Critical COVID-19 With Respiratory FailurePhase 2/3COVID-AIVNCT04311697
Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure
A Phase 2/3 study of Critical COVID-19 With Respiratory Failure and Acute Respiratory Distress Syndrome (ARDS), run by APR Applied Pharma Research s.a. at 10 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Critical COVID-19 With Respiratory Failure, Acute Respiratory Distress Syndrome (ARDS), Corona Virus Infection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 203 participants
- Where
- 10 sitesUnited States
- Study dates
- 15 May 2020to 22 Feb 2021
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Critical COVID-19 with respiratory failure
- Physician determination that patient is on maximal conventional medical therapy
Who cannot join
- Pregnancy (pregnant women may apply for open label treatment under compassionate care IND
- Age <18 years
- Mechanical ventilation for more than 7 days in primary cohort. Mechanical ventilation>21 days in the exploratory cohort
- Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU protocol
- Irreversible condition (other than COVID-19) with projected fatal course
- ECMO
Show all 17Show fewer
- Current or recent (within 30 d) enrollment in another investigational trial of anti-IL6 drug;
- Active diagnosis of Acquired immune deficiency syndrome;
- Transplant patients currently immunosuppressed;
- Chemotherapy-induced neutropenia (granulocyte count <1000/mm3);
- Cardiogenic shock; congestive heart failure - NYHA Class 3 or 4;
- Recent myocardial infarction - within last 6 months and troponin > 0.5
- Anuria (urine output < 50 ml/d) or other signs of multi-organ failure
- Severe liver disease with portal hypertension;
- Recent stroke or head trauma within last 12 months
- Increased intracranial pressure, or other serious neurologic disorder;
- 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
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
Hendrick Health
Abilene, Texas, 79601
Texas Health Harris Methodist Hospital
Fort Worth, Texas, 76104
Texas Health Hospital Frisco
Frisco, Texas, 75033
St. Jude Medical Center
Fullerton, California, 92835
Houston Methodist Hospital
Houston, Texas, 77030
University of California - Irvine
Irvine, California, 92697
University of Louisville Hospital
Louisville, Kentucky, 40202
Miller School of Medicine / University of Miami Medical Center
Miami, Florida, 33136
Baptist Hospital of Miami
Miami, Florida, 33176
Heartland/Mosaic Health
Saint Joseph, Missouri, 64506
About this study
Official title: ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure
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.
Read the 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.
- Conditions
- Critical COVID-19 With Respiratory Failure, Acute Respiratory Distress Syndrome (ARDS), Corona Virus Infection, Acute Lung Injury
- Being tested
- Aviptadil by intravenous infusion + standard of care, Normal Saline Infusion + standard of care
- Keywords
- COVID-19, ARDS, Aviptadil, Acute Respiratory Distress Syndrome, Respiratory Failure
- Medical subject headings
- Respiratory Distress Syndrome, Coronavirus Infections, Acute Lung Injury, COVID-19, Respiratory Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Aviptadil by intravenous infusion + standard of careDrug
Also called ZYESAMI (aviptadil) +SOC
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.
Normal Saline Infusion + standard of careDrug
Also called Placebo+SOC
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.
| Study group | Role | What they receive |
|---|---|---|
| Aviptadil IV in escalating doses + standard of care | Experimental | Patients will be administered Aviptadil IV in escalating doses of 50 pmol, 100 pmol, 150 pmol/kg/hr Receives: Drug: Aviptadil by intravenous infusion + standard of care |
| Placebo + standard of care | Experimental | Patients will first be treated with placebo infusion + maximal intensive care Receives: Drug: Normal Saline Infusion + standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Day 28
Secondary outcomes (3)
Number of Participants Alive at Day 60
Survival probability on logistic regression through day 60
Measured: Day 60
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.
Measured: Day 60
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.
Measured: Day 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2020
- Study start15 May 2020
- Primary completion22 Feb 2021
- Study completion22 Feb 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Critical COVID-19 With Respiratory FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 203 participants (actual)
Sponsor and investigators
- Lead sponsor
- APR Applied Pharma Research s.a.
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jonathan C Javitt, MD, MPH, Study chair, NeuroRx, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04311697
- Sponsor's protocol ID
- COVID-AIV
- Acronym
- COVID-AIV
- Status last verified
- Sep 2021
- First submitted
- 14 Mar 2020
- Last updated
- 24 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NeuroRx will share study protocol and statistical analysis plan upon request by qualified researchers
- Expanded access
- Available
Publications
Youssef JG, Lavin P, Schoenfeld DA, Lee RA, Lenhardt R, Park DJ, Fernandez JP, Morganroth ML, Javitt JC, Jayaweera D. The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial. Crit Care Med. 2022 Nov 1;50(11):1545-1554. doi: 10.1097/CCM.0000000000005660. Epub 2022 Aug 29.
PubMed 36044317
Study at a glance
From the registry record, last updated by the sponsor on 24 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure
- ClinicalTrials.gov ID
- NCT04311697
- Acronym / sponsor ID
- COVID-AIV / COVID-AIV
- Conditions
- Critical COVID-19 With Respiratory Failure, Acute Respiratory Distress Syndrome (ARDS), Corona Virus Infection, Acute Lung Injury
- Keywords
- COVID-19, ARDS, Aviptadil, Acute Respiratory Distress Syndrome, Respiratory Failure
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 203 participants (actual)
- Lead sponsor
- APR Applied Pharma Research s.a.University, hospital or other
- Study start
- 15 May 2020 (actual)
- Primary completion
- 22 Feb 2021 (actual)
- Study completion
- 22 Feb 2021 (actual)
- First posted
- 17 Mar 2020 (actual)
- Results
- Posted 24 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| Aviptadil IV in escalating doses + standard of care | Experimental | Drug: Aviptadil by intravenous infusion + standard of carePatients will be administered Aviptadil IV in escalating doses of 50 pmol, 100 pmol, 150 pmol/kg/hr |
| Placebo + standard of care | Experimental | Drug: Normal Saline Infusion + standard of carePatients will first be treated with placebo infusion + maximal intensive care |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Critical COVID-19 with respiratory failure
- Physician determination that patient is on maximal conventional medical therapy
Key exclusion criteria (17 listed)
- Pregnancy (pregnant women may apply for open label treatment under compassionate care IND
- Age <18 years
- Mechanical ventilation for more than 7 days in primary cohort. Mechanical ventilation>21 days in the exploratory cohort
- Mean Arterial Pressure < 65 mm Hg with use of pressor per ICU protocol
- Irreversible condition (other than COVID-19) with projected fatal course
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Aviptadil by intravenous infusion + standard of careAlso: ZYESAMI (aviptadil) +SOCAviptadil 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. | Drug | Aviptadil IV in escalating doses + standard of care |
| Normal Saline Infusion + standard of careAlso: Placebo+SOCSaline 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. | Drug | Placebo + standard of care |
Primary outcome
Resolution of Respiratory Failure (Alive and Free of Respiratory Failure)
Time frame: 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
3 secondary outcomes
Number of Participants Alive at Day 60
Time frame: Day 60
Number of Participants Achieving a Score of 6-8 on NIAID Ordinal Score Through Day 60
Time frame: Day 60
Oxygenation Index as Measured by PaO2:FiO2 Ratio
Time frame: Day 7
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36044317Youssef JG, Lavin P, Schoenfeld DA, Lee RA, Lenhardt R, Park DJ, Fernandez JP, Morganroth ML, Javitt JC, Jayaweera D. The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial. Crit Care Med. 2022 Nov 1;50(11):1545-1554. doi: 10.1097/CCM.0000000000005660. Epub 2022 Aug 29.
- Individual participant dataSharing planned: Yes. NeuroRx will share study protocol and statistical analysis plan upon request by qualified researchers
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jonathan C Javitt, MD, MPH study chair
NeuroRx, Inc.
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study of Critical COVID-19 With Respiratory Failure and Acute Respiratory Distress Syndrome (ARDS), run by APR Applied Pharma Research s.a. at 10 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Resolution of Respiratory Failure (Alive and Free of Respiratory Failure) (time frame: Day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04311697, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2023.