Table 1 Characteristics of studies included

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)