OFF episode quality of life impact scale (OFFELIA): A new measure of quality of life for off episodes in Parkinson's disease.

INTRODUCTION: OFF Episodes occur in people with Parkinson's disease when their medication wears off, and motor and/or non-motor symptoms emerge. Existing measures used to assess OFF Episodes focus on the time spent in OFF Episodes through diaries or by identifying symptoms, but they are limited in their ability to capture the severity and functional impact of OFF episodes. The aim of this study was to develop and validate a new instrument, called "OFFELIA," that measures the impact of OFF episodes on the quality of life of individuals with Parkinson's disease. METHODS: Participants completed a cross-sectional questionnaire, "Impact and Communication on OFF Periods," while enrolled in the online clinical study Fox Insights. The data collected was used to develop OFFELIA. Psychometric testing was performed on 18 candidate items using classical, exploratory factor analysis, and item response theory methods. RESULTS: 569 individuals with Parkinson's disease completed the questionnaire. All items were retained for the final measure, with 17 items aggregated into two multi-item scales (functioning and psychological well-being) and one item reported separately as it did not function well with the other items (employment). Known group comparisons based on average duration, frequency and unpredictability of OFF episodes indicated that OFFELIA subscales were more sensitive than existing generic and condition-specific measures. CONCLUSION: Initial evidence supports the validity of OFFELIA, a new instrument that assesses the impact of OFF periods on daily life. This instrument can be used in assessing clinical therapeutic strategies targeting OFF episodes in Parkinson's disease.

Advanced-Stage Parkinson's Disease: From Identification to Characterization Using a Nationwide Database.

Background: As Parkinson's disease (PD) progresses, response to oral medications decreases and motor complications appear. Timely intervention has been demonstrated as effective in reducing symptoms. However, current instruments for the identification of these patients are often complicated and inadequate. It has been suggested that anti-PD intensified therapy (IT) can serve as a proxy for increased burden of disease. Objective: To explore whether IT aligns with events reflecting advanced PD (APD) burden. Methods: This was a retrospective analysis of PD beneficiaries in the second-largest healthcare provider in Israel. Patients with PD diagnosed between January 2000 and June 2018 and treated with levodopa (l-dopa) ≥5 times/day and/or ≥1000 mg l-dopa equivalent daily dose were defined as the IT cohort (n = 2037). Treated patients with PD not fulfilling this criterion were defined as the nonintensified therapy (NIT) cohort (n = 3402). Point prevalence and 5- and 10-year cumulative incidence of IT were assessed. Baseline demographic and comorbidities, 1-year healthcare resource use, health costs, and time to clinical events were assessed and compared between cohorts. Results: IT was associated with significantly (P < 0.05) higher healthcare resource use compared with NIT. In turn, IT patients incurred higher healthcare costs (P < 0.001) and were at greater risk for mortality, hospitalization, disability, and device-aided therapy use (P < 0.001, for all comparisons). Conclusions: Treatment intensity can serve as an objective and robust indicator of more APD. This readily extractable marker can be easily integrated into electronic medical record alerts to actively target more advanced patients and to guide risk-appropriate care.

Long-Term Persistence and Monotherapy with Device-Aided Therapies: A Retrospective Analysis of an Israeli Cohort of Patients with Advanced Parkinson's Disease.

INTRODUCTION: Patients with advanced Parkinson's disease (PD) may require device-aided therapies (DAT) for adequate symptom control. However, long-term, real-world efficacy and safety data are limited. This study aims to describe real-world, long-term treatment persistence for patients with PD treated with levodopa-carbidopa intestinal gel (LCIG). The study also aims to describe patient profiles, treatment discontinuation rates, co-medication patterns, monotherapy rates, and rates of healthcare visits and their associated costs for patients receiving all forms of DAT (deep brain stimulation [DBS], continuous subcutaneous apomorphine infusion [CSAI], or LCIG). METHODS: In this retrospective analysis of the Israeli Maccabi Healthcare Services database, adult patients with PD were analyzed in three cohorts, based on DAT (DBS, CSAI, or LCIG). The primary endpoint was LCIG treatment persistence 12 months after initiation. RESULTS: This analysis included 161 DAT-treated patients (LCIG, n = 62; DBS, n = 76; CSAI, n = 23). Among those who discontinued, the mean time to discontinuation was 86.4 months for LCIG and 42.4 months for CSAI (p = 0.046). Twelve months after initiation, 14.3% LCIG, 10.7% DBS, and 5.9% CSAI patients were not receiving any additional anti-parkinsonian therapy. At the last recorded visit, 28.6% LCIG, 13.3% DBS, and 5.9% CSAI patients received DAT as monotherapy. During the first 12 months after initiation, 45.2% LCIG, 65.2% CSAI, and 1.3% DBS patients had no reported hospitalization days. Annual healthcare visit costs decreased following LCIG initiation (US$9491 vs. $8146) and increased following DBS ($4113 vs. $7677) and CSAI ($6378 vs. $8277). CONCLUSION: DAT are well maintained in patients with advanced PD. These retrospective data suggest that patients receiving LCIG may have higher long-term persistence rates compared with patients receiving CSAI. A subgroup of patients was treated with DAT as monotherapy without additional oral anti-parkinsonian therapy, with LCIG showing the highest rates.

The Cost Effectiveness of Levodopa-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson's Disease in England.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disease, which significantly impacts patients' quality of life and is associated with high treatment and direct healthcare costs. In England, levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of levodopa-responsive advanced Parkinson's disease with troublesome motor fluctuations when available combinations of medicinal products are unsatisfactory. OBJECTIVE: We aimed to determine the cost effectiveness of LCIG compared to the standard of care for patients with advanced Parkinson's disease in England, using real-world data. METHODS: A Markov model was adapted from previous published studies, using the perspective of the English National Health System and Personal and Social Services to evaluate the cost effectiveness of LCIG compared to standard of care in patients with advanced Parkinson's disease over a 20-year time horizon. The model comprised 25 health states, defined by a combination of the Hoehn and Yahr scale, and waking time spent in OFF-time. The base case considered an initial cohort of patients with an Hoehn and Yahr score of ≥ 3, and > 4 h OFF-time. Standard of care comprised standard oral therapies, and a proportion of patients were assumed to be treated with subcutaneous apomorphine infusion or injection in addition to oral therapies. Efficacy inputs were based on LCIG clinical trials where possible. Resource use and utility values were based on results of a large-scale observational study, and costs were derived from the latest published UK data, valued at 2017 prices. The EuroQol five-dimensions-3-level (EQ-5D-3L) instrument was used to measure utilities. Costs and quality-adjusted life-years were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Total costs and quality-adjusted life-years gained for LCIG vs standard of care were £586,832 vs £554,022, and 2.82 vs 1.43, respectively. The incremental cost-effectiveness ratio for LCIG compared to standard of care was £23,649/quality-adjusted life-year. Results were sensitive to the healthcare resource utilisation based on real-world data, and long-term efficacy of LCIG. CONCLUSIONS: The base-case incremental cost-effectiveness ratio was estimated to be within the acceptable thresholds for cost effectiveness considered for England.

Patterns of Daily Motor-Symptom Control with Carbidopa/Levodopa Enteral Suspension Versus Oral Carbidopa/Levodopa Therapy in Advanced Parkinson's Disease: Clinical Trial Post Hoc Analyses.

INTRODUCTION: A clinical trial in advanced Parkinson's disease (APD) has established the superiority of carbidopa/levodopa enteral suspension (CLES) in reducing total patient "off" time (OFF) and increasing total "on" time without troublesome dyskinesia (ON-woTD) over orally administered immediate-release carbidopa/levodopa tablets (IR-CL). However, temporal patterns of these improvements throughout the waking day have not been examined. In this analysis, time to ON-woTD after waking and patterns of motor-symptom control throughout the waking day were compared between CLES and IR-CL. METHODS: Post hoc analyses of APD patient-diary data from the phase 3 randomized controlled trial were used to compare changes in time to ON-woTD after waking, motor-symptom control throughout the waking day, occurrence of extreme fluctuations between OFF and "on" with troublesome dyskinesia, and motor-state transitions with CLES versus IR-CL from baseline to week 12. RESULTS: The sample included 33 CLES-treated and 30 IR-CL-treated patients. Among the CLES group, the percentage of patient days achieving ON-woTD within 30 min of waking was three times higher at week 12 versus baseline (33% vs. 11%, p = 0.0043); no significant change occurred with IR-CL. When the waking day was divided into four 4-h periods, CLES versus IR-CL treatment produced significantly greater reductions in OFF during three periods, and two periods had increased ON-woTD. Fewer CLES-treated patients had extreme fluctuations at week 12 (3% vs. 23%, p = 0.0224) compared to IR-CL-treated patients. From baseline to week 12, CLES-treated patients had greater reductions in the average number of motor-state transitions compared to IR-CL-treated patients (- 1.6, p = 0.0295). CONCLUSION: CLES-treated patients experienced a more rapid onset of ON-woTD after waking and greater consistency of ON-woTD throughout their waking day than IR-CL-treated patients.

In advanced Parkinson's disease, patients' motor-symptom states (such as "on" time without troublesome dyskinesia [good "on" time] and "off" time), and the timing at which they occur, can impact patients' quality of life and ability to complete activities of daily living. Carbidopa/levodopa enteral suspension is administered continuously into the jejunum, potentially reducing some of the motor-state variation that is common with orally administered carbidopa/levodopa, including delayed "on" time after waking and transitions between "off" and "on" throughout the day. In post hoc analyses of clinical trial data, patterns of motor-states across the waking day were compared between carbidopa/levodopa enteral suspension and orally administered immediate-release carbidopa/levodopa at week 12. Outcomes included time to good "on" after waking; occurrence of extreme fluctuations between "off" time and "on" time with troublesome dyskinesia; time in each motor-state during 4-h intervals across the day; and frequency of motor-state transitions. Three times as many carbidopa/levodopa enteral suspension-treated patients achieved good "on" within 30 min of waking after 12 weeks versus baseline, whereas no significant change was observed for the orally administered immediate-release carbidopa/levodopa group. Compared to orally administered immediate-release carbidopa/levodopa-treated patients, fewer carbidopa/levodopa enteral suspension-treated patients experienced extreme fluctuations, had greater reductions in motor-state transitions, and greater reductions in duration of "off" during three of the four intervals in the day. These findings provide a first look at the impact of carbidopa/levodopa enteral suspension on motor-state patterns throughout the day, and suggest that carbidopa/levodopa enteral suspension provides more consistent motor-symptom control and predictable benefit throughout the day than orally administered carbidopa/levodopa.

Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries.

BACKGROUND: The burden of Parkinson's disease (PD) worsens with disease progression. However, the lack of objective and uniform disease classification challenges our understanding of the incremental burden in patients with advanced Parkinson's disease (APD) and suboptimal medication control. The 5-2-1 criteria was proposed by clinical consensus to identify patients with advancing PD. Our objective was to evaluate the screening accuracy and incremental clinical burden, healthcare resource utilization (HCRU), and humanistic burden in PD patients meeting the 5-2-1 screening criteria. METHODS: Data were drawn from the Adelphi Parkinson's Disease Specific Program (DSP™), a multi-country point-in-time survey (2017-2020). People with PD who were naive to device-aided therapy and on oral PD therapy were included. Patients meeting the 5-2-1 screening criteria had one or more of the three clinical indicators of APD: (i) ≥5 doses of oral levodopa/day, OR (ii) "off" symptoms for ≥2 h of waking day, OR (iii) ≥1 h of troublesome dyskinesia. Clinician assessment of PD stage was used as the reference in this study. Clinical screening accuracy of the 5-2-1 criteria was assessed using area under the curve and multivariable logistic regression models. Incremental clinical, HCRU, and humanistic burden were assessed by known-group comparisons between 5 and 2-1-positive and negative patients. RESULTS: From the analytic sample (n = 4714), 33% of patients met the 5-2-1 screening criteria. Among physician-classified APD patients, 78.6% were 5-2-1 positive. Concordance between clinician judgment and 5-2-1 screening criteria was > 75%. 5-2-1-positive patients were nearly 7-times more likely to be classified as APD by physician judgment. Compared with the 5-2-1-negative group, 5-2-1-positive patients had significantly higher clinical, HCRU, and humanistic burden across all measures. In particular, 5-2-1-positive patients had 3.8-times more falls, 3.6-times higher annual hospitalization rate, and 3.4-times greater dissatisfaction with PD treatment. 5-2-1-positive patients also had significantly lower quality of life and worse caregiver burden. CONCLUSIONS: 5-2-1 criteria demonstrated potential as a screening tool for identifying people with APD with considerable clinical, humanistic, and HCRU burden. The 5-2-1 screening criteria is an objective and reliable tool that may aid the timely identification and treatment optimization of patients inadequately controlled on oral PD medications.

Psychometric Properties of Clinical Indicators for Identification and Management of Advanced Parkinson's Disease: Real-World Evidence From G7 Countries.

INTRODUCTION: Standardized and validated criteria to define advanced Parkinson's disease (PD) or identify patient eligibility for device-aided therapy are needed. This study assessed the psychometric properties of clinical indicators of advanced PD and eligibility for device-aided therapy in a large population. METHODS: This retrospective analysis of the Adelphi Parkinson's Disease Specific Programme collected data from device-aided therapy-naïve people with PD in G7 countries. We assessed the presence of 15 clinical indicators of advancing PD and seven indicators of eligibility for device-aided therapy in patients classified with advanced PD or as eligible for device-aided therapy by the treating physician. Accuracy was assessed using area under the curve (AUC) and multivariable logistic regression models. Construct validity was examined via known-group comparisons of disease severity and burden among patients with and without each clinical indicator. RESULTS: Of 4714 PD patients, 14.9% were classified with advanced PD and 17.5% as eligible for device-aided therapy by physician judgment. The presence of each clinical indicator was 1.9- to 7.3-fold more likely in patients classified with advanced PD. Similarly, the presence of device-aided therapy eligibility indicators was 1.8- to 5.5-fold more likely in patients considered eligible for device-aided therapy. All indicators demonstrated high clinical screening accuracy for identifying advanced PD (AUC range 0.84-0.89) and patients eligible for device-aided therapy (AUC range 0.73-0.80). The Unified Parkinson's Disease Rating Scale (UPDRS) score, cognitive function, quality of life, and caregiver burden were significantly worse in indicator-positive patients. CONCLUSION: Specific clinical indicators of advanced PD and eligibility for device-aided therapy demonstrated excellent psychometric properties in a large sample, and thus may provide an objective and reliable approach for patient identification and treatment optimization.

Advanced Parkinson's disease (PD) refers to the stage of disease when motor complications are difficult to manage with standard therapy. Patients reaching this stage of the disease may benefit from a treatment change from pills to the so-called device-aided therapies. However, there is currently no unanimous definition of advanced PD, which makes it challenging to identify suitable candidates for device-aided therapies. There is urgent need to define specific features (or 'clinical indicators') to support healthcare professionals and patients in the identification of advanced PD as well as to define suitability for device-aided therapy. This study aimed to assess the accuracy of 15 clinical indicators and seven device-aided therapy eligibility criteria using information from a large database of 4714 patients in G7 countries. Physicians classified 14.9% of patients as having advanced PD and 17.5% were judged to be eligible for device-aided therapy. Each clinical indicator or device-aided therapy eligibility indicator was detected more frequently in patients classified as having advanced PD and in patients considered eligible for device-aided therapy, respectively. All indicators had high accuracy for identifying advanced PD and device-aided therapy-eligibility. These previously identified clinical indicators of advanced PD and device-aided therapy eligibility may provide an objective and reliable approach for patient screening and treatment optimization.

Validation and clinical value of the MANAGE-PD tool: A clinician-reported tool to identify Parkinson's disease patients inadequately controlled on oral medications.

INTRODUCTION: Making Informed Decisions to Aid Timely Management of Parkinson's Disease (MANAGE-PD) is a clinician-reported tool designed to facilitate timely identification and management of patients with advancing Parkinson's disease (PD) with suboptimal symptom control while on standard therapy. The objective of this study was to evaluate the validity and clinical value of the tool. METHODS: Driven by structured inputs from a steering committee and panel of PD experts, the tool was developed to classify patients into 3 categories. Validity and clinical value were elucidated using a two-pronged approach: (i) hypothetical patient vignettes (n = 10) developed based on the MANAGE-PD tool and rated by 17 PD specialists and 400 general neurologists (GN) and (ii) patients with PD (n = 2546) managed in real-world clinical settings. Vignette validity was based on concordance between PD experts' clinical judgement and MANAGE-PD vignette categorization. Patient-level data was used for known-group comparisons (validity) and discordant pair analysis (clinical value). RESULTS: The tool demonstrated strong validity and clinical value among PD specialists (intraclass coefficient [ICC] 0.843; Fleiss weighted kappa [ƙweighted] 0.79) and GN (ICC 0.690; ƙweighted 0.65) using patient vignettes. MANAGE-PD also demonstrated real-world validity and clinical value based on ability to identify patients with incrementally higher clinical, economic, and humanistic PD burden across categories of the tool (p < 0.01). CONCLUSIONS: MANAGE-PD demonstrated robust validity and clinical value in identifying patients with suboptimal PD symptom control. Clinical use of MANAGE-PD may complement treatment decision-making and facilitate timely and comprehensive management of patients with advancing PD.

The Long-Term Impact of Levodopa/Carbidopa Intestinal Gel on 'Off'-time in Patients with Advanced Parkinson's Disease: A Systematic Review.

INTRODUCTION: Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson's disease (PD) when other treatments have not given satisfactory results. Reduction in 'off'-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on 'off'-time. METHODS: Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and 'off'-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: 'off'-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson's Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes. RESULTS: Twenty-seven studies were included in this review. The improvement in 'off'-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. 'Off'-time was reduced from baseline to end of follow-up by 38-84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of 'off'-time demonstrated mean relative reductions of 47-82% at 3-6 months and up to 83% reduction at 3-5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device. CONCLUSION: In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing 'off'-time. INFOGRAPHIC: Video Abstract.

By synthesising publications from scientific journals, this article shows that levodopa/carbidopa intestinal gel (LCIG; also known as carbidopa/levodopa enteral suspension or the tradenames Duodopa® and Duopa®) may have benefits for patients with advanced Parkinson's disease that last for 12 months or more. Pills taken by mouth for Parkinson's disease often do not work as well after a few years. This means the symptoms of Parkinson's disease, such as shaking or slow movements, etc., re-emerge despite medication (known as 'off'-time). To reduce the amount of 'off'-time, people with advancing Parkinson's disease may switch from pills to other types of treatments, for example, those that use devices to deliver the drug into the body, such as LCIG. LCIG has been available for many years and is known to help patients by reducing 'off'-time. Despite this, less is known about how long the benefits of LCIG last. By summarising all information available on the long-term use of LCIG, this report shows that when patients have been taking LCIG for at least 12 months, they have 2­4 h less 'off'-time each day than they did before starting the LCIG treatment. This effect is maintained for 3­5 years after starting LCIG treatment. There were no unexpected side effects with long-term use of LCIG. The time not spent in 'off' may allow people with advanced Parkinson's to increase their independence in daily activities.

Impact of carbidopa-levodopa enteral suspension on quality of life and activities of daily living in patients with advanced Parkinson's disease: Results from a pooled meta-analysis.

INTRODUCTION: To estimate the impact of carbidopa/levodopa enteral suspension (CLES) on key patient-centered outcomes in patients with advanced Parkinson's disease (PD). METHODS: A comprehensive literature review identified relevant studies, from which data were meta-analyzed over 3-month intervals up to 24 months. Patient-centered outcomes of interest included mean (95% CI) changes from baseline (Δ) in quality of life (QoL), measured using PD-specific (PDQ-8, PDQ-39) and generic (EQ-5D) instruments; activities of daily living (ADL), measured in On and Off states using UPDRS Part II; and motor symptoms (i.e., Off time/day and motor examination [measured in On and Off states using UPDRS Part III]). RESULTS: The pooled meta-analysis included data from 26 studies evaluating 1556 patients on CLES. At 3 months, all outcomes showed significant improvement: QoL (ΔPDQ-39 = -10.26 [-11.54, -8.97], ΔEQ-5DVAS = 15.42 [12.58, 18.26]); ADL (ΔUPDRS IION = -4.32 [-5.63, -3.01]); motor symptoms (ΔOff time hours/day = -3.48 [-4.15, -2.82], ΔUPDRS IIION = -6.20 [-9.88, -2.51]). At 24 months, there were statistically significant mean improvements in QoL (ΔPDQ-39 = -7.74 [-12.40, -3.07], ΔEQ-5DVAS = 11.18 [6.90, 15.45]) and ADL (ΔUPDRS IIOFF = -3.88 [-5.34, -2.42]), and Off time (-4.21 [-5.16, -3.26] hours/day). CONCLUSIONS: Impact of CLES on significantly reducing Off time/day was observed to be rapid and durable (i.e., remained consistent across 24 months). Most QoL and ADL measures showed a consistent pattern of improvement with initiation of treatment and remained significantly improved from baseline at 24 months.

Low Sustainment of High-Dose Oral Medication Regimens for Advanced Parkinson's Disease in Medicare Beneficiaries.

BACKGROUND: Increasing doses of oral antiparkinson medications are indicated in advanced Parkinson's disease (PD), but little is known about sustainment of high-dose regimens. OBJECTIVE: To investigate sustainment of high-dose oral medication regimens in Medicare beneficiaries with incident advanced PD. METHODS: This retrospective cohort study utilized 100%fee-for-service Medicare claims from 2011-2013. We identified advanced PD using a pharmacy claims-based proxy and selected patients who initiated a new high-dose oral medication regimen (daily levodopa equivalent dose [LED] >1000 mg/day for ≥30 days) in 2012. In the following 12 months, we examined: 1) annual proportion of days covered (PDC)≥0.80 and 2) presence of a ≥ 90 day continuous gap at varying dosage thresholds: the initial >1000 mg/day, >800 mg/day, >500 mg/day, or >0 mg/day. RESULTS: We identified 9,405 patients with advanced PD (mean age 77.4 [SD 6.8] years; 53%men). Only 5%maintained a regimen of >1000 mg/day at PDC ≥0.80; 75% had a ≥ 90-day gap in that dosage level. At a dosage threshold of >800 mg/day, 20% had a PDC ≥0.80 and 53% had a ≥ 90-day gap; at >500 mg/day, 56% had a PDC ≥0.80 and 19%had a ≥ 90-day gap; and at >0 mg/day (any dose), 76% had a PDC ≥0.80 and only 10%had a≥90-day gap. CONCLUSION: Few patients with advanced PD sustained a high-dose oral medication regimen in the year following initiation, but most sustained a substantially lower-dose regimen. Strategies to improve advanced PD treatment are needed.

Burden of Parkinson's Disease by Severity: Health Care Costs in the U.S. Medicare Population.

BACKGROUND: Current understanding of the health care costs of Parkinson's disease (PD) and the incremental burden of advanced disease is incomplete. OBJECTIVES: The aim of this study was to assess the direct economic burden associated with advanced versus mild/moderate PD in a prevalent national sample of elderly U.S. Medicare beneficiaries with a PD diagnosis. METHODS: Analyzing 100% fee-for-service Medicare claims from 2013, we defined advanced PD with a medication-based algorithm and calculated all-cause and PD-related costs for the overall sample and by disease severity. We measured primary PD-related costs (based on claims with a primary diagnosis of PD) and any PD-related costs (based on claims with PD in any diagnostic field). Generalized linear models were used to estimate risk-adjusted mean cost differences between the advanced and mild/moderate PD groups for the calendar year. RESULTS: The final sample (N = 144,703) had mean observed all-cause, primary PD-related, and any PD-related costs of $23,041 (SD, $34,045), $3429 (SD, $7431), and $9924 (SD, $22,140), respectively. Twenty percent of patients were classified as advanced PD. Costs varied substantially; any PD-related mean costs were $483 for the lowest patient decile (which included 1% of the advanced group) and $48,145 for the highest decile (which included 15% of the advanced group). Incremental risk-adjusted costs of advanced PD were $5818 (95% confidence interval [CI]: $5411-$6225) for all-cause costs, $3644 (95% CI: $3484-$3806) for primary PD-related costs, and $6088 (95% CI: $5779-$6398) for any PD-related costs. CONCLUSIONS: Elderly Medicare beneficiaries with PD had substantial variation in PD-related costs. Advanced PD was associated with a larger economic burden than mild/moderate PD. © 2020 International Parkinson and Movement Disorder Society.

Use of a medication-based algorithm to identify advanced Parkinson's disease in administrative claims data: Associations with claims-based indicators of disease severity.

INTRODUCTION: Lack of a gold standard definition for advanced Parkinson's Disease (APD), coupled with absence of disease severity information in diagnostic codes, hinders use of large administrative databases for conducting population health and comparative effectiveness studies. METHODS: Using pharmacy claims data, we created an algorithm to identify APD: any 30-day average levodopa equivalent dose (LED) >1000 mg/day. Using 2013 100% U.S. Medicare claims, we applied this algorithm and used multivariate logistic regression to examine associations between assigned APD status and claims-based indicators of PD severity (any deep brain stimulation, fall, hallucinations, walker, wheelchair, specialty bed, dementia diagnosis, skilled nursing facility, hospice), adjusting for sociodemographic, clinical, and treatment characteristics. Levodopa >1000 mg/day, levodopa >800 mg/day and LED >800 mg/day were used in sensitivity analysis. RESULTS: In our sample (N = 144,703), 20% were assigned APD status based on the LED >1000 mg/day cut-off. This group had significantly higher odds of having each claims-based indicator, compared with those assigned mild-moderate PD status. Odds ratios were highest for indicators for any DBS (OR: 2.96; 95% CI:2.75-3.19) and specialty bed (OR:2.15, 95% CI: 1.99-2.32) and lowest for fall (OR:1.27; 95% CI:1.20-1.34) and dementia diagnosis (OR:1.21; 95% CI:1.18-1.25). Results based on alternative approaches were similar. CONCLUSIONS: Medicare patients classified as having APD via a pharmacy claims-based algorithm had higher odds of having claims-based clinical markers of APD, compared with patients categorized as having mild-moderate PD. This proxy strategy could facilitate future claims-based studies and warrants further refinement and validation using medical records or other clinical sources.

The Social Value of Improvement in Activities of Daily Living among the Advanced Parkinson's Disease Population.

OBJECTIVES: Quantify the value of functional status (FS) improvements consistent in magnitude with improvements due to levodopa-carbidopa intestinal gel (LCIG) treatment, among the advanced Parkinson's disease (APD) population. METHODS: The Health Economic Medical Innovation Simulation (THEMIS), a microsimulation that estimates future health conditions and medical spending, was used to quantify the health and cost burden of disability among the APD population, and the value of quality-adjusted life-years gained from FS improvement due to LCIG treatment compared to standard of care (SoC). A US-representative Parkinson's disease (PD)-comparable cohort was constructed in THEMIS based on observed PD patient characteristics in a nationally representative dataset. APD was defined from the literature and clinical expert input. The PD and APD cohorts were followed from 2010 over their remaining lifetimes. All individuals were ages 65 and over at the start of the simulation. To estimate the value of FS improvement due to LCIG treatment, decreases in activities of daily living (ADL) limitations caused by LCIG treatment were calculated using data from a randomized, controlled, double-blind, double-dummy clinical trial and applied to the APD population in THEMIS. RESULTS: Total burden of disability associated with APD was $17.7 billion (B). From clinical trial data, LCIG treatment versus SoC lowers the odds of difficulties in walking, dressing, and bathing by 76%, 42% and 39%, respectively. Among the APD population, these reductions generated $2.6B in value to patients and cost savings to payers. The added value was 15% of the burden of disability associated with APD and offsets 15% of the cost of LCIG treatment. CONCLUSIONS: FS improvements, consistent with improvements due to LCIG treatment, in the APD population created health benefits and reduced healthcare costs in the US.

Efficacy and safety of glecaprevir/pibrentasvir in renally impaired patients with chronic HCV infection.

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection increases the risk of incident chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD). Previously available direct-acting antiviral regimens are not approved for patients with advanced CKD across all HCV genotypes. METHODS: EXPEDITION-5 is a phase 3 study to evaluate efficacy and safety of the fixed-dose combination of glecaprevir and pibrentasvir (G/P) for chronic HCV infection (genotype 1 through 6) in adults without cirrhosis or with compensated cirrhosis and with stage 3b, 4 or 5 CKD. Patients received approved duration of G/P according to HCV genotype, cirrhosis status and prior HCV treatment experience. The primary efficacy endpoint was percentage of patients with sustained virologic response at 12 weeks post-treatment (SVR12). RESULTS: Among the 101 patients enrolled in the study, 24% had predialysis CKD and 76% were on dialysis. Eighty-four patients were treated with G/P for 8 weeks, 13 patients for 12 weeks and four patients for 16 weeks. Fifty-five per cent of patients had genotype 1, 27% had genotype 2, 15% had genotype 3 and 4% had genotype 4, and none had genotype 5 or 6 infection. The SVR12 rate was 97% (98/101, 95% confidence interval, 91.6-99.0). No patients experienced virologic failure. Adverse events (AEs) reported in at least 5% of the patients were pruritus, bronchitis, hypertension and generalized pruritus. Serious AEs were reported in 12% of patients; none related to study drug. CONCLUSIONS: G/P treatment yielded high SVR12 rates irrespective of the presence of stage 3b, 4 or 5 CKD. No safety signals were detected. CLINICALTRIALS. GOV IDENTIFIER: This Phase 3 clinical trial was funded by AbbVie and registered with clinicaltrials.gov as NCT03069365 (EXPEDITION-5).

The effect of functional status impairment on nursing home admission risk among patients with advanced Parkinson's disease.

Aims: To estimate the relationship between functional status (FS) impairment and nursing home admission (NHA) risk in Parkinson's disease (PD) patients, and quantify the effect of advanced PD (APD) treatment on NHA risk relative to standard of care (SoC).Materials and methods: PD patients were identified in the Medicare Current Beneficiary Survey (MCBS) (1992-2010). A working definition based on the literature and clinical expert input determined APD status. A logit model estimated the relationship between FS impairment and NHA risk. The effect of levodopa-carbidopa intestinal gel (LCIG) on NHA risk relative to SoC was simulated using clinical trial data (control: optimized oral levodopa-carbidopa IR, ClinicalTrials.gov NCT00660387 and NCT0357994).Results: Non-advanced PD and APD significantly increased NHA risk when controlling for demographics (p < 0.01). APD status was no longer significant after controlling for FS limitations, implying that FS limitations explain the increased NHA risk in APD patients. Reduced impairment in FS in patients with APD treated with LCIG reduced risk of NHA by 13.5% relative to SoC.Limitations: This study applies clinical trial results to real-world data. LCIG treatment might have a different effect on NHA risk for the nationally representative population than the effect measured in the trial. Both data sources employ different instruments to measure FS, instrument wording and study follow-up differed, which might bias our estimates. Finally, there lacks consensus on a definition of APD. The prevalence of APD in this study is high, perhaps due to the specific definition used.Conclusions: Patients with APD experience a higher risk in NHA than those with non-advanced disease. This increased risk in NHA in patients with APD is explained by greater limitations in FS. The relative reduction in risk of NHA for the APD population treated with LCIG is quantitatively similar to doubling Medicaid home care services.

The long-term direct and indirect economic burden among Parkinson's disease caregivers in the United States.

BACKGROUND: Parkinson's disease is a progressive, disabling neurodegenerative disorder associated with significant economic burden for patients and caregivers. The objective of this study was to compare the direct and indirect economic burden of Parkinson's patients' caregivers with demographically matched controls in the United States, in the 5 years after first diagnosis of Parkinson's disease. METHODS: Policyholders (18-64 years old) linked to a Parkinson's disease patient (≥2 diagnoses of Parkinson's disease; first diagnosis is the index date) from January 1, 1998 to March 31, 2014, were selected from a private-insurer claims database and categorized as Parkinson's caregivers. Eligible Parkinson's caregivers were matched 1:5 to policyholders with a non-Parkinson's dependent (controls). Multivariable regression adjusted for baseline characteristics estimated direct costs (all-cause insurer cost [medical and prescription] and comorbidity-related medical costs; patient out-of-pocket costs) and indirect costs (disability and medically related absenteeism costs). Income progression was also compared between cohorts. RESULTS: A total of 1211 eligible Parkinson's caregivers (mean age, 56 years; 54% female) were matched to 6055 controls. In adjusted analyses, Parkinson's caregivers incurred significantly higher year 1 total all-cause insurer costs ($8999 vs $7117) and medical costs ($7081 vs $5568) (both P < 0.01) and higher prescription costs (range for years 1-5, $2506-2573 vs $1405-$1687) and total out-of-pocket costs ($1259-1585 vs $902-$1192) in years 1-5 (all P < 0.01). Parkinson's caregivers had significantly higher adjusted indirect costs in years 1-3 (range for years 1-3, $2054-$2464 vs $1681-$1857; all P < 0.05) and higher cumulative income loss over 5 years ($5967 vs $2634 by year 5; P for interaction = 0.03). CONCLUSIONS: Parkinson's caregivers exhibited higher direct and indirect costs and greater income loss compared with matched controls. © 2018 International Parkinson and Movement Disorder Society © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Lifestyle-related attitudes: do they explain self-rated health and life-satisfaction?

BACKGROUND: Strategies to improve public health may benefit from targeting specific lifestyles associated with poor health behaviors and outcomes. The aim of this study was to characterize and examine the relationship between health and lifestyle-related attitudes (HLAs) and self-rated health and life-satisfaction. METHODS: Secondary analyses were conducted on data from a 2012 community wellness survey in Kirklees, UK. Using a validated HLA tool, respondents (n = 9130) were categorized into five segments: health conscious realists (33%), balanced compensators (14%), live-for-todays (18%), hedonistic immortals (10%), and unconfident fatalists (25%). Multivariate regression was used to examine whether HLAs could explain self-rated health using the EQ-5D visual analog scale (EQ-VAS) and life-satisfaction. Health conscious realists served as the reference group. RESULTS: Self-rated health differed by HLA, with adjusted mean EQ-VAS scores being significantly higher (better) among balanced compensators (1.15, 95% CI 0.27, 2.03) and lower scores among unconfident fatalists (- 9.02, 95% CI - 9.85, - 8.21) and live-for-todays (- 1.96, 95% CI - 2.80, - 1.14). Balanced compensators were less likely to report low life-satisfaction (OR 0.75, 95% CI 0.62, 0.90), while unconfident fatalists were most likely to have low life-satisfaction (OR 3.51, 95% CI 2.92, 4.23). SIGNIFICANCE: Segmentation by HLA explained differences in self-rated health and life-satisfaction, with unconfident fatalists being a distinct segment with significantly worse health perceptions and life-satisfaction. Health promotion efforts may benefit from considering the HLA segment that predominates a patient group, especially unconfident fatalists.

Effect of Levodopa-carbidopa Intestinal Gel on Non-motor Symptoms in Patients with Advanced Parkinson's Disease.

Background: Levodopa-carbidopa intestinal gel (LCIG; carbidopa-levodopa enteral suspension in the United States), delivered via percutaneous gastrojejunostomy (PEG-J) and titrated in the inpatient setting, is an established treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. However, long-term prospective data on the efficacy of LCIG on non-motor symptoms and the safety of outpatient titration are limited. Methods: In this 60-week, open-label phase 3b study, LCIG titration was initiated in an outpatient setting following PEG-J placement in PD patients. The efficacy of LCIG on motor and non-motor symptoms, quality of life, and safety was assessed. Results: Thirty-nine patients were enrolled in the study and 28 patients completed the treatment. A majority of patients (54%) completed outpatient titration within the first week of LCIG infusion. LCIG led to significant reductions from baseline in Non-Motor Symptom Scale (NMSS) total score (least squares mean ± SE = -17.6 ± 3.6, P < 0.001) and 6 of the NMSS domain scores (sleep/fatigue, attention/memory, gastrointestinal tract, urinary, sexual function, miscellaneous) at week 12. These reductions were maintained at week 60 with the exception of the urinary domain. "Off" time (-4.9 ± 0.5 hours/day, P < 0.001) and "On" time without troublesome dyskinesia (-4.3 ± 0.6 hours/day, P < 0.001) were improved at week 60. Adverse events (AEs) were reported in 37 (95%) patients. Conclusions: LCIG treatment led to reductions in non-motor symptom burden and motor fluctuations in advanced PD patients. The safety profile was consistent with previous studies that used inpatient titration and outpatient titration did not appear to pose additional risk.

The cost-effectiveness of levodopa/carbidopa intestinal gel compared to standard care in advanced Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is an incurable, progressive neurological condition, with symptoms impacting movement, walking, and posture that eventually become severely disabling. Advanced PD (aPD) has a significant impact on quality-of-life (QoL) for patients and their caregivers/families. Levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of advanced levodopa-responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of therapy have not given satisfactory results. AIMS: To determine the cost-effectiveness of LCIG vs standard of care (SoC) for the treatment of aPD patients. METHODS: A Markov model was used to evaluate LCIG vs SoC in a hypothetical cohort of 100 aPD patients with severe motor fluctuations from an Irish healthcare perspective. Model health states were defined by Hoehn & Yahr (H&Y) scale-combined with amount of time in OFF-time-and death. SoC comprised of standard oral therapy ± subcutaneous apomorphine infusion and standard follow-up visits. Clinical efficacy, utilities, and transition probabilities were derived from published studies. Resource use was estimated from individual patient-level data from Adelphi 2012 UK dataset, using Irish costs, where possible. Time horizon was 20 years. Costs and outcomes were discounted at 4%. Both one-way and probabilistic sensitivity analyses were conducted. RESULTS: The incremental cost-effectiveness ratio for LCIG vs SOC was €26,944/quality adjusted life year (QALY) (total costs and QALYs for LCIG vs SoC: €537,687 vs €514,037 and 4.37 vs 3.49, respectively). LCIG is cost-effective at a payer threshold of €45,000. The model was most sensitive to health state costs. CONCLUSION: LCIG is a cost-effective treatment option compared with SoC in patients with aPD.