A Randomized, Double-Blind, Parallel Group 24 Week Placebo-Controlled Efficacy and Safety Study with a 28 Week Long Term Extension, of Nebulized Fluticasone Propionate (FP) /Formoterol Fumarate (FF) Combination Compared with FP and FF Monotherapy in Patients with COPD

INTERVENTION: Product Name: Fluticasone Propionate/Formoterol Fumarate Inhalation Suspension Pharmaceutical Form: Inhalation solution INN or Proposed INN: Formoterol Fumerate CAS Number: 43229‐80‐7 Other descriptive name: FORMOTEROL FUMARATE Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 10‐ INN or Proposed INN: Fluticasone Propionate CAS Number: 80474‐14‐2 Other descriptive name: FLUTICASONE PROPIONATE Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 500‐ Pharmaceutical form of the placebo: Inhalation solution Route of administration of the placebo: Inhalation use Product Name: Fluticasone Propionate/Formoterol Fumarate Inhalation Suspension Pharmaceutical Form: Inhalation solution INN or Proposed INN: Formoterol Fumarate CAS Number: 43229‐80‐7 Other descriptive name: FORMOTEROL FUMARATE Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 10‐ INN or Proposed INN: Fluticasone Propionate CAS Number: 80474‐14‐2 Other descriptive name: FLUTICASONE PROPIONATE Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 250‐ Pharmaceutical form of the placebo: Inhalation solution Route of administration of the placebo: Inhalation use Product Name: Formoterol Fumarate Inhalation Solution Pharmaceutical Form: Inhalation solution INN or Proposed INN: Formoterol Fumarate CAS Number: 43229‐80‐7 Other descriptive name: FORMOTEROL FUMARATE Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Inhalation solution Route of administration of the placebo: Inhalation use Product Name: Fluticasone Propionate Inhalation Suspension Pharmaceutical Form: Inhalation solution INN or Proposed INN: Fluticasone Propionate CAS Number: 80474‐14‐2 Other descriptive name: FLUTICASONE PROPIONATE Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 500‐ Pharmaceutical form of the pl CONDITION: Chronic Obstructive Pulmonary Disease ; MedDRA version: 17.0 Level: PT Classification code 10009033 Term: Chronic obstructive pulmonary disease System Organ Class: 10038738 ‐ Respiratory, thoracic and mediastinal disorders Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] SECONDARY OUTCOME: Secondary end point(s): 24 week placebo‐controlled period ; Secondary Efficacy endpoints: ; • Rescue medication usage ; ‐ Change from baseline in no. of puffs of albuterol during a 24‐hour period (averaged over each successive 4 week treatment interval and over the entire 24‐week period). ; ‐ Change from baseline in percentage of rescue free 24‐hour periods (during each successive 4 week treatment interval and over the entire 24‐week treatment period). ; • Other spirometry ; ‐ Change from baseline in pre‐dose FEV1 on Days 15, 29, 57, 85 and 127. ; ‐ Change from baseline in pre‐dose FVC on Days 15, 29, 57, 85, 127 and 169. ; ‐ Change from baseline in 2‐hour post‐dose FEV1 on Days 1 and 85. ; ‐ Change from baseline in 2‐hour post‐dose FVC on Days 1, 85 and 169. ; ‐ Onset of action (as measured by time to increase from pre‐dose to post‐dose FEV1 on Day 1 of = 100 mL or =12% on Day 1). ; ‐ Peak FEV1 up to 2 hours post‐dose on Day 1. ; ‐ FEV1 AUC0‐12 on Days 1 and 169 (subset of patients). ; ‐ Trough FEV1 at 12 hours post‐dose on Days 1 and 169 (subset of patients). ; • AECOPD ; ‐ Proportion of patients with investigator‐reported AECOPD (mild, moderate or severe, and moderate‐or‐severe) up to Day 169. ; ‐ Time from Day 1 to first investigator‐reported AECOPD (mild, moderate or severe, and moderate‐or‐severe). ; ‐ Duration of investigator‐reported AECOPD (mild, moderate or severe, and moderate‐or‐severe). PRIMARY OUTCOME: Main Objective: To determine the efficacy, as defined by FEV1 2‐hours post‐dose on Day 169, of FP/FF 500/10 fixed dose combination compared with FP inhalation suspension 500µg BID, in order to assess the contribution of the LABA component (FF) to the efficacy of the combination.; ; To determine the efficacy, as defined by pre‐dose FEV1 on Day 169, of FP/FF 500/10 and FP/FF 250/10 fixed dose combinations compared with FF inhalation solution 10µg BID, in order to assess the contribution of the ICS component (FP) to the efficacy of the combination. Primary end point(s): 24 week placebo‐controlled period; Co‐primary efficacy endpoints:; ‐ Change from baseline in pre‐dose FEV1 at Day 169.; ‐ Change from baseline in 2‐hour post‐dose FEV1 at Day 169.; ; 28‐week extension period; Primary endpoints – Safety; ‐ AEs/SAEs; ‐ Change from baseline in pre‐dose vital signs (pulse rate, systolic and diastolic blood pressure) at Days 197, 281 and 365.; ‐ Change from baseline in pre‐dose 12‐lead ECG parameters at Days 197, 281 and 365.; ‐ Change from baseline in clinical chemistry and hematology parameters at Day 365.; ‐ Change from baseline in visual acuity, IOP and LOCS III lens grades to Day 365 (subset of patients). Secondary Objective: ‐ To assess the efficacy of FP/FF 500/10 and FP/FF 250/10 compared with placebo by evaluating quality of life (via SGRQ) and symptoms (via BDI/TDI), AECOPD and rescue medication use over 24 weeks.; ; ‐ To evaluate the long‐term safety of treatment with the combination FP/FF inhalation suspension at doses of FP/FF 500/10 and FP/FF 250/10µg BID for up to 52 weeks. Timepoint(s) of evaluation of this end point: 24 week placebo‐controlled period; ‐ Both endpoints for will be assessed at Day 169.; ; 28‐week extension period; ‐ All but two endpoints will be assessed at Day 365 and some at Days 197 and 281. ; ‐ Proportion of patients with patient‐reported AECOPD via EXACT‐PRO up to Day 169. ; ‐ Time from Day 1 to first patient‐reported AECOPD via EXACT‐PRO. ; ‐ Duration of patient‐reported AECOPD via EXACT‐PRO. ; • Change from baseline in SGRQ total score and individual domain scores on Day 85 and Day 169. ; • TDI focal score on Days 15, 29, 57, 85, 127 and 169. ; Safety endpoints: ; • Adverse events (AEs)/serious AEs (SAEs). ; • Change from baseline in pre‐dose vital signs (pulse rate, systolic and diastolic blood pressure) at Days 15, 29, 57, 85, 127 and 169. ; • Change from baseline in post‐dose vital signs (pulse rate, systolic and diastolic blood pressure) at Days 1, 85 and 169. ; • Change from baseline in pre‐ and post‐dose 12‐lead ECG parameters at Days 1, 85, 169. ; • Change from baseline in clinical chemistry and hematology parameters at Day 169. ; • Change from baseline in visual acuity, IOP and LOCS III lens grades to Day 169 (subset of patients). ; ; 28‐week extension period: ; Secondary endpoints – efficacy ; • Rescue medication usage ; ‐ Change from baseline in no. of puffs of albuterol during a 24‐hour period (averaged over each successive 4 week treatment interval and over the entire 52‐week treatment period). ; ‐ Change from baseline in percentage of rescue free 24‐hour periods (during each successive 4 week treatment interval and over the entire 52‐week treatment period). ; • Change from baseline in pre‐dose FEV1 and FVC at Days 197, 281 and 365. ; • AECOPD ; ‐ Proportion of patients up to Day 365 with investigator‐reported AECOPD (mild, moderate or severe, and moderate‐or‐severe). ; ‐ Time from Day 1 to first investigator‐reported AECOPD (mild, moderate or severe, and moderate‐or‐severe). ; ‐ Duration of investigator‐reported AECOPD (mild, moderate or severe, and moderate‐or‐severe). ; ‐ Proportion of patients up to Day 365 with patient‐reported AECOPD via EXACT‐PRO. ; ‐ Time from Day 1 to first patient‐reported AECOPD via EXACT‐PRO. ; ‐ Duration of patient‐reported AECOPD via EXACT‐PRO. ; • Change from baseline SGRQ total score and individual domain scores at Days 281 and 365. Timepoint(s) of evaluation of this end point: Please refer to section 5.2 of the current Protocol, dated 05 June 2014 INCLUSION CRITERIA: 1. Males and females at least 40 years of age. Females may be of either childbearing or non‐childbearing potential. All females of childbearing potential must be using an acceptable, highly effect method of contraception and must also have a negative urine pregnancy test at screening. 2. A clinical diagnosis for at least 6 months prior to screening of COPD according to Global initiative for Obstructive Lung Disease guidelines (GOLD, 2014). 3. History of at least 10 pack‐years of tobacco smoking. 4. Spirometry at Visit 1 and Visit 2 following 4 puffs (360 µg) albuterol pMDI via spacer showing: a) post‐bronchodilator FEV1 =70% of predicted normal (Global Lung Function Initiative reference range; Quanjer et al, 2012) and, b) post‐bronchodilator FEV1/FVC ratio <0.7 5. Capable of self‐administering nebulized study medication, assessed at device training at Visit 1 and as witnessed on self‐administered dosing at Visit 1 and Visit 2. 6. Abl