Formoterol Dose Ranging Study (ACHIEVE Duaklir USA Phase IIb)

This is a prospective, randomized, double-blind, 5-period incomplete unbalanced crossover,
placebo and active comparator (open-label) controlled, multicenter clinical trial to assess
the efficacy and safety of three doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID
administered via Pressair® compared to placebo and to open-label formoterol fumarate (20 μg
BID and 40 μg single dose) administered as an inhalation solution via a standard jet
nebulizer (with a mouthpiece) connected to an air compressor (Perforomist® Inhalation
Solution). The drug product is an inhalation powder comprising of micronized aclidinium
bromide and micronized formoterol fumarate with α-lactose monohydrate as the carrier,
presented in a breathactuated device-metered dry-powder inhaler (DPI). It has been approved
under the trademarks of Genuair® and/or Pressair® in some territories.

Inclusion Criteria:

- Adult male or non-pregnant, non-lactating female patients aged ≥40.

- Patients with a diagnosis of COPD (GOLD guidelines, 2016) for a period of at least 6
months prior to Visit 1.

- Patients with moderate to severe stable COPD: post-bronchodilator FEV1 ≥ 30% and <80%
of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Visit 1.

- Patients with reversible airway obstruction defined as an increase in FEV1 of at least
12% and 200 mL over the baseline value after four inhalations of albuterol sulfate 108
µg via a pMDI at Visit 1.

- Current or former-smokers, with a smoking history of ≥ 10 pack-years.

- Patients able to perform acceptable and repeatable pulmonary function testing for FEV1
according to the American Thoracic Society (ATS)/European Respiratory Society (ERS)
2005 criteria at Visit 1.

- Patients eligible and able to participate in the study and who had signed an Informed
Consent Form prior to initiation of any study-related procedures.

Exclusion Criteria:

- Patients with asthma.

- Any respiratory tract infection (including the upper respiratory tract) or COPD
exacerbation (including the mild COPD exacerbation) within 6 weeks prior to Visit 1 or
during the run-in period.

- Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than
24 hours is considered a hospitalization) within 3 months prior to Visit 1.

- Clinically significant respiratory conditions other than COPD.

- Patients who in the investigator's opinion may need to start a pulmonary
rehabilitation program during the study and/or patients who started/finished it within
3 months prior to Visit 1.

- Use of long-term oxygen therapy (≥ 15 hours/day).

- Patients who do not maintain regular day/night, waking/sleeping cycles including night
shift workers.

- Clinically significant cardiovascular conditions.

- Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or
hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension.

- Patients with history of long QT syndrome or whose QTc (calculated according to
Fridericia's Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralized reading
report assessed at Visit 1.

- Patients with clinically significant abnormalities in the laboratory tests, ECG
parameters (other than QTc) or in the physical examination at Visit 1 that might
compromise patient safety.

- Patients with a history of hypersensitivity reaction to an inhaled medication or any
component thereof, including paradoxical bronchospasm.

- Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute
urinary retention or symptomatic unstable prostate hypertrophy.

- History of malignancy of any organ system (including lung cancer), treated or
untreated, within the past 5 years other than basal or squamous cell skin cancer.

- Patients with any other serious or uncontrolled physical or mental dysfunction.

- Patients with a history (within 2 years prior to screening) of drug and/or alcohol
abuse that may prevent study compliance based on the Investigator judgment.

- Patients unlikely to be cooperative or who cannot comply with the study procedures.

- Patients treated with any investigational drug within 30 days (or 6 half-lives,
whichever is longer) prior to Visit 1.

- Patients who intended to use any concomitant medication not permitted by this protocol
or who had not undergone the required washout period for a particular prohibited
medication.

- Patients unable to give consent, or patients of consenting age but under guardianship,
or vulnerable patients.

- Any other conditions that, in the investigator's opinion, might render the patient to
be unsuitable for the study.

- Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff
and/or site staff), or patients employed by or relatives of the employees of the site
or sponsor.

- Previous randomization in the present study D6571C00002.