Additional Controller Medication Research Articles

Tezepelumab for Severe Asthma: One Drug Targeting Multiple Disease Pathways and Patient Types.

Asthma is a heterogeneous inflammatory disease of the airways, affecting many children, adolescents, and adults worldwide. Up to 10% of people with asthma have severe disease, associated with a higher risk of hospitalizations, greater healthcare costs, and poorer outcomes. Patients with severe asthma generally require high-dose inhaled corticosteroids and additional controller medications to achieve disease control; however, many patients remain uncontrolled despite this intensive treatment. The treatment of severe uncontrolled asthma has improved with greater understanding of asthma pathways and phenotypes as well as the advent of targeted biologic therapies. Tezepelumab, a monoclonal antibody, blocks thymic stromal lymphopoietin, an epithelial cytokine that has multifaceted effects on the initiation and persistence of asthma inflammation and pathophysiology. Unlike other biologic treatments, tezepelumab has demonstrated efficacy across severe asthma phenotypes, with the magnitude of effects varying by phenotype. Here we describe the anti-inflammatory effects and efficacy of tezepelumab across the most relevant phenotypes of severe asthma. Across clinical studies, tezepelumab reduced annualized asthma exacerbation rates versus placebo by 63-71% in eosinophilic severe asthma, by 58-68% in allergic severe asthma, by 67-71% in allergic and eosinophilic severe asthma, by 34-49% in type 2-low asthma, and by 31-41% in oral corticosteroid-dependent asthma. Furthermore, in all these asthma phenotypes, tezepelumab demonstrated higher efficacy in reducing exacerbations requiring hospitalizations or emergency department visits versus placebo. In patients with severe uncontrolled asthma, who commonly have multiple drivers of inflammation and disease, tezepelumab may modulate airway inflammation more extensively, as other available biologics block only specific downstream components of the inflammatory cascade.

Phenotyping of Severe Asthma in the Era of Broad-Acting Anti-Asthma Biologics

Severe asthma is associated with significant morbidity and mortality despite maximal use of inhaled corticosteroids and additional controller medications, and has a high economic burden. Biologic therapies are recommended for the management of severe, uncontrolled asthma to help prevent exacerbations and to improve symptoms and health-related quality of life. Effective management of severe asthma requires consideration of clinical heterogeneity that is driven by varying clinical and inflammatory phenotypes, which are reflective of distinct underlying disease mechanisms. Phenotyping patients using a combination of clinical characteristics such as age of onset or comorbidities and biomarker profiles, including blood eosinophil counts, and levels of fractional exhaled nitric oxide and serum total immunoglobulin E, is important for the differential diagnosis of asthma. Additionally, phenotyping is beneficial for risk assessment, selection of treatment, and monitoring of treatment response in patients with asthma. This review describes the clinical and inflammatory phenotypes of asthma, provides an overview of biomarkers routinely used in clinical practice and those that have recently been explored for phenotyping, and aims to assess the value of phenotyping in severe asthma management in the current era of biologics.

Effects of Tezepelumab on Quality of Life of Patients with Moderate-to-Severe, Uncontrolled Asthma: Systematic Review and Meta-Analysis.

To assess the effects of tezepelumab on quality of life (QoL) in patients with moderate-to-severe, uncontrolled asthma. Tezepelumab improves pulmonary function tests (PFTs) and reduces the annualized asthma exacerbation rate (AAER) in patients with moderate-to-severe, uncontrolled asthma. We searched MEDLINE, Embase, and Cochrane Library from inception to September 2022. We included randomized controlled trials comparing tezepelumab versus placebo in patients aged ≥ 12years with asthma on medium- or high-dose inhaled corticosteroids with ≥ 1 additional controller medication for ≥ 6months and who had ≥ 1 asthma exacerbation in the 12months before enrollment. We estimated effects measures with a random-effects model. Of 239 records identified, three studies were included, with a total of 1,484 patients. Tezepelumab significantly decreased biomarkers of T helper 2-driven inflammation, including blood eosinophil count (MD -135.8 [95% CI -164.37, -107.23]) and fractional exhaled nitric oxide (MD -9.64 [95% CI -13.75, -5.53]); improved PFTs, including pre-bronchodilator forced expiratory volume in 1s (MD 0.18 [95% CI 0.08-0.27]); reduced the AAER (MD 0.47 [95% CI 0.39-0.56]); improved asthma-specific health-related QoL in the Asthma Control Questionnaire-6 (MD -0.33 [95% CI -0.34, -0.32]), Asthma Quality of Life Questionnaire for 12 Years and Older (MD 0.34 [95% CI 0.33, -0.35]), Asthma Symptom Diary (MD -0.11 [95% CI -0.18, -0.04]), and European Quality of Life 5 Dimensions 5 Levels Questionnaire (SMD 3.29 [95% CI 2.03, 4.55]) scores, although not clinically important; and did not change key safety outcomes, including any adverse event (OR 0.78 [95% CI 0.56-1.09]).

A Retrospective Claims Database Study to Clarify Disease Burden of Severe Asthma Patients with Type 2 High or Low Inflammation

The disease burden of severe asthma patients stratified by type 2 (T2) biomarkers is not well studied in large patient samples, especially for T2-low severe asthma patients. Using a Japanese medical record database, we investigated disease and economic burdens in T2-high and T2-low severe asthma patients. Data of severe asthma patients (receiving high-dose inhaled corticosteroids and additional asthma-related controller medications or oral corticosteroids [OCS] prescription [≥183 days] during the 1-year baseline period) were analyzed in the Real World Data database, comprising electronic medical records from Japanese medical institutions. Severe asthma patients were stratified into a T2-high population with higher eosinophils (≥150 cells/μL) and/or higher total immunoglobulin E (IgE, ≥75 IU/mL) or a T2-low population with lower eosinophils (<150 cells/μL) and lower total IgE (<75 IU/mL). The incidence of asthma exacerbation events and drug costs were analyzed for each population. Different T2 thresholds were explored, including eosinophil count 300 cells/μL and/or IgE 150 IU/mL. Of the 732 severe asthma patients, 599 (81.8%) patients had T2-high type, and 133 (18.2%) had T2-low type. Proportions of the T2-high patients (30.6%) with asthma exacerbations, defined as a composite outcome, including OCS burst, injectable steroid use, and hospitalization, were similar to those of T2-low type (34.6%). The annual drug cost was similar between T2-high (175,487 JPY) and T2-low (165,322 JPY) populations. In this large-scale study, both T2-high and T2-low severe asthma patients in Japan were shown to have a high disease burden and high economic burden, suggesting an unmet treatment need.

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY NUMBER OF ADDITIONAL ASTHMA CONTROLLER MEDICATIONS: RESULTS FROM THE PHASE 3 NAVIGATOR STUDY

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY NUMBER OF ADDITIONAL ASTHMA CONTROLLER MEDICATIONS: RESULTS FROM THE PHASE 3 NAVIGATOR STUDY

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH UNCONTROLLED ASTHMA DESPITE RECEIVING TREATMENT FOR MODERATE OR SEVERE DISEASE: POOLED ANALYSIS OF PATHWAY AND NAVIGATOR STUDIES

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH UNCONTROLLED ASTHMA DESPITE RECEIVING TREATMENT FOR MODERATE OR SEVERE DISEASE: POOLED ANALYSIS OF PATHWAY AND NAVIGATOR STUDIES

PASSAGE: A PHASE 4, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS AND SAFETY OF TEZEPELUMAB IN PATIENTS WITH SEVERE ASTHMA, INCLUDING UNDER-REPRESENTED GROUPS

PASSAGE: A PHASE 4, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS AND SAFETY OF TEZEPELUMAB IN PATIENTS WITH SEVERE ASTHMA, INCLUDING UNDER-REPRESENTED GROUPS

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA BY SMOKING HISTORY: POST HOC ANALYSIS OF THE PHASE 3 NAVIGATOR STUDY

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA BY SMOKING HISTORY: POST HOC ANALYSIS OF THE PHASE 3 NAVIGATOR STUDY

One-year safety and tolerability of tezepelumab in Japanese patients with severe uncontrolled asthma: results of the NOZOMI study

Objective To assess the long-term safety of tezepelumab in Japanese patients with severe uncontrolled asthma. Methods This phase III, 52-week, open-label, single-arm study (NOZOMI, NCT04048343) evaluated the safety/tolerability of subcutaneous (SC) tezepelumab 210 mg every 4 weeks (Q4W) in Japanese patients aged 12–80 years with severe uncontrolled asthma using medium- to high-dose inhaled corticosteroids and at least one additional asthma controller medication, with/without oral corticosteroids. Exploratory outcomes included efficacy (asthma exacerbations, lung function, and asthma control), pharmacokinetic parameters, and immunogenicity. Results Among 65 patients (median age 52 years), 39 (60%) experienced 94 adverse events (AEs; predominantly nasopharyngitis [13/65]) of mild (49.2%), moderate (7.7%), or severe (3.1%) intensity. Two patients had transient injection site erythema related to tezepelumab. Four patients reported serious AEs unrelated to tezepelumab and one AE led to treatment discontinuation. AEs of special interest were infrequent and generally mild/moderate. Apart from a decrease in blood eosinophils (an expected pharmacodynamic effect), no notable trends/clinically relevant changes in hematology, clinical chemistry, or urinalysis parameters were observed. Among exploratory outcomes, tezepelumab was associated with a low annualized asthma exacerbation rate over the study period (0.11/patient-year), improved lung function (mean [standard deviation] change from baseline of 0.075 [0.226] L in pre-dose/pre-bronchodilator forced expiratory volume in 1 s), and better asthma control versus baseline (responder rate: 71.4% at Week 52). Conclusion Tezepelumab 210 mg SC Q4W in Japanese patients with severe uncontrolled asthma showed safety/tolerability profiles similar to international data, with low exacerbation rates and improvements in lung function and asthma control.

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY BASELINE BMI IN THE NAVIGATOR STUDY

EFFICACY OF TEZEPELUMAB IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA GROUPED BY BASELINE BMI IN THE NAVIGATOR STUDY

EFFECT OF TEZEPELUMAB ON LUNG FUNCTION IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA IN THE PHASE 3 NAVIGATOR STUDY

EFFECT OF TEZEPELUMAB ON LUNG FUNCTION IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA IN THE PHASE 3 NAVIGATOR STUDY

Functionality and Performance of an Accessorized Pre-Filled Syringe and an Autoinjector for At-Home Administration of Tezepelumab in Patients with Severe, Uncontrolled Asthma.

BackgroundTezepelumab is an anti-thymic stromal lymphopoietin monoclonal antibody in development for the treatment of severe asthma. This study assessed the functionality and performance of an accessorized pre-filled syringe (APFS) and an autoinjector (AI) for administration of tezepelumab in the clinic and at home.MethodsThis phase 3, multicenter, randomized, open-label, parallel-group study (PATH-HOME, ClinicalTrials.gov identifier: NCT03968978) was conducted in patients aged 12–80 years with asthma that was uncontrolled despite treatment with medium- to high-dose inhaled corticosteroids plus at least one additional controller medication. Patients received six subcutaneous doses of tezepelumab 210 mg via APFS or AI. The first dose was administered by a healthcare professional, and patients or caregivers administered subsequent doses. First, second, third and final doses were administered in the clinic; fourth and fifth doses were administered at home. The primary endpoint was the proportion of successful administrations of tezepelumab. Secondary endpoints included the functionality and performance of the devices, Asthma Control Questionnaire (ACQ)-6 score, pharmacokinetics and safety.ResultsOverall, 216 patients were randomized (APFS, n=111; AI, n=105). Tezepelumab was successfully administered via APFS by 91.7% of the participants (100/109) and via AI by 92.4% (97/105). Overall, 95.4–97.1% of at-home administrations were successful across device groups. Malfunction occurred in 6 of 655 dispensed APFSs and 5 of 624 dispensed AIs. Clinically meaningful improvements in ACQ-6 score were observed after 24 weeks in 81.1% and 76.2% of the patients in the APFS and AI groups, respectively. Tezepelumab pharmacokinetics were consistent between device groups and with previous studies. The most common adverse event was nasopharyngitis (9.3%). Injection-site reactions occurred in 5.7% and 0% of the patients in the AI and APFS groups, respectively.ConclusionThis study demonstrated that the APFS and AI were functional and reliable, and performed equally well at home and in the clinic.

DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma

BackgroundTezepelumab 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.MethodsDESTINATION 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.DiscussionDESTINATION 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 registrationNCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma

BackgroundPatients 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.MethodsNAVIGATOR (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.DiscussionNAVIGATOR 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 registrationNCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.

Updated Evaluation of Dupilumab in the Treatment of Asthma: Patient Selection and Reported Outcomes.

Uncontrolled asthma continues to be a problem for many patients with moderate-to-severe allergic asthma. Dupilumab, which blocks the receptors for interleukin-4 and interleukin-13, has been effective in reducing asthma exacerbations, improving forced expiratory volume in one second (FEV1), and reducing oral corticosteroid use. When selecting patients for dupilumab, it is important to consider entry criteria for the original studies, subgroups that have responded best, and the presence of comorbid diseases that may also respond to dupilumab. Factors that were considered when selecting patients likely to respond to dupilumab in asthma studies include: failure of moderate or high dose inhaled steroids in combination with an additional controller medication, baseline FEV1 reversibility of 12% or greater, and Asthma Control Questionnaire > 1.5. The baseline characteristics that predicted a better response to dupilumab included blood eosinophils > 150 cells/mm3 and fractional exhaled nitric oxide > 25 parts per billion. Comorbidities that may also respond to treatment with dupilumab include atopic dermatitis, chronic rhinosinusitis, and allergic rhinitis. A combination of these factors should be considered when selecting the patients most likely to benefit from dupilumab.

Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma

IntroductionFor patients with eosinophilic asthma with allergic characteristics, understanding the key drivers of exacerbations is important to identify optimal treatment strategies. Benralizumab is an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody that significantly reduces exacerbation frequency for patients with severe, uncontrolled eosinophilic asthma. We evaluated the predictive value of baseline blood eosinophil counts vs. serum immunoglobulin E (IgE) concentrations on exacerbation risk and the association of these variables with benralizumab treatment effect.MethodsAnalyses were performed with data pooled from the phase III SIROCCO and CALIMA benralizumab trials. Crude annual asthma exacerbation rates (AERs) were determined for placebo as a function of baseline blood eosinophil counts and serum IgE concentrations with prespecified blood eosinophil count categories (< 150, ≥ 150 to < 300, ≥ 300 to < 450, ≥ 450 cells/µL) and IgE concentration quartiles (< 62.0, ≥ 62.0 to < 176.2, ≥ 176.2 to < 453.4, and ≥ 453.4 kU/L). We compared AERs for patients receiving benralizumab 30 mg every 8 weeks (first three doses every 4 weeks) vs. placebo for overlapping baseline blood eosinophil count categories and serum IgE concentration quartiles via a regression approach and by continuously using locally weighted regression smoothing analysis.ResultsExacerbation risk for patients with severe asthma receiving placebo increased with increasing baseline blood eosinophil counts but not with increasing serum IgE concentrations. Addition of baseline atopy status did not influence the relationship between IgE concentrations and exacerbation risk for patients receiving placebo. Patients with blood eosinophil counts ≥ 300 cells/µL had consistent decreases in exacerbation risk with benralizumab relative to placebo across all serum IgE concentration quartiles.ConclusionBaseline blood eosinophil counts, but not serum IgE concentrations, are an important predictor of exacerbation risk. Patients with severe eosinophilic asthma treated with benralizumab had consistent reductions in exacerbation risk, regardless of IgE concentrations.Clinical Trial RegistrationClinicalTrials.gov: SIROCCO, NCT01928771; CALIMA, NCT01914757.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-019-01191-2) contains supplementary material, which is available to authorized users.

Tiotropium in children and adolescents with asthma

BackgroundAsthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium—a long-acting muscarinic antagonist—as add-on therapy to an inhaled corticosteroid with or without a long-acting β2-agonist provides clinical benefit with a safety profile similar to placebo. ObjectiveTo review published evidence on the efficacy and safety of tiotropium as add-on a long-acting muscarinic antagonist therapy in children and adolescents with asthma that is uncontrolled despite use of an inhaled corticosteroid with or without additional controller medication(s). MethodsWe searched PubMed from inception until June 12, 2018, for randomized controlled trials of children and adolescents aged 1 to 17 years treated with tiotropium and reporting a primary outcome of any pulmonary function test and a secondary outcome of adverse events. ResultsOverall, 7 randomized controlled trials of 1902 preschool children (aged 1-5 years; n = 102), school-age children (aged 6-11 years; n = 905), and adolescents (aged 12-17 years; n = 895) with moderate to severe asthma were included in the analysis. Once-daily tiotropium (5, 2.5, or 1.25 μg) improved lung function parameters, including peak and trough forced expiratory volume in 1 second, vs placebo. Commonly reported adverse events across treatment groups included asthma worsening or exacerbations, decreased peak expiratory flow rate, nasopharyngitis, viral respiratory tract infection, and respiratory tract infection. ConclusionOnce-daily tiotropium as add-on therapy is efficacious and safe in adolescents and children with moderate to severe asthma. These results support the expanded indication by regulatory authorities for add-on tiotropium in patients 6 years or older.

Burden of Asthma and Role of 2.5µg Tiotropium Respimat® as an Add-On Therapy: A Systematic Review of Phase 2/3 Trials.

IntroductionTiotropium, a long-acting muscarinic antagonist, is approved for maintenance treatment of asthma in patients at least 6 years of age in the USA. We systematically reviewed published evidence on the efficacy and safety of 2.5 µg tiotropium Respimat® add-on therapy to inhaled corticosteroid (ICS) with or without additional controller medication(s) in children, adolescents, and adults with asthma.MethodsWe searched PubMed from inception until October 3, 2018, for phase 2 and 3 randomized controlled trials (RCTs) evaluating the effects of 2.5 µg tiotropium Respimat® on lung function parameters in patients with asthma. We extracted adjusted mean differences for lung function data and adverse events (AEs) from relevant articles.ResultsOverall, 11 RCTs (three phase 2 and eight phase 3 studies) including 3244 patients (2.5 µg tiotropium Respimat®, n = 1642; placebo, n = 1602) met the predefined inclusion criteria. Once-daily 2.5 µg tiotropium Respimat® improved lung function parameters, including peak and trough forced expiratory volume in 1 s and peak and trough forced vital capacity, versus placebo. Overall, the safety profile of 2.5 µg tiotropium Respimat® was comparable to that of placebo, with the most commonly reported AEs being asthma worsening, reduction in peak expiratory rate, nasopharyngitis, and respiratory tract infections.ConclusionOn the basis of the results of phase 2 and 3 studies, 2.5 µg tiotropium Respimat® as add-on to ICS therapy was safe and associated with consistent improvements in lung function in patients with asthma of varying severities across different age groups.FundingDevelopment of the manuscript was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01062-w) contains supplementary material, which is available to authorized users.

Update on immunogenicity in severe asthma: Experience with mepolizumab

Update on immunogenicity in severe asthma: Experience with mepolizumab

Safety and efficacy of tiotropium in children aged 1–5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial

Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms. This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed. Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death. To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children. Boehringer Ingelheim.