Efficacy and safety of Tanimilast in Asthmatics uNcontrolled on ICS-containinG backgrOund maintenance therapy

Prior treatment

• Cardiovascular diseases: subjects who have a clinically significant (CS) cardiovascular condition according to Investigator’s judgement, such as but not limited to: congestive heart failure (New York Heart Association (NYHA) class IV); unstable or acute ischaemic heart disease in the last year prior to screening; history of sustained and non-sustained cardiac arrhythmias diagnosed in the last 6 months prior to screening and not controlled with a rate control strategy; high degree impulse conduction blocks (>2nd degree atrioventricular block type 2); persistent, long standing or paroxysmal atrial fibrillation
• Previous medical history, evidence of an uncontrolled intercurrent illness, or any clinically relevant abnormal findings in haematology, clinical chemistry, or urinalysis that in the opinion of the Investigator and/or medical monitor may compromise the safety of the subject in the study or interfere with evaluation of the IMP or reduce the subject’s ability to participate in the study. Subjects with well-controlled comorbid disease (i.e.,hypertension, hyperlipidaemia, gastroesophageal reflux disease) on a stable treatment regimen for at least 15 days prior to screening are eligible; Subjects with a diagnosis of depression, generalised anxiety disorder, suicidal ideation or behaviour that may, according to the Investigator’s judgement, place the subject at undue risk
• Drugs with hepatoxicity potential: subjects receiving treatment with any drug known to have a well-defined potential for hepatotoxicity (i.e., isoniazide, nimesulide, ketoconazole) and strong inhibitors of cytochrome P450 (CYP)3A4/5 (i.e.,itraconazole) within the previous 3 months before the screening visit
• Alcohol/drug abuse: Subjects with a known or suspected history of alcohol and/or drug abuse within 12 months prior to screening
• Surgery: Subjects with major surgery (i.e., aortic and major vascular surgery, cystectomy, pneumonectomy, liver transplantation, oesophagostomy, duodeno-pancreatic surgery, etc.) in the 3 months prior to screening visit or planned during the trial; low-risk procedures are allowed during the trial (i.e., endoscopic procedures, cataract surgery, superficial breast surgery, partial mastectomy without lymph node dissection, etc.)
• Subjects treated with monoamine oxidase inhibitors (MAOIs) and tricyclic anti-depressants
• Subjects receiving any therapy that could interfere with the study drugs according to Investigator’s opinion
• Participation in an investigational trial: Subjects who have received an investigational drug within 2 months or six half-lives (whichever is greater) prior to screening visit, or have been previously randomised in this trial, or are currently participating in another clinical trial
• Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 2 weeks, or associated complications/symptoms, which have not resolved within 14 days prior to screening or randomization
• Vaccination: Subjects having received a vaccination within 2 weeks prior to screening or during the run-in period
• Recent exacerbation or respiratory tract infection: hospitalisation, emergency room admission or use of SCS for an asthma exacerbation or a documented diagnosis of lower respiratory tract infection that required antibiotics or an unresolved respiratory tract infection within 4 weeks prior to screening visit or during the run-in period
• Subjects using SCS medication in the 4 weeks or slow-release corticosteroids in the 12 weeks prior to randomization
• Asthma requiring use of biologics: subjects currently receiving asthma treatment or having received treatment within 6 months prior to randomisation with injectable monoclonal antibodies (e.g.,omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, tezepelumab, etc.)

Other illness

• Subjects with a diagnosis of depression, generalised anxiety disorder, suicidal ideation or behaviour that may, according to the Investigator’s judgement, place the subject at undue risk
• Liver diseases: subjects with severe hepatitis, chronic active hepatitis, or evidence of uncontrolled chronic liver disease according to the Investigator’s opinion
• Contra-indications to IMP: Subjects with a history of allergy or hypersensitivity to β2-agonists, corticosteroids, phosphodiesterase-4 inhibitors or any of the excipients contained in any of the formulations used in the trial or a medical condition that in the Investigator’s opinion would contra-indicate study participation
• History of “at risk” asthma: history of near fatal asthma or of a past hospitalisation for asthma in intensive care unit which, in the judgement of the Investigator, may place the subject at undue risk
• Respiratory disorders other than asthma: subjects with known respiratory disorders other than asthma. This can include but is not limited to: Chronic obstructive pulmonary disease (COPD), α1-antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease
• Lung resection: subjects with a history of lung volume resection
• Smoking status: Current smoker (including e-cigarettes), ex-smoker with a smoking history of 10 pack-years (pack-years = the number of cigarette packs per day times the number of years), or current use of inhaled or oral cannabis products. Ex-smokers must have stopped smoking for ≥1 year (≥6 months for e-cigarettes)

Lab values

• Subjects treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing agent before the screening), nonselective β-blocking drugs, quinidine, quinidine like anti-arrhythmic, or any medication with a QTc prolongation potential or a history of QTc prolongation
• For females only: pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive serum human chorionic gonadotropin (β-HCG) laboratory test

Age

• Cancer or history of cancer: subjects with active cancer or a history of cancer with <5 years disease-free survival time (e.g., when there is evidence of local recurrence or metastases). Localised carcinoma (e.g., basal cell carcinoma, in situ carcinoma of the cervix adequately treated) is acceptable

Other

• Run-in compliance: e-Diary completion compliance <75% at randomization
• ECG criteria: any abnormal and CS 12-lead ECG that in the Investigator's opinion would affect efficacy or safety evaluation or place the subjects at risk. Male subjects with a QTcF >450 msec and female subjects with a QTcF >470 msec at screening are not eligible (not applicable for subjects with permanent atrial fibrillation and for subjects with pacemaker); not applicable for subjects for subjects with permanent atrial fibrillation and for subjects with pacemaker)
• Patients mentally or legally incapacitated or patients accommodated in an establishment as a result of an official or judicial order

• Informed consent: Subject’s written informed consent obtained prior to any study-related procedures
• Females are eligible to enter the study if they are of: - non-childbearing potential i.e. physiologically incapable of becoming pregnant (e.g. postmenopausal women defined as being amenorrhoeic for ≥12 consecutive months without an alternative medical cause) or women permanently sterilized. - Women of childbearing potential with fertile partners: they must have a negative pregnancy test at screening and they or/and their partners must agree to use 1 or more of the following acceptable contraceptive measures: - Placement of an intrauterine device or intrauterine hormone releasing system; - Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); - Progesterone only hormonal contraception associated with inhibition of ovulation (oral, injectable,implantable); - Bilateral tubal occlusion; - Vasectomised partner; Reliable contraception should be maintained throughout the study. - Women of childbearing potential (WOCBP) with non-fertile male partners (contraception is not required in this case)
• Sex and age: Male or female subjects aged ≥18 and ≤75 years
• Diagnosis of asthma: A documented history of physician-diagnosed asthma for at least 1 year and with diagnosis before the age of 50 years
• Stable asthma therapy: a stable maintenance treatment with fixed combination of medium to high dose of ICS plus LABA for at least 3 months prior to screening. Medium and high doses of ICS are defined according to Global Initiative for Asthma (GINA) 2022
• Lung function: A prebronchodilator Forced expiratory volume in the first second (FEV1) ≤80% of the predicted normal value, after appropriate washout from bronchodilators, at the screening visit and at randomisation visit
• Bronchodilator responsiveness: A demonstrated increase (>12% AND >200mL) in either FEV1 or Forced vital capacity (FVC) from baseline within 30 min after inhalation of 400 μg salbutamol (albuterol) or equivalent
• Poor asthma control: Evidence of poorly controlled or uncontrolled asthma as based on Asthma Control Questionnaire (ACQ-7) score ≥1.5 at screening and at randomization
• History of asthma exacerbations: A documented history of: - At least 1 asthma exacerbation leading to hospitalization within the last 12 months prior to screening; or - 2 or more asthma exacerbations within the last 12 months prior to screening, defined as a worsening of asthma symptoms that leads to any of the following: - an outpatient treatment with Systemic corticosteroids( SCS*); - an inpatient hospitalisation because of asthma; - an emergency room visit that resulted in the use of SCS*; * including oral or parenteral routes (a single depo-injectable dose of corticosteroid will be considered the equivalent to a 3-day course of SCS)
• A cooperative attitude and ability: - to correctly use the inhalers; - to perform all trial-related procedures including technically acceptable spirometry; - to correctly use the electronic diary (e-Diary) and home spirometer;