ABSTRACT
Background: COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vasoactive Intestinal Peptide (VIP) blocks replication of the SARS-CoV-2 virus in alveolar type II cells, inhibits cytokine synthesis, prevents cytopathy, and up regulates surfactant production. Synthetic VIP-aviptadil is a novel strategy to treat patients with COVID-19 and respiratory failure. Methods: This was a prospective, multicenter, randomized, placebo-controlled trial with 196 patients, nasal swab PCR+ for COVID-19 receiving intensive care at 10 U.S. hospitals (6 tertiary care and 4 regional hospitals) to determine if intravenous aviptadil is superior to placebo in achieving recovery from respiratory failure and survival at 60 days post treatment. The analysis was by modified intent to treat (ITT) using a pre-specified logistic regression model. The primary pre-specified endpoint was being alive with no respiratory failure at day 60. Results: There were 213 subjects screened, with 203 eligible and 196 randomized and treated. Baseline characteristics were comparable except for worse NIAID severity for aviptadil (Table 1). All subjects were followed up to 60 days. A favorable trend (OR 1.63;P=.14) was seen for the primary endpoint at 60 days with significance achieved after adjusting for hospital setting. Overall, there was 2.0-fold increased odds of survival (95% CI 1.05-3.88;P<.035) for aviptadil at Day 60 controlling for baseline NIAID score. Odds of survival increased to over 4-fold after adjusting for site of care (Tertiary care vs regional hospital, OR 4.35 (95% CI 1.91, 9.90;P<.035). Logistic regression indicated aviptadil treated patients were also significantly more likely to be discharged earlier than placebo-treated patients (p=0.01). The most common adverse events noted were diarrhea (32.8% vs. 1.5%) and hypotension (26% vs.21.5%) for aviptadil vs. placebo. Additional adverse events occurring more frequently in aviptadil treated patients included acute kidney injury (23.7% vs 20%), hyperkalemia (12.2% vs 6.2%), and atrial fibrillation (11.5% vs 4.6%). Multiple organ dysfunction syndrome (6.9% vs 13.8%) and respiratory failure (12.2% vs 13.8%) occurred more commonly in placebo-treated patients. Conclusion: Treatment with aviptadil demonstrates efficacy in improving the likelihood of recovering from respiratory failure, surviving to 60 days, and reducing hospital stay in critically ill patients with respiratory failure caused by COVID-19.
ABSTRACT
Background: Coronavirus 2019 (COVID-19) has infected millions of people worldwide, with the US reporting the most deaths. Many individuals are at high risk of disease progression, which may result in multi-organ failure and death. Risk factors include advanced age, cardiovascular disease (CVD), and chronic kidney disease (CKD). In addition, more than 40% of hospitalized patients develop acute kidney injury (AKI), with 20% of those requiring dialysis. Several therapeutic agents are in development, but patients with advanced CKD or those requiring immunosuppressive therapy are frequently excluded from participation in clinical trials. RBT-9, a proprietary formulation of stannous protoporphyrin, has organ protective effects, as demonstrated in animal models of kidney, liver, and lung injury. RBT-9 also has antiviral effects, as demonstrated in several enveloped viruses, including influenza, HCV, dengue, and yellow fever. A Phase 2, randomized, placebo-controlled study was designed to evaluate the effect of RBT-9 on progression of COVID-19 infection in high-risk individuals. Methods: This study will enroll up to 252 subjects with documented SARS-CoV-2 infection who are at risk of progression based on age (≥70 years) or comorbidities, including CKD (all stages, not on dialysis), CVD, chronic lung disease, diabetes mellitus, obesity, and mild hypoxemia. Subjects will be randomized 2:1 to receive a single dose of RBT-9 or placebo and will be followed for 56 days. Results: Study Objectives The primary objective is to evaluate the effect of RBT-9 versus placebo on clinical status measured using the 8-point World Health Organization (WHO) Ordinal Clinical Scale at Day 28. Secondary objectives include time to first occurrence of death from any cause or new/worsened organ dysfunction, survival, AKI incidence, new or worsening heart failure, hospitalization status and duration, ICU status, days on ventilator, vasopressor utilization or ventricular arrythmias. Conclusions: The organ protective and antiviral effects of RBT-9 warrant conduct of this clinical study, which is aimed at preventing progression to severe COVID-19 and organ failure. The first patient is expected to be enrolled in June 2020.