Please select the eligibility criteria that correspond to the clinical trial below.
Title: Study DB2116961, A Multicentre, Randomised, Blinded, Parallel Group Study to Compare UMEC/VI (Umeclidinium/Vilanterol) in a Fixed Dose Combination With Indacaterol Plus Tiotropium in Symptomatic Subjects With Moderate to Very Severe COPD
Brief Summary: This is a Phase IIIb multicentre, randomised, blinded, triple dummy, parallel group study to evaluate the efficacy and safety of UMEC/VI inhalation powder (62.5/25 microgram \[mcg\] Once daily \[QD\]) when administered via ELLIPTA® Dry Powder Inhaler (DPI) compared to indacaterol plus tiotropium (150 mcg/18 mcg respectively QD) administered via individual inhalers over a treatment period of 12 weeks in participants with moderate to very severe Chronic Obstructive Pulmonary Disease (COPD). The purpose of this study is to demonstrate that UMEC/VI (delivered via ELLIPTA DPI), when used in symptomatic moderate to very severe COPD participants, is non-inferior to the combination of indacaterol (delivered via BREEZHALER® inhaler) plus tiotropium (delivered via HANDIHALER® inhaler) on measures of trough forced expiratory volume in one second (FEV1) after 12 weeks of treatment. Participants who met the eligibility criteria at screening (Visit 1) will complete a 5 to 7 day run in period prior to randomisation at Visit 2. Clinic visits will follow at day 2, week 2, week 4, week 8 and week 12 of treatment, plus week 12 + 1 day (Visits 3 to 8). The total duration of study participation will be approximately 14 weeks. ELLIPTA is a registered trademark of the GSK group of companies. HANDIHALER is a registered trademark of Boehringer Ingelheim Pharma GmbH \& Co. KG. BREEZHALER is a registered trademark of Novartis AG.


Options:
A: Inclusion Criteria:

Safety

* Average Corrected QT Interval using Fridericia's formula (QTcF) \<450 msec at screening.
* Forced Expiratory Volume in 1 second (FEV1) \>=80% predicted and a FEV1/Forced Vital Capacity (FVC) ratio \>=0.7 at screening.
* Alanine transaminase (ALT), alkaline phosphatase and bilirubin \<=1.5x Upper Limit Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

Population

* Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and lung function testing. 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 GSK medical monitor consider the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures and outcome.
* Subjects who are current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit and have a pack history of \<=10 pack years. \[number of pack years = (number of cigarettes per day /20) x number of years smoked\]
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* A female subject is eligible to participate as follows: Non-childbearing potential, females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods and women of childbearing potential should have used one of the contraception methods.
* Body Mass Index (BMI) within the range 18.0-33.0 kg/m2 (inclusive).

Exclusion Criteria:

Safety

* Lactating or pregnant females as determined by positive serum or urine hCG test at screening or Day -1.
* A supine mean heart rate outside the range 40-90 beats per minute (bpm) at screening.

Hepatic Disease

* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or a history of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Concurrent Disease

* History of respiratory disease (i.e. history of asthmatic symptoms) in the last 10 years.
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or a positive test for HIV.

Concurrent Medication

* Unable to refrain from the 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.

Population

* A positive pre-study drug/alcohol screen at screening and Day -1.
* 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), or has had 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 or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Subject is mentally or legally incapacitated.
* The subject is unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and pummelos, exotic citrus fruits, grapefruit hybrids or any fruit juices containing these fruits from 7 days prior to the first dose of study medication and for the duration of the study.
B: Inclusion Criteria:

* Type of subject: Outpatient
* Informed Consent: A signed and dated written informed consent prior to study participation.
* Participants 40 years of age or older at Visit 1.
* Gender: Male or female participants. 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 Standard Operating Procedure (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)
* Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society.
* Smoking History: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
* Severity of Disease: A pre and post-albuterol/salbutamol Forced Expiratory Volume in One Second/ Forced Vital Capacity (FEV1/ FVC) ratio of \<0.70 and a pre and post-albuterol/salbutamol FEV1 of \<=70% predicted normal value at Visit 1, calculated using Quanjer reference equations.
* Dyspnoea: A score of \>= 2 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Visit 1.
* QT interval corrected (QTc) Criteria: QTc \<450 milliseconds (msec) or QTc \<480 msec for patients with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The QTc should be based on single or averaged QTc values of triplicate Electrocardiogram (ECGs) obtained over a brief recording period.
* French participants: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

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 conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Allergy rhinitis is not exclusionary.
* Other Diseases/Abnormalities: Participants 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, 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 or beta 2 agonist.
* Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit 1.
* Lung Resection: Participants 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. Specific ECG findings that preclude subject eligibility will be listed in protocol The study investigator will determine the medical significance of any ECG abnormalities not listed.
* Screening labs: Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1 as determined by the study investigator.
* 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: Depot corticosteroids (12 weeks); Oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract infection) (6 weeks); Cytochrome P450 3A4 strong inhibitors ( 6 weeks); Long Acting Beta-Agonist (LABA)/ inhaled corticosteroids (ICS) combination products (e.g. fluticasone/salmeterol, mometasone, furoate/formoterol fumarate, budesonide/formoterol, fumarate), If LABA/ICS therapy is discontinued completely (30 days); If discontinuing LABA therapy and switching to ICS monotherapy (48 hours for salmeterol or formoterol, 14 days for Olodaterol, Indacaterol or, Vilanterol); Use of ICS at a dose \>1000 mcg/day of fluticasone propionate or equivalent (30 days); Initiation or discontinuation of ICS use (30 days); Inhaled long acting beta2-agonists (LABA): Salmeterol, Formoterol (48 hours), Olodaterol, Indacaterol and Vilanterol (14 days); Long acting muscarinic antagonists (LAMA) (Tiotropium, Aclidinium, Glycopyrronium, Umeclidinium) (7 days); LABA/LAMA combination products (Whichever mono component has the longest washout); Roflumilast (14 days); Oral beta-agonists- Long-acting (48 hours), Short-acting(12 hours); Theophyllines (48 hours); Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Inhaled sodium cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4 hours); Inhaled short-acting anticholinergic (short acting muscarinic antagonist \[SAMA\]) products eg ipratropium (4 hours); Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products (SAMA/Short Acting beta2-agonists \[SABA\]) (4 hours); Any other investigational medication (30 days or within 5 drug half-lives)
* Oxygen: Use of Long Term Oxygen Therapy (LTOT).This is defined as oxygen therapy prescribed for greater than 12 hours per 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. Participants 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: 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 would not be able to complete a questionnaire.
* Participants who are pre-screen or screen failures cannot be re-screened.
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:

* Caucasian male or female subjects aged 40-75 years inclusive. The need to recruit only Caucasian subjects is related to the need to rigorously exclude 2D6 poor metabolisers based on genotype.
* Female subjects must be of non-childbearing potential.
* An established clinical history of COPD (ATS/ERS definition).
* 'Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterised 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.'
* Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).
* Subject has FEV1/FVC \< 0.7 post-bronchodilator (salbutamol) dose.
* Subject has 40 ≥ FEV1 ≤ 80% of predicted normal for height, age and gender after inhalation of salbutamol dose.
* Response to ipratropium bromide.
* Subject is able and has given written informed consent to take part in the study.
* Subject is available to complete all study measurements and procedures.
* Subject's BMI is 18.0 - 32.0 kg/m2.
* Subjects have a 24hr Holter recording that is within normal limits 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

Exclusion Criteria:

* Subjects who have a past or present disease of any organ system, which as judged by the Investigator, may affect the outcome of this study.
* The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cannabis, Cocaine and Opiates. The detection of drugs with a legitimate medical use would not be an exclusion to study participation.
* The subject has a positive pre-study alcohol screen. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
* A suspected history of alcohol abuse within the six months previous to the screening visit.
* The subject has tested positive for hepatitis C antibody, hepatitis B surface antigen or HIV (if determined by local SOP's).
* Subject has received an investigational drug within 30 days of screening.
* The subject is currently taking medication which is known to be a CYP 2D6 inhibitor/substrate.
* The subject has donated a unit (400ml) of blood within 60 days of screening, or, intends to donate during the study.
* The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium bromide, atropine and any of its derivatives or lactose/milk protein.
* Subject is unable to use the DISKUS™/HandiHaler devices correctly.
* Subject has prostatic hypertrophy, bladder outlet obstruction, or narrow angle glaucoma.
* Subjects with a 2D6 poor metaboliser genotype (Caucasian).
* The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet (American Association of Respiratory Care 2001 guidelines for body plethysmography)
* Received antibiotic therapy for either a lower respiratory tract infection or for COPD exacerbation within the 4 weeks prior to Screening.

Respiratory criteria

* Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, allergic rhinitis, or asthma.
* Subject has poorly controlled COPD, defined as either: acute worsening of COPD that is managed by the subject at home by treatment with corticosteroids in the 6 weeks prior to screening visit Or more than two exacerbations in the previous 6 months prior to screening that required a course of oral corticosteroids or antibiotics, or, for which the subject was hospitalised.
* Subject has participated in a Pulmonary Rehabilitation Program within 4 weeks prior to screening visit or will enter a program during the study.
* Subject has had a respiratory tract infection in the 4 weeks prior to the screening visit.

Cardiovascular criteria

* Current congestive heart failure (greater than NYHA I), myocardial infarction (within 3-years of the screening date) or ischaemic heart disease requiring regular therapy (such as β blockers, long-acting nitrates, calcium antagonists or nicorandil). Aspirin, Clopidogrel and statins are allowed.
* A history of clinically significant arrhythmia or clinically important 24hr 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, the QTc(B) of all 3 screening ECGs are not within 10% of the mean, or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave)
* Mobitz type II or third degree heart block.
* Risk factors for torsades de pointes (heart failure NYHA II-IV, chronic hypokalaemia, familial long QT syndrome).
* Elevated resting blood pressure or a mean blood pressure equal to or higher than 150/95 mmHg at screening. A history of hypertension is acceptable provided control has been achieved for \> 3 months prior to screening with diuretic only.
* A mean heart rate outside the range 50-100 bpm at screening (from vital signs measurement).

Concurrent medication criteria

* Subject requires treatment with inhaled cromolyn sodium or nedocromil, oral β2-agonists, nebulised β2-agonists, nebulised anticholinergics or leukotriene modifiers.
* Subject is unable to abstain from xanthines (other than caffeine) 13-15 days prior to the first dose of study medication until completion of the study (last study-related procedure at the follow-up visit).
* Subject is unable to abstain from short-acting inhaled bronchodilators from 6hrs prior to screening until after completion of screening, or, from 6hrs prior to the administration of study medication until after completion of any given treatment period (i.e. the last assessment in a dosing period).
* Subject is unable to abstain from long-acting inhaled bronchodilators from 72hrs prior to the screening until after completion of all treatment periods (i.e. the last assessment in the final dosing period).
* Subject has changed dose of inhaled corticosteroids within the last 4 weeks, or, will be unable to maintain a constant dose of inhaled corticosteroids during the study.
* Subject is receiving treatment with long term or short-term oxygen therapy or requires nocturnal positive pressure ventilation (CPAP or NIPPV).
* Subject is receiving treatment with beta-blockers, except eye drops, Diltiazem or Verapamil.
* Subject is receiving co-medication with drugs which are commonly recognised to prolong the QTc interval (e.g. quinolones, amiodarone, disopyramide, quinidine, sotalol, chlorpromazine, haloperidol, ketoconazole, terfenadine, cisapride and terodiline).

Answer: B