Qualitative Study of the Patient Experience with Venglustat for Gaucher Disease Type 3 in a Phase 2 Open-Label, Multicenter, Multinational Study (LEAP).

INTRODUCTION: Gaucher disease type 3 (GD3) is a genetic, progressive lysosomal storage disorder characterized by visceral manifestations and chronic neurologic symptoms (e.g., horizontal ophthalmoplegia/supranuclear gaze palsy, ataxia, dystonia). The investigational agent venglustat is being studied in combination with imiglucerase as potential treatment for systemic and neuronopathic manifestations of GD3 in a single-arm, open-label, phase 2 trial (LEAP; N = 11). To understand perceived changes in GD3 symptoms from the perspectives of patients, caregivers, and clinicians, we conducted a qualitative case study of selected LEAP participants. METHODS: Four patients in LEAP (age range, 20-28 years), four of their caregivers, and three clinicians involved in LEAP were interviewed individually by moderators using semi-structured guides. Clinicians' perceptions were based on observation of interviewed patients and those in LEAP who were not interviewed, as well as information provided by other staff involved in LEAP, patients, and caregivers. RESULTS: Reported changes in GD3 symptoms varied among patients and among reporters. Only eye movement was spontaneously mentioned as improved by at least one patient, caregiver, and clinical expert. Symptom improvement also varied in terms of time to improvement. Within the first weeks, improvements were seen in understanding new information or complex instructions, remembering the weekday, eye movement, tremor, and seizures. Changes in alertness, engagement and responsiveness, memory, and concentration appeared after months or a year. Most caregivers and all clinical experts reported greater patient independence (e.g., increased ability to perform activities of daily living or travel independently during the trial) as a perceived treatment effect on a GD3 impact. For one patient who perceived benefits from venglustat therapy, pharmacokinetic analyses during LEAP found low to undetectable venglustat levels in their plasma and cerebrospinal fluid. CONCLUSION: Outcomes from this study provide insights into GD3 symptoms and the early signaling of changes reported during venglustat therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02843035.

A retrospective study of morbidity and mortality of chronic acid sphingomyelinase deficiency in Germany.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, potentially fatal lysosomal storage disease that exhibits a broad spectrum of clinical phenotypes. There is a need to expand the knowledge of disease mortality and morbidity in Germany because of limited information on survival analysis in patients with chronic ASMD (type B or type A/B). METHODS: This observational, multicentre, retrospective cohort study was conducted using medical records of patients with the first symptom onset/diagnosis of ASMD type B or type A/B between 1st January 1990 and 31st July 2021 from four German medical centres. Eligible medical records were abstracted to collect data on demographic characteristics, medical history, hospitalisation, mortality, and causes of death from disease onset to the last follow-up/death. Survival outcomes were estimated using the Kaplan-Meier analysis. Standardised mortality ratio (SMR) was also explored. RESULTS: This study included 33 chart records of patients with ASMD type B (n = 24) and type A/B (n = 9), with a median (interquartile range [IQR]) age of 8.0 [3.0-20.0] years and 1.0 [1.0-2.0] years, respectively, at diagnosis. The commonly reported manifestations were related to spleen (100.0%), liver (93.9%), and respiratory (77.4%) abnormalities. Nine deaths were reported at a median [IQR] age of 17.0 [5.0-25.0] years, with 66.7% of overall patients deceased at less than 18 years of age; the median [IQR] age at death for patients with ASMD type B (n = 4) and type A/B (n = 5) was 31.0 [11.0-55.0] and 9.0 [4.0-18.0] years, respectively. All deaths were ASMD-related and primarily caused by liver or respiratory failures or severe progressive neurodegeneration (two patients with ASMD type A/B). The median (95% confidence interval [CI]) overall survival age since birth was 45.4 (17.5-65.0) years. Additionally, an SMR [95% CI] analysis (21.6 [9.8-38.0]) showed that age-specific deaths in the ASMD population were 21.6 times more frequent than that in the general German population. CONCLUSIONS: This study highlights considerable morbidity and mortality associated with ASMD type B and type A/B in Germany. It further emphasises the importance of effective therapy for chronic ASMD to reduce disease complications.

Diagnostic odyssey for patients with acid sphingomyelinase deficiency (ASMD): Exploring the potential indicators of diagnosis using quantitative and qualitative data.

Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and potentially fatal lysosomal storage disease. This two-part international study aimed to understand physician, patient, and caregivers' experiences during the ASMD diagnostic journey. Qualitative interviews were conducted with patients with ASMD type B or A/B, caregivers (for patients <18 years), and physicians (January 2018-May 2019). A quantitative patient chart review was then performed by physicians (1-3 charts per physician) (April to May 2020). Overall, 12 physicians and 27 patients (self-reported, n = 11; caregiver-reported, n = 16) completed qualitative interviews. Symptoms first presented at approximately 2 years, with physician visits 2 months-1 year later. On average, diagnosis took 3 years and average age at diagnosis was 5 years. During childhood, all patients reported abdominal enlargement and 67% had respiratory issues. Adult patients frequently reported fatigue (64%) and heart problems (36%). In the quantitative study, 86 physicians reviewed 193 ASMD patient charts. At initial presentation, most patients reported abdominal enlargement (pediatric, 55%; adolescents/adults, 39%). Time to diagnosis ranged 0-10 years for patients with ASMD type A/B or type B, and most patients (85%) received an incorrect initial diagnosis. Diagnosis of ASMD can be challenging, and is often delayed due to disease heterogeneity and misdiagnoses.

Assessment of health state utilities associated with adult and pediatric acid sphingomyelinase deficiency (ASMD).

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) type B is a rare genetic disorder leading to enlargement of the spleen and liver, pulmonary dysfunction, and other symptoms. Cost-utility analyses are often conducted to quantify the value of new treatments, and these analyses require health state utilities. Therefore, the purpose of this study was to estimate utilities associated with varying levels of severity of adult and pediatric ASMD type B. METHODS: Seven adult and seven child health state vignettes describing ASMD were developed based on published literature, clinical trial results, and interviews with clinicians, patients with ASMD, and parents of children with ASMD. The health states were valued in time trade-off interviews with adult general population respondents in the UK. RESULTS: Interviews were completed with 202 participants (50.0% female; mean age = 41.3 years). The health state representing ASMD without impairment had the highest mean utility for both the adult and child health states (0.92/0.94), and severe ASMD had the lowest mean utility (0.33/0.45). Every child health state had a significantly greater utility than the corresponding adult health state. Differences between adult/child paired states ranged from 0.02 to 0.13. Subgroup analyses explored the impact of parenting status on valuation of child health states. DISCUSSION: Greater severity of ASMD was associated with lower mean utility. Results have implications for valuation of pediatric health states. The resulting utilities may be useful in cost-utility modeling estimating the value of treatment for ASMD.

Survival of patients with chronic acid sphingomyelinase deficiency (ASMD) in the United States: A retrospective chart review study.

Background: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients. Methods: This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan-Meier survival analyses from birth until death. Results: The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD "non-type A" (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications. Conclusion: Patients with chronic ASMD in the United States have poor survival and significant burden of illness.

Impact of Potential Symptoms and Risks Associated with Acid Sphingomyelinase Deficiency on Patients and Caregivers: A Best-Worst Scaling Study.

Purpose: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and potentially fatal disease affecting major organs; its symptoms present heterogeneously. Data on the most bothersome symptoms for patients with ASMD types B or A/B and their caregivers or parents are limited. We conducted a survey to quantify the relative impact of potential ASMD symptoms and risks for patients and parents/caregivers. Patients and Methods: Twenty respondents, recruited via National Niemann-Pick Disease Foundation (United States) and Niemann-Pick United Kingdom, took a preference survey: 11 patients who had a self-reported diagnosis of ASMD types B or A/B and 9 parents who had a child with ASMD types B or A/B. Using object-case best-worst scaling, we explored the most and least bothersome among a set of 15 ASMD symptoms/risks selected based on clinical input and qualitative research with patients and caregivers. In 15 experimentally designed questions containing five items each, respondents ranked the symptoms/risks, irrespective of their experiences with them. Data were analyzed using a conditional multinomial logit model. Results: Patients reported constant abdominal pain, severe pain in bones and joints, and severe fatigue to be the most bothersome potential symptoms or risks, followed by a chance of bleeding in the spleen. The next most bothersome potential symptom was constant shortness of breath. Easy bruising and noticeable abdominal enlargement were among the least bothersome symptoms. The most bothersome symptom for parents was bleeding in the spleen. Conclusion: Patients and parents had similar perceptions of the most bothersome potential symptoms/risks. Despite the small sample size typical of rare disease studies, understanding patient preferences is important for such diseases and can inform shared decision-making.

Healthcare Service Use Patterns Among Patients with Acid Sphingomyelinase Deficiency Type B: A Retrospective US Claims Analysis.

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease. Patients with ASMD type B experience multiple morbidities, potentially leading to early mortality. Before the 2022 approval of olipudase alfa for non-neuronopathic ASMD manifestations, only symptom management was offered. Data on healthcare services used by patients with ASMD type B are limited. This analysis used medical claims data to evaluate real-world healthcare service use by patients with ASMD type B in the United States of America (USA). METHODS: The IQVIA Open Claims patient-level database (2010-2019) was cross-examined. Two patient cohorts were identified: the primary analysis cohort, which included patients with at least two claims associated with ASMD type B (ICD-10 code E75.241) and more total claims with ASMD type B than any other ASMD types, and the sensitivity analysis cohort, which included patients with a high probability of having ASMD type B identified using a validated machine-learning algorithm. Claims for ASMD-associated healthcare services were recorded, including outpatient visits, emergency department (ED) visits, and inpatient hospitalizations. RESULTS: The primary analysis cohort included 47 patients; a further 59 patients made up the sensitivity analysis cohort. Patient characteristics and healthcare service use were similar in both cohorts and were consistent with established characteristics of ASMD type B. Overall, 70% of the primary analysis cohort from this study were aged < 18 years, and the liver, spleen, and lungs were the most frequently affected organs. Cognitive, developmental, and/or emotional problems and respiratory/lung disorders caused most outpatient visits; respiratory/lung disorders accounted for most ED visits and hospitalizations. CONCLUSION: This retrospective analysis of medical claims data identified patients with ASMD type B who had characteristics typical of this condition. A machine-learning algorithm detected further cases with a high probability of having ASMD type B. High use of ASMD-related healthcare services and medications was observed in both cohorts.

Acid sphingomyelinase deficiency (ASMD) type B, historically known as Niemann­Pick type B, is a rare illness. People with acid sphingomyelinase deficiency type B experience damage to many organs of the body (such as the liver and lungs), which may lead to early death. Until recently, no treatment has been available, and people were only treated for their symptoms. Now, a treatment called olipudase alfa has been approved in Europe, Japan, and the USA. People with ASMD type B may need lots of tests, surgeries, medications, and physician visits; however, we do not know how often these healthcare services are used. This study used medical claims to find out more about the healthcare services used by people with ASMD type B. To find as many people with ASMD type B as possible, we identified two groups of people. The first group included people with diagnosis codes for ASMD type B, the other group was identified as having a high likelihood of ASMD type B. The people in each group were similar in age and the illnesses/symptoms they had. The liver, spleen, and lungs were the most frequently damaged organs, and most physician visits were for mental, developmental, and/or emotional problems, and breathing or lung diseases. Breathing or lung disease and bleeding problems caused the most emergency department visits and hospitalizations. Overall, the use of healthcare services was high in people with ASMD type B. This study shows the need for specific treatments for people with ASMD.

Impact and burden of acid sphingomyelinase deficiency from a patient and caregiver perspective.

Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease (NPD) types A, A/B, and B, is a rare, progressive, potentially fatal lysosomal storage disease with a spectrum of phenotypes. Little is known about how ASMD symptoms affect the lives of patients and their caregivers. In a cross-sectional qualitative study conducted in the US and UK, and in collaboration with the National Niemann-Pick Disease Foundation (US) and Niemann-Pick UK, we investigated the symptom experience of patients with ASMD types B and A/B and explored how the disease impacts their and their caregivers' lives. The study included 17 adult patients (mean age 38.7 years, 12 female), three caregivers of adults with ASMD, 12 pediatric/adolescent patients with ASMD (mean age 10.5 years, six female), and 12 caregivers of pediatric/adolescent patients with ASMD. The most commonly reported disease manifestations were respiratory (n = 26, 89.7%), abdominal (n = 25, 86.2%), and musculoskeletal symptoms (n = 23, 79.3%); excessive bleeding or bruising (n = 20, 69%); fatigue (n = 20, 69%); gastrointestinal symptoms (n = 18, 62.1%); and headache (n = 15, 51.7%). ASMD was reported to negatively impact patients' physical function (n = 23, 79.3%), self-esteem (n = 18, 62.1%), emotions (n = 16, 55.2%), social function and relationships (n = 16, 55.2%), and personal care (n = 9, 31%). Providing care for individuals with ASMD negatively affected caregivers' emotional well-being (n = 12, 80%), social function (n = 4, 26.7%), relationships (n = 6, 40%), and financial security (n = 7, 46.7%). The physical toll of providing care, the need for lifestyle changes, and the responsibility for making medical decisions added to the burden for caregivers. Alternatively, some caregivers noted that caring for a loved one enhanced their spirituality, providing them with a different outlook on life and a deeper personal resolve. This study showed that ASMD is a substantial burden for patients and caregivers, with long-term physical, emotional, social, and financial impacts. The study confirmed commonly known manifestations of ASMD, especially respiratory problems, but also identified less recognized ones, such as dermatological complications. The data collected and insight gained from this study should enhance clinical care, help evaluate new treatments, and inform health care decision making for patients with ASMD.

Patient and caregiver perspectives on burden of disease manifestations in late-onset Tay-Sachs and Sandhoff diseases.

BACKGROUND: The GM2 gangliosidoses (GM2), Tay-Sachs and Sandhoff diseases, are rare, autosomal recessive genetic disorders caused by mutations in the lysosomal enzyme ß-hexosaminidase A (HEXA) or ß-hexosaminidase B (HEXB) genes, respectively. A minority of patients have a late-onset form of disease that presents from late-childhood to adulthood and has a slowly progressive course with prolonged survival. Little research has been published documenting patient experiences with late-onset Tay-Sachs and Sandhoff diseases and how the disease impacts their daily lives and functioning. This study explored the most frequent symptoms and functional impacts experienced by patients with late-onset GM2 gangliosidosis through interviews with patients and caregivers. METHODS: A qualitative research study design was employed, using three focus groups and 18 one-on-one interviews with patients who were recruited at the National Tay-Sachs and Allied Diseases Annual Family Conference. Transcripts were generated from the discussions, and patient quotes were analyzed using a content analysis approach. Concepts were aggregated into symptom and functional impacts, and the frequency of mention in the focus groups and individual interviews was calculated. KEY FINDINGS: Many of the frequently described symptoms [muscle weakness (n = 19, 95%), "clumsy" gait (n = 12, 60%), fatigue (n = 10, 50%)] and impacts [difficulty walking (n = 19, 95%), falling (n = 17, 85%), and climbing stairs (n = 16, 80%)] disclosed by patients and caregivers were similar to those previously reported in the literature. However, less frequently described symptoms such as gastrointestinal issues (n = 4, 20%) and coughing fits (n = 5, 25%) have been expanded upon. This study evaluated the immediate impact of these symptoms on the patients' lives to highlight the burden of these symptoms and the functional limitations on daily living activities, independence, and emotional well-being. The findings were used to develop a conceptual disease model that could serve as a foundation for patient-centered outcomes in clinical trials and provide insights to the medical community that may benefit patient care. CONCLUSIONS: This study contributes to the current understanding of symptoms associated with late-onset GM2 gangliosidosis, and further identifies the many consequences and impacts of the disease. These symptoms and impacts could be measured in clinical trials to examine the effects of novel treatments from the patient perspective.

Personal and societal costs of multiple sclerosis in the UK: A population-based MS Registry study.

OBJECTIVES: To investigate through survey and data linkage, healthcare resource use and costs (except drugs), including who bears the cost, of multiple sclerosis in the United Kingdom by disease severity and type. METHODS: The United Kingdom Multiple Sclerosis Register deployed a cost of illness survey, completed by people with multiple sclerosis and linked this with data within the United Kingdom Multiple Sclerosis Register and from their hospital records. Resource consumption was categorised as being medical or non-medical and costed by National Health Service and social services estimates for 2018. RESULTS: We calculated £509,003 in non-medical costs over a year and £435,488 in medical costs generated over 3 months. People with multiple sclerosis reported self-funding 75% of non-medical costs with non-medical interventions having long-term potential benefits. Costs increased with disability as measured by patient-reported Expanded Disability Status Score and Multiple Sclerosis Impact Scale, with Multiple Sclerosis Impact Scale physical being a more powerful predictor of costs than the patient-reported Expanded Disability Status Score. Two distinct groups were identified: medical and non-medical interventions (n = 138); and medical interventions only (n = 399). The medical and non-medical group reported increased disease severity and reduced employment but incurred 80% more medical costs per person than the medical-only group. CONCLUSIONS: The importance of disability in driving costs is illustrated with balance between medical and non-medical costs consistent with the United Kingdom health environment. People with multiple sclerosis and their families fund a considerable proportion of non-medical costs but non-medical interventions with longer term impact could affect future medical costs.

Challenges Associated with Estimating Utility in Wet Age-Related Macular Degeneration: A Novel Regression Analysis to Capture the Bilateral Nature of the Disease.

INTRODUCTION: The estimation of utility values for the economic evaluation of therapies for wet age-related macular degeneration (AMD) is a particular challenge. Previous economic models in wet AMD have been criticized for failing to capture the bilateral nature of wet AMD by modelling visual acuity (VA) and utility values associated with the better-seeing eye only. METHODS: Here we present a de novo regression analysis using generalized estimating equations (GEE) applied to a previous dataset of time trade-off (TTO)-derived utility values from a sample of the UK population that wore contact lenses to simulate visual deterioration in wet AMD. This analysis allows utility values to be estimated as a function of VA in both the better-seeing eye (BSE) and worse-seeing eye (WSE). RESULTS: VAs in both the BSE and WSE were found to be statistically significant (p < 0.05) when regressed separately. When included without an interaction term, only the coefficient for VA in the BSE was significant (p = 0.04), but when an interaction term between VA in the BSE and WSE was included, only the constant term (mean TTO utility value) was significant, potentially a result of the collinearity between the VA of the two eyes. The lack of both formal model fit statistics from the GEE approach and theoretical knowledge to support the superiority of one model over another make it difficult to select the best model. CONCLUSION: Limitations of this analysis arise from the potential influence of collinearity between the VA of both eyes, and the use of contact lenses to reflect VA states to obtain the original dataset. Whilst further research is required to elicit more accurate utility values for wet AMD, this novel regression analysis provides a possible source of utility values to allow future economic models to capture the quality of life impact of changes in VA in both eyes. FUNDING: Novartis Pharmaceuticals UK Limited.

Interactive web-based pulmonary rehabilitation programme: a randomised controlled feasibility trial.

OBJECTIVES: The aim of this study was to determine if an interactive web-based pulmonary rehabilitation (PR) programme is a feasible alternative to conventional PR. DESIGN: Randomised controlled feasibility trial. SETTING: Participants with a diagnosis of chronic obstructive pulmonary disease were recruited from PR assessments, primary care and community rehabilitation programmes. Patients randomised to conventional rehabilitation started the programme according to the standard care at their referred site on the next available date. PARTICIPANTS: 103 patients were recruited to the study and randomised: 52 to conventional rehabilitation (mean (±SD) age 66 (±8) years, Medical Research Council (MRC) 3 (IQR2-4)); 51 to the web arm (mean (±SD) age 66 (±10) years, MRC 3 (IQR2-4)). Participants had to be willing to participate in either arm of the trial, have internet access and be web literate. INTERVENTIONS: Patients randomised to the web-based programme worked through the website, exercising and recording their progress as well as reading educational material. Conventional PR consisted of twice weekly, 2 hourly sessions (an hour for exercise training and an hour for education). OUTCOME MEASURES: Recruitment rates, eligibility, patient preference and dropout and completion rates for both programmes were collected. Standard outcomes for a PR assessment including measures of exercise capacity and quality of life questionnaires were also evaluated. RESULTS: A statistically significant improvement (p≤0.01) was observed within each group in the endurance shuttle walk test (WEB: mean change 189±211.1; PR classes: mean change 184.5±247.4 s) and Chronic Respiratory disease Questionnaire-Dyspnoea (CRQ-D; WEB: mean change 0.7±1.2; PR classes: mean change 0.8±1.0). However, there were no significant differences between the groups in any outcome. Dropout rates were higher in the web-based programme (57% vs 23%). CONCLUSIONS: An interactive web-based PR programme is feasible and acceptable when compared with conventional PR. Future trials maybe around choice-based PR programmes for select patients enabling stratification of patient care. TRIAL REGISTRATION NUMBER: ISRCTN03142263; Results.

The Community In-reach Rehabilitation and Care Transition (CIRACT) clinical and cost-effectiveness randomisation controlled trial in older people admitted to hospital as an acute medical emergency.

Objective: To compare the clinical and cost-effectiveness of a Community In-reach Rehabilitation and Care Transition (CIRACT) service with the traditional hospital-based rehabilitation (THB-Rehab) service. Design: Pragmatic randomised controlled trial with an integral health economic study. Settings: Large UK teaching hospital, with community follow-up. Subjects: Frail older people aged 70 years and older admitted to hospital as an acute medical emergency. Measurements: Primary outcome: hospital length of stay; secondary outcomes: readmission, day 91-super spell bed days, functional ability, co-morbidity and health-related quality of life; cost-effectiveness analysis. Results: A total of 250 participants were randomised. There was no significant difference in length of stay between the CIRACT and THB-Rehab service (median 8 versus 9 days; geometric mean 7.8 versus 8.7 days, mean ratio 0.90, 95% confidence interval (CI) 0.74­1.10). Of the participants who were discharged from hospital, 17% and 13% were readmitted within 28 days from the CIRACT and THB-Rehab services, respectively (risk difference 3.8%, 95% CI −5.8% to 13.4%). There were no other significant differences in any of the other secondary outcomes between the two groups. The mean costs (including NHS and personal social service) of the CIRACT and THB-Rehab service were £3,744 and £3,603, respectively (mean cost difference £144; 95% CI −1,645 to 1,934). Conclusion: The CIRACT service does not reduce major hospital length of stay nor reduce short-term readmission rates, compared to the standard THB-Rehab service; however, a modest (<2.3 days) effect cannot be excluded. Further studies are necessary powered with larger sample sizes and cluster randomisation. Trial registration: ISRCTN 94393315, 25th April 2013

Simulation Modelling in Ophthalmology: Application to Cost Effectiveness of Ranibizumab and Aflibercept for the Treatment of Wet Age-Related Macular Degeneration in the United Kingdom.

BACKGROUND: Previously developed models in ophthalmology have generally used a Markovian structure. There are a number of limitations with this approach, most notably the ability to base patient outcomes on best-corrected visual acuity (BCVA) in both eyes, which may be overcome using a different modelling structure. Simulation modelling allows for this to be modelled more precisely, and therefore may provide more accurate and relevant estimates of the cost effectiveness of ophthalmology interventions. OBJECTIVE: This study aimed to explore the appropriateness of simulation modelling in ophthalmology, using the disease area of wet age-related macular degeneration (wAMD) as an example. METHODS: A de novo economic model was built using a patient-level simulation, which compared ranibizumab with aflibercept in wAMD. Disease progression was measured using BCVA. Health-related quality of life (HRQoL) was estimated using a regression analysis linking BCVA in each eye to utility. The analysis was from the perspective of the National Health Service in the UK. Five different regression models were explored and were based on BCVA in either one eye or both eyes. RESULTS: The model outputs provide some evidence to support the hypothesis that the analyses using the two-eye models for estimating HRQoL generate a more accurate estimation of incremental quality-adjusted life-years (QALYs) associated with the positive treatment effect for ranibizumab versus aflibercept. Second-order analysis broadly supported these findings, and showed that the variation in incremental costs was slightly lower than in incremental QALYs. The second-order analysis estimated similar incremental costs and a greater overall variation in incremental QALYs than the first-order analysis, suggesting important non-linearities within the model. CONCLUSIONS: This analysis suggests that patient-level simulation models may be well suited to representing the real-world patient pathway in wAMD, particularly when aspects of disease progression cannot be adequately captured using a Markov structure. The benefits of a simulation approach can be demonstrated in the modelling of HRQoL as a function of BCVA in both eyes.

Has Metal-On-Metal Resurfacing Been a Cost-Effective Intervention for Health Care Providers?-A Registry Based Study.

BACKGROUND: Total hip replacement for end stage arthritis of the hip is currently the most common elective surgical procedure. In 2007 about 7.5% of UK implants were metal-on-metal joint resurfacing (MoM RS) procedures. Due to poor revision performance and concerns about metal debris, the use of RS had declined by 2012 to about a 1% share of UK hip procedures. This study estimated the lifetime cost-effectiveness of metal-on-metal resurfacing (RS) procedures versus commonly employed total hip replacement (THR) methods. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cost-utility analysis using a well-established multi-state semi-Markov model from an NHS and personal and social services perspective. We used individual patient data (IPD) from the National Joint Registry (NJR) for England and Wales on RS and THR surgery for osteoarthritis recorded from April 2003 to December 2012. We used flexible parametric modelling of NJR RS data to guide identification of patient subgroups and RS devices which delivered revision rates within the NICE 5% revision rate benchmark at 10 years. RS procedures overall have an estimated revision rate of 13% at 10 years, compared to <4% for most THR devices. New NICE guidance now recommends a revision rate benchmark of <5% at 10 years. 60% of RS implants in men and 2% in women were predicted to be within the revision benchmark. RS devices satisfying the 5% benchmark were unlikely to be cost-effective compared to THR at a standard UK willingness to pay of £20,000 per quality-adjusted life-year. However, the probability of cost effectiveness was sensitive to small changes in the costs of devices or in quality of life or revision rate estimates. CONCLUSION/SIGNIFICANCE: Our results imply that in most cases RS has not been a cost-effective resource and should probably not be adopted by decision makers concerned with the cost effectiveness of hip replacement, or by patients concerned about the likelihood of revision, regardless of patient age or gender.

The Cost-Effectiveness of Ranibizumab Treat and Extend Regimen Versus Aflibercept in the UK.

INTRODUCTION: Wet age-related macular degeneration (AMD) is a chronic eye condition that causes severe deterioration of vision and even blindness. Current wet AMD treatment in the UK involves the vascular endothelial growth factor inhibitors ranibizumab and aflibercept. Patients with wet AMD require frequent and long-term monitoring for treatment to be effective, contributing to a substantial resource burden at wet AMD centers. The European license for ranibizumab was recently updated with an individualized 'treat and extend' (T&E) regimen, comprising a structured monitoring and treatment protocol. This study evaluated the cost-effectiveness of ranibizumab T&E versus aflibercept within a UK setting. METHODS: An individual patient-level simulation model was developed utilizing treatment effects from a network meta-analysis of randomized controlled trials. The model was conducted from a UK National Health Service (NHS) perspective over a lifetime horizon and the base case utilized probabilistic sensitivity analysis to assess uncertainty in the model. Additional scenario analyses were conducted to assess the impact of changes to the model inputs. RESULTS: Ranibizumab T&E was found to be more effective and less costly than aflibercept, providing, on average, an additional 1.058 quality-adjusted life years (QALYs) and a cost-saving of £19,604 over a lifetime horizon. At list price, ranibizumab T&E was found to be cost-effective versus aflibercept in 100% of simulations at a willingness-to-pay threshold of £20,000 per QALY. The robustness of the results was tested in several scenario analyses; ranibizumab T&E was found to be more effective, and less costly, than aflibercept in the vast majority of cases. CONCLUSION: This evaluation suggests that treating patients with ranibizumab according to the T&E regimen could be a better use of NHS resources than aflibercept, and could, therefore, be considered as a first-line regimen for patients with wet AMD in the UK. FUNDING: Novartis Pharmaceuticals UK Limited.

A randomised controlled trial of six weeks of home enteral nutrition versus standard care after oesophagectomy or total gastrectomy for cancer: report on a pilot and feasibility study.

BACKGROUND: Poor nutrition in the first months after oesophago-gastric resection is a contributing factor to the reduced quality of life seen in these patients. The aim of this pilot and feasibility study was to ascertain the feasibility of conducting a multi-centre randomised controlled trial to evaluate routine home enteral nutrition in these patients. METHODS: Patients undergoing oesophagectomy or total gastrectomy were randomised to either six weeks of home feeding through a jejunostomy (intervention), or treatment as usual (control). Intervention comprised overnight feeding, providing 50 % of energy and protein requirements, in addition to usual oral intake. Primary outcome measures were recruitment and retention rates at six weeks and six months. Nutritional intake, nutritional parameters, quality of life and healthcare costs were also collected. Interviews were conducted with a sample of participants, to ascertain patient and carer experiences. RESULTS: Fifty-four of 112 (48 %) eligible patients participated in the study over the 20 months. Study retention at six weeks was 41/54 patients (76 %) and at six months was 36/54 (67 %). At six weeks, participants in the control group had lost on average 3.9 kg more than participants in the intervention group (95 % confidence interval [CI] 1.6 to 6.2). These differences remained evident at three months (mean difference 2.5 kg, 95 % CI -0.5 to 5.6) and at six months (mean difference 2.5 kg, 95 % CI -1.2 to 6.1). The mean values observed in the intervention group for mid arm circumference, mid arm muscle circumference, triceps skin fold thickness and right hand grip strength were greater than for the control group at all post hospital discharge time points. The economic evaluation suggested that it was feasible to collect resource use and EQ-5D data for a full cost-effectiveness analysis. Thematic analysis of 15 interviews identified three main themes related to the intervention and the trial: 1) a positive experience, 2) the reasons for taking part, and 3) uncertainty of the study process. CONCLUSIONS: This study demonstrated that home enteral feeding by jejunostomy was feasible, safe and acceptable to patients and their carers. Whether home enteral feeding as 'usual practice' is a cost-effective therapy would require confirmation in an appropriately powered, multi-centre study. TRIAL REGISTRATION: UK Clinical Research Network ID 12447 (main trial, first registered 30 May 2012); UK Clinical Research Network ID 13361 (qualitative substudy, first registered 30 May 2012); ClinicalTrials.gov NCT01870817 (first registered 28 May 2013).

Setting benchmark revision rates for total hip replacement: analysis of registry evidence.

OBJECTIVE: To compare 10 year revision rates for frequently used types of primary total hip replacement to inform setting of a new benchmark rate in England and Wales that will be of international relevance. DESIGN: Retrospective cohort study. SETTING: National Joint Registry. PARTICIPANTS: 239 000 patient records. MAIN OUTCOME MEASURES: Revision rates for five frequently used types of total hip replacement that differed according to bearing surface and fixation mode, encompassing 62% of all primary total hip replacements in the National Joint Registry for England and Wales. Revision rates were compared using Kaplan-Meier and competing risks analyses, and five and 10 year rates were estimated using well fitting parametric models. RESULTS: Estimated revision rates at 10 years were 4% or below for four of the five types of total hip replacement investigated. Rates differed little according to Kaplan-Meier or competing risks analysis, but differences between prosthesis types were more substantial. Cemented prostheses with ceramic-on-polyethylene bearing surfaces had the lowest revision rates (1.88-2.11% at 10 years depending on the method used), and cementless prostheses with ceramic-on-ceramic bearing surfaces had the highest revision rates (3.93-4.33%). Men were more likely to receive revision of total hip replacement than were women, and this difference was statistically significant for four of the five prosthesis types. CONCLUSIONS: Ten year revision rate estimates were all less than 5%, and in some instances considerably less. The results suggest that the current revision rate benchmark should be at least halved from 10% to less than 5% at 10 years. This has implications for benchmarks internationally.

Total hip replacement and surface replacement for the treatment of pain and disability resulting from end-stage arthritis of the hip (review of technology appraisal guidance 2 and 44): systematic review and economic evaluation.

BACKGROUND: Total hip replacement (THR) involves the replacement of a damaged hip joint with an artificial hip prosthesis. Resurfacing arthroplasty (RS) involves replacement of the joint surface of the femoral head with a metal surface covering. OBJECTIVES: To undertake clinical effectiveness and cost-effectiveness analysis of different types of THR and RS for the treatment of pain and disability in people with end-stage arthritis of the hip, in particular to compare the clinical effectiveness and cost-effectiveness of (1) different types of primary THR and RS for people in whom both procedures are suitable and (2) different types of primary THR for people who are not suitable for hip RS. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, The Cochrane Library, Current Controlled Trials and UK Clinical Research Network (UKCRN) Portfolio Database were searched in December 2012, with searches limited to publications from 2008 and sample sizes of ≥ 100 participants. Reference lists and websites of manufacturers and professional organisations were also screened. REVIEW METHODS: Systematic reviews of the literature were undertaken to appraise the clinical effectiveness and cost-effectiveness of different types of THR and RS for people with end-stage arthritis of the hip. Included randomised controlled trials (RCTs) and systematic reviews were data extracted and risk of bias and methodological quality were independently assessed by two reviewers using the Cochrane Collaboration risk of bias tool and the Assessment of Multiple Systematic Reviews (AMSTAR) tool. A Markov multistate model was developed for the economic evaluation of the technologies. Sensitivity analyses stratified by sex and controlled for age were carried out to assess the robustness of the results. RESULTS: A total of 2469 records were screened of which 37 were included, representing 16 RCTs and eight systematic reviews. The mean post-THR Harris Hip Score measured at different follow-up times (from 6 months to 10 years) did not differ between THR groups, including between cross-linked polyethylene and traditional polyethylene cup liners (pooled mean difference 2.29, 95% confidence interval -0.88 to 5.45). Five systematic reviews reported evidence on different types of THR (cemented vs. cementless cup fixation and implant articulation materials) but these reviews were inconclusive. Eleven cost-effectiveness studies were included; four provided relevant cost and utility data for the model. Thirty registry studies were included, with no studies reporting better implant survival for RS than for all types of THR. For all analyses, mean costs for RS were higher than those for THR and mean quality-adjusted life-years (QALYs) were lower. The incremental cost-effectiveness ratio for RS was dominated by THR, that is, THR was cheaper and more effective than RS (for a lifetime horizon in the base-case analysis, the incremental cost of RS was £11,284 and the incremental QALYs were -0.0879). For all age and sex groups RS remained clearly dominated by THR. Cost-effectiveness acceptability curves showed that, for all patients, THR was almost 100% cost-effective at any willingness-to-pay level. There were age and sex differences in the populations with different types of THR and variations in revision rates (from 1.6% to 3.5% at 9 years). For the base-case analysis, for all age and sex groups and a lifetime horizon, mean costs for category E (cemented components with a polyethylene-on-ceramic articulation) were slightly lower and mean QALYs for category E were slightly higher than those for all other THR categories in both deterministic and probabilistic analyses. Hence, category E dominated the other four categories. Sensitivity analysis using an age- and sex-adjusted log-normal model demonstrated that, over a lifetime horizon and at a willingness-to-pay threshold of £20,000 per QALY, categories A and E were equally likely (50%) to be cost-effective. LIMITATIONS: A large proportion of the included studies were inconclusive because of poor reporting, missing data, inconsistent results and/or great uncertainty in the treatment effect estimates. This warrants cautious interpretation of the findings. The evidence on complications was scarce, which may be because of the absence or rarity of these events or because of under-reporting. The poor reporting meant that it was not possible to explore contextual factors that might have influenced study results and also reduced the applicability of the findings to routine clinical practice in the UK. The scope of the review was limited to evidence published in English in 2008 or later, which could be interpreted as a weakness; however, systematic reviews would provide summary evidence for studies published before 2008. CONCLUSIONS: Compared with THR, revision rates for RS were higher, mean costs for RS were higher and mean QALYs gained were lower; RS was dominated by THR. Similar results were obtained in the deterministic and probabilistic analyses and for all age and sex groups THR was almost 100% cost-effective at any willingness-to-pay level. Revision rates for all types of THR were low. Category A THR (cemented components with a polyethylene-on-metal articulation) was more cost-effective for older age groups. However, across all age-sex groups combined, the mean cost for category E THR (cemented components with a polyethylene-on-ceramic articulation) was slightly lower and the mean QALYs gained were slightly higher. Category E therefore dominated the other four categories. Certain types of THR appeared to confer some benefit, including larger femoral head sizes, use of a cemented cup, use of a cross-linked polyethylene cup liner and a ceramic-on-ceramic as opposed to a metal-on-polyethylene articulation. Further RCTs with long-term follow-up are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003924. FUNDING: The National Institute for Health Research Health Technology Assessment programme.