- Male or female subjects between, and including, the ages of 40 and 80 years.
- Subjects with a diagnosis, for at least 6 months, of moderate to severe COPD (GOLD)
and who meet the criteria for Stage II-III disease: Subjects must have a
post-bronchodilator FEV1/FVC ratio
(inclusive) of the predicted value for age, height, race and sex using European
Community for Coal and Steel ECCS standards or NHANES III standards.
- Subjects must have a smoking history of at least 10 pack-years* and meet one of the
following criteria: They are current smokers, or they are ex-smokers who have
abstained from smoking for at least 6 months.
- Subjects treated with tiotropium bromide (SPIRIVA HandiHaler) 18 microgram daily for
at least 1 month prior to screening.
- Subjects must have had stable disease for at least 1 month prior to screening. During
the screening and run-in phase subjects must be able to manage disease symptoms
adequately with tiotropium bromide +/- salbutamol (albuterol) rescue medication
(subjects should not use >10 actuations [100 microgram/actuations] daily for more than
2 consecutive days), without reliance on other therapies including oral or inhaled
corticosteroids, other long-acting bronchodilators, nebulizer therapy, theophylline,
roflumilast or regular oxygen.
- A COPD exacerbation requiring treatment with oral steroids or hospitalization for the
treatment of COPD within 3 months of screening.
- History of a lower respiratory tract infection or significant disease instability
during the month preceding screening or during the time between screening and
randomization.
- History or presence of respiratory failure, cor pulmonale or right ventricular
failure.
- Subjects with home oxygen therapy (either PRN or long-term oxygen therapy).
- Any clearly documented history of adult asthma or other chronic respiratory disorders
(eg, bronchiectasis, pulmonary fibrosis, pneumoconiosis).
- Known previous diagnosis of Hepatitis B or C or HIV infection (specific screening is
not required).
- History of cancer (other than cutaneous basal cell) in the previous 5 years.
- Active or past history of GI hemorrhage of any etiology, peptic ulceration, erosive
esophagitis, gastric outlet obstruction or inflammatory bowel disease.
- Regular use of aspirin at a dose greater than 325 mg/day.
- History within the previous 6 months of: myocardial infarction, cardiac arrhythmia
(eg, atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter,
supraventricular tachycardia, ventricular tachycardia), left ventricular failure,
unstable angina, coronary angioplasty, coronary artery bypass grafting (CABG) or
cerebrovascular accident (including transient ischemic attacks).
- A family history of long QT syndrome.
- Presenting with: Any condition possibly affecting oral drug absorption (eg,
gastrectomy or clinically significant diabetic gastroenteropathy).
- Any clinically significant skin lesions as described in Common Terminology Criteria
for Adverse Events for Dermatology (CTCAE) Version 3.0.
- Any clinically significant active systemic or cutaneous infection including herpetic
lesions.
- Congestive heart failure requiring treatment New York Heart Association (NYHA) Class
III-IV.
- ECG abnormalities at screening or randomization, including those listed below:
Subjects with pre-randomization evidence of QTcF prolongation (defined as >450 ms) at
screening or baseline (Week 0) are not eligible for randomization. This assessment is
based on a confirmed mean of the triplicate ECG recordings and is made by the
investigator at the time of ECG collection.
- Predominant heart rhythm other than normal sinus rhythm eg, atrial fibrillation,
atrial flutter, supraventricular tachycardia.
- Atrioventricular (AV) block greater than first degree.
- Resting heart rate >100 or
- Evidence of previous myocardial infarction in the absence of clinical history
consistent with these findings.
- Evidence of acute ischemia.