Aviptadil fails to improve clinical outcomes in COVID-19 patients with acute hypoxaemic respiratory failure: Lancet

"Treatment with aviptadil did not improve the primary ordinal outcome or survival at day 90 compared to placebo in participants hospitalized for COVID-19 associated respiratory failure," the researchers reported. "Other secondary endpoints also did not show efficacy for aviptadil."

These data confirm the high mortality experienced by COVID-19 patients with acute hypoxaemic respiratory failure with the current standard of care and clearly establish that aviptadil was not superior to placebo in shortening the time to recovery or reducing the risk of death in this population.

Considering that there is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure, whose 60-day mortality remains at 30-50%, Prof Samuel M Brown, Intermountain Medical Center, Salt Lake City, UT, USA, and colleagues compared aviptadil and remdesivir with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. Aviptadil is a lung-protective neuropeptide, and remdesivir is a nucleotide prodrug of an adenosine analogue.

TESICO, a randomized trial conducted at 28 sites in the USA, consisted of hospitalized adult patients with acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within four days of the onset of respiratory failure. Participants were assigned randomly to both study treatments in a factorial design of 2 × 2 or to just one of the agents. Randomization for each site was stratified by disease severity (invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO] versus high-flow nasal oxygen or non-invasive ventilation).

Four strata were defined by remdesivir and aviptadil eligibility, as follows:

1. Eligible for aviptadil and remdesivir randomization, participants were randomized in a 1:1:1:1 ratio to intravenous aviptadil plus remdesivir, aviptadil matched placebo plus remdesvir, aviptadil plus remdesivir matched placebo, or aviptadil placebo plus remdesivir placebo.
2. Eligible for randomization to aviptadil only because remdesivir was initiated before randomization.
3. Eligible for aviptadil randomization only because of remdesivir contraindication.
4. Eligible for only remdesivir randomization.

For strata, 2–4 participants, randomization was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for three days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day course. For participants assigned to a placebo for either agent, matched saline placebo was administered in identical volumes.

Four hundred seventy-three participants were enrolled in the study. For aviptadil comparison, 471 were assigned to aviptadil or matched placebo. The modified intention-to-treat population included 461 participants receiving at least a partial infusion of aviptadil (231 participants) or an aviptadil-matched placebo (230 participants).

For the remdesivir comparison, 87 participants were assigned randomly to remdesivir or matched placebo, and all received some infusion of remdesivir (44 participants), or remdesivir matched placebo (43 participants). The modified intention-to-treat analyses for both agents included 85 participants.

The study led to the following findings:

• 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventilation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO.
• The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11.
• Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died.
• The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04).
• The primary safety outcome of death, serious adverse events, organ failure, severe infection, or grade 3 or 4 adverse events up to day 5 occurred in 63% of 231 patients in the aviptadil group compared with 56% of 230 participants in the placebo group (OR 1·40).

"We found no evidence that IV aviptadil improved clinical outcomes among patients with COVID-19-associated acute hypoxaemic respiratory failure compared with placebo; inferences regarding remdesivir were limited by our sample size," the researchers wrote.

"The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding efficacy or safety," they concluded.

Reference:

Brown, S. M., Barkauskas, C. E., Grund, B., Sharma, S., Phillips, A. N., Leither, L., Peltan, I. D., Lanspa, M., Gilstrap, D. L., Mourad, A., Lane, K., Beitler, J. R., Serra, A. L., Garcia, I., Almasri, E., Fayed, M., Hubel, K., Harris, E. S., Middleton, E. A., . . . Wenner, C. (2023). Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): A randomized, placebo-controlled trial. The Lancet Respiratory Medicine. https://doi.org/10.1016/S2213-2600(23)00147-9