Effect of Indacaterol/Glycopyrronium on Pulmonary Perfusion and Ventilation in Hyperinflated Patients with Chronic Obstructive Pulmonary Disease (CLAIM). A Double-Blind, Randomized, Crossover Trial.

Rationale: In the CLAIM study, dual bronchodilation with indacaterol/glycopyrronium (IND/GLY) significantly reduced hyperinflation, which translated into improved cardiac function, measured by left ventricular end-diastolic volume and cardiac output. Pulmonary microvascular blood flow (PMBF) is reduced in chronic obstructive pulmonary disease (COPD); however, the effect of reduced lung hyperinflation on PMBF remains unknown. Objectives: To determine the effect of lung deflation with IND/GLY on PMBF and regional pulmonary ventilation using magnetic resonance imaging (MRI) in hyperinflated patients with COPD. Methods: In this double-blind, randomized, two-period crossover study, gadolinium-enhanced MRI and phase-resolved functional lung MRI were used to measure PMBF and regional ventilation, respectively, in patients with COPD receiving IND/GLY versus placebo. Measurements and Main Results: Sixty-two patients were randomized to receive once-daily IND/GLY (110/50 µg) for 14 days, followed by 14 days of placebo, or vice versa. Treatment periods were separated by a 14-day washout. Sixty patients were included in the per-protocol analysis. MRI measurements showed significant improvements in total PMBF (P = 0.006) and regional PMBF (P values for individual lobes were between 0.004 and 0.022) in response to IND/GLY versus placebo. Regional ventilation was also significantly improved with IND/GLY, as evidenced by a 12.4% increase versus placebo (P = 0.011), a 14.3% relative decrease in ventilation defect percentage of nonventilated/hypoventilated lung tissue (cutoff was defined as 0.075 regional ventilation; P = 0.0002), and a 15.7% reduction in the coefficient of variation of regional ventilation compared with placebo (P < 0.0001). Conclusions: Pharmacologic intervention with IND/GLY improves pulmonary microvascular blood flow and regional ventilation in patients with COPD with hyperinflation. Clinical trial registered with www.clinicaltrials.gov (NCT02442206).

Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study.

BACKGROUND: QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting ß2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. METHODS: This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety. RESULTS: Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). CONCLUSIONS: QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. TRIAL REGISTRATION NUMBER: NCT01120717.

Influence of physicians' risk perception on switching treatments between high- efficacy and non-high-efficacy disease­modifying therapies in multiple sclerosis.

BACKGROUND: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. OBJECTIVE: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. METHODS: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021. RESULTS: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). CONCLUSIONS: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs.

Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial.

BACKGROUND: Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting ß agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown. METHODS: We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack-years, and airflow limitation (FEV1 <80% predicted and post-bronchodilator FEV1: forced vital capacity <0·7). Patients with stable cardiovascular disease were eligible, but those with arrhythmias, heart failure, unstable ischaemic heart disease, or uncontrolled hypertension were not. We randomly assigned participants (1:1) to either receive a combined inhaled dual bronchodilator containing the LABA indacaterol (110 µg as maleate salt) plus the LAMA glycopyrronium (50 µg as bromide salt) once per day for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order. The randomisation was done using lists and was concealed from patients and investigators. The primary endpoint was the effect of indacaterol-glycopyrronium versus placebo on left-ventricular end-diastolic volume measured by MRI done on day 1 (visit 4) and day 15 (visit 5) in treatment period 1 and on day 29 (visit 6) and day 43 (visit 7) in treatment period 2 in the per-protocol population. Left-ventricular end-diastolic volume was indexed to body surface area. Safety was assessed in all participants who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02442206. FINDINGS: Between May 18, 2015, and April 20, 2017, we randomly assigned 62 eligible participants to treatment; 30 to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium. The 62 randomly assigned patients were included in the intent-to-treat analysis. There were two protocol violations and therefore 60 were included in the per-protocol analysis. 57 patients completed both treatment periods. After indacaterol-glycopyrronium treatment, left-ventricular end-diastolic volume increased from a mean 55·46 mL/m2 (SD 15·89) at baseline to a least-squares (LS) mean of 61·76 mL/m2 (95% CI 57·68-65·84), compared with a change from 56·42 mL/m2 at baseline (13·54) to 56·53 mL/m2 (52·43-60·62) after placebo (LS means treatment difference 5·23 mL/m2 [95% CI 3·22 to 7·25; p<0·0001]). The most common adverse events reported with indacaterol-glycopyrronium were cough (in nine patients [15%] of 59) and throat irritation (in seven [12%]). With placebo, the most common adverse events reported were headache (in five patients [8%] of 61) and upper respiratory tract infection (in four [7%]). Two patients had serious adverse events: one (2%) after indacaterol-glycopyrronium (endometrial cancer) and one (2%) after placebo (myocardial infarction); these were not thought to be treatment related. No patients died during the study. INTERPRETATION: This is the first study to analyse the effect of LABA-LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation. Dual bronchodilation with indacaterol-glycopyrronium significantly improved cardiac function as measured by left-ventricular end-diastolic volume. The results are important because of the known association of cardiovascular impairment with COPD, and support the early use of dual bronchodilation in patients with COPD who show signs of pulmonary hyperinflation. FUNDING: Novartis Pharma GmbH.