Maintenance bronchodilator treatment to relieve symptoms in adults with COPD
Spiolto Respimat is a fixed dose combination inhalation solution containing a long acting muscarinic receptor antagonist, tiotropium and a long acting beta2-adrenergic agonist, olodaterol (LAMA/LABA) which is delivered via the Respimat soft mist inhaler device.
Muscarinic receptors are more prominent in the central airways while beta2 adrenoceptors have a higher expression level in the peripheral airways. Therefore the combination of a LAMA and a LABA should provide optimal bronchodilatation in all regions of the lungs.
Spiolto is indicated as a maintenance bronchodilator treatment to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). The recommended dose is tiotropium/olodaterol 5/5mcg given as two puffs once daily, at the same time of the day.1
Respimat is a soft mist inhaler device designed for more effective drug delivery to the lungs. It produces a low velocity, long-lasting aerosol cloud, with a higher fine particle fraction than most other inhalers.2,3 It has a lower throat deposition and higher whole lung deposition than other commercially available devices.4,5
The majority of patients with COPD are already suffering from moderate airflow limitation at diagnosis,6 when initiation of maintenance therapy is recommended.7 Decreasing lung function causes breathlessness and leads to a downward spiral of reduced physical activity, worsening symptoms and further inactivity.8 Decreasing exercise capacity reduces quality of life and increases the risk of disability and death.9
Patients with moderate COPD have a steeper decline in lung function than those with more severe disease.10 Pharmacotherapeutic intervention in patients with moderate COPD has been associated with significant improvements in health status, and reductions in exacerbations and rate of decline of lung function, compared with placebo.11,12
Spiolto received marketing authorisation based on data from the TOviTO clinical trial programme (>15,000 patients), including the pivotal TONADO trials. This programme was designed to evaluate the effect of Spiolto on many of the important clinical outcomes of COPD (e.g. lung function, quality of life, breathlessness, physical activity, ability to exercise, exacerbations).
Studies design
TONADO 1 and TONADO 2 were two 52 week, replicate, randomised, double-blind, active-controlled, parallel-group, multicentre, phase III trials (total n = 5162) in which the efficacy and safety of the tiotropium/olodaterol 5/5mcg combination were compared with the individual components, tiotropium 5mcg or olodaterol 5mcg. All study drugs were administered once-daily in the morning via the Respimat inhaler. Patients received inhaled corticosteroids, rescue medication (salbutamol/albuterol), oral steroids or theophylline preparations as required during treatment.13
The three primary efficacy end points were assessed after 24 weeks of treatment: Forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0–3) response, trough FEV1 response, and St George’s Respiratory Questionnaire (SGRQ) total score. A key secondary efficacy end point was Mahler Transition Dyspnoea Index (TDI) focal score at 24 weeks.
Main inclusion criteria for the studies: Patients aged ≥40 years with a history of moderate to very severe COPD (GOLD stages 2–4); post-bronchodilator FEV1 <80% of predicted normal; post-bronchodilator FEV1/forced vital capacity (FVC) <70%; current or ex-smokers with a smoking history of >10 pack–years.13
Spiolto provided significant improvements in lung function, quality of life and breathlessness
Significant improvements in FEV1 AUC0-3 and trough FEV1 responses (i.e. change from baseline) after 24 weeks (lung function primary end points) were observed in patients treated with the tiotropium/olodaterol combination compared to those treated with tiotropium or olodaterol alone in the individual studies and the combined analysis (p≤0.0001 for all comparisons).
The combination treatment showed a 110ml or 128ml improvement in FEV1 AUC0-3 response vs tiotropium or olodaterol alone, respectively, and a 60ml or 85ml improvement in trough FEV1 response vs tiotropium or olodaterol alone, respectively, in the combined analysis (see figure 1).
Pre-specified combined analysis of SGRQ total score after 24 weeks from both studies (quality of life primary end point) showed significant improvements for the combination treatment compared to tiotropium or olodaterol alone (decrease from baseline of 6.8 units vs 5.6 units [p<0.05] or vs 5.1 units [p<0.01], respectively) (see figure 2). More patients treated with the combination had a clinically meaningful improvement in SGRQ total score (defined as a decrease of at least 4 units from baseline) compared to tiotropium or olodaterol alone (57.5% vs 48.7% [p=0.0001] or vs 44.8% [p<0.0001], respectively) in the combined analysis.
Pooled analysis of Mahler TDI focal score at 24 weeks from both studies (breathlessness secondary end point) revealed significant improvements for the combination treatment compared to tiotropium or olodaterol alone (increase from baseline of 1.98 units vs 1.63 units [p<0.05] or vs 1.56 units [p<0.005], respectively) (see figure 3).
The incidence of adverse events was comparable across all treatment groups, with the majority being mild to moderate in severity. The majority of treatment-emergent adverse events with an incidence of >3% were respiratory events, in particular COPD exacerbations and infections.13
Spiolto improved lung function profile over 24 h
The findings of the TONADO trials are complemented and supported by a randomised, double-blind, 6-week phase III trial (n=219) which showed significant improvements in FEV1AUC from 0 to 24 hours with the tiotropium/olodaterol combination compared with tiotropium or olodaterol alone (treatment difference of 110ml or 115ml [p<0.0001 for both comparisons], respectively).14
Conclusions
Spiolto provided significant improvements in lung function, quality of life and breathlessness over tiotropium or olodaterol alone in patients with moderate to very severe COPD, with a comparable safety profile.
References: 1. Spiolto Respimat SPC (revised March 2016). 2. Anderson P et al. Int J COPD 2006;1(3):251–259. 3. Dalby R, Spallek M, Voshaar T. Int J Pharm 2004;283:1–9. 4. Ciciliani A, Wachtel H, Langguth P. Respiratory Drug Delivery 2014;2:453–456. 5. Ciciliani A et al. Respiratory Drug Delivery Europe 2015;2:357-362. 6. Mapel DW et al. Int J COPD 2011; 6: 573–581. 7. NICE Clinical guideline [CG101]. Available at: https://www.nice.org.uk/guidance/cg101. Last accessed November 2016. 8. Reardon JZ et al. Am J Med 2006; 119 (10 Suppl 1): 32-7. 9. Casaburi R. Am Thorac Soc 2011; 8(4):334-7. 10. Tantucci C, Modina D. Int J Chron Obstruct Pulmon Dis 2012; 7:95-9. 11. Decramer M et al. Lancet. 2009;374(9696):1171–1178. 12. Jenkins CR et al. Respir Res. 2009;10:59. 13. Buhl R et al. Eur Respir J 2015; 45(4):969-79. 14. Beeh KM et al. Pulm Pharmacol Ther 2015;32:53–59. MIMS Ireland Copyright®
Written by Caroline McDermott PhD, Editor, MIMS Ireland
Initiated, funded and reviewed by Boehringer Ingelheim Ltd.
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