Anne-Marie Kirsten

Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD.

BACKGROUND The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD. METHODS In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores. RESULTS Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P < .0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P < .0001 for all except P < .001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P < .05) but not with tiotropium. CONCLUSIONS In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

Efficacy and Safety of Aclidinium Bromide Compared with Placebo and Tiotropium in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: Results from a 6-week, Randomized, Controlled Phase Iiib Study

Abstract Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0–24) at week 6. Secondary and additional endpoints included FEV1 AUC12–24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety. Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0–24 and FEV1 AUC12–24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group. Conclusions: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD). AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St Georges Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout. In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone. In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol. Aclidinium/formoterol achieves significantly greater bronchodilation than salmeterol/fluticasone in stable COPD http://ow.ly/5txx301kAoZ

Clinical Correlates of Reduced Physical Activity in Idiopathic Pulmonary Fibrosis.

Background: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). Objectives: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. Methods: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. Georges Respiratory Questionnaire) as further clinical variables. Results: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. Conclusion: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.

Sarcoidosis with involvement of the paranasal sinuses - a retrospective analysis of 12 biopsy-proven cases

BackgroundExtrapulmonary involvement by sarcoidosis is observed in about 30–40% of patients with sarcoidosis. Little is known about the frequency and clinical characteristics of sinonasal sarcoidosis.MethodsWe retrospectively analyzed 12 cases of biopsy-proven sinonasal sarcoidosis. Patients were identified from a patient population of 1360 patients with sarcoidosis at the Outpatient Clinic for Sarcoidosis and Rare Lung Diseases at LungClinic Grosshansdorf, a tertiary care hospital for respiratory medicine.ResultsThe most frequent signs and symptoms were nasal polyps (4 cases), epistaxis (3 cases), nasal crusts (8 cases) and anosmia (5 cases). Pulmonary sarcoidosis of the patients was staged as stage I (n = 1) and stage II (n = 11) on chest radiographs. Spirometry was normal in 11 patients. 7 patients had a diffusion capacity of the lung for carbon monoxide of less than 90% of predicted. Other organs were affected in 8 patients. All patients received systemic corticosteroid treatment and most patients received topical steroids. 5 patients received steroid sparing agents. Repeated sinus surgery had to be performed in 4 patients.ConclusionsSinonasal involvement is a rare disease manifestation of sarcoidosis with a frequency slightly lower than 1% in our patient population. The clinical course of sinonasal sarcoidosis can be complicated by relapse despite systemic immunosuppressive treatment and repeated sinus surgery.

Multi-analyte profiling of inflammatory mediators in COPD sputum--the effects of processing.

Prior to using a new multi-analyte platform for the detection of markers in sputum it is advisable to assess whether sputum processing, especially mucus homogenization by dithiothreitol (DTT), affects the analysis. In this study we tested a novel Human Inflammation Multi Analyte Profiling® Kit (v1.0 Luminex platform; xMAP®). Induced sputum samples of 20 patients with stable COPD (mean FEV1, 59.2% pred.) were processed in parallel using standard processing (with DTT) and a more time consuming sputum dispersion method with phosphate buffered saline (PBS) only. A panel of 47 markers was analyzed in these sputum supernatants by the xMAP®. Twenty-five of 47 analytes have been detected in COPD sputum. Interestingly, 7 markers have been detected in sputum processed with DTT only, or significantly higher levels were observed following DTT treatment (VDBP, α-2-Macroglobulin, haptoglobin, α-1-antitrypsin, VCAM-1, and fibrinogen). However, standard DTT-processing resulted in lower detectable concentrations of ferritin, TIMP-1, MCP-1, MIP-1β, ICAM-1, and complement C3. The correlation between processing methods for the different markers indicates that DTT processing does not introduce a bias by affecting individual sputum samples differently. In conclusion, our data demonstrates that the Luminex-based xMAP® panel can be used for multi-analyte profiling of COPD sputum using the routinely applied method of sputum processing with DTT. However, researchers need to be aware that the absolute concentration of selected inflammatory markers can be affected by DTT.

HOPE-preservation of paraffin-embedded sputum samples–A new way of bioprofiling in COPD

Induced sputum is a non-invasive sampling technique for the analysis of airway inflammation in various lung diseases and comprises valuable potential for the identification of biomarkers and therapeutic targets by molecular methods. In the context of biobanking with preservation of induced sputum samples for subsequent analyses we applied the HEPES-glutamic acid buffer-mediated organic solvent protection effect (HOPE)-technique for preparation of induced sputum samples. Induced sputum samples of 20 patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 12 healthy controls were collected. Cell pellets of induced sputum samples were preserved with HOPE and subsequently embedded in paraffin. Immunostaining of paraffin-block sections for interleukin-8, interleukin-17, myeloperoxidase, matrixmetalloproteinase-9, CD68, and CD8 revealed distinct signals without antigen retrieval. Moreover, RNA was extracted and successfully used for transcription microarray analysis. Sputum samples preserved by the HOPE-technique display a tool to address scientific approaches in pulmonary research, which can enable the identification of new biomarkers and therapeutic targets in respiratory diseases.

Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension

The TOMORROW trial of nintedanib comprised a randomised, placebo-controlled, 52-week period followed by a further blinded treatment period and an open-label extension. We assessed outcomes across these periods in patients randomised to nintedanib 150 mg twice daily or placebo at the start of TOMORROW. The annual rate of decline in FVC was −125.4 mL/year (95% CI −168.1 to −82.7) in the nintedanib group and −189.7 mL/year (95% CI −229.8 to −149.6) in the comparator group. The adverse event profile of nintedanib remained consistent throughout the studies. These results support a benefit of nintedanib on slowing progression of idiopathic pulmonary fibrosis beyond 52 weeks.

Physical activity, airway resistance and small airway dysfunction in severe asthma

Asthma is a chronic airway disease with a heterogeneous clinical presentation [1], and a subset of ∼5–10% of patients suffer from severe disease [2]. Chronic obstructive pulmonary disease (COPD) is different from asthma with respect to underlying pathobiology but shares some clinical features with severe asthma, for instance fixed airway obstruction and small airway dysfunction [3, 4]. In COPD, the consequences of the disease for physical activity in daily life have been studied intensively [5–7]; in contrast, only few data are available on patients with asthma [8]. Measurements of physical activity in adult patients with stable asthma of different severity grades are lacking, and associations with airway physiology have not been evaluated. Physical activity is reduced in severe asthma; impulse oscillometry was a better predictor than spirometry http://ow.ly/6WdN305D9aV

Diagnose und Therapie der Sarkoidose

Die Sarkoidose ist eine systemische Granulomatose mit oft charakteristischem radiologischen Bild und einer Kompartimentierung immunkompetenter Zellen in der Lunge. Das histologische Korrelat sind epitheloidzellige Granulome. Die Ätiologie ist bisher unbekannt. Männer sind ungefähr genauso häufig betroffen wie Frauen. Die Inzidenz wird in Deutschland auf 10/100 000 und die Prävalenz auf 50/100 000 geschätzt.