PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study

Inclusion Criteria: 1. Provision of signed and dated informed consent form 2. Started willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, age ≥ 12 years 4. No change in asthma medications for the past 2 months and use of medium or high dose inhaled corticosteroids (ICS) (defined by Table 1A) + an additional asthma controller/biologic (defined in Tables 1B and 1C). Participants entered into the run-in on medium dose ICS will be switched to high dose ICS. They must meet all entry criteria at the time of randomization including the criteria for uncontrolled asthma as assessed by symptoms during the two weeks prior to the randomization. 5. Baseline poor or uncontrolled asthma, defined as meeting at least one of the following: 1. Forced Expiratory Volume in one second (FEV1) \<80% predicted (for adults ≥18) or FEV1\<90% (pediatric participants \<18) AND with 12% bronchodilator reversibility 2. Poor symptom control - Asthma Control Questionnaire (ACQ-6) Score ≥1.5 3. ≥1 exacerbation defined as a documented burst of systemic corticosteroids (\>3 days for adults and adolescents or \>1 day for adolescents treated with dexamethasone) in prior year for those not receiving chronic oral corticosteriod (OCS) or an increase in \>50% of baseline corticosteroid dose for ≥3 days in those receiving chronic OCS. * For patients on a biologic agent, at least one asthma exacerbation must have occurred at least 2 months after the initiation of the biologic agent. The definition of acceptable documentation for asthma exacerbations can be found in Section 6.5.3. 6. Evidence of asthma demonstrated by either bronchodilator reversibility or methacholine responsiveness either during the run-in or by historical evidence of either criterion if testing was performed under the same standards of the PrecISE Network at a PrecISE recruitment center. These criteria are defined as: 1. An increase in FEV1 ≥12% (and 200 ml) after up to 8 puffs of albuterol OR 2. Positive methacholine defined as provocative concentration causing a 20% decrease in FEV1 (PC20) ≤16 mg/ml, or provocative dose causing a 20% decline in FEV1 (PD20) ≤400 mcg/ml 7. Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout study duration 8. Owns a device compatible with the eDiary system used for CompEx, that is, an iOS 11+ device such as iPhone, iPad or iPod, or a smartphone or tablet running on Android 5.0+ Exclusion Criteria: 1. Current participation in an interventional trial (e.g. drugs, diets, etc.) 2. Enrollment in a clinical trial where the study medication was administered within the past 60 days or within 5 half-lives (whichever is greater) 3. Physician diagnosis of other chronic pulmonary disorders associated with asthma-like symptoms, including, but not limited to, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways 4. Receiving one or more immune-modulating therapies for diseases other than asthma 5. Receiving methotrexate, mycophenolate (CellCept®), or azathioprine (Imuran®) 6. Receiving aero allergen immunotherapy and not on at least 3 months of maintenance allergen immunotherapy 7. Underwent a bronchial thermoplasty within the last two years 8. Born before 35 weeks of gestation 9. Uncontrolled hypertension, defined as systolic blood pressure \>160 mm/Hg, or diastolic blood pressure \>100 mm/Hg 10. History of malignancy except non-melanoma skin cancer within the last five years 11. History of smoking 1. If \<30 years old: Smoked for ≥5 pack-years\* * Can still be enrolled if \<30, smoked \<5 5 pack years and none in past year, and normal (negative) urine cotinine 2. If 30-39 years old: Smoked for ≥10 pack years * Can still be enrolled if ≥30, smoked \<10 pack years and none in past year, provided participant demonstrates a normal (negative) urine cotinine 3. If ≥40 years old: Smoked ≥15 pack years * Can still be enrolled if ≥40 years old, smoked \<15 pack years and none in the last year, provided participant demonstrates normal (negative) urine cotinine. Patients with a smoking history of ≥10 to \<15 pack years will also need to demonstrate a normal Diffusing Capacity for Carbon Monoxide (DLCO) (\>70% predicted) \* Smoking equivalent pack years. One pack of cigarettes a day for 1 year is equivalent to: <!-- --> 1. 1 cigar or pipe per day for 1 year 2. Smoked hookah or shisha =1 session per day for 1 year 3. Vaped e-cigarettes =0.5 mLs e-liquid per day for 1 year, or =1 cartridge/tank/pod per day for 1 year 4. 1 use of marijuana per day for 1 year 12. Active use of any inhalant \>1 time per month in the past year 1. Active smoking of conventional tobacco, inhaling of marijuana or other drugs, or vaping of e-cigarettes or vape pods \>1 time per month in the past year 2. Any form of tobacco qualifies, such as: 1 cigarette, 1 hookah or shisha sessions, 1 cigar, 1 pipe, etc. 3. Any electronic (e)-device included: e-cigarette e-cig, mod, vape pen, JUUL vaping device, e-cigar, e-hookah, e-pipe, vape pods, etc. 4. Any form of inhaled marijuana, including smoking marijuana leaves or inhaling tetrahydrocannabinol (THC) via e-cigarette or device 13. Substance abuse within the last year 14. Unwillingness to practice medically acceptable birth control or complete abstinence during the study, current pregnancy, or lactation. Medically acceptable birth control/abstinence is defined as: 1. Career, lifestyle, or sexual orientation precludes intercourse with a male partner 2. For those in a monogamous relationship that precludes sexual activity with other partners, one of the sexual partners has been sterilized by vasectomy (in males) or hysterectomy and/or bilateral salpingo-oophorectomy (in females) 3. Use of highly effective methods of birth control defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Contraception should be used for at least 1 month prior to screening, throughout study participation and for an additional 16 weeks after the end of the final test treatment. * Pregnancy tests will be given to each female participant prior to study enrollment and at each clinic visit * Each male participant will agree to inform his sexual partner(s) of the potential for harm to an unborn child. If a sexual partner becomes pregnant while he is participating in the study, he will notify study staff within 24 hours of receiving medical confirmation. His partner will be advised to promptly notify her doctor * Any pregnancy (of a participant or a partner) will be monitored for adverse events with respect to pregnancy outcome until one month after birth. 15. Requirement for daily systemic corticosteroids above 10 mg of prednisone (or equivalent) per day for the past 2 months 16. Respiratory infection within 1 month of screening 17. Intubation for asthma in the last 12 months 18. Use of warfarin, current or last 30 days 19. Any clinically significant abnormal findings in the history, physical examination, vital signs, electrocardiogram, hematology or clinical chemistry during run-in period, which in the opinion of the site investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study 20. Additional exclusions for specific interventions (and not for others) are listed in the Appendices I-VI, Section 5.2 Safety Exclusion Criteria: Participants who meet the following criteria will be excluded from the study: 1. Hemoglobin \<10 g/dL 2. Absolute Neutrophil Count (ANC) \<1000/µl for black participants, \<1500/µl for other participants 3. Lymphocytes \<500/µl 4. Platelet count \<100,000/µl 5. Alanine Transaminase (ALT)/Aspartate Aminotransferase (AST) \>2x upper limits of normal (ULN) 6. Bilirubin ≥2x ULN 7. Estimated glomerular filtration rate (eGFR) \<60 ml/min/1.73 sq m 8. Positive Human Immunodeficiency Virus, Types 1 \& 2 (HIV 1\&2) Ab/Ag immunoassay followed by a confirmatory positive test (Geenius™ HIV-1/HIV-2 antibody differentiation immunoassay) 9. Positive Hepatitis B surface Ag (active infection) or Hepatitis B core total antibody (marker of past infection that could reactivate) 10. Positive Hepatitis C RNA test following positive Hepatitis C Antibody 11. EKG with significant clinical findings A positive QuantiFERON-TB tuberculosis (TB) Gold test requires further screening. A participant may be included in PrecISE if at least one of the following criteria are met: 1. A chest radiograph (CXR) done within the last six months of the test that shows no evidence of active TB 2. A chest CT scan done within the last six months of the test that shows no evidence of active TB 3. Documentation of adequate treatment for latent TB In cases of an indeterminate QuantiFERON-TB test result, a second blood specimen must be drawn. A chest x-ray is not required if the participant has a negative QuantiFERON-TB Gold test. Comorbid Conditions: Comorbidities are commonly present in severe asthma. Specific questionnaires will be used to identify common comorbidities as follows: 1. Sleep apnea: STOP-BANG Questionnaire 2. GERD (GERD- Questionnaire) 3. VCD (Pittsburgh Vocal Cord Dysfunction (VCD) index) 4. Chronic Rhinitis Sinusitis (Sinonasal questionnaire-SNQ5) 5. Depression-Anxiety (Hospital anxiety and depression Scale: HADS) These questionnaires are best used as screening tools. As such they typically have high sensitivity but relatively low specificity. Many of their symptoms overlap with the symptoms reported by participants with asthma who do not suffer from these conditions. Therefore, participants who meet the established cut offs for these questionnaires will need to be evaluated by the investigator to consider the clinical significance of the positive questionnaire based on history and physical and available testing. The investigator will need to judge the presence, severity and control of a specific condition and determine if it is sufficiently controlled to keep the participant in the PrecISE protocol. If the comorbid condition(s) is/are not adequately controlled, the investigator may refer the participant for further evaluation/treatment, prior to enrollment in PrecISE. Rescreening is permitted (after at least four weeks) to determine if the participant is able to move forward in PrecISE once the comorbid condition(s) is/are under adequate control. It is expected that some of the participants may also have other conditions such as cardiovascular disease, diabetes and obesity. These should be evaluated clinically as part of the complete history and physical done at initial evaluation. Their inclusions should be based on the investigator clinical judgement in line with good clinical practice principles.