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Full length article| Volume 109, ISSUE 10, P1312-1319, October 01, 2015

Tiotropium + olodaterol shows clinically meaningful improvements in quality of life

Open AccessPublished:August 12, 2015DOI:https://doi.org/10.1016/j.rmed.2015.08.002
Tiotropium + olodaterol shows clinically meaningful improvements in quality of life
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      Highlights

      • •
        Two placebo-controlled 12-week studies investigated tiotropium + olodaterol in COPD.
      • •
        Tiotropium + olodaterol 5/5 μg improved SGRQ total score by >4 units versus placebo.
      • •
        Tiotropium + olodaterol 5/5 μg significantly improved SGRQ score versus tiotropium.
      • •
        FEV1 was improved with tiotropium + olodaterol 5/5 μg versus placebo and tiotropium.
      • •
        Incidence of AEs was similar between treatment groups.

      Abstract

      Background

      Tiotropium + olodaterol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease (COPD). The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olodaterol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD.

      Methods

      In these two replicate, double-blind, parallel-group, placebo-controlled trials, patients were randomised to receive tiotropium + olodaterol 5/5 μg, 2.5/5 μg, tiotropium 5 μg or placebo for 12 weeks, via the Respimat® inhaler. Primary end points were St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) response and trough FEV1 response.

      Results

      In OTEMTO 1 and 2, tiotropium + olodaterol 5/5 μg improved SGRQ total score by 4.89 (95% confidence interval [CI] −6.90, −2.88) and 4.56 (95% CI −6.50, −2.63) units versus placebo (both p < 0.0001), and 2.49 (95% CI −4.47, −0.51; p < 0.05) and 1.72 (95% CI −3.63, 0.19) units versus tiotropium 5 μg. Tiotropium + olodaterol 2.5/5 μg significantly improved SGRQ score compared to placebo. Both doses significantly improved FEV1 AUC0–3 response compared to placebo and tiotropium 5 μg. Tiotropium + olodaterol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo (both studies) and separated from tiotropium 5 μg in OTEMTO 2. Adverse-event incidence was similar between treatment groups.

      Conclusion

      Tiotropium + olodaterol improved lung function and quality of life compared to placebo and tiotropium 5 μg.

      Trial registration

      ClinicalTrials.gov: NCT01964352 and NCT02006732.

      Keywords

      Abbreviations:

      AE (adverse event), AUC0–3 (area under the curve from 0 to 3 h), COPD (chronic obstructive pulmonary disease), FEV1 (forced expiratory volume in 1 s), GOLD (Global initiative for chronic Obstructive Lung Disease), FVC (forced vital capacity), LABA (long-acting β2-agonist), LAMA (long-acting muscarinic antagonist), MCID (minimum clinically important difference), SGRQ (St George's Respiratory Questionnaire), TDI (Transition Dyspnoea Index)

      1. Introduction

      Tiotropium was the first once-daily long-acting muscarinic antagonist (LAMA) to be approved for the treatment of chronic obstructive pulmonary disease (COPD) and has now been developed in a fixed-dose combination with the once-daily long-acting β2-agonist (LABA) olodaterol. Olodaterol is approved for the treatment of COPD and has an early onset of action and a 24-h effect on lung function [
      • Ferguson G.T.
      • Feldman G.J.
      • Hofbauer P.
      • Hamilton A.
      • Allen L.
      • Korducki L.
      • et al.
      Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies.
      Int. J. Chron. Obstr. Pulm. Dis. 2014; 9: 629-645https://doi.org/10.2147/COPD.S61717
      ,
      • Feldman G.J.
      • Bernstein J.A.
      • Hamilton A.
      • Nivens M.C.
      • Korducki L.
      • LaForce C.
      The 24-h FEV1 time profile of olodaterol once daily via Respimat® and formoterol twice daily via Aerolizer® in patients with GOLD 2–4 COPD: results from two 6-week crossover studies.
      Springerplus. 2014; 3: 419
      ,
      • Lange P.
      • Aumann J.-L.
      • Hamilton A.
      • Tetzlaff K.
      • Ting N.
      • Derom E.
      The 24 hour lung function time profile of olodaterol once daily versus placebo and tiotropium in patients with moderate to very severe chronic obstructive pulmonary disease.
      J. Pulm. Respir. Med. 2014; 4: 196https://doi.org/10.4172/2161-105X.1000196
      ,
      • Koch A.
      • Pizzichini E.
      • Hamilton A.
      • Hart L.
      • Korducki L.
      • De Salvo M.C.
      • et al.
      Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.
      Int. J. Chron. Obstr. Pulm. Dis. 2014; 9: 697-714https://doi.org/10.2147/COPD.S62502
      ]. The efficacy and tolerability of olodaterol was demonstrated in a large Phase III programme [
      • Ferguson G.T.
      • Feldman G.J.
      • Hofbauer P.
      • Hamilton A.
      • Allen L.
      • Korducki L.
      • et al.
      Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies.
      Int. J. Chron. Obstr. Pulm. Dis. 2014; 9: 629-645https://doi.org/10.2147/COPD.S61717
      ,
      • Feldman G.J.
      • Bernstein J.A.
      • Hamilton A.
      • Nivens M.C.
      • Korducki L.
      • LaForce C.
      The 24-h FEV1 time profile of olodaterol once daily via Respimat® and formoterol twice daily via Aerolizer® in patients with GOLD 2–4 COPD: results from two 6-week crossover studies.
      Springerplus. 2014; 3: 419
      ,
      • Lange P.
      • Aumann J.-L.
      • Hamilton A.
      • Tetzlaff K.
      • Ting N.
      • Derom E.
      The 24 hour lung function time profile of olodaterol once daily versus placebo and tiotropium in patients with moderate to very severe chronic obstructive pulmonary disease.
      J. Pulm. Respir. Med. 2014; 4: 196https://doi.org/10.4172/2161-105X.1000196
      ,
      • Koch A.
      • Pizzichini E.
      • Hamilton A.
      • Hart L.
      • Korducki L.
      • De Salvo M.C.
      • et al.
      Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.
      Int. J. Chron. Obstr. Pulm. Dis. 2014; 9: 697-714https://doi.org/10.2147/COPD.S62502
      ,
      • Maleki-Yazdi M.R.
      • Beck E.
      • Hamilton A.L.
      • Korducki L.
      • Koker P.
      • Fogarty C.
      A randomised, placebo-controlled, Phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-acting β2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease.
      Respir. Med. 2015; 109: 596-605https://doi.org/10.1016/j.rmed.2015.02.012
      ]. Combination therapies are commonly used in COPD and their use is supported by the Global initiative for chronic Obstructive Lung Disease (GOLD) report [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.
      2014
      http://www.goldcopd.org/uploads/users/files/GOLD_Report2014_Feb07.pdf
      ].
      Data from the tiotropium + olodaterol Phase III studies have demonstrated significant improvements in lung function to a greater extent than tiotropium and olodaterol monocomponents, with no additional safety concerns [
      • Buhl R.
      • Maltais F.
      • Abrahams R.
      • Bjermer L.
      • Derom E.
      • Ferguson G.
      • et al.
      Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4).
      Eur. Respir. J. 2015; 45: 969-979https://doi.org/10.1183/09031936.00136014
      ,
      • Derom E.
      • Westerman J.
      • Groenke L.
      • Hamilton A.
      • Li C.
      • Beeh K.M.
      The 24-hour lung function profile of once-daily tiotropium and olodaterol fixed-dose combination compared with placebo and monotherapies in chronic obstructive pulmonary disease.
      Am. J. Respir. Crit. Care Med. 2014; 189 (abs A6727)
      ]. The TONADO studies were two large replicate Phase III trials that demonstrated improvements in lung function and St George's Respiratory Questionnaire (SGRQ) total score over 52 weeks with tiotropium + olodaterol versus the monocomponents in patients with moderate to very severe COPD.
      In the TONADO studies, it was not possible to include a placebo arm due to the 52-week duration and the inclusion of patients with very severe COPD. The effects of bronchodilator therapies on patient-reported outcomes are best investigated in placebo-controlled studies in order to understand whether the minimum clinically important difference (MCID) compared to placebo is achieved. The novelty of the OTEMTO studies was the inclusion of a placebo arm; the study design involved a shorter duration and the exclusion of patients with GOLD 4 disease in order to allow this. In addition, both the tiotropium + olodaterol 2.5/5 μg and 5/5 μg doses were included to investigate differences in effect size between the two doses.
      The objective of the OTEMTO studies was to evaluate the effect of tiotropium + olodaterol on lung-function improvement and health-related quality of life after 12 weeks of treatment compared to placebo and tiotropium 5 μg in patients with moderate to severe COPD.

      2. Methods

      2.1 Study design

      These were two replicate, multinational, double-blind, parallel-group, placebo-controlled studies (OTEMTO 1, 1237.25, NCT01964352; OTEMTO 2, 1237.26, NCT02006732) in which patients were randomised to receive one of four treatments once daily for 12 weeks, all delivered via the Respimat® inhaler: placebo, tiotropium 5 μg, tiotropium + olodaterol 2.5/5 μg and tiotropium + olodaterol 5/5 μg (Fig. 1).
      Figure thumbnail gr1
      Fig. 1OTEMTO study design. R, randomisation.
      After completing an initial screening visit, patients entered a 2-week screening period prior to randomisation. A follow-up visit took place ∼3 weeks after last dose of study medication.

      2.2 Patients

      Patients aged ≥40 years with moderate to severe COPD (GOLD 2–3; post-bronchodilator forced expiratory volume in 1 s [FEV1] ≥30% and <80% of predicted normal), FEV1/forced vital capacity (FVC) <70% predicted and a smoking history of >10 pack-years were included. Patients were excluded if they had a history of asthma, another significant disease, COPD exacerbation or symptoms of lower respiratory tract infection within the previous 3 months, unstable or life-threatening cardiac arrhythmia, hospitalisation for heart failure within the past year, a history of myocardial infarction within 1 year of screening or a history of life-threatening pulmonary obstruction.
      Patients were allowed to continue their inhaled corticosteroid therapy (if they were on a stable dose for 6 weeks prior to screening). LAMAs or LABAs other than study medication were prohibited during the screening or treatment periods, and short-acting muscarinic antagonists were permitted only during the screening period. Open-label salbutamol was provided as rescue medication for use throughout the study.

      2.3 Study outcomes

      The three primary end points, measured at 12 weeks, were SGRQ total score, FEV1 area under the curve from 0 to 3 h (AUC0–3) response (change from baseline) and trough FEV1 response. Trough FEV1 was defined as the mean of the FEV1 values at 23 h post-dose and 23 h 50 min post-dose.
      The secondary end points were Mahler Transition Dyspnoea Index (TDI) focal score and, trough FVC and FVC AUC0–3 responses. All adverse events (AEs) and serious AEs were reported, vital signs were monitored and 12-lead electrocardiogram recordings were taken for all patients at screening and at Week 12, with any abnormalities reported as AEs.

      2.4 Assessments

      Pulmonary function testing was performed according to American Thoracic Society/European Respiratory Society guidelines [
      • Miller M.R.
      • Hankinson J.
      • Brusasco V.
      • Burgos F.
      • Casaburi R.
      • Coates A.
      • et al.
      Standardisation of spirometry.
      Eur. Respir. J. 2005; 26: 319-338https://doi.org/10.1183/09031936.05.00034805
      ] and tests were performed in triplicate, with the highest FEV1 and FVC being reported. Pulmonary function tests were performed at 1 h pre-dose, 10 min pre-dose, 5, 15 and 30 min post-dose and 1, 2 and 3 h post-dose at baseline and Week 12, and at 10 min pre-dose only after 2 and 6 weeks of treatment. The final trough FEV1 measurement was taken the day after the Week 12 visit (at 23 h and 23 h 50 min post-dose). Further information about the spirometry methodology is provided in the Supplementary material.
      Patients completed the SGRQ at baseline and at Weeks 6 and 12, before any other assessments at that visit. The questionnaire consists of 16 questions about patients' recollections of their symptoms over the past month (Questions 1–8) and their current state, including activity levels and impact on functioning (Questions 9–16). Patients completed the questionnaire in the clinic.
      The Mahler Baseline Dyspnoea Index was administered at baseline and used as the baseline value for analyses of TDI score. The TDI was administered at Week 6 and Week 12 and consists of an interview to measure the level and extent of activities patients can perform before feeling breathless, relative to their baseline performance. The interviews were conducted by trained clinic staff.

      2.5 Statistical analysis

      The pre-specified analyses of the study were designed to test tiotropium + olodaterol versus placebo for all of the primary end points; the hypothesis testing strategy is presented in Supplementary Fig. S1. Assuming standard deviations of 0.226 L for FEV1 AUC0–3 and 0.225 L for trough FEV1, and a two-sided alpha of 0.05, a sample size of 200 patients per group per trial was required to provide 90% power to detect a difference of 0.073 L in FEV1 AUC0–3 and trough FEV1. Assuming a standard deviation of 14 units for SGRQ score, 400 patients per group were required in the combined data set for OTEMTO 1 and 2 to provide 90% power to detect a difference of 3.2 units in SGRQ total score and 98% power to detect a difference of 4 units in SGRQ total score.
      Two replicate studies were conducted to demonstrate duplication of the data, with each individual study powered to detect a change in the primary end points. In addition, the data from the two studies were combined in the pre-specified analysis of the SGRQ total score, providing greater power for this end point.
      The primary analyses were intent-to-treat analyses, performed on the full analysis set, defined as all patients who received at least one dose of study medication and had baseline and at least one post-baseline measurement for any of the primary end points. Changes from baseline in FEV1 AUC0–3 and trough FEV1 were analysed using a restricted maximum likelihood-based mixed effects model repeated measures, including the fixed categorical effects of treatment, test day and treatment-by-test-day interaction, as well as the continuous fixed covariates of baseline and baseline-by-test-day interaction.
      A responder analysis on the SGRQ total score was performed, with patients classed as responders if their improvement in SGRQ total score was ≥4.0 units, and a logistical regression, which included the fixed categorical effect of treatment and baseline as fixed continuous covariate, was used to calculate the odds ratio of responder between treatment groups.

      3. Results

      3.1 Patient disposition and baseline characteristics

      In OTEMTO 1, 1054 patients were enrolled, 814 patients were randomised and 812 treated, with 93.7% of patients completing the trial (Fig. 2a).
      Figure thumbnail gr2
      Fig. 2Patient disposition in (a) OTEMTO 1 and (b) OTEMTO 2. T, tiotropium; O, olodaterol; AE, adverse event.
      In OTEMTO 2, of the 1107 patients enrolled, 809 were randomised and treated, and 94.4% of patients completed the trial (Fig. 2b). In both studies, discontinuation rates were highest in the placebo arm (Fig. 2). Patient demographics and baseline characteristics were similar between groups, and between trials (Table 1).
      Table 1Patient demographics and baseline characteristics (treated set).
      OTEMTO 1OTEMTO 2
      PlaceboT 5 μgT + O 2.5/5 μgT + O 5/5 μgPlaceboT 5 μgT + O 2.5/5 μgT + O 5/5 μg
      Patients, n204 (100.0)203 (100.0)202 (100.0)203 (100.0)202 (100.0)203 (100.0)202 (100.0)202 (100.0)
      Male, n (%)127 (62.3)124 (61.1)116 (57.4)114 (56.2)117 (57.9)130 (64.0)126 (62.4)133 (65.8)
      Mean (SD) age, years65.1 (8.3)64.9 (8.2)64.7 (8.2)64.7 (8.9)64.0 (8.3)64.7 (8.4)64.4 (8.6)65.2 (8.5)
      Smoking status, n (%)
       Ex-smoker116 (56.9)105 (51.7)104 (51.5)92 (45.3)107 (53.0)112 (55.2)112 (55.4)110 (54.5)
       Current smoker88 (43.1)98 (48.3)98 (48.5)111 (54.7)95 (47.0)91 (44.8)90 (44.6)92 (45.5)
      Pre-bronchodilator
       Mean (SD) FEV1, L1.383 (0.527)1.306 (0.458)1.326 (0.505)1.315 (0.491)1.333 (0.493)1.403 (0.511)1.348 (0.478)1.358 (0.467)
       Mean (SD) FVC, L2.906 (0.826)2.775 (0.853)2.797 (0.878)2.802 (0.860)2.757 (0.837)2.805 (0.858)2.740 (0.826)2.807 (0.826)
      Post-bronchodilator
      Post-bronchodilator results were obtained after 4 puffs of 100 μg salmeterol.
       Mean (SD) FEV1, L1.578 (0.539)1.494 (0.471)1.510 (0.521)1.502 (0.502)1.530 (0.527)1.585 (0.514)1.521 (0.474)1.566 (0.482)
       Mean (SD) FEV1 % predicted56.3 (12.8)54.7 (12.8)55.5 (13.7)54.9 (12.0)54.3 (13.4)55.9 (12.2)54.5 (12.7)54.8 (12.8)
       Mean (SD) FVC, L3.192 (0.860)3.063 (0.881)3.082 (0.924)3.105 (0.891)3.071 (0.898)3.060 (0.874)2.996 (0.845)3.122 (0.887)
       Mean (SD) FEV1/FVC, %49.7 (10.9)49.6 (10.5)49.4 (10.1)49.0 (10.3)50.2 (10.5)52.4 (10.7)51.3 (10.0)50.9 (10.0)
      GOLD, n (%)
      Although the inclusion criteria only included patients with GOLD 2–3 COPD, 4 patients (0.5%) in each trial were classed as GOLD 4 and 1 (0.1%) in OTEMTO 1 as GOLD 1, based on their entrance spirometry results.
       10 (0.0)1 (0.5)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
       2140 (68.6)127 (62.6)132 (65.3)130 (64.0)122 (60.4)137 (67.5)129 (63.9)125 (61.9)
       363 (30.9)73 (36.0)69 (34.2)73 (36.0)79 (39.1)66 (32.5)70 (34.7)77 (38.1)
       41 (0.5)2 (1.0)1 (0.5)0 (0.0)1 (0.5)0 (0.0)3 (1.5)0 (0.0)
      Baseline pulmonary medication, n (%)
      Any156 (76.5)160 (78.8)161 (79.7)162 (79.8)156 (77.2)158 (77.8)145 (71.8)142 (70.3)
      ICS71 (34.8)77 (37.9)78 (38.6)85 (41.9)71 (35.1)71 (35.0)83 (41.1)72 (35.6)
      LAMA83 (40.7)64 (31.5)61 (30.2)77 (37.9)59 (29.2)77 (37.9)69 (34.2)70 (34.7)
      SAMA13 (6.4)18 (8.9)21 (10.4)20 (9.9)16 (7.9)15 (7.4)12 (5.9)9 (4.5)
      LABA78 (38.2)78 (38.4)80 (39.6)73 (36.0)76 (37.6)81 (39.9)81 (40.1)82 (40.6)
      SABA101 (49.5)112 (55.2)107 (53.0)100 (49.3)107 (53.0)109 (53.7)89 (44.1)93 (46.0)
      SD, standard deviation; FEV1, forced expiratory volume in 1 s; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist; SAMA, short-acting muscarinic antagonist; LABA, long-acting β2-agonist; SABA, short-acting β2-agonist.
      a Post-bronchodilator results were obtained after 4 puffs of 100 μg salmeterol.
      b Although the inclusion criteria only included patients with GOLD 2–3 COPD, 4 patients (0.5%) in each trial were classed as GOLD 4 and 1 (0.1%) in OTEMTO 1 as GOLD 1, based on their entrance spirometry results.

      3.2 Primary end points

      3.2.1 SGRQ

      Tiotropium + olodaterol 5/5 μg improved SGRQ total score at 12 weeks by 4.89 units and 4.56 units versus placebo (p < 0.0001) in OTEMTO 1 and 2, respectively (Fig. 3); the improvement compared to tiotropium 5 μg was 2.49 units (p = 0.0136) and 1.72 units (p = 0.0780), respectively (Table 2). Tiotropium + olodaterol 2.5/5 μg also significantly improved SGRQ score compared to placebo in both studies (by 4.12 and 3.67 units) (Fig. 3), though differences compared to tiotropium 5 μg were not significant (Table 2). In addition, there was a numerically greater improvement in SGRQ with tiotropium + olodaterol 5/5 μg compared to tiotropium + olodaterol 2.5/5 μg. Data from the combined analysis of the two studies are presented in Supplementary Table S1.
      Figure thumbnail gr3
      Fig. 3SGRQ total score difference from placebo in OTEMTO 1 and 2 after 12 weeks (full analysis set). T, tiotropium; O, olodaterol; SE, standard error; SGRQ, St George's Respiratory Questionnaire.
      Table 2SGRQ total score in OTEMTO 1 and 2 after 12 weeks (full analysis set).
      TreatmentSGRQ total score
      Mean (SE)Mean (SE) difference95% CI
      OTEMTO 1
      Common baseline mean42.43 (0.62)
      T + O 5/5 μg37.14 (0.71)
       versus placebo−4.89 (1.02)***−6.90, −2.88
       versus T 5 μg−2.49 (1.01)*−4.47, −0.51
      T + O 2.5/5 μg37.92 (0.71)
       versus placebo−4.12 (1.02)***−6.13, −2.11
       versus T 5 μg−1.72 (1.01)−3.70, 0.26
      T + O 5/5 μg
       versus T + O 2.5/5 μg−0.77 (1.00)−2.74, 1.20
      T 5 μg39.64 (0.72)
       versus placebo−2.40 (1.03)*−4.42, −0.38
      Placebo42.04 (0.74)
      OTEMTO 2
      Common baseline mean42.70 (0.62)
      T + O 5/5 μg38.01 (0.68)
       versus placebo−4.56 (0.99)***−6.50, −2.63
       versus T 5 μg−1.72 (0.97)−3.63, 0.19
      T + O 2.5/5 μg38.91 (0.69)
       versus placebo−3.67 (0.99)**−5.61, −1.72
       versus T 5 μg−0.82 (0.98)−2.74, 1.10
      T + O 5/5 μg
       versus T + O 2.5/5 μg−0.90 (0.97)−2.80, 1.01
      T 5 μg39.73 (0.69)
       versus placebo−2.85 (0.99)*−4.80, −0.90
      Placebo42.58 (0.71)
      *p < 0.05; **p < 0.001; ***p < 0.0001.
      OTEMTO 1: placebo, n = 186; T 5 μg, n = 192; T + O 2.5/5 μg, n = 199; T + O 5/5 μg, n = 196; OTEMTO 2: placebo, n = 184; T 5 μg, n = 192; T + O 2.5/5 μg, n = 195; T + O 5/5 μg, n = 197.
      SGRQ, St George's Respiratory Questionnaire; SE, standard error; CI, confidence interval; T, tiotropium; O, olodaterol.

      3.2.2 FEV1 AUC0–3

      Both tiotropium + olodaterol dose strengths significantly improved FEV1 AUC0–3 response after 12 weeks compared to placebo (0.331 L and 0.299 L with tiotropium + olodaterol 5/5 μg, and 0.300 L and 0.284 L with tiotropium + olodaterol 2.5/5 μg, in OTEMTO 1 and 2, respectively; all comparisons p < 0.0001). There were no significant differences between tiotropium + olodaterol doses. Significant differences versus tiotropium 5 μg were also observed with both doses (all comparisons p < 0.0001) (Fig. 4; Supplementary Table S2).
      Figure thumbnail gr4
      Fig. 4(a) FEV1 AUC0–3 and (b) trough FEV1 response difference from placebo after 12 weeks in OTEMTO 1 and 2 (full analysis set). T, tiotropium; O, olodaterol; SE, standard error; FEV1, forced expiratory volume in 1 s; AUC0–3, area under the curve from 0 to 3 h.

      3.2.3 Trough FEV1

      Tiotropium + olodaterol 5/5 μg significantly improved trough FEV1 response after 12 weeks by 0.162 L and 0.166 L compared to placebo (p < 0.0001) in OTEMTO 1 and 2 (Fig. 4; Supplementary Table S2).
      Tiotropium + olodaterol 2.5/5 μg significantly improved trough FEV1 response compared to placebo in both studies; the effects of both doses were similar. Both tiotropium + olodaterol doses also had a greater effect than tiotropium 5 μg in OTEMTO 2 (5/5 μg, 0.039 L, p = 0.0395; 2.5/5 μg, 0.042 L, p = 0.0269) but not in OTEMTO 1 (Fig. 4; Supplementary Table S2).

      3.3 Secondary end points

      3.3.1 TDI focal score

      Tiotropium + olodaterol 5/5 μg significantly improved TDI focal score at 12 weeks compared to placebo (2.05 and 1.20 units, p < 0.0001) and tiotropium 5 μg (0.61 and 0.58 units, p < 0.05) (Fig. 5; Supplementary Table S3). Tiotropium + olodaterol 2.5/5 μg improved TDI focal score compared to placebo in both studies, and compared to tiotropium 5 μg in OTEMTO 2 only (Fig. 5; Supplementary Table S3).
      Figure thumbnail gr5
      Fig. 5Mean difference from placebo in TDI score after 12 weeks (full analysis set). T, tiotropium; O, olodaterol; SE, standard error; TDI, Transition Dyspnoea Index.

      3.3.2 FVC AUC0–3 and trough FVC

      Both tiotropium + olodaterol doses increased FVC AUC0–3 versus placebo and tiotropium 5 μg in both studies. Both dose strengths also increased trough FVC compared to placebo but only tiotropium + olodaterol 2.5/5 μg in OTEMTO 2 showed a significant difference from tiotropium 5 μg in trough FVC (Fig. 6; Supplementary Table S4).
      Figure thumbnail gr6
      Fig. 6(a) Mean FVC AUC0–3 and (b) trough FVC response differences from placebo after 12 weeks (full analysis set). T, tiotropium; O, olodaterol; SE, standard error; FVC, forced vital capacity; AUC0–3, area under the curve from 0 to 3 h.

      3.4 Further end points

      3.4.1 SGRQ responder analysis

      Tiotropium + olodaterol 5/5 μg increased the percentage of patients classed as SGRQ responders (improvement from baseline of ≥4.0 units) at 12 weeks compared to placebo and tiotropium 5 μg (Supplementary Table S5). In OTEMTO 1, the responder rates were 31.2%, 41.7%, 46.2% and 53.1% with placebo, tiotropium 5 μg, tiotropium + olodaterol 2.5/5 μg and 5/5 μg, respectively, with tiotropium + olodaterol 5/5 μg and 2.5/5 μg significantly separating from placebo (odds ratios 2.495 [p < 0.0001], 1.898 [p = 0.0026], respectively) and tiotropium + olodaterol 5/5 μg separating from tiotropium 5 μg (odds ratio 1.583; p = 0.0249). In OTEMTO 2, responder rates were 32.6%, 41.1%, 47.2% and 51.8% with placebo, tiotropium 5 μg, tiotropium + olodaterol 2.5/5 μg and 5/5 μg, respectively. Tiotropium + olodaterol 5/5 μg and 2.5/5 μg significantly separated from placebo (odds ratios 2.219 [p = 0.0002], 1.846 [p = 0.0040]) and tiotropium + olodaterol 5/5 μg separated from tiotropium 5 μg (odds ratio 1.536; p = 0.0359) (Supplementary Table S5).

      3.5 Safety end points

      Incidence of AEs was broadly similar across treatment groups, with a higher incidence of AEs leading to discontinuation in the placebo groups compared to the treatment groups in both studies (Supplementary Table S6). Incidences of AEs in the “cardiac disorders” Systems Organ Class were 0.0–3.0% with tiotropium + olodaterol, 1.0–1.5% with tiotropium 5 μg and 2.0–3.9% with placebo. Incidence of vascular disorders is shown in Supplementary Table S6. No safety concerns were raised from vital signs.

      4. Discussion

      OTEMTO 1 and 2 demonstrated that tiotropium + olodaterol 5/5 μg improves lung function and health-related quality of life after 12 weeks compared to placebo and tiotropium 5 μg. Tiotropium + olodaterol 5/5 μg improved SGRQ total score by 4.89 and 4.56 units compared to placebo in OTEMTO 1 and 2, respectively, which is greater than the threshold of 4 units considered to be clinically meaningful [
      • Jones P.W.
      Interpreting thresholds for a clinically significant change in health status in asthma and COPD.
      Eur. Respir. J. 2002; 19: 398-404https://doi.org/10.1183/09031936.02.00063702
      ]. This suggests that the significant improvements in lung function demonstrated here using tiotropium + olodaterol 5/5 μg have clinically meaningful effects on patients' lives.
      There has been much debate regarding the clinical benefit of anticholinergic + β-adrenergic combination therapies in COPD, as improvements in lung function with these combinations have often been associated with only small or inconsistent improvements in patient-reported outcomes compared to monotherapies [
      • Decramer M.
      • Anzueto A.
      • Kerwin E.
      • Kaelin T.
      • Richard N.
      • Crater G.
      • et al.
      Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
      Lancet Respir. Med. 2014; 2: 472-486https://doi.org/10.1016/S2213-2600(14)70065-7
      ,
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      Respir. Med. 2014; 108: 1752-1760https://doi.org/10.1016/j.rmed.2014.10.002
      ]. Here we show that tiotropium + olodaterol 5/5 μg consistently achieved improvements in mean SGRQ total score greater than the MCID threshold while tiotropium monotherapy did not, and there was an ∼1.5-fold increase in the odds ratio of being an SGRQ responder with tiotropium + olodaterol 5/5 μg compared to tiotropium. Tiotropium + olodaterol 2.5/5 μg did not achieve the MCID in mean SGRQ score and had a lower responder rate than tiotropium + olodaterol 5/5 μg. Overall, tiotropium + olodaterol 5/5 μg provided patients with COPD with a greater opportunity for a clinically significant improvement in health status compared to the other active treatments in this study.
      A relationship exists in COPD between improvements in FEV1 and patient-reported outcomes, with greater bronchodilation linked to greater symptomatic benefit. However, the level of change seen in patient-reported outcomes in several studies with anticholinergic + β-adrenergic combinations compared to monotherapies has not met the criteria for the MCID. Several potential reasons may explain this, including lack of statistical power, as patient-reported outcomes are often secondary end points and the studies are not specifically powered for these end points. Furthermore, MCID values were established for comparison to placebo, so a value of 4 units for SGRQ is probably not appropriate for determining the additional value when comparing two active treatments. The OTEMTO studies were formally powered to detect differences between tiotropium + olodaterol and placebo for SGRQ total score as a primary end point.
      Similarly, other once-daily anticholinergic + β-adrenergic combinations have also demonstrated improvements in SGRQ total score compared to placebo [
      • Bateman E.D.
      • Ferguson G.T.
      • Barnes N.
      • Gallagher N.
      • Green Y.
      • Henley M.
      • et al.
      Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study.
      Eur. Respir. J. 2013; 42: 1484-1494https://doi.org/10.1183/09031936.00200212
      ,
      • Donohue J.F.
      • Maleki-Yazdi M.R.
      • Kilbride S.
      • Mehta R.
      • Kalberg C.
      • Church A.
      Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD.
      Respir. Med. 2013; 107: 1538-1546https://doi.org/10.1016/j.rmed.2013.06.001
      ]; indacaterol + glycopyrronium improved SGRQ total score by 2.13 units compared to tiotropium Handihaler 18 μg after 26 weeks, though it did not reach the 4-unit threshold versus placebo [
      • Bateman E.D.
      • Ferguson G.T.
      • Barnes N.
      • Gallagher N.
      • Green Y.
      • Henley M.
      • et al.
      Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study.
      Eur. Respir. J. 2013; 42: 1484-1494https://doi.org/10.1183/09031936.00200212
      ,
      • van der Molen T.
      • Cazzola M.
      Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes.
      Prim. Care Respir. J. 2012; 21: 101-108
      ]. A difference of 2.10 units between umeclidinium + vilanterol and tiotropium has also been observed after 24 weeks [
      • Maleki-Yazdi M.R.
      • Kaelin T.
      • Richard N.
      • Zvarich M.
      • Church A.
      Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.
      Respir. Med. 2014; 108: 1752-1760https://doi.org/10.1016/j.rmed.2014.10.002
      ], though in two other studies there was no significant difference versus tiotropium monotherapy [
      • European Medicines Agency
      Anoro Summary of Product Characteristics.
      2014
      http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002751/human_med_001754.jsp&mid=WC0b01ac058001d124
      ]. The magnitude of SGRQ difference between tiotropium + olodaterol 5/5 μg and tiotropium monotherapy was larger in the pooled analysis of the OTEMTO studies (2.10 units) than in the TONADO studies (1.23 units) [
      • Buhl R.
      • Maltais F.
      • Abrahams R.
      • Bjermer L.
      • Derom E.
      • Ferguson G.
      • et al.
      Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4).
      Eur. Respir. J. 2015; 45: 969-979https://doi.org/10.1183/09031936.00136014
      ].
      The improvement in health-related quality of life with tiotropium + olodaterol is further supported by the improvement in breathlessness measured using TDI focal score: tiotropium + olodaterol 5/5 μg increased TDI focal score by 2.05 (OTEMTO 1) and 1.20 (OTEMTO 2) units compared to placebo, which is greater than the 1-unit threshold for clinically important improvement [
      • Witek Jr., T.J.
      • Mahler D.A.
      Minimal important difference of the transition dyspnoea index in a multinational clinical trial.
      Eur. Respir. J. 2003; 21: 267-272https://doi.org/10.1183/09031936.03.00068503a
      ]. Statistically significant improvements compared to tiotropium 5 μg were also observed, suggesting that the benefits of combined therapy on FEV1 in comparison to tiotropium 5 μg lead to incremental improvements in dyspnoea.
      The improvement in FEV1 AUC0–3 observed with tiotropium + olodaterol 5/5 μg in the OTEMTO studies is also in line with the effect sizes observed versus tiotropium 5 μg in the TONADO studies. Greater improvements in trough FEV1 versus tiotropium 5 μg were reported in the TONADO trials and versus tiotropium 5 μg and placebo in the VIVACITO study (improvement of 0.207 L versus placebo) than the OTEMTO trials [
      • Buhl R.
      • Maltais F.
      • Abrahams R.
      • Bjermer L.
      • Derom E.
      • Ferguson G.
      • et al.
      Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4).
      Eur. Respir. J. 2015; 45: 969-979https://doi.org/10.1183/09031936.00136014
      ,
      • Derom E.
      • Westerman J.
      • Groenke L.
      • Hamilton A.
      • Li C.
      • Beeh K.M.
      The 24-hour lung function profile of once-daily tiotropium and olodaterol fixed-dose combination compared with placebo and monotherapies in chronic obstructive pulmonary disease.
      Am. J. Respir. Crit. Care Med. 2014; 189 (abs A6727)
      ].
      It is interesting to note that while there appeared to be only a small difference in lung function between the two doses of tiotropium + olodaterol, there was a separation in SGRQ score, with only the 5/5 μg dose showing a statistically significant improvement in SGRQ total score versus tiotropium monotherapy (OTEMTO 1 and combined analysis).
      Beyond the lung-function effect, combination of tiotropium with a LABA has been shown to improve respiratory muscle strength [
      • Canto N.D.
      • Ribeiro J.P.
      • Neder J.A.
      • Chiappa G.R.
      Addition of tiotropium to formoterol improves inspiratory muscle strength after exercise in COPD.
      Respir. Med. 2012; 106: 1404-1412https://doi.org/10.1016/j.rmed.2012.05.012
      ], as well as reducing hyperinflation, leading to improved physical performance [
      • Berton D.C.
      • Reis M.
      • Siqueira A.C.
      • Barroco A.C.
      • Takara L.S.
      • Bravo D.M.
      • et al.
      Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD.
      Respir. Med. 2010; 104: 1288-1296
      ]. Thus, given the improvement in health-related quality of life with tiotropium + olodaterol, it will be interesting to investigate its effects on overall physical performance. The data from the studies reported here, together with others, suggest that FEV1 alone may not fully capture the impact of a treatment on patients' lives, and patient-centred outcomes such as the SGRQ may help to investigate this [
      • van der Molen T.
      • Cazzola M.
      Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes.
      Prim. Care Respir. J. 2012; 21: 101-108
      ].
      The incidence of AEs was similar between treatment groups, with no increase in incidence with tiotropium + olodaterol compared to tiotropium alone or placebo. This was similar to the TONADO studies, in which there was no increase in AEs with tiotropium + olodaterol compared to tiotropium [
      • Buhl R.
      • Maltais F.
      • Abrahams R.
      • Bjermer L.
      • Derom E.
      • Ferguson G.
      • et al.
      Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4).
      Eur. Respir. J. 2015; 45: 969-979https://doi.org/10.1183/09031936.00136014
      ].
      The discontinuation rate was higher in the placebo arm than in the treatment arms in these studies, most likely accounted for by the most severely ill patients dropping out of the studies. With higher discontinuation in the placebo arm, we would have expected to see a positive placebo effect but in these studies this was not the case, and the placebo arm remained relatively stable in terms of lung function and SGRQ score.
      Possible weaknesses of these studies are the short duration and a lack of patients with GOLD 4 COPD but these aspects were important as they allowed comparisons between tiotropium + olodaterol and placebo in SGRQ score and lung function, which provided valuable data.

      5. Conclusions

      The OTEMTO studies demonstrated improvements in lung function with tiotropium + olodaterol over placebo and tiotropium 5 μg that were translated into clinically significant improvements in symptoms and health-related quality of life. Tiotropium + olodaterol 5/5 μg demonstrated a greater effect on SGRQ than tiotropium + olodaterol 2.5/5 μg.

      Conflicts of interest

      Dave Singh reports grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Therevance and Verona, and personal fees from Genentech and SkyePharma
      Gary T. Ferguson reports grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees from GlaxoSmithKline, grants and personal fees from Novartis, AstraZeneca, Pearl Therapeutics and Sunovian, and grants from Forest.
      Roger Abrahams reports grants and personal fees from Boehringer Ingelheim and GlaxoSmithKline, and grants from Forest, Pearl Therapeutics and Pfizer.
      Olaf Schmidt reports grants, personal fees and non-financial support from Boehringer Ingelheim, Pfizer, Almirall, AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Takeda, Amgen, Cephalon, Genentech/Roche, Teva and MSD.
      Lars Grönke, Christoph Hallmann and Nathan Bennett are employees of Boehringer Ingelheim.
      Josef Bolitschek and Leif Bjermer disclose no conflicts of interest.

      Acknowledgements

      The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. They take full responsibility for the scope, direction, content of, and editorial decisions relating to, the manuscript, were involved at all stages of development and have approved the submitted manuscript. The authors received no compensation related to the development of the manuscript. This work was supported by Boehringer Ingelheim Pharma GmbH & Co. KG . Medical writing assistance was provided by Claire Scofield of Complete HealthVizion, which was contracted and compensated by Boehringer Ingelheim Pharma GmbH & Co. KG.
      The authors gratefully acknowledge the contributions of Lesley Towse (Boehringer Ingelheim, UK), who was the Trial Clinical Monitor on both trials, and the trial teams who conducted the trials.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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      Article Info

      Publication History

      Published online: August 12, 2015
      Accepted: August 7, 2015
      Received in revised form: July 27, 2015
      Received: April 15, 2015

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      DOI: https://doi.org/10.1016/j.rmed.2015.08.002

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      • Clinical improvement by tiotropium plus olodaterol
        Respiratory MedicineVol. 125
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          We read with interest the article by Singh et al. (October 2015) [1] on clinically meaningful improvement in quality of life by tiotropium + olodaterol. We would like to hear from the authors two points. In this study, patients were allowed to continue their inhaled corticosteroid (ICS) therapy, and 34.8–41.9% of patients had ICS in each group of the patients.
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