Oliver Kornmann

Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison

Indacaterol is a novel, inhaled, once-daily, ultra-long-acting &bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily &bgr;2-agonist, salmeterol, as an active control. Patients with moderate-to-severe COPD were randomised to 6 months double-blind treatment with indacaterol (150 &mgr;g once daily), salmeterol (50 &mgr;g twice daily) or placebo. The primary efficacy end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV1) after 12 weeks. 1,002 patients were randomised and 838 (84%) completed the study. Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo (p<0.001) and by 60 mL over salmeterol (p<0.001). Both active treatments improved health status (St Georges Respiratory Questionnaire) and dyspnoea (transition dyspnoea index) compared with placebo, with differences between them favouring indacaterol. Safety profiles were similar across the treatment groups, and both indacaterol and salmeterol were well tolerated. Once-daily treatment with 150 &mgr;g indacaterol had a significant and clinically relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 &mgr;g salmeterol. Indacaterol should prove a useful additional treatment for patients with COPD.

Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.

BACKGROUND The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). METHODS We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1). RESULTS After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo. CONCLUSIONS Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).

Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany

Omalizumab is a humanized monoclonal anti-immunoglobulin E (IgE) antibody indicated in Europe for the treatment of uncontrolled severe persistent allergic (IgE-mediated) asthma despite optimal therapy with inhaled corticosteroids and long-acting beta(2) agonists. Between 2005 and 2007 280 patients (58% female, mean age 44+/-16 yrs., 46% on oral corticosteroids, median serum IgE level 235IU/ml) who met the EU criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab by 134 physicians as part of a post-marketing surveillance trial and were followed-up for 6 months. The median follow-up time was 195 days, the patients were treated with a median dose of 450mg omalizumab every 4 weeks. After 6 months there was a marked effect of omalizumab treatment on daily (-76%) and nocturnal symptoms (-84%), exacerbations (-82%), unscheduled health care contacts (-81%), hospitalizations (-78%) and quality of life (Mini-AQLQ: score increase from 2.9 to 4.5). Overall, efficacy of omalizumab was rated as excellent or good by the majority of physicians (82%) and patients (86%). In 19 patients (7%) omalizumab-related adverse events were recorded. This post-marketing surveillance trial confirms the marked and clinically relevant effect of omalizumab on asthma symptoms and level of asthma control in the majority of patients with severe persistent allergic (IgE-mediated) asthma in a real-life situation.

A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison.

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400microg or placebo via multi-dose dry powder inhaler, or indacaterol 400microg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC(22-24h)) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC(22-24h) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200microg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile.

Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown aetiology. Increased oxidant burden and antioxidant, e.g. glutathione (GSH), deficiency in the lower respiratory tract have been thought to play a role in the progression of IPF. Sputum induction is a safe noninvasive tool to study inflammation in the respiratory tract. The aim of the present study was to evaluate the direct measurement of GSH in induced sputum supernatant. Sixteen IPF patients and 15 healthy, nonsmoking subjects underwent sputum induction. Total GSH in sputum, saliva and plasma was measured spectrophotometrically. Sputum GSH was decreased more then four-fold in IPF patients when compared to healthy subjects (mean GSH 1.4±0.34 µM versus 5.8±0.98 µM). Salivary GSH was generally low or undetectable in all subjects. Plasma GSH levels were lower in IPF patients (0.26±0.1 versus 0.74±0.16 µM). In IPF patients, there was a borderline correlation of sputum GSH levels with disease duration and lung-function impairment. These data confirm the established role of oxidant/antioxidant imbalance in the pathogenesis of idiopathic pulmonary fibrosis, and show the potential of induced sputum to directly study inflammatory processes and surrogate markers in interstitial lung diseases like idiopathic pulmonary fibrosis.

Sputum levels of metalloproteinase-9 and tissue inhibitor of metalloproteinase-1, and their ratio correlate with airway obstruction in lung transplant recipients: relation to tumor necrosis factor-α and interleukin-10

BACKGROUND Chronic transplant rejection is characterized by progressive narrowing of small airways caused by matrix remodeling and fibrosis. Matrix-metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in the turnover of extracellular matrix. METHODS To clarify the contribution of MMPs and TIMPs to airway inflammation in patients after lung transplantation (LTx), we used enzyme immunoassays to measure induced sputum concentrations of MMP-9, TIMP-1, and controlling cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 of 30 LTx patients and 15 control subjects. RESULTS Sputum concentrations of MMP-9, TIMP-1, the MMP-9:TIMP-1 ratio, and TNF-alpha were higher in LTx patients than in control subjects (p < 0.04, all comparisons). The MMP-9, MMP-9:TIMP-1, and TNF-alpha levels were also significantly higher in LTx patients with chronic rejection compared with those with stable organ function (p < 0.03, all comparisons), whereas IL-10 levels were higher in the latter group (p = 0.05). In all LTx patients, MMP-9 and the MMP-9:TIMP-1 ratio were negatively correlated with forced expiratory volume in 1 second values (rho = -0.47, p = 0.01, and rho = -0.53, p = 0.003, respectively). We found that MMP-9 positively correlated with sputum neutrophils and TNF-alpha whereas MMP-9 and TIMP-1 did not correlate with IL-10. CONCLUSIONS These data underline the possible contribution of proteases such as MMP-9 to chronic transplant rejection, and suggest that an imbalance of MMP-9 and TIMP-1 may be involved in the pathogenesis of airway obstruction after LTx. We found that MMP-mediated inflammation seems to be controlled by TNF-alpha whereas IL-10 might elicit anti-inflammatory effects through different pathways.

Measurement of exhaled nitric oxide: Comparison of different analysers

Background and objective:  Exhaled nitric oxide (NO) is used as a surrogate marker to monitor eosinophilic airway inflammation, assist in diagnosis, and support treatment decisions for asthma patients. The aim of this study was to compare five NO analysers: Medisoft (M), Aerocrine Niox (N), Aerocrine Niox flex (NF), Aerocrino Niox mino (NM) and EcoMedics (E).

Sputum induction leads to a decrease of exhaled nitric oxide unrelated to airflow

Measurement of exhaled nitric oxide (eNO) and analysis of induced sputum are both established noninvasive methods for studying airway inflammation in asthma. Both methods are often used sequentially within short time frames. The aim of the present study was to evaluate the influence of sputum induction on eNO in adults and to follow the kinetics of airway eNO production after induction in relation to forced expiratory volume in one second (FEV1). eNO and FEV1 were measured in 41 adult patients (aged 29 (range 23–50) yrs, 56% male) with asymptomatic atopy or mild asthma (mean FEV1 97.2±3% predicted) prior to and immediately after sputum induction with hypertonic saline (4%). Sputum induction with isotonic saline was also performed in 13 subjects (control group). Repeatability of eNO decrease after sputum induction was also studied in 27 patients on separate occasions and kinetics of eNO production after sputum induction were followed over 24 h in another 10 patients. Sputum induction with hypertonic, but not isotonic, saline led to a marked decrease in eNO (log) immediately after the procedure (pre: 3.85±0.13 parts per billion (ppb); post: 3.24±0.14 ppb). This decrease was shown to be highly reproducible and not related to a fall in FEV1 following sputum induction. While FEV1 returned to baseline within 1 h, decreased eNO levels were observed over 4 h and returned to baseline after 24 h. Hypertonic saline sputum induction leads to a prolonged reduction in exhaled nitric oxide in adult atopics that is reproducible within subjects and not related to a reduction in airflow following sputum induction. This methodological interference should be taken into account when sputum induction and exhaled nitric oxide measurements are performed in the same subject.

Use of a portable device to record maximum inspiratory flow in relation to dyspnoea in patients with COPD

Forced inspiratory measures have been described to reflect the reduction in dyspnoea upon bronchodilation in severe COPD. Based on this we evaluated the applicability and usefulness of a portable device for the assessment of forced inspiration. In 37 patients with COPD (GOLD II/II/IV n = 16/15/6, mean ± SD FEV(1) 46.2 ± 15.4%pred) lung function was recorded prior to inhalation of 24 μg formoterol and 30 min later. Assessments comprised spirometry including forced inspiration, body plethysmography, maximum inspiratory flow (InCheck, Clement Clarke), and changes in dyspnoea via visual analogue scale (VAS). The sequence was repeated on a second day to assess reproducibility. Bronchodilation by formoterol was detectable in all functional indices (p < 0.05 each) except total lung capacity. FEV(1) improved by (mean ± SD) 11.1 ± 10.3%, forced inspiratory volume in 1s (FIV(1)) by 11.6 ± 13.5%, inspiratory peak flow (PIF) by 10.7 ± 16.2%, and inspiratory flow determined by the InCheck device (IF-IC) by 11.9 ± 14.4%. Remarkably, the changes of IF-IC (p < 0.001) but not those of other measures except FIV(1) (p < 0.05) were related to those of dyspnoea. Effects on IF-IC showed reproducibility comparable to that of other indices. The results suggest that a simple, portable device for recording forced inspiration could be useful in monitoring COPD, as a functional correlate of acute changes in dyspnoea.

Dissimilarity between seasonal changes in airway responsiveness to adenosine-5'-monophosphate and methacholine in patients with grass pollen allergic rhinitis: relation to induced sputum.

Background: In patients with allergic rhinitis, bronchial hyperresponsiveness (BHR) and airway inflammation may increase during pollen exposure. BHR can be assessed by adenosine-5′-monophosphate (AMP) or methacholine challenge. It has been suggested that BHR to AMP is more closely related to airway inflammation than BHR to methacholine. Seasonal allergic rhinitis offers a dynamic model to study changes in BHR and airway inflammation during natural allergen exposure. Methods: We measured BHR [provocative concentration causing a 20% fall (PC20) in forced expiratory volume in 1 s (FEV1)] to AMP and methacholine, and induced sputum cells in 16 rhinitis patients before and during the 2001 grass pollen season. Results: There was a decrease in PC20 methacholine during pollen exposure (geometric mean PC20 from 3.22 to 1.73 mg/ml, p = 0.0023), whereas no reduction was observed for PC20 AMP (p = 0.11). There was no increase in sputum eosinophils [pre: 0.69% (95% confidence interval 0.22–2.07); during: 1.85 (0.55– 5.6), p = 0.31]. Although the correlation of log PC20 methacholine and log PC20 AMP at baseline was good (r = 0.76, p = 0.001), individual seasonal changes (doubling concentrations) in PC20 methacholine were not correlated with changes in PC20 AMP (ρ = 0.21, p = 0.44). There was no correlation between baseline log PC20 methacholine or seasonal changes in PC20 methacholine and sputum eosinophils (p > 0.12, all correlations). In contrast, there was a significant correlation between seasonal changes in PC20 AMP and changes in sputum eosinophils (ρ = –0.59, p = 0.025). Conclusions: These data show dissimilarity between seasonal changes in PC20 AMP and methacholine in patients with seasonal allergic rhinitis. Moreover, PC20 AMP seems to be more closely related to sputum eosinophils than PC20 methacholine. The clinical significance of this discrepancy is unclear.