Chronic Obstructive Pulmonary Disease, COPD, Moderate to Very Severe COPD
Conditions
Brief summary
The Objectives of this study are to assess the safety of Aclidinium bromide on major adverse cardiovascular events (MACE), to assess the overall safety of Aclidinium bromide and to assess whether Aclidinium bromide reduces moderate or severe COPD exacerbations. This study is a double-blind, randomized, placebo controlled, parallel-group study to evaluate the effect of Aclidinium bromide on the cardiovascular safety and COPD exacerbations in patients with moderate to very severe COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.
Interventions
400 μg, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)
DRUGPlacebo
Dose matched placebo, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)
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 130 Years
Healthy volunteers
No
Inclusion criteria
* 1\. Male or female outpatients ≥ 40 years of age * 2\. Current or former cigarette smokers with a smoking history of at least 10 pack-years * 3\. A diagnosis of stable, moderate to very severe COPD (GOLD, 2015) with a post-bronchodilator FEV \< 80% FEV1/forced vital capacity (FVC) ratio \< 70% * 4\. Must have at least one of the following 4 criteria: 1. Documented cerebrovascular disease (stroke or transient ischemic attack, carotid stenosis) 2. Documented coronary artery disease (angina, MI, angioplasty/stent/bypass) 3. Documented peripheral vascular disease or history of claudication 4. At least 2 of the following atherothrombotic risk factors as determined by the PI: 1. Male ≥ 65 years or female ≥ 70 years 2. Diabetes 3. Dyslipidemia 4. Hypertension 5. Waist circumference inches males ≥ 40 in or in females ≥ 38 inches 6. Evidence of renal dysfunction (eGFR \< 60) and microalbuminuria (eGFR is based on modification of diet in renal disease \[MDRD\] equation, microalbuminuria is defined as ≥ 30-300 mcg/mg creatinine on a spot urine or ≥30 mg creatinine on a 24hr urine test) * 5\. Maintained stable respiratory medications for 2 weeks prior to randomization (Appendix II) * 6\. Able to perform pulmonary function test (PFT) maneuvers and follow study procedures * 7\. Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (HCG) pregnancy test at Visit 1A and be practicing medically acceptable method of contraception. Otherwise, female patients should be at least 1 year postmenopausal, surgically sterile (defined as having a hysterectomy or tubal ligation). * 8\. Should understand study procedures and be willing to participate in the study as indicated by signing the ICF
Exclusion criteria
* 1\. Significant diseases other than COPD or cardiovascular disease (e.g., metastatic cancer) which, in the opinion of the PI, may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study * 2\. Unstable or life threatening cardiovascular disease or COPD as determined by the PI * 3\. Patients with comorbid lung disease such as asthma, cystic fibrosis, bronchiectasis, interstitial lung disease, or pulmonary thromboembolic disease * 4\. Planned lung transplant or lung volume reduction surgery * 5\. Currently treated with a combination of LAMA and LABA/ICS therapy. * 6\. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within 5 years prior to screening. Patients with treated basal cell and squamous cell (skin) carcinoma are allowed * 7\. Respiratory infection or COPD exacerbation at Screening and/or within 4 weeks prior to screening * 8\. Uncontrolled infection resulting from human immunodeficiency virus (HIV) and/or active hepatitis * 9\. Reported history of drug or alcohol abuse within the past 12 months * 10\. History of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm) * 11\. History of acute urinary retention, treatment refractory benign prostatic hyperplasia (BPH), bladder neck obstruction, or narrow-angle glaucoma (Note: Patients with controlled, stable BPH are not excluded) * 12\. Patients unable to use a multidose DPI or a pressurized metered-dose inhaler * 13\. Treatment with any other investigational drug within 30 days (or 6 half-lives, whichever is longer) before Visit 1A * 14\. Women who are pregnant or breastfeeding * 15\. Use of any prohibited medication listed in Appendix II * 16\. Employee or immediate relative of an employee of AstraZeneca, any of its affiliates or partners, or the study center
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Subject Per Year During the First Year of Treatment | 12 months | The rate (number of events per subject per year) of moderate or severe COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline inhaled corticosteroids (ICS) use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable. |
| Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis | At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU) | To assess the cardiovascular (CV) safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated composite MACE with treatment group, baseline CV severity, and smoking status as factors. MACE for the analyses was defined as any adjudicated event which was a composite of the total of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (on-study analysis). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Hospitalizations Due to COPD Exacerbation Per Subject Per Year During the First Year of Treatment- on Treatment Analysis | 12 months | To assess whether aclidinium bromide reduces moderate or severe COPD exacerbations. The rate of hospitalization (number of events per subject per year) due to COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline ICS use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable. |
| Number of Participants With Major Adverse Cardiovascular Event (MACE) or Other Serious Cardiovascular Events of Interest - On-study Analysis | At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU) | To assess the CV safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated MACE or other serious CV events of interest with treatment group, baseline CV severity, and smoking status as factors. Other serious CV events included events from Cardiac tachyarrhythmias plus preferred terms (PTs) Tachycardia, Heart rate increase, and Palpitation; Cardiac failure; Bradycardia and PTs Sinus arrest and Sinus bradycardia; Conduction defects; Conditions associated with Central nervous system haemorrhages and cerebrovascular accidents; and selected PTs included in the Other ischemic heart disease. |
Countries
Canada, United States
Participant flow
Recruitment details
This study was conducted at 522 study centers in North America; 35 centers in Canada and 487 centers in the US. A total of 4000 subjects were planned to be enrolled. A total of 3630 subjects were randomized (1:1) to aclidinium bromide 400 μg twice a day (BID) or placebo BID. Rescue medication (albuterol/salbutamol) was provided for all subjects.
Pre-assignment details
Informed consent form was signed; inclusion/exclusion, smoking status, electrocardiogram, pregnancy test, Pulmonary function testing, Chronic obstructive pulmonary disease (COPD) exacerbation were assessed. Out of 3635 subjects, 5 subjects were duplicated, who, in violation of protocol entrance criteria, entered the study more than once.
Participants by arm
| Arm | Count |
|---|---|
| Aclidinium Bromide Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization. | 1,791 |
| Placebo Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization. | 1,798 |
| Total | 3,589 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | discontinued treatment | 345 | 372 |
| Overall Study | due to study closure | 164 | 186 |
| Overall Study | excluded from FAS | 21 | 20 |
| Overall Study | withdrew from the study | 272 | 303 |
Baseline characteristics
| Characteristic | Aclidinium Bromide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 67.1 Years STANDARD_DEVIATION 8.5 | 67.2 Years STANDARD_DEVIATION 8.3 | 67.2 Years STANDARD_DEVIATION 8.4 |
| Age, Customized >=40 - <60 years | 340 Participants | 325 Participants | 665 Participants |
| Age, Customized >=60 - <70 years | 724 Participants | 725 Participants | 1449 Participants |
| Age, Customized >=70 years | 727 Participants | 748 Participants | 1475 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Asian | 8 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 165 Participants | 138 Participants | 303 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 1603 Participants | 1650 Participants | 3253 Participants |
| Sex: Female, Male Female | 732 Participants | 752 Participants | 1484 Participants |
| Sex: Female, Male Male | 1059 Participants | 1046 Participants | 2105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 75 / 1,791 | 64 / 1,798 |
| other Total, other adverse events | 1,105 / 1,791 | 1,065 / 1,798 |
| serious Total, serious adverse events | 409 / 1,791 | 356 / 1,798 |
Outcome results
Primary
Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis
To assess the cardiovascular (CV) safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated composite MACE with treatment group, baseline CV severity, and smoking status as factors. MACE for the analyses was defined as any adjudicated event which was a composite of the total of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (on-study analysis).
Time frame: At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU)
Population: The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aclidinium Bromide | Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis | Number of subjects with events | 69 Participants |
| Placebo | Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis | Number of subjects with events | 76 Participants |
Comparison: Composite MACE95% CI: [0.64, 1.23]
Primary
Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Subject Per Year During the First Year of Treatment
The rate (number of events per subject per year) of moderate or severe COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline inhaled corticosteroids (ICS) use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable.
Time frame: 12 months
Population: The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aclidinium Bromide | Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Subject Per Year During the First Year of Treatment | 0.44 Events per subject per year |
| Placebo | Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Subject Per Year During the First Year of Treatment | 0.57 Events per subject per year |
Secondary
Number of Participants With Major Adverse Cardiovascular Event (MACE) or Other Serious Cardiovascular Events of Interest - On-study Analysis
To assess the CV safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated MACE or other serious CV events of interest with treatment group, baseline CV severity, and smoking status as factors. Other serious CV events included events from Cardiac tachyarrhythmias plus preferred terms (PTs) Tachycardia, Heart rate increase, and Palpitation; Cardiac failure; Bradycardia and PTs Sinus arrest and Sinus bradycardia; Conduction defects; Conditions associated with Central nervous system haemorrhages and cerebrovascular accidents; and selected PTs included in the Other ischemic heart disease.
Time frame: At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU)
Population: The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aclidinium Bromide | Number of Participants With Major Adverse Cardiovascular Event (MACE) or Other Serious Cardiovascular Events of Interest - On-study Analysis | Number of subjects with events | 168 Participants |
| Placebo | Number of Participants With Major Adverse Cardiovascular Event (MACE) or Other Serious Cardiovascular Events of Interest - On-study Analysis | Number of subjects with events | 160 Participants |
Secondary
Rate of Hospitalizations Due to COPD Exacerbation Per Subject Per Year During the First Year of Treatment- on Treatment Analysis
To assess whether aclidinium bromide reduces moderate or severe COPD exacerbations. The rate of hospitalization (number of events per subject per year) due to COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline ICS use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable.
Time frame: 12 months
Population: The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aclidinium Bromide | Rate of Hospitalizations Due to COPD Exacerbation Per Subject Per Year During the First Year of Treatment- on Treatment Analysis | 0.07 Events per subject per year |
| Placebo | Rate of Hospitalizations Due to COPD Exacerbation Per Subject Per Year During the First Year of Treatment- on Treatment Analysis | 0.10 Events per subject per year |
p-value: 0.00695% CI: [0.48, 0.89]Negative Binomial Regression model