Chronic Obstructive Pulmonary Disease
Conditions
Brief summary
The overall objective of this study is to assess the efficacy and safety of treatment with PT003 (GFF MDI), PT005 (FF MDI), PT001 (GP MDI), and open-label tiotropium bromide inhalation powder compared with each other and Placebo MDI over 24 weeks in subjects with moderate to very severe COPD.
Interventions
DRUGGFF MDI
GFF MDI administered as two puffs Bis in Di.e. Twice Daily (BID)
DRUGGP MDI
GP MDI administered as two puffs BID
DRUGFF MDI
FF MDI administered as two puffs BID
DRUGOpen-label tiotropium bromide inhalation powder (Spiriva® Handihaler®)
Taken as 1 capsule daily containing 18 µg of open-label tiotropium via the Handihaler dry powder inhaler (DPI)
DRUGPlacebo MDI
Inhaled placebo administered as two puffs BID
Sponsors
Pearl Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female subjects at least 40 years of age and no older than 80 at Visit 1. * 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. * Average f the -60 and the -30 min pre-dose FEV1 assessments must be \< 80% predicted normal value calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations. * Subjects willing and, in the opinion of the investigator, able to adjust current COPD therapy as required by the protocol Key
Exclusion criteria
* Significant diseases other than COPD, i.e. disease or condition which, in the opinion of the investigator, may put the patient 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 * Current diagnosis of asthma or alpha-1 antitrypsin deficiency * Other active pulmonary disease such as active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnea * Hospitalized due to poorly controlled COPD within 3 months prior to screening or during the Screening Period * Poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to screening or during the Screening Period * Lower respiratory tract infections that required antibiotics within 6 weeks prior to screening or during the Screening Period * Unstable ischemic heart disease, left ventricular failure, or documented myocardial infarction within 12 months of enrollment. * Recent history of acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass graft within the past three months * Congestive heart failure (CHF) New York Heart Association (NYHA) Class III/IV) * Clinically significant abnormal 12-lead ECG * Abnormal liver function tests defined as aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin ≥ 1.5 times upper limit of normal at Visit 1 and on repeat testing * Cancer not in complete remission for at least five years * History of hypersensitivity to β2-agonists, glycopyrronium or other muscarinic anticholinergics, lactose/milk protein or any component of the MDI Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | Baseline and at Week 24 | Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | Baseline and Weeks 2 to 24 | Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) over 24 weeks. FEV1 was assessed at multiple time points post-baseline,and a modelbased average of all visits starting from Week 2 through week 24 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average FEV1 post-baseline. |
| St. George's Respiratory Questionnaire (SGRQ) Score | Baseline and at Week 24 | 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. |
| Rescue Ventolin Hydrofluoroalkane (HFA) Use | Baseline and at Week 24 | Change from baseline in average daily rescue Ventolin HFA use |
| Onset of Action as Assessed by FEV1 | Assessed for 5- and 15-minute post dose on Day 1 | Defined as the first time-point using the 5- and 15-minute post dose measurements where the difference in FEV1 from Placebo was statistically significant |
| Peak Change From Baseline in FEV1 Within 2 Hours Post-dose | Baseline and at Week 24 | Peak change from baseline in forced expiratory volume in 1 second (FEV1) within 2 hours post-dose |
Countries
Australia, New Zealand, United States
Participant flow
Recruitment details
Conducted at 160 sites throughout the US, Australia, and New Zealand from June 2013 - February 2015. Study participation was a maximum of 32 weeks.
Pre-assignment details
Study was a multicenter, randomized, double-blind, parallel group, chronic dosing, active- and placebo-controlled study; each patient was randomized to receive 1 of 5 possible treatments over the course of a 24-week treatment period
Participants by arm
| Arm | Count |
|---|---|
| GFF MDI (PT003) Glycopyrronium Formoterol Fumarate (GFF) Metered Dose Inhaler (MDI) 14.4/9.6 mcg | 526 |
| GP MDI (PT001) Glycopyrronium (GP) MDI 14.4 mcg | 451 |
| FF MDI (PT005) Formoterol Fumarate (FF) MDI 9.6 mcg | 449 |
| Spiriva® Handihaler® (Open-label) Open-label tiotropium bromide inhalation powder 18 mcg | 451 |
| Placebo Placebo MDI | 219 |
| Total | 2,096 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Administrative Reasons / Missing | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Adverse Event | 33 | 31 | 19 | 20 | 11 |
| Overall Study | Lack of Efficacy | 7 | 12 | 9 | 3 | 9 |
| Overall Study | Lost to Follow-up | 10 | 7 | 8 | 5 | 0 |
| Overall Study | Physician Decision | 1 | 5 | 3 | 3 | 7 |
| Overall Study | Protocol-Specified Criteria | 13 | 10 | 8 | 5 | 7 |
| Overall Study | Protocol Violation | 3 | 0 | 5 | 4 | 1 |
| Overall Study | Withdrawal by Subject | 31 | 41 | 30 | 21 | 24 |
Baseline characteristics
| Characteristic | GFF MDI (PT003) | GP MDI (PT001) | FF MDI (PT005) | Spiriva® Handihaler® (Open-label) | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 8.4 | 62.9 Years STANDARD_DEVIATION 8.4 | 63.0 Years STANDARD_DEVIATION 8.3 | 63.0 Years STANDARD_DEVIATION 8.6 | 62.5 Years STANDARD_DEVIATION 8.3 | 62.8 Years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 236 Participants | 196 Participants | 203 Participants | 182 Participants | 97 Participants | 914 Participants |
| Sex: Female, Male Male | 290 Participants | 255 Participants | 246 Participants | 269 Participants | 122 Participants | 1182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 73 / 526 | 59 / 451 | 57 / 452 | 58 / 451 | 47 / 220 |
| serious Total, serious adverse events | 44 / 526 | 36 / 451 | 29 / 452 | 36 / 451 | 16 / 220 |
Outcome results
Primary
Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24
Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24
Time frame: Baseline and at Week 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GFF MDI (PT003) | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | 0.126 Liters |
| GP MDI (PT001) | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | 0.066 Liters |
| FF MDI (PT005) | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | 0.062 Liters |
| Spiriva® Handihaler® (Open-label) | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | 0.105 Liters |
| Placebo | Change From Baseline in Morning Pre-dose Trough FEV1 at Week 24 | -0.024 Liters |
Secondary
Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks
Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) over 24 weeks. FEV1 was assessed at multiple time points post-baseline,and a modelbased average of all visits starting from Week 2 through week 24 inclusive was calculated. The change values reported in the table represent the change between the baseline and the average FEV1 post-baseline.
Time frame: Baseline and Weeks 2 to 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GFF MDI (PT003) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.150 Liters |
| GP MDI (PT001) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.091 Liters |
| FF MDI (PT005) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.086 Liters |
| Spiriva® Handihaler® (Open-label) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.122 Liters |
| Placebo | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | -0.007 Liters |
Secondary
Onset of Action as Assessed by FEV1
Defined as the first time-point using the 5- and 15-minute post dose measurements where the difference in FEV1 from Placebo was statistically significant
Time frame: Assessed for 5- and 15-minute post dose on Day 1
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| GFF MDI (PT003) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.185 Liters |
| GFF MDI (PT003) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.226 Liters |
| GP MDI (PT001) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.042 Liters |
| GP MDI (PT001) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.101 Liters |
| FF MDI (PT005) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.182 Liters |
| FF MDI (PT005) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.212 Liters |
| Spiriva® Handihaler® (Open-label) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.117 Liters |
| Spiriva® Handihaler® (Open-label) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.048 Liters |
| Placebo | Onset of Action as Assessed by FEV1 | 5 min post dose | -0.002 Liters |
| Placebo | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.022 Liters |
Comparison: At 5 min post dosep-value: <0.0001ANCOVA
Comparison: At 15 min post dosep-value: <0.0001ANCOVA
Comparison: At 5 min post dosep-value: <0.0001ANCOVA
Comparison: At 15 min post dosep-value: <0.0001ANCOVA
Comparison: At 5 min post dosep-value: <0.0001ANCOVA
Comparison: At 15 min post dosep-value: <0.0001ANCOVA
Secondary
Peak Change From Baseline in FEV1 Within 2 Hours Post-dose
Peak change from baseline in forced expiratory volume in 1 second (FEV1) within 2 hours post-dose
Time frame: Baseline and at Week 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GFF MDI (PT003) | Peak Change From Baseline in FEV1 Within 2 Hours Post-dose | 0.356 Liters |
| GP MDI (PT001) | Peak Change From Baseline in FEV1 Within 2 Hours Post-dose | 0.223 Liters |
| FF MDI (PT005) | Peak Change From Baseline in FEV1 Within 2 Hours Post-dose | 0.263 Liters |
| Spiriva® Handihaler® (Open-label) | Peak Change From Baseline in FEV1 Within 2 Hours Post-dose | 0.259 Liters |
| Placebo | Peak Change From Baseline in FEV1 Within 2 Hours Post-dose | 0.065 Liters |
Secondary
Rescue Ventolin Hydrofluoroalkane (HFA) Use
Change from baseline in average daily rescue Ventolin HFA use
Time frame: Baseline and at Week 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GFF MDI (PT003) | Rescue Ventolin Hydrofluoroalkane (HFA) Use | -0.8 Puffs / Day |
| GP MDI (PT001) | Rescue Ventolin Hydrofluoroalkane (HFA) Use | -0.5 Puffs / Day |
| FF MDI (PT005) | Rescue Ventolin Hydrofluoroalkane (HFA) Use | -0.8 Puffs / Day |
| Spiriva® Handihaler® (Open-label) | Rescue Ventolin Hydrofluoroalkane (HFA) Use | -0.4 Puffs / Day |
| Placebo | Rescue Ventolin Hydrofluoroalkane (HFA) Use | 0.3 Puffs / Day |
Secondary
St. George's Respiratory Questionnaire (SGRQ) Score
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.
Time frame: Baseline and at Week 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GFF MDI (PT003) | St. George's Respiratory Questionnaire (SGRQ) Score | -3.1 Scores on a scale |
| GP MDI (PT001) | St. George's Respiratory Questionnaire (SGRQ) Score | -1.2 Scores on a scale |
| FF MDI (PT005) | St. George's Respiratory Questionnaire (SGRQ) Score | -2.4 Scores on a scale |
| Spiriva® Handihaler® (Open-label) | St. George's Respiratory Questionnaire (SGRQ) Score | -2.7 Scores on a scale |
| Placebo | St. George's Respiratory Questionnaire (SGRQ) Score | -0.8 Scores on a scale |