A Multicenter Phase 2 Randomized Controlled Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients with COVID-19 Pneumonia

Giovanni Landoni, Lorenzo Piemonti, Antonella d'Arminio Monforte, Paolo Grossi, Alberto Zangrillo, Enrico Bucci, Marcello Allegretti, Giovanni Goisis, Elizabeth M Gavioli, Neal Patel, Maria De Pizzol, Georgea Pasedis, Flavio Mantelli, Giovanni Landoni, Lorenzo Piemonti, Antonella d'Arminio Monforte, Paolo Grossi, Alberto Zangrillo, Enrico Bucci, Marcello Allegretti, Giovanni Goisis, Elizabeth M Gavioli, Neal Patel, Maria De Pizzol, Georgea Pasedis, Flavio Mantelli

Abstract

Introduction: Acute lung injury and acute respiratory distress syndrome are common complications in patients with coronavirus disease 2019 (COVID-19). Poor outcomes in patients with COVID-19 are associated with cytokine release syndrome. Binding of interleukin-8 (CXCL8/IL-8) to its chemokine receptors, CXCR1/2, may mediate this inflammatory process. The aim of this clinical trial was to determine if CXCR1/2 blockade with reparixin can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. The dose and safety of reparixin have been investigated in clinical trials of patients with metastatic breast cancer.

Methods: This was a phase 2, open-label, multicenter, randomized study in hospitalized adult patients with severe COVID-19 pneumonia from May 5, 2020 until November 27, 2020. Patients were randomized 2:1 to receive 1200 mg reparixin orally three times daily or standard of care (SOC) for up to 21 days. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensive care unit admission, and/or use of rescue medication.

Results: Fifty-five patients were enrolled between reparixin (n = 36) and SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared with the SOC group (16.7% [95% CI 6.4-32.8%] vs. 42.1% [95% CI 20.3-66.5%], P = 0.02). The sensitivity analysis based on the Cox regression model provided an adjusted hazard ratio of 0.33 with statistical significance lower than 0.05 (95% CI 0.11-0.99; P = 0.047). Reparixin treatment appeared to be well tolerated.

Conclusion: In patients with severe COVID-19, reparixin led to an improvement in clinical outcomes when compared with the SOC. A larger phase 3 clinical study is needed to confirm these results.

Trial registration: EudraCT identifier, 2020-001645-40; registered May 6, 2020 (retrospectively registered), and clinicaltrials.gov (NCT04794803) on March 8, 2021.

Keywords: COVID-19; CXCR1/2; IL-8; Reparixin; SARS-COV-2.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of the enrolled patients. Both the full analysis and safety sets consisted of all randomized patients who received at least one dose of reparixin. The full analysis was analyzed according to the intent-to-treat (ITT) principle and was used to determine efficacy results. The safety set was used to determine safety results
Fig. 2
Fig. 2
Primary endpoint analysis: time to composite endpoint of clinical events. The Kaplan–Meier estimate shows that reparixin prolonged the time to achieving at least one clinical event as compared with the placebo group

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