AVIPTADIL IN ACUTE RESPIRATORY DISTRESS SYNDROME ASSOCIATED WITH COVID-19 INFECTION

Dr. Bhupesh Dewan* and Siddheshwar Shinde

ABSTRACT

Aim: This study is aimed at evaluating efficacy and safety of Intravenous Aviptadil as an add-on to the “Standard of Care” treatment in severe COVID-19 patients with respiratory failure. Design, Setting and Participants: A randomized, multicentric, double-blind, placebo-controlled, comparative Phase III clinical trial was conducted at 8 geographically distributed sites across India between April 2021 to October 2021. The study enrolled 150 participants who were tested and confirmed cases of severe COVID-19 with respiratory failure and acute respiratory distress syndrome. Interventions: 12-hour intravenous infusions of Aviptadil over 3 successive days in ascending doses given as 0.166 mcg/kg/hr on Day 1 (equivalent to one 10 mL vial of 150 mcg), 0.332 mcg/kg/hr on Day 2 (equivalent to two 10 mL vials of 150 mcg each) and 0.498 mcg/kg/hr on Day 3 (equivalent to three 10 mL vials of 150 mcg each). Methodology: Severe COVID-19 patients with respiratory failure were randomized in two groups in a ratio of 1:1, to receive either Aviptadil or Placebo. Both the study drugs were given as an add-on to the standard of care (SOC). The SOC was kept as close as possible to the COVID-19 treatment guidelines specified by the Government of India. The study site staff, investigator and patients were masked to the treatment allocation. The primary endpoint of the study was resolution of respiratory failure whereas the secondary endpoints were improvement in WHO 7-point ordinal scale, improvement in PaO2:FiO2 ratio, survival of the patients and incidences of adverse events. Results: After the completion of treatment in Aviptadil group, an improvement was observed in the primary outcome of resolution of respiratory failure. Proportion of patients on Aviptadil demonstrated statistically significant odds, 2.1-fold, (p=0.0410) of being free of respiratory failure (no oxygen requirement) at Day 3 and 2.6-fold (p=0.0035) at day 7 as compared to the placebo group. An earlier resolution from the respiratory failure, with a median duration of 7 days was noted in the Aviptadil-treated group as compared to 14 days in the placebo group. A higher proportion of patients on Aviptadil shifted to the milder clinical state (32.43% vs 17.80%; p=0.0410 on Day 3 and 70.27% vs 45.21%; 0.0035 on Day 7) without the requirement of oxygen than the placebo group. A reduction of severity (based on WHO 7-point ordinal scale) in clinical status were also observed on Day 14 (p = 0.0005 by Wilcoxon rank sum test) and Day 28 (p = 0.0009 by Wilcoxon rank sum test). There were 68.42% Aviptadil-treated patients who showed 2 or more points improvement on the WHO 7-point ordinal scale as compared to 44.59% in the placebo group (p=0.003; Pearson chi2 test; odds ratio, 2.69; 95% CI, 1.38-5.24) on Day 7. On day 28, patients in the Aviptadil group had higher odds (1.38) of an improvement on WHO 7-point ordinal scale as compared to placebo with SOC. Aviptadil reduced the risk of death by 20% (relative risk 0.80; 95% CI: 0.35, 1.66) in ARDS. Patients treated with Aviptadil demonstrated significant improvement in PaO2/FiO2 ratio vs. placebo from day 2 to over the week (p<0.05) and beyond. There were 15 deaths in the Aviptadil group and 18 deaths in the placebo group. No deaths were attributed to the Investigational products. COVID-19–related mortality occurred in 22% patients of the study population, due to respiratory failure caused by underlying medical conditions. Conclusion: Use of Aviptadil was safe and effective in improving the resolution of respiratory failure, shortening the time to recovery, decreasing respiratory distress and preventing death in respiratory failure patients. The rapidity and magnitude of clinical effect suggests a highly specific role of Aviptadil in combating the lethal effects of Acute Respiratory Distress Syndrome associated with COVID-19.

Keywords: COVID-19, Vasoactive Intestinal Peptide (VIP), Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Alveolar Type II.