While asthma therapy is becoming more individualized based on asthma phenotypes, more research is needed to tailor newer therapies to individuals. Inhaled corticosteroid (ICS) medications are the foundation of care for all individuals with persistent asthma. But ICS use is not without possible long term side effects.

This study will compare two currently available approaches to reduce AEX in primary care patients: (1) use of inhaled corticosteroids (ICS) as part of rescue therapy, also known as MART (Maintenance And Reliever Therapy) or PARTICS (Patient Activated Reliever Trigger Inhaled Corticosteriods) therapy - either of these therapies will be called Rescue-Inhaled Corticosteroids or R-ICS pronounced "Ricks," and (2) use of azithromycin (AZ) as a preventive therapy. These treatments will be studied both individually and in combination.

Design. Four arm, patient level randomized trial (N=3200). Comparators: Rescue inhaled corticosteroids (R-ICS) versus azithromycin versus R-ICS plus azithromycin versus control patients. All arms will include home monitoring of asthma symptoms using various web application approaches. R-ICS therapy will consist of a corticosteriod/formoterol inhaler, a stand-alone ICS inhaler used with usual rescue therapy or when available a combination corticosteroid/albuterol inhaler, the initial azithromycin dose will be 500mg (10mg/Kg) three times a week and may be titrated down to 250mg (10mg/Kg) three times per week for side effects. Exacerbations will be blindly adjudicated. Individuals who experience three exacerbations in < 12 months will have their treatments "stepped-up,"unless in the dual treatment arm; control participants going to R-ICS and single therapy participants to dual therapy. Individuals completing either of the azithromycin arms will be offered up to 12 additional months of follow-up after stopping the azithromycin only.

Inclusion Criteria:

1. A clinical asthma diagnosis for at least 1 year;

2. 13-75 years of age;

3. A prescription for an ICS either used regularly, or on an as needed controller, not reliever, schedule - ICS or ICS + LABA or ICS+LABA+LAMA;

4. A current ACT total score of <20 OR an exacerbation requiring 72 hours or more of systemic steroids or a hospitalization of at least 24 hours > 30 days and < 365 days prior to enrollment;

5. Able to provide consent (adolescents: assent) in English or Spanish; (i.e., cognitively impaired individuals are deemed not to be able to provide consent and thus do not meet inclusion criteria.);

6. Patients with a coexisting clinical diagnosis of COPD are eligible if they meet any one of the following criteria:

   (i) Never smoker without secondary lung disease causing airway obstruction. (ii) Current or former smoker with obstruction on PFTs, but normal diffusing capacity of the lungs for carbon monoxide (DLCO) in the past 24 months.

7. Patients on medications that may interact with azithromycin but are not totally excluded may be enrolled if they agree to a cardiac rhythm strip after consent and prior to randomization (or have an ECG within the prior 24 months as a baseline assessment) and a repeat rhythm strip after one week if randomized to one of the azithromycin arms of the study.

Exclusion Criteria:

1. Another family member living in the same household already enrolled in study;
2. Life expectancy <1 year (operationalized by the question to the patient's asthma care clinician "Would you be surprised if this person died in the next 12 months? If yes - include, if no - exclude);
3. No ICS prescribed for the individual (does not have to be using the ICS inhaler);
4. Active treatment for hematological or solid organ cancer other than basal cell or skin squamous cell cancer (if participant is > 12 months out from original therapy and may be on a cancer maintenance drug that is not otherwise contraindicated they are eligible for the study);
5. Allergy to macrolides or conditions for which macrolide administration may possibly be hazardous (e.g., acute or chronic hepatitis, cirrhosis, or other liver disease; end-stage renal disease; uncorrected hypokalemia or hypomagnesemia; clinically significant bradycardia; or history of prolonged cardiac repolarization and QT interval or evidence of prolonged cardiac repolarization on rhythm strip and QT interval or torsades de pointes);
6. On daily or every other day oral steroids for any reason;
7. A course of systemic steroids for an asthma exacerbation or an overnight hospitalization for an asthma exacerbation in the past month (can wait and re-check eligibility after one month);
8. Currently on R-ICS or any antibiotic therapy expected to last more than 30 days. If on antibiotics less than 30 days, individual can enroll after they have stopped their current antibiotic for 72 hours. Individuals on biologics can be enrolled if they have been on a stable dose for > 6 months and meet the ACT or exacerbation criteria as well as all other criteria after being on the stable does of the biologic.
9. On a medication with known risk (i.e., that is associated with prolonged QT and associated with torsades de pointes even when taken as recommended)- absolute contraindication to eligibility- Full lists in Appendix B;
10. Specified medications for which close monitoring has been recommended in the setting of macrolide administration (digoxin, warfarin, theophylline, ergotamine or dihydroergotamine, cyclosporine, hexobarbital, phenytoin or nelfinavir).

Analyzable data set will be submitted to PCORI at the conclusion of the study. This will include the final cleaned and locked data set that contains all the data used in conducting the analyses reported in the PCORI Final Research Report and is de-identified in accordance with the HIPAA Privacy. Rule (45 C.F.R. § 164.514(b)).

Anticipated date is no later than 6/31/31.

Users interested in obtaining study data will need to complete a Restricted Data Use Agreement, specify the reason for the request, and obtain IRB approval or notice of exemption for their research.