ABSTRACT
Introduction: The clinical progression of severe coronavirus disease 2019 (COVID-19) is associated with uncontrolled activation of inflammatory cytokines that results in excessive tissue injury, among which is interleukin-8 (IL-8). Aim(s): To assess the efficacy and safety of reparixin, an inhibitor of IL-8 receptors, as add-on therapy to the standard of care for severe COVID-19 pneumonia. Method(s): This was a Phase 3, multicenter, randomized, placebo-controlled study in hospitalized adult patients with COVID-19 requiring oxygen support and/or noninvasive ventilation. From February to July 2021, patients were randomized 2:1 to oral reparixin or placebo in addition to the standard of care for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure. This study was funded by Dompe Farmaceutici SpA (ClinicalTrials.gov: NCT04878055). Result(s): Of the 278 randomized patients, 185 patients in the reparixin group and 94 patients in the placebo group were included in the primary intention-to-treat analysis. The proportion of patients alive and free of respiratory failure at day 28 was greater in the reparixin group but not statistically significant (n=152 (89.4%) vs. n=71 (85.5%), OR: 1.63, 95% CI: 0.75 - 3.51, p= 0.2). While time to recovery was not different between groups, patients who received reparixin had a lower intensive care unit admission rate. Reparixin was well-tolerated. Conclusion(s): This trial did not meet the primary efficacy endpoint due to the low mortality in both arms, yet reparixin showed a promising trend towards limiting disease progression. A confirmatory Phase 3 study is currently underway.
ABSTRACT
Rationale: Severe coronavirus disease 2019 (COVID-19) is associated with significant morbidity attributed from the complications of acute respiratory distress syndrome. Poor outcomes in severe COVID-19 patients have been related to cytokine release syndrome, which may be mediated by CX- C chemokine ligand 8/interleukin 8 (CXCL8/IL-8) acting through C-X-C chemokine receptor types 1 and 2 (CXCR1/2). The aim of this clinical trial was to determine if CXCR 1/2 blockade by reparixin, an IL-8 inhibitor, can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. Methods: This was a Phase 2, open-label, adaptive, multicenter, randomized trial in hospitalized adult patients, conducted in Italy and Brazil, with severe COVID-19 pneumonia between May and November 2020. Eligible patients had respiratory distress (respiratory rate ≥30 breaths/minute without oxygen and/or partial arterial oxygen pressure (PaO2)/fraction of inspiration O2 (FiO2) >100 to <300 mmHg), pneumonia confirmed by chest imaging, and elevated inflammatory markers. Patients were randomized 2:1 to receive oral reparixin 1200mg three times daily or the standard of care (SOC) for up to 21 days. Patients were followed for up to seven days after the end of treatment. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensivecare unit admission, and/or use of rescue medication. This study was funded by Dompé Farmaceutici SpA (ClinicalTrials.gov: NCT04794803). Results: Fifty-five patients were enrolled and included in the final analysis comparing reparixin (n = 36) to the SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared to the SOC group (16.7% [95% CI: 6.4-32.8%] vs 42.1% [95% CI: 20.3-66.5%], p=0.02). After controlling for covariates, this statistical significance was maintained with a hazard ratio of 0.33 (95% CI, 0.11 to 0.99;p = 0.047). Reparixin treatment appeared to be well-tolerated with no discontinuation of therapy. Conclusions: In patients with severe COVID-19, reparixin led to a significant improvement in clinical outcomes when compared to the SOC. The results of this phase 2 study allowed progression to a Phase 3 clinical trial to further explore the efficacy and safety of reparixin for the treatment of severe COVID- 19.