Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS), Corona Virus Infection, Critical COVID-19 With Respiratory Failure
Conditions
Keywords
COVID-19, ARDS, Aviptadil, Acute Respiratory Distress Syndrome, Respiratory Failure
Brief summary
Novel Corona Virus (SARS-CoV-2) is known to cause Respiratory Failure, which is the hallmark of Acute COVID-19, as defined by the new NIH/FDA classification. Approximately 50% of those who develop Critical COVID-19 die, despite intensive care and mechanical ventilation. Patients with Critical COVID-19 and respiratory failure, currently treated with high flow nasal oxygen, non-invasive ventilation or mechanical ventilation will be treated with ZYESAMI (aviptadil), a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) plus maximal intensive care vs. placebo + maximal intensive care. Patients will be randomized to intravenous Aviptadil will receive escalating doses from 50 -150 pmol/kg/hr over 12 hours.
Detailed description
Acute Lung Injury, which triggers Critical COVID-19 is a known lethal complication of Corona Virus (SARS-CoV-2) infection. Conventional medical therapy, including intensive care and respiratory support is associated with an 80% mortality. Aviptadil, a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) has been awarded FDA Orphan Drug Designation for the treatment of ARDS and admitted to the FDA CoronaVirus Technology Accelerator Program. VIP binds to VPAC1 receptors on the pulmonary Alveolar Type II (ATII) cell. ATII cells comprise only 5% of lung epithelial cells but are critical for oxygen transfer, surfactant production, and maintenance of Alveolar Type 1 cells. 70% of VIP binds to this receptor. The Type II cell is also the cell selectively attacked by the SARS-CoV-2 virus via the ACE2 surface receptor. Nonclinical studies demonstrate that VIP is highly concentrated in the lung and specifically bound to the ATII cell, where it prevents NMDA-induced caspase-3 activation in the lung, inhibits IL6 and TNFa production, protects against HCl-induced pulmonary edema, and upregulates surfactant production, These and other effects have been observed in numerous animal model systems of lung injury in mice, rats, guinea pigs, sheep, swine, and dogs. In these models, Aviptadil restores barrier function at the endothelial/alveolar interface and thereby protects the lung and other organs from failure. Aviptadil ihas a demonstrated 20 year history of safety in phase 2 trials for Sarcoid, Pulmonary Fibrosis, Bronchospasm, and a phase I trial in ARDS. In that phase I trial, 8 patients with severe ARDS on mechanical ventilation were treated with ascending doses of VIP. Seven of the 8 patients were successfully extubated and were alive at the five day timepoint. Six left the hospital and one died of an unrelated cardiac event. Five phase 2 trials of aviptadil have been conducted under European regulatory authority. Numerous healthy volunteer studies have shown that i.v. infusion of Aviptadil is well tolerated with few adverse effects including alterations in blood pressure, heart rate, or ECG. In addition to published studies of human use, Aviptadil has been used on a compounded basis in certain ICUs for many years in the belief that it preserves life and restores function in pulmonary hypertension, ARDS, and Acute Lung Injury (ALI). In this study, patients who are hospitalized for Critical COVID-19 infection with respiratory failure will be randomly allocated to Aviptadil administered by intravenous infusion in addition to maximal intensive care vs. maximal intensive care alone. Primary endpoints will be improvement in blood oxygenation and mortality.
Interventions
DRUGAviptadil by intravenous infusion + standard of care
Aviptadil by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures.
DRUGNormal Saline Infusion + standard of care
Saline by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures.
Sponsors
APR Applied Pharma Research s.a.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomized, placebo-controlled trial with identical drug and placebo infusion bags
Intervention model description
Multicenter trial, initially conducted at a single center with a safety/futility assessment following enrollment of 30 patients, expanded to 196 total patients at 12 study sites
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Critical COVID-19 with respiratory failure * Physician determination that patient is on maximal conventional medical therapy
Exclusion criteria
1. Pregnancy (pregnant women may apply for open label treatment under compassionate care IND 2. Age \<18 years 3. Mechanical ventilation for more than 7 days in primary cohort. Mechanical ventilation\>21 days in the exploratory cohort 4. Mean Arterial Pressure \< 65 mm Hg with use of pressor per ICU protocol 5. Irreversible condition (other than COVID-19) with projected fatal course 6. ECMO 7. Current or recent (within 30 d) enrollment in another investigational trial of anti-IL6 drug; 8. Active diagnosis of Acquired immune deficiency syndrome; 9. Transplant patients currently immunosuppressed; 10. Chemotherapy-induced neutropenia (granulocyte count \<1000/mm3); 11. Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4; 12. Recent myocardial infarction - within last 6 months and troponin \> 0.5 13. Anuria (urine output \< 50 ml/d) or other signs of multi-organ failure 14. Severe liver disease with portal hypertension; 15. Recent stroke or head trauma within last 12 months 16. Increased intracranial pressure, or other serious neurologic disorder; 17. Liquid Diarrhea more than 3x/day; defined as more than 3 non-bloody watery stools within a 24-hour period, requiring additional fluid and electrolyte supplementation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resolution of Respiratory Failure (Alive and Free of Respiratory Failure) | Day 28 | Participant is Alive and Free of Respiratory Failure (without subsequent relapse over 7 days) determined as no longer requiring acute care or more than low flow oxygen |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Alive at Day 60 | Day 60 | Survival probability on logistic regression through day 60 |
| Number of Participants Achieving a Score of 6-8 on NIAID Ordinal Score Through Day 60 | Day 60 | Achievement of score 6-8 on NIAID Ordinal Scale through day 60 The NIAID score is the patient's status on the following 8-point scale:1)Death2)Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO),3)Hospitalized, on non-invasive ventilation or high flow oxygen devices4)Hospitalized, requiring supplemental oxygen5)Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)6)Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care7)Not hospitalized, limitation on activities and/or requiring home oxygen8)Not hospitalized, no limitations on activities-- a lower NIAID score is a worse outcome. |
| Oxygenation Index as Measured by PaO2:FiO2 Ratio | Day 7 | oxygenation index (also known as Respiratory Distress Ratio) as measured by PaO2:FiO2 ratio (Respiratory Distress while on mechanical ventilation). RDR: PaO2:FiO2 represents an intermediate clinical endpoint that is known to be predictive of survival. RDR can only be measured in patients on mechanical ventilation because of its reliance on arterial blood gas measurements that are not routinely collected in non-intubated patients. A higher score indicates a better clinical outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in IL-6 | Day 28 | Change in IL-6, an inflammatory marker |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care Patients will be administered Aviptadil IV in escalating doses of 50 pmol, 100 pmol, 150 pmol/kg/hr
Aviptadil by intravenous infusion + standard of care: Aviptadil by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures. | 131 |
| Placebo + Standard of Care Patients will first be treated with placebo infusion + maximal intensive care
Normal Saline Infusion + standard of care: Saline by intravenous infusion + standard of care (SOC). SOC is defined not to include extracorporeal mechanical oxygenation. Those requiring ECMO will be withdrawn from the study as treatment failures. | 65 |
| Total | 196 |
Baseline characteristics
| Characteristic | Aviptadil IV in Escalating Doses + Standard of Care | Total | Placebo + Standard of Care |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 12.61 | 61.0 years STANDARD_DEVIATION 3.4 | 62.7 years STANDARD_DEVIATION 12.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 66 Participants | 105 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 91 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 8 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 15 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 110 Participants | 167 Participants | 57 Participants |
| Region of Enrollment United States | 131 participants | 196 participants | 65 participants |
| Sex: Female, Male Female | 46 Participants | 61 Participants | 15 Participants |
| Sex: Female, Male Male | 85 Participants | 135 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 46 / 131 | 30 / 65 |
| other Total, other adverse events | 102 / 131 | 49 / 65 |
| serious Total, serious adverse events | 58 / 131 | 32 / 65 |
Outcome results
Primary
Resolution of Respiratory Failure (Alive and Free of Respiratory Failure)
Participant is Alive and Free of Respiratory Failure (without subsequent relapse over 7 days) determined as no longer requiring acute care or more than low flow oxygen
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | Resolution of Respiratory Failure (Alive and Free of Respiratory Failure) | 72 Participants |
| Placebo + Standard of Care | Resolution of Respiratory Failure (Alive and Free of Respiratory Failure) | 33 Participants |
Secondary
Number of Participants Achieving a Score of 6-8 on NIAID Ordinal Score Through Day 60
Achievement of score 6-8 on NIAID Ordinal Scale through day 60 The NIAID score is the patient's status on the following 8-point scale:1)Death2)Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO),3)Hospitalized, on non-invasive ventilation or high flow oxygen devices4)Hospitalized, requiring supplemental oxygen5)Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)6)Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care7)Not hospitalized, limitation on activities and/or requiring home oxygen8)Not hospitalized, no limitations on activities-- a lower NIAID score is a worse outcome.
Time frame: Day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | Number of Participants Achieving a Score of 6-8 on NIAID Ordinal Score Through Day 60 | 76 Participants |
| Placebo + Standard of Care | Number of Participants Achieving a Score of 6-8 on NIAID Ordinal Score Through Day 60 | 35 Participants |
Secondary
Number of Participants Alive at Day 60
Survival probability on logistic regression through day 60
Time frame: Day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | Number of Participants Alive at Day 60 | 85 Participants |
| Placebo + Standard of Care | Number of Participants Alive at Day 60 | 35 Participants |
Secondary
Oxygenation Index as Measured by PaO2:FiO2 Ratio
oxygenation index (also known as Respiratory Distress Ratio) as measured by PaO2:FiO2 ratio (Respiratory Distress while on mechanical ventilation). RDR: PaO2:FiO2 represents an intermediate clinical endpoint that is known to be predictive of survival. RDR can only be measured in patients on mechanical ventilation because of its reliance on arterial blood gas measurements that are not routinely collected in non-intubated patients. A higher score indicates a better clinical outcome.
Time frame: Day 7
Population: only patients with observations were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | Oxygenation Index as Measured by PaO2:FiO2 Ratio | 139.2 PaO2:FiO2 ratio | Standard Deviation 77 |
| Placebo + Standard of Care | Oxygenation Index as Measured by PaO2:FiO2 Ratio | 116.2 PaO2:FiO2 ratio | Standard Deviation 41.77 |
Other Pre-specified
Change in IL-6
Change in IL-6, an inflammatory marker
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | Change in IL-6 | 19.8 IL-6 picogram/mL | Standard Deviation 39.9 |
| Placebo + Standard of Care | Change in IL-6 | 23.5 IL-6 picogram/mL | Standard Deviation 39.7 |