COPD
Conditions
Keywords
COPD
Brief summary
Study for subjects 40 to 65 years-old with a diagnosis of moderate to severe COPD. Aclidinium bromide 400 mcg 2x a day will be given as an active comparator.
Detailed description
This is a randomized, six-way crossover study to determine the efficacy and dose-response profile of SUN101. The study population will consist of subjects 40 to 65 years-old (inclusive), with a diagnosis of moderate to severe COPD. Aclidinium bromide 400 mcg bid will be given as an active comparator. The study will be double-blind for SUN-101 and placebo and will be open-label for aclidinium.
Interventions
DRUGAclidinium
Aclidinium 400 mcg bid
DRUGPlacebo
Placebo
DRUGSUN101 3 mcg
SUN-101 3 mcg bid
DRUGSUN-101 6.25 mcg
SUN-101 6.25 mcg bid
DRUGSUN-101 12.5 mcg
SUN-101 12.5 mcg bid
DRUGSUN-101 50 mcg
SUN-101 50 mcg bid
Sponsors
Sunovion Respiratory Development Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients 40 to 65 years-old, inclusive. 2. A clinical diagnosis of moderate to severe COPD according to the GOLD 2011 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 ≥ 40% and ≤ 70% of predicted normal during Screening. 5. Post bronchodilator (following inhalation of ipratropium bromide) FEV1/FVC ratio ≤ 0.70 during Screening. 6. Post bronchodilator (following inhalation of ipratropium bromide) improvement in FEV1 ≥ 12% and ≥ 100 mL during Screening. 7. Ability to perform reproducible spirometry according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines (2005). 8. Female of child bearing potential (only) must have a negative serum pregnancy test at Screening and be neither breastfeeding nor intending to become pregnant during study participation. Females of childbearing potential must be instructed to and agree to avoid pregnancy during the study. Female subjects of child bearing potential must use an adequate method of birth control from Screening until 30 days after receiving study drug and use contraception in addition to their partners using a barrier method. Acceptable forms of contraception are as follows: * Abstinence * Barrier methods: condoms, diaphragms, cervical caps; with a spermicide foam, gel, film, cream or suppository; * Oral contraceptives * Non hormone containing intrauterine methods: intrauterine devices or systems. 9. Willing and able to remain at the study site for at least 24 hours at Day 7 of each Treatment Period. 10. Willing and able to attend all study visits and adhere to all study assessments/procedures. 11. Willing and able to provide written informed consent
Exclusion criteria
1. Current evidence or recent history of any clinically significant and unstable disease (other than COPD) or abnormality in the opinion of the Investigator that would put the subject at risk or which would compromise the quality of the study data; including but not limited to cardiovascular disease, myocardial infarction, cardiac failure, uncontrolled hypertension, life threatening arrhythmias, uncontrolled diabetes, neurologic or neuromuscular disease, liver disease, gastrointestinal disease or electrolyte abnormalities. 2. Current evidence or history of a clinically significant abnormality of cardiac rhythm and/or conduction including Holter monitoring prior to randomization. 3. Primary diagnosis of asthma. 4. 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. 5. Recent history of COPD exacerbation requiring hospitalization or need for increased treatments for COPD within 6 weeks prior to Screening. 6. Use of daily oxygen therapy \> 10 hours per day. 7. Use of systemic steroids within 3 months prior to Screening. 8. Respiratory tract infection within 6 weeks prior to or during Screening. 9. History of tuberculosis, bronchiectasis or other non-specific pulmonary disease. 10. History of urinary retention or bladder neck obstruction type symptoms. 11. History of narrow angle glaucoma. 12. Prolonged QTcF interval (males \> 450 msec and females \>470 msec) during Screening, or history of long QT syndrome. 13. Recent history (previous 12 months) of excessive use or abuse of alcohol or narcotic/illegal drugs. 14. History of hypersensitivity or intolerance to aerosol medications, beta-2 agonists, or anticholinergics. 15. Participation in another investigational drug study where drug was received within 30 days prior to Screening, or current participation in another investigational drug trial. 16. Subject is a staff member of the clinical site or a relative of a clinical site staff member.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | Baseline and Day 7 | Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the average of the 2 spirometry values collected at 23 hours 15 minutes, and 23 hours 45 minutes post-morning dose on Day 7 of each Treatment Period. The FEV1 values within 6 hours after the use of rescue medication were considered as missing. Baseline was calculated as the mean of the FEV1 values at 45 minutes and 15 minutes prior to the morning dose at Day 1 of each Treatment Period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Standardized Change From Baseline in FEV1 AUC(0-12hours) | Day 7 | The standardized FEV1 AUC(0-12) on Day 7 was calculated using the trapezoidal rule from the changes in FEV1 from the baseline value (the mean of the two FEV1 values at 45 minutes and 15 minutes prior to morning dose at Day 1 of the respective Treatment Periods) and dividing by the actual length of the time interval). |
| Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | Over 7 days | A treatment emergent adverse event (TEAE) is any TEAE that occurred on or after the first dose of study medication, any SAE with a missing start date and a stop date on or after the first dose of study medication, or any TEAE with both a missing start and stop date. |
| Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | Over 7 days | A treatment emergent adverse event (TEAE) is any TEAE that occurred on or after the first dose of study medication, any SAE with a missing start date and a stop date on or after the first dose of study medication, or any TEAE with both a missing start and stop date. |
Countries
United States
Participant flow
Pre-assignment details
Eligible subjects will be randomized to one of 12 treatment sequences. There will be a minimum of a 7-day washout period between each treatment visit. At each visit, subjects will receive one dose of study medication according to the sequence assigned.
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 4 | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 6 | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 1 | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Washout Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 4 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants |
| Age, Continuous | 54.6 years STANDARD_DEVIATION 5.88 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 86 Participants |
| Region of Enrollment United States | 96 Participants |
| Sex: Female, Male Female | 50 Participants |
| Sex: Female, Male Male | 46 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 92 | 6 / 91 | 4 / 92 | 6 / 90 | 5 / 92 | 10 / 94 |
| serious Total, serious adverse events | 1 / 92 | 0 / 91 | 2 / 92 | 1 / 90 | 0 / 92 | 3 / 94 |
Outcome results
Primary
Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo.
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the average of the 2 spirometry values collected at 23 hours 15 minutes, and 23 hours 45 minutes post-morning dose on Day 7 of each Treatment Period. The FEV1 values within 6 hours after the use of rescue medication were considered as missing. Baseline was calculated as the mean of the FEV1 values at 45 minutes and 15 minutes prior to the morning dose at Day 1 of each Treatment Period
Time frame: Baseline and Day 7
Population: Efficacy Population: all subjects who were randomized to treatment, received at least one dose of study medication, and had at least one trough FEV1 evaluation and the corresponding baseline FEV1 for at least one treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | -0.0282 liters | Standard Error 0.03 |
| SUN-101 3 mcg | Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | -0.0156 liters | Standard Error 0.03 |
| SUN-101 6.25 mcg | Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | 0.0540 liters | Standard Error 0.0238 |
| SUN-101 12.5 mcg | Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | 0.0806 liters | Standard Error 0.03 |
| SUN-101 50 mcg | Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | 0.1092 liters | Standard Error 0.03 |
| Aclidinium 400 mcg | Change From Baseline in Trough FEV1 at Treatment Visit Day 7 Compared to Placebo. | 0.1285 liters | Standard Error 0.03 |
Comparison: An mixed effects model was used with mean change from baseline in trough FEV1 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: 0.97395% CI: [-0.0318, 0.0569]LS Mean (SE)
Comparison: An mixed effects model was used with mean change from baseline in trough FEV1 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: 0.001495% CI: [0.038, 0.1264]LS Mean (SE)
Comparison: An mixed effects model was used with mean change from baseline in trough FEV1 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: <0.000195% CI: [0.0644, 0.1532]LS Mean (SE)
Comparison: An mixed effects model was used with mean change from baseline in trough FEV1 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlationp-value: <0.000195% CI: [0.0931, 0.1818]LS Mean (SE)
Comparison: An mixed effects model was used with mean change from baseline in trough FEV1 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: <0.000195% CI: [0.1121, 0.2012]LS Mean (SE)
Secondary
Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment)
A treatment emergent adverse event (TEAE) is any TEAE that occurred on or after the first dose of study medication, any SAE with a missing start date and a stop date on or after the first dose of study medication, or any TEAE with both a missing start and stop date.
Time frame: Over 7 days
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 11 participants |
| SUN-101 3 mcg | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 22 participants |
| SUN-101 6.25 mcg | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 23 participants |
| SUN-101 12.5 mcg | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 24 participants |
| SUN-101 50 mcg | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 14 participants |
| Aclidinium 400 mcg | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 24 participants |
| TOTAL | Number of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 62 participants |
Secondary
Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment)
A treatment emergent adverse event (TEAE) is any TEAE that occurred on or after the first dose of study medication, any SAE with a missing start date and a stop date on or after the first dose of study medication, or any TEAE with both a missing start and stop date.
Time frame: Over 7 days
Population: Safety population was defined as all subjects who were randomized to treatment and received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 12.0 percentage of participants |
| SUN-101 3 mcg | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 24.2 percentage of participants |
| SUN-101 6.25 mcg | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 25.0 percentage of participants |
| SUN-101 12.5 mcg | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 26.7 percentage of participants |
| SUN-101 50 mcg | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 15.2 percentage of participants |
| Aclidinium 400 mcg | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 25.5 percentage of participants |
| TOTAL | Percentage of Subjects With Treatment-emergent Adverse Events (Overall and by Treatment) | 64.6 percentage of participants |
Secondary
Standardized Change From Baseline in FEV1 AUC(0-12hours)
The standardized FEV1 AUC(0-12) on Day 7 was calculated using the trapezoidal rule from the changes in FEV1 from the baseline value (the mean of the two FEV1 values at 45 minutes and 15 minutes prior to morning dose at Day 1 of the respective Treatment Periods) and dividing by the actual length of the time interval).
Time frame: Day 7
Population: Efficacy Population: all subjects who were randomized to treatment, received at least one dose of study medication, and had at least one trough FEV1 evaluation and the corresponding baseline FEV1 for at least one treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Standardized Change From Baseline in FEV1 AUC(0-12hours) | -0.0203 Liters | Standard Error 0.0315 |
| SUN-101 3 mcg | Standardized Change From Baseline in FEV1 AUC(0-12hours) | 0.0323 Liters | Standard Error 0.0316 |
| SUN-101 6.25 mcg | Standardized Change From Baseline in FEV1 AUC(0-12hours) | 0.0639 Liters | Standard Error 0.0315 |
| SUN-101 12.5 mcg | Standardized Change From Baseline in FEV1 AUC(0-12hours) | 0.1052 Liters | Standard Error 0.0316 |
| SUN-101 50 mcg | Standardized Change From Baseline in FEV1 AUC(0-12hours) | 0.1760 Liters | Standard Error 0.0315 |
| Aclidinium 400 mcg | Standardized Change From Baseline in FEV1 AUC(0-12hours) | 0.1699 Liters | Standard Error 0.0316 |
Comparison: An mixed effects model was used with standardized FEV1 AUC(0-12) on Day 7 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: 0.004695% CI: [0.0163, 0.0888]LS Mean (SE)
Comparison: An mixed effects model was used with standardized FEV1 AUC(0-12) on Day 7 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: <0.000195% CI: [0.0478, 0.1206]LS Mean (SE)
Comparison: An mixed effects model was used with standardized FEV1 AUC(0-12) on Day 7 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: <0.000195% CI: [0.089, 0.1621]LS Mean (SE)
Comparison: An mixed effects model was used with standardized FEV1 AUC(0-12) on Day 7 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: <0.000195% CI: [0.1601, 0.2325]LS Mean (SE)
Comparison: An mixed effects model was used with standardized FEV1 AUC(0-12) on Day 7 as the response, with factors for treatment, period, sequence, baseline FEV1 as a covariate and a random effect for subject nested within sequence. The Kenward and Roger correction to the degrees of freedom was used. An unstructured covariance model was used to model intrasubject correlation.p-value: <0.000195% CI: [0.1537, 0.2268]LS Mean (SE)