Inclusion Criteria:

• Subject is male or female (of non-child bearing potential) > 40 years of age and < 75 years of age.
• Non- child bearing potential is defined as physiologically incapable of becoming pregnant, including females who are post menopausal ( more than 2 years without menses with appropriate clinical history ie age, history of vasomotor symptoms-estradiol and FSH levels may be checked if indicated) and females who are surgically sterile (hysterectomy, tubal ligation or bilateral oophorectomy.
• Subject diagnosed with COPD (stage II) in accordance with ATS/ERS guidelines (see Appendix 2: COPD Guidelines).
• Subject is a smoker or an ex smoker with a 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)
• Subject has FEV1 < 80 % of predicted normal for height, age, gender after inhalation of salbutamol
• Response to ipratropium bromide defined as:

Either an increase in FEV1 of > 12 % and > 150 mLwithin 2 hour following inhalation of 80 µcg ipratropium bromide at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hour following inhalation of 80 µcg ipratropium bromide within 6 months of screening and an increase in FEV1 of > 6 % and > 100 mL within 2 h following inhalation of 80 mg ipratropium bromide at the screening visit (in order to allow for potential fluctuations in the response to ipratropium bromide in patients known to be responders to ipratropium bromide)

• Response to salbutamol defined as:

Either an increase in FEV1 of > 12 % and > 150 mL within 2 hour following inhalation of 400 mg salbutamol at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hour following inhalation of 400 mg salbutamol within 6 months of screening and an increase in FEV1 of > 6 % and >100 mL within 2 h following inhalation of 400 mg salbutamol at the screening visit (in order to allow for potential fluctuations in the response to salbutamol in patients known to be responders to salbutamol)

• Body mass index within the range 18-35 kilograms/metre² (kg/m²).
• Subject is able and willing to give written informed consent to take part in the study.
• Subject is available to complete all study measurements

Exclusion Criteria:

• Subjects who have a past or present disease, which as judged by the Investigator and medical monitor may affect the outcome of the study or the safety of the subject
• Women who are pregnant or lactating
• An unwillingness of subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as IUD, diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants or tubal ligation if the woman could become pregnant from the time of the first dose study medication until 90 days post-dose
• The subject has a positive urine drug screen. A minimum list of drugs that will be screened for include Amphetamines, barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.
• The subject has a positive alcohol test (breath or urine) predose.
• A history, or suspected history, of alcohol abuse within the 6 months before the screening visit.
• A positive test for hepatitis C antibody, hepatitis B surface antigen, or HIV.
• The subject has participated in a clinical study with another New Chemical Entity within the past 2 months or a participated in a clinical study with any other drug during the previous month.
• The subject has donated a unit of blood within the 56 days or intends to donate within 56 days after completing the study.
• The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet.
• Subject has an FEV1 < 50 % of predicted for age, height and gender after inhalation of salbutamol.
• The subject has a diagnosis of active tuberculosis, lung cancer, sarcoidosis, bronchiectasis, lung fibrosis, pulmonary hypertension or with a primary diagnosis of asthma
• The subject has a known allergy or hypersensitivity to ipratropium, salbutamol, tiotropium, salmeterol or lactose
• A subject in whom ipratropium, salbutamol, tiotropium and/or salmeterol is contraindicated
• Subjects with lung volume reduction surgery within 12 months of screening
• Poorly controlled COPD defined as:

Either: acute worsening of COPD that is managed by the subject at home by treatment with increased corticosteroids or antibiotics in the 6 weeks before screening Or: more than 2 exacerbations in the previous 12 months before screening that required a course of oral steroids or antibiotics, and/or required hospitalisation

• Subject has had a respiratory tract infection in the 4 weeks before screening
• Subject requires treatment with inhaled cromolyn sodium, theophyline, oral beta agonists, nebulised anticholinergics or leukotriene antagonists
• Subject is unable to abstain from long acting beta agonist from 72 hours before screening and throughout the dosing period
• Subject is unable to abstain from tiotropium from 28 days before screening and throughout the dosing period
• Subject is predicted to be unable to abstain from short acting inhaled beta agonists (to be used as rescue medication during the study) for 6 hours before screening and before study visits, when required, until all post dose lung function tests have been completed for a given study day.
• Subject has received oral corticosteroids within the 6 weeks before screening
• Subject is receiving > 1000 mg FP (or equivalent) a day of inhaled corticosteroid or has changed dose within the 6 weeks before screening or is predicted not to be able to maintain a constant dose during the study
• Subject is receiving oxygen therapy or nocturnal positive pressure treatment
• Subject has prostate hypertrophy or narrow angle glaucoma
• The subject is unable to use the dosing devices correctly.
• Subject with carcinoma that has not been in complete remission for at least 5 years (with the exception of carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma if the subject is considered cured)
• A history of congestive heart failure, coronary insufficiency or cardiac arrhythmia
• Abnormal 12- lead ECG abnormality which is either clinically significant or may interfere with QTc measurement
• A supine mean heart rate outside the range 40-90 beats per minute (bpm) at screening.
• Elevated supine blood pressure higher than 160/95 at screening.
• Subject is receiving a diuretic and/ or beta adrenergic antagonist.
• Subject has a serum potassium level below the reference range at screening.
• Strict vegetarians;
• Shift-worker unable to comply with the study;
• Inability to understand the protocol requirements, instructions and study-related restrictions; the nature, scope and possible consequences of the study;
• Unlikely to complete the study; e.g., uncooperative attitude, inability to return for Follow-up Visits;
• Subject is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff, or relative thereof directly involved in the conduct of the study;
• Vulnerable individuals (e.g., persons kept in detention).