Please select the eligibility criteria that correspond to the clinical trial below.
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).
Brief 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.


Options:
A: 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
B: Inclusion Criteria:

* Completion of the treatment phase of the lead-in study, LAC-MD-31
* Written informed consent obtained from the patient before the initiation of any study specific procedures
* No medical contraindication as judged by the PI
* Compliance with LAC-MD-31 study procedures and IP dosing.

Exclusion Criteria:

* No specific exclusion criteria
C: Inclusion criteria:

* COPD Subjects
* A COPD subject will be eligible for inclusion in this study only if all of the following criteria apply:
* Male or female subjects, aged 40-75 years inclusive
* A baseline (post-bronchodilator) FEV1 \<80% of predicted normal and a baseline (post-bronchodilator) FEV1/FVC ratio 70%
* Current or ex-smokers with a smoking history of at least 10 pack-years (number of pack years = (number of cigarettes per day / 20) x number of years smoked e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years).
* A signed and dated written informed consent is obtained prior to participation
* Able to comply with the requirements of the protocol and be available for study visits over 3 years

Control Subjects - Current/Ex Smokers

* A control subject will be eligible for inclusion in this study only if all of the following criteria apply:
* Male or female subjects, aged 40-75 years inclusive, who are free from significant disease as determined by history, physical examination and screening investigations
* Baseline (post-bronchodilator) FEV1 \>85% of predicted normal. FEV1/FVC ratio \>70%
* Current or ex-smokers with a smoking history of at least 10 pack-years (number of pack years = (number of cigarettes per day / 20) x number of years smoked e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years).
* A signed and dated written informed consent is obtained prior to participation.
* Able to comply with the requirements of the protocol and be available for study visits over 3 years

Control Subjects - Non-smokers

* A non-smoking control subject will be eligible for inclusion in this study only if all of the following criteria apply:
* Male or female subjects, aged 40-75 years inclusive, who are free from significant disease as determined by history, physical examination and screening investigations
* Baseline (post-bronchodilator) FEV1 \>85% of predicted normal. FEV1/FVC ratio \>70%
* Non-smokers with a smoking history of \< 1 pack-year (number of pack years = (number of cigarettes per day / 20) x number of years smoked).
* A signed and dated written informed consent is obtained prior to participation.
* Able to comply with the requirements of the protocol and be available for study visits over 3 years

Exclusion Criteria:

COPD Subjects

* A COPD subject will not be eligible for inclusion in this study if any of the following criteria apply:
* Known respiratory disorders, or disorders identified at screening/visit 1 (including identification on the first CT scan), other than COPD (e.g.: lung cancer, sarcoidosis, tuberculosis, lung fibrosis, cystic fibrosis)
* Known history of significant inflammatory disease, other than COPD (e.g. rheumatoid arthritis and Lupus)
* Known to be severely alpha-1-antitrypsin deficient (PI SZ or ZZ)
* Having undergone lung surgery (e.g. lung reduction, lung transplant)
* Have cancer or have had cancer in the 5 years prior to study entry
* Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study or impact on subject safety
* Is enrolled in a long term blinded drug study (subjects in open label studies may be considered and subjects in short blinded studies (approx less than 12 weeks may be considered following consultation with sponsor) or a study where there is significant radiation exposure (e.g.: CT scans)
* Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse
* Have received a blood transfusion in the 4 weeks prior to study start
* Has experienced a moderate or severe exacerbation (requiring oral corticosteroid, antibiotics or hospitalisation) within the last 4 weeks. All courses of oral corticosteroids and antibiotics must be completed at least 2 weeks before study start
* Is on long term oral corticosteroids (long term is considered use for more than 3 consecutive months)
* Unable to walk
* Subject is a participating investigator, sub-investigator, study co-ordinator, or employee of a participating investigator, or is an immediate family member of the aforementioned.

Control Subjects

* A control subject will not be eligible for inclusion in this study if any of the following criteria apply:
* Known respiratory disorders, or disorders identified at screening/visit 1 including identification on the first CT scan (e.g.: COPD, asthma, lung cancer, sarcoidosis, tuberculosis, lung fibrosis)
* Known history of significant inflammatory disease (eg rheumatoid arthritis and Lupus)
* Known to be severely alpha-1-antitrypsin deficient (PI SZ or ZZ)
* Having undergone lung surgery (e.g. lung reduction, lung transplant)
* Have cancer or have had cancer in the 5 years prior to study entry
* Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study
* Is enrolled in a long term blinded drug study (subjects in open label studies may be considered and subjects in short blinded studies (approx less than 12 weeks may be considered following consultation with sponsor) or a study where there is significant radiation exposure (e.g.: CT scans)
* Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse.
* Have received a blood transfusion in the 4 weeks prior to study start
* Is on long term oral corticosteroids (long term is considered use for more than 3 consecutive months)
* Subject is a participating investigator, sub-investigator, study co-ordinator, or employee of a participating investigator, or is an immediate family member of the aforementioned.
D: Inclusion Criteria:

* Adult male or non-pregnant, non-lactating female aged ≥40.
* Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years
* Patients with a clinical diagnosis of COPD according to GOLD guidelines 2013, with a post-bronchodilator FEV1 \<80%, and FEV1/FVC \< 70% at Screening Visits
* Symptomatic patients with a COPD assessment test (CAT) ≥10 at Screening and Randomisation Visits
* Patient must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Screening Visits
* Patients 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
* Development of a respiratory tract infection or COPD exacerbation within 6 weeks (or 3 months if hospitalisation was required) before the Screening Visit or during the run-in period
* Clinically significant respiratory conditions
* Type I or uncontrolled Type II diabetes, uncontrolled hypo- or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension
* Patients who, in the investigator's opinion, may need to start a pulmonary rehabilitation programme during the study and/or patients who started/finished it within 3 months prior to Screening Visit
* Use of long-term oxygen therapy (≥15 hours/day)
* Patients treated on daily basis with triple therapy (LABA+LAMA+ICS) within 4 weeks prior to the Screening Visit
* Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers
* Clinically significant cardiovascular conditions
* Patient with clinically relevant abnormalities in the results of the clinical laboratory tests, ECG parameters or in the physical examination at the Screening Visit
* Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm)
* Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy
* Patient with known non-controlled history of infection with human immunodeficiency virus (HIV) and/or active hepatitis
* History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer
* Patient with any other serious or uncontrolled physical or mental dysfunction
* Patient with a history (within 2 years prior to Screening Visit) of drug and/or alcohol abuse that may prevent study compliance based on investigator judgment
* Patient unlikely to be cooperative or that can't comply with the study procedures
* Patient treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening Visit
* Patient who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required stabilization periods for prohibited medication
* Any other conditions that, in the investigator's opinion, might indicate the patient to be unsuitable for the study

Answer: A