Antiviral for Adult Patients Hospitalized for SARS-CoV-2 Infection: a Randomized, Phase 2/3, Multicenter, Placebo Controlled, Adaptive, Multi-arm, Multi-stage Clinical Trial - Coalition Brazil COVID-19 IX: REVOLUTIOn

We have planned an randomized, adaptive, placebo-controlled, double-blind study to be carried out in 3 seamless stages. The first two stages are phase 2 studies with a third stage phase 3 to be conducted conditional to success of the first phase 2 and second phase 2 stages including efficacy and safety.

In particular, there is great interest in the possibility of combining the phase II and phase III stages of the development process and this is the focus here. Phase II trials can be thought of as part of the learning stage where dose selection and appropriate treatment groups are assessed together with initial indications of their effects. Phase III trials are usually more confirmatory in nature where the treatment effects of the selected treatments are assessed in a full-scale trial. Seamless phase II/III trials are concerned with combining these two aspects into a single trial. There are a clearly advantages of speed in that the dose selection and treatment effects are assessed within a single trial rather than establishing separate trials. In addition, all data available for the selected dose are used in the analysis rather than just those from the second stage with a consequent gain in power. The savings in the number of patients is achieved by applying a form of screening of competing treatments in the initial phase and abandoning those that are ineffective before the end of the study following pre-established premises of futility. Effect estimates, confidence intervals and p values need some statistical adjustments to allow for this, otherwise they will be biased towards a benefit of the treatment. This study design, starting with a phase II, could give us a treatment regimen composed of one or more repurposed antivirals drugs that could improve the clinical outcomes of those hospitalized with COVID-19 reducing time to recovery and the need for respiratory support. It will be conducted in about 60 Brazilian hospitals.

Selection of drugs rationale

• Atazanavir: Atazanavir is a potent inhibitor of HIV-1 protease and is not associated with significant dyslipidemia, as observed with other protease inhibitors.15 It was approved by the FDA on January 29, 201516,17 as a combination of atazanavir and cobicistat. Atazanavir can also be combined with ritonavir18 In a protease-free cell assay, atazanavir blocked the major protease activity of SARS-Cov-2 at a concentration of 10 μM. In in vitro models of viral infection/replication performed on Vero cells, a human pulmonary epithelial cell line and primary human monocytes, atazanavir inhibited SARS-CoV-2 replication; in addition, the concentrations of interleukin 6 (IL-6) and tumor necrosis factor type alpha (TNF-α) induced by the virus were reduced.10 Currently, no clinical study is registered on the ClinicalTrials.com website to assess the effects of atazanavir in the context of COVID-19.
• Daclastavir: Daclatasvir is a direct-acting antiviral that inhibits HCV replication by binding to the N- terminal of the NS5A protein, affecting viral RNA replication. NS5A is a multifunctional protein in the HCV replicative cycle, involved in the enrollment of cell lipid bodies, RNA binding and replication, protein phosphorylation, cell signaling and antagonism of interferon pathways.19 In an in vitro study, daclatasvir consistently inhibited the production of SARS-CoV-2 infectious particles in Vero cells, in the HuH-7 cell line and in Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Daclatasvir reached early events during the replication cycle of SARS-CoV-2 and prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the cytokine storm typical of SARS-CoV-2 infection.20
• Sofosbuvir/daclastavir:

Sofosbuvir (SOVALDI®) is a nucleotide analog directed against HCV NS5B polymerase, clinically approved with potent antiviral effects on the hepatitis C virus with several genotypes21. It is proposed that the drug could be a potential option in the treatment of COVID-19 especially at the beginning of the disease and before the invasion of the virus in the cells of the lung parenchyma, based on the similarity between the replication mechanisms of HCV and coronavirus22. In vitro, sofosbuvir showed EC50 values of 6.2 and 9.5 µM in HuH-7 (hepatoma) and Calu-3 (type II pneumocytes) cells respectively, although inactive in Vero cells (these cells are unable to make this conversion sofosbuvir in the pro-drug to active form)11.