Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate to severe COPD - A randomised, multicentre, crossover trial.

BACKGROUND: Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium. METHODS: In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 µg and tiotropium 18 µg via the Breezhaler® and Handihaler® devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV1 AUC 0-2h). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sRaw), all measured by body plethysmography. RESULTS: Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV1 AUC0-2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p < 0.01) and FEV1 at 15 min post-dose (least square mean treatment difference = 36 mL; 95% CI: 14, 58 mL; p < 0.01). Both treatments showed similar improvements in FRCpleth, RV, and IC. Glycopyrronium showed statistically significant improvement in sRaw compared with tiotropium over the first 90 min after dosing, with the difference of 0.184 kPa × s at 90 min post-dose (95% CI: 0.315,0.054 kPa × s; p < 0.01). CONCLUSIONS: Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV1 response seen with glycopyrronium. TRIAL REGISTRATION: ClinicalTrials.govNCT01922271.

Effects of indacaterol/glycopyrronium (QVA149) on lung hyperinflation and physical activity in patients with moderate to severe COPD: a randomised, placebo-controlled, crossover study (The MOVE Study).

BACKGROUND: Physical activity limitation is common in chronic obstructive pulmonary disease (COPD), and is associated with worse health status, and increased hospitalisation and mortality. Long-acting bronchodilators, either alone or in combination, have been shown to improve exercise intolerance. However, none of these studies were designed with physical activity as primary outcome. This study assessed the effect of indacaterol/glycopyrronium fixed dose combination (IND/GLY) 110/50 µg once daily (OD) versus placebo on lung hyperinflation (inspiratory capacity [IC]) and physical activity in patients with moderate-to-severe COPD. METHODS: In this multicentre, randomised, double-blind, placebo-controlled crossover study, patients received IND/GLY or placebo OD in two 21-day treatment periods (14-day washout between periods). Eligible patients were ≥40 years of age, current or ex-smokers (smoking history ≥10 pack-years), with post-salbutamol forced expiratory volume in 1 s (FEV1) 40-80 % predicted, and FEV1:forced vital capacity <0.70. The co-primary endpoints were peak IC after 21 days and average daily activity-related energy expenditure. Key secondary endpoints were average number of steps per day and the duration of at least moderate activity per day. Peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days were other secondary endpoints. RESULTS: A total of 194 patients were randomised (65.5 % male, mean age 62.8 years, mean FEV1 61.6 % predicted), with 183 (94.3 %) completing the study. Compared with placebo, IND/GLY significantly increased peak IC after 21 days (difference 202 mL, p < 0.0001), activity-related energy expenditure (difference 36.7 kcal/day, p = 0.040), and the average number of steps per day (difference 358, p = 0.029), with a trend towards an improvement in the duration of at least moderate activity (difference 4.4 min, p = 0.264). IND/GLY was associated with statistically significant improvements versus placebo in peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days. The incidence of treatment-emergent adverse events was 22.8 % with IND/GLY and 22.9 % with placebo. CONCLUSIONS: In this study, compared with placebo, IND/GLY reduced hyperinflation, and, despite no patient education or lifestyle advice, improved daily physical activity levels. This suggests that IND/GLY has the potential to impact two of the main clinical concerns in the care of patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01996319 .

The Long-Term Effectiveness and Safety of Omalizumab on Patient- and Physician-Reported Asthma Control: A Three-Year, Real-Life Observational Study.

INTRODUCTION: Allergic asthma is a chronic inflammatory disease caused by immunoglobulin E (IgE)-mediated allergy. Omalizumab is a monoclonal anti-IgE antibody for the treatment of severe allergic asthma (SAA). OBJECTIVES: The primary objective of the study was to assess asthma-related control in patients with SAA receiving omalizumab therapy. Secondary objectives included quality of life, treatment effectiveness, rate of severe exacerbations, and safety. METHODS: This was a prospective, multi-centre, non-interventional study to assess patient-related long-term outcomes of omalizumab treatment in Germany. This 3-year study enrolled patients aged ≥ 18 years with SAA. Asthma control was assessed using the asthma control questionnaire (ACQ-6) and physician-assessed global evaluation of treatment effectiveness (GETE). Exacerbations were recorded, and quality of life was assessed using the mini-asthma quality of life questionnaire (mini-AQLQ). RESULTS: Of 161 patients screened, 153 participated in this study. Most patients (92.2%) had been receiving prior omalizumab therapy for mean (SD) 2.9 (2.3) years. Omalizumab slightly decreased mean ACQ-6 score from 2.0 (1.22) at baseline to 1.7 (1.23) at the end of the 3-year treatment period [difference: -0.18 (1.07), P = 0.340]. Post-hoc analyses of ACQ-6 for the small number of treatment-naïve patients showed a decrease in mean (SD) ACQ-6 from 2.7 (1.08) at baseline to 1.4 (1.40) after 3 years of omalizumab treatment. Mini-AQLQ increased from 4.5 (1.26) at baseline to 4.7 (1.48) after 3 years [difference: 0.26 (1.35), P = 0.186]. GETE was reported as excellent or good for most patients (67.46-84.69%) and more than two-thirds had no severe exacerbation. There were no unexpected safety signals during the study period and no tachyphylaxis was observed. CONCLUSIONS: In conclusion, despite most patients receiving prior omalizumab treatment for approximately 3 years, there was no decrease in effectiveness or safety over the subsequent 3 years during this study. This supports the long-term use of omalizumab in maintaining asthma control and quality of life. FUNDING: Novartis Pharma GmbH, Germany.

Non-allergic severe asthma: is it really always non-allergic? The IDENTIFY project.

BACKGROUND: This differential diagnosis of allergic vs non-allergic asthma is typically made on the basis of sensitization to allergens, such that absence of sensitization could result in a patient being managed as having non-allergic asthma. In Germany, the number of specific allergen tests is limited and non-standardized (across clinicians and laboratories), with the potential for false negative diagnoses. IDENTIFY aimed to gain data on sensitizations toward aeroallergens in patients with severe asthma who had tested negative to perennial aeroallergens in previous tests. METHODS: This was a single visit, non-randomized, non-interventional study conducted in 87 centers across Germany. The only inclusion criteria were that patients had to be adults (at least 18 years of age) with a diagnosis of severe asthma (receiving at least Global Initiative for Asthma Step IV therapy), and who had previously tested negative to perennial aeroallergens. Patients were then tested for sensitization to a panel of 35 perennial aeroallergens, with positive sensitization indicated by CAP ≥ 0.35 kU/L. RESULTS: Of 588 patients recruited, 454 had complete and valid data, and had previously tested negative to perennial aeroallergens. Overall, 43.6% of the analyzed patients tested positive for at least one of the included aeroallergens, with 18.7% testing positive for three or more, and 4.2% positive for more than ten. The five most common sensitizations were to Staphylococcus aureus enterotoxin B, Aspergillus fumigatus, Candida albicans, Dermatophagoides farinae, and Rhizopus nigricans, each of which tested positive in at least 9.7% of the population. CONCLUSIONS: In this group of patients being managed as having non-allergic asthma (and who had all previously tested negative to perennial aeroallergens), a high proportion tested positive to a broad panel of aeroallergens. A diagnosis of allergic asthma therefore cannot be excluded purely on the basis of standard aeroallergen panels.

A two-year evaluation of the 'real life' impact of COPD on patients in Germany: The DACCORD observational study.

INTRODUCTION: DACCORD is an observational, non-interventional study being conducted in German primary and secondary care centres. The study aims to describe the impact of disease (including exacerbations) and treatments over 2 years on 'real-life' patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years and, on recruitment, were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and randomised clinical trial participation. Exacerbations data were collected every 3 months. COPD medication, COPD Assessment Test (CAT) and forced expiratory volume in 1 s (FEV1) were recorded at baseline and after 1 and 2 years. RESULTS: A total of 6122 patients were recruited, 3137 (51.2%) of whom completed the 2-year visit. The mean age of these patients was 65.6 years, 59% were male, 69% had mild or moderate airflow limitation, and their mean COPD Assessment Test (CAT) total score was 20.3. Overall, there was a trend towards decreasing COPD exacerbation rates over the 2-year follow-up period, with rates of 0.390 during Year 1 and 0.347 during Year 2. Rates were lower in patients with no exacerbation during the 6 months prior to entry (0.263 and 0.251 during Years 1 and 2, respectively), with 51.6% of patients having no exacerbation during the 6 months prior to entry and over the 2-year follow-up. Approximately 50% of the overall population experienced a clinically relevant improvement from baseline in CAT total score at Year 1 and 2. When assessed by treatment class (or classes), persistence to medication was high (77.8% in Year 1 and 71.4% in Year 2). CONCLUSIONS: Overall, the 2-year follow-up data from DACCORD suggest that for most patients with COPD exacerbations are a rare event. For the majority of patients, the focus should be on managing symptoms, and the impact that these symptoms have on their daily lives. Even for those patients who do exacerbate, although prevention of exacerbations is an important factor, management of symptoms should be a key consideration. DACCORD also suggests that COPD disease progression is not inevitable - providing patients are receiving pharmacological treatment.

"Real-life" inhaled corticosteroid withdrawal in COPD: a subgroup analysis of DACCORD.

Many patients with chronic obstructive pulmonary disease (COPD) receive inhaled corticosteroids (ICSs) without a clear indication, and thus, the impact of ICS withdrawal on disease control is of great interest. DACCORD is a prospective, noninterventional 2-year study in the primary and secondary care throughout Germany. A subgroup of patients were taking ICS prior to entry - 1,022 patients continued to receive ICS for 2 years; physicians withdrew ICS on entry in 236 patients. Data from these two subgroups were analyzed to evaluate the impact of ICS withdrawal. Patients aged ≥40 years with COPD, initiating or changing COPD maintenance medication were recruited, excluding patients with asthma. Demographic and disease characteristics, prescribed COPD medication, COPD Assessment Test, exacerbations, and lung function were recorded. There were few differences in baseline characteristics; ICS withdrawn patients had shorter disease duration and better lung function, with 74.2% of ICS withdrawn patients not exacerbating, compared with 70.7% ICS-continued patients. During Year 1, exacerbation rates were 0.414 in the withdrawn group and 0.433 in the continued group. COPD Assessment Test total score improved from baseline in both groups. These data suggest that ICS withdrawal is possible with no increased risk of exacerbations in patients with COPD managed in the primary and secondary care.

A year in the life of German patients with COPD: the DACCORD observational study.

INTRODUCTION: Randomized interventional trials generally recruit highly selected patients. In contrast, long-term, noninterventional studies can reflect standard of care of real-life populations. DACCORD (Die ambulante Versorgung mit langwirksamen Bronchodilatatoren: COPD-Register in Deutschland [Outpatient Care With Long-Acting Bronchodilators: COPD Registry in Germany]) is an ongoing observational study, conducted in primary and secondary care in Germany, aiming to describe the impact of disease and treatments on real-life patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients had a clinical and spirometry diagnosis of COPD, were aged ≥40 years, and were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and participation in a randomized clinical trial. Exacerbation data were collected every 3 months. COPD medication, COPD Assessment Test, and forced expiratory volume in 1 second (FEV1) were recorded at the end of the 1 year period. RESULTS: In the 6 months prior to baseline, 26.5% of the 3,974 patients experienced ≥1 exacerbation, compared with 26.1% over the 1-year follow-up (annualized rate 0.384). Importantly, only previous exacerbations and not poor lung function alone predicted an increased exacerbation risk. There was a general shift to lower disease severity from baseline to 1 year, predominantly as a consequence of a lower proportion of patients considered at high risk due to exacerbations. COPD Assessment Test mean change from baseline was -1.9, with 48.9% of patients reporting a clinically relevant improvement. Overall persistence to medication was high, with 77.2% of patients still receiving the same class of medication at 1 year. CONCLUSION: DACCORD suggests that in clinical practice, the large majority of COPD patients are symptomatic but seldom exacerbate and that widely used tools and treatment recommendations do not reflect this fully.

The 'real-life' COPD patient in Germany: The DACCORD study.

INTRODUCTION: DACCORD is an ongoing, longitudinal, non-interventional study within the German COPD National Prospective Registry. This manuscript describes the baseline characteristics of the first 5924 participants, recruited between November 2012 and November 2013. METHODS: The main inclusion criteria are a physician diagnosis of COPD, age ≥40 years, and initiating or changing COPD maintenance medication. Data collected included: Demographic and disease characteristics; prescribed medication; symptoms; COPD Assessment Test (CAT); modified Medical Research Council dyspnoea score (mMRC); exacerbations; comorbidities; and forced expiratory volume in 1 s (FEV1). RESULTS: Approximately 60% of the population are male, with mean age of 65.7 years and FEV1 61.6% predicted. On entry to the study the majority of patients reported symptoms, most commonly exertional dyspnoea (85.9%) and cough (65.7%). According to GOLD 2010, 48.6% of patients were classified as GOLD II. GOLD 2011 classification was influenced by the symptoms criterion: 43.7 and 45.3% of patients were classified as GOLD B or D using CAT, compared with 26.4 and 34.0%, respectively, using mMRC. The majority of patients were receiving a LAMA-containing regimen, with 39.4% overall receiving ICS. A total of 78.3% of patients reported at least one comorbidity, most commonly cardiovascular. CONCLUSION: In conclusion, DACCORD is a large, prospective, non-interventional study that provides an informative and intriguing picture of the typical COPD patient in Germany.

The growth rate of Mycobacterium smegmatis depends on sufficient porin-mediated influx of nutrients.

Mycobacteria have a unique outer membrane (OM) that is thicker than any other known biological membrane. Nutrients cross this permeability barrier by diffusion through porins. MspA is the major porin of Mycobacterium smegmatis. In this study we showed that three paralogues of MspA, namely MspB, MspC and MspD are also porins. However, only the mspA and mspC genes were expressed in the wild-type strain. None of the single deletion mutants displayed a significant OM permeability defect except for the mspA mutant. Deletion of the mspA gene caused activation of transcription of mspB and/or mspD in three independent strains by unknown chromosomal mutations. It is concluded that mspB and mspD provide backup porins for M. smegmatis. This also indicated that a minimal porin-mediated OM permeability is essential for survival of M. smegmatis. Electron microscopy in combination with quantitative image analysis of protein gels revealed that the number of pores per cell dropped from 2400 to 800 and 150 for the DeltamspA and DeltamspA DeltamspC mutant (ML10) respectively. The very low number of pores correlated well with the at least 20-fold lower channel activity of detergent extracts of the ML10 strain and its 15- and 75-fold lower permeability to nutrient molecules such as serine and glucose respectively. The amount of Msp porin and the OM permeability of the triple porin mutant lacking mspA, mspC and mspD was not altered. The growth rate of M. smegmatis dropped drastically with its porin-mediated OM permeability in contrast to porin mutants of Escherichia coli. These results show that porin-mediated influx of nutrients is a major determinant of the growth rate of M. smegmatis.