Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease Clinical Trial

Official title:

A Phase III, Randomized, Double-blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Tolerability of Two Fixed Dose Combinations of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide, Formoterol Fumarate and Placebo for 24- Weeks Treatment in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease (COPD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01437397
• Other study ID #: LAC-MD-31
• Status: Completed
• Phase: Phase 3
• First received: September 19, 2011
• Last updated: September 23, 2016
• Start date: September 2011
• Est. completion date: February 2013

Study information

• Verified date: September 2016
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationNew Zealand: Medsafe
• Study type: Interventional

Clinical Trial Summary

The purpose of this Phase III study is to assess the maintenance bronchodilator effects of the fixed dose combination versus monotherapies. This study will also assess the effects of the fixed dose combination in terms of COPD symptoms, disease related health status and the long-term safety and tolerability of the fixed dose combination. This study will include a 24 week treatment period, preceding by a run-in period, followed by a two week follow up visit. All patients will be randomized to one of four treatment arms or placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1692
• Est. completion date: February 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Male or female patients at least 40 years of age

• Current or former cigarette smoker 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 GOLD guidelines and stable airway obstruction. Patients had to have a postbronchodilator FEV1/FVC ratio < 70% at Visit 1 (GOLD, 2010)

• Post-albuterol/salbutamol FEV1 values = 30% and < 80% of predicted value. FEV1 was measured at the Screening Visit (Visit 1) 10 to 15 minutes after inhalation of albuterol/salbutamol. Predicted normal used for calculation purposes were based on National Health and Nutrition Examination Survey III predicted values (Hankinson et al, 1999)

• Able to perform acceptable and repeatable pulmonary function testing for FEV1 according to ATS/ERS criteria (Miller et al, 2005) at Screening Visit (Visit 1) and throughout their participation in the trial

• Negative serum ß-human chorionic gonadotropin pregnancy test at Visit 1 and must have been using hormonal contraceptives or a barrier method plus a spermicidal agent; otherwise at least 1-year postmenopausal or surgically sterile, defined as having a hysterectomy or tubal ligation (applied to female patients only)

• Judged by the Principal Investigator to be in otherwise good stable health based on medical history, physical examination, ECGs, and routine laboratory data evaluations

• Patients previously randomized in an aclidinium monotherapy trial were permitted as long as it had been at least 6 months since the completion of their previous trial participation

• Able to understand the study procedures and be willing to participate in the study as indicated by signing the informed consent

Exclusion Criteria:

• Hospitalization for an acute COPD exacerbation within 3 months before Visit 1

• Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the 6 weeks before Visit 1. Patients who developed a respiratory tract infection or COPD exacerbation during the washout or run-in period were discontinued from the study before randomization

• Any clinically significant respiratory conditions other than COPD, including active tuberculosis, history of interstitial lung disease, pulmonary thromboembolic disease, history of a1-antitrypsin deficiency, pulmonary resection, lung volume surgery, or any other thoracic surgery during the past 12 months, history of bronchiectasis secondary to respiratory diseases other than COPD (eg, cystic fibrosis, Kartagener syndrome), post organ transplantation, or expected to require thoracotomy or other lung surgery during the study

• Clinical history suggesting that the patient had asthma as opposed to COPD (Study Physician was to be contacted to discuss eligibility, if necessary)

• Chronic use of oxygen therapy = 15 hours/day

• Body mass index(BMI) = 40 kg/m2

• Patients who intended to start a pulmonary rehabilitation program during the trial were excluded, as well as those who finished or started it within 3 months prior to Screening Visit

• Clinically significant cardiovascular conditions including: myocardial infarction within the previous 6 months; newly diagnosed arrhythmia within the previous 3 months; unstable angina; unstable arrhythmia that had required changes in pharmacological therapy or other intervention within the previous 6 months; the presence of an automated implantable cardioverter-defibrillator; history of thoracic surgery within the past year before screening; hospitalization within the previous 12 months for heart failure of New York Heart Association functional class III (marked limitation of physical activity and only comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea), or class IV (unable to carry out any physical activity without discomfort) (Criteria Committee of the New York Heart Association criteria, 1994)

• Any uncontrolled infection that may have placed the patient at risk resulting from human immunodeficiency virus, active hepatitis and/or patients with diagnosed active tuberculosis

• QTcB > 470 msec in the resting ECGs performed at Screening (Visit 1), as indicated in the centralized ECG vendor generated report. Patients who were on a stable dose of medication that may prolong the QTc, but had a documented, stable, and normal QTc, could have been considered

• QTcB > 470 msec in the resting ECGs performed before randomization at Visit 2, as indicated in the paper tracing generated by the Sponsor-provided ECG equipment

• Clinically relevant abnormalities in the results of the clinical laboratory tests, in ECG parameters other than QTc, or in the physical examination or vital signs at Visit 1 except for those related to COPD

• History of drug or alcohol abuse within the previous 5 years

• Any other serious or uncontrolled physical or mental condition/disease that, as judged by the Investigator, could have placed the patient at higher risk derived from his/her participation in the study, could have confounded the results of the study, or would be likely to have prevented the patient from complying with the requirements of the study or completing the study. If there was a history of such disease, but the condition had been stable for more than 1 year and was judged by the Investigator not to interfere with the patient's participation in the study, the patient may have been included, with the documented approval of the Study Physician

• History of hypersensitivity reaction to inhaled anticholinergics, beta-2 agonists, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm) or a history of acute urinary retention, symptomatic benign prostatic hyperplasia, bladder neck obstruction, or narrow-angle glaucoma. (Note: Patients who had well controlled, stable, asymptomatic benign prostatic hyperplasia were not to be excluded)

• Sitting, resting systolic BP = 160 mm Hg and/or diastolic BP = 100 mm Hg at Visit 1 and Visit 2

• Unable to use a multidose dry-powder inhaler or a pressurized metered-dose inhaler

• Treatment with any other investigational product within 30 days (or 6 half-lives, whichever was longer) before Visit 1

• Previous participation in a clinical trial with aclidinium bromide in an FDC therapy

• Pregnant or breastfeeding

• Current diagnosis of cancer (present in the patient) other than basal or squamous cell skin cancer. Patients who had a history of cancer must have been cleared before Visit 1 (Screening) on a case-by-case basis

• Patients who did not maintain regular day/night, waking/sleeping cycles (eg, night shift workers)

• Patients who intended to use any concomitant medication not permitted by this protocol or who had not undergone the required washout period for a particular prohibited medication (Appendix III of the protocol, which can be found in Appendix 16.1.1 of this report)

• Patients who were unlikely to be compliant with study requirements (eg, take their medication, complete their electronic diaries, attend clinic at the required times)

• Patients who were employees or relatives of employees of the investigative study center, FRI, Almirall, SA, or Pharmaceutical Product Development (PPD, Inc.)

• Patients who had any other conditions that, in the Investigator's opinion, might have indicated the patient to be unsuitable for the study or supported excluding the patient from the study

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Aclidinium Bromide/Formoterol Fumarate
Inhaled Aclidinium/formoterol FDC high dose, twice per day
• Aclidinium Bromide/Formoterol Fumarate
Inhaled Aclidinium/formoterol FDC low dose, twice per day
• Aclidinium Bromide
Inhaled Aclidinium 400 µg, twice per day
• Formoterol Fumarate
Inhaled Formoterol 12 µg, twice per day
• placebo
Inhaled dose-matched placebo, twice per day

Locations

Country	Name	City	State
Australia	Forest Investigative Site 2253	Adelaide	Western Australia
Australia	Forest Investigative Site 1981	Bedford Park	South Australia
Australia	Forest Investigative Site 2250	Clayton	Victoria
Australia	Forest Investigative Site 1990	Daw Park	South Australia
Australia	Forest Investigative Site 1972	Fitzroy	Victoria
Australia	Forest Investigative Site 1986	Geelong	Victoria
Australia	Forest Investigative Site 1991	New Lambton	New South Wales
Australia	Forest Investigative Site 1985	Parkville	Victoria
Australia	Forest Investigative Site 1987	Redcliffe	Queensland
Australia	Forest Investigative Site 2251	Toorak Gardens	South Australia
Australia	Forest Investigative Site 1973	Woolloongabba	Queensland
Canada	Forest Investigative Site 1904	Langley	British Columbia
Canada	Forest Investigative Site 1952	Montreal	Quebec
Canada	Forest Investigative Site 1859	Quebec
Canada	Forest Investigative Site 1877	Sarina	Ontario
Canada	Forest Investigative Site 1896	Sarnia	Ontario
Canada	Forest Investigative Site 0943	Saskatoon	Saskatchewan
Canada	Forest Investigative Site 1171	Toronto	Ontario
Canada	Forest Investigative Site 2203	Toronto	Ontario
Canada	Forest Investigative Site 0905	Vancouver	British Columbia
Canada	Forest Investigative Site 0976	Winnipeg	Manitoba
New Zealand	Forest Investigative Site 1027	Auckland
New Zealand	Forest Investigative Site 1970	Christchurch
New Zealand	Forest Investigative Site 1964	Dunedin
New Zealand	Forest Investigative Site 1967	Dunedin
New Zealand	Forest Investigative Site 1968	Hamilton
New Zealand	Forest Investigative Site 1965	Tauranga
New Zealand	Forest Investigative Site 1980	Tauranga
New Zealand	Forest Investigative Site 1025	Wellington
United States	Forest Investigative Site 1982	Albany	Georgia
United States	Forest Investigative Site 1949	Albuquerque	New Mexico
United States	Forest Investigative Site 1833	Altoona	Pennsylvania
United States	Forest Investigative Site 1822	Anaheim	California
United States	Forest Investigative Site 1892	Ann Arbor	Michigan
United States	Forest Investigative Site 1827	Anniston	Alabama
United States	Forest Investigative Site 1440	Arlington	Texas
United States	Forest Investigative Site 1920	Athens	Alabama
United States	Forest Investigative Site 1900	Atlanta	Georgia
United States	Forest Investigative Site 0987	Austell	Georgia
United States	Forest Investigative Site 1924	Baltimore	Maryland
United States	Forest Investigative Site 1814	Bangor	Maine
United States	Forest Investigative Site 1821	Bay Pines	Florida
United States	Forest Investigative Site 1609	Bellevue	Nebraska
United States	Forest Investigative Site 1120	Bellingham	Washington
United States	Forest Investigative Site 1889	Bend	Oregon
United States	Forest Investigative Site 1162	Birmingham	Alabama
United States	Forest Investigative Site 1493	Birmingham	Alabama
United States	Forest Investigative Site 1937	Birmingham	Alabama
United States	Forest Investigative Site 1879	Boerne	Texas
United States	Forest Investigative Site 2033	Bowling Green	Kentucky
United States	Forest Investigative Site 1831	Bozeman	Montana
United States	Forest Investigative Site 1154	Brandon	Florida
United States	Forest Investigative Site 1944	Brandon	Florida
United States	Forest Investigative Site 1957	Brentwood	Tennessee
United States	Forest Investigative Site 1483	Buena Park	California
United States	Forest Investigative Site 1891	Cadiz	Ohio
United States	Forest Investigative Site 1134	Canton	Ohio
United States	Forest Investigative Site 1828	Canton	Georgia
United States	Forest Investigative Site 1861	Carrollton	Texas
United States	Forest Investigative Site 1802	Charleston	South Carolina
United States	Forest Investigative Site 1905	Charleston	South Carolina
United States	Forest Investigative Site 2072	Charleston	South Carolina
United States	Forest Investigative Site 1392	Charlotte	North Carolina
United States	Forest Investigative Site 1559	Cherry Hill	New Jersey
United States	Forest Investigative Site 1587	Chesterfield	Missouri
United States	Forest Investigative Site 1806	Cincinnati	Ohio
United States	Forest Investigative Site 1885	Cincinnati	Ohio
United States	Forest Investigative Site 1903	Cincinnati	Ohio
United States	Forest Investigative Site 2028	Cincinnati	Ohio
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United States	Forest Investigative Site 1364	Clearwater	Florida
United States	Forest Investigative Site 1875	Clearwater	Florida
United States	Forest Investigative Site 0679	Coeur d' Alene	Idaho
United States	Forest Investigative Site 1361	Columbus	Ohio
United States	Forest Investigative Site 1433	Columbus	Ohio
United States	Forest Investigative Site 1816	Corsicana	Texas
United States	Forest Investigative Site 1811	Covington	Louisiana
United States	Forest Investigative Site 1832	Cumberland	Rhode Island
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United States	Forest Investigative Site 0670	DeLand	Florida
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United States	Forest Investigative Site 1858	Eagle	Idaho
United States	Forest Investigative Site 1089	East Providence	Rhode Island
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United States	Forest Investigative Site 2085	Fort Mitchell	Kentucky
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United States	Forest Investigative Site 1912	Normal	Illinois
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United States	Forest Investigative Site 1884	Olive Branch	Mississippi
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United States	Forest Investigative Site 1911	Omaha	Nebraska
United States	Forest Investigative Site 1812	Opelousas	Louisiana
United States	Forest Investigative Site 1145	Ormond Beach	Florida
United States	Forest Investigative Site 1519	Owensboro	Kentucky
United States	Forest Investigative Site 1094	Panama City	Florida
United States	Forest Investigative Site 1803	Pembroke Pines	Florida
United States	Forest Investigative Site 974	Pensacola	Florida
United States	Forest Investigative Site 1443	Philadelphia	Pennsylvania
United States	Forest Investigative Site 1379	Phoenix	Arizona
United States	Forest Investigative Site 1863	Phoenixville	Pennsylvania
United States	Forest Investigative Site 1146	Pittsburgh	Pennsylvania
United States	Forest Investigative Site 1826	Plano	Texas
United States	Forest Investigative Site 1619	Plymouth	Minnesota
United States	Forest Investigative Site 1137	Pueblo	Colorado
United States	Forest Investigative Site 1153	Raleigh	North Carolina
United States	Forest Investigative Site 2051	River Forest	Illinois
United States	Forest Investigative Site 2064	Riverside	California
United States	Forest Investigative Site 1118	Rochester	Minnesota
United States	Forest Investigative Site 2098	Rochester	New York
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United States	Forest Investigative Site 1866	Sacramento	California
United States	Forest Investigative Site 1876	Saint Petersburg	Florida
United States	Forest Investigative Site 1823	Salisbury	North Carolina
United States	Forest Investigative Site 1936	Salt Lake City	Utah
United States	Forest Investigative Site 0526	San Angelo	Texas
United States	Forest Investigative Site 1895	San Antonio	Texas
United States	Forest Investigative Site 1125	San Diego	California
United States	Forest Investigative Site 1898	San Diego	California
United States	Forest Investigative Site 2009	San Diego	California
United States	Forest Investigative Site 1817	Sarasota	Florida
United States	Forest Investigative Site 1918	Scottsboro	Alabama
United States	Forest Investigative Site 1330	South Burlington	Vermont
United States	Forest Investigative Site 1121	Spartanburg	South Carolina
United States	Forest Investigative Site 1573	Spokane	Washington
United States	Forest Investigative Site 1878	Spokane	Washington
United States	Forest Investigative Site 1977	Spokane	Washington
United States	Forest Investigative Site 1856	Springfield	Missouri
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United States	Forest Investigative Site 2079	St. Charles	Missouri
United States	Forest Investigative Site 1829	St. Cloud	Florida
United States	Forest Investigative Site 1399	St. Louis	Missouri
United States	Forest Investigative Site 1599	St. Louis	Missouri
United States	Forest Investigative Site 1874	St. Petersburg	Florida
United States	Forest Investigative Site 1342	Stevensville	Michigan
United States	Forest Investigative Site 2090	Sylvania	Ohio
United States	Forest Investigative Site 0988	Tacoma	Washington
United States	Forest Investigative Site 1870	Tacoma	Washington
United States	Forest Investigative Site 2082	Tamarac	Florida
United States	Forest Investigative Site 2047	Tampa	Florida
United States	Forest Investigative Site 2053	Tampa	Florida
United States	Forest Investigative Site 1449	Tipton	Pennsylvania
United States	Forest Investigative Site 1530	Toledo	Ohio
United States	Forest Investigative Site 1374	Torrance	California
United States	Forest Investigative Site 1487	Troy	Michigan
United States	Forest Investigative Site 1813	Tustin	California
United States	Forest Investigative Site 1862	Uniontown	Pennsylvania
United States	Forest Investigative Site 1883	Vista	California
United States	Forest Investigative Site 1976	Waterbury	Connecticut
United States	Forest Investigative Site 1327	Wheat Ridge	Colorado
United States	Forest Investigative Site 1872	Wheaton	Maryland
United States	Forest Investigative Site 1185	Winter Park	Florida
United States	Forest Investigative Site 1860	Winter Park	Florida
United States	Forest Investigative Site 2089	Woodstock	Georgia
United States	Forest Investigative Site 1393	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Morning pre-dose (trough) Forced Expiratory Volume in one second (FEV1) at Week 24		Change from Basline (Week 0) to 24 Weeks	No
Primary	Morning one-hour post-dose FEV1 at Week 24		Change from Basline (Week 0) to 24 Weeks	No
Secondary	Change from baseline in George's Respiratory Questionnaire (SGRQ) total score		Change from Basline (Week 0) to 24 Weeks	No
Secondary	Improvement in Transition Dyspnea Index (TDI) score		Change from Basline (Week 0) to 24 Weeks	No

External Links

•   CSR Synopsis