Background: Double-blind studies have demonstrated that motor complications in Parkinson's disease (PD) can be reduced with continuous delivery of levodopa. The DopaFuse system is a novel, intraoral micropump that attaches to a retainer and uses a propellant to deliver levodopa/carbidopa (LD/CD) continuously into the mouth. Objectives: Evaluate the safety, pharmacokinetics, and efficacy of LD/CD delivered via the DopaFuse system compared to treatment with intermittent doses of standard oral LD/CD in PD patients with motor fluctuations. Methods: This was a 2-week, open-label study (NCT04778176) in 16 PD patients treated with >= 4 levodopa doses/day and experiencing motor fluctuations. On Day 1 (clinic setting) patients received their usual dose of standard LD/CD; DopaFuse therapy was initiated on Day 2, and on Day 3 patients received DopaFuse plus a morning oral LD/CD dose. Patients returned home on Days 4-14 and returned for in-clinic assessment on Day 15. Results: Continuous DopaFuse delivery of LD/CD was associated with reduced variability in plasma levodopa levels compared to oral LD/CD (mean +/- SD levodopa Fluctuation Index reduced from 2.15 +/- 0.59 on Day1 to 1.50 +/- 0.55 on Day 2 (P = 0.0129) and to 1.03 +/- 0.53 on Day 3 (P < 0.0001)). This pharmacokinetic improvement translated into significantly reduced OFF time with DopaFuse therapy (reduction of -1.72 +/- 0.37 h at Day 15; P = 0.0004) and increased ON time without severe dyskinesias (increase of 1.72 +/- 0.37 h at Day 15; P = 0.0004) versus oral LD/CD administration. DopaFuse therapy was not associated with any clinically significant adverse events. Conclusions: Continuous delivery of LD/CD using the DopaFuse system was associated with significantly less variability in plasma levodopa concentrations and reductions in OFF time compared to treatment with standard oral LD/CD therapy and was well tolerated. (c) 2024 International Parkinson and Movement Disorder Society.

Background Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. Methods We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2 center dot 5 mg or 5 center dot 0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. Findings The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2 center dot 5 mg and 5 center dot 0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0 center dot 39 (95% CI -2 center dot 96 to 2 center dot 18; p=0 center dot 77) for 2 center dot 5 mg and 0 center dot 36 (-2 center dot 28 to 3 center dot 00; p=0 center dot 79) for 5 center dot 0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2 center dot 5 mg NLY01, 79 [93%] of 85 on 5 center dot 0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2 center dot 5 mg, 64 [75%] for 5 center dot 0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2 center dot 5 mg, 49 [58%] for 5 center dot 0 mg, and 16 [19%] for placebo). No deaths occurred during the study. Interpretation NLY01 at 2 center dot 5 and 5 center dot 0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable.

Background and ObjectivesVamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).MethodsA randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.ResultsA total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.DiscussionImprovements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.Trial Registration InformationClinicalTrials.gov Identifier: NCT03439670.Classification of EvidenceThis study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Importance:Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. Objective:To investigate outcomes after 30 months of open-label vamorolone treatment. Design, Setting, and Participants:This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Interventions:Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Main Outcomes and Measures:Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Results:Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. Conclusions and Relevance:This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. Trial Registration:ClinicalTrials.gov Identifier: NCT03038399.

This nonrandomized controlled trial examines efficacy of vamorolone treatment for Duchenne muscular dystrophy among boys compared with glucocorticoid treatment.

Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

Background As Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements. Objectives This substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration. Methods Participants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and >= 3 hours after start of levodopa infusion. Results Of 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration. Conclusions VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background: No pharmacological treatment has been demonstrated to provide a functional benefit for persons with Huntington’s disease (HD). Pridopidine is a sigma-1-receptor agonist shown to have beneficial effects in preclinical models of HD. Objective: To further explore the effect of pridopidine on Total Functional Capacity (TFC) in the recent double-blind, placebo-controlled PRIDE-HD study. Methods: We performed post-hoc analyses to evaluate the effect of pridopidine on TFC at 26 and 52 weeks. Participants were stratified according to baseline TFC score and analyzed using repeated measures (MMRM) and multiple imputation assuming missing not-at-random (MNAR) and worst-case scenarios. Results: The pridopidine 45 mg bid dosage demonstrated a beneficial effect on TFC for the entire population at week 52 of 0.87 (nominal p = 0.0032). The effect was more pronounced for early HD participants (HD1/HD2, TFC = 7–13), with a change from placebo of 1.16 (nominal p = 0.0003). This effect remained nominally significant using multiple imputation with missing not at random assumption as a sensitivity analysis. Responder analyses showed pridopidine 45 mg bid reduced the probability of TFC decline in early HD patients at Week 52 (nominal p = 0.02). Conclusion: Pridopidine 45 mg bid results in a nominally significant reduction in TFC decline at 52 weeks compared to placebo, particularly in patients with early-stage HD.

Background Many patients with Parkinson's disease have potentially disabling off episodes that are not predictably responsive to levodopa. In this study, we assessed the safety and efficacy of apomorphine sublingual film as an on-demand therapy for off episodes in patients with Parkinson's disease. Methods This randomised, double-blind, placebo-controlled study was done by movement disorder specialists at 32 sites in the USA and one in Canada. Patients with Parkinson's disease who had 2 h or more of off time per day with predictable morning off periods, were responsive to levodopa, and were on stable doses of anti-parkinsonian medication were eligible. In an open-label titration phase, increasing doses of apomorphine sublingual film (10-35 mg) were administered until a tolerable full on response was achieved. Patients were then randomly assigned (1:1) with an interactive web-response system to receive the effective dose of apomorphine sublingual film or matching placebo in a 12-week, double-blind maintenance phase. Randomisation was not stratified, and the block size was four. All patients and study personnel were masked to treatment assignments. The primary endpoint was the in-clinic change from predose to 30 min post-dose in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 (motor) score at week 12, analysed on a modified intention-to-treat population by use of a mixed-effect model for repeated measures. Safety analyses were done on all enrolled patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT02469090. Findings Between June 18, 2015, and Dec 11, 2017, 109 patients were enrolled and randomly assigned to receive apomorphine sublingual film (n=54) or placebo (n=55). All patients received the assigned study treatment, and 34 (63%) of 54 patients receiving apomorphine sublingual film and 46 (84%) of 55 receiving placebo completed the study. Least squares mean (SE) change from predose to 30 min post-dose in MDS-UPDRS part 3 score at week 12 was -11-1 (SE 1.46, 95% CI -14.0 to -8.2) with apomorphine sublingual film and -3.5 (1.29, -6.1 to -0.9) with placebo (difference -7.6, SE 1.96, 95% CI -11.5 to -3.7; p.O.0002). Mild-to-moderate oropharyngeal events were the most common side-effect, reported in 17 (31%) of 54 patients receiving apomorphine sublingual film and in four (7%) of 55 patients receiving placebo, leading to treatment discontinuation in nine (17%) patients treated with apomorphine and in one (2%) patient treated with placebo. Other treatment-emergent adverse events were transient nausea (in 15 [28%J patients receiving apomorphine sublingual film), somnolence (seven [13%]), and dizziness (five [9%]). Orthostatic hypotension, syncope, dyskinesia, hallucinations, prolongation of the QT interval, and impulse control disorders were infrequent (prevalence <= 2% of all patients) or did not occut One patient treated with apomorphine sublingual film (with known cardiac risk factors) had a fatal cardiac arrest. Interpretation Although nearly a third of patients discontinued treatment primarily because of oropharyngeal side-effects, apomorphine sublingual film provided an efficacious, on-demand treatment for off episodes for most patients with Parkinson's disease in this trial. The long-term safety and efficacy of apomorphine sublingual film are currently being investigated. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4-6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from -7.4% (95% CI: -9.1, -5.8) for the Off-Idebenone periods to -3.8% (95% CI: -4.8, -2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was -5.9% (95% CI: -8.0, -3.9) for the Off-Idebenone periods (N = 9) and reduced to -1.9% (95% CI: -3.2, -0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials. (C) 2020 The Authors. Published by Elsevier B.V.

BackgroundMultiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder of the central nervous system (CNS). While current MS therapies target the inflammatory processes, no treatment explicitly targets mitochondrial dysfunction and resulting axonal loss. Therefore, the aim of this study was to determine whether idebenone inhibits mitochondrial dysfunction and accumulation of disability in primary progressive MS (PPMS) and to enhance understanding of pathogenic mechanisms of PPMS progression using cerebrospinal fluid (CSF) biomarkers.MethodsThe double-blind, placebo-controlled Phase I/II clinical trial of Idebenone in patients with Primary Progressive MS (IPPoMS; NCT00950248) was an adaptively designed, baseline-versus-treatment, placebo-controlled, CSF-biomarker-supported trial. Based on interim analysis of the 1-year pre-treatment data, change in the area under the curve of Combinatorial Weight-Adjusted Disability Score (CombiWISE) became the primary outcome, with >80% power to detect ≥40% efficacy with 28 patients/arm treated for 2 years in baseline versus treatment paradigm. Changes in traditional disability scales and in brain ventricular volume were secondary outcomes. Exploratory outcomes included CSF biomarkers of mitochondrial dysfunction (Growth/differentiation factor 15 [GDF15] and lactate), axonal damage (neurofilament light chain [NFL]), innate immunity (sCD14), blood brain barrier leakage (albumin quotient) and retinal nerve fiber layer thinning.ResultsIdebenone was well tolerated but did not inhibit disability progression or CNS tissue destruction. Concentrations of GDF15, secreted predominantly by astrocytes and choroid plexus epithelium in vitro, increased after exposure to mitochondrial toxin rotenone, validating the ability of this biomarker to measure intrathecal mitochondrial damage. CSF GDF15 levels correlated strongly with age and MS patients had CSF levels of GDF15 significantly above age-adjusted healthy volunteers, with highest levels measured in PPMS. Idebenone did not change CSF GDF15 levels.ConclusionMitochondrial dysfunction exceeding normal aging reflected by age-adjusted CSF GDF15 is present in the majority of PPMS patients, but it is not inhibited by idebenone.

Introduction: In DMD, weakness of inspiratory and expiratory muscles results in impaired respiratory function and loss of volume. Aims and Objectives: In the Phase III DELOS trial, idebenone reduced the rate of respiratory function decline over 52 weeks. The aim of the current analysis was to characterize the long-term effects of idebenone on inspiratory and expiratory measures. Methods: SYROS is a long term, real-world study in 18 former DELOS patients who transitioned to idebenone under Expanded Access Programs following a variable untreated period. Inspiratory function was assessed by measuring the largest flow during an inspiratory FVC maneuver (maximum inspiratory flow; V’I, max(FVC)), and by measuring the inspiratory flow reserve (IFR%) – the ratio between tidal inspiratory flow (V’I, max(t)) and V’I, max (FVC). Expiratory function was assessed by calculating the annualized decline in FVC and PEF, expressed as percent predicted (%p). Comparisons were made between treated and untreated periods. Results: Patients were treated for an average (min-max) of 4.2 (2.4–6.1) years (y), versus an untreated period of 2.1 (1.0-5.5)y. During the untreated period (mean duration: 1.6y), the mean (SD) annual rate of IFR% decline was –6.5 (9.8), compared to 1.9 (7.2) during the treated period (mean duration 3.3y). Similar changes were seen for V’I, max(FVC) and absolute IFR. The annual rate of FVC%p decline was almost halved (4.1% vs 7.5%) with PEF%p showing a similar trend (2.3% vs 6.4%). Conclusions: The beneficial, long-term treatment effect of idebenone was consistently observed across both inspiratory and expiratory measures of respiratory function.

Introduction: In the 52-week, Phase III DELOS study, idebenone slowed the rate of respiratory function loss and decreased respiratory complications; however, data beyond one year is limited. Aims and Objectives: To evaluate the effect of long-term idebenone treatment on reducing the frequency of respiratory complications in a real world study. Methods: SYROS is a real-world study in 18 former DELOS patients who transitioned to idebenone under Expanded Access Programs following a variable untreated period. Patients were managed according to routine clinical practice. Data on time to clinically relevant worsening (defined as time to first relative decline of at least 10% in FVC percent predicted (%p) from baseline), frequency of bronchopulmonary adverse events (BAEs), hospitalizations and systemic antibiotic use were collected. Comparisons were made between treated and untreated periods. Results: Patients were treated for an average (min-max) of 4.5 (2.4–7.2) years, versus 2.0 (0.7–5.5) untreated years. There was a 56% risk reduction in time to a first 10% FVC%p decline. The risk of BAEs was reduced by 72% comparing treated versus untreated periods, leading to fewer hospitalizations due to respiratory causes (0.06 vs 0.15 events per year), and fewer occurences of systemic antibiotic use (0.04 vs 0.15 events per year). Conclusion: Real-world data suggests maintaining treatment with idebenone continues to slow respiratory function decline in patients with DMD, in turn reducing the occurence and severity of clinically relevant pulmonary morbidity.

Background: Laboratory and clinical evidence indicate that continous delivery of levodopa is associated with reduced motor complications compared to standard intermittent levodopa. Objective: To assess the pharmacokinetics and efficacy of continuous oral delivery of L-dopa/carbidopa in PD patients with motor fluctuations. Methods: Eighteen PD patients with motor fluctuations were enrolled in an open-label study comparing pharmacokinetics and efficacy measures between standard intermittent oral L-dopa/carbidopa and "continuous" oral L-dopa/carbidopa. Continuous treatmentwas operationally defined as sips of an L-dopa dispersion at 5-to 10-minute intervals. On day 1, patients received their usual oral L-dopa/carbidopa doses. On day 2, patients received L-dopa/carbidopa dose by "continuous" oral administration. On day 3, patients received a single dose of oral L-dopa/carbidopa followed by continuous administration of L-dopa/carbidopa. Each study period was 8 hours, and the total L-dopa/carbidopa dose administered was the same on each day. Analyses of variability were primarily-based samples drawn between 4 and 8 hours when subjects were in a relative steady state. Results: There was less variability in plasma L-dopa concentration with continuous versus intermittent oral L-dopa/carbidopa treatment (fluctuation index was 0.99 +/- 0.09 vs. 1.38 +/- 0.12 [P < 0.001] and coefficient of variation was 0.35 +/- 0.03 vs. 0.49 +/- 0.04 [P < 0.001]). Mean OFF time was decreased by 43% (P < 0.001) with continuous oral L-dopa therapy. No safety or tolerability issues were observed. Conclusions: Continuous oral delivery of L-dopa/carbidopa was associated with less plasma variability and reduced off time in comparison to standard intermittent oral L-dopa/carbidopa therapy. (c) 2019 International Parkinson and Movement Disorder Society

BACKGROUND:Loss of pulmonary function is a main cause of early morbidity and mortality in patients with Duchenne muscular dystrophy (DMD). Standard of care guidelines recommend regular assessment of pulmonary function by hospital-based spirometry to detect onset and monitor progression of pulmonary function decline.OBJECTIVE:To assess the feasibility of home-based monitoring of pulmonary function by a hand-held device (HHD) in adolescent and adult patients with DMD over a period of 12 months.METHODS:In the phase III randomized placebo-controlled DELOS trial in 10-18 year old DMD patients, peak expiratory flow (PEF) measurements were collected weekly at home by the patient (assisted by parent/caregiver) using a peak flow meter HHD. Adherence to the use of the HHD was assessed and 12-month changes in PEF as percent of predicted (PEF% p) for the idebenone (N = 31) and the placebo treatment groups (N = 33) from HHD-derived data were compared to results from hospital-based spirometry.RESULTS:A total of 2689 individual HHD assessments were analysed. Overall adherence to the use of the HHD over the course of the 12-month study duration was good (75.9%, SD 21.5%) and PEF% p data obtained at the same day by HHD and standard spirometry correlated well (Spearman's rho 0.80; p < 0.001). Several analysis methods of HHD-derived data for PEF% p consistently demonstrate that idebenone treatment slowed the decline in PEF% p compared to placebo, which supports the statistically significant difference in favour of idebenone for PEF% p measured by standard spirometry.CONCLUSIONS:This study demonstrates that home-based monitoring of pulmonary function in adolescent patients with DMD using a HHD is feasible, provides reliable data compared to hospital-based spirometry and is therefore suitable for use in clinical practice and for clinical trials.

Background: Respiratory failure leads to high disease burden and early mortality in DMD. Standard of care guidelines recommend routine respiratory function monitoring to guide patient management and improve patient outcomes. Aims and objectives: We compared a hand-held device that allows home-based monitoring to hospital-based spirometry measures in patients with DMD. Methods: Respiratory function data were prospectively collected from 64 DMD patients aged 10-18 years, and not taking concomitant glucocorticoids, participating in the randomized controlled phase III DELOS trial. Patients were treated with idebenone (900 mg/d) or placebo. Spirometry was conducted during hospital visits at baseline and at 3-month intervals over 12 months. Patients also measured peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) weekly at home using the ASMA-1 device (Vitalograph). Both the changes at 3-month intervals (standard spirometry) and the weekly changes (ASMA-1 device) in PEF as percent of predicted (PEF%p) were analyzed with a mixed model for repeated measures. Results: The weekly changes in PEF%p (ASMA1-device) compared well with those from hospital-based measurements. Weekly ASMA-1 data indicated a stabilization of PEF%p in the idebenone group versus a natural history consistent decline in the placebo group. Conclusion: Home based measuring of PEF%p and FEV1%p is a reliable method of monitoring respiratory function in pediatric and adolescent patients with DMD, in addition to hospital-based monitoring. These data further support the efficacy of idebenone in slowing respiratory function decline in DMD.