Clinical trial NCT01462942: Long-term Efficacy and Safety of Aclidinium Bromide/Formoterol Fumarate Fixed-Dose Combination
Official title: Efficacy and Safety of Aclidinium Bromide/Formoterol Fumarate Fixed-dose Combinations Compared With Individual Components and Placebo When Administered to Patients With Stable Chronic Obstructive Pulmonary Disease.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: COPD
Bronchitis
Chronic
Emphysema
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2011-11-01
Enrollment: 2443
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective is to provide data supporting the use of LAS40464 as an efficacious and safe maintenance bronchodilator treatment of patients with Chronic Obstructive Pulmonary Disease (COPD).

Detailed description: This Phase III study seeks to confirm the long-term bronchodilator efficacy and effects on COPD related health status and other secondary parameters as well as the safety of two doses of the combination of aclidinium bromide/formoterol FDC (FDC 400/12 μg and 400/6 μg) compared with aclidinium bromide monotherapy 400 μg, formoterol monotherapy 12 μg and placebo.

Eligibility criteria: Inclusion Criteria:

* Adult male or non-pregnant, non-lactating female aged ≥40. Women of childbearing potential are allowed to enter the trial if they show to have a negative serum pregnancy test at the Screening Visit and are using, during the last two months before the Screening Visit, at least one medically approved and highly effective method of birth control defined as those which result in a low failure rate (i.e less than 1% per year) when used consistently and correctly such as implants, injectables, oral contraceptives combined with at least one barrier method, hormonal Intrauterine Devices (IUDs), sexual abstinence or vasectomy of the partner.
* Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years.
* Patient with a clinical diagnosis of stable COPD according to the Global Initiative for Chronic Lung Disease "GOLD" Guidelines at the Screening Visit.
* Patient whose FEV1/FVC (Forced Vital Capacity) at the Screening Visit measured between 10-15 minutes post inhalation of 400 micrograms of salbutamol is \< 70% (i.e., 100 x Post-salbutamol FEV1 /FVC \< 70%).
* Patient with a diagnosis of moderate to severe COPD according to the GOLD Guidelines classification (stages II and III) at the Screening Visit: FEV1 measured between 10-15 minutes post inhalation of 400 micro grams of salbutamol is 30% \< FEV1 \< 80% of the predicted normal value (i.e., 100 x Post-salbutamol FEV1/ Predicted FEV1 must be \< 80% and ≥ 30%).
* Patient must be able to perform repeatable pulmonary function testing for FEV1 according to American Thoracic Society/European Respiratory Society "ATS/ERS" 2005 criteria at Screening Visit.
* Patient who is eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained.

Exclusion Criteria:

* History or current diagnosis of asthma.
* Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the 6 weeks before Screening Visit.
* Patient hospitalised for COPD exacerbation within 3 months prior to Screening Visit.
* Clinically significant respiratory conditions defined as:

  * Known active tuberculosis.
  * History of interstitial lung or massive pulmonary thromboembolic disease.
  * Pulmonary resection or lung volume reduction surgery within 12 months prior to Screening Visit.
  * History of lung transplantation.
  * History of bronchiectasis secondary to respiratory diseases others than COPD (e.g., cystic fibrosis, Kartagener's syndrome, etc).
  * Known a1-antitrypsin deficiency.
* Patients who in the Investigator's opinion might have needed to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to screening.
* Use of long-term oxygen therapy (≥ 15 hours/day).
* Patients who did not maintain regular day/night, waking/sleeping cycles including night shift workers (eg, history of sleep apnoea syndrome, any condition related to sleep disturbances such as restless-legs syndrome or somnambulism).
* Clinically significant cardiovascular conditions defined as:

  * Myocardial infarction within the 6 months prior to screening.
  * Thoracic surgery within 12 months prior to screening.
  * Unstable angina or unstable arrhythmia which had required changes in the pharmacological therapy or other intervention within 12 months prior to screening, or newly diagnosed arrhythmia within the previous 3 months prior to screening.
  * Hospitalisation within 12 months prior to screening for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association.
* Patients (with or without pharmacological therapy) with resting systolic blood pressure (SBP)

  ≥200 mmHg, a resting diastolic blood pressure (DBP) ≥120 mmHg, or a resting heart rate ≥105 beats per minute (bpm) at screening and at Visit 1 prior to randomisation.
* Patients with interval corrected for heart rate "QTc" \[calculated according to formulae (QTc=QT/RR1/2) \> 470 msec as indicated in the centralised reading report assessed at Screening Visit.
* Patients with clinically relevant abnormalities in the clinical laboratory tests, ECG parameters (other than QT interval corrected using Bazett's formula \[QTcB\]) or in the physical examination at screening, if the abnormality defined a disease state listed as exclusion criteria, except for those related to COPD.
* Patients with a history of hypersensitivity reactions to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm). Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction or acute urinary retention.
* Patients with symptomatic non-stable prostate hypertrophy. (However, patients with well-controlled, stable, asymptomatic benign prostatic hypertrophy were not excluded).
* Patients with known uncontrolled history of infection with human immunodeficiency virus and/or active hepatitis.
* Current diagnosis of cancer other than basal or squamous cell skin cancer.
* Life expectancy of less than 1 year.
* Patients with any other serious or uncontrolled physical or mental dysfunction that, as judged by the Investigator, could have placed the patient at higher risk from his/her participation in the study, could have confounded the results of the study, or is likely to prevent the patient from complying with the requirements of the study, or completing the study.
* Patients with a history (within 2 years prior to screening) of drug and/or alcohol abuse that might have prevented study compliance based on the Investigator judgment.
* Patients unlikely to be cooperative (eg, take the medication, complete the Patient Diaries or attend the clinic at the required times).
* Patients unable to properly use a DPI or pMDI inhaler device or to perform spirometry measurements.
* Patients previously randomised in a study involving aclidinium bromide/formoterol FDC.
* Patients previously randomised in a study involving aclidinium bromide monotherapy except when participation finished at least 6 months before screening.
* Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to screening.
* 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.
* Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients.
* Patients employed, or relatives of employees at the study centre, Almirall or Forest Laboratories.
* Any other conditions that, in the Investigator's opinion, might have indicated the patient to be unsuitable for the study.

Primary outcomes:
measure: Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1)
timeFrame: Baseline and Week 24
measure: Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1)
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Change in Transition Dyspnoea Index (TDI) Focal Score
timeFrame: Baseline and Week 24
measure: Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score
timeFrame: Baseline and Week 24
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Almirall Investigational Site #2
city: Salzburg
country: Austria
facility: Almirall Investigational Site #3
city: Edegem
country: Belgium
facility: Almirall Investigational Site #3
city: Genk
country: Belgium
facility: Almirall Investigational Site #2
city: Ruse
country: Bulgaria
facility: Almirall Investigational Site #6
city: Sevlievo
country: Bulgaria
facility: Almirall Investigational Site #10
city: Sofia
country: Bulgaria
facility: Almirall Investigational Site #8
city: Sofia
country: Bulgaria
facility: Almirall Investigational Site #2
city: Sofia
country: Bulgaria
facility: Almirall Investigational Site #11
city: Zagreb
country: Croatia
facility: Almirall Investigational Site #2
city: Zagreb
country: Croatia
facility: Almirall Investigational Site #4
city: Brno
country: Czech Republic
facility: Almirall Investigational Site #8
city: Jindrichuv Hradec
country: Czech Republic
facility: Almirall Investigational Site #3
city: Karlovy Vary
country: Czech Republic
facility: Almirall Investigational Site #10
city: Liberec
country: Czech Republic
facility: Almirall Investigational Site #9
city: Ostrava Hrabuvka
country: Czech Republic
facility: Almirall Investigational Site #16
city: Praha 3
country: Czech Republic
facility: Almirall Investigational Site #2
city: Praha 5 - Radotin
country: Czech Republic
facility: Almirall Investigational Site #6
city: Praha 5
country: Czech Republic
facility: Almirall Investigational Site #12
city: Praha 6
country: Czech Republic
facility: Almirall Investigational Site #15
city: Praha 8
country: Czech Republic
facility: Almirall Investigational Site #14
city: Strakonice
country: Czech Republic
facility: Almirall Investigational Site #11
city: Tabor
country: Czech Republic
facility: Almirall Investigational Site #1
city: Hillerød
country: Denmark
facility: Almirall Investigational Site #4
city: København NV
country: Denmark
facility: Almirall Investigational Site #1
city: Odense
country: Denmark
facility: Almirall Investigational Site #5
city: Silkeborg
country: Denmark
facility: Almirall Investigational Site #2
city: Espoo
country: Finland
facility: Almirall Investigational Site #7
city: Jyväskylä
country: Finland
facility: Almirall Investigational Site #8
city: Tampere
country: Finland
facility: Almirall Investigational Site #1
city: Tampere
country: Finland
facility: Almirall Investigational Site #6
city: Turku
country: Finland
facility: Almirall Investigational Site #3
city: Lille cedex
country: France
facility: Almirall Investigational Site #6
city: Marseille cedex 6
country: France
facility: Almirall Investigational Site #10
city: Montpellier cedex 5
country: France
facility: Almirall Investigational Site #11
city: Pessac
country: France
facility: Almirall Investigational Site #1
city: Rennes
country: France
facility: Almirall Investigational Site #3
city: Toulouse
country: France
facility: Almirall Investigational Site #8
city: Vieux Conde
country: France
facility: Almirall Investigational Site #12
city: Berlin
country: Germany
facility: Almirall Investigational Site #2
city: Berlin
country: Germany
facility: Almirall Investigational Site #12
city: Berlin
country: Germany
facility: Almirall Investigational Site #19
city: Berlin
country: Germany
facility: Almirall Investigational Site #11
city: Berlin
country: Germany
facility: Almirall Investigational Site #24
city: Bochum
country: Germany
facility: Almirall Investigational Site #16
city: Bonn
country: Germany
facility: Almirall Investigational Site #23
city: Dresden
country: Germany
facility: Almirall Investigational Site #15
city: Dresden
country: Germany
facility: Almirall Investigational Site #10
city: Frankfurt
country: Germany
facility: Almirall Investigational Site #5
city: Frankfurt
country: Germany
facility: Almirall Investigational Site #13
city: Haltern in Westfalen
country: Germany
facility: Almirall Investigational Site #33
city: Hamburg
country: Germany
facility: Almirall Investigational Site #7
city: Hamburg
country: Germany
facility: Almirall Investigational Site #21
city: Hessen
country: Germany
facility: Almirall Investigational Site #36
city: Land Niedersachsen
country: Germany
facility: Almirall Investigational Site #32
city: Luebeck
country: Germany
facility: Almirall Investigational Site #1
city: Mainz
country: Germany
facility: Almirall Investigational Site #6
city: Marburg
country: Germany
facility: Almirall Investigational Site #20
city: Muenchen
country: Germany
facility: Almirall Investigational Site #34
city: Nuernberg
country: Germany
facility: Almirall Investigational Site #18
city: Reinfeld
country: Germany
facility: Almirall Investigational Site #22
city: Sachsen
country: Germany
facility: Almirall Investigational Site #35
city: Sachsen
country: Germany
facility: Almirall Investigational Site #27
city: Sachsen
country: Germany
facility: Almirall Investigational Site #28
city: Sachsen
country: Germany
facility: Almirall Investigational Site #25
city: Schwerin
country: Germany
facility: Almirall Investigational Site #8
city: Witten
country: Germany
facility: Almirall Investigational Site #4
city: Balassagyarmat
country: Hungary
facility: Almirall Investigational Site #4
city: Budapest
country: Hungary
facility: Almirall Investigational Site #16
city: Budapest
country: Hungary
facility: Almirall Investigational Site #12
city: Budapest
country: Hungary
facility: Almirall Investigational Site #17
city: Budapest
country: Hungary
facility: Almirall Investigational Site #6
city: Budapest
country: Hungary
facility: Almirall Investigational Site #14
city: Budapest
country: Hungary
facility: Almirall Investigational Site #5
city: Deszk
country: Hungary
facility: Almirall Investigational Site #1
city: Komarom
country: Hungary
facility: Almirall Investigational Site #9
city: Miskolc
country: Hungary
facility: Almirall Investigational Site #2
city: Mosonmagyarovar
country: Hungary
facility: Almirall Investigational Site #15
city: Nagykanizsa
country: Hungary
facility: Almirall Investigational Site #13
city: Nyiregyhaza
country: Hungary
facility: Almirall Investigational Site #3
city: Torokbalint
country: Hungary
facility: Almirall Investigational Site #7
city: Zalaegerszeg
country: Hungary
facility: Almirall Investigational Site #11
city: Genova
country: Italy
facility: Almirall Investigational Site #15
city: Parma
country: Italy
facility: Almirall Investigational Site #3
city: Pisa
country: Italy
facility: Almirall Investigational Site #5
city: Siena
country: Italy
facility: Almirall Investigational Site #1
city: Buchon-si
country: Korea, Republic of
facility: Almirall Investigational Site #7
city: Gyeonggi-do
country: Korea, Republic of
facility: Almirall Investigational Site #4
city: Seoul
country: Korea, Republic of
facility: Almirall Investigational Site #8
city: Seoul
country: Korea, Republic of
facility: Almirall Investigational Site #6
city: Seoul
country: Korea, Republic of
facility: Almirall Investigational Site #3
city: Seoul
country: Korea, Republic of
facility: Almirall Investigational Site #5
city: Seoul
country: Korea, Republic of
facility: Almirall Investigational Site #2
city: Seoul
country: Korea, Republic of
facility: Almirall Investigational Site #1
city: Beek
country: Netherlands
facility: Almirall Investigational Site #8
city: Breda
country: Netherlands
facility: Almirall Investigational Site #7
city: Eindhoven
country: Netherlands
facility: Almirall Investigational Site #13
city: Leiderdorp
country: Netherlands
facility: Almirall Investigational Site #1
city: Rotterdam
country: Netherlands
facility: Almirall Investigational Site #9
city: Velp
country: Netherlands
facility: Almirall Investigational Site #11
city: Zoetermeer
country: Netherlands
facility: Almirall Investigational Site #10
city: Bialystok
country: Poland
facility: Almirall Investigational Site #26
city: Bialystok
country: Poland
facility: Almirall Investigational Site #3
city: Bielsko-Biala
country: Poland
facility: Almirall Investigational Site #19
city: Bydgoszcz
country: Poland
facility: Almirall Investigational Site #23
city: Gdynia
country: Poland
facility: Almirall Investigational Site #21
city: Katowice
country: Poland
facility: Almirall Investigational Site #5
city: Katowice
country: Poland
facility: Almirall Investigational Site #22
city: Krakow
country: Poland
facility: Almirall Investigational Site #7
city: Krakow
country: Poland
facility: Almirall Investigational Site #9
city: Lodz
country: Poland
facility: Almirall Investigational Site #6
city: Lodz
country: Poland
facility: Almirall Investigational Site #1
city: Lublin
country: Poland
facility: Almirall Investigational Site #14
city: Olawa
country: Poland
facility: Almirall Investigational Site #8
city: Poznan
country: Poland
facility: Almirall Investigational Site #2
city: Poznan
country: Poland
facility: Almirall Investigational Site #11
city: Poznan
country: Poland
facility: Almirall Investigational Site #4
city: Torun
country: Poland
facility: Almirall Investigational Site #13
city: Torun
country: Poland
facility: Almirall Investigational Site #18
city: Warszawa
country: Poland
facility: Almirall Investigational Site #10
city: Warszawa
country: Poland
facility: Almirall Investigational Site #15
city: Warszawa
country: Poland
facility: Almirall Investigational Site #16
city: Brasov
country: Romania
facility: Almirall Investigational Site #1
city: Bucuresti
country: Romania
facility: Almirall Investigational Site #9
city: Bucuresti
country: Romania
facility: Almirall Investigational Site #18
city: Bucuresti
country: Romania
facility: Almirall Investigational Site #7
city: Bucuresti
country: Romania
facility: Almirall Investigational Site #10
city: Constanta
country: Romania
facility: Almirall Investigational Site #17
city: Constanta
country: Romania
facility: Almirall Investigational Site #2
city: Craiova
country: Romania
facility: Almirall Investigational Site #3
city: Deva
country: Romania
facility: Almirall Investigational Site #8
city: Iasi
country: Romania
facility: Almirall Investigational Site #6
city: Iasi
country: Romania
facility: Almirall Investigational Site #16
city: Targu Mures
country: Romania
facility: Almirall Investigational Site #5
city: Moscow
country: Russian Federation
facility: Almirall Investigational Site #2
city: Moscow
country: Russian Federation
facility: Almirall Investigational Site #1
city: Novosibirsk
country: Russian Federation
facility: Almirall Investigational Site #9
city: St. Petersburg
country: Russian Federation
facility: Almirall Investigational Site #7
city: St. Petersburg
country: Russian Federation
facility: Almirall Investigational Site #12
city: Banska Bystrica
country: Slovakia
facility: Almirall Investigational Site #6
city: Bardejov
country: Slovakia
facility: Almirall Investigational Site #5
city: Bratislava
country: Slovakia
facility: Almirall Investigational Site #3
city: Nove Zamky
country: Slovakia
facility: Almirall Investigational Site #1
city: Spisska Nova Ves
country: Slovakia
facility: Almirall Investigational Site #4
city: Sturovo
country: Slovakia
facility: Almirall Investigational Site #9
city: Vysne Hagy
country: Slovakia
facility: Almirall Investigational Site #10
city: Amanzimtoti
country: South Africa
facility: Almirall Investigational Site #1
city: Cape Town, Western Cape
country: South Africa
facility: Almirall Investigational Site #15
city: Cape Town
country: South Africa
facility: Almirall Investigational Site #16
city: Cape Town
country: South Africa
facility: Almirall Investigational Site #2
city: Pretoria
country: South Africa
facility: Almirall Investigational Site #12
city: Pretoria
country: South Africa
facility: Almirall Investigational Site #13
city: Pretoria
country: South Africa
facility: Almirall Investigational Site #3
city: Roodepoort
country: South Africa
facility: Almirall Investigational Site #8
city: Somerset West
country: South Africa
facility: Almirall Investigational Site #5
city: Barcelona
country: Spain
facility: Almirall Investigational Site #7
city: Barcelona
country: Spain
facility: Almirall Investigational Site #12
city: Caceres
country: Spain
facility: Almirall Investigational Site #10
city: Canet de Mar
country: Spain
facility: Almirall Investigational Site #3
city: Malaga
country: Spain
facility: Almirall Investigational Site #1
city: Oviedo
country: Spain
facility: Almirall Investigational Site #9
city: Sevilla
country: Spain
facility: Almirall Investigational Site #8
city: Göteborg
country: Sweden
facility: Almirall Investigational Site #2
city: Lund
country: Sweden
facility: Almirall Investigational Site #1
city: Lund
country: Sweden
facility: Almirall Investigational Site #6
city: Malmö
country: Sweden
facility: Almirall Investigational Site #3
city: Vällingby
country: Sweden
facility: Almirall Investigational Site #4
city: Crimea Oblast
country: Ukraine
facility: Almirall Investigational Site #18
city: Dnipropetrovsk
country: Ukraine
facility: Almirall Investigational Site #12
city: Donetsk
country: Ukraine
facility: Almirall Investigational Site #9
city: Ivano-Frankivsk
country: Ukraine
facility: Almirall Investigational Site #11
city: Kharkiv
country: Ukraine
facility: Almirall Investigational Site #17
city: Kharkov
country: Ukraine
facility: Almirall Investigational Site #1
city: Kyiv
country: Ukraine
facility: Almirall Investigational Site #15
city: Kyiv
country: Ukraine
facility: Almirall Investigational Site #2
city: Kyiv
country: Ukraine
facility: Almirall Investigational Site #3
city: Kyiv
country: Ukraine
facility: Almirall Investigational Site #4
city: Kyiv
country: Ukraine
facility: Almirall Investigational Site #5
city: Lugansk
country: Ukraine
facility: Almirall Investigational Site #6
city: Mykolaiv
country: Ukraine
facility: Almirall Investigational Site #8
city: Vinnytsya
country: Ukraine
facility: Almirall Investigational Site #10
city: Birmingham
country: United Kingdom
facility: Almirall Investigational Site #6
city: Bradford
country: United Kingdom
facility: Almirall Investigational Site #12
city: Cambridge
country: United Kingdom
facility: Almirall Investigational Site #10
city: Cardiff
country: United Kingdom
facility: Almirall Investigational Site #13
city: Chorley
country: United Kingdom
facility: Almirall Investigational Site #5
city: Glasgow
country: United Kingdom
facility: Almirall Investigational Site #2
city: Hull
country: United Kingdom
facility: Almirall Investigational Site #11
city: Liverpool
country: United Kingdom
facility: Almirall Investigational Site #14
city: London
country: United Kingdom
facility: Almirall Investigational Site #1
city: Manchester
country: United Kingdom
facility: Almirall Investigational Site #4
city: Manchester
country: United Kingdom
facility: Almirall Investigational Site #8
city: Newcastle upon Tyne
country: United Kingdom
facility: Almirall Investigational Site #18
city: Reading
country: United Kingdom
facility: Almirall Investigational Site #7
city: Stockton on Tees
country: United Kingdom
facility: Almirall Investigational Site #16
city: West midlands
country: United Kingdom
facility: Almirall Investigational Site #15
city: Wirral
country: United Kingdom
facility: Almirall Investigational Site #17
Study officials:
affiliation: AstraZeneca
name: Esther Garcia, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Singh D, D'Urzo AD, Donohue JF, Kerwin EM, Molins E, Chuecos F, Ribera A, Jarreta D. An Evaluation Of Single And Dual Long-Acting Bronchodilator Therapy As Effective Interventions In Maintenance Therapy-Naive Patients With COPD. Int J Chron Obstruct Pulmon Dis. 2019 Dec 6;14:2835-2848. doi: 10.2147/COPD.S217710. eCollection 2019.
citation: Singh D, D'Urzo AD, Chuecos F, Munoz A, Garcia Gil E. Reduction in clinically important deterioration in chronic obstructive pulmonary disease with aclidinium/formoterol. Respir Res. 2017 May 30;18(1):106. doi: 10.1186/s12931-017-0583-0.
citation: Bateman ED, Chapman KR, Singh D, D'Urzo AD, Molins E, Leselbaum A, Gil EG. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015 Aug 2;16(1):92. doi: 10.1186/s12931-015-0250-2.
citation: Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E, Caracta C, Gil EG, Leselbaum A. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med. 2014 Nov 18;14:178. doi: 10.1186/1471-2466-14-178.