A negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure

In The Lancet Respiratory Medicine, Samuel M Brown and colleagues¹ report the results of a multicentre, randomised controlled trial of aviptadil, the synthetic form of the 28-amino-acid neuropeptide vasoactive intestinal peptide, in patients with hypoxaemic respiratory failure associated with COVID-19. Although the trial also incorporated a remdesivir treatment group, less than a hundred patients were enrolled, so we will limit our comments to patients receiving the vasoactive intestinal peptide.

Vasoactive intestinal peptide is a neurotransmitter with vasodilatory and immunomodulatory properties; it is probably best known for its association with diarrhoea in the rare setting of a vasoactive intestinal peptide-secreting pancreatic tumour. However, the actions of vasoactive intestinal peptide extend far beyond the gut, with evidence of expression in many organs, including the CNS and the lungs. Preclinical data indicate that vasoactive intestinal peptide inhibits SARS-CoV-2 replication in vitro,² in addition to increasing lung surfactant production and dampening monocyte activation.³ Thus, vasoactive intestinal peptide could have both antiviral and host-modulating properties that make it an excellent candidate to treat severe COVID-19. In 2022, a small randomised trial of around 200 patients with COVID-19 and respiratory failure assessed the effect of intravenous vasoactive intestinal peptide for 3 days. Although there was no difference in the primary endpoint (ie, alive and free from respiratory failure at day 60), there was a significant improvement in survival at 60 days. Significant improvements in oxygenation and a decrease in the cytokine IL-6 were also observed.⁴

On this basis, the TESICO investigators enrolled 461 patients with COVID-19 hypoxaemic respiratory failure and randomly assigned them to receive a 12-h infusion of aviptadil (or placebo) daily for 3 days.¹ The primary endpoint was a six-category ordinal outcome based on the patient's status (eg, whether they were at home and off supplemental oxygen) 90 days later. Although the study was meticulously conducted, there was no evidence of benefit from aviptadil in the primary or secondary endpoints.

Why was this study negative given the encouraging earlier trial? Although the first study only enrolled about half as many patients, size alone is unlikely to explain the current findings. Instead, the disparate findings suggest a systematic difference between the patients enrolled in the two trials. In terms of severity, both trials enrolled patients with similarly severe disease, with only slightly more patients in the larger trial requiring mechanical ventilation. The ethnic makeup of the study populations could partly explain the differences in outcome. Notably, in Brown and colleagues' study there was a relatively strong signal for efficacy in the primary endpoint for the subgroup of patients of Hispanic ethnicity (odds ratio 2·71, 95% CI 1·37–5·33).¹ This finding is potentially important, since about half of the participants in the earlier smaller trial were of Hispanic ethnicity, compared with only about a quarter in Brown and colleagues' trial. Of course, as the TESICO investigators noted, these results must be viewed with caution given the large number of subgroups assessed.¹

In the earlier trial, treatment with vasoactive intestinal peptide caused a reduction in IL-6, which correlated with improved oxygenation and survival.⁴ Unfortunately, IL-6 levels were not measured in the present study,¹ which might have helped as an indicator of the biological activity of the drug. Concomitant use of anti-inflammatory drugs is one of the few differences between the present study¹ and its predecessor.⁴ In the current study,¹ almost 20% of patients were on a Janus kinase (JAK) inhibitor, compared with no patients in the smaller study.⁴ The biological effects of vasoactive intestinal peptide act in part through the JAK pathway,5, 6 and previous pharmacological inhibition of the JAK pathway might block any added benefit of vasoactive intestinal peptide. However, this effect is unlikely to fully explain the difference between the trials, given both the small number of patients receiving JAK inhibitors and the fact that they were fairly equally distributed between the vasoactive intestinal peptide and control groups. Finally, unlike the smaller trial,⁴ Brown and colleagues' study reported a significant lowering of blood pressure by aviptadil alongside higher rates of vasopressor use afterwards. It is possible that any potential benefit from aviptadil was obscured by concomitant harm due to worsened haemodynamics.¹

We might never understand why vasoactive intestinal peptide initially looked promising but was ultimately found to not have a significant effect, an unfortunately too common fate for interventions in critical care.⁷ What is clear is that in COVID-19-associated hypoxaemic respiratory failure, therapies that target only the virus have not been sufficient to prevent death.8, 9 We now know that modulation of the host response is necessary to mitigate tissue injury and to improve survival. The success of host-modulating drugs, such as IL-6-blocking antibodies, JAK inhibitors, and even dexamethasone highlights the fact that understanding a severe infection sometimes means more than just understanding the pathogen. Optimising the host response during acute respiratory distress syndrome or sepsis—for example, by enhancing vascular integrity¹⁰ or modulating neutrophil activation—represent important avenues for ongoing research before the next pandemic.

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ASS consults for Cellenkos and SaNOtize in relation to therapies for COVID-19. WLL is listed as a co-inventor on the use of vasculotide for influenza-induced lung injury and on the use of ultrasound and microbubbles to treat acute respiratory distress syndrome.