Study Summary: ENERGITO
Beeh KM, Derom E, Echave-Sustaeta JM, et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat(®) is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler(®) (ENERGITO(®) study). Int J Chron Obstruct Pulmon Dis. 2016;11:193-205. doi: 10.2147/COPD.S95055.
A number of treatment options are available for individuals with chronic obstructive pulmonary disease (COPD), and the most effective strategy for maintenance treatment for optimizing lung function has not yet been identified. Long-acting bronchodilators, such as long-acting β2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are currently implemented as maintenance therapeutics for patients with COPD and moderate to very severe airway limitation. Tiotropium used as a once-daily LAMA monotherapy has been shown to demonstrate long-term improvements in a range of health parameters including quality of life, exacerbation risk, and lung function. Evidence from phase III studies indicates that olodaterol, a LAMA, can be used in combination with tiotropium as a potent maintenance therapy for COPD; this combination provides a range of synergistic benefits in patients with moderate to very severe COPD. Another common treatment option is the combination of an inhaled corticosteroid (ICS) and a LABA, which is recommended for use in individuals at high risk of exacerbation with severe to very severe airflow limitation (groups C and D) based on Global initiative for chronic Obstructive Lung Disease (GOLD) severity criteria; however, in clinical practice, this combination is often used among patients with low exacerbation risk and less severe COPD.
Beeh et al conducted the ENERGITO phase IIIb study to evaluate various combination regimens and assess the most effective approach for maintenance treatment in individuals with moderate to severe COPD. Investigators recruited study participants who were at least 40 years of age with a history of smoking 10 or more packs per year and who had moderate to severe COPD (GOLD stage 2 or 3). Participants were randomized into 4 groups in order to evaluate 2 combination therapies (each at 2 differing treatment dosages) for effect on lung function after 6 weeks. In this study, 2 groups (n = 216, n = 214) received a LAMA/LABA combination treatment regimen of once-daily tiotropium in combination with olodaterol administered as 2 consecutive inhalations from the Respimat inhaler (one group at a dose of 5/5 µg, the other at a dose of 2.5/5 µg). The other 2 groups of patients (n = 217, n = 211) received a LAMA/ICS combination treatment regimen of twice-daily salmeterol and fluticasone propionate delivered via Accuhaler system with a single inhalation in the morning followed by another inhalation in the evening 12 hours later (one group at a dose of 50/500 µg, the other at a dose of 50/250 µg).
After 6 weeks of combination therapy, the primary end point of the adjusted mean change in the baseline value of forced expiratory volume in 1 second area under the curve from 0 to 12 hours (FEV1 AUC0—12) was evaluated; results are shown in the Table. Treatment comparisons for the primary end point revealed statistically significant improvements (P <0.0001) in lung function in patients treated with tiotropium and olodaterol combination therapy compared with patients treated with salmeterol and fluticasone combination therapy at either dose. Patients treated with the lower dose of 2.5/5 µg tiotropium and olodaterol showed improvements of +103 mL and +106 mL, compared with those treated with 50/250 µg or 50/500 µg salmeterol and fluticasone, respectively. Patients treated with 5/5 µg tiotropium and olodaterol saw improvements of +125 mL and +129 mL, compared with patients treated with salmeterol and fluticasone at 50/250 µg or 50/500 µg, respectively. The primary end point data reveal that patients treated with the higher dosage combination of tiotropium and olodaterol displayed greater improvements in lung function than those treated with the lower dosage combination.
Interestingly, the FEV1 AUC response trends between comparisons of treatments were maintained throughout the 24-hour dosing interval, as seen in the Table. Significant (P <0.0001) improvements in lung function were observed in the key secondary end point of forced expiratory volume in 1 second area under the curve from 0 to 24 hours (FEV1 AUC0-24) response in groups treated with 5/5 µg of tiotropium and olodaterol compared with salmeterol and fluticasone dose at 50/500 ug and 50/250 µg—improvements of +86 mL and +82 mL, respectively, were observed. Similar significant improvements (P <0.05) were observed in FEV1 AUC12—24 responses in patient groups treated with either dosage of tiotropium and olodaterol compared with salmeterol and fluticasone propionate. Overall, the FEV1 AUC data shown in the Table reveal that after 6 weeks of treatment, patients who received the 5/5 µg dosage of tiotropium and olodaterol combination therapy displayed greater improvements in lung function than those who received the 2.5/5 µg dosage, and treatment with tiotropium and olodaterol at either dose significantly improved lung function compared with salmeterol and fluticasone treatment.
Changes in forced vital capacity (FVC) parameters after 6 weeks of treatment were significantly greater with tiotropium and olodaterol combination therapy compared with salmeterol and fluticasone propionate. The improved FVC profile is maintained over the full 24-hour interval, signifying that treatment with a combination of bronchodilators allows for increased airflow and reduced air trapping, enabling hyperinflation of the lung. Additionally, FVC results may indicate that patients treated with either dosage of tiotropium and olodaterol have improvements in small airways, which are commonly dysfunctional in those with COPD.
The most common adverse events reported during the ENERGITO study were COPD worsening, cough, and nasopharyngitis. Adverse events occurred at a similar rate across all treatment groups, with 29.7% to 37% of patients reporting at least 1 adverse event. Severe adverse events were recorded in approximately 10% of all patients across treatment groups. Fewer than 3% of patients from each treatment group experienced severe adverse events leading to discontinuation of study medication. Fatal adverse events were reported in 2 patients treated with the 5/5 μg dose of tiotropium and olodaterol combination therapy.
The results of the phase IIIb ENERGITO study indicate that a once-daily LAMA/LABA regimen of tiotropium and olodaterol can significantly improve lung functionality compared with a LABA/ICS therapy of twice-daily salmeterol and fluticasone, and suggest that dual bronchodilation may be a potent strategy for maintenance treatment in individuals with moderate to severe COPD. Tiotropium and olodaterol combination should be considered as a viable treatment option, as this study revealed LABA/ICS therapy may not be the most effective treatment for improving lung function in patients with moderate to severe pulmonary impairments. Further investigations may reveal additional clinical benefits in exacerbation risk, exercise capacity, and overall quality of life in patients treated with once-daily tiotropium and olodaterol, compared with LABA/ICS combination therapy.