Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study.

BACKGROUND: Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting ß2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. METHODS: This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 µg, 150 µg) or medium-dose MF-IND (160 µg, 150 µg) once daily via Breezhaler; high-dose MF (800 µg [400 µg twice daily]) or medium-dose MF (400 µg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed. FINDINGS: Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. INTERPRETATION: Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control. FUNDING: Novartis Pharmaceuticals.

Omalizumab treatment and exercise capacity in severe asthmatics - results from a pilot study.

BACKGROUND: In patients with moderate to severe allergic asthma, clinical effectiveness of omalizumab, an approved anti-IgE-reacting substance, is usually assessed by pulmonary function testing (PFT), symptom scores and physicians judgement. AIMS: We postulate that cardiopulmonary exercise testing (CPET) may provide an additional option to verify symptomatic changes in patients with allergic asthma. METHODS: Ten consecutive patients with allergic asthma were treated with omalizumab. Prior to and after 16 weeks of treatment all patients underwent PFT and symptom-limited CPET. Results were compared to 10 asthmatic controls without omalizumab medication. Symptoms were assessed according to investigators judgement (IGETE). RESULTS: All 20 patients showed a significantly impaired exercise capacity at baseline [peak oxygen uptake (VO(2)) 71 ± 16% predicted]. In patients with omalizumab, peakVO(2) increased from 13.8 (8.4-21.4) to 16.8 (11.2-23.9) ml/kg/min (p < 0.05), VO(2) at anaerobic threshold increased by 22% [9.8 (3.3-15.2) to 12.3 (6.7-14.4) ml/kg/min (p < 0.05)]. There was no improvement in the controls. The increase in VO(2) was significantly correlated to the improvement in symptoms. All patients revealed dynamic hyperinflation under exercise with a decreasing extent with omalizumab treatment. CONCLUSION: This study suggests that CPET may provide additional and useful tools to assess and verify the individual clinical response to omalizumab treatment. An improvement in exercise capacity can reliably mirror changes in quality of life and IGETE. Patients with omalizumab experience significant improvements in their initially impaired exercise capacity. CPET can be safely accomplished in patients with severe asthma.

Nerve growth factor synthesis in human vascular smooth muscle cells and its regulation by dexamethasone.

BACKGROUND: Neurotrophins are involved in inflammatory pathways influencing several cells in healthy states and in diseases such as bronchial asthma. Recent studies have shown that nerve growth factor (NGF) is expressed in various non-neuronal cells. Furthermore, little is known about the different origins and regulation of NGF. In the present study, the expression of NGF and its regulation by dexamethasone was investigated in cultured human smooth muscle cells derived from umbilical veins (HSMC) and human iliacal arteries (HISMC). METHODS: Vascular smooth muscle cells were prepared. The presence of NGF was demonstrated by APAAP staining, western blotting, ELISA, and reverse transcription polymerase chain reaction. Vascular smooth muscle cells were incubated with dexamethasone, and cells and supernatants were collected for the measurement of NGF. RESULTS: Vascular smooth muscle cells demonstrate mRNA for NGF. Proteins were detectable by western blot, ELISA, and APAAP staining. NGF Protein and mRNA were suppressed after incubation with dexamethasone (0.1 microM) for 48 h in the vascular smooth muscle cells. NGF protein was also detected in cell supernatant and was suppressed by dexamethasone as well. CONCLUSION: These data indicate that vascular smooth muscle cells are a source of circulating NGF and thus may be involved in inflammatory responses mediated by neurotrophins. The suppression of NGF synthesis by dexamethasone might be a hint of further anti-inflammatory mechanisms of glucocorticoids.

Impact of pulmonary hypertension on gas exchange and exercise capacity in patients with pulmonary fibrosis.

Pulmonary hypertension is a relevant interceding morbidity in patients with pulmonary fibrosis that has significant impact on exercise tolerance and outcome. The aim of this study was to further characterize the exercise intolerance, dyspnoea and ventilatory inefficiency of patients with pulmonary fibrosis in the presence or absence of pulmonary hypertension via cardiopulmonary exercise testing. Thirty-four patients underwent pulmonary function testing, symptom-limited exercise testing on a bicycle and dyspnoea evaluation according to the BORG scale. Pulmonary hypertension was assessed by echocardiography and in a subset of patient's right heart catheterization. Sixteen of 34 patients with pulmonary fibrosis revealed pulmonary hypertension. While all study patients did not differ in lung functions and demographic characteristics, patients suffering from pulmonary hypertension showed a significantly impaired exercise tolerance and worsened ventilatory inefficiency. The extent of pulmonary artery pressure elevation impacted significantly on ventilatory inefficiency. In addition, the increased ventilatory requirements significantly influenced the extent of dyspnoea in patients with pulmonary hypertension. We conclude that pulmonary hypertension has a significant impact on exercise capacity and dyspnoea in patients with interstitial lung disease (ILD). The further impairment of exercise capacity as well as the extent of dyspnoea in patients with interceding PHT is attributable to a significantly impaired ventilatory inefficiency.

Basophil histamine release decreases during omalizumab therapy in allergic asthmatics.

BACKGROUND: Omalizumab is an established add-on therapy efficacious in allergic diseases with additional anti-inflammatory activity in the treatment of asthma. The evaluation of responders to anti-IgE treatment is critical to maximize benefit/risk/cost ratio. The aim of the study was to monitor the efficacy of anti-IgE treatment by ex vivo basophil histamine release. METHODS: Seventeen patients with allergic asthma were enrolled and received omalizumab at a dose of > or =0.016 mg/kg/IgE every 4 weeks. Histamine release from basophils was evaluated fluorometrically after dose-dependent allergen challenge at baseline and after 16 weeks of treatment. Maximal histamine release and cellular sensitivity to the allergen were calculated. Clinical measurements consisted of body plethysmography, skin prick test, beta2-agonist usage, serum free IgE levels, peripheral eosinophils and investigator ratings of global evaluation of treatment effectiveness. RESULTS: Maximal histamine release and cellular sensitivity to the allergen were significantly decreased in the omalizumab group compared to placebo. These changes were accompanied by significant changes in the clinical markers airway resistance, beta-agonist usage, skin prick test wheal area and investigator ratings of global evaluation of treatment effectiveness. CONCLUSIONS: Omalizumab therapy decreases basophil histamine release and cellular sensitivity with high effectivity of 95.8% (median). The decline of ex vivo basophil responses does not always parallel individual clinical improvement. Basophil-based stimulation tests should be further evaluated before being regarded as useful parameters monitoring omalizumab therapy.

Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma.

BACKGROUND: Omalizumab is a recombinant monoclonal anti-IgE antibody with proven efficacy in allergic diseases and further anti-inflammatory potency in the treatment of asthma. OBJECTIVES: To explore the anti-inflammatory mechanism of omalizumab, we investigated the induction of immunologic changes leading to eosinophil apoptosis and examined T-lymphocyte cytokine profiles in patients with allergic asthma. METHODS: Nineteen patients with allergic asthma were enrolled and received omalizumab at a dose of at least 0.016 mg/kg/IgE (IU/mL) every 4 weeks. Peripheral eosinophils and T-lymphocyte cytokine profiles were evaluated by fluorescence-activated cell sorting before treatment (baseline), at 12 weeks of treatment, and 12 weeks after discontinuation of treatment with omalizumab or placebo. RESULTS: Markers of eosinophil apoptosis (Annexin V) were significantly increased in omalizumab recipients compared with placebo, whereas no changes in markers of necrosis (7-amino-actinomycin) or eosinophil activation CD69 or Fas receptor (CD95) were detected. GM-CSF+ lymphocytes were reduced in omalizumab recipients compared with placebo. Fewer IL-2+ and IL-13+ lymphocytes were evident in omalizumab recipients than in the placebo group. There were no significant differences in IL-5, IFN-gamma, or TNF-alpha between the omalizumab and placebo groups. CONCLUSION: These findings provide further evidence that omalizumab has additional anti-inflammatory activity demonstrated by induction of eosinophil apoptosis and downregulation of the inflammatory cytokines IL-2 and IL-13. Further studies are needed to determine the underlying mechanisms. CLINICAL IMPLICATIONS: These findings support the critical role of IgE in the regulation of inflammation in allergic asthma: influencing the inflammation is the key to control the more severe type of asthma.

Regulation of NGF and BDNF by dexamethasone and theophylline in human peripheral eosinophils in allergics and non-allergics.

BACKGROUND: Recent studies have shown that the neurotrophins NGF and BDNF are produced by eosinophils. The influence of neurotrophins in allergic diseases including asthma has been described. The regulation by pharmacological substance remains unclear. OBJECTIVES: The aim of this study was to assess whether approved pharmacological substances in the treatment of asthma such as corticosteroids or theophylline regulate neurotrophins on a cellular level. METHODS: Eosinophils were purified by negative immunoselection from allergics and non-allergic donors. Eosinophils were incubated with dexamethasone and theophylline and supernatants were collected for measurement of neurotrophic factors. The content of neurotrophins in eosinophil lysates was determined by ELISA. Regulation of stored NGF and BDNF was demonstrated by Western-blotting and flow cytometry while influence on transcription level was demonstrated by RT-PCR. RESULTS: Eosinophils produce and release the neurotrophins NGF and BDNF at different levels in allergics and non-allergics. Dexamethason lead to a significant downregulation of NGF in eosinophils of allergics. The levels of BDNF were not significantly reduced. Theophylline did not influence the levels of NGF nor BDNF significantly. CONCLUSIONS: The production of the neurotrophin NGF was downregulated by an established substance such as dexamethasone. This might further contribute to the pharmacological potential of corticosteroids in allergic asthma.

Neuronal plasticity in persistent perennial allergic rhinitis.

OBJECTIVE: Persistent perennial allergic rhinitis belongs to the most frequent diseases in occupational and environmental medicine. Because the innervation may play a role in the pathogenesis of the disease, the present study analyzed nasal mucosal nerve profiles. METHODS: Neuropeptide-containing nerve fibers were examined using immunohistochemistry and related to eosinophil and mast cell numbers. RESULTS: In contrast to constant numbers of mast cells, there was a significant increase in the number of eosinophils. Immunohistochemistry for calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and neuropeptide tyrosine (NPY) revealed abundant staining of mucosal nerves. Semiquantitative assessment of nerve fiber neuropeptide density demonstrated a significant increase of VIP-positive fibers in rhinitis tissues. CONCLUSIONS: The present data indicate a differential regulation of neuropeptide-containing nerve fibers with increased numbers of VIPergic fibers suggesting a modulatory role of the upper airway innervation in perennial allergic rhinitis.

Monocytes of allergics and non-allergics produce, store and release the neurotrophins NGF, BDNF and NT-3.

INTRODUCTION: Recent studies have shown that neurotrophins (NTs) are involved in inflammatory processes. Elevated plasma levels of NTs were found allergic diseases with the highest levels in allergic asthma. However, the exact cellular sources involved in the regulation and release of neurotrophins in allergic inflammation are still not well defined. OBJECTIVE: The aim of this study was to assess whether monocytes of allergic and non-allergic subjects produce, store and release the neurotrophins NGF, BDNF and NT-3. METHODS: Monocytes of allergic and non-allergic donors were purified by immunomagnetic selection. APAAP-staining for the presence of NTs and their receptors was performed. RT-PCR and Western blot evaluated the production and storage of NTs. Monocytes were incubated and supernatants were collected for measurement of neurotrophic factors after stimulation with lipopolysaccharide (LPS) as inflammatory stimulus. The neurotrophin content in lysates and cell culture supernatants was determined by ELISA. RESULTS: Human monocytes express the neurotrophins NGF, BDNF and NT-3 but also their specific receptors TrkA, TrkB and TrkC. RT-PCR amplification of isolated mRNA demonstrated expression of the examined neurotrophins. Proteins were detectable by Western blot. NTs were found in the monocyte lysates and supernatants at different levels in allergic and non-allergic donors. Cell stimulation with LPS leads to release of NGF and NT3. CONCLUSIONS: Monocytes, produce, store and release NGF, BDNF and NT-3. They are a possible source of elevated neurotrophin levels found in allergy and asthma.

Immunological and clinical changes in allergic asthmatics following treatment with omalizumab.

IgE plays a key role in allergic asthma. We investigated whether omalizumab treatment of patients with moderate to severe allergic asthma leads to changes in inflammatory mediators and clinical symptoms. This sub-study was conducted on 35 patients with a positive skin prick test (SPT) requiring daily administration of beclomethasone dipropionate (500-1,000 microg), who participated in a multicentre, randomised, double-blind, placebo-controlled study. Omalizumab or placebo was administered at 0.016 mg/kg/IgE every 4 weeks. Patients recorded peak expiratory flow, asthma symptom score and beta(2)-agonist use in daily diaries and spirometry was performed at each visit. beta(2)-Agonist use and SPT wheal reaction decreased significantly (p < 0.05). Circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 decreased significantly (p < 0.01). IL-5 and IL-8 decreased in the omalizumab group compared to baseline. The other circulating mediators did not demonstrate any changes. Histamine release was significantly reduced (p < 0.01). Airway resistance (p < 0.05) and the provocative concentration inducing a 20% decrease in FEV(1) (p < 0.05) were measured before, after 16 weeks, and 3 months after completion of treatment. Both parameters decreased significantly (p < 0.05). Peripheral eosinophil count decreased significantly compared to placebo (p < 0.01). These findings suggest that omalizumab has potential as a novel treatment for allergic asthma.