Eric Derom

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4).

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) response, trough FEV1 response and St Georges Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD. Lung function/symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate-very severe COPD http://ow.ly/DIKiY

Primary care spirometry

Primary care spirometry is a uniquely valuable tool in the evaluation of patients with respiratory symptoms, allowing the general practitioner to diagnose or exclude chronic obstructive pulmonary disease (COPD), sometimes to confirm asthma, to determine the efficacy of asthma treatment and to correctly stage patients with COPD. The use of spirometry for case finding in asymptomatic COPD patients might become an option, once early intervention studies have shown it to be beneficial in these patients. The diagnosis of airway obstruction requires accurate and reproducible spirometric measurements, which should comply with the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. Low acceptability of spirometric manoeuvres has been reported in primary care practices. This may hamper the validity of the results and affect clinical decision making. Training and refresher courses may produce and maintain good-quality testing, promote the use of spirometric results in clinical practice and enhance the quality of interpretation. Softening the stringent ATS/ERS criteria could enhance the acceptability rates of spirometry when used in a general practice. However, the implications of potential simplifications on the quality of the data and clinical decision making remain to be investigated. Hand-held office spirometers have been developed in recent years, with a global quality and user-friendliness that makes them acceptable for use in general practices. The precision of the forced vital capacity measurements could be improved in some of the available models.

Effects of Pulmonary Rehabilitation in Patients With Restrictive Lung Diseases

BACKGROUND Pulmonary rehabilitation programs improve exercise tolerance, muscle strength, and dyspnea in patients with COPD. The aim of the study was to assess prospectively the effectiveness and feasibility of pulmonary rehabilitation in patients with restrictive lung diseases. METHODS In a prospective, nonrandomized, noncontrolled study, patients with an established diagnosis of restrictive lung disease (RLD) participated in a 24-week outpatient multidisciplinary rehabilitation program. Pulmonary function, exercise capacity, muscle force, and dyspnea were measured at inclusion, after 12 and 24 weeks of rehabilitation. Primary outcome was the change in 6-min walk distance (6MWD) after 12 weeks of rehabilitation. RESULTS Twenty-nine patients out of 31 patients (57 +/- 17 years of age; 21 men; FEV(1): 1.4 +/- 0.7 L) completed the 12-week rehabilitation program and 26 patients the 24-week rehabilitation program. At inclusion, exercise tolerance (maximal oxygen consumption [V(O(2))max]: 63% +/- 27% predicted; 6MWD: 390 +/- 140 m) and quadriceps force ([QF] 61% +/- 21% predicted) were reduced, and dyspnea, assessed using the Chronic Respiratory Disease Questionnaire (CRDQ), was increased (CRDQ item dyspnea [CRDQd]: 16 +/- 6 points). Exercise capacity, muscle force, and CRDQd improved significantly after 12 weeks (6MWD: 445 +/- 142 m; V(O(2))max: 69% +/- 30% predicted; QF: 73% +/- 25% predicted; CRDQd: 20 +/- 6 points) (P < .05). Further improvements were noted after 24 weeks (6MWD: 463 +/- 146 m; CRDQd: 22 +/- 6 points). CONCLUSIONS Patients with RLD respond well after 12 weeks of pulmonary rehabilitation, and even better results were seen after 24 weeks. Clinically significant improvements were obtained in the majority of the patients after 24 weeks.

Onset and duration of action of single doses of formoterol inhaled via turbuhaler

The aim of the study was to investigate the time of onset and the duration of the bronchodilating effect of different doses of formoterol administered via Turbuhaler in patients with moderate asthma. Thirty-one patients (five women) with a mean forced expiratory volume in 1 s (FEV1) of 1.97 +/- 0.54 1 and a mean reversibility of 31 +/- 14% of baseline were included in this double-blind, randomized, placebo-controlled and cross-over study. The patients inhaled single doses of placebo, i.e. 6, 12, 24, or 48 micrograms formoterol fumarate, on 5 separate days. Serial measurements of specific airways conductance (SGAW) and FEV1 were performed at regular time intervals for 12 h. The majority of the patients had at least a 50% increase in SGAW within 1-4 min after administration of all active treatments. The maximum increase in FEV1 over placebo was dose-dependent: 12% (6 micrograms), 18% (12 micrograms), 19% (24 micrograms), and 26% (48 micrograms) (P < 0.001). Twelve hours after administration of 6, 12, 24, and 48 micrograms formoterol, the mean increase in FEV1 was still 7%, 15%, 18%, and 27%, respectively, above the value following placebo. Headache was the most frequently reported adverse event in all treatments including placebo. After inhalation of 48 micrograms, three patients experienced mild tremor lasting for less than 1 h; likewise, one patient experienced the same event for 3 h after placebo. Formoterol administered via Turbuhaler10 gave a rapid and dose-related bronchodilating effect lasting for 12 h and was well tolerated.

Time course of bronchodilating effect of inhaled formoterol, a potent and long acting sympathomimetic.

BACKGROUND: Most of the currently available inhaled beta 2 agonists are short acting bronchodilators. The aim of this study was to compare the rate of onset and duration of the bronchodilating activity of formoterol and salbutamol. METHODS: Fourteen patients with reversible airways obstruction received placebo, 200 micrograms salbutamol, and 12, 24, and 48 micrograms formoterol from a metered dose inhaler, according to a double blind, randomised crossover design. Forced expiratory volume in one second (FEV1) and specific airways conductance (sGaw) were measured over 12 hours. RESULTS: Salbutamol and all doses of formoterol caused a significant and substantial increase in sGaw one minute after inhalation. The mean maximum increase in FEV1 was 58% (8%) after 200 micrograms salbutamol compared with 63% (11%), 62% (10%), and 74% (10%) after 12, 24, and 48 micrograms formoterol, respectively. The mean maximum increase in FEV1 occurred 57 (12) minutes after administration of salbutamol compared with 137 (16), 141 (21), and 161 (33) minutes after 12, 24, and 48 micrograms formoterol respectively. The bronchodilating effect of salbutamol did not differ from placebo after six hours. In contrast, the mean increase in FEV1 12 hours after 12 micrograms formoterol (26% (8%) of baseline) significantly exceeded the change after placebo. Tremor was recorded in four patients after 48 micrograms formoterol. CONCLUSION: Formoterol is a potent, fast acting bronchodilator with a long duration of action.

The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours

The duration of the protective effect of 50 and 100 micrograms of inhaled salmeterol against methacholine-induced bronchoconstriction was compared with that of 200 micrograms of inhaled salbutamol in 12 patients with asthma with a baseline FEV1 of at least 70% and a provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) greater than or equal to 8 mg/ml. The study was placebo controlled, double blind, randomized, and crossover. The bronchodilating effect was no longer significant 4 hours after inhalation of salbutamol, whereas the effect was still present 12 hours after administration of 50 and 100 micrograms of salmeterol. All active treatments caused PC20 to increase at 1 hour (p less than 0.05). PC20 (milligrams per milliliter) thus reached 3.7 +/- 0.8 after placebo, 13.8 +/- 3.0 after 50 micrograms of salmeterol, 23.2 +/- 4.7 after 100 micrograms of salmeterol, and 13.9 +/- 3.4 after 200 micrograms of salbutamol. The protective effect of 200 micrograms of salbutamol was no longer significant at 4 hours, whereas both doses of salmeterol protected against methacholine challenge up to 12 hours after inhalation (p less than 0.01). An increased incidence of tremor (2/12) and palpitations (2/12) was recorded after inhalation of 100 micrograms of salmeterol. We conclude that inhalation of 50 or 100 micrograms of salmeterol causes a long-lasting bronchodilatation and protects against methacholine-induced bronchoconstriction for at least 12 hours.

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler ®

In vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, while a corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drug between the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler(R) than for the corresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher, both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors such as the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle of inhalation via Turbuhaler.

Indacaterol, a novel inhaled β2-agonist, provides sustained 24-h bronchodilation in asthma

The present study examined the bronchodilator and safety profiles of single-dose indacaterol in intermittent or persistent asthma. In the present double-blind crossover study, 42 patients were randomised to receive single doses of indacaterol (50, 100, 200 and 400 µg) or placebo via a hydrofluoroalkane pressurised metered-dose inhaler. The primary efficacy comparisons were the per cent changes in forced expiratory volume in one second (FEV1 ) between indacaterol and placebo 30 min and 21 h post-dose. All doses resulted in prolonged bronchodilation, with indacaterol 200 and 400 µg meeting pre-specified efficacy criteria. The mean percentage increases in FEV1 from placebo with indacaterol 200 and 400 µg were 7.6 and 14.9%, respectively, at 30 min, and 7.5 and 10.4%, respectively, at 21 h post-dose. At these doses, changes in mean FEV1 relative to placebo were statistically significant from 5 min to 25 h, inclusive. At 5 min, the geometric least squares mean values for FEV1 were 3.08 and 3.22 L for the 200 and 400 µg doses, respectively, compared with 2.99 L for placebo. At 24 h after dosing, the baseline-adjusted geometric least square mean FEV1 was 3.13, 3.11, 3.24 and 3.30 L for indacaterol 50, 100, 200 and 400 µg, respectively, and 2.98 L for placebo. All treatments were well tolerated. Once-daily indacaterol at doses of 200 and 400 µg provided sustained 24-h bronchodilation, with a rapid onset and a good tolerability and safety profile.

Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose‐dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double‐blind within‐solution (1.25, 2.5, 5 µg, and placebo), and open‐label powder 18 µg, crossover study, including 4‐week treatment periods. Primary end points were peak plasma concentration (Cmax,ss), and area under the plasma concentration–time profile (AUC0–6h,ss), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5–7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73–89%) for Cmax,ss and 76% (70–82%) for AUC0–6h,ss, indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.

Inspiratory muscle training protocol for patients with chronic obstructive pulmonary disease (IMTCO study): a multicentre randomised controlled trial

Introduction Inspiratory muscle training (IMT) has been applied during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). However, it remains unclear if the addition of IMT to a general exercise training programme leads to additional clinically relevant improvements in patients with COPD. In this study, we will investigate whether the addition of IMT to a general exercise training programme improves 6 min walking distance, health-related quality of life, daily physical activity and inspiratory muscle function in patients with COPD with inspiratory muscle weakness. Methods and analysis Patients with COPD (n=170) with inspiratory muscle weakness (Pi,max <60 cm H2O or <50%pred) will be recruited to a multicentre randomised placebo controlled trial of IMT and allocated into one of the two groups. Patients in both groups will follow a 3 month general exercise training programme, in combination with home-based IMT. IMT will be performed with a recently developed device (POWERbreathe KH1). This device applies an inspiratory load that is provided by an electronically controlled valve (variable flow resistive load). The intervention group (n=85) will undertake an IMT programme at a high intensity (≥50% of their Pi,max), whereas the placebo group (n=85) will undertake IMT at a low training intensity (≤10% of Pi,max). Total daily IMT time for both groups will be 21 min (6 cycles of 30 breaths). Improvement in the 6 min walking distance will be the primary outcome. Inspiratory muscle function, health-related quality of life and daily physical activity will be assessed as secondary outcomes. Ethics and dissemination Ethics approval has been obtained from relevant centre committees and the study has been registered in a publicly accessible clinical trial database. The results will be easily interpretable and should immediately be communicated to healthcare providers, patients and the general public. Results This can be incorporated into evidence-based treatment recommendations for clinical practice. ClinicalTrials.gov NCT01397396.