Quantum Leap Healthcare Collaborative (QLHC) announced in collaboration with NRx Pharmaceuticals, Inc. (NRx), that the nebulized form of ZYESAMI® (Aviptadil), in the I-SPY COVID Trial of Critical COVID-19 patients has been stopped. The I-SPY COVID Trial, (NCT04488081) is a phase 2, open label, adaptive platform trial designed to rapidly screen potential agents that could substantially improve treatment for severely and critically ill COVID-19 patients. QLHC is the sponsor of the I-SPY COVID TRIAL. The trial is structured to identify those agents with a big impact, those that could have the potential to reduce the time to recovery (defined as reduction in oxygen demand) by approximately 50% or risk of mortality in critically ill COVID-19 patients.
Aviptadil is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP) and was selected because of the potential to reduce inflammation and stabilize the air sacs of those hospitalized because of critical injury from acute respiratory distress syndrome (ARDS), which is the major cause of death in those critically ill from COVID-19. The intravenous form of ZYESAMI is currently being tested in the ACTIV-3b Phase 3 trial being conducted by the National Institutes of Health, a separate clinical trial of critically ill patients, which continues enrolling. The nebulized form was selected for inclusion in the I-SPY COVID Trial to determine whether this simpler form of delivery via self-inhalation through a mouthpiece would be effective in speeding recovery from and/or preventing death from COVID-19-related ARDS.
The study enrolled COVID-19 patients, on High Flow Nasal Cannula (COVID Scale 5), Mechanical Ventilation (COVID Scale 6), or Mechanical Ventilation with additional organ failure (COVID Scale 7).
COVID Scale on Day 1 | Aviptadil n=51 | Control n=67 | TOTAL n=118 |
5 | 44 (88%) | 59 (88.1%) | 103 (88%) |
6 | 1 (2%) | 7 (10.4%) | 8 (6.8%) |
7 | 5 (10%) | 1 (1.5%) | 6 (5.1%) |
The Data Monitoring Committee recommended concluding the open label Aviptadil arm of the I-SPY COVID Trial after 118 patients (51 on study drug and 67 on concurrent controls) were enrolled. Enrollment was stopped because the agent met the predefined futility criterion, with a greater than 90% probability that the hazard rate for recovery is less than 1.5 when compared to standard treatment (Pr(HR < 1.5) ≥ 0.9), and that the chance that the hazard rate for mortality being less than 1 is less than 50% (Pr(HRm<1.0) <0.5). The data from nebulized Aviptadil patients were compared to those from 67 patients concurrently randomized to the control arm, which included treatment with dexamethasone and remdesivir as backbone therapy. Patients assigned to the Aviptadil arm received backbone therapy in combination with 100 micrograms of nebulized Aviptadil for inhalation as an aerosol mist three times per day for up to 14 days. After all patients had reached 28 days of follow-up, the data suggested there was a low probability that the addition of this dose of nebulized Aviptadil to backbone therapy via mouthpiece administration, would improve outcomes in this population. At the time of discontinuation, the hazard ratio for recovery favored placebo (HRr 0.56 (95% CI 0.34-0.89)). The drug was administered across 29 sites active in the trial at the time the drug was released from the trial.
NRx previously concluded a study of intravenous Aviptadil in critically ill COVID-19 patients with positive results. The findings in the current I-SPY study may be due to the difficulty of effectively delivering nebulized medications via mouthpiece to critically ill patients when they are on high flow oxygen (6 liters or more) or nebulized into the breathing circuit for mechanically ventilated patients. Factors including high oxygen flow rates, rapid breathing and mechanical ventilation may reduce nebulized medication delivery to the air sacs. Accordingly, nebulized administration of Aviptadil at the dose used at flow rates above 6L per minute is not appropriate in this patient population.
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