Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Brief summary
This is a multicenter, randomized, double-blind, parallel group, chronic-dosing (24 weeks), placebo-controlled study to assess the efficacy and safety of Glycopyrrolate (GP and Formoterol Fumarate (FF) combination metered-dose inhaler (MDI) (GFF; PT003), GP MDI (PT001), and FF MDI (PT005) compared with Placebo MDI in subjects with moderate to very severe COPD.
Interventions
DRUGGFF MDI (PT003)
GFF MDI administered as two puffs BID
DRUGGP MDI (PT001)
GP MDI administered as two puffs BID
DRUGFF MDI (PT005)
FF MDI administered as two puffs BID
DRUGPlacebo
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. * Subjects with FEV1/FVC ratio of \<0.70 and FEV1 \<80% predicted normal and ≥750 mL if FEV1 \<30% of predicted normal value. * 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 NYHA Class III/IV) * Clinically significant abnormal 12-lead ECG * Abnormal liver function tests defined as AST, 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 | 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 | 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 model-based 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. |
| Peak FEV1 | At week 24 | Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 |
| St. George Respiratory Questionnaire (SGRQ) Score | 24 weeks | Change from baseline in the SGRQ total score at Week 24. 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 HFA Use | 24 weeks | Change from baseline in average daily rescue Ventolin HFA use over 24 weeks |
| Onset of Action as Assessed by FEV1 | 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 |
Countries
United States
Participant flow
Recruitment details
Conducted at 140 sites throughout the United States from July 2013 - February 2015. Study participation was a maximum of 32 weeks.
Pre-assignment details
A multicenter, randomized, double-blind, parallel group, chronic dosing, active- and placebo-controlled study; each participant was randomized to receive 1 of 4 possible treatments over the course of a 24-week treatment period (With a randomization of 7:6:6:3 GFF MDI, GP MDI, FF MDI and Placebo MDI)
Participants by arm
| Arm | Count |
|---|---|
| FF MDI (PT005) FF MDI 9.6 mcg administered as two puffs BID | 437 |
| GP MDI (PT001) GP MDI 14.4 mcg administered as two puffs BID | 439 |
| GFF MDI (PT003) GFF MDI 14.4/9.6 mcg administered as two puffs BID | 510 |
| Placebo MDI Inhaled placebo administered as two puffs BID | 223 |
| Total | 1,609 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative reasons | 5 | 1 | 2 | 2 |
| Overall Study | Adverse Event | 21 | 14 | 23 | 19 |
| Overall Study | Lack of Efficacy | 3 | 8 | 4 | 7 |
| Overall Study | Lost to Follow-up | 8 | 9 | 8 | 4 |
| Overall Study | Physician Decision | 7 | 5 | 2 | 4 |
| Overall Study | Protocol-specified criteria | 15 | 15 | 10 | 7 |
| Overall Study | Protocol Violation | 6 | 2 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 28 | 21 | 29 | 15 |
Baseline characteristics
| Characteristic | FF MDI (PT005) | GP MDI (PT001) | GFF MDI (PT003) | Placebo MDI | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 7.8 | 62.8 Years STANDARD_DEVIATION 8.4 | 62.8 Years STANDARD_DEVIATION 8.2 | 64.2 Years STANDARD_DEVIATION 8.7 | 62.9 Years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 190 Participants | 197 Participants | 238 Participants | 98 Participants | 723 Participants |
| Sex: Female, Male Male | 247 Participants | 242 Participants | 272 Participants | 125 Participants | 886 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 438 | 12 / 439 | 22 / 510 | 10 / 223 |
| serious Total, serious adverse events | 37 / 438 | 37 / 439 | 36 / 510 | 15 / 223 |
Outcome results
Primary
Change From Baseline in Morning Pre-dose Trough FEV1
Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) at Week 24.
Time frame: At Week 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Change From Baseline in Morning Pre-dose Trough FEV1 | 0.061 Liters |
| GP MDI (PT001) | Change From Baseline in Morning Pre-dose Trough FEV1 | 0.063 Liters |
| GFF MDI (PT003) | Change From Baseline in Morning Pre-dose Trough FEV1 | 0.116 Liters |
| Placebo MDI | Change From Baseline in Morning Pre-dose Trough FEV1 | 0.013 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 model-based 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: Over 24 weeks
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.080 Liters |
| GP MDI (PT001) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.082 Liters |
| GFF MDI (PT003) | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.137 Liters |
| Placebo MDI | Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks | 0.008 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: Day 1
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FF MDI (PT005) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.175 Liters |
| FF MDI (PT005) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.212 Liters |
| GP MDI (PT001) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.052 Liters |
| GP MDI (PT001) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.109 Liters |
| GFF MDI (PT003) | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.237 Liters |
| GFF MDI (PT003) | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.192 Liters |
| Placebo MDI | Onset of Action as Assessed by FEV1 | 15 min post dose | 0.022 Liters |
| Placebo MDI | Onset of Action as Assessed by FEV1 | 5 min post dose | 0.006 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 FEV1
Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24
Time frame: At week 24
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Peak FEV1 | 0.268 Liters |
| GP MDI (PT001) | Peak FEV1 | 0.223 Liters |
| GFF MDI (PT003) | Peak FEV1 | 0.350 Liters |
| Placebo MDI | Peak FEV1 | 0.083 Liters |
Secondary
Rescue Ventolin HFA Use
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks
Time frame: 24 weeks
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | Rescue Ventolin HFA Use | -0.7 Puffs / Day |
| GP MDI (PT001) | Rescue Ventolin HFA Use | -0.4 Puffs / Day |
| GFF MDI (PT003) | Rescue Ventolin HFA Use | -1.0 Puffs / Day |
| Placebo MDI | Rescue Ventolin HFA Use | 0.0 Puffs / Day |
Secondary
St. George Respiratory Questionnaire (SGRQ) Score
Change from baseline in the SGRQ total score at Week 24. 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: 24 weeks
Population: Intent-to-Treat population with evaluable data (no imputation) for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| FF MDI (PT005) | St. George Respiratory Questionnaire (SGRQ) Score | -2.3 Scores on a scale |
| GP MDI (PT001) | St. George Respiratory Questionnaire (SGRQ) Score | -2.2 Scores on a scale |
| GFF MDI (PT003) | St. George Respiratory Questionnaire (SGRQ) Score | -3.0 Scores on a scale |
| Placebo MDI | St. George Respiratory Questionnaire (SGRQ) Score | -1.2 Scores on a scale |