A randomised, double-blind, placebo- and active-controlled parallel group study to assess the efficacy of 12 weeks of once daily treatment of two doses of orally inhaled tiotropium + olodaterol fixed dose combination (delivered by the Respimat inhaler) in patients with Chronic Obstructive Pulmonary Disease (COPD)

The COPD treatment guidelines advise treatment with bronchodilators with
different mechanisms of action. Short-acting anticholinergics and
beta2-agonists in fixed dose combinations have shown to be effective and safe
and are user-friendly to patients. Once daily fixed dose combinations of
long-acting anticholinergics and beta2-agonists are not yet available.
Tiotropium bromide is a registered once daily long-acting anticholinergic for
the treatment of COPD and will be combined with a once daily long-acting
beta2-agonist, olodaterol, in this study. Olodaterol is being developed for the
treatment of COPD. It is expected that the combination of these two once daily
bronchodilators with different mechanisms of action will provide an optimal
long term bronchdilation and is user-friendly.

Earlier studies established a satisfactory safety and tolerability profile of 4
weeks once daily treatment with tiotropium + olodaterol and also provided
evidence of the additional bronchodilator efficacy of tiotropium + olodaterol
FDC compared with tiotropium monotherapy or olodaterol monotherapy. Based on
the evidence of the efficacy and safety of the fixed dose combination of
tiotropium and olodaterol up to 4 weeks treatment in patients with COPD, it is
considered appropriate to progress into the next phase of clinical development
and conduct long-term, confirmatory trials to provide substantial evidence of
the efficacy and safety of tiotropium + olodaterol FDC in patients with COPD.

Currently two identical studies are running with a treatment phase of 1 year.
However, in these studies a placebo arm is missing. The present study 1237.25
and its replicate 1237.26 have been designed to allow for the inclusion of a
placebo control arm by restricting the treatment duration to 12 weeks and
restricting the study population to patients with moderate to severe COPD. The
comparison with placebo is intended to provide further evidence of the maximal
clinical efficacy of tiotropium + olodaterol FDC. The active control arm (5 *g
tiotropium) has been included to allow for cross-trial comparisons (i.e.
comparison of the relative efficacy of tiotropium + olodaterol FDC vs.
tiotropium observed in
studies 1237.25/1237.26 with the relative efficacy of tiotropium + olodaterol
FDC vs. tiotropium observed in the other 1 yr studies.

The objective of the proposed study (1237.25) is to evaluate maximal treatment
effect in FEV1 and SGRQ after 12-weeks treatment with two different doses of
tiotropium + olodaterol FDC (5*g/ 5*g and 5*g/ 2.5*g) by comparison with
placebo in patients with COPD.

After signing informed consent and completing an initial screening visit (Visit
1), patients will enter a 2 week run-in period to ensure clinical stability
(i.e. no exacerbations).
Patients who meet all the inclusion criteria and none of the exclusion criteria
will be randomized at Visit 2 into one of the following treatmentarms:
1) tiotropium + olodaterol ( 5 / 5 *g) fixed dose combination inhalation
solution, delivered once daily via the RESPIMAT
2) tiotropium + olodaterol (2.5 / 5 *g) fixed dose combination inhalation
solution, delivered once daily via the RESPIMAT
3) tiotropium (5 *g) inhalation solution, delivered once daily via the
RESPIMAT, and
4) placebo inhalation solution, delivered once daily via the RESPIMAT.
The treatment will take 12 weeks. Patients will be evaluated for an additional
21 days following completion of the treatment period, or, in case of early
discontinuation, after the final dose of study medication. During these 3 weeks
the patient may return to his/her usual medication as used before the study.
An interactive voice response system (IVRS) will be used for randomization to a
treatment arm. It is a double-blind, placebo and actively controlled randomised
study with parallel groups.

During twelve weeks a once daily inhalation of studymedication with the
Respimat® inhaler with one of the following treatment arms (randomisation
1:1:1:1) - fixed dose combinatie tiotropium-olodaterol 2.5 *g / 5 *g - fixed
dose combinatie tiotropium-olodaterol 5 *g / 5 *g - tiotropium 5 *g , and -
placebo. During five visits spirometry will be performed. , body
plethysmography during Visit 1 and in total 7 cycle ergometry tests will be
done.

During the course of the study each patient performs 5 times spirometry. In
principle, no serious risks are involved in spirometry. Nevertheless, risks and
discomforts associated with lung function testing may include shortness of
breath, dizziness, or headache during the breathing tests. Should this occur,
the patient may receive treatment. During the study two times (or if necessary
three times) a physical examination is performed. During three visits the
patient will be asked to complete questionnaires. In addition the patient Apart
from that ijgt de patient aan het begin van het onderzoek een (electronisch)
dagboekje mee om iedere dag de PEF waarde te meten. PEF is de maximale
volumestroom bij geforceerde uitademing, vanuit volledige inspiratie,
uitgedrukt in liters per minuut. Ook wordt het gebruik van rescue medicatie
geregistreerd in het dagboekje.

During the screeningperiod some medication will be washed-out. For this reason,
all patients will receive Ventolin as rescue medication already at start of
screeningperiod and may also be used during the treatmentperiod. Besides that,
Atrovent may be used during screeningperiod. Oral and inhaled corticosteroids
are also accepted throughout the study. There are also some restrictions for a
patient in terms of food and fluid intake as well as in physical activities
performed in the period before each visit. Inhalation of studymedication may
cause side effects. Normally, these side effects are mild and they usually
disappear with continued treatment. Safety monitoring will include
bloodsampling, measurement of vital signs and ECG monitoring. Bloodsampling may
also cause some inconvenience.
The total time spent for each patient is 14-19.5 hours.