Trial Outcomes & Findings for Evaluate the Effect of Aclidinium Bromide on Long-term Cardiovascular Safety and Exacerbations in Moderate to Very Severe COPD Patients. (NCT NCT01966107)

NCT ID: NCT01966107

Last Updated: 2018-12-06

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

3635 participants

Primary outcome timeframe

12 months

Results posted on

2018-12-06

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	1812	1818
Overall Study Full Analysis Set	1791	1798
Overall Study COMPLETED	1010	937
Overall Study NOT COMPLETED	802	881

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study excluded from FAS	21	20
Overall Study discontinued treatment	345	372
Overall Study due to study closure	164	186
Overall Study withdrew from the study	272	303

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aclidinium Bromide n=1791 Participants 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.	Placebo n=1798 Participants 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.	Total n=3589 Participants Total of all reporting groups
Age, Continuous	67.1 Years STANDARD_DEVIATION 8.5 • n=5 Participants	67.2 Years STANDARD_DEVIATION 8.3 • n=7 Participants	67.2 Years STANDARD_DEVIATION 8.4 • n=5 Participants
Age, Customized >=40 - <60 years	340 Participants n=5 Participants	325 Participants n=7 Participants	665 Participants n=5 Participants
Age, Customized >=60 - <70 years	724 Participants n=5 Participants	725 Participants n=7 Participants	1449 Participants n=5 Participants
Age, Customized >=70 years	727 Participants n=5 Participants	748 Participants n=7 Participants	1475 Participants n=5 Participants
Sex: Female, Male Female	732 Participants n=5 Participants	752 Participants n=7 Participants	1484 Participants n=5 Participants
Sex: Female, Male Male	1059 Participants n=5 Participants	1046 Participants n=7 Participants	2105 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Asian	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	165 Participants n=5 Participants	138 Participants n=7 Participants	303 Participants n=5 Participants
Race/Ethnicity, Customized White	1603 Participants n=5 Participants	1650 Participants n=7 Participants	3253 Participants n=5 Participants
Race/Ethnicity, Customized Other	7 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Aclidinium Bromide n=1791 Participants 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.	Placebo n=1798 Participants 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.
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 Interval 0.4 to 0.5	0.57 Events per subject per year Interval 0.52 to 0.64

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Aclidinium Bromide n=1791 Participants 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.	Placebo n=1798 Participants 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.
Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis Number of subjects with events	69 Participants	76 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Aclidinium Bromide n=1791 Participants 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.	Placebo n=1798 Participants 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.
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 Interval 0.05 to 0.08	0.10 Events per subject per year Interval 0.08 to 0.13

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Aclidinium Bromide n=1791 Participants 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.	Placebo n=1798 Participants 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.
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	160 Participants

Adverse Events

Aclidinium Bromide

Serious events: 409 serious events

Other events: 1105 other events

Deaths: 75 deaths

Placebo

Serious events: 356 serious events

Other events: 1065 other events

Deaths: 64 deaths

Serious adverse events

Other adverse events

Additional Information

AstraZeneca Clinical

Study Information Center

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee This submission /document contains trade secrets and confidential commercial information, disclosure of which is prohibited without providing advance notice to AstraZeneca and opportunity to object.
Publication restrictions are in place

Restriction type: OTHER

Measure	Aclidinium Bromide n=1791 participants at risk 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.	Placebo n=1798 participants at risk 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.
Infections and infestations Bronchitis	3.9% 70/1791 • Number of events 85 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	4.1% 74/1798 • Number of events 92 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Infections and infestations Pneumonia	2.6% 46/1791 • Number of events 51 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.9% 52/1798 • Number of events 57 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Infections and infestations Sinusitis	3.6% 65/1791 • Number of events 87 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.5% 63/1798 • Number of events 73 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Infections and infestations Upper Respiratory Tract Infection	4.8% 86/1791 • Number of events 104 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	5.6% 101/1798 • Number of events 117 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Infections and infestations Urinary Tract Infection	5.0% 90/1791 • Number of events 122 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	4.7% 84/1798 • Number of events 104 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Infections and infestations Viral Upper Respiratory Tract Infection	4.4% 78/1791 • Number of events 95 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.7% 67/1798 • Number of events 77 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Blood and lymphatic system disorders Anaemia	2.2% 40/1791 • Number of events 40 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.1% 38/1798 • Number of events 39 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Nervous system disorders Headache	3.2% 57/1791 • Number of events 74 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.6% 65/1798 • Number of events 84 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Nervous system disorders Dizziness	2.5% 44/1791 • Number of events 46 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.3% 42/1798 • Number of events 45 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Cardiac disorders Atrial Fibrillation	1.5% 27/1791 • Number of events 30 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.2% 40/1798 • Number of events 44 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Vascular disorders Hypertension	3.6% 64/1791 • Number of events 66 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.1% 56/1798 • Number of events 60 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.7% 48/1791 • Number of events 52 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.9% 70/1798 • Number of events 74 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Respiratory, thoracic and mediastinal disorders Cough	3.7% 67/1791 • Number of events 71 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.4% 62/1798 • Number of events 66 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Gastrointestinal disorders Diarrhoea	3.2% 58/1791 • Number of events 62 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.4% 62/1798 • Number of events 67 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Gastrointestinal disorders Constipation	3.4% 60/1791 • Number of events 65 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.9% 53/1798 • Number of events 53 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	2.1% 38/1791 • Number of events 38 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	1.3% 23/1798 • Number of events 23 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Gastrointestinal disorders Nausea	4.3% 77/1791 • Number of events 83 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.2% 57/1798 • Number of events 64 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Musculoskeletal and connective tissue disorders Arthralgia	2.8% 50/1791 • Number of events 53 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.5% 45/1798 • Number of events 51 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Musculoskeletal and connective tissue disorders Muscle Spasms	2.2% 40/1791 • Number of events 44 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	1.9% 34/1798 • Number of events 36 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Musculoskeletal and connective tissue disorders Back Pain	3.9% 69/1791 • Number of events 72 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.0% 54/1798 • Number of events 57 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	1.6% 28/1791 • Number of events 31 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.1% 38/1798 • Number of events 40 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Musculoskeletal and connective tissue disorders Pain In Extremity	2.0% 35/1791 • Number of events 37 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.1% 38/1798 • Number of events 41 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
General disorders Oedema Peripheral	2.7% 48/1791 • Number of events 54 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	3.4% 61/1798 • Number of events 70 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Psychiatric disorders Anxiety	1.9% 34/1791 • Number of events 35 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.	2.2% 39/1798 • Number of events 42 • Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.