Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe COPD

Study Overview
=================
Brief Summary
-----------------
A chronic dosing (24 weeks) study to assess the efficacy and safety GFF MDI; PT003), FF MDI; PT005, and GP MDI; PT001) in subjects with moderate to very severe COPD, compared with placebo.

Detailed Description
-----------------
A randomized, double-blind, chronic dosing (24 weeks), placebo-controlled, parallel group, multi-center study to assess the efficacy and safety of glycopyrronium and formoterol fumarate inhalation aerosol (GFF; PT003), formoterol fumarate inhalation aerosol (FF; PT005), and glycopyrronium inhalation aerosol (GP; PT001) in subjects with moderate to very severe COPD, compared with placebo.

Official Title
-----------------
A Randomized, Double-Blind, Chronic Dosing (24 Weeks), Placebo-Controlled, Parallel Group, Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects With Moderate to Very Severe COPD, Compared With Placebo

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: GFF MDI (PT003)
* Drug: FF MDI (PT005)
* Drug: GP MDI (PT001)
* Drug: Placebo MDI


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to acceptable contraceptive methods used consistently and correctly for the duration of the study. Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS). Current or former smokers with a history of at least 10 pack-years of cigarette smoking. Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of <0.70. FEV1 must be <80% predicted normal value calculated using the Third National Health and Nutrition Examination Survey (NHANES III) reference equations. (Or reference norms applicable to other regions). Exclusion Criteria: Significant diseases other than COPD, ie, disease or condition which, in the opinion of the Investigator, may put the subject at risk because of participation in the study or may influence either the results of the study or the subject's ability to participate in the study. Women who are pregnant or lactating or women of childbearing potential who are not using an acceptable method of contraception. Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma. Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening) or during the Screening Period (Visit 1 to Visit 4). Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening Period (Visit 1 to Visit 4). Subjects with a diagnosis of angle closure glaucoma will be excluded, regardless of whether or not they have been treated. Subjects with a diagnosis of open angle glaucoma who have intraocular pressure controlled with medication(s) are eligible. Subjects who have a history of hypersensitivity to β2-agonists, glycopyrronium or other muscarinic anticholinergics, or any component of the MDI.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GFF MDI (PT003)<br>Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID) | Drug: GFF MDI (PT003)<br>* Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID)<br>* Other names: Glycopyrronium and Formoterol Fumarate Metered Dose Inhaler (GFF MDI; PT003); Glycopyrronium and Formoterol Fumarate Inhalation Aerosol;|
| Experimental: FF MDI (PT005)<br>Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID) | Drug: FF MDI (PT005)<br>* Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol administered as 2 inhalations twice-daily (BID)<br>* Other names: Formoterol Fumarate Metered Dose Inhaler (FF MDI; PT005); Formoterol Fumarate Inhalation Aerosol;|
| Experimental: GP MDI (PT001)<br>Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol administered as 2 inhalations twice-daily (BID) | Drug: GP MDI (PT001)<br>* Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol administered as 2 inhalations twice-daily (BID)<br>* Other names: Glycopyrronium Metered Dose Inhaler (GP MDI; PT001); Glycopyrronium Inhalation Aerosol;|
| Placebo Comparator: Placebo MDI<br>Placebo (matching) for GFF MDI, FF MDI, and GP MDI administered as 2 inhalations twice-daily (BID) | Drug: Placebo MDI<br>* Placebo (matching) for GFF MDI, FF MDI, and GP MDI administered as 2 inhalations twice-daily (BID)<br>* Other names: Placebo (matching) for GFF MDI, FF MDI, and GP MDI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 of Treatment (US/China Approach) | For the US/China approach, the primary endpoint was the change from baseline in morning pre-dose trough FEV1 at Week 24 of treatment | at week 24 | 
| Change From Baseline in Morning Pre-dose Trough FEV1 Over Weeks 12-24, Japan Approach | Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach | over weeks 12-24 | 
| Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks. Primary Endpoint, EU/SK/TW Approach, Secondary Endpoint US/China Approach. | Change from baseline in morning pre-dose trough FEV1 over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach. | over 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TDI Focal Score Over 24 Weeks, US/China and EU/SK/TW Approach | TDI focal score over 24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9 | over 24 Weeks | 
| TDI Focal Score Over Weeks 12-24 Japan Approach | TDI focal score over 12-24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9 | over Weeks 12-24 | 
| TDI Focal Score Over 24 Weeks - US/China and EU/SK/TW Approaches -Symptomatic Population | TDI focal score over 24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9 | over 24 Weeks | 
| TDI Focal Score Over Weeks 12-24 - Japan Approach - Symptomatic Population | TDI focal score over 12-24 Weeks as a Model-Based Average (ITT Population) The TDI is an instrument which measures the changes in the participant's dyspnea from Baseline. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9 | over weeks 12-24 | 
| Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing at Week 24 US/China Approach | Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 US/China approach | at week 24 | 
| Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over Weeks 12-24 Japan Approach | Peak change from baseline in FEV1 within 2 hours post-dosing over weeks 12-24 Japan approach | over weeks 12-24 | 
| Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks EU/SK/TW Approach | Peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks EU/SK/TW approach | over 24 weeks | 
| Change From Baseline in SGRQ Total Score at Week 24, US/China Approach | Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life | at week 24 | 
| Change From Baseline in SGRQ Total Score Over Weeks 12-24 , Japan & EU/SK/TW Approach | Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life | over weeks 12-24 | 
| Change From Baseline in SGRQ Total Score at Week 24 in Symptomatic Population, US/China Approach | Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life | at week 24 | 
| Change From Baseline in SGRQ Total Score Over Weeks 12-24, in Symptomatic Population, Japan & EU/SK/TW Approach | Change from baseline in the SGRQ total score. The SGRQ is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of GFF MDI, FF MDI and GP MDI on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. Change from Baseline in total score of -4 units or lower is considered as clinically meaningful improvement in quality of life | over weeks 12-24 | 
| Change From Baseline in Average Daily Rescue Ventolin Use Over 24 Weeks in RVU Population, All Approaches | Change from baseline in average daily rescue Ventolin use over 24 weeks in RVU population, all approaches | over 24 weeks | 
| FEV1 Measured at 5 Minutes Post-dose on Day 1 | Onset of Action as Assessed by FEV1 Day 1 at 5 Minutes Post-Dose. Reported is the FEV1 measured at 5 minutes post-dose on Day 1 as the first time point when the difference from Placebo was statistically significant | Assessed at 5-minutes post dose on Day 1 | 
| FEV1 Measured at 15 Minutes Post-dose on Day 1 | Onset of Action as Assessed by FEV1 Day 1 at 15 Minutes Post-Dose. Reported is the FEV1 measured at 15 minutes post-dose on Day 1 as the first time point when the difference from Placebo was statistically significant | Assessed at 15-minute post dose on Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD