Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double Blind, Parallel Group Study to Assess the Efficacy and Safety of 12 Weeks of Once Daily, Orally Inhaled, Co-administration of Olodaterol 5µg (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) Compared to Once Daily, Orally Inhaled, Co-administration of Placebo (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) in Patients With Chronic Obstructive Pulmonary Disease (COPD)[ANHELTO TM 1]
Brief Summary: The overall objective of this study is to assess efficacy and safety of 12 weeks, once daily, orally inhaled co-administration of olodaterol 5 µg (delivered by the Respimat® Inhaler) and tiotropium (delivered by the Handihaler® as Spiriva Handihaler®), compared to tiotropium (Spiriva Handihaler®) monotherapy on lung function in patients with COPD.


Options:
A: Inclusion Criteria :

1. Male or female adults aged ≥40 years, who had signed an informed consent form prior to initiation of any study-related procedure.
2. Patients with severe to very severe Chronic Obstructive Pulmonary Disease COPD (Stage III or IV) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines 2008.
3. Current or ex-smokers with a smoking history of at least 10 pack years (Ten pack-years were defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years).
4. Patients with a post-bronchodilator Forced Expiratory Volume in one second ( FEV1) \<50% of the predicted normal value, and post-bronchodilator FEV1/ Forced Vital Capacity (FVC) \<0.70 at Visit 2 (day -14). (Post refers to 1 h after sequential inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol).
5. A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics.

Exclusion Criteria:

1. Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy test).
2. Women of child-bearing potential
3. Patients requiring long term oxygen therapy (\> 15 h a day) on a daily basis for chronic hypoxemia.
4. Patients who had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to visit 1 or between visit 1 (Day -21) and Visit 3 (Day 1).
5. Patients who developed a COPD exacerbation during a period between visit 1 and 3 were ineligible but were permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation.
6. Patients who had a respiratory tract infection within 4 weeks prior to visit 1 (Day -21)

   • Patients who developed an upper or lower respiratory tract infection during the screening period (up to visit 3 (Day 1) were not eligible, but were permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection
7. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), clinically significant bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension.
8. Patients with lung lobectomy, or lung volume reduction or lung transplantation.
9. 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, history of myocardial infarction, arrhythmia (excluding chronic stable Atrial Fibrillation (AF). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study
   * history of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin
   * uncontrolled hypo- or hyperthyroidism, hypokalemia or hyper adrenergic state
   * narrow-angle glaucoma
   * Symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. (Patients with a Transurethral Resection of Prostate (TURP) were excluded from the study. Patients who underwent full re-section of the prostate could be considered for the study, as well as patients who were asymptomatic and stable on pharmacological treatment for the condition).
   * any condition which might have compromised patient safety or compliance, interfered with evaluation, or precluded completion of the study
10. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count \> 600/mm3 (at visit 2), or onset of symptoms prior to 40 years. Patients without asthma were excluded if their eosinophil count was \>600/mm3 at visit 2.
11. Patients with allergic rhinitis who used H1 antagonists or intranasal corticosteroids intermittently (treatment with a constant dose was permitted).
12. Patients with eczema (atopic), known high immunoglobulin E (IgE) levels or a known positive skin prick test in the last 5 years.
13. Patients with known history and diagnosis of alpha-1 antitrypsin deficiency.
14. Patients who were participating in the active phase of a supervised pulmonary rehabilitation program.
15. Patients with Type I or uncontrolled Type II diabetes.
16. Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or drugs of a similar class or any component thereof:

    * anticholinergic agents
    * long and short acting beta-2 agonists
    * sympathomimetic amines.
17. Patients with a history of long QT syndrome or whose corrected QT interval (QTc) measured at visit 2 (Day -14) (Fridericia method) was prolonged (\>450 ms for males and females) as confirmed by the central ECG assessor.
18. Patients with a clinically significant abnormality on the screening or baseline ECG who in the judgment of the investigator would be at potential risk if enrolled into the study. (These patients could not be re-screened).
19. Patients who needed treatments for COPD and allied conditions after the start of the study (visit 1)
20. Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis) unless they had been stabilized
21. Patients taking other prohibited medications
22. Patients unable to use a dry powder inhaler (e.g. single dose dry powder inhaler (SDDPI), HandiHaler® device, or pressurized Metered Dose Inhaler (MDI) (rescue medication).
23. Patients unable to use an electronic patient diary.
24. Patients who were, in the opinion of the investigator known to be unreliable or non-compliant.
25. Patients who used other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of visit 1 (day -21), whichever was longer.
26. Patients who had live attenuated vaccination within 30 days prior to the screening visit or during the run-in period. Inactivated influenza vaccination, pneumococcal vaccination or any other inactivated vaccine was acceptable provided it was not administered within 48 hours prior to screening and randomization visits.

No additional exclusions were applied by the investigator, in order to ensure that the study population was representative of all eligible patients.
B: Inclusion criteria:

1. All patients must sign an informed consent consistent with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions.
2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have a relatively stable airway obstruction with a post-bronchodilator FEV1 = 30 % and \< 80% of predicted normal and a post-bronchodilator FEV1/FVC \<70% at Visit 1.
3. Male or female patients, 40 years of age or older.
4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years
5. Patients must be able to: perform technically acceptable pulmonary function tests, and maintain records(paper diary).
6. Patients must be able to inhale medication in a competent manner from the Respimat Inhaler as well as the Handihaler.

Exclusion criteria:

1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patients ability to participate in the study.
2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST \>x2 ULN, ALT \>x2 ULN, bilirubin \>x2 ULN or creatinine \>x2 ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients).
3. Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count =600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition.
4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists).
5. A diagnosis of paroxysmal tachycardia (\>100 beats per minute) (due to the known class side effect profile of ß2-agonists).
6. A history of myocardial infarction within 1 year of screening visit (Visit 1).
7. Unstable or life-threatening cardiac arrhythmia.
8. Hospitalization for heart failure within the past year.
9. Known active tuberculosis.
10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed).
11. A history of life-threatening pulmonary obstruction.
12. A history of cystic fibrosis.
13. Clinically evident bronchiectasis.
14. A history of significant alcohol or drug abuse.
15. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1).
16. Patients being treated with oral or patch ß-adrenergics.
17. 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.
18. 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.
19. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program.
20. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1).
21. Patients with known hypersensitivity to ß-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution.
22. Patients with known hypersensitivity to anticholinergic drugs, lactose, or any other components of the HandiHaler®.
23. Pregnant or nursing women.
24. Women of childbearing potential not using a highly effective method of birth control\*. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years.

    \* as per ICH M3(R2) a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year).
25. Patients who have previously been randomised in this study or are currently participating in another study.
26. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
C: Inclusion Criteria:

* Diagnosis of COPD
* 10 pack-year or greater history of cigarette smoking
* Post-bronchodilator FEV1/FVC of \<0.7
* Predicted FEV1 of 70% of normal or less
* Modified Medical Research Council (mMRC) dyspnea score of 2 or greater

Exclusion Criteria:

* Women who are pregnant, lactating, or planning to become pregnant
* Respiratory disorders other than COPD, including a current diagnosis of asthma
* Clinically significant non-respiratory diseases or abnormalities that are not adequate controlled
* Significant allergy or hypersensitivity to anticholinergics, beta-agonist, or the excipients of magnesium stereate or lactose used in the inhaler delivery device
* Hospitalization for COPD or pneumonia within 12 weeks prior to screening
* Lung volume reduction surgery within 12 weeks prior to screening
* Abnormal and clinically significant ECG findings at screening
* Clinically significant laboratory findings at screening
* Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong cytochrome P450 3A4 inhibitors, high dose inhaled steroids (\>1000mcg fluticasone propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short- and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or nedocromil sodium, or investigational medicines for defined time periods prior to the screening visit
* Use of long-term oxygen therapy (12 hours or greater per day)
* Regular use of nebulized treatment with short-acting bronchodilators
* Participation in the acute phase of a pulmonary rehabilitation program
* A know or suspected history of alcohol or drug abuse
* Affiliation with the investigational site
* Previous use of GSK573719 or GW642444 alone or in combination, including the combination of fluticasone furoate and GW64244
D: Inclusion criteria:

1. All patients must sign an informed consent
2. All patients must have a diagnosis of chronic obstructive pulmonary disease (COPD) must meet the following spirometric criteria:

a post-bronchodilator forced expiratory flow in 1 second (FEV1) =\<30% of predicted normal and \<80% of predicted normal and a post bronchodilator FEV1 / forced vital capacity (FVC) \<70% at Visit 1 4. Male or female patients, 40 years of age or older. 5. Patients must be current or ex-smokers with a smoking history of more than 10 pack years

Exclusion criteria:

* Patients with a significant disease other than COPD;
* Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis;
* Patients with a history of asthma or a total blood eosinophil count \>=600/mm3.
* Patients with any of the following conditions:

a diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists) a diagnosis of paroxysmal tachycardia - Patients with any of the following conditions: a history of myocardial infarction within 1 year of screening visit a diagnosis of clinically relevant cardiac arrhythmia a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years

* Patients who have undergone thoracotomy with pulmonary resection
* Patients being treated with the following concomitant medications:

medications that prolong the QT/QTc interval oral Beta-adrenergics 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

- Pregnant or nursing women

Answer: B