Evaluate the Effect of Aclidinium Bromide on Long-term Cardiovascular Safety and Exacerbations in Moderate to Very Severe COPD Patients.

Study Overview
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Brief Summary
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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.

Official Title
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Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV Study to Evaluate the Effect of Aclidinium Bromide on Long-term Cardiovascular Safety and COPD Exacerbations in Patients With Moderate to Very Severe COPD (ASCENT COPD)

Conditions
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COPD, Chronic Obstructive Pulmonary Disease, Moderate to Very Severe COPD

Intervention / Treatment
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* Drug: Aclidinium Bromide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Documented cerebrovascular disease (stroke or transient ischemic attack, carotid stenosis) Documented coronary artery disease (angina, MI, angioplasty/stent/bypass) Documented peripheral vascular disease or history of claudication At least 2 of the following atherothrombotic risk factors as determined by the PI: Male ≥ 65 years or female ≥ 70 years Diabetes Dyslipidemia Hypertension Waist circumference inches males ≥ 40 in or in females ≥ 38 inches 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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aclidinium Bromide<br>Two-week washout/run-in period [for patients on a long-acting muscarinic antagonist (LAMA)] followed by a maximum of 36-month double-blind treatment period. | Drug: Aclidinium Bromide<br>* 400 μg, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)<br>|
| Placebo Comparator: Placebo<br>Two-week washout/run-in period [for patients on a long-acting muscarinic antagonist (LAMA)] followed by a maximum of 36-month double-blind treatment period. | Drug: Placebo<br>* Dose matched placebo, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12 months | 
| 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). | At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 12 months | 
| 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. | At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU) |