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Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure
Phase 2, PHASE3 trial testing Aviptadil by intravenous infusion + standard of care in Critical COVID-19 With Respiratory Failure in 203 participants. Completed in 22 February 2021.
| Lead sponsor | APR Applied Pharma Research s.a. |
|---|---|
| Phase | Phase 2, PHASE3 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | quadruple |
| Primary purpose | treatment |
| Enrollment | 203 |
| Start date | 15 May 2020 |
| Primary completion | 22 February 2021 |
| Estimated completion | 22 February 2021 |
| Sites | 10 locations across United States |
APR Applied Pharma Research s.a. — full company profile →
Adults 18 to 100, any sex, with Critical COVID-19 With Respiratory Failure or Acute Respiratory Distress Syndrome (ARDS). Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
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
| Group | Value | 95% CI |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | 72 | |
| Placebo + Standard of Care | 33 |
Survival probability on logistic regression through day 60
| Group | Value | 95% CI |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | 85 | |
| Placebo + Standard of Care | 35 |
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 activit
| Group | Value | 95% CI |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | 76 | |
| Placebo + Standard of Care | 35 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | 139.2 | ± 77.0 |
| Placebo + Standard of Care | 116.2 | ± 41.77 |
Change in IL-6, an inflammatory marker
| Group | Value | 95% CI |
|---|---|---|
| Aviptadil IV in Escalating Doses + Standard of Care | 19.8 | ± 39.9 |
| Placebo + Standard of Care | 23.5 | ± 39.7 |
Time frame: AEs were collected from administration of informed consent through the subject's hospital discharge. Any ongoing AE was followed through 60 days.. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Aviptadil IV in Escalating… | Placebo + Standard of Care |
|---|---|---|---|
| COVID-19 | Infections and infestations | — | — |
| respiratory failure | Respiratory, thoracic and mediastinal disorders | — | — |
| multiple organ dysfunction syndrome | General disorders | — | — |
| acute kidney injury | Renal and urinary disorders | — | — |
| cardiac arrest | Cardiac disorders | — | — |
| pulseless electrical activity | Cardiac disorders | — | — |
| septic shock | Infections and infestations | — | — |
| acute respiratory failure | Respiratory, thoracic and mediastinal disorders | — | — |
| bradycardia | Cardiac disorders | — | — |
| sepsis | Infections and infestations | — | — |
| oxygen saturation decreased | Metabolism and nutrition disorders | — | — |
| hyperkalaemia | Metabolism and nutrition disorders | — | — |
| pneumothorax | Respiratory, thoracic and mediastinal disorders | — | — |
| hypotension | Vascular disorders | — | — |
| klebsiella infection | Infections and infestations | — | — |
| pneumonia infection | Infections and infestations | — | — |
| oxygen consumption increased | Investigations | — | — |
| brain oedema | Nervous system disorders | — | — |
| acute respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | — | — |
| hypoxia | Respiratory, thoracic and mediastinal disorders | — | — |
| shock haemorrhagic | Vascular disorders | — | — |
| blood loss anaemia | Blood and lymphatic system disorders | — | — |
| cardio-respiratory arrest | Cardiac disorders | — | — |
| cardiogenic shock | Cardiac disorders | — | — |
| myocardial infarction | Cardiac disorders | — | — |
| Reaction | System | Aviptadil IV in Escalating… | Placebo + Standard of Care |
|---|---|---|---|
| diarrhoea | Gastrointestinal disorders | — | — |
| hypotension | Vascular disorders | — | — |
| acute kidney injury | Renal and urinary disorders | — | — |
| COVID-19 | Infections and infestations | — | — |
| deep vein thrombosis | Vascular disorders | — | — |
| hyperkalaemia | Metabolism and nutrition disorders | — | — |
| respiratory failure | Respiratory, thoracic and mediastinal disorders | — | — |
| atrial fibrillation | Cardiac disorders | — | — |
| flushing | Vascular disorders | — | — |
| bradycardia | Cardiac disorders | — | — |
| constipation | Gastrointestinal disorders | — | — |
| multiple organ dysfunction syndrome | General disorders | — | — |
| anaemia | Blood and lymphatic system disorders | — | — |
| leukocytosis | Blood and lymphatic system disorders | — | — |
| acute respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | — | — |
| pneumothorax | Respiratory, thoracic and mediastinal disorders | — | — |
| septic shock | Infections and infestations | — | — |
| infusion related reaction | Injury, poisoning and procedural complications | — | — |
| anxiety | Psychiatric disorders | — | — |
| restlessness | Psychiatric disorders | — | — |
| pneumomediastinum | Respiratory, thoracic and mediastinal disorders | — | — |
| thrombocytopenia | Blood and lymphatic system disorders | — | — |
| cardiac arrest | Cardiac disorders | — | — |
| pulseless electrical activity | Cardiac disorders | — | — |
| tachycardia | Cardiac disorders | — | — |
| ventricular tachycardia | Cardiac disorders | — | — |
| pyrexia | General disorders | — | — |
| hyponatraemia | Metabolism and nutrition disorders | — | — |
| metabolic acidosis | Metabolism and nutrition disorders | — | — |
| tachypnoea | Respiratory, thoracic and mediastinal disorders | — | — |
| sinus tachycardia | Cardiac disorders | — | — |
| gastrointestinal haemorrhage | Gastrointestinal disorders | — | — |
| sepsis | Infections and infestations | — | — |
| mechanical ventilation complication | Injury, poisoning and procedural complications | — | — |
| alanine aminotransferase increased | Investigations | — | — |
| aspartate aminotransferase increased | Investigations | — | — |
| oxygen saturation decreased | Investigations | — | — |
| protein total decreased | Investigations | — | — |
| urine output decreased | Investigations | — | — |
| hypernatraemia | Metabolism and nutrition disorders | — | — |
Most-reported serious reactions: COVID-19, respiratory failure, multiple organ dysfunction syndrome, acute kidney injury, cardiac arrest, pulseless electrical activity, septic shock, acute respiratory failure.
Data from ClinicalTrials.gov NCT04311697 adverse events section.
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.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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