COPD
Conditions
Brief summary
This is a randomized, double-blind, multi-center, parallel-group study to assess the efficacy and safety of PT010 relative to PT003 and PT009 on COPD exacerbations subjects with moderate to very severe COPD.
Detailed description
A randomized, double-blind, multi-center, parallel-group study to assess the efficacy and safety of PT010 relative to PT003 and PT009 on COPD exacerbations over a 52-week treatment period in subjects with moderate to very severe COPD.
Interventions
Budensonide, Glycopyrronium, and Formoterol Fumarate
Glycopyrronium, and Formoterol Fumarate
DRUGBGF MDI 160/14.4/9.6 μg
Budensonide, Glycopyrronium, and Formoterol Fumarate
Budensonide, and Formoterol Fumarate
Sponsors
Pearl Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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 (FEV1)/Forced vital capacity (FVC) ratio must be \<0.70 and FEV1 must be \<65% predicted normal value calculated using NHANES III reference equations (or reference norms applicable to other regions). * Subjects with history of exacerbations. Please refer to the study protocol for the complete inclusion criteria list.
Exclusion criteria
* Significant diseases or conditions other than COPD, 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 are planning to become pregnant during the course of the study, 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) * 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) * Immune suppression or severe neurological disorders affecting control of the upper airway or other risk factors that in the opinion of the Investigator would put the subject at substantial risk of pneumonia. * Subjects with a diagnosis of narrow angle glaucoma, who, in the opinion of the Investigator, have not been adequately treated. * Subjects who have a history of hypersensitivity to β2-agonists, budesonide or any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or any other component of the IMPs. Please refer to the study protocol for the complete inclusion criteria list.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Rate of Moderate or Severe Exacerbations | 52-week treatment period | Adjusted Rate of Moderate or Severe Exacerbations |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Moderate or Severe COPD Exacerbation | 52 Weeks | Time to first moderate or severe COPD exacerbation (proportion with event reported as median time was not reached, statistical analyses are based upon time to event) |
| Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks | 24 Weeks | Change from baseline in average daily rescue Ventolin HFA use over 24 weeks |
| Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score | at Week 24 | Percentage of subjects achieving a minimal clinically important difference (MCID) of 4 units or more in SGRQ (St. George's Respiratory Questionnaire) total score at Week 24 |
| Time to Death (All Cause) | 52 Weeks | Subject Deaths (all cause) |
| Rate of Severe COPD Exacerbations | 52 Weeks | Rate of severe COPD exacerbations |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, China, Czechia, France, Germany, Hungary, Italy, Japan, Mexico, Netherlands, New Zealand, Peru, Poland, Russia, Serbia, South Africa, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 26 countries between July 2015 and July 2019.
Pre-assignment details
Subjects who successfully complete the Screening Period will then be randomized in a 1:1:1:1 scheme to BGF MDI 320/14.4/9.6 μg BID, BGF MDI 160/14.4/9.6 μg BID, BFF MDI 320/9.6 μg BID, or GFF MDI 14.4/9.6 μg BID, respectively.
Participants by arm
| Arm | Count |
|---|---|
| BGF MDI 320/14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 μg | 2,137 |
| BGF MDI 160/14.4/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 160/14.4/9.6 μg | 2,121 |
| GFF MDI 14.4/9.6 μg Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 μg | 2,120 |
| BFF MDI 320/9.6 μg Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg | 2,131 |
| Total | 8,509 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative Reasons | 12 | 9 | 11 | 5 |
| Overall Study | Adverse Event | 118 | 113 | 147 | 138 |
| Overall Study | enrolled in >1 studies | 18 | 11 | 19 | 15 |
| Overall Study | Lack of Efficacy | 103 | 102 | 171 | 135 |
| Overall Study | Lost to Follow-up | 25 | 21 | 19 | 15 |
| Overall Study | Major Protocol Deviation | 24 | 26 | 22 | 25 |
| Overall Study | missing PI Signature | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 23 | 33 | 38 | 28 |
| Overall Study | Protocol Specified Criteria | 20 | 10 | 9 | 12 |
| Overall Study | Randomized but not treated | 1 | 5 | 4 | 5 |
| Overall Study | Withdrawal by Subject | 104 | 94 | 123 | 130 |
Baseline characteristics
| Characteristic | BGF MDI 320/14.4/9.6 μg | BGF MDI 160/14.4/9.6 μg | GFF MDI 14.4/9.6 μg | BFF MDI 320/9.6 μg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 7.6 | 64.6 Years STANDARD_DEVIATION 7.6 | 64.8 Years STANDARD_DEVIATION 7.6 | 64.6 Years STANDARD_DEVIATION 7.6 | 64.7 Years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 400 Participants | 393 Participants | 426 Participants | 401 Participants | 1620 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1690 Participants | 1680 Participants | 1649 Participants | 1683 Participants | 6702 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 47 Participants | 48 Participants | 45 Participants | 47 Participants | 187 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 33 Participants | 40 Participants | 30 Participants | 39 Participants | 142 Participants |
| Race (NIH/OMB) Asian | 162 Participants | 166 Participants | 157 Participants | 166 Participants | 651 Participants |
| Race (NIH/OMB) Black or African American | 78 Participants | 88 Participants | 75 Participants | 64 Participants | 305 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 43 Participants | 44 Participants | 50 Participants | 46 Participants | 183 Participants |
| Race (NIH/OMB) White | 1819 Participants | 1783 Participants | 1808 Participants | 1816 Participants | 7226 Participants |
| Sex: Female, Male Female | 877 Participants | 823 Participants | 876 Participants | 852 Participants | 3428 Participants |
| Sex: Female, Male Male | 1260 Participants | 1298 Participants | 1244 Participants | 1279 Participants | 5081 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 | 27 / 2,144 | 42 / 2,124 | 47 / 2,125 | 35 / 2,136 |
| other Total, other adverse events | 337 / 2,144 | 361 / 2,124 | 292 / 2,125 | 336 / 2,136 |
| serious Total, serious adverse events | 426 / 2,144 | 445 / 2,124 | 433 / 2,125 | 440 / 2,136 |
Outcome results
Primary
Adjusted Rate of Moderate or Severe Exacerbations
Adjusted Rate of Moderate or Severe Exacerbations
Time frame: 52-week treatment period
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BGF MDI 320/14.4/9.6 μg | Adjusted Rate of Moderate or Severe Exacerbations | 1.08 Moderate or Severe Exacerbations | Standard Error 0.04 |
| BGF MDI 160/14.4/9.6 μg | Adjusted Rate of Moderate or Severe Exacerbations | 1.07 Moderate or Severe Exacerbations | Standard Error 0.04 |
| GFF MDI 14.4/9.6 μg | Adjusted Rate of Moderate or Severe Exacerbations | 1.42 Moderate or Severe Exacerbations | Standard Error 0.05 |
| BFF MDI 320/9.6 μg | Adjusted Rate of Moderate or Severe Exacerbations | 1.24 Moderate or Severe Exacerbations | Standard Error 0.04 |
p-value: <0.000195% CI: [0.69, 0.83]Negative Binomial Regression
p-value: 0.002795% CI: [0.79, 0.95]Negative Binomial Regression
p-value: <0.000195% CI: [0.69, 0.83]Negative Binomial Regression
p-value: 0.00295% CI: [0.79, 0.95]Negative Binomial Regression
Secondary
Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks
Change from baseline in average daily rescue Ventolin HFA use over 24 weeks
Time frame: 24 Weeks
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BGF MDI 320/14.4/9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks | -1.2 Puffs |
| BGF MDI 160/14.4/9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks | -1.0 Puffs |
| GFF MDI 14.4/9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks | -0.7 Puffs |
| BFF MDI 320/9.6 μg | Change From Baseline in Average Daily Rescue Ventolin HFA Use Over 24 Weeks | -0.8 Puffs |
p-value: <0.000195% CI: [-0.68, -0.34]Linear Repeated Measures
p-value: <0.000195% CI: [-0.54, -0.2]Linear Repeated Measures
p-value: <0.000195% CI: [-0.53, -0.18]Linear Repeated Measures
p-value: 0.012795% CI: [-0.39, -0.05]Linear Repeated Measures
Secondary
Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score
Percentage of subjects achieving a minimal clinically important difference (MCID) of 4 units or more in SGRQ (St. George's Respiratory Questionnaire) total score at Week 24
Time frame: at Week 24
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BGF MDI 320/14.4/9.6 μg | Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score | 1068 Participants |
| BGF MDI 160/14.4/9.6 μg | Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score | 1024 Participants |
| GFF MDI 14.4/9.6 μg | Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score | 893 Participants |
| BFF MDI 320/9.6 μg | Percentage of Subjects Achieving a MCID of 4 Units or More in SGRQ Total Score | 949 Participants |
p-value: <0.000195% CI: [1.199, 1.539]Regression, Logistic
p-value: 0.000595% CI: [1.1, 1.41]Regression, Logistic
p-value: <0.000495% CI: [1.133, 1.454]Regression, Logistic
p-value: 0.010395% CI: [1.039, 1.333]Regression, Logistic
Secondary
Rate of Severe COPD Exacerbations
Rate of severe COPD exacerbations
Time frame: 52 Weeks
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BGF MDI 320/14.4/9.6 μg | Rate of Severe COPD Exacerbations | 0.13 Severe Exacerbations | Standard Error 0.01 |
| BGF MDI 160/14.4/9.6 μg | Rate of Severe COPD Exacerbations | 0.14 Severe Exacerbations | Standard Error 0.01 |
| GFF MDI 14.4/9.6 μg | Rate of Severe COPD Exacerbations | 0.15 Severe Exacerbations | Standard Error 0.01 |
| BFF MDI 320/9.6 μg | Rate of Severe COPD Exacerbations | 0.16 Severe Exacerbations | Standard Error 0.01 |
p-value: 0.655295% CI: [0.69, 1.03]Negative Binomial Regression
p-value: 0.022195% CI: [0.66, 0.97]Negative Binomial Regression
p-value: 0.215795% CI: [0.72, 1.08]Negative Binomial Regression
p-value: 0.064795% CI: [0.69, 1.01]Negative Binomial Regression
Secondary
Time to Death (All Cause)
Subject Deaths (all cause)
Time frame: 52 Weeks
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BGF MDI 320/14.4/9.6 μg | Time to Death (All Cause) | 28 Participants |
| BGF MDI 160/14.4/9.6 μg | Time to Death (All Cause) | 39 Participants |
| GFF MDI 14.4/9.6 μg | Time to Death (All Cause) | 49 Participants |
| BFF MDI 320/9.6 μg | Time to Death (All Cause) | 34 Participants |
p-value: 0.011195% CI: [0.34, 0.87]Regression, Cox
p-value: 0.340195% CI: [0.472, 1.296]Regression, Cox
p-value: 0.26995% CI: [0.518, 1.201]Regression, Cox
p-value: 0.591895% CI: [0.716, 1.796]Regression, Cox
Secondary
Time to First Moderate or Severe COPD Exacerbation
Time to first moderate or severe COPD exacerbation (proportion with event reported as median time was not reached, statistical analyses are based upon time to event)
Time frame: 52 Weeks
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BGF MDI 320/14.4/9.6 μg | Time to First Moderate or Severe COPD Exacerbation | 1026 Participants |
| BGF MDI 160/14.4/9.6 μg | Time to First Moderate or Severe COPD Exacerbation | 1013 Participants |
| GFF MDI 14.4/9.6 μg | Time to First Moderate or Severe COPD Exacerbation | 1056 Participants |
| BFF MDI 320/9.6 μg | Time to First Moderate or Severe COPD Exacerbation | 1085 Participants |
p-value: 0.003595% CI: [0.807, 0.959]Regression, Cox
p-value: 0.05795% CI: [0.814, 0.966]Regression, Cox
p-value: 0.001195% CI: [0.794, 0.944]Regression, Cox
p-value: 0.001995% CI: [0.801, 0.951]Regression, Cox