Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double-blind, Active-controlled Parallel Group Study to Evaluate the Effect of 52 Weeks of Once Daily Treatment of Orally Inhaled Tiotropium + Olodaterol Fixed Dose Combination Compared With Tiotropium on Chronic Obstructive Pulmonary Disease (COPD) Exacerbation in Patients With Severe to Very Severe COPD. [DYNAGITO]
Brief Summary: The overall objective is to assess the effect of once daily tiotropium + olodaterol fixed dose combination compared to 5 µg tiotropium (both delivered with the Respimat® inhaler) on moderate to severe COPD exacerbation in patients with severe to very severe COPD.


Options:
A: Inclusion criteria:

* All patients must sign an informed consent consistent with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) - Good Clinical Practice (GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions.
* All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator forced expiratory volume in one second \>=30% and \<80% of predicted normal; Global Initiative for Chronic Obstructive Lung Disease grade II - III, and a post-bronchodilator Tiffeneau index \<70% at Visit 1.
* Male or female patients, aged \>=40 years and \<=75 years.
* Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded.

Exclusion criteria:

* Patients with a significant disease other than chronic obstructive pulmonary disease.
* Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis.
* Patients with a history of asthma.
* A diagnosis of thyrotoxicosis.
* A diagnosis of paroxysmal tachycardia (\>100 beats per minute).
* A history of myocardial infarction within 1 year of screening visit.
* Unstable or life-threatening cardiac arrhythmia.
* Hospitalized for heart failure within the past year.
* Known active tuberculosis.
* A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years.
* A history of life-threatening pulmonary obstruction and patients with chronic respiratory failure.
* A history of cystic fibrosis.
* Clinically evident bronchiectasis.
* A history of significant alcohol or drug abuse.
* Any contraindications for exercise testing.
* Patients who have undergone thoracotomy with pulmonary resection.
* Patients being treated with any oral ß-adrenergics.
* Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day.
* Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigators opinion will be unable to abstain from the use of oxygen therapy during clinic visits.
* Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit or patients who are currently in a pulmonary rehabilitation program.
* Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea, such as arthritis in the leg, angina pectoris or claudication or morbid obesity.
* Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit.
* Patients with known hypersensitivity to ß-adrenergics drugs, anticholinergic drugs, benzalkonium chloride, disodium edentat, or any other component of the Respimat® inhalation solution delivery system.
* Pregnant or nursing women.
* Women of childbearing potential not using highly effective methods of birth control.
* Patients who have previously been randomized in this study or are currently participating in another study.
B: Inclusion Criteria:

* Male and female adults aged ≥ 40 years
* Patients with moderate COPD according to the GOLD criteria 2013
* Current or ex-smokers who have a smoking history of at least 10 pack years
* Patients with airflow limitation indicated by a postbronchodilator FEV1 ≥50% and \<80% of the predicted normal value and a post-bronchodilator FEV1/FVC \<0.7 at Visit 2. Post- bronchodilator refers to within 10-15 min of inhalation of 400 μg (4x100 μg) of salbutamol
* Patients who, at Visit 1, have been for at least 3 months on a stable dose of one of the following COPD baseline treatments: \*Any SABA monotherapy (such as, but not limited to, salbutamol) \*Any SAMA monotherapy (such as, but not limited to, ipratropium) \*Any SABA and SAMA in free or FDC (such as, but not limited to, salbutamol/ipratropium) \*Any LABA monotherapy (such as, but not limited to, formoterol, salmeterol, indacaterol) \*Any LAMA monotherapy (such as, but not limited to, tiotropium, aclidinium) except glycopyrronium bromide (NVA237) \*Any LABA and ICS in free (ICS such as, but not limited to, beclomethasone, fluticasone) or FDC (such as, but not limited to, salmeterol/fluticasone, formoterol/budesonide).
* Patients with an mMRC score ≥1 at Visit 1.

Exclusion Criteria:

* Patients with conditions contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or to drugs of similar chemical classes or any component thereof: Anti-cholinergic agents, Long- and short-acting 2-adrenergic agonists, Sympathomimetic amines, Lactose or any of the other excipients of the trial medication.
* Patients with narrow-angle glaucoma or urinary retention, severe renal impairment (history of estimated glomerular filtration rate below 30 ml/min/1.73 m2 within 12 months prior to visit 1), including those with end-stage renal disease requiring dialysis.
* Patients with active/ clinical history of asthma.If the Investigator finds clear and compelling evidence that a patient was misdiagnosed with asthma in the past, then the burden of proof is on the Investigator to properly document this previous misdiagnosis. This documentation must include the rationale for this change in diagnosis including reference to the differential diagnosis that supports this decision.
* Patients with a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
* Patients who have a post-bronchodilator FEV1 decrease more than 10% compared to pre-bronchodilator FEV1 result at Visit 2 (see Appendix 5 for details).
* A documented history of \>1 COPD exacerbation requiring treatment with systemic corticosteroids or antibiotics and/or hospitalization in the previous 12 months.
* Patients who have NOT had a COPD exacerbation in the previous 12 months and develop a COPD exacerbation between screening (Visit 1) and (Visit 2) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation. (Patients suffering an exacerbation between Visit 1 and Visit 2 can only be re-screened in case it is the first one in the previous 12 months. In case this COPD exacerbation has led to an alteration of the patient COPD treatment, before this patient can be re-screened 3 months of stable COPD treatment will be required as described in Inclusion Criterion 6).
* Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to): \*Unstable ischemic heart disease, left ventricular failure (NYHA Class III \& IV), history of myocardial infarction,arrhythmia (excluding chronic stable atrial fibrillation). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study.\*Uncontrolled hypo-or hyperthyroidism, hypokalaemia or hyperadrenergic state. \*Any condition which might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study
* History of resting QTc (Fridericia preferred, but Bazett acceptable) \>450 msec (male) or \>460 msec (female) within five years before Visit 1.
* Patients who are treated with glycopyrronium bromide (NVA237) at visit 1 are not allowed to be included into the trialPatients on non-selective beta-blockers. Those patients may enter the study after non-selective beta-blocker withdrawal during a 7-day wash-out period.
* Patients receiving any other prohibited COPD-related medications specified in Table 5-2 Prohibited COPD related medications must undergo the required wash-out period prior to Visit 2.
* Patients who are, in the opinion of the investigator known to be unreliable or non-compliant.
* Patients with a body mass index (BMI) of more than 40 kg/m2.
* Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer.
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
C: Key Inclusion Criteria:

* Participant in/completion of previous 24-week PINNACLE Phase III Trial.
* Male or female subjects at least 40 years of age and no older than 80 at Visit 1.
* Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS)
* Current or former smokers with a history of at least 10 pack-years of cigarette smoking.
* Subjects with FEV1/forced vital capacity (FVC) ratio of \<0.70 and FEV1 \<80% predicted normal and ≥750 mL if FEV1 \<30% of predicted normal value.
* Subjects willing and, in the opinion of the investigator, able to adjust current COPD therapy as required by the protocol

Key Exclusion Criteria:

* Significant diseases other than COPD, i.e. disease or condition which, in the opinion of the investigator, may put the patient at risk because of participation in the study or may influence either the results of the study or the subject's ability to participate in the study
* Current diagnosis of asthma or alpha-1 antitrypsin deficiency
* Other active pulmonary disease such as active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnea
* Hospitalized due to poorly controlled COPD within 3 months prior to screening or during the Screening Period
* Poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to screening or during the Screening Period
* Lower respiratory tract infections that required antibiotics within 6 weeks prior to screening or during the Screening Period
* Unstable ischemic heart disease, left ventricular failure, or documented myocardial infarction within 12 months of enrollment.
* Recent history of acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass graft within the past three months
* Congestive heart failure (CHF) New York Heart Association (NYHA) Class III/IV)
* Clinically significant abnormal 12-lead electrocardiogram (ECG)
* Abnormal liver function tests defined as alanine transaminase (ALT), aspartate transaminanse (AST), or total bilirubin ≥ 1.5 times upper limit of normal at Visit 1 and on repeat testing
* Cancer not in complete remission for at least five years
* History of hypersensitivity to β2-agonists, glycopyrronium or other muscarinic anticholinergics, lactose/milk protein or any component of the MDI

Other protocol-defined inclusion/exclusion criteria may apply
D: Inclusion criteria:

* Male or female patients, 40 years of age or older.
* Diagnosis of COPD with a documented post-bronchodilator Forced expiratory volume in one second (FEV1)\< 60% of predicted normal and a post-bronchodilator FEV1/ forced vital capacity (FVC) \<70% at Visit 1
* Documented history of at least one moderate to severe COPD exacerbation in the previous 12 months requiring treatment with systemic corticosteroids and/or antibiotics and/or related hospitalization.
* Symptomatically stable as defined by: no evidence of COPD exacerbation requiring use of either antibiotics and/or steroids 4 weeks prior to visit 1 and no evidence of change in their usual COPD medication 4 weeks prior to visit 1.
* Current or ex-smokers with a smoking history of more than 10 pack years.

Exclusion criteria:

* Significant disease other than COPD.
* Clinically relevant abnormal baseline haematology, blood chemistry or creatinine \> x2 ULN will be excluded regardless of clinical condition. ( A repeat laboratory evaluation can be conducted if deemed necessary by the investigator.)
* Current documented diagnosis of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma
* A diagnosis of thyrotoxicosis
* A history of myocardial infarction within 6 months of screening visit.
* Life-threatening cardiac arrhythmia.
* Known active tuberculosis.
* Any malignancy unless free of disease for at least 5 years (patients with treated basal cell carcinoma or squamous cell skin cancers are allowed).
* A history of cystic fibrosis.
* Clinically relevant bronchiectasis.
* Patients with severe emphysema requiring endobronchial interventions within 6 months prior to screening
* A history of significant alcohol or drug abuse in the opinion of the investigator.
* Patients who have undergone thoracotomy with pulmonary resection
* Patients being treated with oral or patch ß-adrenergics.
* Patients being treated with oral corticosteroid medication at unstable doses
* Patients being treated with antibiotics for any reasons within 4 weeks of screening visit
* Patients being treated with PDE4 inhibitors within 3 months of screening visit
* Patients who have taken an investigational drug within one month or six half-lives
* Pregnant or nursing women.
* Women of childbearing potential not using a highly effective method of birth control.

Answer: D