Efficacy Safety Study of Arformoterol/Tiotropium Combination Versus Either Therapy Alone in Chronic Obstructive Pulmonary Disease (COPD)

• Time-normalized Area From Study Baseline Curve for FEV1 Over 0-12 Hours (nAUC0-12B) [ Time Frame: 0-12 hours following two weeks of dosing ] [ Designated as safety issue: No ]
• Time Normalized Area Under the Change From Study Baseline Curve for FEV1 Over 12-24 Hours (nAUC12-24B) [ Time Frame: Following 2 weeks of dosing ] [ Designated as safety issue: No ]
• Change in FEV1 From Study Baseline to the 24-hour Timepoint (Trough) [ Time Frame: Following 2 weeks of dosing ] [ Designated as safety issue: No ]
  Trough FEV1 is defined as the measurement collected approximately 24 hours after the first in-clinic double-blind dose at Week 0. Change is calculated as Week 2 24 hour post first dose FEV1 - Week 0 pre-first dose FEV1.
• Change in FEV1 From Study Baseline at Each Assessed Timepoint Post First Dose of Study Medication [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Baseline is FEV1 measurement collected prior to the first double-blind dose at week 0. Change defined as Week 0 FEV1 - Week 2 pre first dose FEV1.
• Change in FEV1 Percent of Predicted From Study Baseline at Each Assessed Timepoint Post First Dose of Study Medication [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Baseline is FEV1 collected prior to first double-blind dose at week 0. Change is defined as Week 0 FEV1 percent predicted - Week 2 pre first dose FEV1 percent predicted.
• Peak Change in FEV1 Over 12 Hours Post Dose From Study Baseline [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  12 hour peak change in FEV1 is defined as maximum of the post dose changes through the nominal 12 hour assessment.
• Time to Onset in Participants Who Achieved a 10% Increase in FEV1 From Visit Predose After 2 Weeks [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Analyzed from end of dosing to 12 hours.
• Time to Onset in Participants Who Achieved a 15% Increase in FEV1 From Visit Predose After 2 Weeks [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Analyzed from end of dosing to 12 hours.
• Change in Inspiratory Capacity From Study Baseline to the 24 Hour Timepoint (Trough) Following 2 Weeks of Dosing [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Trough Inspiratory Capacity is defined as the measurement collected approximately 24 hours after the first in clinic double-blind treatment dose at week 0. Change is calculated as Week 2 24 hr post dose IC - Week 0 pre first dose IC.
• Change in Forced Vital Capacity (FVC) From Study Baseline at Each Assessed Post Dose Timepoint [ Time Frame: 2 Weeks ] [ Designated as safety issue: No ]
• Levalbuterol Metered Dose Inhaler (MDI) (Rescue Medication) Use in Days Per Week [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Overall: Average of the levalbuterol usage in days per week over the 2 week period. Mean number of days/week=number of days levalbuterol used during time period, divided by number of days in the period, multiplied by 7. An actuation is one puff of levalbuterol.
• Levalbuterol Metered Dose Inhaler (MDI) Rescue Medication Use in Actuations Per Day [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  Overall: Average of the usage in number of actuations per day over the 2 week period. An actuation is one puff of levalbuterol. Mean number of actuations/day=number actuations used during time period, divided by number of days in time period.
• Transition Dyspnea Index (TDI) Focal Score [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  TDI Focal score (range -9 to 9) is defined as the sum of function impairment, magnitude of task, and magnitude of effort (each on a -3 to 3 scale). A score of -9 is maximum worsening and 9 is maximum improvement.
• Number of Participants With a >= 1 Unit of Improvement in the TDI Focal Score [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  A Greater than or Equal to 1 unit of Improvement in the TDI Focal Score is considered to be clinically important.
• Percentage of Participants With a >=1 Unit Improvement in Transition Dysnea Index (TDI) Focal Score [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  A Greater than or Equal to 1 unit of Improvement in the TDI Focal Score is considered to be clinically important.

The purpose of this study is to evaluate and compare the efficacy of arformoterol twice a day and tiotropium once a day (dosed sequentially) versus tiotropium once a day alone in subjects with Chronic Obstructive Pulmonary Disease (COPD).

This study is a multicenter, randomized, modified-blind, double-dummy two-week parallel-group efficacy and safety study of arformoterol tartrate inhalation solution twice daily, tiotropium inhalation powder once daily and arformoterol tartrate inhalation solution twice daily and tiotropium inhalation powder once daily (dosed sequentially) in subjects with COPD. This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.

• Chronic Obstructive Pulmonary Disease
• Bronchitis
• Emphysema

• Drug: Arformoterol Tartrate Inhalation Solution
  Arformoterol tartrate inhalation solution 15 mcg twice daily and placebo inhalation powder once daily.
  Other Name: Brovana®
• Drug: Tiotropium
  Placebo inhalation solution twice daily and tiotropium inhalation powder 18 mcg once daily.
  Other Name: Spiriva
• Drug: Arformoterol and Tiotropium
  Arformoterol tartrate inhalation solution 15 mcg twice daily and Tiotropium inhalation powder 18 mcg once daily.
  Other Names:

  • Brovana
  • Spiriva
• Drug: Placebo
  Placebo inhalation solution and placebo inhalation powder

• Active Comparator: Arformoterol 15 mcg twice daily
  Arformoterol 15 mcg twice daily/Placebo Inhalation Powder
  Interventions:

  • Drug: Arformoterol Tartrate Inhalation Solution
  • Drug: Placebo
• Active Comparator: Tiotropium 18 mcg once daily
  Tiotropium 18 mcg once daily/Placebo Inhalation Solution
  Interventions:

  • Drug: Tiotropium
  • Drug: Placebo
• Experimental: Arformoterol /Tiotropium
  Arformoterol 15 mcg twice daily/Tiotropium 18 mcg once daily
  Intervention: Drug: Arformoterol and Tiotropium

Inclusion Criteria:

• Male and female subjects must be at least 45 years old at the time of consent.
• Subjects must have a pre-established primary clinical diagnosis of COPD.
• Subjects must have a baseline FEV1 of ≤65% of predicted normal value at Visit 1.
• Subjects must have a FEV1 ≥ 0.70L at Visit 1.

Exclusion Criteria:

• Subjects who do not have a FEV1/forced vital capacity (FVC) ratio of ≤70% at Visit 1.
• Subjects who do not have a ³15 pack-year smoking history and a baseline breathlessness severity grade of ³2 (Modified Medical Research Council [MMRC] Dyspnea Scale Score) at Visit 1.