ACT-20 in Patients With Severe COVID-19 Pneumonia

The primary objective of this study is determine the safety and efficacy of ACT-20-MSC (allogenic human umbilical derived mesenchymal stem cells) and ACT-20-CM (allogenic human umbilical derived mesenchymal stem cells in conditioned media) in patients with moderate to severe COVID-19 pneumonia.

This study will assess the safety and efficacy of ACT-20-MSC and ACT-20-CM administered intravenously to subjects with moderate to severe COVID-19 related pneumonia in two parts.

Part 1 is an open-label study of 10 subjects, 5 with moderate COVID-19 pneumonia and 5 with severe COVID-19 pneumonia. Of these 10 subjects, 5 will receive ACT-20-CM and 5 will receive ACT-20-MSC resuspended in ACT-20-CM.

Part 2 is a randomized, blinded, placebo-controlled study of 60 patients, 30 with moderate COVID-19 pneumonia and 30 with severe COVID-19 pneumonia. Randomization will be 1:1:1 ACT-20-MSC in ACT-20-CM, ACT-20-CM or placebo. The placebo is MEM-α, a widely used sterile culture media that contains non-essential amino acids, nucleosides, vitamins, glucose, sodium pyruvate and lipoic acid.

Subjects treated at each investigative site will provide written informed consent prior to the conduct of any study-related procedures. Thereafter, they will be screened and those meeting the inclusion/exclusion criteria will be enrolled into the trial and undergo all the study procedures including the intravenous administration of the investigational medical product (IMP = ACT-20-MSC in ACT-20-CM or ACT-20-CM) or placebo. The IMP will be administered in addition to any standard of care treatment the subject is receiving.

Subjects will be assessed daily while in hospital. Following discharge from hospital, subjects will be following for an additional three month period.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female patients age 18 to 85, inclusive
2. Confirmed positive test for COVID-19 by standard reverse transcriptase polymerase chain reaction (RT-PCR) assay or equivalent
3. On mechanical ventilation (n=35), or high-flow O2 support (n=35) and:

   1. Disease severity level of "moderate" (PaO2/FiO2 of 100-200) (n=35), or "severe" (PaO2/FiO2 \< 100) (n=35) as established using the Berlin Criteria for ARDS (Barbas, Isola \& Caser, 2014; Baron \& Levy, 2016).
   2. Positive end-expiratory airway pressure (PEEP) ≥ 5 cmH2O
   3. Oxygen saturation ≤ 93%
4. Non-cardiogenic bilateral pulmonary edema on frontal chest radiograph that cannot be explained by effusion, collapsed lung or lung nodule
5. Able to understand and provide voluntary informed consent

Exclusion Criteria:

1. Unable to understand and provide voluntary informed consent
2. Current infection with HIV-1, HIV-2, Hepatitis B, Hepatitis C or HTLV
3. History of malignancy, other than non-melanoma skin cancer or non-metastatic prostate cancer
4. Currently receiving extracorporeal life support or high-frequency oscillatory ventilation
5. Weight \> 150 kg
6. Current severe chronic respiratory disease, as demonstrated by:

   1. PaCO2 \> 50 mm Hg, or
   2. history of use of home oxygen
7. Major trauma within the past 7 days
8. Lung transplant recipient
9. WHO Class III or IV pulmonary hypertension
10. Documented deep vein thrombosis or pulmonary embolism within the past 3 months
11. Currently pregnant or lactating
12. Currently participating in another clinical trial, or participation in another clinical trial within 30 days of enrollment
13. Hypersensitivity to Dextran-40 or Dimethyl Sulfoxide (DMSO)
14. Current pharmacotherapy using hydroxychloroquine or Interleukin-6 inhibitors
15. History of CVA or MI within 180 days of study enrollment