| Eligibility |
Inclusion Criteria:
1. Male or female patients 40 to 80 years of age, as of the screening visit (SV), who
have signed an informed consent prior to initiation of any study related procedures.
2. Diagnosis of COPD as defined by the Global Initiative for Chronic Obstructive Lung
Disease (GOLD) guidelines.
3. A measured post-bronchodilator (albuterol 360 mcg) forced expiratory volume in 1
second (FEV1) =30% and <80% of predicted normal at the SV. Predicted normal will be
determined using National Health and Nutrition Examination Survey (NHANES) III
standard values for Caucasians, African Americans and Mexican-Americans with
adjustments to predicted values made for Asian American patients.
4. A measured post-bronchodilator (albuterol 360 mcg) FEV1/forced vital capacity (FVC)
<0.70 at the SV.
5. A minimum body weight of 40 kg. (Note: For patients participating in the
pharmacokinetic [PK] sub study a minimum body weight of 50 kg is required.)
6. If female, is currently not pregnant, breast feeding, or attempting to become pregnant
(for 4 weeks before the SV and throughout the duration of the study), and is of
non-childbearing potential, defined as:
- =1 year post-menopausal (6 months of spontaneous amenorrhea is permitted,
provided there is a local record of serum follicle stimulating hormone >40 mIU/mL
and this is source documented) or
- Surgically sterile (bilateral tubal ligation, bilateral oophorectomy,
salpingectomy, or hysterectomy)
Or is of childbearing potential, has a negative serum pregnancy test, and is willing
to commit to using a consistent and acceptable method of birth control, as defined
below, for the duration of the study:
- Systemic contraception used for =1 month prior to screening, including birth
control pills, transdermal patch, vaginal ring, implants, or injectables or
- Double barrier methods (spermicide with any of the following: condoms, cervical
cap, diaphragm, and vaginal contraceptive film) or
- Intrauterine device (IUD) with a low failure rate defined as <1% per year (use of
copper IUDs is not acceptable) Or is of childbearing potential and is not
sexually active, has a negative serum pregnancy test, and, in the event the
patient becomes sexually active, is willing to commit to using a consistent and
acceptable method of birth control, as defined above, for the duration of the
study. At the discretion of the investigator, total abstinence is acceptable in
cases where the age, career (eg, priest), lifestyle, and/or sexual orientation of
the patient ensures compliance.
7. Current or ex-smoker with =10 pack-year smoking history (number of cigarette packs
smoked per day multiplied by the number of years smoked; eg, 2 packs/day for 3 years
equals a 6 pack-year history).
8. Patient is free of any other medical conditions or concomitant treatment that could
interfere with study conduct, influence the interpretation of study
observations/results, or put the patient at increased risk during the study.
9. Able to perform technically acceptable and reproducible spirometry per American
Thoracic Society/European Respiratory Society (ATS/ERS) 2005 guidelines and study
guidelines, as defined in the protocol and study reference manual; this includes able
to tolerate withdrawal of applicable medications during required spirometry
assessments.
10. Able to perform acceptable peak expiratory flow measurements.
11. Able to maintain records (patient daily diary) during the study period as required by
the protocol.
12. Able to demonstrate the proper inhalation techniques required for correct use of all
delivery devices (BAI and dry powder inhaler [DPI]) required in the study.
13. Capable of understanding the requirements, risks, and benefits of study participation,
and, as judged by the investigator, capable of giving informed consent and being
compliant with all study requirements.
Exclusion Criteria:
Chronic Obstructive Pulmonary Disease
1. Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for
in vitro fertilization during the study period or for 30 days following the patient's
last study related visit (for eligible patients only, if applicable).
2. Current evidence of a clinically significant or uncontrolled disease including, but
not limited to: cardiovascular (eg, uncontrolled hypertension, congestive heart
failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary
heart disease), hepatic, renal, hematological, neuropsychological, endocrine (eg,
uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison's disease,
Cushing's syndrome), gastrointestinal (eg, poorly controlled peptic ulcer,
gastroesophageal reflux disease), or pulmonary (other than COPD such as asthma,
sarcoidosis, non cystic fibrosis bronchiectasis, cystic fibrosis, bronchopulmonary
dysplasia or a diagnosis of alpha 1 antitrypsin deficiency). Significant is defined as
any disease that, in the opinion of the investigator, would put the safety of the
patient at risk through participation, or which could affect the endpoint analysis if
the disease/condition worsened during the study.
3. History of and/or current diagnosis of asthma.
4. History of a life-threatening COPD exacerbation - defined for this protocol as a COPD
episode that required intubation or was associated with respiratory arrest.
5. Thoracotomy with pulmonary resection.
6. Current congestive heart failure, history or current evidence of myocardial infarction
(within 1 year of the SV), or current history of active ischemic heart disease
(exertional or intermittent angina).
7. History or current evidence of clinically significant cardiac arrhythmia or
abnormality, including a diagnosis on screening ECG. Findings that are always
considered clinically significant and will exclude the patient from study
participation include, but are not limited to, the following:
- ventricular rate <45 beats per minute (bpm) or >100 bpm
- PR interval >240 msec
- evidence of 2nd- or 3rd-degree atrioventricular block (excluding MobitzI)
- evidence of supraventricular or ventricular ectopy or arrhythmias
- corrected QT interval (QTc) (Bazett's or Fridericia's method) >500 msec
- nonspecific intraventricular conduction delay >120 msec
- ST-T wave abnormalities (excluding nonspecific ST-T wave abnormalities)
indicative of acute ischemia/infarction
- right or left complete bundle branch block
- artificial pacemaker
8. The patient has a medical condition that may potentially be aggravated by an
anticholinergic drug such as tiotropium, eg:
- The patient has a history or presence of glaucoma (particularly angle-closure
glaucoma)
- The patient has symptomatic prostatic hyperplasia.
- The patient has a known history or any current evidence of renal impairment or
urinary retention (eg, bladder outlet obstruction). This includes abnormal renal
function test results at screening.
9. History of malignancy (excluding treated non-melanoma skin cancers) within the past 5
years, regardless of the clinical significance or current stability of the disease.
10. History of silent (or active) infections, including positive tests for human
immunodeficiency virus (HIV) 1, HIV2, hepatitis B, hepatitis C, or tuberculosis.
11. Occurrence of any upper or lower respiratory infection, including but not limited to
the common cold and flu, sinusitis, tonsillitis, pneumonia, bronchitis, or an ear
infection (including otitis media and externa) which is not resolved by 4 weeks or
more prior to the SV/informed consent.
12. Occurrence of a COPD exacerbation which is not resolved by 4 weeks or more prior to
the SV/informed consent.
• Note: An exacerbation of COPD is defined as any worsening of the patient's baseline
COPD symptoms requiring any treatment beyond study medication, rescue albuterol or the
patient's regular maintenance treatment. This includes requiring the use of systemic
corticosteroids, antibiotics and/or emergency room visit or hospitalization.
13. Patients who require regular use of daytime oxygen therapy.
14. Patients who have started or stopped an exercise rehabilitation program within 4 weeks
of the SV.
15. Known or suspected hypersensitivity or idiosyncratic reaction to tiotropium, or to any
ingredients used in the study medication formulations.
16. Severe allergy to milk protein.
17. Significant adverse drug reactions, including allergy or hypersensitivity reactions,
to atropine or any anticholinergic substance related pharmacologically to atropine
(eg, ipratropium or oxitropium).
18. Use of any prohibited concomitant medications within the required (per protocol)
washout periods prior to the SV.
19. Treatment with orally administered (excluding orally inhaled) ß-adrenergic agonists
(ie, oral albuterol).
20. Recent initiation of treatment or dose titration with ß-adrenergic receptor
antagonists (eg, non-selective ß-receptor blocking agents such as ß-blocking
anti-hypertensive products) administered by any route. Permitted exceptions are: (1)
Patients treated on a stable dose of non-selective ß-receptor blocking agents for 3
months prior to SV or longer may be considered for enrollment if expected to maintain
the same dose throughout the study and (2) Patients on a stable dose of
cardioselective ß1 adrenergic receptor antagonists (eg, atenolol, metaprolol,
bisoprolol) for at least 1 week prior to the SV are permitted if expected to maintain
the same dose throughout the study.
21. Treatment with drugs commonly recognized to prolong the QTc interval (eg, quinolones,
amiodarone, disopyramide, quinidine, sotalol, chlorpromazine, haloperidol,
ketoconazole, terfenadine, cisapride, and terodiline).
22. Treatment with strong cytochrome P450 (CYP) 2D6 or CYP3A4 inducers or inhibitors (eg,
quinidine, ketoconazole and gestodene) within 30 days prior to the SV.
23. For patients using an inhaled corticosteroid, initiation or change in the dose of
inhaled corticosteroids within the last 30 days prior to the SV, and/or the patient is
not expected to maintain a stable dose of inhaled corticosteroids during the course of
the study.
24. For patients using maintenance oral corticosteroids for COPD, the average daily dose
should not be greater than10 mg of prednisone equivalent per day and the dose should
have been stable over the 6 weeks prior to the SV. The patient's prior oral
corticosteroid (OCS) dose should be maintained without change during the study. (Note
that oral steroid bursts completed 6 weeks or more prior to screening are acceptable.)
25. Exposure to any investigational drug within 30 days or 6 half-lives (whichever is
longer) prior to the SV.
26. Has a history of alcohol and/or substance abuse within the past 5 years. aa.
Vulnerable patients (eg, persons kept in detention). bb. The patient is an employee of
the study site or has an immediate family member or household member involved with the
conduct of the study (including participation in the study).
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