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The development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including body worn sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions. The Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson's Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability. The results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility. ISRCTN12051706.

Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease. LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21–55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014–000418–75, and is now complete. Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI –1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference –1·76% [95% CI –2·67 to –0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]). Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments. Teva Pharmaceutical Industries.

The mechanism of tardive dyskinesia (TD) is complex and not well understood. Dopamine-receptor blockade in the nigrostriatal pathway may lead to a hyperdopaminergic state that can interfere with mechanisms of movement control, leading to TD. Medications for the treatment of movement disorders, including TD, typically require fine-tuning of doses to optimize control of abnormal movements; however, doses are often not titrated sufficiently. The vesicular monoamine transporter 2 inhibitor deutetrabenazine is an FDA-approved treatment for TD in adults. This post hoc analysis examined dosing patterns in patients with TD according to baseline Abnormal Involuntary Movement Scale (AIMS) item 8 score, a clinician-rated global judgment of the overall severity of abnormal movements. Patients who completed the pivotal 12-week studies, ARM-TD and AIM-TD, were eligible to enroll in the 3-year, open-label extension study. Deutetrabenazine was initiated at 12 mg/day and titrated in a response-driven manner on a weekly basis in intervals of 6 mg/day for 6 weeks, up to a maximum dose of 48 mg/day, based on dyskinesia control and tolerability. Further dose adjustments during the long-term maintenance period were permitted on a weekly basis. Subgroups were defined by AIMS item 8 scores of either 0/1/2 or 3/4 at baseline. Total daily dose categories and treatment exposure over time were evaluated in each subgroup. A total of 336 patients were included in the analysis (baseline AIMS item 8 scores 0/1/2, n = 117; scores 3/4, n = 219). At week 15, the proportions of patients by deutetrabenazine total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 10% and 3%; ≥24 to ≤36, 41% and 48%; >36 to ≤48, 49% and 49%. At week 54, proportions by total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 11% and 4%; ≥24 to ≤36, 42% and 41%; >36 to ≤48, 46% and 55%; >48, 1% and 0. Similar patterns were observed at weeks 106 and 145 across total daily dose categories. For scores 0/1/2, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 36.9 ± 1.04 (n = 108), 37.1 ± 1.22 (n = 90), 37.7 ± 1.32 (n = 76), and 37.9 ± 1.44 (n = 64). For scores 3/4, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 39.2 ± 0.65 (n = 186), 39.8 ± 0.75 (n = 150), 40.3 ± 0.88 (n = 112), and 40.5 ± 0.99 (n = 97). Dosing decisions in the treatment of TD are individualized, as treatment response is likely driven by complex factors. Findings from this analysis suggest that in order to achieve adequate control of TD symptoms, patients benefit from response-driven titration of deutetrabenazine to doses >24 mg/day, regardless of the baseline severity of abnormal movements assessed by AIMS item 8. These results highlight the importance of patient-driven titration of deutetrabenazine until adequate movement control is achieved, while maintaining safety/tolerability in the treatment of TD. Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.

BackgroundThere are no established treatment guidelines for tardive dyskinesia (TD) based on movement severity. The 12-week ARM-TD and AIM-TD studies in TD patients with baseline Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) ≥6 showed clinically significant improvements in AIMS score with deutetrabenazine versus placebo. Patients who completed these studies were eligible for the open-label extension (OLE) trial. This post-hoc analysis evaluated deutetrabenazine in TD patients with severe movements.MethodsSubgroups were defined by upper quartile of baseline total AIMS score (local rating). Endpoints were: change and percent change from baseline in AIMS score, and percent of patients achieving ≥50% AIMS reduction from baseline.Results337 patients were analyzed. The upper quartile of baseline total AIMS score was 14. Subgroups were defined as >14 and ≤14 at baseline, respectively (n=64 vs 273); data are presented at Week 145 (n=40 vs 120). Mean treatment duration was 880.5 and 760.8 days. Mean±SE daily doses were 41.1±1.6mg and 38.9±1.0mg. Mean±SE change from baseline in AIMS score was –11.0±0.8 versus –5.1±0.3; percent change from baseline was –60.1%±3.6% versus –55.9%±3.0%. More patients with AIMS score >14 had ≥50% AIMS reduction (73% vs 65%). Less patients discontinued (38% vs 51%); reasons included withdrawal by subject (16% vs 25%), adverse event (3% vs 11%), and lost to follow-up (6% vs 7%). Withdrawal due to lack of efficacy was uncommon (5% vs 2%).ConclusionsPatients with baseline total AIMS score >14 had clinically meaningful reductions in AIMS score, suggesting deutetrabenazine has long-term benefit in these patients.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Background Asthma affects over 1 million children across the UK, and preventative treatment is guided subjectively by patient symptoms. Spirometry is an objective test of lung function and can be used in children to guide treatment. However, current guidelines do not indicate how asthma treatment should change in the context of changing spirometry results. This study will evaluate how spirometry can be used to guide asthma treatment and reduce the risk for asthma attacks in children. Methods This is a multi-centre, randomised controlled trial. Children aged 6–15 years, who have a diagnosis of asthma and have had an exacerbation requiring oral or intravenous corticosteroids in the previous 12 months, will be eligible. Exclusion criteria include being unable to provide spirometry measurement at baseline assessment, having another chronic respiratory condition and being currently treated with maintenance oral steroids or biologicals. Participants will be recruited in both primary and secondary care settings and will be randomised to either receive asthma treatment guided by spirometry plus symptoms (intervention group) or asthma treatment guided by symptoms only (standard care group). Within the spirometry group, treatment recommendations will be dependent on changes in spirometry measurements. Participants will attend assessments 3, 6, 9 and 12 months post-randomisation, where treatment recommendations will be made. The primary outcome is the number of asthma attacks per participant requiring treatment with 1–7 days of oral or intravenous corticosteroid over 12 months, as recorded by the participant or parent. Secondary outcomes include time to first attack, any asthma attack, adverse events, dose of inhaled corticosteroids, asthma control and quality of life. Adherence to inhaled corticosteroid treatment is measured by an electronic logging device. Discussion This study will evaluate whether asthma treatment guided by spirometry will reduce future asthma attacks in children. Our findings may be relevant to national and international asthma guidelines. Trial registration ISRCTN, ISRCTN31849868. Registered on 01.07.2022. Prospectively registered.

BackgroundTardive dyskinesia (TD) is an involuntary movement disorder that is more prevalent in older patients. However, there is limited information on TD treatment for this population. In two 12-week pivotal trials (ARM-TD and AIM-TD), TD patients demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) score with deutetrabenazine versus placebo.MethodsPatients who completed ARM-TD or AIM-TD enrolled in an open-label extension (OLE) study. This post hoc analysis assessed change and percent change from baseline in AIMS score, response rates for ≥50% AIMS improvement, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety in younger (<55 years) and older (≥55 years) patients.ResultsThis analysis included 119 younger and 218 older patients enrolled in the OLE. Data presented at Week 145 (mean±SE): total deutetrabenazine dose was 39.4±1.39mg/day and 39.5±1.04mg/day in younger and older patients, respectively. Changes from baseline in AIMS score were –6.7±0.62 and –6.5±0.47, respectively (percent changes of –61.4%±4.10% and –54.6%±3.01%). The majority of younger and older patients achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%) and achieved ≥50% AIMS response (76% and 62%). Deutetrabenazine was generally well tolerated in both groups. Exposure-adjusted incidence rates (incidence/patient-years) were <0.01 and 0.02 for akathisia, 0.07 (both) for somnolence and sedation, 0.04 and 0.11 for parkinson-like events, and 0.06 and 0.09 for depression in younger and older patients, respectively.ConclusionsDeutetrabenazine treatment was associated with sustained improvements in AIMS score and was well tolerated in both younger and older TD patients.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Background Those experiencing homelessness and problem substance use find it challenging to access the healthcare and treatment they need. The Supporting Harm Reduction through Peer Support (SHARPS) feasibility study demonstrated that Peer Navigators can help these individuals to improve their service engagement, increase access to opioid substitution therapy, and lead to reductions in drug use and risky injection practices. Specifically, participants indicated that the lived experience of Peer Navigators was particularly helpful by enabling the development of trusting relationships. A cluster randomised controlled trial (cRCT) will now assess the effectiveness and cost-effectiveness of a Peer Navigator intervention with this population. Methods A two-arm, pragmatic, cRCT will be conducted with embedded cost-effectiveness and mixed methods process evaluations. Individuals will be recruited who are as follows: over the age of 18 years; experiencing/at risk of homelessness and self-report problem substance use; and attending The Salvation Army (TSA) homelessness services across 20 included clusters (towns/cities). Each cluster will be randomised (1:1) to either the intervention or control arm using covariate-constrained allocation based on area-level characteristics. The target sample size is 550 participants in total. A co-produced peer-delivered harm reduction, relational intervention lasting 12 months will be delivered to those in the intervention arm. Usual care will be social care via TSA Support Workers delivered within homelessness services. The co-primary outcomes will be mental health and quality of life, with harmful substance use, risk taking behaviours, social functioning, physical health, social outcomes, housing status, therapeutic alliance/accessibility, service utilisation, and relational empathy chosen as secondary outcomes. Data collection points are baseline, 6 and 12 months, for all measures. The primary timepoint of interest is 12 months after baseline measurement. Economic outcomes will be incremental cost per quality-adjusted life year (QALY) and per year in full capability (YFC) gained with the intervention versus standard homelessness service care, inclusive of costs to the NHS, local government and criminal justice, and the third-sector host organisation. The EQ-5D-5L and ICECAP-A will be used to calculate QALYs and YFC respectively. We will also conduct a cost-consequence analysis. Discussion The results of this trial will be used to inform whether the SHARPS intervention has a positive impact on those experiencing homelessness and problem substance use and if it is cost-effective to roll it out across social care services. Trial registration ISRCTN11094645 ( https://doi.org/10.1186/ISRCTN11094645 , registered April 5, 2024).

ObjectivesTo identify suitable patients for glaucoma home monitoring and explore clinicians’ perceptions of the possible benefits and risks of home monitoring within the National Health Service.DesignAn online survey composed of open-ended and closed-ended questions.SettingSecondary care.ParticipantsGlaucoma specialists registered with the UK and Eire Glaucoma Society.Outcome measuresAgreement with clinical scenarios.ResultsThe estimated response rate was 68% (n=49). Of 49 participants, 92% (n=45) were consultant ophthalmologists and 71% (n=35) had over 10-year experience. There was a poor agreement regarding an ideal glaucoma patient for home monitoring, with only one scenario achieving over 60% agreement. Most participants believed that home monitoring would be most suitable for low-risk scenarios, rather than high-risk, due to fear of missing progression. In relation to acceptability, key facilitators included the potential to increase healthcare capacity and promote patient safety. However, low clinician trust in equipment reliability and fear of patient harm were reported as concerns.ConclusionsThere was no clear consensus on which patients would benefit most from glaucoma home monitoring. While many clinicians believe home monitoring may enhance healthcare, there were also many concerns about the technologies themselves. Further work to address clinician concerns is warranted.Research Registry registration number6213.

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.

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 .