Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GSK573719/GW642444 Inhalation Powder and the Individual Components Delivered Once-Daily Via a Novel Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease
Brief Summary: This is a phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GSK573719/GW642444 Inhalation Powder, GSK573719 Inhalation Powder, GW642444 Inhalation Powder and Placebo when administered once-daily via a Novel Dry Powder Inhaler over a 24-week treatment period in subjects with COPD. Subjects who meet eligibility criteria at Screening (Visit 1) will complete a 7 to14 day run-in period followed by a randomization visit (Visit 2) then a 24-week treatment period. There will be a total of 9 clinic study visits. A follow-up phone contact for adverse event assessment will be conducted approximately one week after the last study visit (Visit 9 or Early Withdrawal). The total duration of subject participation in the study will be approximately 27 weeks. A subset of subjects at selected sites will also perform 24-hour serial spirometry and Holter monitoring during the study and provide serial blood samples for pharmacokinetic analysis. Sparse pharmacokinetic sampling for population pharmacokinetic analyses will be obtained from non-subset subjects. The primary measure of efficacy is clinic visit trough (pre-bronchodilator and pre-dose) FEV1 on Treatment Day 169. Safety will be assessed by adverse events, 12-lead ECGs, vital signs, clinical laboratory tests, and 24 hour Holter monitoring (subset only).


Options:
A: Inclusion Criteria:

* Adult male or non-pregnant, non-lactating female aged ≥40.
* Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years
* Patients with a clinical diagnosis of COPD according to GOLD guidelines 2013, with a post-bronchodilator FEV1 \<80%, and FEV1/FVC \< 70% at Screening Visits
* Symptomatic patients with a COPD assessment test (CAT) ≥10 at Screening and Randomisation Visits
* Patient must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Screening Visits
* Patients eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained

Exclusion Criteria:

* History or current diagnosis of asthma
* Development of a respiratory tract infection or COPD exacerbation within 6 weeks (or 3 months if hospitalisation was required) before the Screening Visit or during the run-in period
* Clinically significant respiratory conditions
* Type I or uncontrolled Type II diabetes, uncontrolled hypo- or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension
* Patients who, in the investigator's opinion, may need to start a pulmonary rehabilitation programme during the study and/or patients who started/finished it within 3 months prior to Screening Visit
* Use of long-term oxygen therapy (≥15 hours/day)
* Patients treated on daily basis with triple therapy (LABA+LAMA+ICS) within 4 weeks prior to the Screening Visit
* Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers
* Clinically significant cardiovascular conditions
* Patient with clinically relevant abnormalities in the results of the clinical laboratory tests, ECG parameters or in the physical examination at the Screening Visit
* Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm)
* Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy
* Patient with known non-controlled history of infection with human immunodeficiency virus (HIV) and/or active hepatitis
* 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
* Patient with any other serious or uncontrolled physical or mental dysfunction
* Patient with a history (within 2 years prior to Screening Visit) of drug and/or alcohol abuse that may prevent study compliance based on investigator judgment
* Patient unlikely to be cooperative or that can't comply with the study procedures
* Patient treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening Visit
* Patient who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required stabilization periods for prohibited medication
* Any other conditions that, in the investigator's opinion, might indicate the patient to be unsuitable for the study
B: Inclusion Criteria:

* Type of subject: Outpatient
* A signed and dated written informed consent prior to study participation
* Male or female subjects, 40 years of age or older at Visit 1
* 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 post-menopausal or surgically sterile). - A female is eligible to enter and participate in the study if she is of: Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods as listed in the protocol used consistently and correctly.
* An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: Chronic obstructive pulmonary disease is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences
* Smoking history: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years (number of pack years = \[number of cigarettes per day/20\] x number of years smoked \[e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years\]). Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack year history
* Severity of disease: A pre and post-salbutamol FEV1/Forced Vital Capacity (FVC) ratio of \<0.70 and a post-salbutamol FEV1 of \>=30% and \<=70% of predicted normal values calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations at Visit 1
* Dyspnea: A score of \>=2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1

Exclusion Criteria:

* Women who are pregnant or lactating or are planning on becoming pregnant during the study
* A current diagnosis of asthma
* Other Respiratory Disorders: Known α-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject, who, in the opinion of the investigator, has any other significant respiratory condition in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Inactive tuberculosis in more than one lobe is exclusionary. Allergic rhinitis is not exclusionary
* Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for \<5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). 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
* Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic
* Hospitalization for pneumonia within 12 weeks prior to Visit 1
* History of COPD Exacerbation: A documented history of at least one COPD exacerbation in the 12 months prior to Visit 1 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 volume, or sputum purulence
* Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1)
* 12-Lead Electrocardiogram (ECG): An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility.
* Medication Prior to Spirometry: Unable to withhold salbutamol for the 4 hour period required prior to spirometry testing at each study visit
* Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids - 12 weeks, Systemic, oral or parenteral corticosteroids - 6 weeks, Antibiotics (for lower respiratory tract infection) - 6 weeks, Cytochrome P450 3A4 strong inhibitors - 6 weeks, Herbal medications potentially containing oral or systemic steroids - 6 weeks, Inhaled corticosteroids (ICS) - 30 days, Long-acting beta2-agonist (LABA)/ICS combination products - 30 days, Phosphodiesterase 4 (PDE4) inhibitors (e.g., roflumilast) - 14 days, Inhaled long-acting anticholinergics - 7 days, Theophyllines - 48 hours, Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) - 48 hours, Oral beta2-agonists Long-acting-48 hours/Short-acting - 12 hours, Inhaled long acting beta2-agonists (LABA, e.g., salmeterol, formoterol, indacaterol) - 48 hours, Inhaled sodium cromoglycate or nedocromil sodium - 24 hours, Inhaled short acting beta2-agonists - 4 hours, Inhaled short-acting anticholinergics - 4 hours, Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products - 4 hours, Any other investigational medication - 30 days or within 5 drug half-lives (whichever is longer)
* Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., \<=12 hours per day) is not exclusionary
* Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., salbutamol) via nebulized therapy.
* Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded
* Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1
* Affiliation with Investigator Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator
* Inability to read: A subject will not be eligible for the study if in the opinion of the investigator the subject cannot read
C: Inclusion Criteria:

* Smoking history of at least 10 pack years
* Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) (moderate-to-severe as classified by the Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] Guidelines, 2009)
* Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) \>40% and \< 80% of the predicted normal value and post-bronchodilator FEV1/Forced Vital Capacity (FVC) \<70%

Exclusion Criteria:

* Patients who have had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the last year.
* Patients requiring long term oxygen therapy on a daily basis for chronic hypoxemia.
* Patients who have had a respiratory tract infection within 4 weeks prior to Visit 1.
* Patients with concomitant pulmonary disease
* Patients with a history of asthma
* Any patient with lung cancer or a history of lung cancer (within last 5 years)
* Patients with a history of certain cardiovascular co-morbid conditions
D: Inclusion Criteria:

* Diagnosis of COPD
* 10 pack-year or greater history of cigarette smoking
* Post-bronchodilator FEV1/FVC of \<0.7
* Predicted FEV1 of 70% of normal or less
* Modified Medical Research Council (mMRC) dyspnea score of 2 or greater

Exclusion Criteria:

* Women who are pregnant, lactating, or planning to become pregnant
* Respiratory disorders other than COPD, including a current diagnosis of asthma
* Clinically significant non-respiratory diseases or abnormalities that are not adequately controlled
* Significant allergy or hypersensitivity to anticholinergics, beta2-agonists, or the excipients of magnesium stereate or lactose used in the inhaler delivery device
* Hospitalization for COPD or pneumonia within 12 weeks prior to screening
* Lung volume reduction surgery within 12 weeks prior to screening
* Abnormal and clinically significant ECG findings at screening
* Clinically significant laboratory findings at screening
* Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong cytochrome P450 3A4 inhibitors, high dose inhaled steroids (\>1000mcg fluticasone propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short- and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or nedocromil sodium, or investigational medicines for defined time periods prior to the screening visit
* Use of long-term oxygen therapy (12 hours or greater per day)
* Regular use of nebulized treatment with short-acting bronchodilators
* Participation in the acute phase of a pulmonary rehabilitation program
* A know or suspected history of alcohol or drug abuse
* Affiliation with the investigational site
* Previous use of GSK573719 or GW642444 alone or in combination, including the combination of fluticasone furoate and GW642444

Answer: D