A randomized, double-blind, placebo controlled, multicentre study to determine the effect of QVA149 on lungfunction in patients with Chronic Obstructive Pulmonary Disease (COPD).

Currently, there is no fixed-dose combination of a long-acting ß2-agonist and a
long-acting muscarinic antagonist. Combivent® (albuterol (salbutamol) sulfate
and ipratropium bromide) is a short-acting fixed dose combination of a ß2-
agonist and a muscarinic antagonist indicated for the treatment of COPD and
administered with two inhalations four times daily. Published studies have
shown that the complementary mechanisms of action of a long-acting ß2-agonist
(formoterol) and a long-acting muscarinic antagonist (tiotropium bromide)
significantly improve bronchodilation in COPD patients compared to the
respective monotherapies.

The purpose of this study is to evaluate the effects of QVA149 300/50, a fixed
dose combination of QAB149 300µg and NVA237 50µg, versus placebo and two doses
of QAB149 300µg and 600µg, in terms of lung function in patients with moderate
to severe stable COPD before proceeding to phase III development.

This is a randomized, double-blind, 4 period cross-over, multi-centre study to
evaluate the efficacy and safety of QVA149 300/50 versus placebo and two doses
of QAB149 in patients with moderate to severe stable COPD. Patients entered
into this study will be 40 years old or older with a diagnosis of moderate to
severe COPD and will have experienced no COPD exacerbations in the 6 weeks
preceding visit 1.

Screening visit 1
An initial screening visit (Visit 1) will be used to assess suitability for the
study, to obtain relevant background information and to obtain informed consent
(informed consent may be obtained by the investigator prior to Visit 1 to allow
patients sufficient time to consider participation in this study). Patients who
are currently using a prohibited medication will enter a washout period of up
to 7 days before returning for the second screening visit (Visit 2). Screening
visit 2 Patients not using any prohibited medication will proceed directly to
the second screening visit (i.e. Visits 1 and 2 may be combined for patients
not taking prohibited medication). At this screening visit patients will
undergo further tests including screening spirometry and a ß2agonist
bronchodilator reversibility test. Patients who meet the inclusion / exclusion
criteria at this screening visit will return to the study centre on the next
day, or as soon as possible afterwards for the baseline / randomization visit
(Visit 3).

Study Treatment Periods
At the baseline visit (Visit 3), patients whose eligibility is confirmed will
be randomized to one of the available treatment sequences in this four period
cross-over design. Patients will then enter the first of four double-blind, 7
day treatment periods. Patients will be assessed on consecutive days at the
beginning and end of each treatment period (the first and second days and the
seventh and eighth days). The assessment to address the primary objective
(trough FEV1) will be performed on the eighth day of each treatment period.
On the first day of each treatment period patients will be required to remain
at the study centre until 4 hours after taking study medication. Patients will
then return on the next day to complete the 23h 15min and 23h 45min post dose
spirometry. On the seventh day of the treatment period patients will be
required to remain at the study centre until 12 hours after taking study
medication and will return on the next day (eighth day) to complete the 23h
15min and 23h 45min post dose spirometry. In total patients will be required to
attend the study centre for 18 visits. In a subgroup of patients
pharmacokinetic sampling will be performed on the seventh and eighth days of
each of the four treatment periods.
Patients will complete all four study periods according to the randomization
sequence with a 7 day wash out between study periods during which the use of a
fixed dose combination of a short acting ß2 agonist and short acting muscarinic
antagonist as indicated is permitted if considered necessary by the
investigator (this combination may also be used during the screening period if
deemed necessary by the investigator). The last dose should not be taken later
than 8h before the next study visit.
During the study patients will be permitted to use allowable COPD medications
described in section 5.1, and will be provided with a salbutamol/albuterol
inhaler to use as rescue medication during the four 7 day treatment periods.
Patients will be asked to abstain wherever possible from using rescue
medication during study visits, and in the six hours prior to
attending a study visit.

QVA149 300/50mcg
QAB149 600mcg
QAB149 300mcg
placebo

salbutamol as rescue medication
inhalatiecorticosteroïd
Combivent or Berodual during the wash-out periods

It cannot be guaranteed that the health of each individual patient will improve
by participating in this study. Patients will be checked up regularly during
this study and medication will be provided at no costs. The results of this
study might help other patients with COPD.
Possible discomforts of the study are:
Physical Examination 6 times, reversibility test once, spirometry during 17
visits (12 hours postdose and 4 hours postdose at certain visits), blood
collection at 10 visits, urine collection at 9 visits, EGCs will be taken
during 17 visits and 3 pregnancy tests will be taken, if applicable.