Study Objectives:Narcolepsy is a chronic condition affecting the sleep/wake cycle that is challenging to diagnose. Epidemiological data from large US-focused studies remain limited, with no validated claims-based case selection definitions for narcolepsy. We estimated the prevalence/incidence of diagnosed narcolepsy (type 1 [NT1], type 2 [NT2], overall) in an insured US population using validated, claims-based narcolepsy case definitions. Materials and Methods:This observational study used HealthVerity administrative claims-linked electronic medical records to develop case definitions identifying individuals with NT1, NT2, and overall narcolepsy from diagnosis, medication, and procedure codes. Claims-based case definition performance (NT1, NT2, overall narcolepsy) was assessed using positive predictive values (PPVs). Prevalence (per 100 000 persons, on December 31, 2023) and annual incidence (per 100 000 person-years [PY], 2020 - 2023) were calculated/adjusted using PPVs for each case definition. Results:Unadjusted point prevalence among individuals with ≥12 months of continuous enrollment were 15.5/100 000 (NT1), 51.1/100 000 (NT2), and 67.0/100 000 (overall narcolepsy). Unadjusted incidence rates were stable from 2020 - 2023 for NT1 (range, 2.0 - 2.3/100 000 PY) but declined across years for NT2 (9.1 - 7.6/100 000 PY) and overall narcolepsy (11.3 - 9.6/100 000 PY). PPVs (95% confidence interval) of NT1, NT2, and overall narcolepsy were 0.81 (0.72 - 0.88), 0.84 (0.75 - 0.91), and 0.80 (0.71 - 0.87), contributing to epidemiologic estimates being reduced by ~20% after PPV adjustment. Prevalence and incidence were higher in females than males. Individuals with NT1 were ~ 4 years younger versus NT2. Conclusions:Validated definitions for narcolepsy can reduce potential misclassification. Our findings highlight a relatively low NT1 prevalence in the US. In contrast, NT2 prevalence estimates were > 3 times higher than NT1.

Background: Estimation of prevalence and incidence of narcolepsy and idiopathic hypersomnia (IH) is challenging owing to symptomatic overlap, underdiagnosis, and misdiagnosis, and epidemiological data are lacking in Asian populations. We estimated the prevalence and incidence of narcolepsy and IH in Japan. Methods: The Japan Medical Data Center (JMDC) database includes healthcare claims data for employed individuals <= 74 years of age. Narcolepsy and IH cases were defined by >= 2 diagnosis codes within 12 months, or a multiple sleep latency test with >= 1 diagnosis code within 12 months. Estimated point-prevalences of diagnosed narcolepsy and IH were calculated for December 31, 2019. Incidences of narcolepsy and IH were estimated for the period January 1, 2014 to December 31, 2019. Results: Of 7,075,869 individuals enrolled in the database on December 31, 2019, 6,110,751 (86.4 %) had >= 12 months' continuous enrollment and were eligible for inclusion in the prevalence population. Age-sex standardized overall prevalences of narcolepsy and IH were 37.5 (95 % confidence intervals 35.9-39.1) and 7.7 (7.0-8.4) per 100,000 persons, respectively. Prevalence for both conditions peaked at age 20-29 years and declined with increasing age. Age-sex standardized overall incidences of narcolepsy and IH were 5.1 (4.8-5.4) and 1.2 (1.0-1.5) per 100,000 person-years, respectively. Narcolepsy and IH incidences peaked in the 10-19 and 20-29 years age groups then declined with increasing age. Conclusions: This claims-based study provides updated estimates for the prevalence and incidence of narcolepsy in Japan, and the first estimates for prevalence and incidence of IH in Japan.

Background Narcolepsy is a chronic disorder that requires lifelong management; however, few studies have evaluated disease burden of narcolepsy. We estimated the healthcare burden of narcolepsy in Japan using data from the Japan Medical Data Center health insurance claims database. Methods This was a retrospective analysis of clinical burden, healthcare resource utilization, and costs among incident narcolepsy cases and matched controls identified between January 1, 2014 and December 31, 2019. Results Of the 1317 incident cases; 889 (with 1778 controls) were analyzed for healthcare burden, 626 (with 1252 controls) for clinical journey, and 439 (no controls) for treatment patterns. The most common baseline comorbidity was non-narcolepsy sleep disorder (41.6% cases vs 3.0% controls), including insomnia (28.5% vs 2.6%) and sleep apnea (10.8% vs 0.3%; both p<0.001). The most common nonsleep disorder comorbidities were depression (35.0% vs 2.6%), anxiety (30.4% vs 2.7%), and headache/migraine (18.1% vs 5.5%; all p<0.001). Compared to controls, narcolepsy cases had more prescription claims in the year following index date (82.8% vs 9.5%; p<0.001), higher rates of outpatient (2291.8 vs 674.9 visits/100 person-years; p<0.001) and inpatient claims (56.8 vs 5.1/100 person-years; p<0.001), and longer hospital stays (mean 2.9 vs 0.5 days; p<0.001). Similarly, median HCRU costs were higher in cases than controls (total annual healthcare costs, $2531 vs $266; community pharmacy claims, $826 vs $47 per person; and outpatient claim costs, $1053 vs $188 per person year). Conclusions Narcolepsy carries a substantial comorbidity burden, a high rate of medication prescribing, and high healthcare resource use in Japan.

Background Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials. Methods We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies. Results In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials. Conclusion This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.

Understanding patient clinical progression is a key gateway to planning effective clinical trials and ultimately enabling bringing treatments to patients in need. In a rare disease like amyotrophic lateral sclerosis (ALS), studies of disease natural history critically depend on collaboration between clinical centers, regions, and countries to enable creation of platforms to allow patients, caregivers, clinicians, and researchers to come together and more fully understand the condition. Rare disease registries and collaborative platforms such as those developed in ALS collect real-world data (RWD) in standardized formats, including clinical and biological specimen data used to evaluate risk factors and natural history of disease, treatment patterns and clinical (ClinROs) and patient- reported outcomes (PROs) and validate novel endpoints. Importantly, these data support the development of new therapeutics by supporting the evaluation of feasibility and design of clinical trials and offer valuable information on real-world disease trajectory and outcomes outside of the clinical trial setting for comparative purposes. RWD may help to accelerate therapy development by identifying and validating outcome measures and disease subpopulations. RWD can also make potential contributions to the evaluation of the safety and effectiveness of new indications for approved products and to satisfy post-approval regulatory and market access requirements. There is a lack of amalgamated information on available registries, databases, and other sources of real-world data on ALS; thus, a global review of all available resources was warranted. This targeted review identifies and describes ALS registries, biobanks and collaborative research networks that are collecting and synthesizing RWD for the purposes of increasing patient awareness and advancing scientific knowledge with the hope of expediting future development of new therapies.

Three cases of ileus have been published among dipeptidyl peptidase-4 (DPP-4) inhibitor users in Japan. The purpose of this study was to estimate and compare incidence rates of ileus among alogliptin users and users of other DPP-4 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and voglibose.

Objective: Patients with major depressive disorder (MDD) often discontinue antidepressant therapy pre- maturely risking relapse, despite United Kingdom (UK) guidelines recommending therapy for up to at least six months after remission. More information is needed on the patterns of antidepressant discontinuation in UK primary care. Objectives of the study were to assess the patterns, incidence and predictors of therapy discontinuation among MDD patients initiating treatment with selective serotonin reuptake inhibitors (SSRIs). Methods: This was a retrospective cohort study using general practices registered with the General Practice Research Database (GPRD). 15,274 patients with MDD receiving a first ever prescription (index) for an SSRI between 2006-2008 were identified in GPRD. Discontinuation (including temporary gaps) and cessation of antidepressant therapy were examined over follow-up. Predictors of incidence of discontinuation in the six months after index were assessed. Results: Incidence of discontinuation of antidepressant therapy over follow-up was 80.05 per 100 person years (95% CI 78.94 - 81.17). At six months after index 42% of patients had discontinued and 33% had ceased therapy altogether. Lower discontinuation of index SSRI therapy in the first six months after initiation was associated with higher age, higher body mass index (BMI), and comorbid irritable bowel syndrome. Higher discontinuation was associated with paroxetine or fluoxetine at index, and a more recent index calendar year. Conclusions: There is a significant risk of discontinuation of antidepressant therapy in the 6 months after initiation of treatment for MDD. This finding requires awareness by the general practitioner (GP) to ensure implementation of optimal treatment regimens, and minimization of therapy non-compliance among MDD patients.

Objective: Adjunctive therapy is often used for treatment of major depressive disorder (MDD) following an inadequate response to an antidepressant.However, there is little information regarding its practice within primary care in the United Kingdom (UK).Objectives of the study were to examine incidence and predictors of adjunctive pharmacotherapy among patients with MDD treated with selective serotonin reuptake inhibitors (SSRIs) by UK general practitioners (GPs).Methods: The General Practice Research Database was used to identify 15,274 MDD patients prescribed first-line treatment with SSRIs from 2006-2008 (latest patient follow-up towards end of 2010).Treatment trajectories were identified and classified as adjunctive therapy, combination therapy, drug switches, dose increases, and restart of therapy.Incidence and predictors of adjunctive therapy were assessed, and healthcare resource utilization was evaluated.Results: Overall incidence of adjunctive therapy was 3.07/100 person years (95% CI 2.90 -3.25).Patients prescribed adjunctive therapy were more likely to be female (IRR 1.15, p = 0.03), of higher age (IRRs 1.51 -2.60, p ≤ 0.001), and had a greater depression severity score (IRR 1.02, p = 0.003).Presence of irritable bowel syndrome (IRR 1.53, p = 0.001), and an increasing Charlson Comorbidity Index (IRR 1.15, p = 0.01) were associated with a higher incidence of adjunctive therapy.MDD-related general practitioner consultations among patients who received adjunctive therapy was lower compared with patients receiving other treatment interventions (IRRs 0.79 -0.87, p ≤ 0.001).Conclusions: Adjunctive therapy is infrequently utilized relative to other treatment options for management of MDD among patients who are inadequate responders to their SSRI treatments in UK primary care; however some groups are more likely to receive adjunctive therapy than others.

For patients with major depressive disorder (MDD), adjunctive therapy is often a second treatment step following a partial response to an antidepressant. Although the role of adjunctive treatment is supported in practice guidelines, there is little information regarding the actual practice of adjunctive therapy, particularly for patients seen in primary care. The objectives of the study were to examine the incidence and predictors of adjunctive pharmacotherapy among patients with MDD treated with selective serotonin reuptake inhibitors (SSRIs) by primary care physicians (PCPs) in the UK (UK). The General Practice Research Database was used to identify 15,274 patients with MDD who were prescribed first-line treatment with SSRIs from 2006-2008. Treatment trajectories were identified and classified as adjunctive therapy, drug switches, dose increases, discontinuation, and restart of therapy. Incidence and predictors of adjunctive therapy were assessed. Comparisons in healthcare resource utilization were made between patients receiving adjunctive therapy and patients receiving other treatment strategies. Overall incidence of adjunctive therapy was 3.07/100 person years (95% CI 2.90-3.25). Patients prescribed adjunctive therapy were more likely to be female (IRR 1.17, p=0.02), of higher age (IRRs 1.53-2.41, p<0.001), and had greater depression severity (IRR 1.02, p=0.004). Presence of postherpetic neuropathy (IRR 3.06, p=0.01), irritable bowel syndrome (IRR 1.33, p=0.01), and an increasing Charlson Comorbidity Index (IRR 1.08, p=0.03) were associated with a higher incidence of adjunctive therapy. MDD-related general practitioner consultations were lower among those prescribed adjunctive therapy compared with patients receiving other treatment interventions (IRRs 0.79-0.87, p<0.001). Incidence of adjunctive treatment was relatively low and was associated with several patient demographics, a higher burden of illness, and less PCP visits. The incidence of adjunctive therapy suggests that it is infrequently used in the management of MDD among patients who are partial responders to SSRI treatment in UK primary care.