Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double-blind, Placebo-controlled, Dose Ascending, 2-cohort, Parallel Group Study to Examine the Safety, Tolerability and Pharmacokinetics of Once-daily Inhaled Doses of GSK573719 Formulated With the Excipient Magnesium Stearatein COPD Subjects for 7 Days
Brief Summary: The study drug which is an inhaled bronchodilator (lung airway relaxant)has been given to both healthy volunteers and to COPD patients before. This study will assess a new formulation of GSK573719. Many drugs are known to deteriorate over time. To make the study medicine less likely to deteriorate in its container, it is mixed with an inactive substance that helps to to maintain the quality of the study medicine. Previous studies have looked at GSK573719 with another inactive substance called Cellobiose Octaacetate (COA). This study will be looking at a new formulation of GSK573719 using Magnesium Stearate (MgSt) as the inactive substance. MgSt itself is not a medicine but is approved as a food ingredient and has also has been approved to be used in a number of marketed medical inhalers. The purpose of this study is to assess the safety and tolerability of compound GSK573719 with Magnesium Stearate for once-daily treatment of COPD(Chronic Obstructive Pulmonary Disease). This drug will be given to 2 groups of 12 people for 7 days. Group 1 will receive 250mcg or placebo and group 2 will receive 1000mcg or placebo. Group 2 will not be dosed until at least 6 people have completed dosing in group 1 without any significant safety concerns. The following safety measures will be assessed including: ECGs, heart rate, blood pressure, blood samples for safety labs, lung function and 24 hour monitoring of the heart. We will also take blood and urine samples to measure medication levels in the body.

GlaxoSmithKline will be funding the research and it will be recruiting at Synexus in 7 of their centres in the UK.


Options:
A: Inclusion Criteria:

* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Japanese ethnic origin defined as having been born in Japan with four ethnic Japanese grandparents and able to speak Japanese.
* Male or female between 20 and 65 years of age inclusive, at the time of signing the informed consent.
* A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\].
* Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until completion of the follow-up visit.
* Body weight \> or equal to 45 kg and BMI within the range 18-28 kg/m2 inclusive.
* AST, ALT, alkaline phosphatase and bilirubin \< or equal to 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Average QTcB or QTcF \< 450 msec; or QTc \< 480 msec in subjects with Bundle Branch Block taken from triplicate assessments at screening.
* No clinically active and relevant abnormality on 12-lead ECG or 24h Holter ECG at screening.
* Normal spirometry (FEV1 ≥ 80% of predicted, FEV1/FVC ≥ 70%).
* Non-smokers (never smoked or not smoking for \>6 months with \<10 pack years history (Pack years = (cigarettes per day smoked/20) x number of years smoked))
* A signed and dated written informed consent is obtained from the subject
* The subject is capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the consent form
* Available to complete the study

Exclusion Criteria:

* Any clinically important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or ECG (12-lead). A 24hr Holter monitoring recording outside normal limits.
* A history of breathing problems (i.e. history of asthmatic symptomatology, unless asthma in childhood that has now resolved and no longer requires maintenance therapy which should not be an exclusion).
* A mean QTc(B) value at screening \>450msec, or an ECG that is not suitable for QT measurements (e.g. LBBB or poorly defined termination of the T wave).
* A history of elevated resting blood pressure or a mean blood pressure higher than 140/90 mmHg at screening.
* A mean heart rate outside the range 40-90 bpm at screening.
* The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates and benzodiazepines. The detection of drugs with a legitimate medical use would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
* A positive test for HIV antibody.
* History of regular alcohol consumption within 3months of the study defined as:

an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). Under Australian guidelines, one standard unit defined as 10g of ethanol, is equivalent to 250ml of full-strength beer, 470 ml of light-strength beer, 100 ml of wine and 30ml of spirits.

* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* Unwillingness or inability to follow the procedures outlined in the protocol. 17. Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products prior to screening.
* The subject is unable to use the novel dry powder inhaler correctly.
* The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium, atropine and any of its derivatives.
* Any adverse reaction including immediate or delayed hypersensitivity to any β2 agonist or sympathomimetic drug.
* The subject has a known allergy or hypersensitivity to milk protein or the excipients lactose monohydrate and MgSt.
* Subject is kept under regulatory of judicial order in an institution.
* Any female of childbearing potential.
* Subject is mentally or legally incapacitated.
B: Inclusion Criteria:

* Type of subject: Outpatient.
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Age: Subjects 40 years of age or older at Visit 1.
* 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 post-menopausal 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 1 year with an appropriate clinical profile, e.g. age appropriate, \>45 years, in the absence of hormone replacement therapy.

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):

* Abstinence
* Oral Contraceptive, either combined or progestogen alone
* Injectable progestogen
* Implants of levonorgestrel
* Estrogenic vaginal ring
* Percutaneous contraceptive patches
* Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label
* Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records.
* Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

  * Bronchodilator Treatment: Subjects must have been prescribed tiotropium either via the HandiHaler device or Respimat for at least 3 months prior to screening (Visit 1).
  * COPD Diagnosis: A diagnosis of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[Celli, 2004\].
  * 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.

Note: Pipe and/or cigar use cannot be used to calculate pack-year history

* Severity of Disease: A pre and post-albuterol/salbutamol FEV₁/FVC ratio of \<0.70 and post-albuterol/salbutamol FEV₁ of ≤70% and ≥50% predicted normal values calculated using reference equations at Visit 1 \[Quanjer, 2012\].
* Dyspnoea: A score of ≥1 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Visit 1.

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
* Asthma: 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 conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. 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.
* Exacerbations: Has had more than 1 moderate or severe COPD exacerbation in the past 12 months. Subjects with a moderate exacerbation within 6 weeks or severe exacerbations within 10 weeks prior to Visit 1 are excluded from study.

A moderate COPD exacerbation is defined as worsening symptoms of COPD that require treatment with oral/systemic corticosteroids and/or antibiotics. A severe exacerbation is defined as worsening symptoms of COPD that require in-patient hospitalization.

* Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, 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.
* Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
* 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead ECG which causes the underlying rhythm and ECG to be obscured. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. Specific ECG findings that preclude subject eligibility are listed in Appendix 3. The study investigator will determine the medical significance of any ECG abnormalities not listed in Appendix 3.

Appendix 3:

* Sinus tachycardia ≥120 bpm. \*Note: sinus tachycardia ≥120bpm should be confirmed by two additional readings at least 5 minutes apart.
* Sinus bradycardia \<45bpm. \*Note: Sinus bradycardia \<45bpm should be confirmed by two additional readings at least 5 minutes apart.
* Multifocal atrial tachycardia.
* Supraventricular tachycardia (\>100bpm).
* Atrial fibrillation with rapid ventricular response (rate \>120bpm).
* Atrial flutter with rapid ventricular response (rate \>120bpm).
* Ventricular tachycardias (non sustained, sustained, polymorphic, or monomorphic).
* Ventricular flutter.
* Ventricular fibrillation.
* Torsades de Pointes.
* Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block.
* AV dissociation.
* 2:1 AV block.
* Trifascicular Block.
* For subjects with QRS duration \<120 ms: QTc(F) ≥450msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave).
* For subjects with QRS duration≥120: QTc(F) ≥480msec or an ECG that is unsuitable for QT measurements (e.g., poor defined termination of the T wave).
* Myocardial infarction (acute or recent) \* Note: Evidence of an old (resolved) myocardial infarction is not exclusionary

  * Medication Prior to Spirometry: Unable to withhold albuterol/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.

Use as maintenance treatment in the 3 months prior to Visit 1 is not permitted. Maintenance treatment is defined as use for ≥ 14 consecutive days (at any time in the 3 months prior to Visit 1).

* Inhaled Corticosteroid (ICS)/Inhaled long acting beta2-agonists combinations
* Phosphodiesterase 4 (PDE4) inhibitors
* LABA
* Other Long acting muscarinic antagonists (does not include tiotropium)
* LAMA/LABA combinations
* Theophyllines
* Oral beta2-agonists (long-acting and short-acting) Use within 12 weeks is not permitted.
* Depot corticosteroids Use within 6 weeks is not permitted.
* Systemic, oral or parenteral corticosteroids
* Antibiotics (for lower respiratory tract infection)
* Cytochrome P450 3A4 strong inhibitors Use within 4 hours is not permitted.
* Inhaled short acting beta2-agonists, short-acting anticholinergics, and short-acting anticholinergic/short- acting beta2-agonist combination products (Use of study provided prn albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing. Subjects who are taking short acting bronchodilators (beta-agonists or muscarinic antagonists) as their only form of bronchodilation at screening may NOT be recruited into the study).

Any other investigational medication use within 30 days or within 5 drug half-lives (whichever is longer) is not permitted

Note: if a LABA, LAMA (non-tiotropium), ICS/LABA, LAMA/LABA, theophylline, oral beta-agonist,or PDE4 inhibitor was taken on a non-maintenance basis (i.e., \< 14 consecutive days over the 3 months prior to screening) the following minimum washouts must be observed prior to visit 1: twice-daily LABAs and ICS/LABAs = 48 hours; once-daily LABAs and ICS/LABAs= 14 days; LAMAs (excluding tiotropium) = 7 days; once-daily LAMA/LABA = 14 days, twice-daily LAMA/LABA = 7days; theophyllines = 48 hours; oral beta2 agonists = 48 hours; PDE4 inhibitor = 14 days.

* 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., albuterol/salbutamol) via nebulized therapy.
* Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 12 weeks prior to Visit 1 or are in the maintenance phase of a pulmonary rehabilitation program are 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: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
* Inability to Read: In the opinion of the investigator, any subject who is unable to read and/or write would not be able to complete a questionnaire.
C: Inclusion Criteria:

* Type of subject: Outpatient
* Informed Consent: A signed and dated written informed consent prior to study participation
* Age: Subjects 40 years of age or older at Visit 1
* 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 post-menopausal or surgically sterile); or Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods listed in the protocol used consistently and correctly
* Diagnosis: 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 smoking cannot be used to calculate pack year history.
* Severity of disease: A pre and post-salbutamol FEV1/FVC ratio of \<0.70 and a post-salbutamol FEV1 of \>=30% and \<=70% of predicted normal values calculated using 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:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study
* Asthma: A current diagnosis of asthma
* Other Respiratory Disorders: Known alpha-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: 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 ECG: An abnormal and significant electrocardiogram (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.
D: Inclusion Criteria:

* Male or female between 40 and 75 years of age
* A female subject is eligible to participate if she is of:

  * Non childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy, bilateral salpingectomy or bilateral oophorectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL and estradiol \< 40 pg/ml (\<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
* Male subjects must agree to use one of the listed contraception methods. This criterion must be followed from the time of the first dose of study medication until 90 days post-last dose.
* Subject diagnosed with COPD, as defined by the GOLD guidelines.
* BMI within the range 18 - 34 kg/m2 (inclusive).
* Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (Pack years = (cigarettes per day smoked/20) x number of years smoked)).
* Average QTcB or QTcF ≤ 450 msec taken from triplicate assessments at screening; or QTc ≤ 480 msec in subjects with Bundle Branch Block.
* Subject has a post-bronchodilator (400 μg salbutamol) FEV1 of ≥ 35% to ≤ 80% of predicted normal.
* Subject has FEV1/FVC \< 0.7 post-bronchodilator (400 μg salbutamol).
* Subjects have a 24hour holter recording that is within normal limits for the individual and does not demonstrate any clinically important abnormality that, in the opinion of the investigator, would make the subject unsuitable for participation in the study.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Subject is available to complete all study measurements and procedures.

Exclusion Criteria:

* Subjects who have a past or present disease, which as judged by the Investigator, may affect subject safety or influence the outcome of the study.
* The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine and opiates.

The detection of drugs taken for a legitimate medical purpose would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.

* Female subject has a positive pregnancy test.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
* A positive test for HIV antibody (if tested, according to local SOP's).
* History of high alcohol consumption within 1 month of the study defined as:

  * an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* History of sensitivity to any of the study medications, or components thereof (including allergy to milk protein/lactose) or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
* Subject has donated a unit (400 mL) of blood within 60 days of screening or, intends to donate during the study.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* The subject is unable to use the novel dry powder inhaler correctly.
* The subject requires treatment for prostate hypertrophy.
* The subject has a history of narrow angle glaucoma.

Respiratory criteria

* Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the Investigator, compromise the safety of the subject or affect the interpretation of the results.
* Subject has poorly controlled COPD, defined as the occurrence of any of the following:

  * Either: acute worsening of COPD that is managed by the subject at home requiring treatment with corticosteroids in the 2 weeks prior to the screening visit.
  * Or: more than two exacerbations in the previous 4 months prior to the screening visit that required a course of oral corticosteroids or, for which the subject was hospitalised.
* Subject has had a respiratory tract infection in the 2 weeks prior to first dose.

Cardiovascular criteria

* Current congestive heart failure (greater than NYHA II) and myocardial infarction (within 9 months of the screening date).
* A history of clinically significant arrhythmia or clinically important 24 h Holter findings that, in the opinion of the Investigator, would cause a safety concern for entry into the study.
* A mean QTc(B) value at screening \>450msec, or an ECG that is not suitable for QT measurements (e.g. LBBB or poorly defined termination of the T wave).
* Third degree heart block or pacemaker.
* Risk factors for torsades des pointes (heart failure NYHA II-IV, familial long QT syndrome).
* Elevated resting blood pressure or a mean blood pressure equal to or higher than 150/90 mmHg at screening. A history of and treatment for hypertension is acceptable provided control has been achieved for \> 2 months prior to screening.
* A mean heart rate outside the range 50-100 bpm at screening.

Concurrent medication criteria

* Subject requires treatment with nebulised beta-2 agonist or nebulised anticholinergics.
* Subject has received oral or parenteral corticosteroids within 2 weeks of screening.
* Subject is unable to abstain from long-acting bronchodilators from 48 hours prior to the screening and treatment periods (i.e. the last assessment in the dosing period).

(Note, subjects may resume use of their usual medication in between screening and the treatment period if the restrictions in Section 9 Concomitant Medications and Non-Drug Therapies are followed and provided the long acting bronchodilator component is stopped again 48h or more prior to dosing).

* Subject is receiving co-medication with drugs which are commonly recognised to prolong the QTc interval (e.g. quinolones, amiodorane, disopyramide, quinidine, sotalol, chlorpromazine, haloperidol, ketoconazole, terfenadine, cisapride and terodiline).
* Subject requires regular treatment with oral corticosteroids (prednisolone or equivalent).
* Subject is receiving treatment with beta-blockers, except eye drops.
* Subject is receiving treatment with long-term or short-term oxygen therapy, NIPPV or requires nocturnal positive pressure for sleep apnea.

Answer: D