Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-Blind, Multi-Center, Parallel-Group Study to Assess the Efficacy and Safety of PT010 Relative to PT003 and PT009 on COPD Exacerbations Over a 52-Week Treatment Period in Subjects With Moderate to Very Severe COPD (Ethos)
Brief Summary: This is a randomized, double-blind, multi-center, parallel-group study to assess the efficacy and safety of PT010 relative to PT003 and PT009 on COPD exacerbations subjects with moderate to very severe COPD.


Options:
A: Inclusion Criteria:

* Informed Consent: A signed and dated written informed consent prior to study participation
* Type of subject: Outpatient
* Age: Subjects 40 years of age or older at Visit 1
* Gender: Male or female subjects. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, \> 45 years, in the absence of hormone replacement therapy OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to safety follow-up contact): Abstinence; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Estrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS); Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records. Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
* COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society
* Smoking History: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years at screening (visit 1) \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Note: Pipe and/or cigar use cannot be used to calculate pack-year history
* Severity of COPD symptoms: A score of \>=10 on the COPD Assessment Test (CAT) at screening
* Severity of COPD Disease: A post-albuterol/salbutamol FEV1/ Forced Vital Capacity (FVC) ratio of \<0.70 at Screening
* Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening. Note: Subjects receiving only Pro re nata (PRN) COPD medications are not eligible
* History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 \<50% predicted normal and a documented history of \>= 1 moderate or severe COPD exacerbation in the previous 12 months OR a post-bronchodilator 50% \<=FEV1 \< 80% predicted normal and a documented history of \>= 2 moderate exacerbations or a documented history of \>=1 severe COPD exacerbation (hospitalized) in the previous 12 months. Note: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations. Note: A documented history of a COPD exacerbation (e.g., medical record verification) is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation). Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence (color). Subject verbal reports are not acceptable
* Liver function tests: alanine aminotransferase (ALT) \<2x upper limit of normal (ULN); alkaline phosphatase \<=1.5xULN; bilirubin \<=1.5xULN (isolated bilirubin \>1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study
* Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD)
* Alpha1-antitrypsin deficiency: Subjects with Alpha1-antitrypsin deficiency as the underlying cause of COPD
* Other respiratory disorders: Subjects with active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases
* Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening
* Risk Factors for Pneumonia: immune suppression (e.g. human immunodeficiency virus \[HIV\], Lupus) or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis). Patients at potentially high risk (e.g. very low BMI, severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator
* Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). In addition, any subject that experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in period will be excluded
* Other Respiratory tract infections that have not resolved at least 7 days prior to screening
* Abnormal Chest x-ray(CXR): Chest x-ray (posteroanterior and lateral) reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest x-ray at Screening Visit 1 (or historical radiograph or computerised tomography (CT) scan obtained within 3 months prior to screening) that will be over-read by a central vendor. Note: Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation within 3 months of screening must provide a post pneumonia/exacerbation chest x-ray to be over-read by the central vendor or have a chest x-ray conducted at screening. For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz \[BfS\])
* Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study
* Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria
* Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV Heart failure
* Abnormal and clinically significant 12-Lead Electrocardiogram (ECG) finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Principal Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation (AF) with rapid ventricular rate \>120 beats per minute); sustained or nonsustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate (QTcF) \>=500 milliseconds (msec) in patients with QRS \<120 msec and QTcF \>=530 msec in patients with QRS \>=120 msec
* Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator contraindicates study participation
* Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the subject has been considered cured by treatment
* Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy \>3 Liter/minute (L/min) (Oxygen use =\<3L/min flow is not exclusionary)
* Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit
* Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening or subjects who plan to enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded
* Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
* Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits
* Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study
* Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or study site, or immediate family members of the aforementioned that is involved with this study
* Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials
* Medication prior to screening: Use of the following medications within the following time intervals prior to Screening (Visit 1) or during the study: Long term antibiotic therapy Subjects receiving antibiotics for long term therapy are not eligible for the study (Antibiotics are allowed for the short term treatment of an exacerbation or for short term treatment of other acute infections during the study); Systemic, Oral, parenteral corticosteroids 30 days (Except during the study oral/systemic corticosteroids may be used to treat COPD exacerbations/pneumonia) Intra-articular injections are allowed; Any other investigational drug (30 days or 5 half lives whichever is longer)
B: Inclusion Criteria

* Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to acceptable contraceptive methods used consistently and correctly for the duration of the study.
* 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.
* Forced expiratory volume in 1 second (FEV1)/Forced vital capacity (FVC) ratio must be \<0.70 and FEV1 must be \<65% predicted normal value calculated using NHANES III reference equations (or reference norms applicable to other regions).
* Subjects with history of exacerbations.

Please refer to the study protocol for the complete inclusion criteria list.

Exclusion Criteria

* Significant diseases or conditions other than COPD, which, in the opinion of the Investigator, may put the subject 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.
* Women who are pregnant or lactating, or are planning to become pregnant during the course of the study, or women of childbearing potential who are not using an acceptable method of contraception.
* Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma.
* Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening)
* Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening)
* Immune suppression or severe neurological disorders affecting control of the upper airway or other risk factors that in the opinion of the Investigator would put the subject at substantial risk of pneumonia.
* Subjects with a diagnosis of narrow angle glaucoma, who, in the opinion of the Investigator, have not been adequately treated.
* Subjects who have a history of hypersensitivity to β2-agonists, budesonide or any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or any other component of the IMPs.

Please refer to the study protocol for the complete inclusion criteria list.
C: Inclusion Criteria

* Given their signed written informed consent to participate.
* Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to acceptable contraceptive methods used consistently and correctly for the duration of the study.
* Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS), or other local applicable guidelines.
* Current or former smokers with a history of at least 10 pack-years of cigarette smoking.
* Forced expiratory volume in 1 second (FEV1)/Forced vital capacity (FVC) ratio must be \<0.70 and FEV1 must be \<80% predicted normal value calculated using NHANES III reference equations (or reference norms applicable to other regions).
* Required COPD maintenance therapy:
* All Subjects must have been on two or more inhaled maintenance therapies for the management of their COPD for at least 6 weeks prior to Screening. Scheduled SABA and/or scheduled SAMA are considered inhaled maintenance therapies

Please refer to the study protocol for the complete inclusion criteria list.

Exclusion Criteria

* Significant diseases or conditions other than COPD, which, in the opinion of the Investigator, may put the subject 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.
* Women who are pregnant or lactating, or are planning to become pregnant during the course of the study, or women of childbearing potential who are not using an acceptable method of contraception.
* Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma.
* Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening) or during the Screening Period
* Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening Period
* Immune suppression or severe neurological disorders affecting control of the upper airway or other risk factors that in the opinion of the Investigator would put the subject at substantial risk of pneumonia.
* Subjects with a diagnosis of narrow angle glaucoma, who, in the opinion of the Investigator, have not been adequately treated.
* Subjects who have a history of hypersensitivity to β2-agonists, budesonide or any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or any other component of the IMPs.

Please refer to the study protocol for the complete inclusion criteria list.
D: Inclusion :

1. Male and female ≥ 40 years
2. Severe or very severe COPD diagnosed for at least 12 months
3. Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years
4. Post-bronchodilator FEV1 \< 50% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio \< 0.7
5. Documented history of at least one exacerbation in the 12 months
6. Patient under double therapy for at least 2 months prior to screening. Double therapy will be defined by treatment with any of the following:

   Orally inhaled corticosteroid (ICS) and (long-acting beta2-agonist) LABA ICS and long-acting muscarinic antagonist (LAMA) Orally LABA and LAMA Monotherapy with LAMA for at least 2 months prior to screening
7. Symptomatic patient at screening with a CAT score ≥ 10.
8. Cooperative attitude and ability to use correctly the inhalers, the spacer AeroChamber Plus (only to patients who are using a spacer), the electronic devices with COPD questionnaire.

Exclusion :

1. Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS are willing to use one or more of the reliable methods of contraception
2. Patient with a current clinical diagnosis of asthma with a physician-judged need for inhaled or oral corticosteroid therapy
3. Patient requiring use of the following medications:

   Course of systemic steroids \> 3 days for COPD exacerbation in the 4 weeks prior to screening Course of antibiotics for COPD exacerbation \> 7 days in the 4 weeks prior to screening Phosphodiesterase-4 inhibitor in the 4 weeks prior to screening Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening
4. COPD exacerbation requiring prescription of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period
5. Patient treated with non-cardioselective β-blockers in the month preceding the screening or during the run-in period.
6. Patient treated with long-acting antihistamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study or if taken as needed
7. Patient requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia
8. Known respiratory disorders other than COPD which may impact the efficacy of the study drug
9. Patient who have clinically significant cardiovascular condition
10. Patient with atrial fibrillation (AF): Paroxysmal atrial fibrillation, Persistent, Long standing or Permanent
11. Abnormal and clinically significant 12-lead ECG that results in active medical problem which may impact the safety of the patient
12. Patient whose ECG shows QTcF \>450 ms for males or QTcF \>470 ms for females at screening visit are not eligible (not applicable for patient with pacemaker)
13. Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction would prevent use of anticholinergic agents
14. History of hypersensitivity to M3 Antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug
15. Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study drug
16. Patients with hypokalaemia (serum potassium \<3.5 mEq/L or 3.5 mmol/L) or uncontrolled hyperkalaemia
17. Unstable concurrent disease which may impact the results of the study
18. Patients with any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next six months (after V1) or with malignancy for which they are currently undergoing radiation therapy or chemotherapy
19. History of alcohol abuse or substance/drug abuse within 12 months prior to screening visit
20. Participation in another clinical trial if investigational drug was received less than 8 weeks prior to screening visit

Answer: B