Efficacy and safety of crisaborole ointment, 2%, in participants aged ≥45 years with stasis dermatitis: Results from a fully decentralized, randomized, proof-of-concept phase 2a study.

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal topical phosphodiesterase 4 inhibitor approved for the treatment of mild-to-moderate atopic dermatitis. OBJECTIVE: To evaluate the efficacy and safety of crisaborole in stasis dermatitis (SD). METHODS: In this randomized, double-blind, vehicle-controlled, decentralized phase 2a study (NCT04091087), 65 participants aged ≥45 years with SD without active ulceration received crisaborole or vehicle (1:1) twice-daily for 6 weeks. The primary end point was percentage change from baseline in total sign score at week 6 based on in-person assessment. RESULTS: Crisaborole-treated participants had significantly reduced total sign score from baseline versus vehicle based on in-person (nondermatologist) assessment (-32.4% vs -18.1%, P = .0299) and central reader (dermatologists) assessment of photographs (-52.5% vs -10.3%, P = .0004). Efficacy according to success and improvement per Investigator's Global Assessment score and lesional percentage body surface area reached statistical significance based on central reader but not in-person assessments. Skin and subcutaneous tissue disorders were common all-causality treatment-emergent adverse events with crisaborole. LIMITATIONS: Small sample size and short treatment duration were key limitations. In-person assessment was not conducted by dermatologists. CONCLUSION: Crisaborole improved signs and symptoms of SD and was well tolerated. Central reader assessment represents a promising approach for siteless clinical research.

Interpreting the Relationship Among Itch, Sleep, and Work Productivity in Patients with Moderate-to-Severe Atopic Dermatitis: A Post Hoc Analysis of JADE MONO-2.

BACKGROUND: Abrocitinib, an oral, once-daily Janus kinase 1-selective inhibitor, improved itch severity, sleep, and work productivity versus placebo in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: The aim of this study was to investigate relationships among itch, sleep, and work productivity in the phase III JADE MONO-2 clinical trial. METHODS: A repeated-measures longitudinal model was used to examine relationships between itch (using the Peak Pruritus Numerical Rating Scale [PP-NRS] or Nighttime Itch Scale [NTIS]) and sleep disturbance/loss (using the Patient-Oriented Eczema Measure sleep item and SCORing AD Sleep Loss Visual Analog Scale) and, separately, between itch and work productivity (using the Work Productivity and Activity Impairment-Atopic Dermatitis Version 2.0 questionnaire). Mediation modelling was used to investigate the effect of treatment (abrocitinib vs placebo) on work impairment via improvements in itch and sleep. RESULTS: The relationships between itch/sleep and itch/work productivity were approximately linear. PP-NRS scores of 0, 4-6, and 10 were associated with 0 days, 3-4 days, and 7 days per week of disturbed sleep, respectively. PP-NRS or NTIS scores of 0-1, 4-5, and 10 were associated with 0-10%, 20-30%, and >50% overall work impairment, respectively. Seventy-five percent of the effect of abrocitinib on reducing work impairment was indirectly mediated by improvement in itch, followed by sleep. CONCLUSION: These results quantitatively demonstrate that reducing itch severity is associated with improvements in sleep and work productivity. Empirical evidence for the mechanism of action of abrocitinib showed that itch severity is improved, which reduces sleep loss/sleep disruption and, in turn, improves work productivity. CLINICAL TRIAL REGISTRATION: NCT03575871.

Atopic dermatitis (AD), also called atopic eczema, is a common skin disease that is associated with itch and reduced quality of life. Abrocitinib, a recently approved medicine for AD, was shown in clinical trials to improve itch, which is considered the most bothersome symptom to people with AD. Abrocitinib also improved sleep outcomes and work productivity in people with moderate or severe AD. It is unknown if improvement in itch can lead to improvement in sleep and work productivity. We analyzed data from the JADE MONO-2 study, which included 391 people who received treatment with abrocitinib or placebo for 12 weeks. We used mathematical modelling to study relationships between itch and sleep or work productivity. We also wanted to study if the improvements in itch and sleep with abrocitinib treatment had an impact on work productivity. We found that a relationship existed between itch, sleep disturbance, and work impairment; as itch improved, so too did sleep disturbance and work impairment. When people were treated with abrocitinib, they experienced relief from itch, which improved sleep, which in turn reduced work productivity loss. Larger and longer studies are needed to confirm these results. This analysis further informs the expectations of patients with moderate or severe AD as it relates to progression of symptom relief after treatment with abrocitinib.

Abrocitinib Provides Rapid and Sustained Improvement in Skin Pain and Is Associated With Improved Quality of Life Outcomes in Adult and Adolescent Patients With Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Skin pain in atopic dermatitis (AD) increases with disease severity and is associated with substantial quality of life (QoL) burden. OBJECTIVES: To evaluate abrocitinib efficacy on skin pain and QoL in adults and adolescents with moderate-to-severe AD. METHODS: This post hoc analysis included data with abrocitinib administered as monotherapy (pooled phase 2b [NCT02780167] and phase 3 JADE MONO-1 [NCT03349060] and MONO-2 [NCT03575871]) or in combination with topical therapy (phase 3 JADE COMPARE [NCT03720470] and JADE TEEN [NCT03796676]). Patients received oral, once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 or 16 weeks (JADE COMPARE). Skin pain was rated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) skin pain Numerical Rating Scale (NRS) item ("How painful was your skin over the past 24 hours?") on a scale from 0 (not painful) to 10 (extremely painful). Itch (Peak Pruritus NRS) and QoL (Dermatology Life Quality Index or Children's Dermatology Life Quality Index) were assessed. Least squares mean (LSM) change from baseline was analyzed using mixed effects repeated measures modeling. RESULTS: A total of 1822 patients (monotherapy pool, n=942; JADE COMPARE, n=595; JADE TEEN; n=285) were analyzed. LSM change from baseline in PSAAD skin pain score was significantly greater with abrocitinib versus placebo from week 2 through week 12 or 16 across all 3 study populations and occurred in a dose-dependent manner. A greater proportion of patients achieved a ≥4-point improvement from baseline in PSAAD skin pain score with abrocitinib (200 mg and 100 mg) versus placebo in the monotherapy pool (56% and 38% vs 12%; week 12), JADE COMPARE (72% and 52% vs 26%; week 16), and JADE TEEN (51% and 60% vs 31%; week 12). Additionally, a greater proportion of patients achieved a stringent threshold of skin pain improvement (PSAAD skin pain score <2) with abrocitinib versus placebo. Adults and adolescents who achieved a ≥4-point improvement in skin pain reported greater QoL improvement than those who did not achieve a ≥4-point improvement. A positive correlation (≥0.3) was observed between skin pain and QoL and separately between skin pain and itch across the 3 study populations. CONCLUSION: Abrocitinib as monotherapy or in combination with topical therapy improved skin pain and was associated with improved QoL in both adults and adolescents with moderate-to-severe AD across all evaluated studies.

Once-Daily Crisaborole Ointment, 2%, as a Long-Term Maintenance Treatment in Patients Aged ≥ 3 Months with Mild-to-Moderate Atopic Dermatitis: A 52-Week Clinical Study.

BACKGROUND: Topical treatments for atopic dermatitis (AD) used reactively often fail to achieve lasting disease control; many of these therapies are associated with safety concerns that limit long-term use. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD that has potential as a long-term maintenance therapy. OBJECTIVE: The aim was to evaluate the long-term efficacy and safety of crisaborole once daily (QD) compared to vehicle QD as a maintenance therapy to reduce the incidence of flares in patients with AD who previously responded to crisaborole twice daily (BID). METHODS: CrisADe CONTROL was a randomized, double-blind, vehicle-controlled, 52-week, phase III study of patients aged ≥ 3 months with mild-to-moderate AD involving ≥ 5% treatable body surface area. Eligible patients received crisaborole BID during an open-label run-in period of up to 8 weeks. Responders were randomly assigned in the double-blind maintenance period to receive either crisaborole QD or vehicle QD. Responders were defined as patients who achieved Investigator's Static Global Assessment (ISGA) success (ISGA score of 0 [clear] or 1 [almost clear] with a ≥ 2-grade improvement) and ≥ 50% improvement in Eczema Area and Severity Index total score (EASI-50) from baseline. Patients who experienced a flare (ISGA score ≥ 2) during the double-blind maintenance period switched to crisaborole BID for up to 12 weeks. During this period, patients were assessed every 4 weeks; if the flare resolved (ISGA score ≤ 1), patients resumed their assigned treatment. The primary endpoint was flare-free maintenance until onset of the first flare. Key secondary endpoints were number of flare-free days, number of flares, and maintenance of pruritus response until onset of the first flare. The incidence of treatment-emergent adverse events was also analyzed. RESULTS: Overall, 497 patients entered the open-label run-in period with crisaborole BID, of which 270 patients were randomized into the 52-week double-blind maintenance period of the study. Of the 270 patients, 135 were randomly assigned to the crisaborole QD group and 135 were randomly assigned to the vehicle QD group. Median time of flare-free maintenance was longer for patients who received crisaborole versus vehicle (111 vs 30 days, respectively; p = 0.0034). The mean number of flare-free days was higher for patients who received crisaborole versus vehicle (234.0 vs 199.4 days, respectively; p = 0.0346). The mean number of flares was lower for patients who received crisaborole versus vehicle (0.95 vs 1.36, respectively; p = 0.0042). No clear trend was observed in maintenance of pruritus response between crisaborole- and vehicle-treated patients. Crisaborole was well tolerated, with no new or unexpected safety findings when used as maintenance treatment. CONCLUSIONS: Crisaborole QD was effective and well tolerated for long-term maintenance treatment and flare reduction in adult and pediatric patients with mild-to-moderate AD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04040192, 31 July 2019.

Atopic dermatitis (AD) is an immuno-inflammatory skin disease that can last a long time. It causes skin lesions and intense itching. Topical AD treatments used reactively often fail to control the disease over a long period of time. Many are associated with safety concerns that limit long-term use. Crisaborole ointment is a nonsteroidal treatment for the skin and is used to treat mild-to-moderate AD. Previous studies showed that using crisaborole twice daily was effective and had few side effects in patients with mild-to-moderate AD. This study evaluated how effective and safe long-term treatment with once-daily crisaborole was compared with an ointment with no drug (vehicle). The study included patients aged ≥ 3 months with mild-to-moderate AD whose AD improved after previous treatment with twice-daily crisaborole. This study was designed to investigate how much crisaborole reduced the incidence of AD flares over 52 weeks in these patients.The study included 270 patients whose AD had improved after treatment with twice-daily crisaborole. Of these patients, 135 were randomly assigned to receive crisaborole once a day and 135 to receive vehicle once a day. Patients who received crisaborole had a significantly longer time before experiencing AD flares than those who received vehicle. Crisaborole was well tolerated, and no new or unexpected side effects were found when used as a once-daily maintenance treatment for 52 weeks. These results indicate that once-daily treatment with crisaborole could be a potential long-term maintenance treatment option in children and adults with mild-to-moderate AD.

Impact of Crisaborole on Sleep Outcomes in Pediatric Patients with Mild-to-Moderate Atopic Dermatitis.

INTRODUCTION: Using data from three clinical trials, the effect of crisaborole treatment on sleep outcomes for pediatric patients with atopic dermatitis (AD) and their families was examined. METHODS: This analysis comprised patients aged 2 to < 16 years from the double-blind phase 3 CrisADe CORE 1 (NCT02118766) and CORE 2 (NCT02118792) studies, families of patients aged 2 to < 18 years from CORE 1 and CORE 2, and patients aged 3 months to < 2 years from the open-label phase 4 CrisADe CARE 1 study (NCT03356977), all with mild-to-moderate AD who received crisaborole ointment 2% twice daily for 28 days. Sleep outcomes were assessed via the Children's Dermatology Life Quality Index and Dermatitis Family Impact questionnaires in CORE 1 and CORE 2 and the Patient-Oriented Eczema Measure questionnaire in CARE 1. RESULTS: In CORE 1 and CORE 2, a significantly lower proportion of crisaborole-treated patients than vehicle-treated patients reported sleep disruption at day 29 (48.5% versus 57.7%, p = 0.001). The proportion of families whose sleep was affected by their child's AD in the preceding week was also significantly lower in the crisaborole group (35.8% versus 43.1%, p = 0.02) at day 29. At day 29 in CARE 1, the proportion of crisaborole-treated patients who experienced ≥ 1 night of disturbed sleep in the previous week decreased by 32.1% from baseline. CONCLUSION: These results suggest that crisaborole improves sleep outcomes in pediatric patients with mild-to-moderate AD and their families.

Atopic dermatitis (AD), also known as eczema, is a chronic skin disease that causes red or flaky skin patches that can become infected and itch. Children with AD often experience sleep disturbance, including difficulty falling asleep, restless sleep, waking up more frequently, and daytime drowsiness. Problems with sleep quality negatively impact children with AD, as well as their caregivers. Crisaborole ointment is applied to the skin and has been shown to improve the symptoms of AD in children and adults. This study examined how treatment with crisaborole affected sleep quality for children and their caregivers in three clinical trials. Children in these studies took crisaborole for 28 days. Researchers found that crisaborole treatment improved sleep in children with mild-to-moderate AD and their caregivers. This was determined using four measures. First, a smaller proportion of children who were treated with crisaborole experienced sleep disruption compared with those to whom a vehicle was applied (an ointment with no drug). Second, a smaller proportion of caregivers of children with AD who were treated with crisaborole reported effects on their sleep, compared with children to whom a vehicle was applied. Third, a smaller proportion of children with AD who were treated with crisaborole, as well as their caregivers, had ≥ 1 night per week of disturbed sleep after treatment compared with before treatment. Fourth, the caregivers of children treated with crisaborole reported significantly less exhaustion and tiredness because of the child's AD. These results suggest that treatment with crisaborole improves sleep outcomes in children with mild-to-moderate AD and their caregivers.

Real-World Effectiveness of Newly Initiated Systemic Therapy for Atopic Dermatitis in the United States: A Claims Database Analysis.

INTRODUCTION: Atopic dermatitis (AD) is associated with significant quality-of-life and economic burdens. Real-world evidence is needed to identify optimal treatment pathways for AD. Here we evaluate real-world effectiveness of systemic therapies for moderate-to-severe AD in the USA. METHODS: Data (September 2016 to December 2019) were from the IQVIA Health Plan Claims data set (IQVIA, Danbury, CT) from patients aged 12 years or older with AD (ICD-9/10-CM, 691.8/L20.x) initiating a systemic immunosuppressive (SIS) agent (methotrexate, cyclosporine, mycophenolate, or azathioprine) or dupilumab and continuously enrolled for at least 6 months before and after the index date. Indicators of non-response (i.e., adding on/switching systemic therapy, AD-related inpatient/emergency room visits, or incident staphylococcal/streptococcal skin infection) and predictors of non-response were evaluated. Descriptive statistics and Kaplan-Meier rates and times were obtained; Cox regression models were used. RESULTS: In 3249 patients, 45.4% exhibited at least one indicator of non-response, with median time to non-response being longer for dupilumab than for any SIS therapy (27.0 vs 4.0-7.7 months, respectively). Key non-response predictors were age, geographic region, and baseline number of annual AD-related medical visits. CONCLUSION: Non-response was common in patients with AD who required systemic treatment, and non-response indicators occurred significantly more frequently with SIS treatment than with dupilumab treatment.

Predictors of nonresponse to dupilumab in patients with atopic dermatitis: A machine learning analysis.

BACKGROUND: Many patients with atopic dermatitis (AD) have a suboptimal response to systemic therapy. OBJECTIVE: This study assessed predictors of nonresponse to dupilumab in patients with AD. METHODS: Data (April 2017 through June 2019) for patients aged 12 years and above with AD (International Classification of Diseases-9/10-Clinical Modification: 691.8/L20.x) who initiated dupilumab on or after April 1, 2017 (index date) were collected from an electronic health record and insurance claims database. Nonresponse indicators (dupilumab discontinuation, addition of another systemic therapy or phototherapy, addition of a high-potency topical corticosteroid, AD-related hospital visit, AD-related emergency department visit, incident skin infection) were predicted from available demographic and clinical variables using machine learning. RESULTS: Among 419 patients (mean age: 45 years), 145 (35%) experienced at least 1 indicator of nonresponse in the 6-month postindex period. In patients with at least 1 indicator, the most common was dupilumab discontinuation (47% [68/145]). Of note, this analysis could not capture nonmedical reasons for dupilumab discontinuation (eg, cost, access). The most common predictors of nonresponse were a claim for ibuprofen (in 69% of patients with a nonresponse indicator) and a Quan-Charlson Comorbidity Index value of 3 to 4 (59%). CONCLUSION: Systemic dupilumab therapy for AD can be associated with a relatively high prevalence of nonresponse indicators. Factors associated with these indicators-that is, predictors of nonresponse-may be used to optimize disease management.

The Measurement Performance of the Parkinson's Disease Activities of Daily Living, Interference, and Dependence Instrument.

Parkinson's disease is a neurodegenerative disease that can be associated with motor fluctuations that result in substantial negative impact to an individual's activities of daily living. Understanding the patient's perspective about the impact of Parkinson's disease therapies is an important part of drug development and shared treatment decision-making. The objective of this research was to examine the structure, scoring, internal consistency, test-retest reliability, and concurrent and known groups validity of the Parkinson's Disease Activities of Daily Living, Interference and Dependence (PD-AID) instrument, a new, patient-reported outcomes instrument, developed to assess the clinical benefit of Parkinson's disease treatment from the patient's perspective. This was a non-interventional study among persons with mild-to-moderate Parkinson's disease currently using and responding to L-Dopa. The structure of the measure was confirmed applying item response theory to data from baseline, supporting 4 candidate scores. Baseline Patient Global Impression of Severity ratings facilitated known-groups analysis. Data from all participants were used to estimate test-retest reliability. Concurrent validity was assessed using correlations with related measures. Participants (n = 94) were mean age 69 years (mean time since diagnosis 6.9 years); 34 experienced L-Dopa-related dyskinesia. Psychometric models supported 4 candidate scoring regimes for the PD-AID. All exhibited adequate reliability and validity characteristics and strong internal consistency. Correlations with reference measures were in the expected direction and range of magnitude. Analyses supported the PD-AID as fit-for-purpose, producing psychometrically sound scores. Further research to confirm the measurement properties of the PD-AID in an expanded sample and to establish thresholds for meaningful score changes is recommended.

The economic burden of Parkinson disease among Medicare beneficiaries.

BACKGROUND: The progressive nature of Parkinson disease (PD), together with a lack of curative treatments, contributes to its economic burden. OBJECTIVE: To estimate the longitudinal incremental costs attributable to PD among Medicare beneficiaries. METHODS: In this retrospective cohort study, we used data from the Chronic Conditions Data Warehouse to identify Medicare beneficiaries with and without PD-related claims identified from 2006 to 2014 with follow-up until 2015. We grouped PD cases and controls based on their survival profiles using a grouping algorithm that used the following baseline measures: age, race, sex, and comorbidity. We identified 3 survival groups and used them to stratify the descriptive annual cost estimates in the 9 years after the index date. We estimated the incremental 1-, 3-, and 5-year costs of PD using generalized linear models (GLM) that controlled for baseline factors. RESULTS: We identified 27,394 cases and controls who were grouped into 3 survival groups. The mean age of the full study sample was 73 years. No material differences were found in the incremental cost of PD across the survival groups. Based on the multivariable GLM, the 1-year incremental cost of PD was $9,625 (95% CI, $9,054-$10,197). The 3-year incremental cost of PD was $20,832 (95% CI, $19,390-$22,274). The 5-year incremental cost of PD was $27,466 (95% CI, 25,088-$29,844). CONCLUSIONS: Among Medicare beneficiaries, PD is associated with excess costs compared with controls. We did not identify substantial differences in the incremental cost of PD across the survival groups. DISCLOSURES:This study was funded by Pfizer Inc. The funding agreement did not impact the authors' independence in designing the study, collecting the data, interpreting the data, writing the manuscript, and submitting the manuscript for publication. Dr Onukwugha reports grants from Pfizer Inc for the conduct of this study and is an employee of University of Maryland, Baltimore, which received financial support from Pfizer Inc in connection with the development of this manuscript; Dr Shulman reports research funding from Pfizer Inc related to the current work, is an employee of University of Maryland, Baltimore, which received financial support from Pfizer Inc in connection with the development of this manuscript, and reports research funding from the NIH, The Rosalyn Newman Foundation, and the Eugenia and Michael Brin family unrelated to the current work and royalties from Oxford University Press and Johns Hopkins University Press; Ms Myers and Dr Alvir are employees and stockholders of Pfizer Inc; Dr Gray was an employee and stockholder of Pfizer Inc at the time of analysis.

Memory-Assisted Global Impression of Change (MAGIC).

BACKGROUND: The United States Food and Drug Administration is developing a series of patient-focused drug development guidance documents regarding the collection of patient experience data, including methods for understanding treatment benefit from the patient perspective. The goal of this research was to investigate the concern that the global impression of change scale is subject to recall error and thus not optimal for use as an anchor for estimating meaningful within-person change thresholds. We explored whether memory assistance for recalling baseline status would make a difference in how study participants diagnosed with Parkinson's disease (PD) responded to a patient global impression of change (PGIC) and patient global impression static (PGIS) item. METHODS: The research was completed as a secondary objective of a non-interventional 28-day (± 4 days) study among persons with Parkinson's disease and associated motor fluctuations. At baseline, participants completed the PGIS and then recorded a voice message to their future self in which they spoke about how their PD had affected their "day-to-day" activities over the preceding few days. At the final visit, the PGIC and PGIS were completed, after which participants listened to their memory assistance voice recording, and then completed both items for a second time to calculate a memory-assisted global impression static and change scores (MAGIS and MAGIC, respectively). Spearman correlations (ρ) were examined for the pre- and post- memory assistance evaluations. The degree of agreement pre- and post-memory assistance was quantified using the Shrout & Fleiss intraclass correlation coefficient (ICC [2,1]). An ICC(2,1) ≥ 0.7 served as the pre-specified criterion of acceptability for both the ρ and ICC(2,1) values. RESULTS: Participants in the analytic sample were mean age 68.7 and mostly white (91.7%) and male (69.4%). The average length of time since PD diagnosis was 6.5 years. Correlations between the PGIS and MAGIS were ρ = 0.88; correlations between PGIC and MAGIC were ρ = 0.86. The estimated ICC(2,1) for both the PGIS/MAGIS and PGIC/MAGIC exceeded target success criterion of ICC(2,1) ≥ 0.70. CONCLUSION: Our results show that the MAGIS/MAGIC methodology is feasible and that memory assistance did not substantially alter the PGIS/PGIC scores at the final visit.

Patient and caregiver preferences on treatment attributes for atopic dermatitis.

BACKGROUND: The expanding number of potential treatment options for atopic dermatitis (AD) highlights the need to better understand the treatment preferences of individuals with AD. OBJECTIVE: This study identified attributes that most greatly influenced treatment preferences of adults/adolescents/caregivers of children with mild/moderate/severe AD. METHODS: Adults (≥18 years), adolescents (12-17 years), and caregivers of children (2-11 years) with mild, moderate, or severe AD in the United States (US) and United Kingdom (UK) participated in semistructured interviews. Thematic analysis was used to identify and generate themes across the interview results describing the treatment attributes of greatest importance to participants. RESULTS: Qualitative interviews were conducted with 35 adults, 35 caregivers, and 33 adolescent participants across both countries (n = 103; US = 51; UK = 52) and all severity groups (mild = 43; moderate = 47; severe = 13). The most important treatment attributes included efficacy (96.1%; speed and duration of symptom relief), mode of administration (66.0%; route of administration, frequency, and convenience), and side effects (55.3%, short-term, long-term, and general). CONCLUSIONS: Efficacy, mode of administration, and side effects were the most important attributes that influenced AD treatment preferences for patients and caregivers across different countries, ages, and disease severity. These results may assist patients/caregivers/clinicians in shared decision-making discussions to improve treatment adherence and outcomes.

Health Care Resource Utilization Associated With Parkinson Disease Among Medicare Beneficiaries.

OBJECTIVE: To compare differences in health care resource utilization (HcRU) over time between Medicare beneficiaries with and without Parkinson disease (PD). METHODS: This retrospective observational study used the Chronic Conditions Data Warehouse (5% Medicare sample) between 2005 and 2015. In a propensity score-matched (age, sex, race, and comorbidity adjusted) sample of beneficiaries with and without PD, we examined all-cause HcRU due to inpatient admissions, emergency department (ED) admissions, skilled nursing facility (SNF) admissions, health care provider encounters, neurologist visits, rehabilitation service visits, and non-PD medication fills. Relative to beneficiaries without PD, we reported adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for beneficiaries with PD using generalized linear models with log link and negative binomial variance functions. RESULTS: A total of 467,064 Medicare enrollees (unmatched sample) met the inclusion criteria. Of these, 3.3% had PD. In the matched sample and relative to beneficiaries without PD, beneficiaries with PD displayed higher rates of inpatient admissions (IRR 1.29, 95% CI 1.24-1.34), ED admissions (IRR 1.31, 95% CI 1.27-1.34), SNF admissions (IRR 2.00, 95% CI 1.92-2.09), health care provider encounters (IRR 1.18, 95% CI 1.16-1.20), neurologist visits (IRR 5.57, 95% CI 5.35-5.78), rehabilitation service visits (IRR 1.47, 95% CI 1.41-1.53), and non-PD medication fills (IRR 1.10, 95% CI 1.08-1.11) over time. CONCLUSION: These results reflect patterns of medical care among Medicare beneficiaries with PD. The findings can help clinicians, payers, and policy makers make evidence-based decisions for the allocation of scarce health care resources for PD management. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Medicare beneficiaries with PD use more health care resources than matched controls without PD.

Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes.

BACKGROUND: Atopic dermatitis imparts a substantial patient burden, including itch, sleep disturbance, and decreased health-related quality of life. OBJECTIVE: This analysis evaluated changes in patient-reported outcomes of disease-specific signs/symptoms and health-related quality of life in adult and adolescent patients with moderate-to-severe atopic dermatitis treated with once-daily oral abrocitinib 200-mg or 100-mg monotherapy. METHODS: Pooled data from one phase IIb (NCT02780167) and two phase III (NCT03349060, JADE MONO-1; NCT03575871, JADE MONO-2) monotherapy trials in adult and adolescent patients with moderate-to-severe atopic dermatitis were analyzed. Patient-reported outcome assessments included: global severity, itch, and multi-item measures that assess other signs and symptoms of atopic dermatitis. Additional patient-reported outcome assessments measured depression, anxiety, fatigue, disease-specific and general health-related quality of life, and work and general productivity among employed patients. RESULTS: Overall, 942 patients were included in this analysis. Improvements were observed from the first post-baseline assessment to week 12 across all patient-reported outcomes, including Patient Global Assessment (PtGA) score of 0/1 (35.5%, 19.8%, and 5.9% for 200 mg, 100 mg, and placebo, respectively), ≥ 4-point improvement in Night Time Itch Scale (NTIS; 57.0%, 42.7%, and 12.7%), change from baseline in Patient-Oriented Eczema Measure (POEM) score (- 11.4, - 8.2, and - 3.4), 1-point improvement in Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD; 75.2%, 65.1%, and 33.5%), Hospital Anxiety and Depression Scales (HADS) anxiety (- 2.0, - 1.7, and - 1.0) and depression (- 1.7, - 1.3, and - 0.1). CONCLUSIONS: Abrocitinib monotherapy improved disease-specific signs/symptoms and health-related quality of life across multiple domains as reported by adult and adolescent patients with moderate-to-severe atopic dermatitis, complementing clinician-reported efficacy and safety outcomes. CLINICAL TRIAL REGISTRATION: NCT02780167 (registered 23 May, 2016), NCT03349060 (registered 21 November, 2017), NCT03575871 (registered 3 July, 2018).

Relationship Among Treatment, Pruritus, Investigator's Static Global Assessment, and Quality of Life in Patients with Atopic Dermatitis.

INTRODUCTION: The Investigator's Static Global Assessment (ISGA) is a 5-point rating scale that is recommended by the US Food and Drug Administration for assessing the severity of atopic dermatitis (AD), and ISGA success is a widely used endpoint in AD clinical studies. In this study, we seek to interpret the relationship of ISGA with treatment, pruritus, and quality of life (QoL) by conducting post hoc analyses of pooled data from two phase 3 crisaborole studies. METHODS: Patients aged ≥ 2 years with baseline ISGA of 2 (mild) or 3 (moderate) were randomly assigned 2:1 to receive crisaborole or vehicle for 28 days. Disease severity, pruritus severity, and QoL were assessed with the ISGA, Severity of Pruritus Scale (SPS), and Dermatology Life Quality Index (DLQI; patients aged ≥ 16 years), or Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years), respectively. The effect of treatment on ISGA and the relationship between ISGA and QoL were analyzed using a longitudinal repeated-measures model. The interrelationship between treatment, disease severity, pruritus, and QoL was analyzed with a mediation model. RESULTS: Overall, 1522 patients (crisaborole, n = 1016; vehicle, n = 506) were included. Estimated longitudinal profiles indicated changes in ISGA by day 8 were large for crisaborole (effect size [ES]: - 0.68) and small for vehicle (ES: - 0.34). There was a direct relationship between ISGA and DLQI and CDLQI severity bands in the longitudinal repeated-measures model. For both QoL mediation models, treatment effects on QoL were mediated indirectly by reduction in pruritus (DLQI, 42.4%; CDLQI, 58.1%) and disease severity (DLQI, 12.2%; CDLQI, 33.1%). CONCLUSIONS: These post hoc analyses suggest that ISGA success is a clinically meaningful endpoint associated with reduction in the severity of pruritus and improvement in QoL.

Improvement in disease severity and pruritus outcomes with crisaborole ointment, 2%, by baseline atopic dermatitis severity in children and adolescents with mild-to-moderate atopic dermatitis.

BACKGROUND/OBJECTIVES: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). This pooled post hoc analysis of two phase 3 trials (NCT02118766, NCT02118792) assessed improvement and time to improvement in Investigator's Static Global Assessment (ISGA) and Severity of Pruritus Scale (SPS) outcomes in pediatric patients with mild-to-moderate AD. METHODS: Patients aged ≥2 years were randomly assigned 2:1 to receive twice-daily crisaborole or vehicle for 28 days. Patients aged 2-17 years were pooled for this analysis. Proportions of patients and time to achieving ISGA success (clear [0] or almost clear [1] with ≥2-grade improvement from baseline), ISGA clear/almost clear, ≥1-grade improvement in ISGA, SPS success (SPS score ≤1 with ≥1-grade improvement), or ≥1-grade improvement in SPS score were analyzed and stratified by baseline ISGA. RESULTS: At first postbaseline assessment (day 8), significantly higher proportions of crisaborole- than vehicle-treated patients achieved ISGA success, ISGA clear/almost clear, ≥1-grade ISGA improvement, SPS success, or ≥1-grade improvement in SPS regardless of baseline ISGA. Differences were significantly greater over time for all outcomes for patients with moderate baseline ISGA and numerically greater for those with mild baseline ISGA. Median times to ISGA and SPS outcomes were shorter for crisaborole versus vehicle. CONCLUSION: Improvement in ISGA and SPS outcomes were observed with crisaborole in pediatric patients with mild-to-moderate baseline AD.

The Parkinson's Disease Activities of Daily Living, Interference, and Dependence Instrument.

BACKGROUND: Individuals with Parkinson's disease often experience periods of off time when their motor symptoms are poorly controlled, significantly impacting their lives. OBJECTIVES: To identify the consequences of motor fluctuations on day-to-day activities and areas of unmet treatment priority among individuals with moderate to advanced Parkinson's disease, to assess whether existing patient-reported outcome instruments adequately capture these consequences and priorities, and based on these evaluations, to adapt an existing or develop a new instrument. METHODS: The research was conducted in 2 stages: concept exploration and content confirmation. Concept exploration included direct input from individuals with Parkinson's disease representing the intended context of use via concept elicitation interviews. Content confirmation and item refinement was achieved through 5 rounds of cognitive debriefing. Final rounds of cognitive debriefing also included usability testing of the draft instrument for electronic data capture. RESULTS: Concept elicitation interviews were conducted among 29 individuals with Parkinson's disease (55% male; mean age 60.8 years). Concept saturation was achieved quickly with more than 90% of concepts identified by the end of the 16th interview. None of the existing outcome instruments were found to be fit for purpose in the intended context of use; therefore, a new instrument was developed. After 5 rounds, cognitive debriefing participants indicated clear and consistent interpretation of the items. CONCLUSIONS: Evidence from this study supports the content validity of the Parkinson's Disease Activities of Daily Living, Interference and Dependence Instrument as the basis of a clinical trial endpoint for capturing priority treatment benefit outcomes to individuals with moderate to advanced Parkinson's disease experiencing motor fluctuations.

Health economic evaluation of patients treated for nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus: secondary analysis of a multicenter randomized clinical trial of vancomycin and linezolid.

PURPOSE: Results from studies comparing health care resource use (HCRU), costs of treatment, and cost-effectiveness of linezolid compared with vancomycin therapy in the treatment of hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia are limited in the published literature. We therefore conducted an analysis to compare the HCRU, costs of treatment, and cost-effectiveness of linezolid compared with vancomycin in the treatment of hospitalized patients with MRSA nosocomial pneumonia using data from a Phase IV clinical trial. The economic effect of moderate to severe adverse events (MSAEs) and the development of renal failure were also evaluated. METHODS: We performed a post hoc analysis of data from a Phase IV, double-blind, randomized, comparator-controlled, multicenter trial that compared linezolid and vancomycin treatment in patients with MRSA nosocomial pneumonia. HCRU and costs were compared based on treatment, development of MSAEs, and development of renal failure using data from the modified intent-to-treat population. Predictors of costs were evaluated using generalized linear models. A piggyback cost-effectiveness analysis was conducted to assess the incremental cost-effectiveness ratio of linezolid versus vancomycin, given the significantly higher clinical success of linezolid compared with vancomycin found in the trial. FINDINGS: Overall, HCRU and costs were similar between the linezolid and vancomycin treatment groups; drug costs were significantly higher and dialysis costs significantly lower for linezolid- compared with vancomycin-treated patients. Total treatment costs were approximately $8000 higher (P = .046) for patients who developed renal failure compared with those who did not. Renal failure occurred more commonly in patients randomized to receive vancomycin (15%) compared with linezolid (4%; P < .001). Region, ventilator-associated pneumonia, clinical failure, and development of renal failure were associated with significantly higher total costs. The point estimate incremental cost-effectiveness ratio for linezolid compared with vancomycin was $16,516 per treatment success, with linezolid dominant in 24% and dominated in <2% of bootstrapped samples. IMPLICATIONS: This phase 4 clinical trial conducted in patients with MRSA-confirmed nosocomial pneumonia reveals that linezolid- compared with vancomycin-treated patients had similar HCRU and total overall costs. Fewer patients developed renal failure during the study while taking linezolid compared with vancomycin, and patients with a documented MSAE or renal failure had increased HCRU and costs. In summary, linezolid may be a cost-effective treatment strategy in MRSA-confirmed nosocomial pneumonia.