COVID-19, ARDS
Conditions
Keywords
COVID-19, ARDS, Extracellular Vesicles, Exosome
Brief summary
To evaluate the safety and efficacy of intravenous administration of bone marrow derived extracellular vesicles, ExoFlo, versus placebo as treatment for moderate-to-severe Acute Respiratory Distress Syndrome (ARDS) in patients with severe COVID-19.
Detailed description
This is a Phase II, double-blinded, placebo-controlled, randomized controlled trial that enrolled 102 subjects that were admitted with COVID-19 associated moderate-to-severe ARDS across 6 sites in the United States.
Interventions
BIOLOGICALExoFlo
Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles
Placebo
Sponsors
Direct Biologics, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blinded
Intervention model description
Multi-center, double-blinded, placebo-controlled, randomized controlled trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form (either by the individual or by the individual's healthcare proxy). 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18-85. 4. COVID-19 positive as defined by positive Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) SARS-CoV-2. 5. Moderate to severe ARDS as defined by modified Berlin definition, \* which includes timing within 1 week of known clinical insult or new or worsening respiratory symptoms; bilateral opacities not fully explained by effusions, or lung collapse; respiratory failure not fully explained by cardiac failure or fluid overload; PaO2/FiO2 ≤ 200 mm Hg. \*Modified Berlin definition used in this study is the full Berlin definition, albeit without the PEEP specification, which implies mechanical ventilation. 6. Hypoxia requiring noninvasive oxygen support such as Nasal Cannula (NC), Nonrebreather (NRB), Bilevel Positive Airway Pressure (BIPAP), Continuous Positive Airway Pressure (CPAP), high flow nasal cannula oxygen (HFNC O2) or mechanical ventilation (MV) despite initiating standard of care. 7. If the candidate is either a male or female of reproductive potential, he or she must agree to use of double barrier method of highly effective birth control contraception such as condoms with oral contraceptive pill or choose to remain abstinent if already practicing abstinence during the screening period. The required duration of usage of double barrier method OR maintenance of abstinence must include the time from the beginning of the screening period until 90 days following the last dose of the study treatment.
Exclusion criteria
1. Vulnerable populations such as pregnant patients, children, individuals with severe physical or mental disabilities who cannot provide meaningful consent. 2. Active malignancy requiring treatment within the last five years. 3. Major physical trauma in the last 5 days, including motor vehicle accidents, assaults, mechanical falls with sequelae of significant bleeding or craniofacial bruising, and surgeries. 4. Active tuberculosis or cystic fibrosis. 5. Severe chronic respiratory disease including chronic obstructive pulmonary disease or pulmonary fibrosis requiring home oxygen \> 5L/min. 6. Use of extracorporeal membrane oxygenation (ECMO) during the current hospitalization. 7. Pre-existing pulmonary hypertension. 8. Severe pre-existing hepatic impairment (presence of cirrhosis, liver function tests (LFTs) ≥ 6x baseline, INR ≥ 2.0). 9. Pre-existing Chronic Kidney Disease (CKD) stage IIIb or End Stage Renal Disease (ESRD) prior to onset of COVID-19 (stage I, II, and IIIa are acceptable) 10. Irreversible coagulopathy (e.g., frequently occluded vascular access despite anticoagulation, precipitous platelet drops concurrent with end-organ damage suggesting consumptive process) or irreversible bleeding disorder (e.g., frequent bleeding from vascular access, endotracheal tubes, and foley). 11. Pneumonia clearly attributable to a non-COVID-19 related process, including aspiration pneumonia or pneumonia that is exclusively bacterial, or originating from a diagnosed alternative virus (e.g., influenza). 12. Patients who are not full code. 13. Endotracheal intubation duration ≤ 24 hours. 14. Moribund-expected survival \< 24 hours. 15. Severe metabolic disturbances on presentation (e.g., ketoacidosis, pH \< 7.3)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of 60-day Mortality Rate | 60 days | To evaluate the 60-day mortality rate for IP 15mL as a treatment for COVID-19 associated moderate to severe ARDS compared to placebo. Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Rates | Days 15, 30, 60 | Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect. |
| Proportion of Discharged Patients | Days 7, 30, 60 | Discharge is an unbiased measure of overall clinical improvement. |
| Time to Discharge | Number of days from the date of randomization until documented discharge from hospital, up to 60 days. | Discharge is an unbiased measure of overall clinical improvement. |
| Incidence of Treatment Emergent Serious Adverse Events | 61 days | Safety comparison performed between IP 15 mL and placebo arms |
| Ventilation Free Days | Within 60 days of follow-up | Number of days for which patients are not on mechanical ventilation. |
Countries
United States
Participant flow
Recruitment details
A total of 121 subjects were screened and 102 subjects were enrolled in the study at 6 investigative sites in the United States from 24 SEP 2020 to 22 MAY 2021.
Pre-assignment details
Subjects that remained eligible per inclusion/exclusion criteria were randomized and equally distributed in the three study arms.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Dose 2 Normal saline 85 mL and ExoFlo 15 mL
ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles | 34 |
| Experimental Dose 1 Normal saline 90 mL and ExoFlo 10 mL
ExoFlo: Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles | 34 |
| Placebo Normal saline 100 mL
Intravenous normal saline: Placebo | 34 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 10 | 14 | 16 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Subjects Discharged from Hospital Prior to End of Study | 1 | 1 | 0 |
| Overall Study | Subjects Whose Status as of the End of Study Was Unknown | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Experimental Dose 2 | Total | Placebo | Experimental Dose 1 |
|---|---|---|---|---|
| Age, Continuous | 56.8 Years STANDARD_DEVIATION 14.97 | 59.1 Years STANDARD_DEVIATION 13.52 | 58.5 Years STANDARD_DEVIATION 11.76 | 62.1 Years STANDARD_DEVIATION 13.47 |
| Age, Customized Age < 65 | 26 Participants | 70 Participants | 24 Participants | 20 Participants |
| Age, Customized Age ≥ 65 | 8 Participants | 32 Participants | 10 Participants | 14 Participants |
| BMI | 34.98 kg/m^2 STANDARD_DEVIATION 9.459 | 34.95 kg/m^2 STANDARD_DEVIATION 9.615 | 34.24 kg/m^2 STANDARD_DEVIATION 8.526 | 35.63 kg/m^2 STANDARD_DEVIATION 10.939 |
| Intubated Prior to Enrolling into the Study | 2 Participants | 7 Participants | 4 Participants | 1 Participants |
| P/F Ratio P/F Ratio < 100 mmHg | 10 Participants | 29 Participants | 10 Participants | 9 Participants |
| P/F Ratio P/F Ratio ≥ 100 mmHg | 7 Participants | 25 Participants | 8 Participants | 10 Participants |
| P/F Ratio Unknown P/F Ratio | 17 Participants | 48 Participants | 16 Participants | 15 Participants |
| P/F Ratio | 115.202 mmHg STANDARD_DEVIATION 61.5299 | 110.634 mmHg STANDARD_DEVIATION 50.661 | 102.952 mmHg STANDARD_DEVIATION 43.0002 | 113.824 mmHg STANDARD_DEVIATION 48.5386 |
| Prior Therapy Convalescent Plasma | 7 Participants | 25 Participants | 9 Participants | 9 Participants |
| Prior Therapy Dexamethasone | 26 Participants | 78 Participants | 27 Participants | 25 Participants |
| Prior Therapy Remdesivir | 17 Participants | 61 Participants | 23 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 6 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 10 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 8 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 21 Participants | 78 Participants | 26 Participants | 31 Participants |
| Respiratory Rate | 23.8 breaths/min STANDARD_DEVIATION 5.38 | 24.5 breaths/min STANDARD_DEVIATION 6.31 | 25.2 breaths/min STANDARD_DEVIATION 7.9 | 24.4 breaths/min STANDARD_DEVIATION 5.41 |
| Sex: Female, Male Female | 12 Participants | 35 Participants | 10 Participants | 13 Participants |
| Sex: Female, Male Male | 22 Participants | 67 Participants | 24 Participants | 21 Participants |
| Time from the First COVID-19 Diagnosis to the First IP Dose Date | 10.0 days STANDARD_DEVIATION 6.55 | 9.5 days STANDARD_DEVIATION 5.09 | 9.5 days STANDARD_DEVIATION 4.12 | 9.1 days STANDARD_DEVIATION 4.36 |
| Total SOFA Score | 3.2 scores on a scale STANDARD_DEVIATION 1.78 | 3.1 scores on a scale STANDARD_DEVIATION 1.64 | 3.2 scores on a scale STANDARD_DEVIATION 1.88 | 2.9 scores on a scale STANDARD_DEVIATION 1.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 34 | 14 / 34 | 16 / 34 |
| other Total, other adverse events | 25 / 34 | 25 / 34 | 22 / 34 |
| serious Total, serious adverse events | 11 / 34 | 18 / 34 | 16 / 34 |
Outcome results
Primary
Evaluation of 60-day Mortality Rate
To evaluate the 60-day mortality rate for IP 15mL as a treatment for COVID-19 associated moderate to severe ARDS compared to placebo. Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect.
Time frame: 60 days
Population: The Intention to Treat Analysis set consisted of all participants who received study drug. The number of subjects who died within 60 days is captured in the Outcome Measure Data Table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental Dose 2 | Evaluation of 60-day Mortality Rate | 10 Participants |
| Experimental Dose 1 | Evaluation of 60-day Mortality Rate | 14 Participants |
| Placebo | Evaluation of 60-day Mortality Rate | 16 Participants |
p-value: 0.1343Chi-squared
Secondary
Incidence of Treatment Emergent Serious Adverse Events
Safety comparison performed between IP 15 mL and placebo arms
Time frame: 61 days
Population: The Safety Analysis Set consisted of all participants who received study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | Any TEAEs- Any Grade | 24 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | Any TEAEs- Grade 3 or 4 | 5 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | Study Treatment-Related Serious TEAEs | 0 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | Serious TEAEs- Any Grade | 10 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | Serious TEAEs- Grade 3 or 4 | 3 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | Study Treatment-Related TEAEs | 0 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Dose Interruption | 1 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Missing Dose or Discontinued the Treatment Early | 0 Participants |
| Experimental Dose 2 | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Death | 10 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | Study Treatment-Related TEAEs | 0 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | Any TEAEs- Any Grade | 26 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Missing Dose or Discontinued the Treatment Early | 0 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Dose Interruption | 0 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | Any TEAEs- Grade 3 or 4 | 9 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | Study Treatment-Related Serious TEAEs | 0 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | Serious TEAEs- Grade 3 or 4 | 7 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Death | 13 Participants |
| Experimental Dose 1 | Incidence of Treatment Emergent Serious Adverse Events | Serious TEAEs- Any Grade | 18 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Death | 16 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | Serious TEAEs- Grade 3 or 4 | 3 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Missing Dose or Discontinued the Treatment Early | 1 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | Study Treatment-Related TEAEs | 1 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | Study Treatment-Related Serious TEAEs | 0 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | Serious TEAEs- Any Grade | 16 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | Any TEAEs- Any Grade | 23 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | Any TEAEs- Grade 3 or 4 | 5 Participants |
| Placebo | Incidence of Treatment Emergent Serious Adverse Events | TEAEs That Led to Dose Interruption | 0 Participants |
Secondary
Overall Survival Rates
Reducing the mortality rate for hospitalized patients with COVID-19 associated ARDS is a measure of the treatment effect.
Time frame: Days 15, 30, 60
Population: The Intention to Treat Analysis set consisted of all participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Dose 2 | Overall Survival Rates | Overall Survival Rate at 30 Days (Kaplan-Meier Method) | 72.7 Survival Percentage |
| Experimental Dose 2 | Overall Survival Rates | Overall Survival Rate at 15 Days (Kaplan-Meier Method) | 78.8 Survival Percentage |
| Experimental Dose 2 | Overall Survival Rates | Overall Survival Rate at 60 Days (Kaplan-Meier Method) | 69.6 Survival Percentage |
| Experimental Dose 1 | Overall Survival Rates | Overall Survival Rate at 30 Days (Kaplan-Meier Method) | 67.7 Survival Percentage |
| Experimental Dose 1 | Overall Survival Rates | Overall Survival Rate at 15 Days (Kaplan-Meier Method) | 77.8 Survival Percentage |
| Experimental Dose 1 | Overall Survival Rates | Overall Survival Rate at 60 Days (Kaplan-Meier Method) | 53.4 Survival Percentage |
| Placebo | Overall Survival Rates | Overall Survival Rate at 15 Days (Kaplan-Meier Method) | 75.8 Survival Percentage |
| Placebo | Overall Survival Rates | Overall Survival Rate at 60 Days (Kaplan-Meier Method) | 51.6 Survival Percentage |
| Placebo | Overall Survival Rates | Overall Survival Rate at 30 Days (Kaplan-Meier Method) | 63.7 Survival Percentage |
Secondary
Proportion of Discharged Patients
Discharge is an unbiased measure of overall clinical improvement.
Time frame: Days 7, 30, 60
Population: The Intention to Treat Analysis Set consisted of all participants who received study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental Dose 2 | Proportion of Discharged Patients | Subjects Who Discharged Within 30 Days | 19 Participants |
| Experimental Dose 2 | Proportion of Discharged Patients | Subjects Who Discharged Within 7 Days | 11 Participants |
| Experimental Dose 2 | Proportion of Discharged Patients | Subjects Who Discharged Within 60 Days | 20 Participants |
| Experimental Dose 1 | Proportion of Discharged Patients | Subjects Who Discharged Within 30 Days | 17 Participants |
| Experimental Dose 1 | Proportion of Discharged Patients | Subjects Who Discharged Within 7 Days | 9 Participants |
| Experimental Dose 1 | Proportion of Discharged Patients | Subjects Who Discharged Within 60 Days | 18 Participants |
| Placebo | Proportion of Discharged Patients | Subjects Who Discharged Within 7 Days | 11 Participants |
| Placebo | Proportion of Discharged Patients | Subjects Who Discharged Within 60 Days | 17 Participants |
| Placebo | Proportion of Discharged Patients | Subjects Who Discharged Within 30 Days | 17 Participants |
Secondary
Time to Discharge
Discharge is an unbiased measure of overall clinical improvement.
Time frame: Number of days from the date of randomization until documented discharge from hospital, up to 60 days.
Population: Intention-to-Treat (ITT) Analysis set consists of all randomized patients. Patients were analyzed according to the randomized treatment arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Dose 2 | Time to Discharge | 22 days |
| Experimental Dose 1 | Time to Discharge | 29 days |
| Placebo | Time to Discharge | NA days |
Secondary
Ventilation Free Days
Number of days for which patients are not on mechanical ventilation.
Time frame: Within 60 days of follow-up
Population: The Intention to Treat Analysis set consisted of all participants who received study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Dose 2 | Ventilation Free Days | 41.3 days | Standard Deviation 25.78 |
| Experimental Dose 1 | Ventilation Free Days | 32.0 days | Standard Deviation 26.23 |
| Placebo | Ventilation Free Days | 33.9 days | Standard Deviation 28.06 |