Chronic Obstructive Pulmonary Disease, COPD
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD
Brief summary
This is a trial of 12 weeks of treatment with nebulized SUN-101 using an Investigational eFlow® Closed System (CS) nebulizer in subjects with chronic obstructive pulmonary disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2014) guidelines.
Detailed description
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, efficacy and safety trial of 12 weeks of treatment with nebulized SUN-101 using an Investigational eFlow® Closed System (CS) nebulizer in approximately 645 subjects with chronic obstructive pulmonary disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD 2014) guidelines. SUN-101 or placebo will be administered twice daily as an oral inhalation using the investigational eFlow CS nebulizer.
Interventions
SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer
SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer
DRUGPlacebo eFlow (CS) nebulizer
Placebo BID eFlow (R) Closed System (CS) nebulizer
Sponsors
Sunovion Respiratory Development 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 No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients age ≥ 40 years, inclusive 2. A clinical diagnosis of COPD according to the GOLD 2014 guidelines 3. Current smokers or ex-smokers with at least 10 pack-year smoking history (eg, at least 1 pack/day for 10 years, or equivalent) 4. Post-bronchodilator (following inhalation of ipratropium bromide) FEV1 \< 80% of predicted normal and \> 0.7 L during Screening (Visit 1) 5. Post-bronchodilator (following inhalation of ipratropium bromide) FEV1/FVC ratio \< 0.70 during Screening (Visit 1) 6. Ability to perform reproducible spirometry according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines (2005) 7. Subject, if female ≤ 65 years of age and of child bearing potential, must have a negative serum pregnancy test at Visit 1. Females of childbearing potential must be instructed to and agree to avoid pregnancy during the study and must use an acceptable method of birth control: a) an oral contraceptive, an intrauterine device (IUD), implantable contraceptive, transdermal or injectable contraceptive for at least 1 month prior to entering the study with continued use throughout the study and for thirty days following participation; b) barrier method of contraception, eg, condom and /or diaphragm with spermicide while participating in the study; and/or c) abstinence 8. Willing and able to provide written informed consent 9. Willing and able to attend all study visits and adhere to all study assessments and procedures
Exclusion criteria
1. Severe comorbidities including unstable cardiac or pulmonary disease or any other medical conditions that would, in the opinion of the Investigator, preclude the subject from safely completing the required tests or the study, or is likely to result in disease progression that would require withdrawal of the subject 2. Concomitant clinically significant respiratory disease other than COPD (eg, asthma, tuberculosis, bronchiectasis or other non-specific pulmonary disease). 3. Recent history of COPD exacerbation requiring hospitalization or need for increased treatments for COPD within 6 weeks prior to Screening (Visit 1). 4. Use of daily oxygen therapy \> 12 hours per day 5. Respiratory tract infection within 6 weeks prior to Screening (Visit 1) 6. Use of oral, intravenous, or intramuscular steroids within 3 months prior to Screening (Visit 1) 7. History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localized basal cell carcinoma of the skin 8. Prolonged QTcF (\> 450 msec for males and \> 470 msec for females) during Screening (Visit 1) as determined from the report provided by the central laboratory, or history of long QT syndrome 9. History of or clinically significant on-going bladder outflow obstruction or history of catheterization for relief of bladder outflow obstruction within the previous 6 months 10. History of narrow angle glaucoma 11. History of hypersensitivity or intolerance to aerosol medications 12. Recent documented history (within the previous 3 months) of substance abuse 13. Significant psychiatric disease that would likely result in the subject not being able to complete the study, in the opinion of the Investigator 14. Participation in another investigational drug study where drug was received within 30 days prior to Screening (Visit 1) or current participation in another investigational drug trial, including a SUN-101 study 15. Previously received SUN-101 (active treatment; formerly known as EP-101) 16. Contraindicated for treatment with, or having a history of reactions/hypersensitivity to anticholinergic agents, beta2 agonists, or sympathomimetic amines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | baseline and Week 12 | All collected Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in this analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR). |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12 | Week 12 | On-treatment Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study | baseline and Week 12 | All collected Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR). |
| Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study | baseline and Week 12 | On-treatment Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR). |
| Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period | Week 0-12 | All collected Participants completed an electronic diary (eDiary) daily (night time) to record the number of puffs of rescue medication inhaled in the previous 24 hours. A negative change from baseline indicates improvement. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR). |
| Number of Subjects With Treatment Emergent Adverse Events (TEAE) | Week 0-12 | On-treatment A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE. |
| Percentage of Subjects With Treatment Emergent Adverse Events (TEAE) | Week 0-12 | A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE. |
| Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) | Week 0-12 | A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE. |
| Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 | baseline and Week 12 | All collected Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR). |
| Number of Subjects Who Discontinue Treatment Due to TEAE | Week 0-12 | A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE. |
| Percentage of Subjects Who Discontinue Treatment Due to TEAE | Week 0-12 | A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE. |
| Number of Subjects With Major Adverse Cardiac Events (MACE) | Week 0-12 | All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact) |
| Percentage of Subjects With Major Adverse Cardiac Events (MACE) | Week 0-12 | All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact) |
| Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE) | Week 0-12 | All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact) Incidence rate: TT= Total Time in years. Total Time (TT) is defined as the time from the first date of study drug until the latter of the date of last contact or 30 days after the date of last dose. Incidence Rate (per 1000 person-years) = n/TT x 1000. |
| Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE) | Week 0-12 | A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE. |
| Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12 | baseline and Week 12 | On-treatment Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR). |
Countries
United States
Participant flow
Pre-assignment details
All enrolled were randomized. All subjects were to be followed for the full 12-week treatment period of the study, whether or not they continued on the study drug, .until the end of the treatment period. One subject randomized in error to the placebo arm was never dosed .
Participants by arm
| Arm | Count |
|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer SUN-101 50 mcg Twice Daily (BID) via e-Flow (R) Closed System (CS) nebulizer
SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CS) nebulizer | 214 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer SUN-101 25 mcg (BID) via e-Flow (R) Closed System (CS) nebulizer
SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg BID eFlow (R) Closed System (CS) nebulizer | 214 |
| Placebo BID Eflow (CS) Nebulizer Placebo (BID) via e-Flow (R) Closed System (CS) nebulizer
Placebo eFlow (CS) nebulizer: Placebo BID eFlow (R) Closed System (CS) nebulizer | 212 |
| Total | 640 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| On Study Treatment | Adverse Event | 9 | 15 | 19 |
| On Study Treatment | Lack of Efficacy | 3 | 0 | 2 |
| On Study Treatment | Lost to Follow-up | 2 | 6 | 1 |
| On Study Treatment | Met Prolonged QT criteria | 1 | 0 | 0 |
| On Study Treatment | non-complicance with study medication | 0 | 2 | 0 |
| On Study Treatment | Protocol Violation | 0 | 0 | 1 |
| On Study Treatment | ranomized in error | 0 | 0 | 1 |
| On Study Treatment | withdrew consent | 9 | 8 | 12 |
| Study Participation | Adverse Event | 1 | 4 | 6 |
| Study Participation | incarceration | 1 | 0 | 0 |
| Study Participation | Lost to Follow-up | 3 | 6 | 2 |
| Study Participation | Met Prolonged QT criteria | 1 | 0 | 0 |
| Study Participation | non-compliance with study drug | 0 | 1 | 0 |
| Study Participation | randomized in error | 0 | 0 | 1 |
| Study Participation | Withdrawal by Subject | 8 | 9 | 15 |
| Study Participation | withdrew consent | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | SUN-101 50 mcg BID eFlow (CS) Nebulizer | SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Placebo BID Eflow (CS) Nebulizer | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 95 Participants | 105 Participants | 101 Participants | 301 Participants |
| Age, Categorical Between 18 and 65 years | 119 Participants | 109 Participants | 111 Participants | 339 Participants |
| Age, Continuous | 62.6 years STANDARD_DEVIATION 9.2 | 63.6 years STANDARD_DEVIATION 8.66 | 63.7 years STANDARD_DEVIATION 9.26 | 63.3 years STANDARD_DEVIATION 9.04 |
| Background long-acting beta(2) agonist (LABA) use background LABA use = no | 147 participants | 145 participants | 143 participants | 435 participants |
| Background long-acting beta(2) agonist (LABA) use background LABA use = yes | 67 participants | 69 participants | 69 participants | 205 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk cerebrovascular disease | 10 participants | 8 participants | 9 participants | 27 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk clinically significant arrhythmia | 8 participants | 7 participants | 6 participants | 19 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk heart failure | 4 participants | 4 participants | 6 participants | 14 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk high cardiovascular risk | 134 participants | 136 participants | 136 participants | 406 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk hypertension | 124 participants | 123 participants | 125 participants | 372 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk ischemic heart disease | 20 participants | 24 participants | 20 participants | 64 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk low cardiovascular risk | 80 participants | 78 participants | 76 participants | 234 participants |
| Cardiovascular risk (low/high) and categories for high cardiovascular risk peripheral arterial disease | 7 participants | 9 participants | 17 participants | 33 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 211 Participants | 212 Participants | 209 Participants | 632 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Forced expiratory volume in one second (FEV1) | 1.3506 liters STANDARD_DEVIATION 0.5538 | 1.3232 liters STANDARD_DEVIATION 0.50179 | 1.13355 liters STANDARD_DEVIATION 0.48612 | 1.3365 liters STANDARD_DEVIATION 0.51414 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 27 Participants | 19 Participants | 72 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 188 Participants | 185 Participants | 192 Participants | 565 Participants |
| Region of Enrollment United States | 214 Participants | 214 Participants | 212 Participants | 640 Participants |
| Sex: Female, Male Female | 87 Participants | 90 Participants | 88 Participants | 265 Participants |
| Sex: Female, Male Male | 127 Participants | 124 Participants | 124 Participants | 375 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 41 / 214 | 47 / 214 | 39 / 212 |
| serious Total, serious adverse events | 8 / 214 | 5 / 214 | 13 / 212 |
Outcome results
Primary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
All collected Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in this analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: baseline and Week 12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.0847 liters | Standard Error 0.01423 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.0921 liters | Standard Error 0.01446 |
| Placebo BID Eflow (CS) Nebulizer | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.0111 liters | Standard Error 0.01452 |
Comparison: The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.p-value: 0.000295% CI: [0.0346, 0.1127]Least Mean Squared (SE)
Comparison: The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.p-value: 0.000195% CI: [0.0416, 0.1204]Least Mean Squared (SE)
Primary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12
On-treatment Spirometry was performed according to internationally accepted standards. Trough FEV1 at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: Week 12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12 | 0.0890 liters | Standard Error 0.01479 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12 | 0.0909 liters | Standard Error 0.01492 |
| Placebo BID Eflow (CS) Nebulizer | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12 | 0.0069 liters | Standard Error 0.01502 |
Comparison: The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures model including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.p-value: <0.000195% CI: [0.0417, 0.1224]Least Mean Squared (SE)
Comparison: The change from baseline in trough FEV1 was analyzed using a mixed model repeated measures model including terms for treatment, cardiovascular risk, background LABA use, visit week, visit week by treatment interaction, and baseline FEV1 as a covariate. An unstructured covariance matrix was used.p-value: 0.000195% CI: [0.0433, 0.1246]Least Mean Squared (SE)
Secondary
Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study
All collected Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: baseline and Week 12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study | -3.825 units on a scale | Standard Error 0.806 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study | -3.225 units on a scale | Standard Error 0.8168 |
| Placebo BID Eflow (CS) Nebulizer | Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study | -0.138 units on a scale | Standard Error 0.8067 |
Secondary
Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study
On-treatment Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: symptoms, activity, and impacts. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is 0 and the highest 100. Higher values correspond to greater impairment of health status. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: baseline and Week 12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study | -3.609 units on a scale | Standard Error 0.8237 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study | -3.637 units on a scale | Standard Error 0.8269 |
| Placebo BID Eflow (CS) Nebulizer | Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study | -0.052 units on a scale | Standard Error 0.8212 |
Secondary
Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12
All collected Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not, and regardless if the values might potentially be affected by other therapies or not Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: baseline and Week 12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 | 0.1090 liters | Standard Error 0.02205 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 | 0.1346 liters | Standard Error 0.2239 |
| Placebo BID Eflow (CS) Nebulizer | Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 | 0.0156 liters | Standard Error 0.02247 |
Secondary
Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12
On-treatment Spirometry was performed according to internationally accepted standards. Trough FVC at Week 12 was defined as the mean of the values collected at two time points 30 minutes apart at approximately 24 hours (± 1 hour) after the previous morning dose. Only on-treatment values (which included only data collected while subjects were taking study drug) are used for this analysis. Values affected by other medication use were set to missing. Non-collected or missing data were not imputed for this analysis. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: baseline and Week 12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12 | 0.1210 liters | Standard Error 0.02332 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12 | 0.1385 liters | Standard Error 0.02354 |
| Placebo BID Eflow (CS) Nebulizer | Change From Baseline in Trough Forced Vital Capacity (FVC)Week 12 | 0.0084 liters | Standard Error 0.02367 |
Secondary
Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period
All collected Participants completed an electronic diary (eDiary) daily (night time) to record the number of puffs of rescue medication inhaled in the previous 24 hours. A negative change from baseline indicates improvement. All collected values were used in the analyses, regardless if the subject remained on randomized treatment or not. Values not collected remained as missing values and were assumed to be missing at random (MAR).
Time frame: Week 0-12
Population: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study One subject randomized in error to the placebo arm was never dosed .~medication. Subjects were analyzed based on the treatment they were randomized to.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period | -0.845 puffs (medication used) | Standard Error 0.1311 |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period | -0.959 puffs (medication used) | Standard Error 0.131 |
| Placebo BID Eflow (CS) Nebulizer | Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period | -0.678 puffs (medication used) | Standard Error 0.1339 |
Secondary
Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE)
All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact) Incidence rate: TT= Total Time in years. Total Time (TT) is defined as the time from the first date of study drug until the latter of the date of last contact or 30 days after the date of last dose. Incidence Rate (per 1000 person-years) = n/TT x 1000.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE) | 64.6 incidence rate |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE) | 63.0 incidence rate |
| Placebo BID Eflow (CS) Nebulizer | Incidence Rate Per 1000 Person-years of Subjects With Major Adverse Cardiac Events (MACE) | 62.2 incidence rate |
Secondary
Number of Subjects Who Discontinue Treatment Due to TEAE
A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects Who Discontinue Treatment Due to TEAE | 9 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects Who Discontinue Treatment Due to TEAE | 15 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects Who Discontinue Treatment Due to TEAE | 19 Participants |
Secondary
Number of Subjects With Major Adverse Cardiac Events (MACE)
All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact)
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | MACE score | 0 Participants |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | cardiovascular death | 0 Participants |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal myocardial infarction | 0 Participants |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal stroke | 0 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal stroke | 0 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal myocardial infarction | 0 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | MACE score | 0 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | cardiovascular death | 0 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | MACE score | 0 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | cardiovascular death | 0 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal myocardial infarction | 0 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal stroke | 0 Participants |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAE)
On-treatment A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects With Treatment Emergent Adverse Events (TEAE) | 114 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects With Treatment Emergent Adverse Events (TEAE) | 101 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects With Treatment Emergent Adverse Events (TEAE) | 111 Participants |
Secondary
Number of Subjects With Treatment Emergent Serious Adverse Events (SAE)
A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) | 8 Participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) | 5 Participants |
| Placebo BID Eflow (CS) Nebulizer | Number of Subjects With Treatment Emergent Serious Adverse Events (SAE) | 13 Participants |
Secondary
Percentage of Subjects Who Discontinue Treatment Due to TEAE
A TEAE is defined as any AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects Who Discontinue Treatment Due to TEAE | 4.2 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects Who Discontinue Treatment Due to TEAE | 7.0 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects Who Discontinue Treatment Due to TEAE | 9.0 percentage of participants |
Secondary
Percentage of Subjects With Major Adverse Cardiac Events (MACE)
All deaths and any other findings suggestive of a potential MACE (including clinically relevant information and SAEs, and all PTs form the SMQs myocardial infarction, other ischemic heart disease, central nervous system hemorrhages and cerebrovascular conditions) were sent to an adjudication committee for review and categorized as CV death, nonfatal MI, and nonfatal stroke. The MACE score was defined as the total number of subjects with CV deaths, nonfatal MIs, and nonfatal strokes. These events were collected for the double-blind period (from the first date of study medication until the date of last contact)
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | cardiovascular death | 0 percentage of participants |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal myocardialinfarction | 0 percentage of participants |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal stroke | 0 percentage of participants |
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | MACE score | 0 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | MACE score | 0 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | cardiovascular death | 0 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal stroke | 0 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal myocardialinfarction | 0 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | MACE score | 0.9 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal myocardialinfarction | 0.9 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | non-fatal stroke | 0 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects With Major Adverse Cardiac Events (MACE) | cardiovascular death | 0 percentage of participants |
Secondary
Percentage of Subjects With Treatment Emergent Adverse Events (TEAE)
A TEAE is defined as any non-serious AE that occurred on or after the first dose of study medication and within 7 days after the last dose of study medication, or any serious AE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent AE is an on-treatment AE.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects With Treatment Emergent Adverse Events (TEAE) | 53.3 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects With Treatment Emergent Adverse Events (TEAE) | 47.2 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects With Treatment Emergent Adverse Events (TEAE) | 52.4 percentage of participants |
Secondary
Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE)
A treatment emergent SAE is defined as any SAE that occurred on or after the first dose of study medication and within 30 days after the last dose of study medication. A treatment emergent SAE is an on-treatment SAE.
Time frame: Week 0-12
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication. One subject randomized in error to the placebo arm was never dosed .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUN-101 50 mcg BID eFlow (CS) Nebulizer | Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE) | 3.7 percentage of participants |
| SUN-101 25 mcg BID e-Flow (CS) Nebulizer | Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE) | 2.3 percentage of participants |
| Placebo BID Eflow (CS) Nebulizer | Percentage of Subjects With Treatment Emergent Serious Adverse Events (SAE) | 6.1 percentage of participants |