Informed consent: Subjects must give their signed and dated written informed consent to participate. (2)
CL Item
Gender: Male or female subjects. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is postmenopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than l year with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. However in questionable cases, a blood sample with FSH > 40 MIU/ml and stradiol <40pg/ml (< l40pmol/L) is confirmatory. OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study screening to follow-up contact): Complete abstinence from intercourse from screening until the follow-up contact; or Male partner is sterile (vasectomy with documentation of azoospermia) prior to female su~ject entry into the study, and this male partner is the sole partner for that subject; or Implants of levonorgestral inserted for at least I month prior to the study medication administration but not beyond the third successive year following insertion; or Injectable progestogen administered for at least I month prior to study medication administration; or Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spennicidal agent (foam/gel/film/cream/suppository); or An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest (3)
CL Item
Age: >=40 years of age at Screening (Visit 1) (4)
CL Item
COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society (5)
CL Item
Tobacco use: Subjects with a current or prior history of >= l O pack-years of cigarette smoking at screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit I. Number of pack years is (number of cigarettes per day /20) x number of years smoked (6)
CL Item
Severity of Disease: Subject with a measured post-albuterol/salbutamol FEY 1/FVC ratio of <=0.70 at Screening (Visit l) Subjects with a measured post-albuterol/salbutamol FEY 1 <=70% of predicted normal values calculated using NHANES [][ reference equations [Hankinson, 1999) at Screening (Visit l) Post-bronchodilator spirometry will be performed approximately l 0- l 5 minutes after the subject has selfadministered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via an MDI with a valved-holding chamber. The FEY 1/FVC ratio and FEY I percent predicted values will be calculated. (7)
CL Item
History of Exacerbations: A documented history (e.g.,medical record verification) of at least one COPD exacerbation in the 12 months prior to Visit l that required either oral corticosteroids, antibiotics and/or hospitalization. Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volwne, or sputum purulence (color). Subject verbal reports are llil1 acceptable. (8)
Risk Factors for Pneumonia: immune suppression (HIV, Lupus, etc) or other risk for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's, Myaesthenia Gravis, etc). (7)
CL Item
A moderate and severe COPD exacerbation that has not resolved at least 14 days prior to Visit l and at least 30 days following the last dose of oral corticosteroids (if applicable). (8)
CL Item
Pneumonia and/or moderate and severe COPD exacerbation at Visit 1 (9)
CL Item
Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular (i .e. pacemaker), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. (10)
CL Item
Peptic Ulcer disease: Su~jects with clinically significant peptic ulcer disease that is uncontrolled. (11)
CL Item
Hypertension: Subjects with clinically significant hypertension that is uncontrolled (12)
CL Item
Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis. (13)
CL Item
Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g. betaagonists, corticosteroid) or components of the inhalation powder ( .g. lactose, magnesium stearate). In addition, patients with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation will also be excluded. (14)
CL Item
Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years (15)
CL Item
Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol or their ipratropium for the 4-hour period required prior to spirometry testing at each study visit. (16)
CL Item
Additional medication: Use of the following medications within the following time intervals prior to Visit l or during the study (17)
CL Item
Oxygen therapy: Subjects receiving treatment with longterm oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e. <= 12 hours per day) is not exclusionary. (18)
CL Item
Sleep apnea: Subjects with clinically significant sleep apnea who require the use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPY) device. (19)
CL Item
Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded. (20)
CL Item
Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits. (21)
CL Item
Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. (1)
CL Item
Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD) (2)
CL Item
al-antitrypsin deficiency: Subjects with a-1 antitrypsin deficiency as the underlying cause of COPD (3)
CL Item
Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases (4)
CL Item
Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (5)
CL Item
Chest X-ray: Chest X-ray (posteroanterior with lateral) reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD or another condition that would hinder the ability to detect an infiltrate on CXR (e.g. cardiomegaly, pleural effusion or scarring etc). All subjects will have a chest xray at Screening Visit 1 (or historical radiograph obtained within 2 weeks prior to screening) that will be over-read by a central vendor. (6)
CL Item
Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study (22)
CL Item
Prior use of study medication/other iuvestigational drugs: Subjects who have previously been randomized in the Phase lla (HZC 111348) study or Phase Ill (i.e. HZCJ 12206, HZCl 12207, HZC\02970, HZCI 10946) studies. Subjects who have received an investigational drug within 30 days of entry into this study (Screening), or within 5 drug half-lives of the investigational drug, whichever is longer (23)
CL Item
Affiliation with investigator site: Study investigators, subinvestigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study. (24)
Subject Status
Item
Was the subject a screen failure at the Screening visit?
boolean
C2348568 (UMLS CUI [1,1]) C1710476 (UMLS CUI [1,2])
Screen failure date
Item
Screen failure date
date
C1710476 (UMLS CUI [1,1]) C0011008 (UMLS CUI [1,2])
Number of exacerbations without oral/systemic corticosteroids and/or antibiotics
Item
Number of exacerbations in the last J 2 months that were managed without oral/systemic corticosteroids and/or antibiotics (not involving hospitalisation)
integer
C0740304 (UMLS CUI [1,1]) C0449788 (UMLS CUI [1,2]) C0087111 (UMLS CUI [2])
Number of exacerbations that required oral/systemic corticosteroids and/or antibiotics
Item
Number of exacerbations in the last 12 months that required oral/systemic corticosteroids and/or antibiotics (not involving hospitalisation)
integer
C0740304 (UMLS CUI [1,1]) C0449788 (UMLS CUI [1,2]) C0087111 (UMLS CUI [2])
Number of exacerbations that required hospitalisation
Item
Number of exacerbations in the last 12 months that required hospitalisation
integer
C0740304 (UMLS CUI [1,1]) C0449788 (UMLS CUI [1,2]) C0019993 (UMLS CUI [2])