Quality of Life and Outcomes Associated with Adverse Effects in Pediatric Patients with Attention-Deficit/Hyperactivity Disorder and Their Parents/Caregivers.

Objectives: To assess quality of life and outcomes associated with adverse effects (AEs) in pediatric patients receiving pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and their parents/caregivers. Methods: An online survey was conducted (10/13/2023-10/20/2023) among parents/caregivers recruited from Dynata's U.S. panel who lived with a pediatric patient (6-17 years) currently treated for ADHD. Patient and parent/caregiver characteristics and outcomes were descriptively reported. Patients were considered to have AEs if they experienced symptoms/complications in the past 30 days that appeared, worsened, or remained unchanged after initiating their latest ADHD treatment. Regression analyses were used to estimate correlations between the number of AEs and key outcomes, including patients' health-related quality of life (HRQoL; based on the Pediatric Quality of Life Inventory) and parents/caregivers' work and activity impairments (based on Work Productivity and Activity Impairment: Caregiver) and mental health (based on Patient Health Questionnaire-4). Results: A total of 401 parents/caregivers from all U.S. regions completed the survey (caregiver median age: 38 years, 58.9% female; patient median age: 11 years; 37.7% female). In the 30 days prior to data collection, 66.8% of patients had AEs (overall mean: 1.2 AEs), with insomnia/sleep disturbances and decreased appetite/weight loss being the most frequently reported (14.2% and 11.7%, respectively). The number of AEs was significantly correlated with reduced patient's HRQoL (including reduced physical, emotional, and school functioning), increased parent/caregiver's work and activity impairment, and a higher likelihood of parents/caregivers having generalized anxiety disorder or major depressive disorder, respectively (all p < 0.001). Conclusions: AEs are common among pediatric patients receiving pharmacological treatment for ADHD and are associated with poorer quality of life and outcomes in pediatric patients and their parents/caregivers. Therapies with better safety profiles may help improve patient's HRQoL and parent/caregiver outcomes.

Treatment Preferences of Adult Patients with Attention-Deficit/Hyperactivity Disorder - A Discrete Choice Experiment.

Background: Understanding patient preferences for treatments may facilitate shared decision-making. This study assessed adult patient preferences for attention-deficit/hyperactivity disorder (ADHD) treatments in a sample of 600 patients in the United States (US). Methods: A web-based discrete choice experiment (DCE) survey was conducted among treated adults with ADHD. Participants were recruited from Dynata's US panel (06/22/2023-07/06/2023). Attributes and levels, identified based on clinical inputs and published data, included efficacy and safety. Participants' preferences were estimated using conditional logistic regression. Willingness to trade-off and attributes' relative importance were calculated. Overall preferences for treatment profiles approximating centanafadine, lisdexamfetamine, atomoxetine, and viloxazine were estimated using adjusted total utilities. Results were stratified by current treatment status. Sensitivity analyses including participants who passed validity tests were conducted. Results: Among the 600 participants (mean age 37.9 years; 66.2% female; 50.8% treated), all attributes had a statistically significant impact on preferences for ADHD treatments (p < 0.001); the most important attribute was improvement in ADHD symptoms (36%), followed by risks of nausea (25%), insomnia (20%), anxiety (8%), dry mouth (6%), and feeling jittery (5%). Together, safety attributes accounted for >60% of relative importance in decision-making. Participants were willing to forgo 0.59, 0.57, 0.49, 0.32, and 0.17 percentage points of symptom improvement to achieve one-percentage-point reduced risk of insomnia, nausea, anxiety, feeling jittery, and dry mouth, respectively. Centanafadine profile had consistently higher adjusted total utilities than its comparators. Similar results were obtained in the subgroup and sensitivity analyses. Conclusion: Efficacy was the most important attribute for patients when making treatment decision, but taken together, AEs had greater relative importance than efficacy alone. Accordingly, a profile resembling that of centanafadine would be preferred by an average patient compared to key competitors due to its favorable safety profile. These findings may help improve treatment decision-making, enhance treatment satisfaction, and foster adherence.

A matching-adjusted indirect comparison of centanafadine versus lisdexamfetamine, methylphenidate and atomoxetine in adults with attention-deficit/hyperactivity disorder: long-term safety and efficacy.

Aim: To compare long-term safety and efficacy outcomes of centanafadine versus lisdexamfetamine dimesylate (lisdexamfetamine), methylphenidate hydrochloride (methylphenidate) and atomoxetine hydrochloride (atomoxetine), respectively, in adults with attention-deficit/hyperactivity disorder (ADHD) using matching-adjusted indirect comparisons (MAICs). Patients & methods: Patient-level data from a centanafadine trial (NCT03605849) and published aggregate data from a lisdexamfetamine trial (NCT00337285), a methylphenidate trial (NCT00326300) and an atomoxetine trial (NCT00190736) were used. Patient characteristics were matched in each comparison using propensity score weighting. Study outcomes were assessed up to 52 weeks and included safety (rates of adverse events [AEs]) and efficacy (mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale [AISRS] or ADHD Rating Scale [ADHD-RS] score). Results: In all comparisons of matched populations, risks of AEs were statistically significantly lower with centanafadine or non-different between centanafadine and comparator; the largest differences in AE rates included upper respiratory tract infection (risk difference in percentage points: 18.75), insomnia (12.47) and dry mouth (12.33) versus lisdexamfetamine; decreased appetite (20.25), headache (18.53) and insomnia (12.65) versus methylphenidate; and nausea (26.18), dry mouth (25.07) and fatigue (13.95) versus atomoxetine (all p < 0.05). Centanafadine had a smaller reduction in the AISRS/ADHD-RS score versus lisdexamfetamine (6.15-point difference; p < 0.05) and no statistically significant difference in the change in AISRS score versus methylphenidate (1.75-point difference; p = 0.13) and versus atomoxetine (1.60-point difference; p = 0.21). Conclusion: At up to 52 weeks, centanafadine showed significantly lower incidence of several AEs than lisdexamfetamine, methylphenidate and atomoxetine; efficacy was lower than lisdexamfetamine and non-different from methylphenidate and atomoxetine.

Assessment of centanafadine in adults with ADHD: a matching adjusted indirect comparison versus methylphenidate hydrochloride extended release (Concerta).

OBJECTIVE: To compare safety and efficacy of centanafadine versus methylphenidate hydrochloride extended release (ER; Concerta) in adults with ADHD. METHODS: Without head-to-head trials, anchored matching-adjusted indirect comparisons (MAIC) of adverse event rates reported across trials and mean change from baseline in Adult ADHD Investigator Symptom Rating Scale (AISRS) score between centanafadine and methylphenidate hydrochloride ER were conducted. Pooled patient-level data from two centanafadine trials (NCT03605680/NCT03605836) and aggregate data from one published methylphenidate hydrochloride ER trial (NCT00937040) were used. Characteristics of individual patients from the centanafadine trials were matched to aggregate baseline characteristics from the methylphenidate hydrochloride ER trial using propensity score weighting. A sensitivity analysis assessed the robustness of the results to the capping of extreme weights (i.e. >99th percentile). RESULTS: Compared with methylphenidate hydrochloride ER, centanafadine was associated with significantly lower risk of dry mouth (risk difference [RD] in percentage points: -11.95), initial insomnia (-11.10), decreased appetite (-8.05), anxiety (-5.39), palpitations (-5.25), and feeling jittery (-4.73) though a significantly smaller reduction in AISRS score (4.16-point). In the sensitivity analysis, the safety results were consistent with the primary analysis but there was no significant difference in efficacy between centanafadine and methylphenidate hydrochloride ER. CONCLUSION: In this MAIC, centanafadine had better safety and possibly lower efficacy than methylphenidate hydrochloride ER. While safety results were robust across analyses, there was no efficacy difference between centanafadine and methylphenidate hydrochloride ER in the sensitivity analysis. Considering its favorable safety profile, centanafadine may be preferred among patients for whom treatment-related adverse events are a concern.

Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release.

BACKGROUND: Head-to-head trials comparing centanafadine, an investigational therapy for adults with attention-deficit/hyperactivity disorder (ADHD), with other treatment options are lacking. OBJECTIVE: To compare safety and efficacy outcomes of centanafadine sustained-release vs lisdexamfetamine dimesylate (lisdexamfetamine), atomoxetine hydrochloride (atomoxetine), and viloxazine extended-release (viloxazine ER), respectively, using matching-adjusted indirect comparison (MAIC). METHODS: This MAIC included patient-level data pooled from 2 centanafadine trials (NCT03605680 and NCT03605836) and published aggregate data from comparable trials of 3 comparators-lisdexamfetamine (NCT00334880), atomoxetine (NCT00190736), and viloxazine ER (NCT04016779)-in adult patients with ADHD. Propensity score weighting was used to match characteristics of individual patients from the centanafadine trials to aggregate baseline characteristics from the respective comparator trials. Safety outcomes were rates of adverse events for which information was available in the centanafadine and respective comparator trials. Efficacy outcome was mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) score (ADHD Rating Scale [ADHD-RS] was used as proxy in the comparison with lisdexamfetamine). Anchored indirect comparisons were conducted across matched populations of the centanafadine and respective comparator trials. RESULTS: After matching, baseline characteristics in the centanafadine trials were the same as those in the respective comparator trials. Compared with lisdexamfetamine, centanafadine was associated with a significantly lower risk of lack of appetite (risk difference [RD] in percentage points: 23.42), dry mouth (19.27), insomnia (15.35), anxiety (5.21), nausea (4.90), feeling jittery (3.70), and diarrhea (3.47) (all P < 0.05) but a smaller reduction in the AISRS/ADHD-RS score (6.58-point difference; P < 0.05). Compared with atomoxetine, centanafadine was associated with a significantly lower risk of nausea (RD in percentage points: 18.64), dry mouth (17.44), fatigue (9.21), erectile dysfunction (6.76), lack of appetite (6.71), and urinary hesitation (5.84) (all P < 0.05) and no statistically significant difference in the change in AISRS score. Compared with viloxazine ER, centanafadine was associated with a significantly lower risk of fatigue (RD in percentage points: 11.07), insomnia (10.67), nausea (7.57), and constipation (4.63) (all P < 0.05) and no statistically significant difference in the change in AISRS score. CONCLUSIONS: In an anchored MAIC, centanafadine showed a significantly better short-term safety profile than lisdexamfetamine, atomoxetine, and viloxazine ER; efficacy was lower than with lisdexamfetamine and comparable (ie, nondifferent) with atomoxetine and viloxazine ER. This MAIC provides important insights on the relative safety and efficacy of common treatment options to help inform treatment decisions in adults with ADHD. Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. STUDY REGISTRATION NUMBERS: NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779.

Real-world patterns and sequences of targeted therapy use in chronic lymphocytic leukemia and small lymphocytic lymphoma in the United States: a longitudinal study.

With increasing focus on novel targeted therapies for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), this longitudinal claims-based study evaluated real-world CLL/SLL treatment sequences, particularly sequential targeted therapy. Among patients with first-line (1 L) treatment in 2014-2017 (N = 2,612; median follow-up = 3 years), the most common 1 L treatment was chemoimmunotherapy (CIT; 44.6%), followed by CD20 (25.2%) and Bruton's tyrosine kinase inhibitors (BTKi; 21.7%). Among those with 1 L in 2018-2021 (N = 4,534; median follow-up = 1 year), these were BTKi (45.5%), CD20 (20.4%), CIT (17.5%), and B-cell lymphoma 2 inhibitor (8.3%). In 2014-2017, the proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 11.2% (80.2% was BTKi→BTKi); in 2018-2021, this proportion was 34.3% (66.4% was BTKi→BTKi). Over time, there was a substantial increase in targeted therapy use in 1 L and sequential targeted therapy, particularly with BTKi→BTKi. Future studies should assess clinical outcomes to determine optimal sequences for CLL/SLL and reasons for restarting BTKi.

Escherichia coli resistance, treatment patterns and clinical outcomes among females with uUTI in Germany: a retrospective physician-based chart review study.

Real-world data were collected to examine antimicrobial resistance (AMR) prevalence, treatment patterns, and clinical outcomes among female patients with uncomplicated urinary tract infection (uUTI) in Germany. Data were from a retrospective physician-based chart review completed by physicians treating patients with uUTI. Non-pregnant women aged ≥ 12 years, with a uUTI diagnosis, an E. coli-positive urine culture between January 2017-December 2019, and susceptibility test results for ≥ 4 drug classes were eligible. Patients were stratified into three cohorts by drug class susceptibility: susceptible to all (SUS), resistant to one or two drug classes (DR1/2), and resistant to ≥ 3 (MDR) drug classes tested. Among 386 eligible patients [SUS (67.1%); DR1/2 (29.0%); MDR (3.9%)], AMR prevalence was highest for FMIs (18.3%) and lowest for fluoroquinolones (5.2%). The most prescribed drugs were fosfomycin in SUS (44.0%), DR1/2 (41.4%), and fluoroquinolones in MDR (40.0%). Treatment for uUTI failed for 8.8% of patients; failure was more likely in MDR versus SUS [adjusted odds ratio [95% CI] = 4.21 [1.14-1.50]; P = 0.031); incidence of recurrent infection in the 6-months post-index period was higher in DR1/2 versus SUS. These findings may have implications for empiric prescribing, suggesting an unmet need for new treatments.

The Economic Burden of Schizophrenia in the United States.

Aim: The economic burden of schizophrenia in the United States (US) was estimated at $155.7 billion in 2013. Since 2013, the US experienced significant health care reforms and treatment advances. This study analyzed recent data and literature to update the US economic burden estimate for schizophrenia.Methods: Direct and indirect costs associated with schizophrenia were estimated using a prevalence-based approach. Direct health care costs were assessed retrospectively using an exact matched cohort design in the IBM Watson Health MarketScan databases from October 1, 2015, through December 31, 2019. Patients with schizophrenia (identified using ICD-10-CM codes F20 and F25) were exactly matched to controls on demographics, insurance type, and index year. Direct non-health care costs were estimated using published literature and government data. Indirect costs were estimated using a human capital approach and the value of quality-adjusted life-years lost. Cost offsets were estimated to account for basic living costs avoided. Excess costs, comparing costs for individuals with and without schizophrenia, were reported in 2019 USD.Results: The estimated excess economic burden of schizophrenia in the US in 2019 was $343.2 billion, including $251.9 billion in indirect costs (73.4%), $62.3 billion in direct health care costs (18.2%), and $35.0 billion in direct non-health care costs (10.2%). The largest drivers of indirect costs were caregiving ($112.3 billion), premature mortality ($77.9 billion), and unemployment ($54.2 billion). Cost offsets, representing $6.0 billion (1.7%), were subtracted from direct non-health care costs.Conclusions: The estimated burden of schizophrenia in the US doubled between 2013 and 2019 and was $343.2 billion in 2019, highlighting the importance of effective strategies and treatment options to improve the management of this difficult-to-treat patient population.

Trends and predictors of biomedical research quality, 1990-2015: a meta-research study.

OBJECTIVE: To measure the frequency of adequate methods, inadequate methods and poor reporting in published randomised controlled trials (RCTs) and test potential factors associated with adequacy of methods and reporting. DESIGN: Retrospective analysis of RCTs included in Cochrane reviews. Time series describes the proportion of RCTs using adequate methods, inadequate methods and poor reporting. A multinomial logit model tests potential factors associated with methods and reporting, including funding source, first author affiliation, clinical trial registration status, study novelty, team characteristics, technology and geography. DATA: Risk of bias assessments for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting, for each RCT, were mapped to bibliometric and funding data. OUTCOMES: Risk of bias on six methodological dimensions and RCT-level overall assessment of adequate methods, inadequate methods or poor reporting. RESULTS: This study analysed 20 571 RCTs. 5.7% of RCTs used adequate methods (N=1173). 59.3% used inadequate methods (N=12 190) and 35.0% were poorly reported (N=7208). The proportion of poorly reported RCTs decreased from 42.5% in 1990 to 30.2% in 2015. The proportion of RCTs using adequate methods increased from 2.6% in 1990 to 10.3% in 2015. The proportion of RCTs using inadequate methods increased from 54.9% in 1990 to 59.5% in 2015. Industry funding, top pharmaceutical company affiliation, trial registration, larger authorship teams, international teams and drug trials were associated with a greater likelihood of using adequate methods. National Institutes of Health funding and university prestige were not. CONCLUSION: Even though reporting has improved since 1990, the proportion of RCTs using inadequate methods is high (59.3%) and increasing, potentially slowing progress and contributing to the reproducibility crisis. Stronger incentives for the use of adequate methods are needed.

Who benefits most in disease management programs: Improving target efficiency.

Disease management programs aim to reduce cost by improving the quality of care for chronic diseases. Evidence of their effectiveness is mixed. Reducing health care spending sufficiently to cover program costs has proved particularly challenging. This study uses a difference in differences design to examine the impact of a diabetes disease management program for high risk patients on preventive tests, health outcomes, and cost of care. Heterogeneity is examined along the dimensions of severity (measured using the proxy of poor glycemic control) and preventive testing received in the baseline year. Although disease management programs tend to focus on the sickest, the impact of this program concentrates in the group of people who had not received recommended tests in the preintervention period. If confirmed, such findings are practically important to improve cost-effectiveness in disease management programs by targeting relevant subgroups defined both based on severity and on (missing) test information.