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Table 1 Primary tiotropium trials and pooled, combined and database analyses included in this review. Publications were limited to those reporting tiotropium Respimat® and tiotropium HandiHaler® data at the licensed doses

From: A systematic review of comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease: does inhaler choice matter?

NCT identifier and citation(s) Study design COPD inclusion criteria Baseline lung function values Patient numbers and treatment groups Endpoints
Primary tiotropium trial publications
NCT02175342
Caillaud D, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:559–65 [26]
Multicentre, randomized, double-blind within device (no blinding between RMT and HH), parallel-group, 3-week dose-ranging Phase II study FEV1/FVC ≤70%
FEV1 30–65% predicted
Smoking history ≥10 pack-years
Mean FEV1 44% predicted n = 202
RMT 5 μg
(n = 25)
HH 18 μg
(n = 25)
Efficacy 1o: mean change in trough FEV1 from baseline to Day 21
2o: FVC and rescue medication use
NCT01222533
Hohlfeld JM, et al. J Clin Pharmacol. 2014;54:405–14 [31]
Comparative, multicentre, placebo-controlled, randomized (double-blind within RMT 1.25, 2.5, 5 μg; open-label HH 18 μg), 5-way crossover trial with 4-week treatment periods FEV1/FVC <70%
FEV1 < 80% predicted
FEV1/FVC 45%
Mean FEV1 54% predicted
n = 154
RMT 5 μg
(n = 150)
HH 18 μg
(n = 146)
Efficacy 1o: trough FEV1 at end of 24-h dosing interval
2o: FVC, peak expiratory flow and rescue medication use
NCT00292448
Ichinose M, et al. Respir Med. 2010;104:228–36 [33]
Randomized, double-blind, double-dummy, 2-way, 4-week crossover, Phase II study of Japanese patients with COPD FEV1/FVC ≤70%
FEV1 ≤ 70% predicted
Current or ex-smokers
FEV1/FVC 42%
Mean FEV1 43% predicted
n = 157
RMT 5 μg
(n = 147)
HH 18 μg
(n = 147)
Efficacy 1o: trough FEV1 response
2o: peak and average FEV1 and FVC
NCT00239447 and NCT00281567
van Noord JA, et al. Respir Med. 2009;103:22–9 [37]
Pre-specified, pooled analysis of two identical, 30-week, double-blind, double-dummy, crossover studies (4-week crossover periods) FEV1/FVC ≤70%
FEV1 ≤ 60% predicted
Mean FEV1 37% predicted n = 207
Included in efficacy and safety analyses:
RMT 5 μg (n = 189)
HH 18 μg (n = 189)
Efficacy 1o: trough FEV1 from baseline to Day 29
2o: trough and peak FVC, FVC AUC(0-12h), peak FEV1 and FEV1 AUC(0-12h) at
Day 29, and the time to therapeutic response
TIOSPIR® 205.452/NCT01126437
Wise RA, et al. N Engl J Med. 2013;369:1491–501 [48]
Randomized, double-blind, double-dummy, parallel-group, event-driven trial, duration 2–3 years FEV1/FVC ≤70%
FEV1 ≤ 70% predicted
Mean post-bronchodilator FEV1 48% predicted for total population n = 17,135
At risk, mortality
RMT 5 μg (n = 5711)
RMT 2.5 μg (n = 5730)
HH 18 μg (n = 5694)
At risk, exacerbation
RMT 5 μg (n = 5705)
RMT 2.5 μg (n = 5724)
HH 18 μg (n = 5687)
Safety 1o: time to all-cause mortality
Efficacy 1o: time to first COPD exacerbation
Secondary outcomes: number of exacerbations; time to the first MACE
TIOSPIR® 205.452/NCT01126437
Anzueto A, et al. Respir Res. 2015;16:107 [24]
Spirometry sub-study
Randomized, double-blind, double-dummy, parallel-group, event-driven trial, duration 2–3 years
FEV1/FVC ≤70%
FEV1 ≤ 70% predicted
Mean post-bronchodilator FEV1 48% predicted for total population n = 1370
RMT 5 μg (n = 461)
HH 18 μg (n = 445)
Trough FEV1 and FVC
Bouloukaki I, et al. Sleep Breath. 2015 [25, 44] Randomized parallel-group trial Mild to moderate COPD (resting arterial oxygen tension >60 mmHg while awake) NR n = 200 randomized
RMT (n =100)
HH (n =100
Patients analysed:
RMT (n = 95)
HH (n = 93)
SaO2 and sleep quality
Pooled, combined and database analyses
Tashkin D, et al. Chest. 2014;146 r_Meeting Abstracts:49A [34] 16 clinical trials (13 tiotropium HandiHaler®, 3 tiotropium Respimat®) Moderate to very severe COPD NR HH 18 μg (13 trials, n = 5646)
Active comparator (2 trials, n = 584)
Placebo (11 trials, n = 4853)
RMT 5 μg (3 trials, n = 2219)
RMT 10 μg (2 trials, n = 619)
Placebo (3 trials, n = 2318)
HRQoL evaluated using the SGRQ
Dahl R, et al. Eur Respir J. 2014;44 Suppl 58:925 [28] Post-hoc, pooled analysis of all placebo-controlled or head-to-head trials of RMT 5 μg and HH 18 μg with vital status follow up (analysed for death) and those with duration of at least 1 year (analysed for exacerbations) COPD NR At risk of mortality, 6 trials:
RMT 5 μg (n = 8760)
HH 18 μg (n = 8680)
Placebo (n = 6053)
At risk of exacerbations, 5 trials:
RMT 5 μg (n = 8314)
HH 18 μg (n = 8673)
Placebo (n = 5612)
Number of deaths
Number of patients with ≥1 exacerbation
Halpin DMG, et al. Int J Chron Obstruct Pulmon Dis. 2015;10:239–59 [30] Pooled analysis of adverse event data from 28 HH and 7 RMT studies FEV1 ≤ 70% of FVC Mean FEV1 41% predicted Patients treated:
RMT 5 μg (n = 3282)
RMT placebo (n = 3283)
HH 18 μg (n = 9647)
HH placebo (n = 8343)
Safety: AEs
Hohlfeld JM, et al. Int J Clin Pract. 2015;69:72–80 [32] Combined analysis of all tiotropium trials in COPD involving Holter ECG monitoring and conducted between 2003 and 2012 FEV1 ≤ 70% of FVC NR 4 trials (n = 727) HH 18 μg
RMT 1.25–10 μg
Safety: incidence of cardiac arrhythmias
Tashkin D, et al. Eur Respir J. 2014;44 Suppl 58:923 [35] Safety analysis in patients with renal impairment included in placebo-controlled trials of once-daily tiotropium Respimat® 5 μg (7 trials) or tiotropium HandiHaler® 18 μg (15 trials) COPD and renal impairment NR n = 10,753 evaluable patients
Normal renal function, mild and moderate renal impairment (respectively):
HH 18 μg (n = 860), (n = 1099), (n = 448)
HH placebo (n = 700), (n = 815), (n = 347)
RMT 5 μg (n = 1104), (n = 1479), (n = 662)
RMT placebo (n = 1040), (n = 1539), (n = 660)
Safety: AEs
Verhamme K, et al. Eur Respir J. 2013; 42 Suppl 57:4632 [38]
Verhamme KM, et al. Eur Respir J. 2013;42: 606–15 [39]
Study of Integrated Primary Care Information Database (large Dutch primary care database) COPD NR n = 11,287 (24,522 episodes of tiotropium use) Safety: comorbidity
  1. Abbreviations: AE adverse event, AUC area under the curve, COPD chronic obstructive pulmonary disease, ECG electrocardiogram, FEV 1 forced expiratory volume in 1 s, FVC forced vital capacity, HH SPIRIVA® HandiHaler®, HRQoL health-related quality of life, MACE major adverse cardiovascular events, NCT National Clinical Trials database, NR not reported, RMT SPIRIVA®, Respimat®, SaO 2 direct measurement of the oxygen content of the blood, SGRQ St George’s Respiratory Questionnaire, TIOSPIR® TIOtropium Safety and Performance In Respimat®