The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

The Economic Burden of Adults with Major Depressive Disorder in the United States (2019).

INTRODUCTION: Previous societal burden estimations for major depressive disorder (MDD) often fail to account for several hidden cost components. This study provides a comprehensive evaluation of societal costs for adults with MDD in the United States (USA) in 2019. The potential impact of a more effective, rapid-acting MDD therapy vs standard of care on the economic burden of MDD was estimated to illustrate the utility of such a framework in evaluating new interventions. METHODS: This study used a prevalence-based human capital approach. Incremental costs (2019 US dollars) per individual with MDD were derived from national survey inputs and published literature and included incremental healthcare costs and indirect costs. For each cost component, the societal costs were extrapolated by multiplying the per-patient costs by the number of individuals with MDD. The impact of a more effective, rapid-acting novel therapy on the economic burden of MDD was then simulated on the basis of these inputs. RESULTS: In 2019, the number of adults with MDD in the USA was estimated at 19.8 million (62.7% female; 32.9% severe MDD), and the incremental societal economic burden of MDD was estimated at $333.7 billion ($382.4 billion in 2023 US dollars), or $16,854 per adult with MDD. The primary cost drivers were healthcare costs ($127.3 billion; 38.1%), household-related costs ($80.1 billion; 24.0%), presenteeism ($43.3 billion; 13.0%), and absenteeism ($38.4 billion; 11.5%). In the simulated scenario, a hypothetical novel therapy with a 50.0% early response rate was associated with a 7.7% reduction in the economic burden of MDD relative to standard of care over 12 months. CONCLUSIONS: The economic burden of MDD is substantial and extends beyond healthcare costs, underscoring the impact of MDD across multiple aspects of life. Such a broad societal perspective should be considered in assessing the impact of the advent of effective, rapid-acting MDD therapies.

Impact of Treating Depression on Associated Comorbidities: A Systematic Literature Review.

Objective: To identify and summarize data that describe the impact of effectively treating major depressive disorder (MDD) on the severity or risk of serious comorbidities.Data Sources: MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and several congresses were searched. Searches included terms related to MDD, randomized controlled trials (RCTs), and physical comorbidities and were restricted to English-language publications. Searches were conducted in November 2019 for the previous 2 years for conference proceedings; no date restriction was applied to the database searches.Study Selection: Included studies were RCTs or meta-analyses that assessed depression therapies. Studies were required to report a statistically significant improvement in depression scores as well as the concurrent impact on comorbidities. A total of 1,997 articles were initially identified for screening.Data Extraction: Two investigators extracted data and assessed study quality.Results: A total of 30 studies, including 24 RCTs (N = 6,333) and 6 meta/pooled analyses of RCTs, were included. Findings in several comorbidity categories were mixed; for example, in half (4 of 8) of the identified studies in people with cardiovascular disease and depression, individuals who received treatment leading to reduced depressive symptoms compared with a control arm also had a significantly decreased incidence of cardiovascular events or significantly improved cardiac disease symptom/severity scores compared with controls. Significant improvements in comorbid disease severity observed alongside improvements in depressive symptoms were also noted in studies of comorbid Parkinson's disease, multiple sclerosis, chronic pain and fibromyalgia, and chronic obstructive pulmonary disease.Conclusions: Effective treatment of MDD may lead to a reduction in the severity of certain serious comorbidities. These results highlight the importance of appropriate and timely treatment of MDD.

The impact of early remission on disease trajectory and patient outcomes in major depression disorder (MDD): A targeted literature review and microsimulation modeling approach based on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

BACKGROUND: While literature has suggested that the duration of a major depressive episode (MDE) may affect both symptomatic and functional outcomes in major depressive disorder (MDD), study designs are limited in their ability to isolate a causal relationship. METHODS: A targeted literature review was conducted using the MEDLINE database to assess whether there was an association between (1) shorter duration of an MDE, or (2) increased rapidity of symptom improvement, and MDD outcomes in adult patients. Given findings from the literature, we hypothesized that rapid symptom improvement could be associated with other longer-term clinical outcomes and used a previously-developed microsimulation model to test this hypothesis. The base case of the model replicated step-therapy treatment patterns, for 10,000 simulated patients, based on lines of therapy related to standard of care, observed remission rates, and observed time to relapse from the STAR*D study. In alternative scenario analyses, the step 1 remission rate was varied by +25 % and +50 % from the base case value to simulate the potential impact of improved earlier remission on disease trajectory and patient-level clinical outcomes. RESULTS: The literature review (N = 35 studies) suggests a statistically significant relationship between the duration of MDE or early symptom improvement and MDD outcomes. The microsimulation model corroborated these findings and demonstrated that increasing the rate of remission in step 1 results in patients experiencing decreased number of treatment steps, faster time to remission, decreased rate of reaching treatment-resistant depression, and delayed time to relapse. LIMITATIONS: Rates of relapse in STAR*D were deemed unreliable due to the high-loss of follow-up; rates of relapse for the MDD DTM were instead derived using parametric extrapolation methods (i.e., exponential, Weibull, log-logistic, Gaussian, log-normal, logistic). Adherence to treatment was assumed to be 100 %; however, non-adherence is expected to result in lower cumulative remission rates. CONCLUSION: Findings from the literature, coupled with quantification through a novel microsimulation model, demonstrate the potential impact of increased remission on disease trajectory and patient outcomes in MDD. While additional analyses with the model may be warranted to explore the impact of novel interventions on population health, including long-term outcomes (i.e., 5-year follow-up, lifetime follow-up), efforts by clinicians to increase remission early in the disease trajectory may improve long-term outcomes.

Rate of Lung Function Decline in People with Cystic Fibrosis Having a Residual Function Gene Mutation.

INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF). METHODS: Rate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006-2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6-12 (children), 13-17 (adolescents), 18-24 (young adults), and ≥ 25 years (adults)] were performed. RESULTS: The estimated annualized rate of ppFEV1 decline was - 0.70 percentage points per year (95% CI -1.09, -0.30) in the F/RF (all) cohort (N = 1242) versus -1.91 percentage points per year (95% CI -2.01, -1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from -0.30 to -1.38. In the F/RF (excluding R117H) cohort, the rate of decline was -1.05 percentage points per year (95% CI -1.51, -0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults]. CONCLUSION: Progressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.

In people with cystic fibrosis, lung function typically decreases over time and is linked to the severity of the disease. How fast lung function decreases (referred to as the rate of lung function decline) in cystic fibrosis depends on the specific mutations (changes) in the CFTR gene (which causes the disease). Lung function decline has been well studied in some mutation groups, but not many previous studies have looked at lung function decline in people with one copy of the F508del-CFTR mutation (which is the most common CFTR mutation and results in little to no functional CFTR protein) and another CFTR mutation called a residual function mutation (referred to as people with F/RF genotypes). We used data from the US Cystic Fibrosis Foundation Patient Registry (which collects information on the health of people in the USA who have cystic fibrosis), to look at the rate of lung function decline in people with F/RF genotypes. We found that people with cystic fibrosis who have F/RF genotypes experience lung function loss over time. We also found that this lung function loss occurred in people of all ages with F/RF genotypes. This finding supports the importance of early treatment to help prevent lung function loss in all people with cystic fibrosis, including people with F/RF genotypes.

Economic burden and antidepressant treatment patterns among patients with major depressive disorder in the United States.

BACKGROUND: The prevalence of major depressive disorder (MDD) continues to rise year over year, resulting in significant economic implications. However, when patients are treated with contemporary standard-of-care antidepressant pharmacotherapies, a suboptimal response is often attained, resulting in frequent treatment changes. OBJECTIVE: To compare health care resource utilization (HCRU) and all-cause medical and pharmacy costs between commercially insured patients with an MDD diagnosis and matched non-MDD patients and explore treatment patterns among patients with MDD initiating antidepressant pharmacotherapy. METHODS: This was a retrospective, observational analysis of IBM MarketScan US commercial claims data. Adults aged 18 years and older with continuous enrollment 12 or more months before and after the patient's first MDD diagnosis from 2017 to 2018 were included in the analysis. HCRU and all-cause medical and pharmacy costs were compared among patients with MDD and a 1:1 exact-matched cohort of non-MDD patients during the same period (Objective 1). Treatment patterns (persistence, discontinuation, switch, combination, and augmentation) were analyzed for patients with MDD starting first-line antidepressant monotherapy for up to 12 months following their antidepressant initiation index date (Objective 2). Time to first treatment change or discontinuation was calculated and treatment patterns were graphically displayed in Sankey diagrams. RESULTS: 625,272 patients with MDD were matched 1:1 to a cohort of non-MDD patients in Objective 1. Patients with MDD had statistically significantly greater all-cause medical (20.4 vs 9.4; P < 0.0001), outpatient (19.5 vs 9.0; P < 0.0001), emergency department (0.51 vs 0.23; P < 0.0001), inpatient (0.35 vs 0.11; P < 0.0001), and any mental health-related (7.7 vs 0.58; P < 0.0001) visits compared with non-MDD patients. Mean all-cause medical costs were $6,809 (P < 0.0001) higher among patients with MDD than among patients without MDD ($13,183 vs $6,374, respectively). In Objective 2, 44,485 patients with MDD who received antidepressant monotherapy as their first-line MDD treatment were examined. Among the first treatment patterns observed following initiation, 19.3% of patients persisted with their first-line therapy, 56.2% discontinued antidepressant therapy, 24.5% experienced a treatment change (switching, adding a second antidepressant, or augmenting their existing therapy). The median days until first treatment change were 65 days for those discontinuing and 47 days for those switching antidepressants. Among the 24.5% of patients with a treatment change, 50.0% experienced another change in therapy within 30 days. CONCLUSIONS: The HCRU and costs accrued for patients with MDD is significantly greater than those for non-MDD patients. A large proportion of patients with MDD experienced treatment changes shortly after initiating their first-line antidepressant therapy. The results of this study highlight the need for reevaluation of the current MDD treatment paradigm. DISCLOSURES: Drs Zhu and Namjoshi are employees of Biogen Inc. and may hold stock. Dr Ferries and Ms Suthoff are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options. Dr Bera has no potential conflicts of interest to disclose. This research was funded by Sage Therapeutics and Biogen. Manuscript editorial services were provided by Boston Strategic Partners, Inc., funded by Sage Therapeutics and Biogen. This work was supported by Sage Therapeutics, Inc., and Biogen. The authors had full editorial control of the manuscript and provided final approval on all content.

Impact of Major Depressive Disorder on Comorbidities: A Systematic Literature Review.

Objective: To summarize the breadth of data exploring the relationship between major depressive disorder (MDD) and both the incidence and the disease course of a range of comorbidities.Data Sources: The authors searched MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and several prespecified congresses. Searches included terms related to MDD and several comorbidity categories, restricted to those published in the English language from 2005 onward.Study Selection: Eligibility criteria included observational studies within North America and Europe that examined the covariate-adjusted impact of MDD on the risk and/or severity of comorbidities. A total of 6,811 articles were initially identified for screening.Data Extraction: Two investigators extracted data and assessed study quality.Results: In total, 199 articles were included. Depression was significantly (P < .05) associated with an increased incidence of dementia and Alzheimer's disease as well as cognitive decline in individuals with existing disease; increased incidence and worsening of cardiovascular disease/events (although mixed results were found for stroke); worsening of metabolic syndrome; increased incidence of diabetes, particularly among men, and worsening of existing diabetes; increased incidence of obesity, particularly among women; increased incidence and worsening of certain autoimmune diseases; increased incidence and severity of HIV/AIDS; and increased incidence of drug abuse and severity of both alcohol and drug abuse.Conclusions: The presence of MDD was identified as a risk factor for both the development and the worsening of a range of comorbidities. These results highlight the importance of addressing depression early in its course and the need for integrating mental and general health care.

Humanistic and economic burden associated with depression in the United States: a cross-sectional survey analysis.

BACKGROUND: Depression (major depressive disorder [MDD]) affects the functioning of patients in many facets of life. Very few large-scale studies to date have compared health and economic related outcomes of those with versus without depression, and across various depression severity groups. We aimed to evaluate humanistic and economic burden in respondents with and without depression diagnosis, and across symptom severity groups. METHODS: Data from the 2017 US National Health and Wellness Survey (NHWS) were utilized. Of the adult respondents (N = 75,004), 59,786 were < 65 years old. Respondents not meeting eligibility criteria were excluded (e.g., those self-reporting bipolar disorder or experiencing depression in past 12 months but no depression diagnosis). Overall, data from 39,331 eligible respondents (aged 18-64 years) were analyzed; and comprised respondents 'with depression diagnosis' (n = 8853; self-reporting physician diagnosis of depression and experiencing depression in past 12 months) and respondents 'without depression diagnosis' (n = 30,478; no self-reported physician diagnosis of depression and not experiencing depression). Respondents with depression were further examined across depression severity based on Patient Health Questionnaire-9 (PHQ-9). Outcome measures included health-related quality-of-life (HRQoL; Medical Outcomes Study 36-item Short Form [SF-36v2]: mental and physical component summary [MCS and PCS]; Short-Form 6 Dimensions [SF-6D]; and EuroQol 5 Dimensions [EQ-5D]), work productivity and activity impairment (WPAI), and health resource utilization (HRU). Multivariate analysis was performed to examine group differences after adjusting covariates. RESULTS: Respondents with depression diagnosis reported significantly higher rates of diagnosed anxiety and sleep problems versus those without depression (for both; P < 0.001). Adjusted MCS, PCS, SF-6D, and EQ-5D scores were significantly lower in respondents with depression versus those without depression (all P < 0.001). Consistently, respondents with depression reported higher absenteeism, presenteeism, and overall WPAI, as well as greater number of provider visits, emergency room visits, and hospitalizations compared with those without depression (all P < 0.001). Further, burden of each outcome increased with an increase in disease severity. CONCLUSIONS: Diagnosed depression was associated with lower health-related quality-of-life and work productivity, and higher healthcare utilization than those without depression, and burden increased with an increase in symptom severity. The results show the burden of depression remains high even among those experiencing minimal symptoms.

Patient-reported health-related quality of life from a randomized, placebo-controlled phase 2 trial of zuranolone in adults with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD), a disabling, potentially life-threatening condition, negatively affects health-related quality of life (HRQoL). This secondary analysis aimed to understand the impact of the neuroactive steroid zuranolone on HRQoL using the Short Form-36v2 Health Survey (SF-36v2). METHODS: Adult patients with MDD and 17-item Hamilton Rating Scale for Depression total score ≥22 were randomized 1:1 to receive zuranolone 30 mg or placebo for 2 weeks, with 4 weeks follow-up. SF-36v2 scores were assessed at Day 15 across 8 domains (Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health) and 2 summary scores (Physical and Mental Component), using a mixed-effects model for repeated measures. Correlations between SF-36v2 scores and clinician-reported efficacy endpoints were assessed using Pearson's correlation. RESULTS: Eighty-nine patients were treated with zuranolone 30 mg (n = 45) or placebo (n = 44). In zuranolone-treated patients, HRQoL improved across all SF-36v2 domains and summary scores at Day 15. Improvements exceeding established minimally important difference thresholds were observed in Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health scores. Improvements in General Health, Vitality, Mental Health, and Mental Component Summary were statistically significant versus placebo (p ≤ 0.025). Clinician-rated endpoints negatively correlated with SF-36v2 scores. LIMITATIONS: The small unipolar depression sample may not be representative of all US MDD patients. HRQoL measures could be impacted by factors unrelated to depression. CONCLUSIONS: Zuranolone-treated patients reported rapid and significant improvements in HRQoL versus placebo at Day 15. HRQoL improvements correlated with improvements in clinician-rated assessments. TRIAL REGISTRATION: clinicaltrials.gov:NCT03000530; https://clinicaltrials.gov/ct2/show/NCT03000530.

The Increasing Economic Burden with Additional Steps of Pharmacotherapy in Major Depressive Disorder.

OBJECTIVES: Major depressive disorder (MDD) is a common and serious disorder with significant impact on patients and families. The goal of this retrospective cohort study was to determine the economic burden among patients with MDD stratified by number of treatment lines needed for episode resolution. METHODS: Truven Health Analytics MarketScan® claims data were used to identify US patients (≥ 18 years) who were diagnosed with MDD and started on an antidepressant between 2013 and 2017. A generalized linear model estimated direct and employment-related costs for the first 12 months following initiation of treatment across cohorts with increasing number of lines of MDD pharmacotherapy. Analyses were adjusted for demographics and clinical factors. RESULTS: A total of 73,597 patients with MDD comprising the commercial (n = 66,459) and Medicare (n = 7138) populations met selection criteria. Patients who completed treatment for their episode with a single line of antidepressant had the lowest total adjusted direct costs (commercial $9975; Medicare $14,628) followed by those who completed with two lines (commercial $11,723; Medicare $15,526) and those treated with three or more lines of antidepressant regimens (commercial $21,259; Medicare $20,964). Patients who completed treatment with two lines as opposed to one incurred significantly higher direct costs (commercial +$1748, p < 0.0001; Medicare +$898, p = 0.0092). Patients who completed treatment with one line had the lowest employment-related costs compared to other groups. CONCLUSIONS: There was an increased economic burden associated with delay of episode resolution as early as the second line compared to the first line in MDD.

Number Needed to Treat and Number Needed to Harm analysis of the zuranolone phase 2 clinical trial results in major depressive disorder.

BACKGROUND: Zuranolone (SAGE-217) is a novel, investigational positive allosteric modulator of GABAA receptors being investigated in major depressive disorder (MDD). This analysis of phase 2 data quantified the benefit and risk of zuranolone (30mg) versus placebo and antidepressants in terms of number needed to treat (NNT) and number needed to harm (NNH). METHODS: Rates of response, remission, and all-cause discontinuation for zuranolone and 11 antidepressant comparators were obtained from the zuranolone phase 2 clinical study (N=89) and a published network meta-analysis, respectively. An indirect treatment comparison was conducted using the Bucher method to compare zuranolone to standard-of-care. RESULTS: Zuranolone demonstrated greater benefit compared to placebo on Day 3 (NNT range for response=4-5, NNT for remission=10) and at Day 15 (NNT=3 for response and remission). Compared to SSRIs and SNRIs, zuranolone at Day 15 showed improved treatment response (NNT=4 [95% CI = 3; 16] and 5 [95% CI = 3; 25], respectively) and remission (NNT=4 [95% CI = 2; 13] and 4 [95% CI = 2; 18], respectively). This was accompanied by a reduction in all-cause discontinuation, with negative NNH values (-57 and -28), respectively. LIMITATIONS: Variations in study design across the included trials may limit the generalizability of results. CONCLUSIONS: With a small positive NNT as early as Day 3 indicating robust benefit and a negative NNH indicating reduced harm, this analysis based on a phase 2 study suggests that patients with MDD may benefit from the benefit-to-risk profile of zuranolone.

The Cystic Fibrosis Impact Questionnaire: qualitative development and cognitive evaluation of a new patient-reported outcome instrument to assess the life impacts of cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) experience significant disease burden, including progressive pulmonary decline and reduced survival. This multicenter qualitative study was conducted to develop a new patient-reported outcome (PRO) measure to assess the impact of CF on patients' quality of life: the Cystic Fibrosis Impact Questionnaire (CF-IQ). Semi-structured qualitative concept elicitation (CE) interviews with patients and caregivers documented CF-related symptoms, impacts, and treatment experiences. Coded interview data were considered alongside existing PROs, published literature, and expert opinion to develop an initial scale. Three rounds of cognitive interviews evaluated respondent comprehension and facilitated refinement of the CF-IQ. RESULTS: Adult (N = 20) and pediatric (N = 22) patients with CF and their parents/caregivers (N = 22) completed CE interviews at 7 US clinics. The sample included patients aged 6-58 years, 57% females, and represented a broad range of disease severity (forced expiratory volume in 1 s range: 22%-127% predicted). Interviews identified 59 unique CF-related impact concepts in domains, including activity limitations (physical, social, leisure), functional limitations (school, work), vulnerability/lack of control, emotional impact, treatment burden, and future outlook. Concept saturation was achieved, and a draft questionnaire was developed. Findings from the cognitive interviews (n = 18) confirmed that instructions, items, and response scales were relevant and clear, and interpreted as intended by patients. CONCLUSION: The CF-IQ is a 40-item novel PRO scale assessing a comprehensive set of patient-relevant concepts to characterize the multifaceted nature of CF. Qualitative interview data support the content validity of the CF-IQ, which is currently undergoing additional psychometric evaluation in patients with CF.

Caregiver Burden Due to Pulmonary Exacerbations in Patients with Cystic Fibrosis.

OBJECTIVE: To describe the poorly understood burden of pulmonary exacerbations experienced by primary caregivers of children (aged 2-17 years) with cystic fibrosis (CF), who frequently require prolonged hospitalizations for treatment of pulmonary exacerbations with intravenous (IV) antibiotics. STUDY DESIGN: In this prospective observational study, 88 caregivers in Germany, Ireland, the United Kingdom, and the US completed a survey during pulmonary exacerbation-related hospitalizations (T1) and after return to a "well state" of health (T2). The impact of pulmonary exacerbations on caregiver-reported productivity, mental/physical health, and social/family/emotional functioning was quantified. RESULTS: Primary caregivers of children with CF reported significantly increased burden during pulmonary exacerbations, as measured by the 12-item Short-Form Health Survey mental health component and the Work Productivity and Activity Impairment: Specific Health Problem absenteeism, presenteeism, work productivity loss, and activity impairment component scores. Compared to the "well state," during pulmonary exacerbations-related hospitalization caregivers reported lower physical health scores on the Child Health Questionnaire-Parent Form 28. Quality-of-life scores on the Caregiver Quality of Life Cystic Fibrosis scale and total support score on the Multidimensional Scale of Perceived Social Support did not differ significantly between T1 and T2. More caregivers reported a negative impact on family/social/emotional functioning during pulmonary exacerbations than during the "well state." CONCLUSIONS: Pulmonary exacerbations necessitating hospitalization impose a significant burden on primary caregivers of children with CF. Preventing pulmonary exacerbations may substantially reduce this burden.

Patient-reported outcomes in patients with cystic fibrosis with a G551D mutation on ivacaftor treatment: results from a cross-sectional study.

BACKGROUND: Clinical studies demonstrate that ivacaftor (IVA) improves health-related quality of life (HRQoL) in patients aged ≥6 years with cystic fibrosis (CF). The real-world impact of IVA and standard of care (SOC) in groups of patients with G551D and F508del mutations, respectively, was assessed using a survey comprising disease-specific and generic HRQoL measures. METHODS: Patients with CF aged ≥12 years, or aged 6-11 years with caregiver support, with either (1) a G551D mutation and receiving IVA (G551D/IVA) for ≥3 months, or (2) homozygous for F508del and receiving SOC before lumacaftor/IVA availability (F508del/SOC), were eligible to participate in a cross-sectional survey. Demographic and clinical characteristics, and HRQoL measures were compared between patient groups, and multiple regression analyses were conducted. RESULTS: After differences in patient demographic and clinical characteristics were controlled for, significantly better scores were observed in the G551D/IVA group than in the F508del/SOC group on multiple domains of the validated Cystic Fibrosis Questionnaire-Revised and the EuroQol 5-dimensions 5-level questionnaire. CONCLUSIONS: G551D/IVA patients reported better HRQoL than F508del/SOC patients on generic and disease-specific measures in a real-world setting.

Measuring recovery in health-related quality of life during and after pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: We explored the time-dependent impact of pulmonary exacerbations (PEx) on health-related quality of life (HRQoL) using Cystic Fibrosis Questionnaire-Revised (CFQ-R) data from 2 large cystic fibrosis (CF) trials. METHODS: This exploratory post-hoc analysis evaluated the impact of PEx on CFQ-R domains of functioning in 80 patients with CF (homozygous for F508del-CFTR), aged ≥14 years randomized to placebo in the TRAFFIC and TRANSPORT trials who experienced 1 PEx. RESULTS: Scores on the CFQ-R were significantly lower within 1 week of PEx start in 8 out of 12 domains (Respiratory Symptoms, Physical Functioning, Emotional Functioning, Health Perceptions, Role Functioning, Social Functioning, Eating, and Vitality). Patients whose PEx was treated with hospitalization or intravenous antibiotics had greater reductions in some domains of HRQoL compared with those treated with oral antibiotics. In the immediate weeks post-PEx, improvement was seen on Emotional Functioning, Respiratory Symptoms, and Health Perceptions, while further decline was seen for Eating, Physical Functioning, Role Functioning, Vitality, and Weight. For some measures (Physical Functioning, Vitality), full recovery to pre-PEx levels took several weeks. CONCLUSIONS: Pulmonary exacerbations have significant effects on multiple domains of HRQoL, and recovery across multiple domains post-PEx can take several weeks. These findings provide insight into the impact of PEx on patient HRQoL and recovery post-PEx. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01807923 and NCT01807949.

Healthcare resource utilization associated with ivacaftor use in patients with cystic fibrosis.

OBJECTIVE: Ivacaftor was approved in 2012 to treat patients with cystic fibrosis (CF) with specific CFTR gene mutations. The objective of this analysis was to analyze the impact of ivacaftor on health resource utilization through analysis of claims data. METHODS: Patients diagnosed with CF aged ≥6 years prescribed ivacaftor between January 1, 2012 and July 31, 2014 with ≥12 months of continuous insurance coverage prior to and following the prescription were identified. All-cause and CF-specific healthcare resource utilization during the pre- and post-prescription periods and ivacaftor adherence levels were studied. RESULTS: The 79 identified patients had a mean age of 20.8 years, and 54% were female. The proportion of patients with inpatient admissions (all-cause and CF-related) was significantly higher in the pre index compared to post index period (p ≤ 0.05). Mean ivacaftor medication possession ratio was 0.8 (SD = 0.3), and 73% of patients had a medication possession ratio >0.80. LIMITATIONS: Only a small number of patients met the inclusion criteria. Additionally, claims data may contain errors or inconsistencies and cannot be used to determine if medications were taken as prescribed. CONCLUSIONS: Ivacaftor therapy was associated with significant reductions in hospitalizations along with high rates of adherence to treatment over 12 months.

Effect of ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation: patient-reported outcomes in the STRIVE randomized, controlled trial.

BACKGROUND: Cystic fibrosis (CF) is an inherited, rare autosomal recessive disease that results in chronically debilitating morbidities and high premature mortality. We evaluated how ivacaftor treatment affected CF symptoms, functioning, and well-being, as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely-used patient-reported outcome (PRO) measure. METHODS: STRIVE, a double-blind, placebo-controlled randomized trial, evaluated ivacaftor (150 mg) in CF patients aged 12+ with the G551D-CFTR mutation for 48 weeks. Treatment effect analysis used a mixed-effects repeated measures model. Treatment benefit analyses applied the cumulative distribution function and a categorical analysis of change scores ("improvement," "no change," or "decline"). Content-based interpretation examined treatment effect on specific item responses. RESULTS: Data from 152 patients with a baseline CFQ-R assessment were analyzed. The treatment effect analysis favored treatment with ivacaftor over placebo on the Body Image, Eating, Health Perceptions, Physical Functioning, Respiratory, Social Functioning, Treatment Burden, and Vitality scales. Findings were supported by the analysis of categorical change. On all CFQ-R scales, the percentage of patients who improved was greater for ivacaftor. In the content-based analysis, the treatment benefit was characterized by better scores across a broad range of domains. CONCLUSIONS: Results illustrate broad benefits of ivacaftor treatment across many domains: respiratory symptoms, physical and social functioning, health perceptions, and vitality, as measured by the CFQ-R. The breadth of improvements reflects the systemic mechanism of action of ivacaftor compared to other therapies. Findings support the patient-reported value of ivacaftor treatment in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00909532.

Impact of early versus late systemic lupus erythematosus diagnosis on clinical and economic outcomes.

BACKGROUND AND OBJECTIVES: Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease that often mimics symptoms of other illnesses, which complicates the ability of healthcare providers to make the diagnosis. The objective of this study was to assess clinical outcomes, resource utilization, and costs between patients with earlier versus later SLE diagnosis. METHODS: Patients aged 18-64 years were identified from a large US commercial claims database between January 2000 and June 2010. Confirmed SLE diagnosis with a claims-based algorithm required either three or more claims for a visit to a rheumatologist on separate dates with an SLE diagnosis (International Classification of Diseases [ICD-9] code 710.0x), two or more claims for visits to a rheumatologist at least 60 days apart with SLE diagnoses, or two or more claims for visits to rheumatologist less than 60 days apart with SLE diagnoses with at least one dispensing for a typical SLE medication. SLE probable onset date was identified during the 12-month baseline period by the second claim for antinuclear antibody tests or prodromal symptoms of SLE. Patients were stratified into early or late diagnosis groups based on time between probable SLE onset and diagnosis (<6 months or ≥6 months, respectively). Each patient observation period began on the date of the first medical claim, with a diagnosis code for SLE that satisfied the inclusion criteria, and ended on the earliest date between health plan disenrollment and 30 June 2010. Patients in each group were propensity-score matched on age, gender, diagnosis year, region, health plan type, and comorbidities. Flare rates and resource utilization were compared post-diagnosis between groups using rate ratios. All-cause and SLE-related costs (adjusted to 2010 US dollars) per patient per month (PPPM) were calculated. RESULTS: There were 4,166 matched patients per group. Post-SLE diagnosis, the early diagnosis group had lower rates of mild (rate ratio [RR] 0.95; 95 % CI 0.93-0.96), moderate (RR 0.96; 95 % CI 0.94-0.99), and severe (RR 0.87; 95 % CI 0.82-0.93) flares compared with the late diagnosis group. The rates of hospitalizations (RR 0.80; 95 % CI 0.75-0.85) were lower for the early diagnosis group than the late diagnosis group. Compared with late diagnosis patients, mean all-cause inpatient costs PPPM were lower for the early diagnosis patients (US$406 vs. US$486; p = 0.016). Corresponding SLE-related hospitalization costs were also lower for early compared with late diagnosis patients (US$71 vs. US$95; p = 0.013). Results were consistent for other resource use and cost categories. CONCLUSIONS: Patients diagnosed with SLE sooner may experience lower flare rates, less healthcare utilization, and lower costs from a commercially insured population perspective. This finding needs to be further explored within the context of background SLE disease activity.

Safety and treatment patterns of angiogenesis inhibitors in patients with advanced renal cell carcinoma in Spain.

OBJECTIVE: To examine real-world safety and treatment patterns of angiogenesis inhibitors for advanced renal cell carcinoma (aRCC) using observational data from two Spanish hospitals. METHODS: A retrospective medical record review was performed for 93 patients with a histological diagnosis of aRCC who received sunitinib, sorafenib, bevacizumab or temsirolimus as first-line angiogenesis inhibitor therapy, between January 2005 and September 2010 at two Spanish hospitals. Data were collected on adverse events (AEs), dosing to calculate relative dose intensity (RDI), treatment modifications and reasons for modifications. RESULTS: Sixty patients received sunitinib, 23 received sorafenib, 6 received bevacizumab, 1 received temsirolimus and 3 received a bevacizumab-temsirolimus combination. 91.7 and 100.0% of patients receiving sunitinib and sorafenib, respectively, experienced ≥ 1 AE; 40.0% and 43.5% had ≥ 1 grade 3/4 AE. Mean RDI for sunitinib and sorafenib were 0.866 (standard deviation (std) = 0.903) and 0.798 (std = 2.154), respectively. Among patients receiving sunitinib, 15.0% discontinued treatment, 43.3% had an interruption and 33.3% had a reduction due to AEs. For sorafenib, these rates were 4.3, 56.5 and 34.8%, respectively. CONCLUSIONS: High rates of AEs were observed which resulted in high rates of treatment interruptions and dose reductions. These results suggest the need for additional treatment options for aRCC with improved tolerability.