Please select the eligibility criteria that correspond to the clinical trial below.
Title: Asthma Clinical Research Network (ACRN) Trial - Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC)
Brief Summary: Typically, people with asthma are initially prescribed a low dose of inhaled corticosteroid (ICS) medication to control asthma symptoms. If a low dose of ICS is ineffective at controlling symptoms, the addition of a second controller medication is recommended. This study will examine the effectiveness of the medication tiotropium bromide combined with a low dose of ICS at maintaining asthma control in people with moderately severe asthma.


Options:
A: Inclusion Criteria:

* Patients with a diagnosis of asthma, (GINA 2015) for a period of at least 1 year prior to Visit 1 (Screening).
* Patients who have used medium or high dose of ICS/LABA combinations for asthma for at least 3 months and at stable medium or high doses of ICS/LABA for at least 1 month prior to Visit 1.
* Patients must be symptomatic at screening despite treatment with mid or high stable doses of ICS/LABA. Patients with ACQ-7 score ≥ 1.5 at Visit 101 and at Visit 102 (before randomization).
* Patients with documented history of at least one asthma exacerbation which required medical care from a physician, ER visit (or local equivalent structure) or hospitalization in the 12 months prior to Visit 1, and required systemic corticosteroid treatment.
* Pre-bronchodilator FEV1 of \< 80 % of the predicted normal value for the patient according to ATS/ERS guidelines after withholding bronchodilators at both visits 101 and 102.
* Withholding period of bronchodilators prior to spirometry: SABA for ≥ 6 hrs, Twice daily LABA (or FDC of ICS/LABA) for ≥ 12 hrs, Once daily LABA (or FDC of ICS/LABA) for ≥ 24 hrs, SAMA for ≥ 8 hrs, Short acting xanthines for 12 hrs, Long acting xanthines for 24 hrs, .
* Washout period of each drug should be kept as close as possible as above and should not be longer. If longer washout period is needed due to scheduling issues, please contact Novartis Medical monitor.
* A one-time repeat of percentage predicated FEV1 (Pre-bronchodilator) at Visit 101 and/or Visit 102 is allowed in an ad-hoc visit. Repeat of Visit 101 spirometry should be done in an ad-hoc visit to be scheduled on a date that would provide sufficient time to receive confirmation from the spirometry data central reviewer of the validity of the assessment before randomization. Run-in medication should be dispensed once spirometry assessment met inclusion criteria (ATS/ERS quality criteria, FEV1 % predicted normal value, and reversibility) as per equipment
* A one-time rescreen is allowed in case the patient fails to meet the criteria at the repeat, provided the patient returned to the required treatment as per inclusion criteria 4
* Patients who demonstrate an increase in FEV1 of 12% and 200 mL within 30 minutes after administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at Visit 101.All patients must perform a reversibility test at Visit 101. If reversibility is not demonstrated at Visit 101 then one of the following criteria need to be met.
* Reversibility should be repeated once.
* Patients may be permitted to enter the study with historical evidence of reversibility that was performed according to ATS/ERS guidelines within 2 years prior to Visit 1.
* Alternatively, patients may be permitted to enter the study with a historical positive bronchoprovocation test that was performed within 2 years prior to Visit 1. If reversibility is not demonstrated at Visit 101 (or after repeated assessment in an ad-hoc visit) and historical evidence of reversibility/bronchoprovocation is not available (or was not performed according to the ATS/ERS guidelines patients must be screen failed
* Spacer devices are permitted during reversibility testing only. The Investigator or delegate may decide whether or not to use a spacer for the reversibility testing

Exclusion Criteria:

* Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit between Visit 1 and Visit 102 they may be re-screened 6 weeks after recovery from the exacerbation.
* Patients who have ever required intubation for a severe asthma attack/exacerbation.
* Patients who have a clinical condition which is likely to be worsened by ICS administration (e.g. glaucoma, cataract and fragility fractures) who are according to investigator's medical judgment at risk participating in the study.
* Patients treated with a LAMA for asthma within 3 months prior Visit 1 (Screening).
* Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or bladder-neck obstruction or severe renal impairment or urinary retention. BPH patients who are stable on treatment can be considered).
* Patients who have had a respiratory tract infection or asthma worsening as determined by investigator within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. Patients may be re-screened 4 weeks after recovery from their respiratory tract infection or asthma worsening.
* Patients with evidence upon visual inspection (laboratory culture is not required) of clinically significant (in the opinion of investigator) oropharyngeal candidiasis at Visit 102 or earlier, with or without treatment. Patients may be re-screened once their candidiasis has been treated and has resolved.
* Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic sinusitis) which in the opinion of the investigator may interfere with the study evaluation or optimal participation in the study.
* Patients with a history of chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant bronchiectasis and active tuberculosis.
* Patients with Type I diabetes or uncontrolled Type II diabetes.
* Patients who, either in the judgment of the investigator or the responsible Novartis personnel, have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study.
* Patients with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blockers, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at the run-in visit (Visit 101) with a resting ventricular rate \< 100/min. At Visit 101 the atrial fibrillation must be confirmed by central reading.
* Patients with a history of myocardial infarction (this should be confirmed clinically by the investigator) within the previous 12 months.
* Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study
* Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia method) is prolonged (\> 450 msec for males and \> 460 msec for females) and confirmed by a central assessor (these patients should not be rescreened).
* Patients with a history of hypersensitivity to lactose, any of the study drugs or to similar drugs within the class including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof.
* Patients who have not achieved an acceptable spirometry result at Visit 101 in accordance with ATS/ERS criteria for acceptability and repeatability. A one-time repeat spirometry is allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on the same day) if the spirometry did not qualify due to ATS/ERS criteria at Visit 101 and/or Visit 102. If the patient fails the repeat assessment, the patient may be rescreened once, provided the patient returns to the required treatment as per inclusion criteria 4.
* Patients unable to use the Concept1 dry powder inhaler, Accuhaler or a metered dose inhaler. Spacer devices are not permitted.
* History of alcohol or other substance abuse.
* Patients with a known history of non-compliance to medication or who were unable or unwilling to complete a patient diary or who are unable or unwilling to use Electronic Peak Flow with e-diary device.
* Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers).
B: Inclusion Criteria:

* 18 years of age or older at the time of signing the informed consent.
* Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least 6 months prior to Visit 0.
* Asthma Control Questionnaire (ACQ)-6 total score of \>0.75 at Visit 1.
* Subjects are eligible if they have required daily Inhaled Corticosteroids (ICS) therapy \>=100 milligram per day (mg/day) fluticasone propionate (FP) or equivalent with or without Long-Acting Beta-2-Agonists (LABA) or Long-Acting Muscarinic Antagonist (LAMA) for at least 12 weeks prior to Visit 0 and there have been no changes in maintenance asthma medications during the 4 weeks immediately prior to Visit 0. Dosing regimen (once or twice daily to equal the total daily dose) should be restricted to the current local product labels.
* A best pre-bronchodilator morning FEV1 \<=85% of the predicted normal value. Predicted values will be based upon the European Respiratory Society (ERS) Global Lung Function Initiative. A best post-bronchodilator FEV1/ forced vital capacity (FVC) \>=0.7 at Visit 1.
* Airway reversibility is defined as \>=12% and \>=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. Note: If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria are met: The \>=9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1; Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of \>=12% and \>=200 milliliter (mL). Should the subject successfully demonstrate airway reversibility (defined as \>=12% and \>=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the 2-week run-in period.
* All subjects must be able to replace their current Short-Acting Beta-2-Agonists (SABA) inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects must be judged capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits.
* Both male and female subjects are eligible to participate in the study. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 5 days after the last dose of study treatment.
* Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form and in this protocol. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.

Inclusion Criteria (for randomization)

* ACQ-6 total score of \>0.75 at Visit 2.
* Spirometry: A best pre-bronchodilator morning FEV1 \<=85% of the predicted normal value at Visit 2. Predicted values will be based upon the ERS Global Lung Function Initiative.
* Alanine aminotransferase (ALT) \<=2 x upper limit of normal (ULN). Alkaline phosphatase \<=1.5 x ULN. Bilirubin \<=1.5 x ULN (isolated bilirubin \>1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Compliance with completion of the Daily electronic diary (eDiary) reporting defined as completion of all questions/assessments on \>=4 of the last 7 days during the run-in period.

Exclusion Criteria:

* Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1.
* Any severe asthma exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of Visit 1, or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids within 12 weeks of Visit 1.
* Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma.
* Women who are pregnant or lactating or are planning to become pregnant during the study.
* 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). Subjects at potentially high risk (e.g., very low Body Mass Index \[BMI\], severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator
* 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 is acceptable if the subject otherwise meets entry criteria.
* Evidence of a clinically significant abnormality in the 12-lead ECG performed during screening or run-in. 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 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 (BPM); 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 by Fridericia's formula (QTcF) \>=500 millisecond (msec) in subjects with QRS \<120 msec and QTcF \>=530 msec in subjects with QRS \>=120 msec.
* 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.
* Subjects with a medical condition such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction should only be included if in the opinion of the Investigator the benefit outweighs the risk and that the condition would not contraindicate study participation.
* 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.
* 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.
* Subjects who are medically unable to withhold their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit.
* Current smoker or a smoking history of \>=10 pack years (e.g., 20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or pipe tobacco).
* Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. This includes marijuana, which is considered an abused drug.
* A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate.
* 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.
* 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.
* In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials.

Exclusion Criteria (for randomization)

* Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management or, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
* Evidence of a moderate asthma exacerbation leading to a change in therapy or severe exacerbation during screening or the run-in period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
* Changes in asthma medication (excluding changes after Visit 0 or run-in medication and albuterol/salbutamol inhalation aerosol provided at Visit 1).
* Evidence of clinically significant abnormal laboratory tests during screening or run-in, which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each Investigator will use his/her own discretion in determining the clinical significance of the abnormality.
C: Inclusion Criteria:

* Male or Female, Hispanic (self-reported), \> 12 years of age
* Moderate to severe asthma requiring treatment with an inhaled corticosteroid
* Diagnosis of asthma for at least 6 months

Exclusion Criteria:

* Subjects requiring treatment with systemic corticosteroids (e.g., oral, parenteral, ocular)
* Any significant disease or disorder that may jeopardize a subject's safety
D: Inclusion Criteria for TALC and BASALT Studies:

* Clinical history consistent with asthma
* Forced expiratory volume in one second (FEV1) greater than 40% of predicted value
* Asthma confirmed by one of the following two criteria:

  1. Beta-agonist reversibility to 4 puffs albuterol of at least 12% OR
  2. Methacholine provocative concentration at 20% (PC20) of 8 milligrams per milliliter (mg/mL) or less when not on an inhaled corticosteroid (ICS), or 16 mg/mL or less when on an ICS
* Need for daily controller therapy (i.e., ICS, leukotriene modifiers, and/or long-acting beta-agonists) based on one or more of the following criteria:

  1. Received prescription for or used asthma controller within the 12 months prior to study entry OR
  2. Experienced symptoms for more than twice a week and not on asthma controller
* If on inhaled steroids (any drug at any dose not exceeding the equivalent of 1000 micrograms (mcg) of fluticasone daily), participant must have been on a stable dose for at least 2 weeks prior to study entry
* Non-smoker (i.e., total lifetime smoking history less than 10 pack-years; no smoking for at least 1 year prior to study entry)
* Willing to use an effective form of birth control throughout the study

Inclusion Criteria for TALC Study:

* Ability to measure morning (AM) peak expiratory flow (PEF) on schedule using electronic peak flow meter (EPFM) and to complete the study diary correctly at least 75% of the time during the interval between Weeks 2 and 4 of the run-in period
* Adherence with study medication dosing at least 75% of the time during the interval between Weeks 2 and 4 of the run-in period
* No asthma exacerbation requiring use of oral corticosteroids or additional asthma medications (including an increased dose of ICS) during the run-in period
* FEV1 greater than 40% of the predicted value

Exclusion Criteria for BASALT and TALC Studies:

* Lung disease other than asthma, including chronic obstructive pulmonary disease (COPD) and chronic bronchitis
* Established or suspected diagnosis of vocal cord dysfunction
* Significant medical illness other than asthma
* History of respiratory tract infection within the 4 weeks prior to study entry
* History of a significant asthma exacerbation within the 4 weeks prior to study entry
* History of life-threatening asthma requiring treatment with intubation and mechanical ventilation in the 5 years prior to study entry
* Hyposensitization therapy other than an established maintenance regimen
* Inability to coordinate use of the delivery devices used in the study, based on the opinion of the investigator or clinical coordinator
* Pregnant

Exclusion Criteria for TALC Study:

* Inability to coordinate use of the medication delivery devices used in the study, based on the opinion of the investigator or clinical coordinator
* Presence at Week 4 of the run-in period of any of the exclusion criteria stipulated for Week 0 of the run-in period (Note: Respiratory tract infections that do not cause the participant to meet exacerbation criteria are not considered exclusionary.)

Answer: D