Video-Based Kinematic Analysis of Movement Quality in a Phase 3 Clinical Trial of Troriluzole in Adults with Spinocerebellar Ataxia: A Post Hoc Analysis.

INTRODUCTION: Traditional methods for assessing movement quality rely on subjective standardized scales and clinical expertise. This limitation creates challenges for assessing patients with spinocerebellar ataxia (SCA), in whom changes in mobility can be subtle and varied. We hypothesized that a machine learning analytic system might complement traditional clinician-rated measures of gait. Our objective was to use a video-based assessment of gait dispersion to compare the effects of troriluzole with placebo on gait quality in adults with SCA. METHODS: Participants with SCA underwent gait assessment in a phase 3, double-blind, placebo-controlled trial of troriluzole (NCT03701399). Videos were processed through a deep learning pose extraction algorithm, followed by the estimation of a novel gait stability measure, the Pose Dispersion Index, quantifying the frame-by-frame symmetry, balance, and stability during natural and tandem walk tasks. The effects of troriluzole treatment were assessed in mixed linear models, participant-level grouping, and treatment group-by-visit week interaction adjusted for age, sex, baseline modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA), and time since diagnosis. RESULTS: From 218 randomized participants, 67 and 56 participants had interpretable videos of a tandem and natural walk attempt, respectively. At Week 48, individuals assigned to troriluzole exhibited significant (p = 0.010) improvement in tandem walk Pose Dispersion Index versus placebo {adjusted interaction coefficient: 0.584 [95% confidence interval (CI) 0.137 to 1.031]}. A similar, nonsignificant trend was observed in the natural walk assessment [coefficient: 1.198 (95% CI - 1.067 to 3.462)]. Further, lower baseline Pose Dispersion Index during the natural walk was significantly (p = 0.041) associated with a higher risk of subsequent falls [adjusted Poisson coefficient: - 0.356 [95% CI - 0.697 to - 0.014)]. CONCLUSION: Using this novel approach, troriluzole-treated subjects demonstrated improvement in gait as compared to placebo for the tandem walk. Machine learning applied to video-captured gait parameters can complement clinician-reported motor assessment in adults with SCA. The Pose Dispersion Index may enhance assessment in future research. TRIAL REGISTRATION-CLINICALTRIALS. GOV IDENTIFIER: NCT03701399.

Exploring the impact of caring for an individual with neurogenic orthostatic hypotension: a qualitative study.

Aim: This study aimed to explore the impact of caring for an individual with neurogenic orthostatic hypotension (nOH). Methods: Informal caregivers of individuals with nOH and either Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies completed semi-structured interviews. Data were analyzed using thematic analysis; the identified concepts were used to develop a conceptual model. Results: Twenty informal caregivers were interviewed. Analysis identified several areas of caregiver impact due to nOH including impact on their time, particularly a need to supervise the patient to prevent falls as well as a lack of freedom and negative physical, work and social impacts. Many reported negative emotional impacts, including worry, stress or fear about the patient falling, depression and frustration. The conceptual model shows the relationships between concepts. Conclusion: The results highlight the wide-ranging impact of nOH, and the specific impact of the fear of falls on informal caregivers' lives.

Neurogenic orthostatic hypotension (nOH) is a type of hypotension (low blood pressure) which causes your blood pressure to fall when you stand up, meaning you can feel dizzy or lightheaded. This study looked at the experience of family members who provide day-to-day caregiving support to someone who has nOH as well as another condition which affects the brain and nerves (neurological condition). These neurological conditions included Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies. Interviews were conducted with informal caregivers (family members) of people with nOH. Caregivers discussed a range of ways in which caring for their family member impacts them, including needing to supervise their family member to make sure they do not fall, as well as having a lack of freedom and feeling worried, stressed, depressed and frustrated.

Health-related quality-of-life and burden for caregivers of individuals with neurogenic orthostatic hypotension.

Aim: This study explores the burden of caring for an individual with neurogenic orthostatic hypotension (nOH) and an underlying neurodegenerative disease (Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies). Materials & methods: A survey including several validated instruments was conducted with informal caregivers of individuals with Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies. Results: Caregivers of patients with nOH (n = 60) reported greater burden across all outcomes compared with those without nOH (n = 60). Receiving pharmacological treatment for nOH was the variable most consistently associated with significantly better caregiver health-related quality-of-life (p < 0.05). Conclusion: This study demonstrates the burden of nOH on informal caregivers and highlights the potential benefit of pharmacological treatment not only for patients but also indirectly, their caregivers.

Neurogenic orthostatic hypotension (nOH) causes blood pressure to fall when you stand up, meaning you can feel dizzy or lightheaded. This study looked at how providing day to day caregiving support to someone who has nOH as well as another neurological condition impacts the caregiver's health and wellbeing. These neurological conditions included Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies. A survey was conducted with informal caregivers (e.g., family members) of people with a neurological condition, with or without nOH. Caregivers completed questions about their own health-related quality-of-life, anxiety, depression and experience of caregiving. Caregivers of patients with nOH reported higher amounts of burden compared with those without nOH. Patients taking a treatment for nOH was most often associated with better caregiver health-related quality-of-life. This study shows the burden nOH can have on informal caregivers and highlights that treatment potentially benefits both patients and, indirectly, caregivers.

A US Time and Motion Pilot Study of Nebulized COPD Therapy in an Inpatient and a Long-Term Care Setting.

INTRODUCTION: There is a lack of quantitative data on healthcare professionals' (HCPs) time dedicated to nebulized chronic obstructive pulmonary disease (COPD) therapy in inpatient and long-term care (LTC) settings. Using time and motion methodology, we quantified HCP time and opportunity costs (time and materials) associated with nebulized COPD therapy in inpatient and LTC settings and estimated efficiencies of changing to once-daily therapy. METHODS: A case report form was built to reflect local nebulization workflow. Primary outcomes were mean active HCP time per predefined task and mean total active HCP time associated with short-acting beta agonist (SABA) and SABA/short-acting muscarinic antagonist (SAMA) combination nebulization processes. RESULTS: Twenty observations occurred within each setting. Inpatient observations included three SABA and 17 SABA/SAMA (from 18 different patients), and LTC observations included five SABA and 15 SABA/SAMA (from eight different patients). Mean total process time was 16.12 min in the inpatient setting (95% CI 14.48-17.76) and 21.0 min in the LTC setting (95% CI 18.8-23.2), with the actual nebulization comprising over 50% of process time for both. In LTC, CIs suggest a difference by cognitive impairment status: mean 24.1 min (95% CI 21.3-26.9) if cognitively impaired versus 19.0 min (95% CI 16.1-21.8) if not. In the inpatient setting, the estimated process time/admission was 7.8 h; a once-daily nebulized drug would require only 2.3 h. In LTC, the estimated process time was 32.1 h/month; a once-daily nebulized drug would require only 13.7 h/month. Estimated nebulization cost was $243/admission for current versus $72 for once-daily dosing in inpatient, and $1177/month versus $504 in LTC. CONCLUSIONS: The nebulization process for COPD patients in both inpatient and LTC settings consumes considerable HCP time. A switch from SABA or SABA/SAMA to a drug with a once-daily nebulization frequency could generate substantial time savings depending on the setting and site characteristics.

The measurement of physical functioning among patients with Tenosynovial Giant Cell Tumor (TGCT) using the Patient-Reported Outcomes Measurement Information System (PROMIS).

BACKGROUND: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size and location. The aim of this study was to identify relevant items, and demonstrate the content validity of custom measures of lower extremity PF from the Patient-Reported Outcomes Measurement Information System Physical Function Physical Function (PROMIS-PF) item bank among patients with TGCT. METHODS: Patients were recruited for qualitative research interviews to identify predominant TGCT symptoms and impacts. Patients completed a checklist to evaluate the relevance of each PROMIS-PF item. The publicly available PROMIS-PF item response theory (IRT) parameters were used to select items representing the range of the latent PF trait. RESULTS: Participants (n = 20) were 75% female, mean age 42.5 years. TGCTs were located in the knee (n = 15), hip (n = 3), and ankle (n = 2). Fifty-four PROMIS-PF items were identified as relevant by ≥20% of the participants. PF concepts discussed by participants during the qualitative interviews were also used to select relevant items. Selected items (n = 13) were used to create a physical function subscale specific to lower extremity tumors. CONCLUSIONS: We describe a novel method of combining qualitative research and IRT-based item information to select a relevant and content valid subset of PROMIS-PF items to assess heterogeneous impacts on PF in TGCT, a rare disease population.

Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.

PURPOSE: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT. The content validity of PROs relevant to patients with TGCT has not been formally investigated, and instruments to evaluate such outcomes do not exist for this condition. METHODS: PRO instruments of potential relevance were evaluated by using a literature review and by clinical and PRO experts. Patients with TGCT were recruited through clinical sites and the Internet for participation in qualitative research interviews to identify predominant symptoms and to test the relevance and content validity of several PRO measures. Select PRO measures were included in a Phase I clinical trial, and preliminary results of the PRO end points are reported descriptively. FINDINGS: Of the 22 subjects who participated in qualitative interviews, 73% were female, and their mean age was 42.5 years (range, 27-56 years). The TGCTs (19 diffuse and 3 localized) were located in the knee (n = 15), hip (n = 3), ankle (n = 2), elbow (n = 1), and forearm (n = 1). The most common symptoms cited were pain (82%), swelling (86%), stiffness (73%), reduced range of motion (64%), and joint instability (64%), which were consistent with clinical expert input and with the content of instruments chosen by PRO experts. The worst pain numeric rating scale, Patient Reported Outcomes Measurement Information System physical functioning items, and the Western Ontario and McMaster Universities Osteoarthritis Index, as well as a worst stiffness numeric rating scale developed for TGCT, were confirmed as meaningful measures of TGCT patient symptoms and were well understood in qualitative interviews. Results from the Phase I trial showed trends of improvement in both pain and stiffness over time. IMPLICATIONS: This study is the first to gather information directly from patients with TGCT regarding their symptom experiences. Pain, stiffness, and physical functioning are important treatment outcomes in patients with TGCT. We have identified content-valid PRO measures of these concepts, which are included in an ongoing Phase III TGCT clinical trial with pexidartinib (PLX3397) (NCT02371369).

Cost analysis of the Hemodialysis Reliable Outflow (HeRO) Graft compared to the tunneled dialysis catheter.

BACKGROUND: In end-stage renal disease patients with central venous obstruction, who have limited vascular access options, the Hemodialysis Reliable Outflow (HeRO) Graft is a new alternative with a lower incidence of complications and longer effective device life compared to tunneled dialysis catheters (TDCs). We undertook an economic analysis of introducing the HeRO Graft in the UK. METHODS: A 1-year cost-consequence decision analytic model was developed comparing management with the HeRO Graft to TDCs from the perspective of the National Health Service in England. The model comprises four 3-month cycles during which the vascular access option either remains functional for hemodialysis or fails, patients can experience access-related infection and device thrombosis, and they can also accrue associated costs. Clinical input data were sourced from published studies and unit cost data from National Health Service 2014-15 Reference Costs. RESULTS: In the base case, a 100-patient cohort managed with the HeRO Graft experienced 6 fewer failed devices, 53 fewer access-related infections, and 67 fewer device thromboses compared to patients managed with TDCs. Although the initial device and placement costs for the HeRO Graft are greater than those for TDCs, savings from the lower incidence of device complications and longer effective device patency reduces these costs. Overall net annual costs are £2600 for each HeRO Graft-managed patient compared to TDC-managed patients. If the National Health Service were to reimburse hemodialysis at a uniform rate regardless of the type of vascular access, net 1-year savings of £1200 per patient are estimated for individuals managed with the HeRO Graft. CONCLUSIONS: The base case results showed a marginal net positive cost associated with vascular access with the HeRO Graft compared with TDCs for the incremental clinical benefit of reductions in patency failures, device-related thrombosis, and access-related infection events in a patient population with limited options for dialysis vascular access.

Economic benefits of safety-engineered sharp devices in Belgium - a budget impact model.

BACKGROUND: Measures to protect healthcare workers where there is risk of injury or infection from medical sharps became mandatory in the European Union (EU) from May 2013. Our research objective was to estimate the net budget impact of introducing safety-engineered devices (SEDs) for prevention of needlestick injuries (NSIs) in a Belgian hospital. METHODS: A 5-year incidence-based budget impact model was developed from the hospital inpatient perspective, comparing costs and outcomes with SEDs and prior-used conventional (non-safety) devices. The model accounts for device acquisition costs and costs of NSI management in 4 areas of application where SEDs are currently used: blood collection, infusion, injection and diabetes insulin administration. Model input data were sourced from the Institut National d'Assurance Maladie-Invalidité, published studies, clinical guidelines and market research. Costs are discounted at 3%. RESULTS: For a 420-bed hospital, 100% substitution of conventional devices by SEDs is estimated to decrease the cumulative 5-year incidence of NSIs from 310 to 75, and those associated with exposure to blood-borne viral diseases from 60 to 15. Cost savings from managing fewer NSIs more than offset increased device acquisition costs, yielding estimated 5-year overall savings of €51,710. The direction of these results is robust to a range of sensitivity and model scenario analyses. The model was most sensitive to variation in the acquisition costs of SEDs, rates of NSI associated with conventional devices, and the acquisition costs of conventional devices. CONCLUSIONS: NSIs are a significant potential risk with the use of sharp devices. The incidence of NSIs and the costs associated with their management can be reduced through the adoption of safer work practices, including investment in SEDs. For a Belgian hospital, the budget impact model reports that the incremental acquisition costs of SEDs are offset by the savings from fewer NSIs. The availability of more robust data for NSI reduction rates, and broadening the scope of the model to include ancillary measures for hospital conversion to SED usage, outpatient and paramedic device use, and transmission of other blood-borne diseases, would strengthen the model.

Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer's disease in Germany using discrete event simulation.

BACKGROUND: Previous cost-effectiveness studies of cholinesterase inhibitors have modeled Alzheimer's disease (AD) progression and treatment effects through single or global severity measures, or progression to "Full Time Care". This analysis evaluates the cost-effectiveness of donepezil versus memantine or no treatment in Germany by considering correlated changes in cognition, behavior and function. METHODS: Rates of change were modeled using trial and registry-based patient level data. A discrete event simulation projected outcomes for three identical patient groups: donepezil 10 mg, memantine 20 mg and no therapy. Patient mix, mortality and costs were developed using Germany-specific sources. RESULTS: Treatment of patients with mild to moderately severe AD with donepezil compared to no treatment was associated with 0.13 QALYs gained per patient, and 0.01 QALYs gained per caregiver and resulted in average savings of €7,007 and €9,893 per patient from the healthcare system and societal perspectives, respectively. In patients with moderate to moderately-severe AD, donepezil compared to memantine resulted in QALY gains averaging 0.01 per patient, and savings averaging €1,960 and €2,825 from the healthcare system and societal perspective, respectively.In probabilistic sensitivity analyses, donepezil dominated no treatment in most replications and memantine in over 70% of the replications. Donepezil leads to savings in 95% of replications versus memantine. CONCLUSIONS: Donepezil is highly cost-effective in patients with AD in Germany, leading to improvements in health outcomes and substantial savings compared to no treatment. This holds across a variety of sensitivity analyses.

An economic evaluation of early assessment for Alzheimer's disease in the United Kingdom.

BACKGROUND: Diagnosing and treating patients with Alzheimer's disease (AD) at an early stage should improve the quality of life of the patient and caregiver. In the United Kingdom, cost-effectiveness of early assessment of individuals presenting with subjective memory complaints and treating those with AD with donepezil was evaluated. METHODS: A discrete event simulation of AD progression and the effect of treatment interventions was developed. Patient-level data from donepezil trials and a 7-year follow-up registry were used to model correlated longitudinal rates of change in cognition, behavior, and function. Other epidemiological and health services data, including estimates of undiagnosed dementia and delays in diagnosis, were based on published sources. Simulated individuals were followed up for 10 years. RESULTS: In the base-case estimates, 17 patients need to be assessed to diagnose one patient with AD, resulting in an average assessment cost of £4100 ($6000; $1 US = £0.68 UK) per patient diagnosed (2007 cost year). In comparison with a scenario without early assessment or pharmacologic treatment, early assessment reduces health care costs by £3600 ($5300) per patient and societal costs by £7750 ($11,400). Savings are also substantial compared with treatment without early assessment, averaging £2100 ($3100) in health care costs, and £5700 ($8400) in societal costs. Results are most sensitive to estimates of patient care costs and the probability of patients reporting subjective memory complaints. In probabilistic sensitivity analysis, early assessment leads to savings or is highly cost-effective in the majority of cases. CONCLUSIONS: Although early assessment has significant up-front costs, identifying AD patients at an early stage results in cost savings and health benefits compared with no treatment or treatment in the absence of early assessment.

Cost effectiveness of donepezil in the treatment of mild to moderate Alzheimer's disease: a UK evaluation using discrete-event simulation.

Recommendations in the UK suggest restricting treatment of Alzheimer's disease with cholinesterase inhibitors, on cost-effectiveness grounds, to patients with moderate cognitive decline. As the economic analyses that informed these recommendations have been the subject of debate, we sought to address the potential limitations of existing models and produce estimates of donepezil treatment cost effectiveness in the UK using the most recent available data and simulation techniques. A discrete-event simulation was developed that predicts progression of Alzheimer's disease through correlated changes in cognition, behavioural disturbance and function. Patient-level data from seven randomized, placebo-controlled donepezil trials and a 7-year follow-up registry provided the basis for modeling longitudinal outcomes. Individuals in the simulation were assigned unique demographic and clinical characteristics and then followed for 10 years, with severity of disease tracked on continuous scales. Patient mix and costs were developed from UK-specific literature. Analyses were run for severity subgroups to evaluate outcomes for sub-populations with disease of mild versus moderate severity from both a healthcare payer and societal perspective. All costs are reported in pound, year 2007 values, and all outcomes are discounted at 3.5% per annum. Over 10 years, treatment of all patients with mild to moderate disease reduces overall direct medical costs by an average of over pound2300 per patient. When unpaid caregiver time is also taken into consideration, savings increase to over pound4700 per patient. Compared with untreated patients, patients receiving donepezil experience a discounted gain in QALYs averaging 0.11, with their caregivers gaining, on average, 0.01 QALYs. For the subset of patients starting treatment with more severe disease, savings are more modest, averaging about pound1600 and pound3750 from healthcare and societal perspectives, respectively. In probabilistic sensitivity analyses, donepezil dominated no treatment between 57% and 62% of replications when only medical costs were considered, and between 74% and 79% of replications when indirect costs were included, with results more favourable for treatment initiation in the mild versus moderate severity stages of the disease. Although the simulation results are not definitive, they suggest that donepezil leads to health benefits and cost savings when used to treat mild to moderately severe Alzheimer's disease in the UK. They also indicate that both benefits and savings may be greatest when treatment is started while patients are still in the mild stages of Alzheimer's disease.

The cost effectiveness of rufinamide in the treatment of Lennox-Gastaut syndrome in the UK.

Lennox-Gastaut syndrome (LGS) is a catastrophic childhood form of epilepsy. The syndrome is characterized by mental impairment, frequent seizures of multiple types that are particularly resistant to treatment, and high rates of seizure-related injury. With the introduction of newer, but more costly, antiepileptic drugs (AEDs), it is important that decision makers are able to assess their value in the management of this rare and difficult-to-treat condition. To evaluate the cost effectiveness, from the UK NHS perspective, of rufinamide in patients with LGS. An individual patient-simulation model was developed to estimate the total treatment-related costs and clinical benefits of rufinamide compared with topiramate and lamotrigine over a 3-year time horizon. The model examines the treatment scenarios of adding rufinamide, lamotrigine or topiramate to older AEDs (standard therapy), or standard therapy alone within a primary-care or community setting. Three placebo-controlled clinical trials of adjunctive AED treatment for children with LGS were analysed. There are no head-to-head comparator studies. Between 98 and 139 patients were randomized in each study and the mean age in each study was 10, 11 and 14 years. A mixed-treatment comparison using a random-effects model was carried out on the number of patients in each response category, using the placebo arms of the respective trials. The primary outcome measure was the percentage of successfully treated patients, defined as >50% reduction in the frequency of total seizures and drop attacks. The hypothesis being tested was formulated after data collection. Costs ( pound, year 2006/07 values) of patient monitoring, switching treatments, hospitalization due to seizure, treatment of adverse effects, and personal and social services were included in the analysis. Results of 10,000 Monte Carlo simulations were bootstrapped to conduct probabilistic sensitivity analysis. Over 3 years, adjunctive rufinamide resulted in higher total costs than topiramate and lamotrigine; however, with more patients being treated successfully, this leads to acceptable incremental cost-effectiveness ratios. If society is prepared to pay at least 250 pounds for a 1% increase in the number of successfully treated LGS patients, in terms of a 50% reduction in the frequency of drop attacks, the probability of the treatment with rufinamide being cost effective is >80%. This cost-effectiveness analysis suggests that rufinamide results in more LGS patients being treated successfully at a reasonable cost from a UK NHS perspective.