Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, Chronic Obstructive Pulmonary Disease, Chronic Bronchitis, Emphysema, Airflow Obstruction, Chronic, Chronic Airflow Obstruction, Chronic Obstructive Airway Disease, Chronic Obstructive Lung Disease
Brief summary
The purpose of this study is to assess the long-term safety and tolerability of inhaled aclidinium bromide/formoterol in patients with moderate to severe, stable chronic obstructive pulmonary disease (COPD).
Interventions
Inhaled aclidinium bromide 400 μg/formoterol fumarate 12 μg, high dose twice per day
DRUGFormoterol Fumarate
Inhaled formoterol fumarate 12 μg, twice per day
Sponsors
AstraZeneca
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
* Current or former cigarette smokers with a cigarette smoking history of at least 10 pack-years * A diagnosis of stable moderate to severe COPD and stable airway obstruction as defined by the Global Initiative for Chronic Obstructive Lung Disease guidelines and stable airway obstruction.
Exclusion criteria
* Patients who have been hospitalized for an acute COPD exacerbation within three months prior to Visit 1 * Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the six weeks before Visit 1. * Patients with any clinically significant respiratory conditions other than COPD * Clinical history that suggests that the patient has asthma as opposed to COPD * Chronic use of oxygen therapy ≥ 15 hours/day * Patients with clinically significant cardiovascular conditions * Patients with uncontrolled infection that may place the patient at risk resulting from human immunodeficiency virus (HIV), active hepatitis and/or patients with diagnosed active tuberculosis * Patients with a history of hypersensitivity reaction to inhaled anticholinergics, * Patients with Stage II hypertension, defined as systolic pressure of 160 and above, and/or diastolic pressure of 100 and above * Current diagnosis of cancer other than basal or squamous cell skin cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE) | Up to study Week 56 ± 3 days | TEAEs were coded Version 16.0 of the Medical Dictionary for Regulatory Activities (MedDRA) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study | Up to study Week 52 | \<0.85 x lower limit of normal (LLN) or \> 1.15 upper limit of normal (ULN) for hemoglobin, hematocrit, red blood cell, platelet, white blood cell, neutrophil and lymphocyte counts \>1.15 × ULN for eosinophil, basophil and monocyte counts \>1.15 x ULN for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, total cholesterol, triglycerides \<0.85 x LLN or \>1.15 ULN for fasting glucose, calcium, phosphorus, total protein and albumin \<0.95 x LLN or \>1.05 x ULN for sodium, potassium and chloride Urinary blood, ketones or pH \<0.85 x LLN or \> 1.15 ULN |
| Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Up to study Week 56 ± 3 days | Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline; Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline; Pulse rate ≥ 110 bpm and increase ≥ 15% from baseline or ≤ 50 bpm and decrease ≥15% from baseline |
| Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | Up to study Week 56 ± 3 days | Potentially clinically significant changes were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR) |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 127 centers in the United States The first patient was screened in September 2011 and the last patient visit was in March 2013
Pre-assignment details
The study consisted of a 2- to 3-week run-in period designed to assess the stability of patients' disease and establish each patient's baseline characteristics 1063 patients were screened for eligibility; 473 were considered screen failures (main reason \[406/473\] inclusion/exclusion criteria not met)
Participants by arm
| Arm | Count |
|---|---|
| Aclidinium/Formoterol 400 μg/12 μg Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler | 392 |
| Formoterol 12 μg Formoterol 12 μg administered BID via dry-powder inhaler | 198 |
| Total | 590 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 26 | 13 |
| Overall Study | COPD exacerbation | 13 | 3 |
| Overall Study | Lack of Efficacy | 23 | 11 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Not listed below | 7 | 6 |
| Overall Study | Protocol Violation | 24 | 12 |
| Overall Study | Withdrawal by Subject | 31 | 15 |
Baseline characteristics
| Characteristic | Aclidinium/Formoterol 400 μg/12 μg | Formoterol 12 μg | Total |
|---|---|---|---|
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 9.3 | 64.7 Years STANDARD_DEVIATION 9.4 | 64.2 Years STANDARD_DEVIATION 9.4 |
| Sex: Female, Male Female | 176 Participants | 89 Participants | 265 Participants |
| Sex: Female, Male Male | 216 Participants | 109 Participants | 325 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 164 / 392 | 88 / 198 |
| serious Total, serious adverse events | 38 / 392 | 21 / 198 |
Outcome results
Primary
Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE)
TEAEs were coded Version 16.0 of the Medical Dictionary for Regulatory Activities (MedDRA)
Time frame: Up to study Week 56 ± 3 days
Population: Safety Population defined as all randomized patients who took at least one dose of double-blind investigational product
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE) | 71.4 Percentage of participants |
| Formoterol 12 μg | Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE) | 65.7 Percentage of participants |
Secondary
Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study
\<0.85 x lower limit of normal (LLN) or \> 1.15 upper limit of normal (ULN) for hemoglobin, hematocrit, red blood cell, platelet, white blood cell, neutrophil and lymphocyte counts \>1.15 × ULN for eosinophil, basophil and monocyte counts \>1.15 x ULN for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, total cholesterol, triglycerides \<0.85 x LLN or \>1.15 ULN for fasting glucose, calcium, phosphorus, total protein and albumin \<0.95 x LLN or \>1.05 x ULN for sodium, potassium and chloride Urinary blood, ketones or pH \<0.85 x LLN or \> 1.15 ULN
Time frame: Up to study Week 52
Population: Patients with available non-potentially clinically significant baseline value and at least one post-baseline assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study | 63.9 Percentage of participants |
| Formoterol 12 μg | Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study | 62.1 Percentage of participants |
Secondary
Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure
Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline; Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline; Pulse rate ≥ 110 bpm and increase ≥ 15% from baseline or ≤ 50 bpm and decrease ≥15% from baseline
Time frame: Up to study Week 56 ± 3 days
Population: Patients with baseline and at least 1 post-baseline assessment of vital signs for each parameter
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Systolic BP ≥180 mmHg and increase ≥20 mmHg | 0.3 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Systolic BP ≤90 mmHg and decrease ≥20 mmHg | 1.5 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Diastolic BP ≥105 mmHg and increase ≥15 mmHg | 0 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Diastolic BP ≤50 mmHg and decrease ≥15 mmHg | 0.3 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Pulse rate ≥ 110 bpm and increase ≥ 15% | 0.8 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Pulse rate ≤ 50 bpm and decrease ≥15% | 0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Pulse rate ≥ 110 bpm and increase ≥ 15% | 0.5 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Systolic BP ≥180 mmHg and increase ≥20 mmHg | 0.5 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Diastolic BP ≤50 mmHg and decrease ≥15 mmHg | 1.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Systolic BP ≤90 mmHg and decrease ≥20 mmHg | 1.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Pulse rate ≤ 50 bpm and decrease ≥15% | 0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure | Diastolic BP ≥105 mmHg and increase ≥15 mmHg | 0.5 Percentage of patients |
Secondary
Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline
Potentially clinically significant changes were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR)
Time frame: Up to study Week 56 ± 3 days
Population: Patients with baseline and at least 1 post-baseline assessment value for each parameter
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcF change from baseline >30 msec | 21.5 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | PR interval ≥200 msec and increase ≥25% from base | 2.8 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcB value >480 msec | 3.1 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | HR ≥110 bpm and decrease ≥15% from baseline | 2.6 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcF value >480 msec | 1.5 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | HR ≤50 bpm and decrease ≥15% from baseline | 4.6 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcB change from baseline >30 msec | 31.1 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QT interval change from baseline >30 msec | 42.0 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QRS interval ≥100 msec and increase ≥25% from base | 2.0 Percentage of patients |
| Aclidinium/Formoterol 400 μg/12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QT interval >480 msec | 3.9 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QRS interval ≥100 msec and increase ≥25% from base | 1.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcB change from baseline >30 msec | 30.3 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcB value >480 msec | 4.5 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcF change from baseline >30 msec | 22.7 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QTcF value >480 msec | 1.5 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QT interval >480 msec | 2.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | PR interval ≥200 msec and increase ≥25% from base | 1.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | HR ≥110 bpm and decrease ≥15% from baseline | 1.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | HR ≤50 bpm and decrease ≥15% from baseline | 4.0 Percentage of patients |
| Formoterol 12 μg | Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline | QT interval change from baseline >30 msec | 44.7 Percentage of patients |