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Background Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies. Methods DESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated. Discussion DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma. Trial registration NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Background Patients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline disease phenotype. This article reports the design and objectives of the pivotal phase 3 NAVIGATOR study. Methods NAVIGATOR (NCT03347279) is an ongoing randomized, double-blind, placebo-controlled trial in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma, who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids ( N  = 1061). The study population includes approximately equal proportions of patients with high (≥ 300 cells/μL) and low (< 300 cells/μL) blood eosinophil counts. The study comprises a 5–6-week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients will receive their prescribed controller medications without change throughout the study. The primary efficacy endpoint is the annualized asthma exacerbation rate during the 52-week treatment period. Key secondary endpoints include the effect of tezepelumab on lung function, asthma control and health-related quality of life. Discussion NAVIGATOR is evaluating the effect of tezepelumab in patients with a broad range of severe asthma phenotypes at baseline, including those with low blood eosinophil counts. The target sample size for NAVIGATOR ( N  = 1060) was achieved, and it is the largest clinical study of tezepelumab in severe, uncontrolled asthma to date. NAVIGATOR aims to further investigate the effect of tezepelumab on exacerbations and build on observations from the phase 2b PATHWAY study, and to demonstrate further the potential of tezepelumab to provide patients with severe, uncontrolled asthma with improvements in lung function, asthma control and health-related quality of life. Trial registration NCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.

Background Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study. Methods SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes. Conclusions SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose. Trial registration NCT03406078 ( ClinicalTrials.gov ). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078

Background In people with chronic obstructive pulmonary disease (COPD) on inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends stepping up to ICS/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) in those with exacerbations or switching to LAMA/LABA in those with major symptoms. However, the effect of stepping up to ICS/LAMA/LABA versus switching to LAMA/LABA on exacerbation risk is unclear. This analysis evaluated the effect of escalating to ICS/LAMA/LABA versus switching to LAMA/LABA or staying on ICS/LABA on lung function and exacerbation rates in symptomatic individuals with COPD without a recent exacerbation history from KRONOS. Methods In KRONOS (NCT02497001), symptomatic participants with moderate-to-very severe COPD (exacerbations in the prior year were not required for inclusion) were randomized to budesonide/glycopyrronium/formoterol fumarate dihydrate 320/14.4/10 μg (BGF), glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg (GFF), budesonide/formoterol fumarate dihydrate 320/10 μg (BFF) via metered-dose inhaler, or budesonide/formoterol fumarate dihydrate 400/12 μg via dry-powder inhaler (BUD/FORM) for 24 weeks. In participants without a recent exacerbation history on ICS/LABA in the 30 days before screening, morning pre-dose trough FEV 1 change from baseline and moderate/severe exacerbation rates over 24 weeks were analyzed post-hoc using linear repeated measures models and negative binomial regression, respectively, and participants escalated to ICS/LAMA/LABA (BGF) were compared with those switching to LAMA/LABA (GFF) or staying on ICS/LABA (BFF or BUD/FORM). Results On stepping up to BGF, least square means (95% confidence interval [CI]) differences for morning pre-dose trough FEV 1 change from baseline over 24 weeks was similar versus switching to GFF (12 [–21, 44] mL) but greater versus staying on ICS/LABA (BGF vs. BFF, 106 [64, 148] mL; BGF vs. BUD/FORM, 55 [12, 97] mL). Moderate/severe exacerbations were experienced by participants in all treatment arms (BGF, 14.9%; GFF, 24.0%; BFF 17.6%; BUD/FORM, 21.2%). Exacerbation risk was reduced when stepping up to BGF versus switching to GFF (rate ratio [95% CI]: 0.57 [0.35, 0.94]); rate ratios (95% CI) for BGF versus remaining on ICS/LABA were 0.93 (0.47, 1.82) with BFF and 0.62 (0.33, 1.18) with BUD/FORM. Conclusions People with symptomatic COPD and no recent exacerbation history previously on ICS/LABA had reduced exacerbation risk after escalating to ICS/LAMA/LABA versus switching to LAMA/LABA, and improved lung function versus staying on ICS/LABA. Trial registration ClinicalTrials.gov registry number NCT02497001 (registration date, 7 July 2015).

Background Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm 3 , and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count – focusing on blood EOS count 100 to < 300 cells/mm 3 – as a function of exacerbation history and COPD severity. Methods In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ) over 12–24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. Results Among patients with blood EOS count 100 to < 300 cells/mm 3 , least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. Conclusions These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm 3 , even if disease severity is moderate and there is no recent history of exacerbations. Trial registration ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

Background Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study. Methods CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants’ type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit. Discussion CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation. Trial registration NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.

Background Tralokinumab is an anti–interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2. Methods The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data. Results FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting tralokinumab efficacy. Discussion A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population. Trial registration STRATOS 1 and 2 are registered on ClinicalTrials.gov ( NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

Tezepelumab is a monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell–derived cytokine implicated in the pathogenesis of asthma. This randomized, placebo-controlled clinical trial showed a reduction in the annualized rate of asthma exacerbations among patients with severe, uncontrolled asthma treated with tezepelumab.

In people with chronic obstructive pulmonary disease (COPD) on inhaled corticosteroid/long-acting [beta].sub.2-agonist (ICS/LABA) therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends stepping up to ICS/long-acting muscarinic antagonist (LAMA)/long-acting [beta]2-agonist (LABA) in those with exacerbations or switching to LAMA/LABA in those with major symptoms. However, the effect of stepping up to ICS/LAMA/LABA versus switching to LAMA/LABA on exacerbation risk is unclear. This analysis evaluated the effect of escalating to ICS/LAMA/LABA versus switching to LAMA/LABA or staying on ICS/LABA on lung function and exacerbation rates in symptomatic individuals with COPD without a recent exacerbation history from KRONOS. In KRONOS (NCT02497001), symptomatic participants with moderate-to-very severe COPD (exacerbations in the prior year were not required for inclusion) were randomized to budesonide/glycopyrronium/formoterol fumarate dihydrate 320/14.4/10 [mu]g (BGF), glycopyrronium/formoterol fumarate dihydrate 14.4/10 [mu]g (GFF), budesonide/formoterol fumarate dihydrate 320/10 [mu]g (BFF) via metered-dose inhaler, or budesonide/formoterol fumarate dihydrate 400/12 [mu]g via dry-powder inhaler (BUD/FORM) for 24 weeks. In participants without a recent exacerbation history on ICS/LABA in the 30 days before screening, morning pre-dose trough FEV.sub.1 change from baseline and moderate/severe exacerbation rates over 24 weeks were analyzed post-hoc using linear repeated measures models and negative binomial regression, respectively, and participants escalated to ICS/LAMA/LABA (BGF) were compared with those switching to LAMA/LABA (GFF) or staying on ICS/LABA (BFF or BUD/FORM). On stepping up to BGF, least square means (95% confidence interval [CI]) differences for morning pre-dose trough FEV.sub.1 change from baseline over 24 weeks was similar versus switching to GFF (12 [-21, 44] mL) but greater versus staying on ICS/LABA (BGF vs. BFF, 106 [64, 148] mL; BGF vs. BUD/FORM, 55 [12, 97] mL). Moderate/severe exacerbations were experienced by participants in all treatment arms (BGF, 14.9%; GFF, 24.0%; BFF 17.6%; BUD/FORM, 21.2%). Exacerbation risk was reduced when stepping up to BGF versus switching to GFF (rate ratio [95% CI]: 0.57 [0.35, 0.94]); rate ratios (95% CI) for BGF versus remaining on ICS/LABA were 0.93 (0.47, 1.82) with BFF and 0.62 (0.33, 1.18) with BUD/FORM. People with symptomatic COPD and no recent exacerbation history previously on ICS/LABA had reduced exacerbation risk after escalating to ICS/LAMA/LABA versus switching to LAMA/LABA, and improved lung function versus staying on ICS/LABA.

In people with chronic obstructive pulmonary disease (COPD) on inhaled corticosteroid/long-acting β -agonist (ICS/LABA) therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends stepping up to ICS/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) in those with exacerbations or switching to LAMA/LABA in those with major symptoms. However, the effect of stepping up to ICS/LAMA/LABA versus switching to LAMA/LABA on exacerbation risk is unclear. This analysis evaluated the effect of escalating to ICS/LAMA/LABA versus switching to LAMA/LABA or staying on ICS/LABA on lung function and exacerbation rates in symptomatic individuals with COPD without a recent exacerbation history from KRONOS. In KRONOS (NCT02497001), symptomatic participants with moderate-to-very severe COPD (exacerbations in the prior year were not required for inclusion) were randomized to budesonide/glycopyrronium/formoterol fumarate dihydrate 320/14.4/10 μg (BGF), glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg (GFF), budesonide/formoterol fumarate dihydrate 320/10 μg (BFF) via metered-dose inhaler, or budesonide/formoterol fumarate dihydrate 400/12 μg via dry-powder inhaler (BUD/FORM) for 24 weeks. In participants without a recent exacerbation history on ICS/LABA in the 30 days before screening, morning pre-dose trough FEV change from baseline and moderate/severe exacerbation rates over 24 weeks were analyzed post-hoc using linear repeated measures models and negative binomial regression, respectively, and participants escalated to ICS/LAMA/LABA (BGF) were compared with those switching to LAMA/LABA (GFF) or staying on ICS/LABA (BFF or BUD/FORM). On stepping up to BGF, least square means (95% confidence interval [CI]) differences for morning pre-dose trough FEV change from baseline over 24 weeks was similar versus switching to GFF (12 [-21, 44] mL) but greater versus staying on ICS/LABA (BGF vs. BFF, 106 [64, 148] mL; BGF vs. BUD/FORM, 55 [12, 97] mL). Moderate/severe exacerbations were experienced by participants in all treatment arms (BGF, 14.9%; GFF, 24.0%; BFF 17.6%; BUD/FORM, 21.2%). Exacerbation risk was reduced when stepping up to BGF versus switching to GFF (rate ratio [95% CI]: 0.57 [0.35, 0.94]); rate ratios (95% CI) for BGF versus remaining on ICS/LABA were 0.93 (0.47, 1.82) with BFF and 0.62 (0.33, 1.18) with BUD/FORM. People with symptomatic COPD and no recent exacerbation history previously on ICS/LABA had reduced exacerbation risk after escalating to ICS/LAMA/LABA versus switching to LAMA/LABA, and improved lung function versus staying on ICS/LABA. ClinicalTrials.gov registry number NCT02497001 (registration date, 7 July 2015).