Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide and Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Aclidinium Bromide/Formoterol Fumarate; Aclidinium Bromide/Formoterol Fumarate; Aclidinium Bromide; Formoterol Fumarate; Placebo
Intervention description: Inhaled Aclidinium/formoterol FDC 400/12μg, twice per day; Inhaled Aclidinium/formoterol FDC 400/6μg, twice per day; Inhaled Aclidinium 400 μg, twice per day; Inhaled Formoterol 12 μg, twice per day; Inhaled dose-matched placebo, twice per day
Intervention MeSH terms: Bromides; Formoterol Fumarate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1692.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD; Chronic Obstructive Pulmonary Disease; Chronic Bronchitis; Emphysema; Airflow Obstruction, Chronic; Chronic Airflow Obstruction; Chronic Obstructive Airway Disease; Chronic Obstructive Lung Disease

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.
    

Eligibility criteria:

        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 β-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 α1-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