Aviptadil did not significantly improve clinical outcomes in COVID-19-associated acute hypoxemic respiratory failure when compared with placebo, according to study findings published in The Lancet Respiratory Medicine.
Previous studies have suggested that both remdesivir and aviptadil, a neuropeptide hormone that has shown positive pleiotropic effects, might be effective in treating patients with COVID-19-associated acute hypoxemic respiratory failure, who have a high mortality rate. The randomized, placebo-controlled TESICO trial (ClinicalTrials.gov Identifier: NCT04843761) compared intravenous (IV) aviptadil with placebo and IV remdesivir with placebo in hospitalized adult patients with acute hypoxemic respiratory failure due to confirmed SARS-CoV-2 infection.
The study design allowed participants to be randomly assigned to both study treatments or matched placebo in a 2×2 factorial design or to 1 agent vs placebo. Aviptadil was administered daily in a 12-hour infusion for 3 days, with a target of 600 pmol/kg on infusion day 1, 1200 pmol/kg on infusion day 2, and 1800 pmol/kg on infusion day 3. Remdesivir was administered as a 200-mg loading dose, followed by 100-mg daily maintenance doses for as long as 10 days. Participants assigned to placebo for either agent received matched saline placebo in identical volumes.
The primary outcome was a 6-category outcome at day 90: (1) at home (residence type before hospitalization) and off oxygen (recovered) for 77 days or more; (2) at home and off oxygen for 49 to 76 days; (3) at home and off oxygen for 1 to 48 days; (4) not hospitalized but either on supplemental oxygen or not at home; (5) hospitalized or in hospice care; or (6) dead.
We found no evidence that intravenous aviptadil improved clinical outcomes among patients with COVID-19-associated acute hypoxemic respiratory failure compared with placebo.
A total of 473 participants were enrolled from April 21, 2021, to May 24, 2022, of whom 471 participants were assigned to aviptadil or matched placebo in the aviptadil comparison. The modified intention-to-treat (ITT) population included 461 participants who had at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). In the remdesivir comparison, 87 participants were assigned to remdesivir or matched placebo, and 85 participants were included in the modified ITT analyses for both drugs.
Among the 461 participants in the modified ITT population, the median age was 57 years (interquartile range, 46-66), 39% were female, and 94% were in an intensive care unit.
For the primary efficacy endpoint of aviptadil vs placebo at day 90, the odds ratio (OR) for being in a better category from a model stratified by baseline disease severity was 1.11 (95% CI, 0.80-1.55; P =.54).
At day 90, 86 patients in the aviptadil group and 83 in the placebo group had died, with a cumulative percentage of 38% in the aviptadil group and 36% in the placebo group (hazard ratio [HR], 1.04; 95% CI, 0.77-1.41). At day 180, the percentages who died were 39% (90 deaths) in the aviptadil group and 38% (86 deaths) in the placebo group (HR, 1.06; 95% CI, 0.79-1.42).
The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3/4 adverse events up to day 5 occurred in 146 (63%) of 231 participants in the aviptadil group vs 129 (56%) of 230 participants in the placebo group (OR, 1.40; 95% CI, 0.94-2.08; P =.10). Up to day 28, 181 (78%) participants in the aviptadil group had the primary safety outcome compared with 172 (75%) in the placebo group (HR, 1.17; 95% CI, 0.95-1.44; P =.15).
Odds ratios varied for the primary endpoint in the 4 subgroups of remdesivir use (P =.038). Regarding the 84 participants in the factorial design, the ORs (aviptadil vs placebo) were 2.11 (95% CI, 0.69-6.46) for patients assigned to remdesivir and 3.78 (1.17-12.24) for those who received the remdesivir placebo.
Among several limitations, the trial had limited power for subgroup analyses, and most participants had not been vaccinated. In addition, COVID-19 treatment guidelines from the National Institutes of Health changed during the TESICO trial, and formal screening logs were not obtained from enrolling sites.
“We found no evidence that intravenous aviptadil improved clinical outcomes among patients with COVID-19-associated acute hypoxemic respiratory failure compared with placebo,” the study authors concluded. “Other lung-related therapies should be sought for this severely underserved population.” The study authors further noted that “inferences regarding remdesivir were limited by our sample size.”
Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.