Effect of budesonide formoterol combined with tiotropium bromide on pulmonary function and inflammatory factors in patients with asthma–COPD overlap syndrome

Objective: To investigate the clinical efficacy of combining budesonide formoterol with tiotropium bromide for treating asthma–chronic obstructive pulmonary disease overlap syndrome (AOCS). Methods: The data of 104 patients with AOCS admitted to our hospital from December 2019 to December 2020 were assessed, randomly and divided into an experimental group (comprising 52 patients, receiving drug combination therapy) and a conventional group (comprising 52 patients, receiving drug therapy alone). Patients’ clinical efficacy, pulmonary function, fractioned exhaled nitric oxide (FeNO), immune function, endothelial function, serum lipid peroxidation injury indexes, adverse reactions, and quality of life scores were compared. Results: Prior to treatment, no significant differences were observed in various pulmonary function indicators, FeNO, immune function, endothelial function, and lipid peroxidation injury indexes between the two groups (P > 0.05). However, after treatment, all observation indexes in both groups improved to different levels, with the experimental group -demonstrating -significantly superior improvement, compared to the conventional group (P < 0.05). We also observed that adverse reactions in the experimental group were significantly lower than in the conventional group (P < 0.05). Conclusion: The combination of budesonide formoterol to tiotropium bromide in treating asthma–COPD overlap syndrome may significantly improve pulmonary function, endothelial function, and immune status of patients and encourage the recovery of serum lipid peroxidation injury; therefore, this may deserve widespread adoption and application (AU)

Tiotropium Bromide Attenuates Mucus Hypersecretion in Patients with Stable Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with stable chronic obstructive pulmonary disease (COPD) have been observed to benefit from tiotropium bromide. However, there are few studies of tiotropium bromide on sputum and sputum viscosity. To evaluate the effect of tiotropium bromide on mucus hypersecretion, a randomized, double-blind controlled trial was performed. METHODS: 120 cases of patients with pulmonary function grade II were divided into two groups, which include the treatment group given tiotropium bromide powder inhalation (18 µg, inhalation, QD) and the control group given formoterol fumarate powder inhalation (12 µg, inhalation, BID) plus ambroxol hydrochloride tablets (60 mg, oral, TID). After 3 months of treatment, the pulmonary function and α 1-acid glycoprotein (α 1-AGP) in sputum were detected, and the changes of glycoprotein and Ca2+ content were evaluated by Miller classification. RESULTS: Three patients (2 cases in the treatment group and 1 case in the control group) were dropped due to loss of follow-up, and 117 cases of patients were enrolled in this study. After 3 months of treatment, the sputum character score, α1-acid glycoprotein, Ca2+ content, and lung function of the two groups were significantly improved; group comparison analyses revealed that there was no significant difference in the content of α 1-AGP, Ca2+ in sputum, and lung function between the two groups (P > 0.05), but the improvement of sputum properties was significant (P < 0.05), and the treatment group was better than the control group (t = -2.77; P = 0.007). CONCLUSIONS: Inhaled tiotropium bromide can effectively inhibit the mucus hypersecretion in stable COPD patients, improve the sputum properties and lung function of patients, and improve the quality of life of patients.

Real-world effectiveness of early intervention with fixed-dose tiotropium/olodaterol vs tiotropium in Japanese patients with COPD: a high-dimensional propensity score-matched cohort analysis.

BACKGROUND: Escalation to triple therapy (long-acting muscarinic antagonist/ß2-agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma. METHODS: In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy. RESULTS: For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy. CONCLUSIONS: ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Comparison of COPD health care utilization and associated costs across patients treated with LAMA+LABA fixed-dose therapies.

BACKGROUND: There is limited clinical trial and/or real-world evidence comparing differences among currently approved fixed-dose combination (FDC) long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) treatments. OBJECTIVE: To compare chronic obstructive pulmonary disease (COPD)-related and all-cause health care resource utilization (HCRU) and costs between COPD patients initiating tiotropium (TIO) + olodaterol (OLO) versus (a) other LAMA + LABA FDCs and (b) umeclidinium (UMEC) + vilanterol (VI), specifically. METHODS: In this retrospective observational study, patients initiating fixed-dose LAMA + LABA therapy (earliest fill date = index date) between January 1, 2014, and September 30, 2018, were identified using administrative claims data from the Optum Research Database. Patients were followed post-index for 1-12 months. Follow-up was censored at the earliest occurrence of index therapy discontinuation or switch, health plan disenrollment, study end date, or reaching the maximum 12-month allowed duration. Propensity score matching of 1:2 was used to balance differences in baseline characteristics between cohorts for each of the 2 comparisons. Annualized population averages of HCRU and costs were calculated for each cohort as [sum of visits (or costs) for all individuals during the follow-up period] ÷ [sum of follow-up on-treatment time for all individuals] × 365 days. RESULTS: After matching, compared with patients who initiated other LAMA + LABAs or UMEC + VI, patients who initiated TIO + OLO had 14.29% and 16.95% fewer mean annualized per-patient COPD-related emergency department (ED) visits (vs. other LAMA + LABAs: 0.49 vs. 0.59, P = 0.005; vs. UMEC + VI: 0.48 vs. 0.56, P = 0.026) and 3.07% and 3.14% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 12.66 vs. 13.07, P = 0.016; vs. UMEC + VI: 12.62 vs. 13.02, P = 0.022), leading to 17.39% and 21.47% lower mean annualized per-patient COPD-related ED costs (vs. other LAMA + LABAs: $289 vs. $368, P = 0.003; vs. UMEC + VI: $285 vs. $345, P = 0.027) and 4.56% and 5.67% lower mean annualized per-patient pharmacy spending (vs. other LAMA + LABAs: $3,570 vs. $3,741, P < 0.001; vs. UMEC + VI: $3,556 vs. $3,770, P < 0.001) in the follow-up period. Similarly, patients in the TIO + OLO cohort had 15.63% and 21.17% fewer mean annualized per-patient all-cause ED visits (vs. other LAMA + LABAs: 1.08 vs. 1.37, P < 0.001; vs. UMEC + VI: 1.08 vs. 1.28, P = 0.001), 8.29% fewer mean annualized per-patient outpatient visits (vs. UMEC + VI: 13.28 vs. 14.48, P = 0.031), 3.41% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 56.92 vs. 58.93, P = 0.028), 19.48% and 22.28% lower mean annualized per-patient all-cause ED costs (vs. other LAMA + LABAs: $755 vs. $971, P < 0.001; vs. UMEC + VI: $749 vs. $930, P < 0.001), and 10.86% lower mean annualized per-patient outpatient setting costs (vs. UMEC + VI: $3,348 vs. $3,756, P = 0.050). There were no statistically significant differences for the other outcome measures. CONCLUSIONS: In a real-world setting, differences in HCRU and costs were observed between FDC LAMA + LABAs, with patients initiating TIO + OLO having lower ED visits/costs, COPD-related pharmacy fills/costs, and all-cause pharmacy use and outpatient visits/costs than those initiating other FDC LAMA + LABAs or UMEC + VI specifically. The remaining HCRU and cost measures were not significantly different. DISCLOSURES: This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI; Ridgefield, CT). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Palli is an employee of BIPI. Xie, Chastek, Elliott, and Bengtson are employees of Optum, which was contracted by BIPI to conduct this study. The authors received no direct compensation related to the development of the manuscript. Part of the results of this study were accepted and presented at the 30th European Respiratory Society (ERS) International Congress (September 7-9, 2020; virtual).

A randomized controlled trial of long-acting muscarinic antagonist and long-acting ß2 agonist fixed-dose combinations in patients with chronic obstructive pulmonary disease.

BACKGROUND: In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting ß2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD. METHODS: We enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC). RESULTS: No significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported. CONCLUSIONS: The three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).

Dual-combination maintenance inhaler preferences in asthma and chronic obstructive pulmonary disease: A patient-centered benefit-risk assessment.

BACKGROUND: A variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective. METHODS: Patient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD. RESULTS: For all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 µg/4.5 µg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 µg/5 µg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 µg/4.5 µg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 µg/4.5 µg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 µg/2.5 µg) soft mist inhaler had the highest PrCP (42.3%). CONCLUSIONS: Patient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes.

Comparing LAMA with LABA and LTRA as add-on therapies in primary care asthma management.

The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the core pharmacological treatment. However, many patients remain poorly controlled, and evidence-based algorithms to decide on the best order and rationale for add-on therapies are lacking. We explore the challenges of asthma management in primary care and review outcomes from randomised controlled trials and meta-analyses comparing the long-acting muscarinic antagonist (LAMA) tiotropium with long-acting ß2-agonists (LABAs) or leukotriene receptor antagonists (LTRAs) as add-on to ICS in patients with asthma. In adults, LAMAs and LABAs provide a greater improvement in lung function than LTRAs as add-on to ICS. In children, results were positive and comparable between therapies, but data are scarce. This information could aid decision-making in primary care, supporting the use of add-on therapy to ICS to help improve lung function, control asthma symptoms and prevent exacerbations.

Randomized controlled trial of triple versus dual inhaler therapy on small airways in smoking asthmatics.

BACKGROUND: Smoking worsens underlying asthma inflammation and also induces resistance to inhaled corticosteroids (ICS). Small airways dysfunction measured by impulse oscillometry (IOS) is associated with worse control. OBJECTIVES: We investigated the effects on small airways of adding long-acting beta-agonist (LABA) alone or with long-acting muscarinic antagonist (LAMA) to ICS in asthmatic smokers. METHODS: Sixteen current smokers were enrolled: mean age 44 year, FEV1 84%, FEF25-75 47%, R5 158%, ACQ 1.69, 20 pack year . Patients were converted to a reference ICS as HFA-BDP during initial run-in at median dose of 800 µg/day. Open label olodaterol 5 µg od (OLO) or olodaterol 5 µg/tiotropium 5 µg od (OLO/TIO) was added to HFA-BDP for median duration of 3 weeks in a randomized cross over design, including run-in and washout periods on HFA-BDP. IOS and spirometry were measured after each treatment (BDP/OLO/TIO or BDP/OLO) and at baseline after run-in and washout (BDP). RESULTS: After chronic dosing, IOS outcomes at trough except for R20 were all significantly improved with OLO/TIO compared to OLO. For the primary end-point of total airway resistance (as R5), the mean difference (95%CI) at trough was 0.06 (0.015-0.10) kPa/l/s, peripheral airways resistance (as R5-R20) 0.03 (0.003-0.06) kPa/l/s, peripheral lung reactance area (as AX) 0.38 (0.08-0.68) kPa/l and resonant frequency (as RF) 2.28 (0.45-4.12) Hz. FEF25-75 at trough was also better with OLO/TIO vs TIO: 0.93 (0.86 - 0.95) l/s while FEV1 was not different. CONCLUSIONS: ICS/LABA/LAMA was superior to ICS/LABA on trough small airway outcomes in asthma patients who smoke.

Asthma exacerbations and worsenings in patients aged 1-75 years with add-on tiotropium treatment.

This review explores the effect of tiotropium Respimat® add-on therapy on asthma exacerbations and worsenings, adverse events (AEs) related to exacerbations and symptoms and any effects on seasonality across the 10 UniTinA-asthma® clinical trials comprising over 6000 patients. When added on to inhaled corticosteroids ± additional therapies, tiotropium significantly reduced the risk of exacerbations and worsenings in adults with symptomatic severe asthma and provided a non-significant improvement in worsenings in adults with symptomatic moderate and mild asthma, which was significant for patients with moderate asthma receiving tiotropium 2.5 µg once daily vs. placebo. Trials in paediatric patients were not powered to assess exacerbations or worsenings, but when AEs related to asthma exacerbations and symptoms were grouped into a composite endpoint and pooled, tiotropium improved outcomes vs. placebo (rate ratio 0.76; 95% confidence interval 0.63, 0.93). The reduction in exacerbations with tiotropium is apparent across all patients during the observed seasonal peaks of these events.

Pulmonary drug absorption and systemic exposure in human: Predictions using physiologically based biopharmaceutics modeling.

Systemic exposure of inhaled drugs is used to estimate the local lung exposure and assess systemic side effects for drugs with local pharmacological targets. Predicting systemic exposure is therefore central for successful development of drugs intended to be inhaled. Currently, these predictions are based mainly on data from in vitro experiments, but the accuracy of these predictions might be improved if they were based on data with higher physiological relevance. In this study, systemic exposure was simulated by applying biopharmaceutics input parameters from isolated perfused rat lung (IPL) data to a lung model developed in MoBi® as an extension to the full physiologically-based pharmacokinetic (PBPK) model in PK-Sim®. These simulations were performed for a set of APIs with a variety of physicochemical properties and formulation types. Simulations based on rat IPL data were also compared to simulations based on in vitro data. The predictive performances of the simulations were evaluated by comparing simulated plasma concentration-time profiles to clinical observations after pulmonary administration. Simulations using IPL-based input parameters predicted systemic exposure well, with predicted AUCs within two-fold of the observed value for nine out of ten drug compounds/formulations, and predicted Cmax values within two-fold for eight out of ten drug compounds/formulations. Simulations using input parameters based on IPL data performed generally better than simulations based on in vitro input parameters. These results suggest that the developed model in combination with IPL data can be used to predict human lung absorption for compounds with different physicochemical properties and types of inhalation formulations.

Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON).

BACKGROUND: The efficacy and safety of once-daily (o.d.) fixed-dose combination of indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF) via Breezhaler® versus concurrent administration of salmeterol/fluticasone (SAL/FLU) twice-daily (b.i.d.) via Accuhaler®+Tiotropium (TIO) o.d. via Respimat® was evaluated in patients with uncontrolled asthma. METHODS: Patients (aged ≥18 years), symptomatic (Asthma Control Questionnaire [ACQ]-7 ≥1.5) despite treatment with long-acting ß2-agonist/inhaled corticosteroid medium- or high-dose, received IND/GLY/MF high- (150/50/160 µg) or medium-dose (150/50/80 µg) o.d. or SAL/FLU high-dose (50/500 µg) b.i.d.+Tio 5 µg o.d. for 24 weeks. The primary objective was to confirm the non-inferiority of either dose of IND/GLY/MF to SAL/FLU high dose + TIO in terms of Asthma Quality of Life Questionnaire (AQLQ). Additional endpoints: ACQ-7, lung function, health status (St George's Respiratory Questionnaire [SGRQ]), exacerbations, and safety after 24 weeks. RESULTS: IND/GLY/MF high- and medium-dose met the primary endpoint, confirming non-inferiority to SAL/FLU high dose + TIO for AQLQ (least square mean treatment difference [Δ]: 0.073 and -0.038, respectively; both p < 0.001). IND/GLY/MF high-dose improved ACQ-7 (Δ: -0.124; p = 0.004), trough FEV1 (Δ: 96 mL; p < 0.001), peak expiratory flow (morning [Δ: 9.56 L/min; p = 0.005], evening [Δ: 9.15 L/min; p = 0.006]) and SGRQ (Δ: -2.00; p = 0.04) versus SAL/FLU high dose + TIO. Improvements in these endpoints were comparable for IND/GLY/MF medium-dose and SAL/FLU high dose + TIO. Adverse events were generally comparable across treatments. CONCLUSIONS: IND/GLY/MF high- and medium-dose o.d. via a single inhaler were non-inferior to SAL/FLU high-dose b.i.d. + TIO o.d. via two inhalers for AQLQ. IND/GLY/MF high-dose o.d. improved lung function, asthma control and health status versus SAL/FLU high dose + TIO, while IND/GLY/MF medium-dose had comparable efficacy but at a corresponding lower steroid dose.

Differences in Real-World Health and Economic Outcomes Among Patients with COPD Treated with Combination Tiotropium/Olodaterol Versus Triple Therapy.

BACKGROUND: The 2018 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends combination long-acting muscarinic antagonists/long-acting beta2-agonists (LAMA + LABA) as preferred maintenance therapy for patients with symptomatic chronic obstructive lung disease (COPD) after monotherapy and stepping up to triple therapy (TT; LAMA + LABA + inhaled corticosteroids [ICS]) in case of further exacerbations. Restrictions on TT recommendations have primarily been driven by higher pneumonia risk associated with regular ICS use. Evidence suggests that TT is overprescribed, which may affect economic and clinical outcomes. OBJECTIVE: To compare health plan-paid costs, COPD exacerbations, and pneumonia diagnoses among patients newly treated with a LAMA + LABA regimen composed of tiotropium (TIO) + olodaterol (OLO) in a fixed-dose combination inhaler (TIO + OLO) or TT in a U.S. Medicare Advantage Part D insured population. METHODS: This retrospective study identified COPD patients aged ≥ 40 years who were initiating TIO + OLO or TT (index regimen) between January 1, 2014, and March 31, 2018, from a national administrative claims database. Continuous insurance coverage for 12 months pretreatment (baseline) and ≥ 30 days posttreatment (follow-up) was required. Patients were followed until the earliest of study end (May 31, 2018), discontinuation of index regimen (≥ 60-day gap in index regimen coverage), switch to a different regimen, or health plan disenrollment. Before analysis of outcomes, TIO + OLO and TT patients were 1:1 propensity score-matched on baseline demographics, comorbidities, COPD medication use, medical resource use, and costs. Cohort differences in post-match outcomes were assessed by Wald Z-test (annualized costs) and Kaplan-Meier method (time to first COPD exacerbation and pneumonia diagnosis). RESULTS: After matching, each cohort had 1,454 patients who were well balanced on baseline characteristics. Compared with TT, the TIO + OLO cohort incurred $7,041 (41.1%) lower mean COPD-related total costs ($10,094 vs. $17,135; P < 0.001); cohort differences in the medical component ($3,666 lower for TIO + OLO) were driven by lower mean acute inpatient costs ($3,053 lower for TIO + OLO). Combined mean COPD plus pneumonia-related medical costs were $5,212 (39.0%) lower for TIO + OLO versus TT ($8,209 vs. $13,421; P = 0.006), and total mean all-cause costs were $9,221 (30.4%) lower for TIO + OLO versus TT ($21,062 vs. $30,283; P < 0.001). Kaplan-Meier analysis found longer time to first severe COPD exacerbation (P = 0.020) and first pneumonia diagnosis (P = 0.002) for TIO + OLO versus TT and a lower percentage of TIO + OLO patients experiencing these events (severe COPD exacerbation: 9.0% vs. 16.1%; pneumonia: 14.5% vs. 19.3%). A secondary analysis, which expanded the TIO + OLO cohort to include any LAMA + LABA regimen, had similar findings for all outcomes. CONCLUSIONS: COPD patients initiating TIO + OLO incurred lower costs to health plans and experienced fewer COPD exacerbation and pneumonia events relative to TT. These findings provide important real-world economic and clinical insight into the GOLD recommendations for TIO + OLO and LAMA + LABA therapy. The study findings also indicate the continued inconsistency between the recommendations and real-world clinical practices pertaining to TT. DISCLOSURES: This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Palli and Franchino-Elder are employees of BIPI. Frazer, DuCharme, Buikema, and Anderson are employees of Optum, which was contracted by BIPI to conduct 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.

Tiotropium in chronic obstructive pulmonary disease - a review of clinical development.

BACKGROUND: Bronchodilators are the mainstay of pharmacological treatment in chronic obstructive pulmonary disease (COPD), and long-acting muscarinic antagonist (LAMA) monotherapy is recommended as initial treatment for Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, and D. MAIN BODY: Tiotropium bromide was the first LAMA available for COPD in clinical practice and, because of its long duration of action, is administered once daily. Tiotropium was initially available as an inhalation powder delivered via a dry-powder inhaler (DPI). Later, tiotropium also became available as an inhalation spray delivered via a soft mist inhaler (SMI). The SMI was designed to overcome or minimize some of the issues associated with other inhaler types (eg, the need for strong inspiratory airflow with DPIs). Results of short- and long-term randomized, controlled clinical trials of tiotropium in patients with COPD indicated tiotropium was safe and significantly improved lung function, health-related quality of life, and exercise endurance, and reduced dyspnea, lung hyperinflation, exacerbations, and use of rescue medication compared with placebo or active comparators. These positive efficacy findings triggered the evaluation of tiotropium in fixed-dose combination with olodaterol (a long-acting ß2-agonist). In this review, we provide an overview of studies of tiotropium for the treatment of COPD, with a focus on pivotal studies. CONCLUSION: Tiotropium is safe and efficacious as a long-term, once-daily LAMA for the maintenance treatment of COPD and for reducing COPD exacerbations. The SMI generates a low-velocity, long-duration aerosol spray with a high fine-particle fraction, which results in marked lung drug deposition. In addition, high inspiratory flow rates are not required.

Comparative measurement properties of constant work rate cycling and the endurance shuttle walking test in COPD: the TORRACTO® clinical trial.

BACKGROUND: Exercise tolerance is an important endpoint in chronic obstructive pulmonary disease (COPD) clinical trials. Little is known about the comparative measurement properties of constant work rate cycle ergometry (CWRCE) and the endurance shuttle walking test (ESWT). The objective of this sub-analysis of the TORRACTO® study was to directly compare the endurance measurement properties of CWRCE and ESWT in patients with COPD in a multicentre, multinational setting. We predicted that both tests would be similarly reliable, but that the ESWT would be more responsive to bronchodilation than CWRCE. METHODS: This analysis included 151 patients who performed CWRCE and ESWT at baseline and week 6 after receiving once-daily placebo, tiotropium/olodaterol (T/O) 2.5/5 µg or T/O 5/5 µg. Reproducibility was assessed by comparing their respective performance at baseline and week 6 in the placebo group. Responsiveness to bronchodilation was assessed by comparing endurance time at week 6 with T/O with baseline values and placebo. The locus of symptom limitation and end-exercise Borg scales for breathing and leg discomfort for both tests were also analysed. RESULTS: The intraclass correlation coefficients for CWRCE and ESWT were 0.56 [95% confidence interval (CI) 0.37-0.71] and 0.75 (95% CI 0.63-0.84). More patients were limited by breathing discomfort during the ESWT than during CWRCE, whereas more patients were limited by leg discomfort or breathing/leg discomfort during CWRCE than the ESWT (p <0.0001). Both tests were responsive to bronchodilator treatment: there was a 19% increase in endurance time from baseline at week 6 (p = 0.0006) assessed with CWRCE, and a 20% increase in endurance time assessed with ESWT (p = 0.0013). CONCLUSIONS: Both exercise tests performed well in a multicentre clinical trial. Although the locus of symptom limitation differed between the two tests, both were reliable and responsive to bronchodilation. For future clinical trials, the choice of test should depend on the study requirements. CLINICALTRIALS.GOV IDENTIFIER: NCT01525615. The reviews of this paper are available via the supplemental material section.

Emerging muscarinic receptor antagonists for the treatment of asthma.

INTRODUCTION: The increased acetylcholine signaling in asthma pathophysiology offers the rationale for the use of LAMAs in the treatment of asthmatic patients. Tiotropium is still the only LAMA approved for use in asthma but there is a real interest in developing novel LAMAs for the treatment of asthma, or at least to extend this indication to other LAMAs already on the market. AREAS COVERED: We examined and discussed trials and research that have studied or are evaluating the role of LAMAs already on the market in asthma and possible novel muscarinic acetylcholine receptor antagonists. EXPERT OPINION: Glycopyrronium and umeclidinium will soon be included in the GINA strategy with the same current indications of tiotropium. It is likely that the choice of the LAMA will be influenced not so much by its pharmacological profile as by the type of triple therapy chosen. It is extremely difficult to identify a new LAMA that is more effective than tiotropium, but is it plausible that new technologies that will allow delivering the drug in a more targeted way and with a lower risk of adverse effects may represent the real progress in the use of LAMAs in asthma in the coming years.

2019 Year in Review: Aerosol Therapy.

Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with Mycobacterium avium complex pulmonary disease. During 2019, lung injury associated to e-cigarette or vaping was reported, including 60 casualties.

The Design of and Rationale for the Effect of Perioperative Inhaled Tiotropium for Patients with Chronic Obstructive Pulmonary Disease in Esophageal Cancer Surgery (EPITOPE): an Open-Label, Randomized, Parallel-Group Study.

INTRODUCTION: Pneumonia is one of the most frequently occurring complications after esophagectomy and is associated with increased operative mortality. Chronic obstructive pulmonary disease (COPD) is known to be a risk factor for pulmonary complications and operative mortality. However, in COPD patients preparing for esophagectomy, preventive measures against postoperative pneumonia have not yet been discovered. In this study, we evaluate the effect of perioperative inhaled tiotropium, a long-acting, antimuscarinic bronchodilator used in the management of COPD, on patients with COPD who undergo esophageal cancer surgery. METHODS/DESIGN: This study investigates the effect of perioperative inhaled tiotropium on patients with COPD who undergo esophagectomy. It is an open-label, randomized controlled trial conducted in a single center (EPITOPE study). A total of 32 enrolled patients are randomly assigned in a 1:1 ratio to either conventional management or inhalation of tiotropium in addition to the conventional management. Patients included in the intervention group receive tiotropium Respimat 5 µg (two inhalations of 2.5 µg) for at least 2 weeks before the esophagectomy. Following the esophagectomy, tiotropium is re-delivered, starting as early as possible and continuing until the postoperative evaluation (between 30 and 44 days after the operation). The primary outcome is the incidence of pneumonia within 30 days after esophagectomy. Secondary outcomes are the incidence of cardiovascular complications within 30 days after esophagectomy, the incidence of any postoperative complications within 30 days after esophagectomy, pulmonary function (preintervention, preoperative, and postoperative), walking distance in the incremental shuttle walking test (preintervention, preoperative, and postoperative), the incidence of adverse events, and mortality within 30 days after esophagectomy. DISCUSSION: The EPITOPE study is the first pilot study on the effects of perioperative inhaled tiotropium on patients with COPD undergoing esophagectomy. After completing this study, we will plan a multicenter RCT with the appropriate outcomes in the future.

COPD clinical control as a predictor of future exacerbations: concept validation in the SPARK study population.

The concept of chronic obstructive pulmonary disease (COPD) control has been proposed to guide treatment decisions in COPD. In this study, we aimed to validate the prospective value of this concept in the SPARK study population. Control was assessed based on COPD stability and impact. Patients with low impact and stability during weeks 1-12 were classified as controlled, and exacerbations were measured during a 52-week follow-up. Of the 2044 patients included a majority were non-controlled (80%), frequently due to high impact. During the follow-up, the rate of moderate/severe exacerbations was significantly lower in controlled patients (rate ratio, 0.56, 95% CI 0.48 to 0.65 p<0.0001) and time-to-first moderate/severe exacerbation was significantly delayed. This study demonstrated an association between control status and risk of exacerbations.

A comparison of tiotropium, long-acting ß2-agonists and leukotriene receptor antagonists on lung function and exacerbations in paediatric patients with asthma.

Diagnosing and treating asthma in paediatric patients remains challenging, with many children and adolescents remaining uncontrolled despite treatment. Selecting the most appropriate pharmacological treatment to add onto inhaled corticosteroids (ICS) in children and adolescents with asthma who remain symptomatic despite ICS can be difficult. This literature review compares the efficacy and safety of long-acting ß2-agonists (LABAs), leukotriene receptor antagonists (LTRAs) and long-acting muscarinic antagonists (LAMAs) as add-on treatment to ICS in children and adolescents aged 4-17 years.A literature search identified a total of 29 studies that met the inclusion criteria, including 21 randomised controlled trials (RCTs) of LABAs versus placebo, two RCTs of LAMAs (tiotropium) versus placebo, and four RCTs of LTRA (montelukast), all as add-on to ICS. In these studies, tiotropium and LABAs provided greater improvements in lung function than LTRAs, when compared with placebo as add-on to ICS. Although exacerbation data were difficult to interpret, tiotropium reduced the risk of exacerbations requiring oral corticosteroids when added to ICS, with or without additional controllers. LABAs and LTRAs had a comparable risk of asthma exacerbations with placebo when added to ICS. When adverse events (AEs) or serious AEs were analysed, LABAs, montelukast and tiotropium had a comparable safety profile with placebo.In conclusion, this literature review provides an up-to-date overview of the efficacy and safety of LABAs, LTRAs and LAMAs as add-on to ICS in children and adolescents with asthma. Overall, tiotropium and LABAs have similar efficacy, and provide greater improvements in lung function than montelukast as add-on to ICS. All three controller options have comparable safety profiles.

Considerations for the Child with Nonatopic Asthma.

Asthma guidelines provide clinicians with evidence-based management strategies for this chronic condition. The preferred therapy for patient with persistent asthma is inhaled corticosteroids. However, ∼40% of the patients with persistent asthma continue to present with symptoms while treated according to the guidelines. Multiple factors are being explored to explain the variability in response to inhaled corticosteroids including asthma phenotype and genetic predisposition among others. The nonatopic asthma phenotype has been described in the literature. These patients tend to have milder symptoms of asthma and typically outgrow their asthma by adolescence. They present with chronic asthma symptoms in the absence of a positive allergy test, either skin prick test or specific immunoglobulin E blood test. Although patients with nonatopic asthma share many characteristics with patients with atopic asthma, there are several studies that suggest a different inflammatory pathway may be involved in their pathophysiology. Therefore, it is possible that children with nonatopic asthma could respond differently to inhaled corticosteroids compared with those with atopic asthma. Currently there is a variable definition of this phenotype. Furthermore, there is a paucity of therapeutic trial directed toward the patients with nonatopic asthma specifically. Future research should be guided toward identifying the inflammatory pathways in nonatopic asthma and potential phenotype-guided therapies.