Background & Aim: Amniotic fluid (AF) has recently been characterized to contain a reserve of extracellular vesicles (EVs) with anti-inflammatory properties.The FDA has recently approved an investigational new drug application of an AF-derived EV biol. in a multicenter, phase I/II randomized, double blinded, placebo trial to evaluate the safety and potential efficacy of Zofin infused i.v. (IV) in patients experiencing prolonged COVID-19 symptoms (Long-Haulers).Methods, Results & Conclusion: Patient population (n = 30) includes those with symptoms consistent with COVID-19 infection for a prolonged period, greater than 6 wk and less than 12 mo.Patients must meet inclusion criteria requirements related to fatigue, extreme body aches, and joint pain.Symptoms must be persistent for a min. of 6 wk after COVID-19 recovery and neg. test.The investigational drug, Zofin, is an allogenic AF-derived EV biol. containing approx. 2.0 x 1011 nanoparticles/mL, 1.4 mg of protein/mL, and 300 ng of hyaluronic acid/mL.The treatment dose will be 1 mL at Day 0, 4, and 8 administered IV and diluted in 100 mL of saline.Patients will be randomized 1:1 into Zofin and placebo groups.The primary endpoint will be safety, where the incidence of grade 3 or 4 or serious adverse events in subjects receiving Zofin will be compared to placebo.Secondly, endpoints for efficacy will include various assessments such as COVID-19 associated symptoms, Fatigue Severity Score, Beck Depression Inventory, Mental Fatigue Questionnaire, pulse oxygen saturation, Heart Rate Variability, and transthoracic echocardiogram measures.Fifteen inflammatory biomarkers will be tested such as Plasma-CRP, D-dimer, TNF-a, IL-4, IL-13, IL-2, GM-CSF, sCD40L, CCL5 (RANTES), CCL3 (MIP-1a), IL-6, IL-10, IFN-g, VEGF, IL-8, and CCL4 (MIP-1b).The study duration will be 6 mo with follow-up at Days 0, 4, 8, 14, 21, 30, 60, 90, and 6 mo.Peripheral blood mononuclear cells will be collected for immune cell activation and response to Zofin.The incidence of adverse events will be characterized by type, severity, duration, and relationship to study meditation within 30 days related to the therapy.The changes in efficacy measurements will be compared to baseline.After unblinding, Zofin safety and potential efficacy will be determined from the placebo group comparison.Results of this trial will provide the first insights into an extracellular vesicle biol.'s effect in COVID-19 Long Haulers.