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 theduration 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 doseinhaled corticosteroids (ICS) (defined by Table 1A) + an additional asthmacontroller/biologic (defined in Tables 1B and 1C). Participants entered into therun-in on medium dose ICS will be switched to high dose ICS. They must meet allentry criteria at the time of randomization including the criteria for uncontrolledasthma 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 thefollowing:

6. FEV1 <80% predicted (for adults ≥18) or FEV1<90% (pediatric participants <18)AND with 12% bronchodilator reversibility

7. Poor symptom control - Asthma Control Questionnaire ( ACQ-6) Score ≥1.5

8. ≥1 exacerbation defined as a documented burst of systemic corticosteroids (>3days for adults and adolescents or >1 day for adolescents treated withdexamethasone) in prior year for those not receiving chronic OCS or an increasein >50% of baseline corticosteroid dose for ≥3 days in those receiving chronicOCS.

• For patients on a biologic agent, at least one asthma exacerbation musthave occurred at least 2 months after the initiation of the biologicagent. The definition of acceptable documentation for asthma exacerbationscan be found in Section 6.5.3.

6. Evidence of asthma demonstrated by either bronchodilator reversibility ormethacholine responsiveness either during the run-in or by historical evidence ofeither criterion if testing was performed under the same standards of the PrecISENetwork at a PrecISE recruitment center. These criteria are defined as:

7. An increase in FEV1 ≥12% (and 200 ml) after up to 8 puffs of albuterol OR

8. Positive methacholine defined as PC20 ≤16 mg/ml, or PD20 ≤400 mcg/ml

9. Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout studyduration

10. 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 withinthe past 60 days or within 5 half-lives (whichever is greater)

3. Physician diagnosis of other chronic pulmonary disorders associated with asthma-likesymptoms, including, but not limited to, cystic fibrosis (CF), chronic obstructivepulmonary disease (COPD), chronic bronchitis, emphysema, severe scoliosis or chestwall deformities that affect lung function, or congenital disorders of the lungs orairways

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 maintenanceallergen 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, ordiastolic blood pressure >100 mm/Hg

10. History of malignancy except non-melanoma skin cancer within the last five years

11. History of smoking

12. If <30 years old: Smoked for ≥5 pack-years*

• Can still be enrolled if <30, smoked <5 5 pack years and none in pastyear, 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 inthe last year, provided participant demonstrates normal (negative) urinecotinine. Patients with a smoking history of ≥10 to <15 pack years willalso need to demonstrate a normal Diffusing Capacity for Carbon Monoxide (DLCO) (>70% predicted) * Smoking equivalent pack years. One pack ofcigarettes 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 =1cartridge/tank/pod per day for 1 year

4. 1 use of marijuana per day for 1 year

5. Active use of any inhalant >1 time per month in the past year

6. 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

7. Any form of tobacco qualifies, such as: 1 cigarette, 1 hookah or shishasessions, 1 cigar, 1 pipe, etc.

8. Any electronic (e)-device included: e-cigarette e-cig, mod, vape pen, JUULvaping device, e-cigar, e-hookah, e-pipe, vape pods, etc.

9. Any form of inhaled marijuana, including smoking marijuana leaves or inhalingTHC (tetrahydrocannabinol) via e-cigarette or device

10. Substance abuse within the last year

11. Unwillingness to practice medically acceptable birth control or complete abstinenceduring the study, current pregnancy, or lactation. Medically acceptable birthcontrol/abstinence is defined as:

12. Career, lifestyle, or sexual orientation precludes intercourse with a malepartner

13. For those in a monogamous relationship that precludes sexual activity withother partners, one of the sexual partners has been sterilized by vasectomy (inmales) or hysterectomy and/or bilateral salpingo-oophorectomy (in females)

14. Use of highly effective methods of birth control defined as those, alone or incombination, 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 anadditional 16 weeks after the end of the final test treatment.

• Pregnancy tests will be given to each female participant prior to studyenrollment and at each clinic visit
• Each male participant will agree to inform his sexual partner(s) of thepotential for harm to an unborn child. If a sexual partner becomespregnant while he is participating in the study, he will notify studystaff within 24 hours of receiving medical confirmation. His partner willbe advised to promptly notify her doctor
• Any pregnancy (of a participant or a partner) will be monitored foradverse events with respect to pregnancy outcome until one month afterbirth.

15. Requirement for daily systemic corticosteroids above 10 mg of prednisone (orequivalent) 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-inperiod, which in the opinion of the site investigator, may put the participant atrisk because of his/her participation in the study, or may influence the results ofthe 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 inthe 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 otherparticipants

3. Lymphocytes <500/µl

4. Platelet count <100,000/µl

5. Alanine Transaminase (ALT)/Aspartate Aminotransferase (AST) >2x upper limits ofnormal (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 immunoassayfollowed by a confirmatory positive test (Geenius™ HIV-1/HIV-2 antibodydifferentiation immunoassay)

9. Positive Hepatitis B surface Ag (active infection) or Hepatitis B core totalantibody (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) 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 noevidence of active TB

2. A chest CT scan done within the last six months of the test that shows no evidenceof active TB

3. Documentation of adequate treatment for latent TB In cases of an indeterminateQuantiFERON-TB test result, a second blood specimen must be drawn. A chest x-ray isnot 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

2. GERD (GERD- Questionnaire)

3. VCD (Pittsburgh vocal cord dysfunction index)

4. Chronic Rhinitis Sinusitis (Sinonasal questionnaire-SNQ5)

5. Depression-Anxiety (Hospital anxiety and depression Scale: HADS) Thesequestionnaires are best used as screening tools. As such they typically have highsensitivity but relatively low specificity. Many of their symptoms overlap with thesymptoms reported by participants with asthma who do not suffer from theseconditions. Therefore, participants who meet the established cut offs for thesequestionnaires will need to be evaluated by the investigator to consider theclinical significance of the positive questionnaire based on history and physicaland available testing. The investigator will need to judge the presence, severityand control of a specific condition and determine if it is sufficiently controlledto keep the participant in the PrecISE protocol. If the comorbid condition(s) is/arenot adequately controlled, the investigator may refer the participant for furtherevaluation/treatment, prior to enrollment in PrecISE. Rescreening is permitted (after at least four weeks) to determine if the participant is able to move forwardin PrecISE once the comorbid condition(s) is/are under adequate control. It isexpected that some of the participants may also have other conditions such ascardiovascular disease, diabetes and obesity. These should be evaluated clinicallyas part of the complete history and physical done at initial evaluation. Theirinclusions should be based on the investigator clinical judgement in line with goodclinical practice principles.