Access to Lung Cancer Screening Among American Indian and Alaska Native Adults: A Qualitative Study.

BACKGROUND: Lung cancer is the leading cause of cancer mortality among American Indian and Alaska Native populations. American Indian and Alaska Native people use commercial tobacco products at higher rates compared with all other races and ethnicities. Moreover, they show lower adherence to cancer screening guidelines. RESEARCH QUESTION: How do American Indian and Alaska Native adults perceive and use lung cancer screening? STUDY DESIGN AND METHODS: We conducted a study in which we recorded and transcribed data from three focus groups consisting of American Indian and Alaska Native adults. Participants were recruited through convenience sampling at a national health conference. Transcripts were analyzed by inductive coding. RESULTS: Participants (n = 58) of 28 tribes included tribal Elders, tribal leaders, and non-Native volunteers who worked with tribal communities. Limited community awareness of lung cancer screening, barriers to lung cancer screening at health care facilities, and health information-seeking behaviors emerged as key themes in discussions. Screening knowledge was limited except among people with direct experiences of lung cancer. Cancer risk factors such as multigenerational smoking were considered important priorities to address in communities. Limited educational and diagnostic resources are significant barriers to lung cancer screening uptake in addition to limited discussions with health care providers about cancer risk. INTERPRETATION: Limited access to and awareness of lung cancer screening must be addressed. American Indian and Alaska Native adults use several health information sources unique to tribal communities, and these should be leveraged in designing screening programs. Equitable partnerships between clinicians and tribes are essential in improving knowledge and use of lung cancer screening.

Effectiveness of a culturally tailored diabetes education curriculum with real-time continuous glucose monitoring in a Latinx population with type 2 diabetes: the CUT-DM with CGM for Latinx randomised controlled trial study protocol.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) is increasing in the Latinx community. Despite telehealth and technology becoming more available, these resources are not reaching the Latinx population. Diabetes education is a cornerstone of treatment; however, access to culturally tailored content is a barrier to the Latinx population. Real-time continuous glucose monitoring (RT-CGM) is a patient-empowering tool that can improve glycaemic control, but it is not readily available for Latinx patients with T2D. We aim to evaluate a culturally tailored diabetes self-management education and support (DSMES) curriculum, using a team-based approach to improve glycaemic control, promote healthy behaviours and enhance patient access with the use of telehealth in Latinx individuals. The primary aim of the study is to evaluate the additive effectiveness of RT-CGM on glycaemia and behavioural changes among Latinx patients undergoing a culturally tailored DSMES. A sub aim of the study is to evaluate family members' change in behaviours. METHODS: We propose a randomised controlled trial of blinded versus RT-CGM with 100 Latinx participants with T2D who will receive DSMES via telemedicine over 12 weeks (n=50 per group). The study will be conducted at a single large federally qualified health centre system. The control group will receive culturally tailored DSMES and blinded CGM. The intervention group will receive DSMES and RT-CGM. The DSMES is conducted by community health educators weekly over 12 weeks in Spanish or English, based on participant's language preference. Patients in the RT-CGM group will have cyclical use with a goal of 50 days wear time. The primary outcomes are changes in haemoglobin A1c and CGM-derived metrics at 3 and 6 months. The secondary outcomes include participants' self-management knowledge and behaviour and household members' change in lifestyle. ETHICS AND DISSEMINATION: The study proposal was approved by the University of Washington ethics/institutional review board (IRB) Committee as minimal risk (IRB ID: STUDY00014396) and the Sea Mar IRB committee. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT05394844.

Food Security and Food Sovereignty: The Difference Between Surviving and Thriving.

Previous research in American Indian and Alaska Native (AI/AN) communities has documented high prevalence of food insecurity. Yet many AI/AN scholars and communities have expressed concerns that the dominant societal conceptions of food security are not reflective of the teachings, priorities, and values of AI/AN communities. Food security initiatives often focus on access to food and, at times, nutrition but little consideration is given to cultural foods, the spirituality carried through foods, and whether the food was stewarded in a way that promotes well-being not just for humans but also for plants, animals, land, and water. Despite the concerns of AI/AN communities that their needs are not centered in dominant societal food conceptualizations and food security programming, the food sovereignty efforts of AI/AN communities have captured national attention as a solution to modern food system inequities. Indigenous Food Sovereignty (IFS) is a holistic approach to food that incorporates values of relationality, reciprocity, and relationships. Fundamental differences exist between food security and food sovereignty, yet dominant society often reduces IFS as a solution to food security, rather than an entirely different food system that is predicated on values that contrast with that of dominant society. Despite calls to decolonize the definition and measurement of food security, we explore whether fixing the concept of food security is a worthy endeavor or whether efforts would be better spent supporting the resurgence and revitalization of AI/AN food values, food knowledge, and community food sovereignty initiatives.

Framing an Indigenous Food Sovereignty Research Agenda.

Access to healthy and appealing food is essential for individuals to be able to live a healthy and quality life. For decades, food security has been a priority issue for public health professionals. Food sovereignty expands upon the concept of food insecurity (i.e., having access to nutritious and culturally relevant food) by incorporating people's rights to define their own food system. The expanded focus of food sovereignty on food systems prioritizes public health professionals' role in supporting environmental- and systems-level initiatives and evaluating their implications for health, economics, and the natural environment. Food sovereignty is of particular importance for Indigenous peoples (i.e., American Indian, Alaska Native, Native Hawaiian, and Pacific Islander communities). Colonization had demonstrable consequences, with many Indigenous communities being forcibly relocated from traditional lands, alongside the destruction of traditional food sources. Indigenous food sovereignty aligns with the sovereign nation status that American Indian tribes and Alaska Native communities have with the United States. Furthermore, the worldviews that incorporate Indigenous communities' relational responsibilities to care for their food systems, according to their traditional practices and beliefs (Coté, 2016; Morrison, 2011), uniquely positions Indigenous peoples to lead food sovereignty initiatives. In this article, we explore what is currently known regarding food sovereignty and health. We then discuss opportunities to expand the evidence on Indigenous food sovereignty's relationships with (1) health and well being, (2) economics, (3) the natural environment, and (4) programming facilitators and barriers.

Measuring Food Security among American Indian and Alaska Native Adults: Validity Evidence Supports the Use of the US Department of Agriculture Module.

BACKGROUND: Inequities in access, availability, and affordability of nutritious foods produced by settler colonialism contribute to high rates of food insecurity among American Indian and Alaska Native (AI/AN) households. Efforts to understand the influences of food security programming among AI/AN individuals in the United States are constrained by the absence of validity evidence for food security assessments for this population. OBJECTIVE: This study assessed whether AI/AN adult responses on the Food Security Survey Module provide an accurate assessment of food security prevalence, especially when compared with other racial and ethnic groups. DESIGN: A correlational design with the cross-sectional 2019 National Health Interview Survey was used to address the research objective. PARTICIPANTS AND SETTING: The 2019 National Health Interview Survey contains a sample (N = 30,052) representative of the resident civilian noninstitutionalized population. MAIN OUTCOME MEASURES: The primary outcome was food security, as characterized by the 10-item US Department of Agriculture Adult Food Security Survey Module. The module evaluates whether insufficient finances result in perceived food shortages and a reduction in the quantity and/or quality of food intake during the prior 30 days. STATISTICAL ANALYSES PERFORMED: Data were analyzed by racial and ethnic subsamples to assess scale dimensionality (confirmatory factor analysis), Item Response Theory item analysis, differential item functioning, and external validity (χ2 tests). RESULTS: Results supported the use of the 10-item module for racial and ethnic groups. However, differential item functioning effect sizes exceeded criteria for the Asian, AI/AN, and Hispanic respondents when compared with White respondents. Food security was not significantly related to all expected correlates in the AI/AN subsample. CONCLUSIONS: Compelling evidence is presented for validity of the FSSM scores in determining food security status of AI/AN adults. Qualitative inquiry that explores how culture influences the way food security is conceptualized and experienced is warranted.

Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol.

BACKGROUND: Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting ß2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance. Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes. OBJECTIVE: To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI]). METHODS: This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs. Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts. RESULTS: After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047). There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations. COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%]). CONCLUSIONS: A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population. Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations. Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes. Study registration number: ClinicalTrials.gov (identifier: NCT05127304). DISCLOSURES: The study was funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Dr Sethi has received honoraria/fees for consulting/speaking from Astra-Zeneca, BIPI, and GlaxoSmithKline. He has received consulting fees for serving on data safety monitoring boards from Nuvaira and Pulmotect. He has received consulting fees from Apellis and Aerogen. His institution has received research funds for his participation in clinical trials from Regeneron and AstraZeneca. Ms Palli was an employee of BIPI at the time the study was conducted. Drs Clark and Shaikh are employees of BIPI. Ms Buysman and Mr Sargent are employees and Dr Bengtson was an employee of Optum, which was contracted by BIPI to conduct this study. Dr Ferguson reports grants and personal fees from Boehringer Ingelheim during the conduct of the study; grants from Novartis, Altavant, and Knopp; grants and personal fees from AstraZeneca, Verona, Theravance, Teva, and GlaxoSmithKline; and personal fees from Galderma, Orpheris, Dev.Pro, Syneos, and Ionis outside the submitted work. He was a paid consultant for BIPI for this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Healthcare Resource Utilization, Cost and Clinical Outcomes in Patients Diagnosed with COPD Initiating Tiotropium Bromide/Olodaterol versus Fluticasone Furoate/Umeclidinium/Vilanterol Based on Exacerbation History.

Background: ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history. Methods: COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated. Results: Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup. Conclusion: These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Improvements in health status with revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist for chronic obstructive pulmonary disease.

BACKGROUND: Replicate, 12-week, phase 3 trials (0126 and 0127) of once-daily nebulized revefenacin 175 µg vs placebo demonstrated significant bronchodilation and improvements in health status in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). This post hoc analysis evaluated improvement in patient-reported outcomes (PROs), including the St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Clinical COPD Questionnaire (CCQ) in both women and men. METHODS: Participants were pooled from the two 12-week studies (411 [51%] women and 401 [49%] men). Changes in PROs were assessed overall and separately in men and women. RESULTS: Revefenacin improved SGRQ and CAT total scores from baseline in both studies; improvement in CCQ total score reached significance only in 0126. In pooled data, a greater proportion of patients achieved clinically meaningful response in SGRQ score (≥4-unit decrease from baseline) with revefenacin vs placebo (odds ratio, 1.5; 95% confidence interval, 1.1-2.1; P = 0.012). Clinically meaningful responses were also seen in CAT (≥2-unit decrease from baseline) and CCQ (≥0.4-unit decrease from baseline) scores with revefenacin vs placebo. When stratified by sex, improvements from baseline in SGRQ, CAT, and CCQ scores following revefenacin vs placebo reached statistical significance only in women. CONCLUSIONS: Maintenance treatment with revefenacin improved health status in patients with moderate to very severe COPD; however, the effect was more pronounced for women than men. CLINICALTRIALS: GOV: NCT02459080; NCT02512510.

Measuring Peak Inspiratory Flow in Patients with Chronic Obstructive Pulmonary Disease.

Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)-a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)-are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.

Food Insecurity among American Indian and Alaska Native People: A Scoping Review to Inform Future Research and Policy Needs.

Food insecurity, defined as insufficient access to nutritious foods, is a social determinant of health that may underpin health disparities in the US. American Indian and Alaska Native (AI/AN) individuals experience many health inequities that may be related to food insecurity, but no systematic analyses of the existing evidence have been published. Thus, the objective of this scoping review was to assess the literature on food insecurity among AI/AN individuals and communities, with a focus on the prevalence of food insecurity and its relations to sociodemographic, nutrition, and health characteristics. Systematic search and data extraction processes were used. Searches were conducted on PubMed as well as peer-reviewed journal and government websites. Of 3174 identified references, 34 publications describing 30 studies with predominantly AI/AN sample populations were included in the final narrative synthesis. Twenty-two studies (73%) were cross-sectional and the remaining 8 (27%) described interventions. The weighted average prevalence of food insecurity across the studies was 45.7%, although estimates varied from 16% to 80%. Most studies used some version of the USDA Food Security Survey Modules, although evidence supporting its validity in AI/AN respondents is limited. Based on the review, recommendations for future research were derived, which include fundamental validity testing, better representation of AI/AN individuals in federal or local food security reports, and consideration of cultural contexts when selecting methodological approaches. Advances in AI/AN food insecurity research could yield tangible benefits to ongoing initiatives aimed at increasing access to traditional foods, improving food environments on reservations and homelands, and supporting food sovereignty.

TRONARTO: A Randomized, Placebo-Controlled Study of Tiotropium/Olodaterol Delivered via Soft Mist Inhaler in COPD Patients Stratified by Peak Inspiratory Flow.

BACKGROUND: Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood. METHODS: TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 µg/5 µg) or matched placebo delivered via the Respimat® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0-3 hours (FEV1 AUC0-3h) and trough FEV1. RESULTS: Overall, 213 patients were randomized, of whom 106 received tiotropium/olodaterol (PIF <60 L/min, 55; PIF ≥60 L/min, 51) and 107 received placebo (PIF <60 L/min, 55; PIF ≥60 L/min, 52). For FEV1 AUC0-3h, the adjusted mean change from baseline versus placebo was 336 mL (95% confidence interval [CI] 246-425 mL; P<0.0001) in the PIF <60 L/min group and 321 mL (95% CI 233-409 mL; P<0.0001) in the PIF ≥60 L/min group. For trough FEV1, the adjusted mean change from baseline versus placebo was 201 mL (95% CI 117-286 mL; P<0.0001) in the PIF <60 L/min group and 217 mL (95% CI 135-299 mL; P<0.0001) in the PIF ≥60 L/min group. CONCLUSION: In the TRONARTO study, which included patients with moderate-to-severe COPD and varying inspiratory flow abilities, treatment with tiotropium/olodaterol resulted in significant lung function improvements versus placebo. This SMI can be used irrespective of the PIF that a patient can generate.

Benefits of budesonide/glycopyrrolate/formoterol fumarate (BGF) on symptoms and quality of life in patients with COPD in the ETHOS trial.

BACKGROUND: We report the long-term effects of triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) vs glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF) on symptoms and health-related quality of life (HRQoL) over 52 weeks in the Phase III ETHOS study of patients with moderate-to-very severe COPD. METHODS: ETHOS was a randomized, double-blind, multi-center, parallel-group study in symptomatic patients with COPD who experienced ≥1 moderate/severe exacerbation in the previous year. Patients received twice-daily BGF 320/18/9.6 µg, BGF 160/18/9.6 µg, GFF 18/9.6 µg, or BFF 320/9.6 µg, administered via a single Aerosphere inhaler, for 52 weeks. RESULTS: The modified intent-to-treat population included 8509 patients (mean age 64.7 years; 59.7% male; mean COPD Assessment Test score, 19.6). BGF significantly reduced rescue medication use vs GFF and BFF (-0.53 puffs/day [p < 0.0001] and -0.35 puffs/day [p = 0.0002], respectively, with BGF 320 over 52 weeks). BGF 320 also significantly improved St George's Respiratory Questionnaire (SGRQ) total score over 24 and 52 weeks vs dual therapies, resulting in the greatest proportion of SGRQ responders vs dual therapies over 24 weeks (52.5% vs 42.5% [GFF] and 45.2% [BFF]) and 52 weeks (47.0% vs 37.8% [GFF] and 41.0% [BFF]). Similar results were observed with BGF 160. Benefits were also observed vs dual therapies in symptomatic endpoints including Transition Dyspnea Index focal score, EXAcerbations of Chronic pulmonary disease Tool total scores and Evaluating Respiratory Symptoms in COPD total scores over 24 and 52 weeks. CONCLUSIONS: BGF triple therapy improved symptoms and HRQoL vs dual therapies over 24 and 52 weeks in patients with moderate-to-very severe COPD.

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy.

PURPOSE: Ensifentrine is an inhaled dual inhibitor of phosphodiesterase (PDE) 3 and 4 that has shown bronchodilatory effects and symptom improvement in clinical studies in patients with chronic obstructive pulmonary disease (COPD), and anti-inflammatory effects in healthy volunteers in a model of COPD-like inflammation. This manuscript reports on the results of the clinical study examining if ensifentrine provides meaningful improvements in lung function when added on to tiotropium over 4 weeks in patients with COPD who have impaired lung function and symptoms despite treatment with tiotropium. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with moderate-to-severe COPD. Patients were randomized to open-label tiotropium once daily (QD) plus (+) blinded escalating doses of ensifentrine or placebo twice daily (BID). Effects on lung function, symptoms and quality of life (QoL) were assessed over 4 weeks. RESULTS: A total of 416 COPD patients were randomized and 413 received at least one dose of blinded study medication + tiotropium. All ensifentrine doses produced a significant and dose-dependent increase in peak forced expiratory volume in 1 second (FEV1) from baseline to Week 4, with placebo-corrected differences of 77.5 mL when added to tiotropium (0.375 mg; 95% CI: 4.8, 150.1 mL; p=0.037) to 124.2 mL (3 mg; 95% CI: 51.0, 196.8 mL; p<0.001). A significant increase in average FEV1 (0-12h) was shown at Week 4 with the 3 mg dose (87.3 mL; 95% CI: 20.0, 154.5 mL; p=0.011). Clinically meaningful and statistically significant improvements in the St. George's Respiratory Questionnaire - COPD (SGRQ-C) additive to tiotropium were observed at Week 4, exceeding the minimally clinically important difference of 4 units with the 1.5 and 3 mg doses. Adverse events were similar in frequency between the ensifentrine and placebo arms. CONCLUSION: This clinical study demonstrated that nebulized ensifentrine added on to tiotropium produced clinically important improvements in lung function and QoL over 4 weeks in COPD patients receiving tiotropium who demonstrated symptoms and lung function impairment, with a safety profile similar to placebo.

Efficacy and Safety of Budesonide/Glycopyrronium/Formoterol Fumarate versus Other Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 µg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.

Peak Inspiratory Flow Rate in COPD: An Analysis of Clinical Trial and Real-World Data.

BACKGROUND: The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has not been fully determined. In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥30 L/min. This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials. METHODS: The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients. This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population. Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations. RESULTS: A total of 1460 (207608/207609) and 3282 (KPNW) patients were included. There was considerable overlap between spirometric PIF distributions for both populations. Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥50 L/min, estimated as equivalent to ELLIPTA PIFR ≥30 L/min. In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF. CONCLUSION: Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥30 L/min through the ELLIPTA DPI. Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities.

Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Exacerbation Outcomes in Patients with COPD without a Recent Exacerbation History: A Subgroup Analysis of KRONOS.

PURPOSE: In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥1 exacerbation in the 12 months prior to the study. PATIENTS AND METHODS: Patients received BGF MDI 320/18/9.6 µg, GFF MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study. RESULTS: Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count. CONCLUSION: In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations.

Benralizumab for adolescent patients with severe, eosinophilic asthma: Safety and efficacy after 3 years of treatment.

BACKGROUND: Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported. OBJECTIVE: We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. METHODS: Patients on benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. RESULTS: Adolescents (N = 86) were treated with benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). CONCLUSIONS: Safety and efficacy profiles in this 2-year extension study (up to 3 years of benralizumab treatment in adolescents) were consistent with previous findings.

Is the natural UV zone important for successful captive propagation of the Panther Chameleon (Furcifer pardalis); are different UVB irradiance exposures that generate a similar dose equally successful?

While we generally understand the optimal ultraviolet B (UVB) environment for the growth and reproduction of female Panther Chameleons Furcifer pardalis, we do not know the relative importance of UVB irradiance and dose for optimal husbandry outcomes. Accordingly, we experimented with Panther Chameleon females to test the hypothesis that UVB dose (irradiance × exposure duration) determines the outcome, regardless of the combination of UVB irradiance and exposure duration generating the dose. We varied UVB irradiance and exposure duration across treatment groups while keeping dose similar and within a range previously documented to result in reproductive success. The growth rate, age of maturity, and measurable vitamin D status were not significantly different among the treatment groups. Individuals in all groups produced viable eggs that successfully hatched. Thus, we found some support for the hypothesis that the UVB dose determines the outcome regardless of UVB irradiance. However, mean egg vitamin D3 concentration and percent hatching were higher in the highest UVB irradiance group, despite similar doses among the three groups. Preliminary field data reveal that this species occupies UV irradiance Zone 4 in Madagascar, the highest zone for reptiles recorded. Only the irradiance of the high UVB irradiance group in our experiment approached this zone and resulted in the best reproductive success. Biosynthesis of vitamin D3 and provisioning to eggs is more efficient when exposure to UVB irradiance is similar to that in their natural environment. Establishing an optimal UVB environment, based on knowledge of the natural UVB environment, is important for the propagation of Panther Chameleons in captivity.

Real-World Evidence: Bridging Gaps in Evidence to Guide Payer Decisions.

Randomized controlled trials (RCTs) are preferred by payers for health technology assessments and coverage decisions. However, the inclusion of a highly selective patient population and the rigorously controlled conditions in RCTs may not be reflective of real-world clinical practice. Real-world evidence (RWE) obtained from an analysis of real-world data (RWD) from observational studies can bridge gaps in evidence not addressed by RCTs and is thus valuable to public and private payers for decision-making. Through a broad literature search to obtain insights into payers' experience, we found that payers have concerns about real-world studies with respect to data quality, poor internal validity, potential bias, and lack of meaningful endpoints. However, they valued RWE to fill evidence gaps not addressed by RCTs, such as high-quality, real-world, long-term effectiveness and safety data; head-to-head drug comparisons; cost analyses for tiering formulary placement; medication use and adherence patterns; identification of relevant responder and non-responder patient subpopulations; and patient-reported outcomes (PROs). RWE can be used to assess clinically meaningful endpoints and gauge the impact of interventions on the quality of healthcare. Here, we review how payers use or can use RWD on the comparative effectiveness and safety of treatments, PROs, medication adherence and persistence, prescribing patterns, healthcare resource utilization, and patient characteristics and/or biomarkers associated with treatment response when making health technology assessments and payer coverage decisions across therapeutic areas.

Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study.

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 µg of BGF (BGF 320), 160/18/9.6 µg of BGF (BGF 160), 18/9.6 µg of GFF, or 320/9.6 µg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.