Table 1.

VA REACH Trial

Regulatory milestones	The FDA provided us an exemption letter for the use of azithromycin and hydroxychloroquine on March 31, 2020. The University of California San Francisco Institutional Review Board provided human subjects’ approval on April 15, 2020.
Inclusion criteria	(a) first COVID-19 positive laboratory test (b) willingness to take the study drug(s) (c) able to be contacted by smart phone (d) willing and able to provide informed consent for participation in the study (e) presence of fever, cough, or shortness of breath within the last 24 hours
Exclusion criteria	Arrythmia, congestive heart failure, renal disease, electrolyte disturbance*
Randomization	Eligible, consented patients could be randomized to a 1:1:1 treatment allocation, stratifying by age (<65 versus ≥65 years), and using randomly permutated blocks (block size of 3) within four geographic areas (Pacific, Continental, Northeast, and Southeast)
Dosing	Azithromycin: 2×250mg by mouth (PO) in the AM on Day 1, followed by 250mg PO every day on Days 2–5 Hydroxychloroquine: 2×200mg PO in the AM and 2×200mg PO in the PM on Day 1, followed by 200mg PO in the AM and 200 mg PO in the PM on Days 2–5. Placebo: provided in identical bubble packs with same number of pills in all arms
Follow-up period	30 days from enrollment
End points	Primary: Days of symptoms (fever, cough, shortness of breath) Secondary: Any symptoms, all-cause hospitalization, all-cause ICU admission, all-cause death
Analysis	The primary efficacy outcome was the time to resolution of common COVID-19 symptoms (fever, shortness of breath, and cough). The secondary outcomes, which would be collected via national VA, included: all-cause hospitalization, all-cause ICU stay, all-cause death, COVID-19-specific hospitalization, COVID19-specific ICU stay, or COVID-19-specific death.The statistical analysis plan was for a blinded, intention-to-treat analysis using Cox regression. Hazard ratios for time until resolution of symptoms, hospitalization, or death were planned as was a per-protocol analysis.
Safety monitoring	Participants were provided with a study email and a study telephone number to contact a study clinician at any hour; participants were questioned daily about potential adverse events as described above using daily surveys and any positive responses would lead to further evaluation by a study clinician; general safety information and guidance about monitoring for potential side effects were provided to patients with the study medication. The patients were required to have a primary care physician in order to be enrolled in the study, and the primary care physician was sent a notification of participant enrollment and an explanation of the study details via VA email.

^*Exclusion Criteria based on National VA Data (a) CKD with eGFR <30mL/min or on dialysis; (b) aspartate transaminase (AST) or alanine transaminase (ALT) >5 times the upper limit of normal; or cirrhosis; (c) hypersensitivity to chloroquine, hydroxychloroquine or other 4-aminoquinolines (e.g., amodiaquine), azithromycin or macrolides; (d) already taking hydroxychloroquine or azithromycin; (e) congestive heart failure with an ejection fraction (EF) <35%; or hospitalization for CHF in past 6 months; (f) AMI in past 2 years; (g) concomitant treatment with any QT prolonging drug; (h) inability to take oral medications; (i) history of cardiac arrest, ventricular fibrillation or ventricular tachycardia in past 5 years; (j) QT prolongation; (k) potassium <3.5 meq/L in any lab in past 2 years; (l) magnesium <1.5 meq/L; (m) any patient who has not had follow-up with their primary care doctors in past 2 years; (n) inability to follow-up (e.g. dementia or evidence of active psychosis in chart); (o) any patient diagnosed with G6PD deficiency; (p) any patient diagnosed with porphyria

Chart Exclusion Criteria(q) symptoms of cough, fever or SOB >5 days, not having an address (e.g., P.O. Box only) Baseline Survey Exclusion Criteria(r) Pregnant, breastfeeding, or interest in becoming pregnant in the next 3 months; (s) receive the majority of their care outside the VA; (t) participating in any other COVID-19 therapeutic trial