Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo when administered to patients with stable chronic obstructive pulmonary disease (COPD).

This aclidinium/formoterol Fix dose combination (FDC) is expected to provide
superior bronchodilation compared with either component, aclidinium and
formoterol, alone and with placebo. Furthermore, administration of 2
bronchodilators in a FDC via a single inhaler may improve treatment compliance
compared with that associated with the use of 2 separate inhalers.

• To assess the long-term bronchodilation of aclidinium/formoterol FDCs
compared to individual components and placebo, when administered twice daily
via inhalation to COPD patients.

• To assess the benefits of aclidinium/formoterol FDCs in COPD symptoms,
disease-related health status and COPD exacerbations compared to individual
components and placebo, when administered twice daily via inhalation to COPD
patients.

• To evaluate the long-term safety and tolerability of aclidinium/formoterol
FDCs compared to individual components and placebo when administered twice
daily via inhalation to COPD patients.

Patients will visit the clinic to sign the informed consent form and will
perform the Screening Visit.
However, certain COPD medications are prohibited for this trial purposes thus,
in case the patient is
treated with any of those, after signing the informed consent form and before
conducting any
assessment at the Screening Visit, the patient will remain in wash-out for a
period that will vary from 1
day to 1 month depending on the specific medication to be washed out.

At Screening Visit inclusion and exclusion criteria will be checked by means of
patient*s medical
history review, COPD status, physical examination, laboratory, blood pressure
and ECG
measurement.

Two to three weeks later, patients still fulfilling inclusion/exclusion
criteria will perform the
Randomisation Visit (Visit 1). At this visit, a 24 week-long treatment period
will start. During this
treatment period each patient will inhale one dose, twice daily, from one out
of the five possible
treatments (in a double-blind fashion).

Patients found to be eligible for inclusion in the study, will be randomly
allocated (like randomly flipping a coin) to one of five treatments arms:
-aclidinium/formoterol FDC 400/12 µg;
aclidinium/formoterol FDC 400/6 µg;
-aclidinium monotherapy 400 µg;
-formoterol monotherapy 12 µg or
-placebo (dummy treatment containing no active ingredient).

The distribution of this random allocation of patients to the study treatment
arms is 2:2:2:2:1, respectively. That means that ther is a 1 out of 9 chance
to receive placebo.

After Randomisation Visit, patients will attend 5 more visits. The first visit
will take place 1 week after
the start of the study treatment period, then at 4, 12, 18 and 24 weeks on
treatment (from Visit 2 to
Visit 6).

At the different visits over the treatment period, pre-morning dose assessments
will include:
Pulmonary Function Test (PFT), blood pressure and ECG measurement,
Baseline/Transition
Dyspnoea Index (BDI/TDI), St. George*s Respiratory Questionnaire (SGRQ) and
EuroQol
questionnaire-5D (EQ-5D). Post-morning dose assessments will be performed over
the next 3 hours
and will include PFTs, blood pressure and ECG measurement.

Laboratory test will be repeated at 12 weeks on treatment (Visit 4) and at the
end of the treatment
period (Visit 6). Also at Visit 6, a physical examination will be repeated.
Two weeks after the last study drug administration (even in case of premature
discontinuation), every
patient will attend a last visit to the clinic (Visit 7) or either receive a
follow-up phone call from the site
(as deemed appropriate by the investigator) in order to assess any on-going or
new adverse events.
Patients will be provided with relief medication (salbutamol pMDI 100µg/puff)
to be used on an as
needed basis, from the time of the informed consent signature until the end of
treatment period (Visit
6).

From Screening Visit to the end of the treatment period (Visit 6), patients
will use, twice daily, an
electronic Patient Diary to record the intake of study drug and relief
medication as well as COPD
symptoms by means of the EXACT questionnaire (evening) or the Night-time and
Early morning
COPD symptoms questionnaire (morning). Patients will also use a paper Patient
Diary to record any
adverse event and the intake of any concomitant medications from Screening
Visit until Follow-up
Contact (Visit 7).

During the entire duration of the study adverse events (including COPD
exacerbations) and the use of
any concomitant medication will be assessed and recorded by the investigator.
In addition to the assessments described above, a subset of 20% of the total
patients will have 24-
hour ECG Holter recording at Screening Visit and at 12 and 24 weeks on study
treatment. Thus,
these patients will need to attend the clinic on 2 consecutive days in 3
occasions to either place or
remove the Holter device.

In a different subset of 20% of total patients, additional spirometry
assessments will be performed at
Randomisation Visit and at 12 and 24 weeks on treatment. On these days,
spirometries will continue
up to 12 hours post-morning dose.

Inhalation of powder.

It is possible that the disease during this trial get worse or even does not
improve. The chance your symptoms worsening is more while receiving the placebo
treatment. The treatment with aclidinium bromide/formoterol can also have
consequences for the future health of the patient, which are not predictable at
this moment.

No specific risk is anticipated with the doses and the dose regimen proposed
for this study.