Stefano Petruzzelli

Beclometasone–formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial

BACKGROUND According to international treatment guidelines, inhaled rapid-acting β2 agonists should be used for the control of symptoms in patients with asthma. We compared the efficacy and safety of an extrafine combination inhaler containing a corticosteroid (beclometasone) plus a rapid-onset, long-acting β2 agonist (formoterol) with a short-acting β2 agonist (salbutamol) as reliever strategies in patients taking beclometasone-formoterol combination as maintenance treatment. METHODS In a double-blind trial undertaken in 183 centres in 14 European countries over 48 weeks, patients (aged ≥18 years) with asthma that was not fully controlled, with a forced expiratory volume in 1 s (FEV1) of at least 60% predicted, had a 2-week run in. During this period, patients were treated with a combination of beclometasone 100 μg and formoterol 6 μg per one inhalation twice daily plus salbutamol 100 μg as required delivered by use of a pressurised metered-dose inhaler. They were then randomly assigned in a 1:1 ratio with a computer-generated randomisation list to receive beclometasone 100 μg plus formoterol 6 μg or salbutamol 100 μg as reliever in addition to maintenance with beclometasone 100 μg plus formoterol 6 μg twice daily. Primary outcome was the time to first severe exacerbation (admission to hospital or visit to emergency department, or use of systemic steroids for ≥3 consecutive days). Secondary outcomes were number of severe exacerbations (events per 100 patients per year), time to and number of mild exacerbations, additional exacerbation variables, lung function, symptom scores, and asthma control. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00861926. FINDINGS 1714 patients were randomly assigned to the as-needed beclometasone-formoterol (n=857) and as-needed salbutamol groups (n=857), and 1701 were analysed (852 and 849, respectively). 326 severe exacerbations were reported by 251 patients during the study, and 99 versus 152 patients had at least one exacerbation during the 48 weeks, respectively. Compared with beclometasone-formoterol plus salbutamol as needed, beclometasone-formoterol for both maintenance and reliever treatment significantly increased the time to first exacerbation (209 days vs 134 days) by 75 days, with a 36% reduction in risk (hazard ratio 0·64 [95% CI 0·49 to 0·82]; p=0·0005), and the estimated probability was 12% and 18%, respectively (p=0·0003). The number of days with mild asthma exacerbations was also lower with as-needed beclometasone-formoterol than with as-needed salbutamol (56·04 days per patient per year vs 65·11 days per patient per year; 0·86 [0·76 to 0·98]; p=0·021). From the run-in period to week 48, both treatments improved symptoms (mean change -1·59 [-1·94 to -1·25] in the as-needed beclometasone-formoterol group vs -1·44 [-1·78 to -1·10] in the as-needed salbutamol group, difference -0·15 [-0·60 to 0·30]; p=0·507), percentage of asthma control days (9·5% [7·3 to 11·8] vs 10·9% [8·7 to 13·1], respectively, -1·4 [-4·3 to 1·6]; p=0·359), use of reliever (-0·29 [-0·38 to -0·20] vs -0·27 [-0·36 to -0·19], respectively, -0·02 [-0·13 to 0·10]; p=0·794), and lung function (FEV1, 0·090 [0·060 to 0·120] vs 0·090 [0·060-0·120], respectively, 0·001 [-0·040 to 0·040]; p=0·969), and were well tolerated (patients with serious adverse events, 32 [4%] and 41 [5%], respectively). INTERPRETATION Our results lend support to the use of the combination of a single inhaled corticosteroid plus a rapid-onset, long-acting β2 agonist for maintenance and relief in patients with moderate to severe asthma and provide encouraging data for the formulation of beclometasone-formoterol for this use. FUNDING Chiesi Farmaceutici.

Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations

The FORWARD study is a randomised, double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate (BDP/FOR), 100/6 μg pMDI, 2 inhalations BID, vs. FOR 12 μg pMDI, 1 inhalation BID, in severe COPD patients with a history of exacerbations. Co-primary endpoints were exacerbation rate over 48 weeks and pre-dose morning FEV(1) at 12 weeks. The ITT population included 1186 patients (69% males, mean age 64 years) with severe airflow limitation (mean post-bronchodilator FEV(1) 42% predicted). Salbutamol as rescue therapy, theophylline and tiotropium (if stable regimen prior to screening) were allowed. Compared to FOR, BDP/FOR: (1) reduced the exacerbation rate (rate ratio: 0.72 [95% confidence interval 0.62-0.84], p < 0.001); (2) improved pre-dose morning FEV(1) (mean difference: 0.069 L [0.043-0.095] p < 0.001); (3) prolonged the time to first exacerbation; (4) improved the SGRQ total score. The percentage of patients with adverse events was similar (52.1% with BDP/FOR and 49.2% with FOR). Pneumonia incidence was low, slightly higher with BDP/FOR (3.8%) than with FOR (1.8%). No difference for laboratory values, ECG or vital signs. Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of patients with severe COPD and history of exacerbations as compared to FOR alone.

Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial

BACKGROUND Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment. METHODS This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850. FINDINGS Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45-0·57) for BDP/FF/G and 0·59 per patient per year (0·53-0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723-0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY. INTERPRETATION In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia. FUNDING Chiesi Farmaceutici.

A trial of beclomethasone/formoterol in copd using exact-pro to measure exacerbations

Combination inhalers containing corticosteroids and long-acting &bgr;-agonists are used to reduce exacerbation rates in patients with severe chronic obstructive pulmonary disease (COPD). The FORWARD (Foster 48-week Trial to Reduce Exacerbations in COPD) clinical trial in severe COPD patients is a comparison of extrafine beclomethasone dipropionate and formoterol in a combination inhaler with extrafine formoterol; the co-primary end-points are exacerbation rates over 48 weeks and improvement in forced expiratory volume in 1 s over 12 weeks. The traditional physician diagnosis of exacerbations is a co-primary outcome, and the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) means of collecting patient-reported outcome data are also being used to enhance the detection of exacerbation events. EXACT data are being collected using a novel application of a digital platform technology. FORWARD is therefore expected to provide information on the ability of EXACT to detect and measure exacerbations in a large clinical trial setting. The study design of FORWARD is described in this article.

Extrafine beclometasone diproprionate/formoterol fumarate: a review of its effects in chronic obstructive pulmonary disease

A fixed-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination of extrafine beclometasone dipropionate and formoterol fumarate (BDP/FF) has been recently approved for use in chronic obstructive pulmonary disease (COPD). Small airway inflammation and remodelling are cardinal features of COPD; therefore, the ability of this extrafine formulation to reach the small, as well as the large, airways is likely to be therapeutically important by enabling treatment of inflammatory processes in the whole bronchial tree. The clinical development of extrafine BDP/FF has demonstrated significant benefits over extrafine FF in terms of lung function improvement and reduction of the exacerbation rate, thus supporting the beneficial effect of an ICS combined to a LABA in COPD patients. Head-to-head comparison studies versus other ICS/LABA combinations have shown that the extrafine formulation enables the clinical benefits to be achieved with a lower dose of ICS. Extrafine BDP/FF showed lung function and dyspnoea improvements comparable to other ICS/LABAs, and a significantly faster onset of action was observed when compared with a salmeterol-containing fixed-dose combination. This review summarises the clinical evidence supporting the efficacy of extrafine BDP/FF in COPD and confirming that extrafine BDP/FF achieves the type of health benefit expected from such a targeted ICS/LABA combination in COPD.

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Tacrolimus is a cornerstone of the immunosuppression regimen for prevention of allograft rejection in kidney and liver transplantations, with efficacy proven in many clinical trials. The currently available and extensively used tacrolimus formulations are flawed by large inter- and intra-individual variability, low bioavailability, wide peak-to-trough fluctuations and a narrow therapeutic index. Drug delivery technology can significantly impact the pharmacologic action of a drug, influencing its pharmacokinetic and subsequent therapeutic profile. LCP-Tacro is a novel, prolonged-release, MeltDose® formulation of tacrolimus designed for once-daily administration. A hallmark differentiation between this formulation and other once- and twice-daily tacrolimus products is the proprietary MeltDose drug delivery technology which is designed to improve the bioavailability of drugs with low water solubility. Considering the studies conducted to date, once-daily LCP-Tacro has shown improved pharmacokinetic properties, rapid achievement of therapeutic trough levels, consistent exposure, non-inferior efficacy and similar safety, with lower tacrolimus dose than other tacrolimus formulations.

Relief of methacholine-induced bronchospasm with extrafine beclomethasone dipropionate/formoterol in comparison with salbutamol in asthma

BACKGROUND Short-acting beta2-agonists like salbutamol and terbutaline are used as rescue medications for acute bronchoconstriction and relief of symptoms due to their rapid onset of action. The aim of this study was to assess whether inhaled beclomethasone dipropionate (BDP)/formoterol fumarate (FF) combination in extrafine formulation is non-inferior to salbutamol in the speed of reverting methacholine-induced bronchoconstriction and symptoms. METHODS Fifty-six asthmatic patients were examined in a multicentre, randomised, double blind, double dummy, active treatment and placebo controlled three period cross-over study. On three different days, a single dose of BDP/FF 100/6 μg in pressurised metered-dose inhaler (pMDI) extrafine formulation or salbutamol 200 μg pMDI or placebo was inhaled after FEV(1) had dropped by 30-45% with methacholine challenge. RESULTS The median time to recovery of FEV(1) to 85% of baseline was similar for BDP/FF and salbutamol (3.66 and 2.15 min, respectively), but significantly longer for placebo (21.1 min). The planned analysis on adjusted mean time to recovery showed that the difference from methacholine-induced bronchoconstriction between BDP/FF and salbutamol was 3.82 min (95% confidence interval: -0.85 to 8.5), therefore greater than 3 min supposed in the study design. The difference between BDP/FF and salbutamol was not clinically significant. The two active treatments were also comparable in terms of the relief of symptoms (as assessed by the Borg dyspnoea scale). CONCLUSIONS BDP/FF combination has a fast onset of action, similar to that of salbutamol, and may represent a good alternative as rescue medication in asthmatic patients.

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

High-dose beclometasone dipropionate/formoterol fumarate in fixed-dose combination for the treatment of asthma

The high-strength formulation of extrafine beclometasone dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 μg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 μg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting β2-agonist combinations.

Inhaled corticosteroid containing combinations and mortality in COPD

There is no solid evidence that any pharmacological treatment reduces mortality in chronic obstructive pulmonary disease (COPD). Two large trials with mortality as an efficacy outcome have been carried out testing a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) and in both, the reduction in mortality failed to reach statistical significance [1, 2]. This could be seen as proof of absence of effect, but given that the TORCH trial [1] resulted in a hazard ratio (HR) of 0.825 (95% CI 0.681–1.002; p=0.052) for the comparison of combined fluticasone propionate and salmeterol with placebo, the interpretation may not be that simple. The other negative trial, the SUMMIT trial [2], only included patients with moderate COPD and increased risk of cardiovascular comorbidity. Combinations containing inhaled corticosteroids may reduce mortality in patients with COPD http://ow.ly/6UCy30lpwEi