Design and Rationale of a Randomized, Double-Blind, Placebo-Controlled, Phase 2/3 Study Evaluating Dociparstat in Acute Lung Injury Associated with Severe COVID-19

Abstract

Introduction: The COVID-19 global pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure threaten to overrun hospital critical care units globally. New agents that address the hyperinflammatory "cytokine storm" and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, with the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding compared to commercially available heparin.

Methods: This study is a randomized, double-blind, placebo-controlled, phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care in hospitalized adults with COVID-19 who require supplemental oxygen. Phase 2 will enroll 12 participants in each of two dose-escalating cohorts to confirm the safety of DSTAT in this population. Following review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, phase 3 will enroll approximately 450 participants randomized to DSTAT or placebo. The primary endpoint is the proportion of participants who survive and do not require mechanical ventilation through day 28.

Discussion: Advances in standard of care, recent emergency use authorizations, and positive data with dexamethasone have likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement in the NIAID score will be essential to provide a measure of drug effect on recovery. Analysis of additional endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble-RAGE, D-dimer), will be performed to further define the effect of DSTAT in patients with COVID-19 infection.

Trial registration: ClinicalTrials.gov identifier; NCT04389840, Registered 13 May 2020.

Keywords: Acute lung injury; COVID-19; Dociparstat; HMGB1; NETs; Neutrophil extracellular traps; P-selectin; Platelet factor 4.

Figures

Fig. 1

Potential of DSTAT in COVID-19. Moderate-to-severe COVID-19 manifests with excessive inflammation, infiltration of activated immune cells into the lungs and coagulation disorders (e.g., clot formation) in the blood and tissues. DSTAT has the potential to prevent and mitigate these severe effects of SARS-CoV-2 infection by inhibiting several pathogenic pathways. (DSTAT, dociparstat sodium; HMGB1, high mobility group box protein 1; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; NETs, neutrophil extracellular traps; PF4, platelet factor 4)

Fig. 2

CMX-DS-004 study schematic. All participants receive randomized treatment for up to 7 days and are followed through day 28. The continuous infusion dose administered in phase 2, cohorts 2 and 3 will be confirmed after review of data by an independent Data Monitoring Committee (DMC) from prior cohort(s). The phase 3 continuous infusion dose will be the same as administered in phase 2, cohort 3