Advances in Therapy最新文献

Introduction: Daily oral antipsychotics (OAPs) are the mainstay of schizophrenia treatment; however, long-acting injectable antipsychotics (LAIs) are associated with better treatment adherence and improved outcomes.

Methods: This study assessed the real-world comparative effectiveness of LAIs and daily OAPs using claims data from a nationally representative sample of fee-for-service Medicare beneficiaries with schizophrenia. Antipsychotic discontinuation, psychiatric hospitalization, and treatment failure were compared relative to different reference groups using within-individual Cox regression models.

Results: The study included 152,835 patients (mean age, 53.5 years; 54.0% male and 61.5% white). LAIs when grouped by dosing intervals were associated with significantly lower risk of antipsychotic discontinuation (hazard ratios [HRs] 0.27-0.69), psychiatric hospitalization (HRs 0.76-0.88), and treatment failure (HRs 0.55-0.74) compared with OAPs. When LAIs of different dosing intervals and OAPs were broken out by type of agent and compared with oral risperidone, second-generation LAIs, specifically LAI paliperidone (every 3 months [Q3M] and monthly [Q1M]), LAI aripiprazole (Q1M), and LAI risperidone (primarily every 2 weeks), had a significantly lower risk of antipsychotic discontinuation (HRs 0.19-0.67), psychiatric hospitalization (HRs 0.76-0.91), and treatment failure (HRs 0.53-0.85). Second-generation LAI paliperidone (Q3M) had the lowest risk for negative outcomes relative to OAPs; this effect was maintained when the reference group was changed to oral risperidone, LAI risperidone, LAI aripiprazole (Q1M), and LAI haloperidol (Q1M) (33-47% lower risk).

Conclusion: Efforts are needed to enhance identification of appropriate candidates for LAIs and increase their uptake, especially longer dosing interval LAIs, in the Medicare population.

Introduction: Incidences of infections with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) are still high and treatment guidelines lack specific recommendations for outpatients with Coronavirus-induced disease 2019 (COVID-19). Phytomedicine ELOM-080, an enhancer of mucociliary clearance (MCC), showed benefits as add-on therapy in hospitalised COVID-19 patients.

Methods: This randomised, double-blind, placebo-controlled proof-of-concept study investigated whether outpatients with mild to moderate acute symptomatic COVID-19 would benefit from a 14-day treatment with ELOM-080 with regard to potential early treatment effects on cough and further typical COVID-19 symptoms. Outpatients with mild to moderate acute symptomatic COVID-19 documented symptom severity and count of coughs on a daily basis. Investigators documented safety and symptom severity during the visits.

Results: This study missed its primary objective, which was reduction in coughing fits in comparison to placebo treatment. In primary analysis, no relevant differences were observed between treatment arms. Data for all randomised patients showed broad heterogeneity in, e.g., time courses of coughing fits, which affected both magnitude and timing of the changes from baseline. However, post hoc analyses with a population with suspected dysfunctional MCC revealed that patients significantly benefitted from treatment with ELOM-080 in terms of reduction in coughing fits (p = 0.0070), difficulty breathing on exertion (p = 0.0252), and earlier remission of symptoms by 1-3 days.

Conclusion: We have shown that patients with dysfunctional MCC benefit from treatment with ELOM-080. These results might be of clinical importance, as up to now no therapy has obtained market approval for the treatment of outpatients with COVID-19.

Trial registration: EudraCT number: 2022-003478-22.

Introduction: Randomized phase III trials showed that using trifluridine/tipiracil (FTD/TPI) in patients with pre-treated metastatic colorectal cancer (mCRC) conferred survival benefit versus placebo. Here, we investigated the effectiveness and safety of FTD/TPI and sought to identify prognostic factors among the mCRC population in Hong Kong.

Methods: A non-interventional, retrospective, multicenter cohort study enrolled patients with mCRC who received FTD/TPI in seven public hospitals in Hong Kong between 2016 and 2020. Overall survival (OS) was the primary endpoint; treatment duration and occurrence of neutropenia were secondary endpoints. We also performed a post hoc analysis to identify factors influencing OS and treatment duration.

Results: Overall, 456 patients were included (median age, 64.0 years; 57.5% men). Approximately half (225/456; 49.3%) had RAS wild-type tumors; the median treatment duration was 12.4 weeks (95% confidence interval [CI] 11.1-13.1). Median OS was 7.59 months (95% CI 7.00-8.21). Overall, 289 (63.4%) patients developed neutropenia of any grade and 159 (34.9%) developed grade ≥ 3 neutropenia. Neutropenia at 1 month occurred in 193 (43.1%) patients. The use of granulocyte colony-stimulating factor for neutropenia was reported for 42 (9.2%) patients. The development of neutropenia, absolute neutrophil count decrease of ≥ 2 grades in 1 month, absence of liver metastasis, and RAS wild-type status were associated with significantly longer OS and, except for RAS wild-type status (not analyzed), longer treatment duration (p < 0.05 for all comparisons).

Conclusion: Our data show that treatment with FTD/TPI offers survival benefits in patients with refractory mCRC in Hong Kong consistent with randomized controlled trials and other real-world studies. Furthermore, the prognosis in patients receiving FTD/TPI appears to be significantly better in those who develop neutropenia, with RAS wild-type status, or those without liver metastases, despite a higher rate of dose reduction in the real-world setting.

Introduction: Fremanezumab, a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) pathway, and gepants, small molecule CGRP receptor antagonists, are both approved for the treatment of migraine or its symptoms. This study assessed effectiveness, tolerability, and migraine-related healthcare resource utilization (HCRU) after the addition of fremanezumab for preventive migraine treatment in patients using gepants for acute treatment.

Methods: Data were extracted during a retrospective chart review from electronic medical records from the Dent Neurologic Institute. Eligible patients were ≥ 18 years old, using gepants (rimegepant or ubrogepant), who initiated fremanezumab between January 1, 2020, and May 1, 2021 (index date: date of fremanezumab initiation) and continued concomitant use of gepants and fremanezumab for ≥ 1 month (post-index; between 7-9 months of follow-up). Outcomes included monthly migraine days (MMD), adverse events (AEs), reasons for discontinuation, and migraine-related HCRU.

Results: A total of 55 patients [female, 93%; mean (SD) age, 43.5 (13.5) years] met the inclusion criteria. All patients were diagnosed with chronic migraine. Patients had an average (SD) MMD of 15.8 (7.4) at the index date. Average (SE) change in MMD from index date to post-index was - 6.5 (1.0) days (p < 0.0001). Five patients (9.1%) experienced AEs post-index; no serious AEs (SAEs) were reported. The number of migraine-related medications used decreased from the index date to post-index by a mean of 0.6 for preventive medications (p = 0.070), and 0.8 for acute medications (p = 0.050). The number of outpatient office-based visits also decreased [mean (SD): 6 months pre-index, 5.8 (4.4) vs. 6 months post-index, 4.1 (4.0); p < 0.0001].

Conclusion: The addition of fremanezumab preventively to gepants for acute migraine treatment was effective, resulted in fewer outpatient office visits, and yielded no SAEs or AEs that were novel to these migraine medication classes.

Introduction: The burden of severe asthma on patients, especially on those with concomitant chronic rhinosinusitis with nasal polyps (CRSwNP), is substantial. Treatment intensification with oral corticosteroids is a common strategy for managing severe asthma exacerbations; however, prolonged exposure to systemic corticosteroids is associated with multisystem toxicity. This study aimed to quantify the association between oral corticosteroid use and annual asthma-related costs in patients with severe asthma with or without CRSwNP.

Methods: This pharmacoeconomic analysis was based on data from the Severe Asthma Network in Italy (SANI) registry. Asthma-related costs were estimated in the context of the Italian healthcare system and included exacerbations requiring treatment intensification, unplanned visits, admissions to hospital and emergency/intensive care units, and lost workdays. For each item, the mean annual cost per patient was estimated based on national tariffs and the frequency of the event. To quantify the association between oral corticosteroid treatment and costs, the study cohort was stratified according to oral corticosteroid use in the 1-year preceding inclusion in the SANI registry.

Results: A total of 669 patients from the SANI registry were included in the present analysis, 255 of whom had concomitant CRSwNP. Corticosteroid use was associated with significantly higher annual disease-related costs per patient compared with no corticosteroid use. Compared with the overall study cohort and patients without CRSwNP, patients with CRSwNP had higher disease-related costs (higher by €1307 and €1869, respectively).

Conclusion: Use of corticosteroids, in particular systemic corticosteroids, is associated with an increase in asthma-related costs. The concomitant presence of CRSwNP impacts negatively on costs. This study suggests that a thorough analysis of costs, expected benefits, and occurrence of adverse events is required when selecting treatment intensification strategies for managing uncontrolled severe asthma.

Introduction: Chronic kidney disease-associated pruritus (CKD-aP) is a common, yet underdiagnosed condition among patients on hemodialysis. Considering the lack of established treatment pathways, we sought to evaluate the use of antidepressant, systemic antihistamines, or gabapentinoid medications among patients with CKD-aP in the year following pruritus assessment.

Methods: We included 6209 patients on hemodialysis in the analysis. We retrospectively extracted clinical and patient-reported data from electronic health records. The intensity of CKD-aP was assessed by KDQOL-36 and 5-D Itch questionnaires. Prescription of antidepressant, antihistamine, and gabapentinoids was ascertained by the occurrence of a relevant active medical order in patients' medical records.

Results: We observed a consistent and graded association between the severity of CKD-aP and the use of antidepressant, systemic antihistamines, and gabapentinoid medications. This association remained consistent and intensified over the duration of the year after pruritus screening. This trend was robust even after accounting for potential confounding factors.

Conclusions: Patterns of antipruritic medication use in a cohort of patients with CKD-aP was identified and the frequent use of off-label treatments in the absence of approved therapies was highlighted. These observations reflect clinical practices aimed at managing severe pruritus but do not imply a causal relationship between the medications and pruritus severity. Even though we cannot exclude the possibility that these drugs have been prescribed to treat medical conditions warranting their use, previous evidence suggested that doctors may also use such medications in an attempt to buffer CKD-aP. These findings underline the importance of further elucidating current treatment strategies adopted in clinical practice to address CKD-aP.

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), is linked to cardiometabolic risk factors such as obesity and type 2 diabetes (T2D). The rising prevalence of MASH and risk of hepatic and extra-hepatic complications emphasize the need for a better understanding of disease progression and associated outcomes. This study aimed to evaluate the incidence of, and demographic and clinical characteristics associated with, progression to MASH-related complications by disease severity in patients with non-cirrhotic MASH or MASH cirrhosis. Alignment between noninvasive tests (NITs) and biopsy-determined fibrosis stage was also assessed.

Methods: This analysis used data from the TARGET-NASH cohort that includes adults with MASH across academic and community sites in the United States. Patients with non-cirrhotic MASH or MASH cirrhosis were stratified by disease severity based on fibrosis stage or cirrhosis. Progression to MASH-related outcomes, including all-cause mortality, cirrhosis, and liver transplantation, was assessed.

Results: Among the 2378 patients included in this analysis, 48% had MASH cirrhosis. Incidence of all-cause mortality increased with disease severity from 0.14/100 person-months (100PM) at fibrosis stage 0-1 (F0-F1) to 2.02/100PM with compensated cirrhosis and 4.62/100PM with decompensated cirrhosis. Compared with patients with F0-F1, risk of progression to cirrhosis was higher in patients with F3 [hazard ratio (HR), 95% confidence interval (CI); 18.66, 10.97-31.73] and F2 (HR, 95% CI; 3.74, 2.00-6.98). Among those who progressed to MASH-related outcomes, 67.9% had T2D and 73.9% had hypertension. Vibration-controlled transient elastography showed better alignment with biopsy-determined fibrosis stage than Fibrosis-4 Index (FIB-4).

Conclusions: Progression to all-cause mortality in patients with MASH was significantly associated with the presence of higher fibrosis stage and cirrhosis. Cardiometabolic comorbidities such as T2D and hypertension were prevalent in patients with MASH progression. Early identification and management of MASH may mitigate disease progression and liver-related complications.

Introduction: This study evaluated the safety and tolerability of fezolinetant in women with vasomotor symptoms (VMS) due to menopause in a pooled analysis of data from three 52-week phase 3 studies (SKYLIGHT 1, 2, and 4).

Methods: SKYLIGHT 1 and 2 were double-blind, placebo-controlled studies where women (≥ 40 to ≤ 65 years), with moderate to severe VMS (minimum average ≥ 7 hot flashes/day) were randomized to once-daily placebo, fezolinetant 30 mg or 45 mg. After 12 weeks, those on placebo were re-randomized to fezolinetant 30 mg or 45 mg, while those on fezolinetant continued on their assigned dose for 40 weeks. SKYLIGHT 4 was a placebo-controlled, double-blind, 52-week safety study. Safety was assessed by frequency of treatment-emergent adverse events (TEAEs) and endometrial events. TEAEs of special interest included liver test elevations and endometrial hyperplasia or cancer or disordered proliferative endometrium.

Results: Totals of 952 participants receiving placebo, 1100 receiving fezolinetant 45 mg, and 1103 receiving fezolinetant 30 mg took ≥ 1 dose of study medication. TEAEs occurred in 55.3%, 62.9%, and 65.4%, respectively; exposure-adjusted results were consistent with these results. Most frequent TEAEs in fezolinetant-treated participants included upper respiratory tract infection (7.7-8.3%), headache (6.8-8.2%), coronavirus disease 2019 (5.8-6.1%), back pain (3.1-3.7%), arthralgia (2.9-3.2%), diarrhea (2.3-3.2%), urinary tract infection (2.9-3.4%), and insomnia (2.0-3.0%). The incidence of drug-related serious TEAEs and associated treatment withdrawals was low. Elevations in liver transaminases occurred in 1.5-2.3% of fezolinetant-treated participants, were typically asymptomatic and transient, resolved on treatment or discontinuation, with no evidence of severe drug-induced liver injury (Hy's law). Endometrial safety results were well within US Food and Drug Administration criteria. Analysis of benign and non-benign neoplasm controlled for exposure demonstrated no increased risk versus placebo.

Conclusion: Pooled data confirm the safety and tolerability of fezolinetant over 52 weeks.

Trial registration: ClinicalTrials.gov identifiers, NCT04003155, NCT04003142, and NCT04003389. Graphical abstract available for this article.

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with exacerbations which can reduce quality of life and increase mortality. Single-inhaler triple therapy (SITT) is recommended for maintenance treatment of COPD among patients experiencing exacerbations despite dual-therapy use. This real-world comparative effectiveness study compared the impact of SITTs, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), and budesonide/glycopyrrolate/formoterol fumarate (BUD/GLY/FORM), on COPD exacerbations and mortality.

Methods: Medicare Fee-for-Service (FFS) patients with COPD initiated on FF/UMEC/VI or BUD/GLY/FORM were identified from the Komodo Research healthcare claims dataset (01/01/2016-12/31/2023). Overlap weighting based on high-dimensional propensity scores evaluated from patient characteristics was used to adjust for baseline confounding. Primary outcome was annualized rate of moderate-severe COPD exacerbations (per patient-year; PPY) compared using rate ratios (RRs) with 95% confidence intervals (CIs) from weighted Poisson regression models. Secondary and exploratory outcomes were risk of moderate-severe COPD exacerbations and all-cause mortality, respectively, evaluated using Kaplan-Meier analysis and hazard ratios (HR) with 95% CIs from Cox proportional hazard models. A secondary analysis was conducted among a mutually exclusive population with Medicare Advantage, Medicaid, or commercial insurance.

Results: Overall, 32,312 FF/UMEC/VI and 12,230 BUD/GLY/FORM Medicare FFS patients were included. After weighting, median follow-up was 9 months. Compared with BUD/GLY/FORM, FF/UMEC/VI users had a 12% lower rate of annualized moderate-severe COPD exacerbations [0.80 and 0.91 PPY; RR (95% CI): 0.88 (0.85-0.92); P < 0.001] and a 10% lower risk of moderate-severe exacerbations at 12 months post-initiation [HR (95% CI): 0.90 (0.87-0.93); P < 0.001], driven by moderate exacerbations. FF/UMEC/VI compared with BUD/GLY/FORM users had 11% lower risk of all-cause mortality at 12 months post-initiation [5.6% vs. 6.4%; HR (95% CI): 0.89 (0.80-0.98); P = 0.020]. Results were consistent among patients with Medicare Advantage, Medicaid, or commercial insurance.

Conclusions: In this real-world comparative effectiveness study, FF/UMEC/VI was associated with significantly lower rate and risk of COPD exacerbations than BUD/GLY/FORM.