Expanded Access to Zofin for Patients With COVID-19

This expanded access protocol will provide access to the investigational product Zofin for patients in outpatient facilities infected with SARS-CoV-2 who have mild to moderate COVID-19, or who are judged by a healthcare provider to be at high risk of progression to moderate disease.

A human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. Common symptoms of COVID-19 include fever, cough, and shortness of breath. The majority of cases result in mild symptoms, but some can progress into pneumonia and multi-organ failure. According to the severity it is divided into mild, normal, severe and critically ill, which is associated with ICU admission and mortality. At present, the standard treatment of COVD-19 patients is oxygen therapy, mechanical ventilation, and medications to maintain blood pressure. As of today, no specific antiviral therapy is available for patients with COVID-19. Immune activation in some patients, and the appearance of cytokine storm syndrome (CSS) is one of the important causes of severe damage to lungs and other organs, which may lead to death. There is an urgent need to develop new interventions to suppress the excessive immune response in a timely manner during the course of disease, protect alveolar function, and reduce lung and systemic organ damage.

Zofin is an acellular, minimally manipulated product, derived from human amniotic fluid (HAF). This product contains over 300 growth factors, cytokines, and chemokines as well as other extracellular vesicles/nanoparticles derived from amniotic stem and epithelial cells. The product contains a mean concentration of 5.24x10\^11 particles/mL with a mean mode size of 125.2nm. Surface marker analysis confirmed the presence of exosome associated proteins CD63, CD81, and CD9 in addition to high expression of CD133. The completed sequencing revealed 102 commonly expressed miRNA (with a 100-copy expression minimum). Bioinformatics analysis linked 63 miRNAs to 1216 RNA targets. Major players in the proinflammatory cytokine cascade found to be targeted by miRNA were discovered in Organicell's product include TNF, IL-6, and IL-8. Additionally, a broader array of pro-inflammatory cytokines is also targeted by the collection of miRNA such as FGF2, IFNB1, IGF1, IL36a, IL37, TGF-B2, VEGFA, CCL8, and CXCL12. It has been suggested in published research that inhibition or suppression of this pro-inflammatory cytokine cascade may reduce the severity of symptoms associated with elevated immune response. Furthermore, the miRNA was found to target 148 genes associated with immune response.

The property of Zofin demonstrates the therapeutic potential as a suppressor of cytokine activation for the reduction of COVID-19 infection severity. This is an open label expanded access protocol to treat subjects using ZofinTM (OrganicellTM Flow) for treatment of mild to moderate COVID-19 due to SARS-Cov-2.

Eligibility Criteria:
Inclusion Criteria:

1. Provide written informed consent
2. Subjects age \> 18 years at the time of signing the Informed Consent Form.
3. Male or Female
4. Must have a clinical diagnosis of COVID-19 by the qualitative reverse-transcription polymerase chain reaction (RT-PCR), with at least one of mild or moderate COVID-19 clinical symptoms which are defined below in #5
5. Individuals with mild to moderately COVID-19 symptoms for outpatient and inpatient population.

   The main symptoms of mild illness are:
   * low grade fever \<38°C (37.5 to 37.9)
   * a dry cough
   * tiredness
   * feeling slightly breathless
   * muscle pain
   * headache
   * sore throat
   * diarrhea

   The main symptoms of moderate illness are:

   In addition to the symptoms patients may get with a mild illness, they may also experience:
   * fever ≥38°
   * a dry and more persistent cough several times an hour
   * tiredness and a need to stay in bed
   * feeling breathless when doing moderate exercise (such as walking upstairs)
   * muscle pain and aches and need to stay in bed
   * headache particularly if you are feeling hot
   * sore throat, soreness from coughing, but no pain
   * diarrhea
   * a dry mouth
6. Adequate venous access
7. For Women of Child-Bearing Potential (WOCBP) only, willingness to use FDA-recommended birth control until 6 months post treatment. The FDA-approved and cleared methods for birth control are listed below:

   * Permanent Sterilization
   * Long-Acting Reversible Contraceptives (LARC)
   * Contraceptive Injection
   * Short-Acting Hormonal Methods
   * Barrier Methods
   * Emergency Contraception

   https://www.fda.gov/consumers/free-publications-women/birth-control
8. Any male subject must agree to use contraceptives and not donate sperm during the study.
9. Must agree to comply with all protocol requirements and be willing to complete all study visits

Exclusion Criteria:

1. Patients who have moderate to severe respiratory distress syndrome due to COVID-19
2. Be a female who is pregnant, nursing, or of childbearing potential while not practicing effective contraceptive methods. Female subjects must undergo a blood pregnancy test at screening which will be within 72 hours of the IP infusion.
3. Inability to perform any of the assessments required.
4. Active listing (or expected future listing) for transplant of any organ.
5. Be a solid organ transplant recipient. This does not include prior cell-based therapy (\>12 months prior to enrollment), bone, skin, ligament, tendon or corneal grafting. Have a history of organ or cell transplant rejection.
6. History of drug abuse (illegal "street" drugs except marijuana (If it is legal use in states where patient resides), or prescription medications not being used appropriately for a pre-existing medical condition or alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, or legal problems arising from the use of alcohol or drugs within the past 24 months
7. Patients with untreated HIV infection. However, patients can be enrolled if have been treated for HIV and the test negative for HIV viral load but still test positive for antibodies.