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Study of Aclidinium Bromide/Formoterol Fumarate Compared With Salmeterol/Fluticasone Propionate in Patients With Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT01908140
Recruitment Status : Completed
First Posted : July 25, 2013
Results First Posted : March 7, 2016
Last Update Posted : March 7, 2016
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease (COPD)
Interventions Drug: Aclidinium Bromide / Formoterol Fumarate
Drug: Salmeterol / Fluticasone
Enrollment 933
Recruitment Details This study was conducted at 140 activated sites. A total of 121 sites randomised patients. The first patient was screened in Oct 2013 and the last patient visit was in Aug 2014.
Pre-assignment Details Patients fulfilling inclusion/exclusion criteria at the time of the screening visit were entered into a run-in period of 14-21 days to assess disease stability.
Arm/Group Title Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Hide Arm/Group Description Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
Period Title: Overall Study
Started 468 465
Completed 402 386
Not Completed 66 79
Reason Not Completed
Other or Progressive Disease             5             12
Lack of Efficacy             7             5
Withdrawal by Subject             23             24
Lost to Follow-up             1             6
Protocol Violation             8             9
Adverse Event             22             23
Arm/Group Title Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone Total
Hide Arm/Group Description Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks Total of all reporting groups
Overall Number of Baseline Participants 467 466 933
Hide Baseline Analysis Population Description
Patients with more than 1 treatment were analysed in the Safety population with the actual treatment assigned; for this reason, the Overall Number of Baseline Participants in the safety population is different than the randomised population.
Age, Customized  
Mean (Standard Deviation)
Unit of measure:  Years
Age (years), mean (SD) Number Analyzed 467 participants 466 participants 933 participants
63.5  (8.1) 63.3  (7.5) 63.4  (7.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 467 participants 466 participants 933 participants
Female
160
  34.3%
166
  35.6%
326
  34.9%
Male
307
  65.7%
300
  64.4%
607
  65.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 467 participants 466 participants 933 participants
Austria 23 24 47
Bulgaria 30 32 62
Canada 12 6 18
Czech Republic 11 14 25
France 10 4 14
Germany 118 136 254
Hungary 50 48 98
Italy 6 5 11
Lithuania 17 10 27
Netherlands 11 11 22
Poland 67 55 122
South Africa 68 66 134
Spain 28 34 62
United Kingdom 16 21 37
1.Primary Outcome
Title Peak Forced Expiratory Volume in One Second (FEV1) at Week 24
Hide Description Peak FEV1 define at the highest value observed in the 3h after the morning IMP administration
Time Frame At Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description

ITT population: randomized patients who took at least one dose of IMP and have a baseline FEV1 assessment.

PP population: subset of ITT constituted by patients who met all inclusion/exclusion criteria liable to affect the efficacy ssessment, attained sufficient compliance to treatment and did not present serious deviations of the protocol.

Arm/Group Title Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Hide Arm/Group Description:
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
Overall Number of Participants Analyzed 389 376
Least Squares Mean (Standard Error)
Unit of Measure: Liters
1.655  (0.011) 1.562  (0.011)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Aclidinium Bromide / Formoterol Fumarate, Salmeterol / Fluticasone
Comments This sample size of 900 had 90% power to show that the lower bound of the two-sided 95% confidence interval for the difference between Aclidinium bromide 400 μg/Formoterol Fumarate 12 μg and SeretideTM AccuhalerTM (50/500 μg) in Peak FEV1 at 24 weeks is above -0,055 L
Type of Statistical Test Non-Inferiority or Equivalence
Comments non-inferiority margin=-0,055 L
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method MMRM
Comments If non-inferiority on the PP was achieved then switch to superiority was tested on the ITT.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.093
Confidence Interval (2-Sided) 95%
0.063 to 0.123
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Transition Dyspnoea Index (TDI) Focal Score at Week 24
Hide Description The TDI includes the same 3 categories as BDI and 7 ratings indicating the magnitude of the change from baseline in each category: from -3 (“major deterioration”) to zero (“no change”) to +3 (“major improvement”). Category scores are added to compute the Focal Score (from -9 to 9)
Time Frame At Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PP population defined as a subset of ITT constituted by patients who met all inclusion/exclusion criteria liable to affect the efficacy ssessment, attained sufficient compliance to treatment and did not present serious deviations of the protocol.
Arm/Group Title Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Hide Arm/Group Description:
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
Overall Number of Participants Analyzed 353 341
Least Squares Mean (Standard Error)
Unit of Measure: TDI Focal Score
1.9  (0.17) 1.9  (0.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Aclidinium Bromide / Formoterol Fumarate, Salmeterol / Fluticasone
Comments The total sample size provided 81% nominal power to show that the lower bound of the two-sided 95 confidence interval for the difference between Aclidinium bromide 400 μg/Formoterol fumarate 12 μg and SeretideTM AccuhalerTM (50/500 μg) in transitional dyspnoea index (TDI) at 24 weeks is above -0,5
Type of Statistical Test Non-Inferiority or Equivalence
Comments non-inferiority limit -0.5 units
Statistical Test of Hypothesis P-Value >0.05
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.001
Confidence Interval (2-Sided) 95%
-0.46 to 0.46
Estimation Comments [Not Specified]
Time Frame 24 Weeks treatment + 2 weeks follow-up (±3 days)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Hide Arm/Group Description Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
All-Cause Mortality
Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   35/467 (7.49%)      33/466 (7.08%)    
Blood and lymphatic system disorders     
Anaemia  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Cardiac disorders     
Coronary Artery Disease  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Cardiac Failure  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Myocardial Infarction  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Cor Pulmonale  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Artrial fibrillation  1  1/467 (0.21%)  1 1/466 (0.21%)  1
Artrial flutter  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Congenital, familial and genetic disorders     
Arrhythmogenic right ventricular dysp  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Eye disorders     
Cataract  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Gastrointestinal disorders     
Hiatus hernia  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Peptic ulcer haemorrhage  1  1/467 (0.21%)  1 0/466 (0.00%)  0
General disorders     
Sudden death  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Chest Pain  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Hepatobiliary disorders     
Gallbladder disorder  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Infections and infestations     
Endometritis  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Varicella  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Pneumonia  1  2/467 (0.43%)  2 4/466 (0.86%)  4
Bronchitis  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Lower respiratory tract and infection  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Lung abscess  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Urosepsis  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Injury, poisoning and procedural complications     
Ankle fracture  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Grastroenteritis radiation  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Forearm fracture  1  0/467 (0.00%)  0 2/466 (0.43%)  2
Radius fracture  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Metabolism and nutrition disorders     
Malnutrition  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Musculoskeletal and connective tissue disorders     
Polymyalgia rheumatica  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Osteoporotic fracture  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Musculoskeletal chest pain  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Spinal column stenosis  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Squamous cell carcinoma of head  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Lung neoplasm malignant  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Small cell lung cancer  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Nervous system disorders     
Ischaemic stroke  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Cerebrovascular accident  1  1/467 (0.21%)  1 1/466 (0.21%)  1
Dementia  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Transient ischaemic attack  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Psychiatric disorders     
Depression  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Schizoaffective disorder depressive  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Suicidal ideation  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Renal and urinary disorders     
Renal failure  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Renal failure acute  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Reproductive system and breast disorders     
Uterine prolapse  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Adnexa uteri mass  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
COPD (exacerbation)  1  13/467 (2.78%)  15 8/466 (1.72%)  9
Respiratory failure  1  2/467 (0.43%)  2 0/466 (0.00%)  0
Vascular disorders     
Hypertensive crisis  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Thrombosis  1  1/467 (0.21%)  1 0/466 (0.00%)  0
Peripheral arterial occlusive disease  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Subclavian artery stenosis  1  0/467 (0.00%)  0 1/466 (0.21%)  1
Hypertension  1  0/467 (0.00%)  0 2/466 (0.43%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Aclidinium Bromide / Formoterol Fumarate Salmeterol / Fluticasone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   124/467 (26.55%)      135/466 (28.97%)    
Infections and infestations     
Nasopharyngitis  1  26/467 (5.57%)  30 28/466 (6.01%)  33
Nervous system disorders     
Headache  1  28/467 (6.00%)  42 32/466 (6.87%)  46
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  70/467 (14.99%)  82 75/466 (16.09%)  81
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
All the information related to this clinical trial is considered strictly confidential and is the property of AstraZeneca. This information will not be given to a third party without the written consent of AstraZeneca. Publication and/or presentation, whether complete or partial, of any part of the data or results of this trial will be subject to revision and written agreement between the investigator and AstraZeneca.
Results Point of Contact
Name/Title: Study Information Center
Organization: AstraZeneca
Phone: 1-877-240-9479
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01908140     History of Changes
Other Study ID Numbers: M/40464/39
2013-000116-14 ( EudraCT Number )
First Submitted: July 23, 2013
First Posted: July 25, 2013
Results First Submitted: August 6, 2015
Results First Posted: March 7, 2016
Last Update Posted: March 7, 2016