For each safety parameter, the last assessment made before the first dose of investigational product in the lead-in study (LAC MD-31) was used as the baseline for all analyses of that safety parameter in this extension study

The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study

Potentially clinically significant change:

>1.15 × upper limit of normal (ULN) for absolute cell count of basophils, eosinophils or monocytes, blood alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, blood urea nitrogen, total cholesterol, creatine kinase, creatinine, gamma glutamyl transferase, lactate dehydrogenase, triglycerides or uric acid <0.85 x lower limit of normal (LLN) or > 1.15 ULN for hematocrit ratio, haemoglobin, lymphocytes or neutrophils absolute cell count, platelet count (thrombocytes), red or white blood cell count, calcium, fasting glucose, phosphorus, total protein, or urinary pH <0.95 x LLN or >1.05 x ULN for chloride, potassium, sodium Urinary glucose ≥0.015, blood or ketones or protein ≥1 or specific gravity >1.1 × ULN

The last assessment made before the first dose of investigational product in the lead-in study was used as the baseline for all safety analyses in the extension study

The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study

The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study

The Combined intent to treat (ITT) Population defined as all patients randomized to a treatment group who took at least 1 dose of double-blind investigational product in the lead-in study (LAC-MD-31) and who had a baseline assessment and at least 1 post-baseline assessment of forced expiratory volume in 1 second (FEV1) in LAC-MD-31

The Combined intent to treat (ITT) Population defined as all patients randomized to a treatment group who took at least 1 dose of double-blind investigational product in the lead-in study (LAC-MD-31) and who had a baseline assessment and at least 1 post-baseline assessment of forced expiratory volume in 1 second (FEV1) in LAC-MD-31

The TDI measures the change from baseline in severity of breathlessness in symptomatic patients. The TDI contains a rating for 3 categories (functional impairment, magnitude of task, magnitude of effort). TDI scale ranges from -3 (major deterioration) to +3 (major improvement) including a 0 score to indicate "no change". The 3 categories are added to obtain a focal score ranging from -9 (including 0) to +9.

The Combined intent to treat (ITT) Population defined as all patients randomized to a treatment group who took at least 1 dose of double-blind investigational product in the lead-in study (LAC-MD-31) and who had a baseline assessment and at least 1 post-baseline assessment of forced expiratory volume in 1 second (FEV1) in LAC-MD-31

St George's Respiratory Questionnaire (SGRQ) measures COPD-specific health outcomes and consists of 3 dimension scores (symptom, activity and impact). SGRQ total score is the sum of these scores and ranges from 0 (best health status) to 100 (worst health status).

The Combined intent to treat (ITT) Population defined as all patients randomized to a treatment group who took at least 1 dose of double-blind investigational product in the lead-in study (LAC-MD-31) and who had a baseline assessment and at least 1 post-baseline assessment of forced expiratory volume in 1 second (FEV1) in LAC-MD-31

Potentially clinically significant change:

Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline Pulse rate ≥110 bpm and increase ≥15% from baseline or ≤50 bpm and decrease ≥15% from baseline Weight increase or decrease ≥7% from baseline

The last assessment made before the first dose of investigational product in the lead-in study was used as the baseline for all safety analyses in the extension study

The Extension Safety Population defined as all patients from the lead-in study (LAC-MD-31) who signed informed consent at Visit 1 of this extension study (last visit of the lead-in study) and who took at least 1 dose of double-blind investigational product in this extension study