, daily smartwatch data streaming patterns were similar, peaking around noon, dropping sharply in the late evening hours around 8 pm, and having a mean of 8.6 daily streaming hours for the PD study and 10.5 h for the HD study. Individual patients tended to have either high or low compliance across all compliance metrics as measured by pairwise correlation. Encouragingly, predefined schedules and app-based reminders fulfilled their intended effect on the timing of medication intake reporting and performance of structured motor tasks at home. CONCLUSIONS: Our findings suggest that maintaining compliance over long durations is feasible, promote the use of predefined app-based reminders, and highlight the importance of patient selection as highly compliant patients typically have a higher adherence rate across the different aspects of the protocol. Overall, these data can serve as a reference point for the design of upcoming remote digital studies. TRIAL REGISTRATION: Trials described in this study include a sub-study of the Open PRIDE-HD Huntington's disease study (TV7820-CNS-20016), which was registered on July 7th, 2015, sponsored by Teva Pharmaceuticals Ltd., and registered on Clinicaltrials.gov as NCT02494778 and EudraCT as 2015-000904-24 .

Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson's Disease following Oral Administration.

BACKGROUND: PF-06412562 is a moderately potent, highly selective oral D1/D5 dopamine receptor partial agonist. OBJECTIVE: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson's disease. METHODS: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using KinesiaTM technology (as the primary end point) and change from baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. RESULTS: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of -10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (-inf, -7.44) at 1.5-2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. CONCLUSIONS: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D1/D5 partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D1 agonists.

Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects.

AIMS: SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS: Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS: Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for Cmax and AUC0-t and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for Cmax and AUC0-t , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0-t . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD. CONCLUSIONS: SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.

Biometric Digital Health Technology for Measuring Motor Function in Parkinson's Disease: Results from a Feasibility and Patient Satisfaction Study.

OBJECTIVES: To assess the feasibility, predictive value, and user satisfaction of objectively quantifying motor function in Parkinson's disease (PD) through a tablet-based application (iMotor) using self-administered tests. METHODS: PD and healthy controls (HCs) performed finger tapping, hand pronation-supination and reaction time tasks using the iMotor application. RESULTS: Thirty-eight participants (19 with PD and 17 HCs) were recruited in the study. PD subjects were 53% male, with a mean age of 67.8 years (±8.8), mean disease duration of 6.5 years (±4.6), Movement Disorders Society version of the Unified Parkinson Disease Rating Scale III score 26.3 (±6.7), and Hoehn & Yahr stage 2. In the univariate analysis, most tapping variables were significantly different in PD compared to HC. Tap interval provided the highest predictive ability (90%). In the multivariable logistic regression model reaction time (reaction time test) (p = 0.021) and total taps (two-target test) (p = 0.026) were associated with PD. A combined model with two-target (total taps and accuracy) and reaction time produced maximum discriminatory performance between HC and PD. The overall accuracy of the combined model was 0.98 (95% confidence interval: 0.93-1). iMotor use achieved high rates of patients' satisfaction as evaluated by a patient satisfaction survey. CONCLUSION: iMotor differentiated PD subjects from HCs using simple alternating tasks of motor function. Results of this feasibility study should be replicated in larger, longitudinal, appropriately designed, controlled studies. The impact on patient care of at-home iMotor-assisted remote monitoring also deserves further evaluation.

Incorporating Site-less Clinical Trials Into Drug Development: A Framework for Action.

PURPOSE: Options for leveraging available telemedicine technologies, ranging from simple webcams and telephones to smartphone apps and medical-grade wearable sensors, are evolving faster than the culture of clinical research. Until recently, most clinical trials relied on paper-based processes and technology. This cost- and labor-intensive system, while slowly changing, remains an obstacle to new drug development. Alternatives that use existing tools and processes for collecting real-world data in home settings warrant closer examination. METHODS: The site-less clinical research organization (CRO) model, whereby pharmacists or other health care professionals provide useful and timely counseling for protocol compliance by regular phone and videoconferencing sessions, is a flexible approach to managing clinical trial participants directly from their homes. An expert panel, including clinical specialists in metabolic or neurodegenerative diseases, health information technology and CRO innovators, and the pharmaceutical industry, met in Dallas, Texas, December 2016, to discuss advancing avenues for site-less CRO and other remote clinical trial practices, taking into account investigator, sponsor, and regulatory perspectives. FINDINGS: Real-time "site-less" management of clinical trials can augment traditional research and development methods by providing data from a broader, more diverse group of patients in real-world practice settings. This methodology also helps to proactively identify safety profile and operational issues. Current use of site-less CRO practices constitutes an important bridge to alternative trial models, including "large simple trials" that strive to answer one or two questions using data derived from representative patient populations treated in typical clinical settings. IMPLICATIONS: Site-less CROs offer a working example of how remote technologies and in-home monitoring methods can address shortcomings of conventional drug development. This model maximizes time and cost, as well as potentially earlier identification of adverse events. Coordinated communication among investigators, sponsors, regulators, and patients will be needed to develop standardized strategies for incorporating site-less CROs into current and future study design.

The First Frontier: Digital Biomarkers for Neurodegenerative Disorders.

Current measures of neurodegenerative diseases are highly subjective and based on episodic visits. Consequently, drug development decisions rely on sparse, subjective data, which have led to the conduct of large-scale phase 3 trials of drugs that are likely not effective. Such failures are costly, deter future investment, and hinder the development of treatments. Given the lack of reliable physiological biomarkers, digital biomarkers may help to address current shortcomings. Objective, high-frequency data can guide critical decision-making in therapeutic development and allow for a more efficient evaluation of therapies of increasingly common disorders.

Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease.

Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington disease (HD). In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128 mouse model of HD. Treatment with laquinimod for 6 months rescued atrophy in the striatum, in certain cortical regions, and in the corpus callosum of YAC128 HD mice. Diffusion tensor imaging showed that white matter microstructural abnormalities in the posterior corpus callosum were improved following treatment with low dose (1 mg/kg) laquinimod, and were paralleled by reduced levels of interleukin-6 in the periphery of YAC128 HD mice. Functionally, treatment with laquinimod (1 and 10 mg/kg) led to modest improvements in motor function and in depressive-like behaviour. Taken together, these results suggest that laquinimod may improve some features of pathology in HD, and provides support for the role of immune activation in the pathogenesis of HD.

Technology in Parkinson's disease: Challenges and opportunities.

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.

Unmet clinical needs in chronic migraine: Rationale for study and design of COMPEL, an open-label, multicenter study of the long-term efficacy, safety, and tolerability of onabotulinumtoxinA for headache prophylaxis in adults with chronic migraine.

BACKGROUND: Chronic migraine is a neurological condition with a large individual and socioeconomic burden of disease. The recently completed Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical development program established the efficacy and safety of onabotulinumtoxinA as a prophylactic treatment for chronic migraine patients. However, clinical questions remain. A long-term evaluation study of onabotulinumtoxinA aims to address some of the remaining questions in the treatment of chronic migraine. The clinical rationale, study design, and treatment plan of this ongoing study are reviewed in this paper. METHODS/DESIGN: The Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) study will enroll approximately 500 adult patients with chronic migraine at international sites. Patients will be evaluated over 108 weeks, following a 4-week baseline period. Qualified subjects will receive 155 U of onabotulinumtoxinA every 12 weeks for 9 open-label cycles. The primary endpoint will be mean change from baseline in frequency of headache days at 108 weeks. Other endpoints will include additional assessments of the efficacy and safety of onabotulinumtoxinA and the effect of onabotulinumtoxinA on quality-of-life measures, disability, and health economic outcomes. The impact of onabotulinumtoxinA on common comorbidities (eg, sleep, anxiety, and fatigue) will also be assessed. DISCUSSION: Recruitment and enrollment are ongoing. Post-approval, open-label studies are often designed to more closely resemble clinical practice and provide an opportunity to continue the evaluation of the efficacy and safety of approved treatments. By creating a large database and analyzing a variety of outcome measures over an extended time frame, the COMPEL study will seek to contribute substantially to the existing knowledge of the chronic migraine population and the long-term management of this debilitating disorder. CLINICAL TRIAL REGISTRATION NUMBER: NCT01516892.

Post-stroke spasticity: predictors of early development and considerations for therapeutic intervention.

OBJECTIVE: The complexities of post-stroke spasticity (PSS), and the resultant difficulties in treating the disability, present a significant challenge to patients, stroke rehabilitation teams, and caregivers. Reducing the severity of spasticity and its long-term complications may be facilitated by early intervention, making identification of stroke patients at high risk for developing spasticity essential. Factors that predict which patients are at risk for the development of PSS are identified. TYPE: Systematic search and review LITERATURE SURVEY: A PubMed search of the following terms was conducted: predictors OR risk factors AND stroke AND spasticity. Studies discussing predictors of early PSS development and factors predictive of motor/functional outcomes and recovery were selected and reviewed in detail. SYNTHESIS: Several predictors of PSS have been proposed, based on studies conducted in patients within 6 months after stroke, including development of increased muscle tone, greater severity of paresis, hemihypesthesia, and low Barthel Index score. Predictors identified in later stages post-stroke (within 12 months) have also proved useful for clinicians, as has the consideration of predictors of motor and functional outcomes and recovery; yet there is a need for additional studies in this area. An understanding of these and other potential predictive factors--such as motor impairment, neurologic and sensory deficit, lesion volume and location, and associated diseases--has not progressed to the same extent and warrants further investigation. CONCLUSION: The studies discussed in this review support the notion that early identification of factors predictive of PSS should significantly affect the course of intervention, help target individuals who would benefit most from specific types and intensities of therapy, and possibly provide better motor and functional outcomes.