. 2022 Dec 15;23:347. doi: 10.1186/s12931-022-02268-3

Table 1.

Characteristics of studies included

Abbreviated reference and countries	Study type, number of arms and randomized patients	Duration	Inclusion criteria	Intervention	Comparator	Outcomes selected for analysis	Main results
Troosters et al. 2018 [12] Australia, Austria, Belgium, Canada, Denmark, Germany, New Zealand, Poland, Portugal, United Kingdom, United States	Parallel, 4 arms, 304 patients	12 weeks	40–75 years, smoking history > 10 pack-years, FEV1 post-bronchodilator 30% to 80% predicted, and FEV1/FVC < 70%	Tiotropium 5 μg/Olodaterol 5 μg, or Tiotropium 5 μg/Olodaterol 5 μg with training program	Tiotropium 5 μg or placebo	ESWT, 6MWT, steps/day, walking intensity, walking time/day	Arithmetic mean (SE) change from baseline, ESWT: - Tiotropium 5 μg/Olodaterol 5 μg: 91.0 (28.0) - Placebo: 31.0 (30.0) Adjusted mean (SE) change from baseline, 6MWT: - Tiotropium 5 μg/Olodaterol 5 μg: 25.76 (7.17) - Tiotropium 5 μg: 6.87 (7.75) - Placebo: 13.89 (8.09) Adjusted mean (SE) change from baseline, steps/day: - Tiotropium 5 μg/Olodaterol 5 μg: 1394.24 (310.22) - Tiotropium 5 μg: 153.19 (317.98) - Placebo: 1098.07 (325.08) Walking intensity and walking time/day results showed in results section
O’Donnell et al. 2017 [13] United States, Argentina, Australia, Austria, Belgium, Canada, Chile, Germany, Italy, Netherlands, New Zealand, Russia, Sweden	Crossover 5 arms, 586 patients	6 weeks	Smoking history > 10 pack-years, post-bronchodilator FEV1/FVC < 0.7; post-bronchodilator FEV1 ≥ 30% and < 80% of predicted	Tiotropium 2.5 g/Olodaterol 5 μg, or Tiotropium 5 μg/Olodaterol 5 μg	Tiotropium 5 μg, olodaterol 5 µg and placebo	CWRCE	Adjusted arithmetic mean (SE) of EET during CWRCE: - At Beginning: - All treatments: 511.6 (SD: 269.4) - At 6 weeks: - Placebo: 470.6 (12.6) - Olodaterol 5 μg: 521.1 (12.6) - Tiotropium 5 μg: 536.2 (12.6) - Tiotropium 2.5 g/Olodaterol 5 μg: 552.1 (12.5) - Tiotropium 5 μg/Olodaterol 5 μg: 554.5 (12.5)
Ichinose et al. 2018 [14] Japan	Crossover 2 arms, 184 patients	6 weeks	Japanese patients ≥ 40 years, with history of smoking > 10 pack-years, with COPD and stable airway obstruction, post-bronchodilator FEV1 < 80% of predicted; post-bronchodilator FEV1/FVC < 0.7 at visit 1; mMRC ≥ 1; 6MWD < 400 m; and a score ≥ 4 on Borg's modified scale following the 6MWD test on visit 2	Tiotropium 5 μg/Olodaterol 5 μg	Tiotropium 5 μg	6MWT, steps/day, duration of activity	Adjusted mean (SD), 6MWT: - At Beginning: - All treatments: 293.8 (93.3) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 311.5 (n.a) - Tiotropium 5 μg: 307.4 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, 6MWT: 4.2 (-6.2–14.5) Adjusted mean, steps/day: - At Beginning: - All treatments: 3723.0 - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 3871.1 - Tiotropium 5 μg: 3793.6 Adjusted mean (95%CI) treatment difference at 6 weeks, steps/day: 77.5 (-92.7–247.7) Adjusted mean (SD), ≥ 2 METs: - At Beginning: - All treatments: 181.4 (82.0) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 191.5 (n.a) - Tiotropium 5 μg: 186.5 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 2 METs: 5.0 (0.39–9.69)
Watz et al. 2017 [15] Canada, Germany, Hungary, Spain	Parallel 2 arms, 267 patients	8 weeks	≥ 40 years, history of smoking, (FRC) ≥ 120% of predicted, post-bronchodilator FEV1 ≥ 40% and < 80% of predicted, FEV1/FVC < 70%, and score ≥ 2 on mMRC dyspnoea scale	Aclidinium 800 μg/Formoterol 24 μg	Placebo	CWRCE, % inactive patients, steps/day, duration of activity, energy expenditure, D-PPAC	Least square mean (95%CI) change from baseline, CWRCE: - Aclidinium 800 μg/Formoterol 24 μg: 45.5 (13.7–77.3) - Placebo: -13.40 (n.a) Treatment difference of % inactive patients: OR:0.27; 95%CI: 0.14–0.51 Least squares mean (SE) change from baseline, steps/day: - Aclidinium 800 μg/Formoterol 24 μg: 621.0 (167.0) - Placebo: -110.0 (167.0) Least squares mean (95%CI) change from baseline, ≥ 3 METs: - Aclidinium 800 μg/Formoterol 24 μg: 8.5 (4.3–12.8) - Placebo: -1.2 (-5.40–3.10) Adjusted mean (95%CI) treatment difference at 4 weeks, ≥ 3 METs: 9.7 (3.8–15.5) Least squares mean (95%CI) change from baseline, energy expenditure: - Aclidinium 800 μg/Formoterol 24 μg: 36.5 (16.8–56.1) - Placebo: − 4.4 (− 24.1 to 15.2) Adjusted mean (CI-95%) treatment difference at 4 weeks, energy expenditure: 40.9 (13.9–67.9) D-PPAC results showed in results section
Minakata et al. 2019 [16] Japan	Crossover 2 arms, 182 patients	6 weeks	≥ 40 years, diagnosed with COPD and GOLD grade II–IV	Tiotropium 5 μg/Olodaterol 5 μg	Tiotropium 5 μg	MET(s)	Adjusted mean (SD), ≥ 1.0–1.5 METs: - At Beginning: - All treatments: 408.4 (90.0) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 407.9 (n.a) - Tiotropium 5 μg: 416.6 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 1.0–1.5 METs: -8.64 (-16.88–-0.40) Adjusted mean (SD), ≥ 2 METs: - At Beginning: - All treatments: 177.30 (64.4) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 179.1 (n.a) - Tiotropium 5 μg: 172.5 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 2 METs: 6.51 (1.17–11.85) Adjusted mean (SD), ≥ 3 METs: - At Beginning: - All treatments: 42.2 (24.7) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 46.1 (n.a) - Tiotropium 5 μg: 43.5 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 3 METs: 2.6 (0.7–4.49)
Singh et al. 2018 [17] United States, Bulgaria, Estonia, Germany, Russia, United Kingdom, Canada, Czech Republic, Denmark, South Africa, Ukraine	Crossover 4 arms, 657 patients	12 weeks	≥ 40 years, with history of smoking > 10 pack-years, FRC at rest > 120% of predicted, FEV1/FVC post-bronchodilator < 70% and FEV1 ≥ 35% and ≤ 70% of predicted	Umeclidinium 62.5 μg/Vilanterol 25 μg	Umeclidinium 62.5 μg, Vilanterol 25 μg, and	ESWT	Least squares mean (SE) change from baseline, ESWT: - Umeclidinium 62.5 μg/ Vilanterol 25 μg: 27.3 (4.4) - Umeclidinium 62.5 μg: 20.4 (7.7) - Vilanterol 25 μg: 12.6 (6.3)
Riley et al. 2018 [18] United States	Crossover 2 arms, 198 patients	12 weeks	≥ 40 years, history of smoking ≥ 10 packages/year; FEV1/FVC < 0.70 and FEV1 post-bronchodilation 30–70% of predicted; FRC at rest ≥ 120% of predicted; score ≥ 2 on mMRC dyspnoea scale	Umeclidinium 62.5 μg/Vilanterol 25 μg	Placebo	ESWT	Least squares mean (SE) change from baseline, ESWT - Umeclidinium 62.5 μg/ Vilanterol 25 μg: -2.1 (9.29) - Placebo: − 5.4 (9.68)
O’Donnell et al. 2018 [19] Canada	Crossover 2 arms, 17 patients	4 weeks	> 40 years, with smoking history > 20 pack-years, post-bronchodilator FEV1 ≥ 50 and < 80% over predicted, FEV1/FVC < 0.7, and activity-related dyspnoea (BDI ≤ 9 or mMRC dyspnoea scale ≥ 2)	Umeclidinium 125 μg/Vilanterol 25 μg	Umeclidinium 125 μg	CWRCE	Mean (SD), CWRCR (min): - At Beginning: - Umeclidinium 125 μg/Vilanterol 25 μg: 7.19 (4.13) - Umeclidinium 125 μg: 6.83 (4.67) - At 4 weeks: - Umeclidinium 125 μg/Vilanterol 25 μg: 7.49 (4.99) - Umeclidinium 125 μg: 7.82 (6.15)
Maltais et al. 2018 [20] United States, Argentina, Canada, Finland, France, Germany, Hungary, Italy, Spain, United Kingdom	Parallel 3 arms, 404 patients	12 weeks	40–75 years, with history of smoking > 10 pack-years; post-bronchodilator FEV1/FVC < 70% and post-bronchodilator FEV1 < 80% and ≥ 30% above predicted	Tiotropium 2.5 μg/Olodaterol 5 μg, or Tiotropium 5 μg/Olodaterol 5 μg	Placebo	CWRCE, ESWT	Adjusted arithmetic mean (SD) of EET during CWRCE: - At Beginning: - Tiotropium 2.5 μg/Olodaterol 5 μg: 490.7 (272.4) - Tiotropium 5 μg/Olodaterol 5 μg: 527.5 (279.2) - Placebo: 502.7 (258.6) - At 12 weeks: - Tiotropium 2.5 μg/Olodaterol 5: 616.35 (SE: 23.41) - Tiotropium 5 μg/Olodaterol 5 μg: 628.32 (SE: 22.94) - Placebo: 549.42 (SE:24.36) Adjusted arithmetic mean (SD) of EET during CWRCE: - At Beginning: - Tiotropium 2.5 μg/Olodaterol 5: 366.7 (206.0) - Tiotropium 5 μg/Olodaterol 5 μg: 373.7 (217.1) - Placebo: 346.3 (186.5) - At 12 weeks: - Tiotropium 2.5 μg/Olodaterol 5: 473.43 (SE: 31.47) - Tiotropium 5 μg/Olodaterol 5 μg: 465.48 (SE: 30.40) - Placebo: 379.95 (SE:33.06)
Maltais et al. 2014 [28] United States, Bulgaria, Estonia, Germany, Russia, United Kingdom, Canada, Czech Republic, Denmark, South Africa, Ukraine	Crossover 6 arms, 655 patients	12 weeks	≥ 40 years, with history of smoking ≥ 10 pack-years, post-bronchodilator FEV1/FVC < 70% and FEV1 ≥ 35% and ≤ 70% of predicted; score ≥ 2 on mMRC dyspnoea scale on visit 1 and FRC at rest ≥ 120% of predicted	Umeclidinium 62.5 μg/ Vilanterol 25 μg or Umeclidinium 125 μg/ Vilanterol 25 μg	placebo	ESWT	Adjusted arithmetic mean (SE) of EET during ESWT, change from baseline: - Umeclidinium 62.5 μg/ Vilanterol 25 μg: 62.9 (10.8) - Umeclidinium 125 μg/ Vilanterol 25 μg: 66.7 (10.99) - Placebo: 19.2 (10.39)
Watz et al. 2016 [21] Germany	Crossover 2 arms, 194 patients	3 weeks	≥ 40 years, with history of smoking ≥ 10 pack-years, post-bronchodilator FEV1 between 40 and 80% of predicted and FEV1/FVC < 0.70 at visit 2	Indacaterol 110 μg/ Glycopyrronium 50 μg	Placebo	Energy expenditure, steps/day, duration of activity	Least squares mean change from baseline, energy expenditure: - Indacaterol 110 μg/Glycopyrronium 50 μg: 5.10 - Placebo: − 31.60 Least squares mean (95%CI) treatment difference, change from baseline, energy expenditure: 36.7 (1.7–71.7) Mean (SD) change from baseline, steps/day: - Indacaterol 110 μg/Glycopyrronium 50 μg: 31.0 (1662.4) - Placebo: − 321.0 (1647.6) Mean (SD) treatment difference, change from baseline, steps/day: 358.0 (2458.0) Least squares mean (95%CI) change from baseline, ≥ 3 METs: - Indacaterol 110 μg/Glycopyrronium 50 μg: − 6.9 (− 13.4 to − 0.40) - Placebo: − 11.3 (− 17.9 to − 4.60) Least squares mean (95%CI) treatment difference, change from baseline, ≥ 3 METs: 4.4 (-3.30–12.1)
Maltais et al. 2020 [22] United States, Argentina, Canada, Finland, France, Germany, Hungary, Italy, Spain, United Kingdom	Parallel 3 arms, 151 patients	12 weeks	40–75 years, post-bronchodilator FEV1 between ≥ 30% and < 80% than predicted, and post-bronchodilator FEV1/FVC < 70%	Tiotropium 2.5 μg/Olodaterol 5 μg, or Tiotropium 5 μg/Olodaterol 5 μg	Placebo	CWRCE, ESWT	Arithmetic mean CWRCE (SE) at week 6: - Placebo: 425.2 (25.3) - Tiotropium 5 μg/Olodaterol 5 μg: 507.0 (27.0) Arithmetic mean ESWT (SE) at 6 weeks6: - Placebo: 375.6 (34.0) - Tiotropium 5 μg/Olodaterol 5 μg: 457.2 (30.3)
Canto et al. 2012 [23] Brazil	Crossover 2 arms, 41 patients	2 weeks	Patients with stable COPD who met GOLD criteria, with a history of smoking > 20 pack-years	Formoterol 24 μg /Tiotropium 18 μg	Placebo/Formoterol 12 μg	Tolerance limit in constant work rate test	Percentage of mean (SD) change from baseline: - Formoterol 24 μg /Tiotropium 18 μg: 84.5 (8.2) - Placebo/Formoterol 12 μg: 40.7 (7.6)
Jayaram et al. 2013 [24] Australia, New Zealand	Crossover 2 arms, 38 patients	6 weeks	Age: 18–80 years, smoking history ≥ 10 pack-years, COPD defined by ATS/ERS criteria	Formoterol 24 μg /Tiotropium 18 μg	Placebo /Tiotropium 5 μg	6MWT	Mean (95%CI) change from baseline, 6MWT: - Formoterol 24 μg /Tiotropium 18 μg: 25.5 (4.4–46.5) - Placebo /Tiotropium 5 μg: − 7.6 (− 23.1 to 7.8) Mean (CI-95%) treatment difference at 6 weeks, ≥ 2 METs: 36.3 (2.4–70.1)
Takahashi et al. 2020 [25] Japan	Parallel, 2 arms, 80 patients	12 weeks	40 to 85 years, untreated, with smoking history ≥ 10 packages/year, post-bronchodilator FEV1 < 80% predicted, and FEV1/FVC < 70%	Tiotropium 5 μg/Olodaterol 5 μg	Tiotropium 5 μg	6MWT, steps/day, MET(s)	Mean (SD), 6MWT: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 470.3 (77.6) - Tiotropium 5 μg: 438.8 (88.1) - At 12 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 475.7 (68.7) - Tiotropium 5 μg: 445.7 (80.6) Mean (SE) change from baseline, steps/day: - Tiotropium 5 μg/Olodaterol 5 μg: 168.1 (392.5) - Tiotropium 5 μg: 37.6 (192.4) Mean (CI-95%) treatment difference at 6 weeks, steps/day: 130.5 (− 750.0 to 1011.1) Mean (SD), ≥ 1.0–1.5 METs: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 299.6 (92.4) - Tiotropium 5 μg: 287.0 (97.1) - Change from baseline: - Tiotropium 5 μg/Olodaterol 5 μg: -38.7 (n.a) - Tiotropium 5 μg: − 4.6 (n.a) Mean (95%CI) treatment difference at 12 weeks, ≥ 1.0–1.5 METs: -34.1 (-70.4–2.2) Mean (SD), ≥ 2 METs: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 138.5 (63.3) - Tiotropium 5 μg: 141.2 (68.5) - Change from baseline: - Tiotropium 5 μg/Olodaterol 5 μg: 10.8 (n.a) - Tiotropium 5 μg: 8.3 (n.a) Mean (95%CI) treatment difference at 12 weeks, ≥ 2 METs: 2.5 (− 19.0 to 24.0) Mean (SD), ≥ 3 METs: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 41.0 (29.0) - Tiotropium 5 μg: 36.1 (24.2) - Change from baseline: - Tiotropium 5 μg/Olodaterol 5 μg: 5.2 (n.a) - Tiotropium 5 μg: 2.5 (n.a) Mean (95%CI) treatment difference at 12 weeks, ≥ 3 METs: 2.7 (-7.4–12.8)
Stringer et al. 2021 [26] United States	Crossover 2 arms, 60 patients	52 weeks	Between 40 and 80 year with a clinical diagnosis of COPD (postalbuterol FEV1/FVC ratio < 0.70) and stable, without change in medications or exacerbation within the prior 4wk Current or ex-smokers with > 10 pack-years smoking history	Formoterol/Glycopyrronium (5/7.2 μg)	Placebo	CWRCE	Mean (95% CI) treatment difference, CWRCE: 55 s (20–90)
Tufvesson et al. 2021 [27] Sweden	Crossover 2 arms, 23 patients	n.a	FEV1 of 40– 80% of predicted normal (%pred) and a ratio of FEV1 to forced vital capacity (FVC) of ⩽0.7	Indacaterol/Glycopyrronium (110/50 μg)	Placebo	CWRCE	Mean (95% CI) treatment difference, CWRCE: 113 s (6–220)