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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®