Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (5 mcg/Day) Over 48 Weeks as add-on Controller Therapy on Top of Usual Care in Patients With Severe Persistent Asthma
Brief Summary: The trial is a randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 5 µg tiotropium over a 48-week treatment period as compared to placebo. Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined as add-on controller therapy on top of usual care in patients with severe persistent asthma. The primary objective of each trial is to evaluate the long term efficacy of tiotropium over placebo on top of usual care in patients with severe persistent asthma as determined by pulmonary function testing, effects on asthma exacerbations, effects on quality of life, on asthma control and health care resource utilisation. The secondary objective of each trial is to compare the long term safety of tiotropium with placebo in this patient population.


Options:
A: Inclusion Criteria:

1. Consent to participate in the study
2. Age 4-11 years old
3. Male or eligible female - Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation
4. Asthma diagnosis for at least 6 months
5. Ability to answer questions regarding asthma control and use a metered dose inhaler and DISKUS
6. A history of clinical varicella infection or recipient of a varicella vaccine in countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids.
7. History of at least once occurrence of asthma exacerbation within the prior 12 months
8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks (Eligible subjects include: subjects with use of short-acting beta-agonist, leukotriene receptor antagonist, theophylline, or cromolyn whose asthma is not well-controlled; subjects on low-dose ICS monotherapy whose asthma is not well-controlled; subjects on low-dose ICS and one or more adjunctive therapy whose asthma is either controlled or not well-controlled asthma; subjects on medium-dose ICS monotherapy whose asthma is either controlled or not well-controlled; and subjects on medium-dose ICS and one or more adjunctive therapy whose asthma is well-controlled)

Exclusion Criteria:

1. History of life-threatening asthma
2. Unstable asthma
3. Current use of high-dose ICS or ICS/LABA therapy to treat asthma symptoms
4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma.
5. Respiratory infection
6. Subjects with only exercise-induced asthma
7. An asthma exacerbation within the last 4 weeks or more than 4 separate exacerbations in the last 12 months
8. Hospitalization for asthma within 4 weeks or more than 2 hospitalizations within the last 12 months
9. Other current evidence of clinically significant uncontrolled disease/conditions of any body or organ system
10. Neurological or psychiatric disease or history of drug or alcohol abuse of a subject or his/her guardian which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements
11. Participation in an interventional study or used any investigational drug for any disease state within the last 30 days
12. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medication
13. Severe hypersensitivity to cow's milk proteins
14. Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, beta-adrenergic blockers; phenothiazines, monoamine oxidase inhibitors, or diuretics
15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole)
16. Affiliation with investigator's site, including a immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
17. A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.
B: 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).
C: Inclusion criteria:

1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).
2. Male or female patients aged at least 18 years but not more than 75 years.
3. All patients must have at least a 5-year history of asthma at the time of enrolment into the trial and the diagnosis of asthma must have been made before the patient´s age of 40.
4. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent
5. All patients must have a history of one or more asthma exacerbation in the past year.
6. Patients must have evidence of treated, severe, persistent asthma in postbronchodilator pulmonary function tests.
7. Patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years
8. Patients must be able to use the Respimat® inhaler correctly
9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the electronic diary/peak flow meter.

Exclusion criteria:

1. Patients with a significant disease other than asthma. 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 trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient´s ability to participate in the trial.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry.
3. Patients with a recent history (i.e. six months or less) of myocardial infarction, hospitalisation for cardiac failure during the past year, any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year, known active tuberculosis, malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (treated basal cell carcinoma allowed), lung diseases other than asthma (e.g. COPD), significant alcohol or drug abuse within the past two years, 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.
4. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).
5. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day.
6. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
7. Pregnant or nursing women or 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/salpingectomy, or post-menopausal for at least two years.
8. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.
9. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®), beta-blocker medication, oral beta-adrenergics, other non-approved and according to international guidelines not recommended ´experimental´ drugs for routine asthma therapy (e.g. TNF-alpha blockers, methotrexate, cyclosporin) within four weeks prior to the Screening Visit (Visit 1) or during the screening period.
10. Patients with any asthma exacerbation or respiratory tract infection in the four weeks prior to the trial.
11. Patients who have previously been randomised in this trial or in the respective twin trial (205.416 versus 205.417) or are currently participating in another trial.
12. Patients with a known narrow-angle glaucoma.

Note:

As with other anticholinergic drugs, tiotropium should be used with caution in patients with prostatic hyperplasia or bladder neck obstruction.

As with all predominantly renally excreted drugs, patients with moderate to severe renal impairment (known creatinine clearance of \<= 50 mL/min) treated with tiotropium should be monitored closely.
D: Inclusion Criteria:

* A subject must be at least 12 years of age, of either sex, and of any race, with a diagnosis of asthma of at least 12 months duration that is consistent with the following definition:

  * The diagnosis of asthma is based upon clinical history and examination, pulmonary function parameters, and response to beta2-agonists, according to international guidelines.
* A subject must have been using a high dose of inhaled glucocorticosteroid (ICS) either alone or in combination with a long-acting beta2 agonist (LABA) for at least 12 weeks prior to Screening, with no use of oral glucocorticosteroids within 30 days prior to Screening. A subject must have been on a stable asthma regimen (daily dose unchanged) for at least 2 weeks prior to Screening. High daily doses of ICS are defined as follows:

  * \>1000 mcg beclomethasone chlorofluorocarbon (CFC)
  * \>500 mcg beclomethasone hydrofluoroalkane (HFA)
  * \>1000 mcg budesonide dry powder inhaler (DPI)
  * \>2000 mcg flunisolide
  * \>500 mcg fluticasone
  * \>400 mcg MF
  * \>2000 mcg triamcinolone acetonide
  * \>320 mcg ciclesonide

Note: Dose delivery by method or modality other than those noted above must be equivalent.

* A subject must have experienced at least one severe exacerbation requiring a course of oral glucocorticosteroid 2 to 12 months prior to Screening.
* If, based upon the medical judgment of the investigator, there is no inherent harm in changing the subject's current asthma therapy, then the subject (and parent/guardian, if applicable) must be willing to discontinue his/her prescribed ICS or ICS/LABA prior to initiating MF MDI run-in medication.
* To document the diagnosis of asthma and assure the subject's responsiveness to bronchodilators before randomization, one of the following methods can be used at the Screening Visit, Day-14, or thereafter, but prior to the Baseline Visit:

  * The subject must demonstrate an increase in absolute FEV1 of at least 12% and at least 200 mL within approximately 15 to 20 minutes after administration of four inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg).
  * The subject must demonstrate a peak expiratory flow (PEF) variability of more than 20% expressed as a percent of the best and lowest morning pre-bronchodilator PEF over at least 1 week.
  * The subject must demonstrate a diurnal variation in PEF of more than 20% based on the difference between the prebronchodilator (before taking albuterol/salbutamol) morning value and the postbronchodilator value (after taking albuterol/salbutamol) from the evening before, expressed as a percentage of the mean daily PEF value. Note: If a subject is to qualify using diurnal variation, the subject should be instructed to perform his/her PEF evaluation after using his/her bronchodilator in the evening.
* At the Screening Visit, the subject's FEV1 must be \>=50% predicted when all restricted medications have been withheld for the appropriate intervals.
* At the Baseline Visit, the subject's FEV1 must be \>=50% and \<=85% predicted when all restricted medications have been withheld for the appropriate intervals.
* The subject (and parent/guardian for a subject under the age of legal consent) must be willing to give written informed consent and be able to adhere to dose and visit schedules.
* A female subject of childbearing potential must be using a medically acceptable, adequate form of birth control. This includes:

  * hormonal contraceptive as prescribed by a physician (oral combined, hormonal vaginal ring, hormonal implant or depot-injectable);
  * medically prescribed intra-uterine device (IUD);
  * medically prescribed topically-applied transdermal contraceptive patch;
  * condom in combination with a spermicide (double-barrier method);
  * monogamous relationship with a male partner who has had a vasectomy. The subject must have started this birth control method at least 3 months prior to Screening (with the exception of condom in combination with spermicide), and must agree to continue its use for the duration of the study. A female subject of childbearing potential who is not currently sexually active must agree and consent to using a medically acceptable method should she become sexually active during the course of this study. Women who have been surgically sterilized or are at least 1 year postmenopausal are not considered to be of childbearing potential. A female subject of childbearing potential must have a negative serum pregnancy test at Screening in order to be considered eligible for the open-label MF MDI Run-in Period.

Exclusion Criteria:

* A subject who demonstrates a change (increase or decrease) in absolute FEV1 of \>20% at any time from the Screening Visit up to and including the Baseline Visit. Pulmonary function tests (PFTs) will be performed in the morning.
* A subject who requires the use of \>8 inhalations per day of short-acting beta agonists (SABA) MDI or \>=2 nebulized treatments per day of 2.5 mg SABA, on any 2 consecutive days from the Screening Visit up to and including the Baseline Visit.
* A subject who experiences a decrease in AM or PM peak expiratory flow (PEF) below the Run-in Period stability limit on any 2 consecutive days prior to randomization.
* A subject who experiences a clinical asthma exacerbation (defined as a deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with additional, excluded asthma medication \[including oral or other systemic corticosteroids, but allowing SABAs\]), at any time from the Screening Visit up to and including the Baseline Visit.
* A subject who has been treated in the emergency room (for a severe asthma exacerbation), or admitted to the hospital for management of airway obstruction, within the last 3 months.
* A subject who has ever required ventilator support for respiratory failure secondary to asthma.
* A subject who has experienced an upper or lower respiratory tract infection (viral or bacterial) within the previous 2 weeks prior to Screening and Baseline Visits. Visits can be rescheduled 2 weeks after complete resolution of the event to re-assess eligibility.
* A subject who is a smoker or ex-smoker and has smoked within the previous year or has had a cumulative smoking history \>10 pack-years.
* A subject with a clinically significant abnormal vital sign.
* A subject with evidence (upon visual inspection, laboratory culture is not required) of clinically significant oropharyngeal candidiasis at Baseline (Visit 3) with or without treatment. If there is evidence of oropharyngeal candidiasis at Screening or Pre-Baseline Visit, the subject may be treated as appropriate and the Baseline Visit can be scheduled upon resolution. If there is evidence of oropharyngeal candidiasis at the Baseline Visit, the subject may be treated as appropriate and the visit can be rescheduled upon resolution.
* A subject with a history of clinically significant renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular, or other significant medical illness or disorder which, in the judgment of the investigator, could interfere with the study, or require treatment that might interfere with the study. Specific examples include (but are not limited to) insulin-dependent diabetes, hypertension being treated with beta blockers, active hepatitis, coronary artery disease, arrhythmia, stroke, severe rheumatoid arthritis, chronic open-angle glaucoma or posterior subcapsular cataracts, acquired immune deficiency syndrome (AIDS), or conditions that may interfere with respiratory function such as clinically diagnosed chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, etc. Other conditions that are well-controlled and stable (eg, hypertension not requiring beta blockers) will not prohibit participation if deemed appropriate per the investigator's judgment.
* A subject who is known to be allergic to or intolerant of ICS, beta2 agonists, or any of the excipients present in the medications used in this study.
* A female subject who is breast-feeding, pregnant, or intends to become pregnant while participating in this study.
* A subject who is a known illicit drug user.
* A subject who is known to be human immunodeficiency virus (HIV) positive (HIV testing will not be conducted in this study).
* A subject who is unable to correctly use an oral MDI inhaler.
* A subject who has been taking any of the restricted medications prior to Screening without meeting the required washout timeframes.
* A subject who cannot adhere to the permitted concomitant medications and prohibited medications.
* A subject participating in this study may not participate in this same study at another investigational site. In addition, a subject cannot participate in a different investigational study at any site, during the same timeframe of this study.
* A subject must not be randomized into this study more than once.
* No person directly associated with the administration of the study may participate as a study subject. No family member of the investigational study staff may participate in this study.
* A subject who previously participated in a trial with MF/F.
* Subjects with a history of significant QTC prolongation (ie, QTc\>500 msec) are excluded from participation in the study.

Answer: C