Nebulised aviptadil “futile” in I-SPY COVID-19 trial

New findings from a phase 2 trial of nebulised aviptadil in critically ill COVID-19 patients showed no benefit of adding this medication to dexamethasone and remdesivir backbone therapy.

The phase 2, open-label, adaptive platform I-SPY COVID-19 Trial (NCT04488081), which was testing, among other compounds, the nebulised form of aviptadil in critically ill COVID-19 patients, has been prematurely stopped. The trial was designed to rapidly screen potential agents that could substantially reduce the time to recovery (defined as a reduction in oxygen demand) by approximately 50% or risk of mortality in these patients. Prof. Carolyn Calfee (University of California at San Francisco, CA, USA) explained that aviptadil is a synthetic form of a human vasoactive intestinal polypeptide (VIP) and was selected because of the potential to reduce inflammation in COVID-19 patients hospitalised for acute respiratory distress syndrome (ARDS), which is the major cause of death in those critically ill from COVID-19 [1]. The intravenous form of aviptadil is currently being tested in the ACTIV-3b phase 3 trial (NCT04843761). The nebulised form of aviptadil to be inhaled through a mouthpiece was selected for inclusion in the I-SPY COVID-19 Trial to determine whether nebulised delivery would be effective in speeding recovery from and/or preventing death from COVID-19-related ARDS.

The study enrolled 118 COVID-19 patients on high flow nasal cannula (COVID scale 5; n=103), mechanical ventilation (COVID scale 6; n=8), or mechanical ventilation with additional organ failure (COVID scale 7; n=6), who were randomised to either receive nebulised aviptadil (n=51; 100 µg of nebulised aviptadil inhaled as an aerosol mist 3x per day for up to 14 days) or to a control group (n=67). All patients received dexamethasone and remdesivir as backbone therapy.

The Data Monitoring Committee recommended stopping enrolment to the aviptadil arm early because the agent met the pre-defined futility criterion, which was set in the I-SPY COVID-19 Trial for when there was a >90% probability that the hazard ratio would be under 1.5 when compared with standard treatment (Pr(HR <1.5) ≥0.9), and when there was a 50% probability for achieving a hazard ratio for mortality of <1.0 (Pr(HRm <1.0) <0.5). The data from nebulised aviptadil patients was compared with that from 67 patients concurrently randomised to the control arm. After all participants had reached 28 days of follow-up, the results suggested a low probability that the addition of this dose of nebulised aviptadil to backbone therapy via mouthpiece administration would improve outcomes in this population; in fact, the data collected until the time of stopping the trial favoured the control arm (HR 0.56; 95% CI 0.34–0.89).

Prof. Calfee speculated that the negative results may be attributed to the difficulty of effectively delivering nebulised medications via mouthpiece to critically ill patients who are on high flow oxygen (≥6 litres) or nebulised into the breathing circuit for mechanically ventilated patients. Factors including high oxygen flow rates, rapid breathing, and mechanical ventilation may have reduced the nebulised medication delivery. Accordingly, nebulised administration of aviptadil at the dose used at flow rates above 6 L per minute is not appropriate in this patient population.

1. Calfee C, et al. The I-SPY COVID Trial: First Results from an Adaptive Platform Phase 2 Trial for Severe COVID-19. Session D94, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.

 

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Posted on 18 July, 2022