IP-10 Predicts Clinical Progression and Response to IL-6 Blockade with Sarilumab in Early COVID-19 Pneumonia. The SARICOR Clinical Trial

Abstract

Background and objectives: SARICOR clinical trial (CT) showed that patients with COVID19 pneumonia and increased levels of interleukin (IL)-6 might benefit from early blockade of IL6-pathway. However, the benefit from this intervention might not be uniform in all patients. We sought to determine if other biomarkers of immunoactivation, besides IL-6, could identify which subgroup of patients benefit the most of this intervention.

Methodology: The SARICOR CT was a phase II, open-label, randomized, multicentre, controlled CT (July 2020-March 2021) in which patients were randomized to receive standard of care (SOC) (control group); SOC plus single dose of Sarilumab 200 mg (Sarilumab-200 group) or SOC plus single dose of Sarilumab 400 mg (Sarilumab-400 group). Patients who had baseline serum samples for cytokine determination (IL-8, IL-10, MCP-1, IP-10) were included in this secondary analysis. Progression to severe respiratory failure requiring high-flow oxygen therapy or mechanical ventilation according to cytokine levels and treatment received was evaluated.  Results: One hundred and one (88%) of 115 patients enrolled in the SARICOR CT had available serum samples (control group: n=33; Sarilumab-200: n=33; Sarilumab-400 n=35). Among all evaluated biomarkers, IP-10 showed the strongest association with treatment outcome. Thus, in patients with IP-10 < 2500 pg/ml, there were no differences in the probability of presenting the primary outcome between treatment groups. Conversely, patients with IP-10 ≥ 2500 pg/ml treated with Sarilumab-400 had a lower probability of progression (13%) compared to the control group (58%) (HR 0.19; 95% CI: 0.04-0.90; p=0.04).Conclusions: IP-10 predicts clinical progression in patients hospitalized with COVID-19 pneumonia and IL-6 levels > 40 pg/ml. Importantly, IP-10 value < 2500 pg/ml might discriminate those individuals with high IL-6 levels who might not benefit of Sarilumab therapy.

Trial Registration Details: The trial was registered in accessible public databases such as the Spanish Clinical Studies Registry (REec), EUDRACT (2020-001531-27), and ClinicalTrials.gov (NCT04357860).

Funding Information: This study has been supported by the Consejeria de Salud y Familias, Junta de Andalucia, Spain (COVID-19 Research Program. Project code COVID-0013-2020). B.G.G. and J.T.C. are supported by General Sub-Directorate of Networks and Cooperative Research Centers, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0001, RD16/0016/0008]—co-financed by the European Regional Development Fund “A Way to Achieve Europe, Operational Program Smart Growth 2014–2020.” J.C.G. is supported by SCReN (Spanish Clinical Research Network) funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion through project PT17/0017/0032 and PT20/0039. R.L.L., C.D.L.F., J.T.-C., and B.G.-G. are supported by the Center of Biomedical Investigation Network for Infectious Diseases (CIBERINFEC) funded by ISCIII through projects CB21/13/00049 and CB21/13/ 00012.

Declaration of Interests: The authors have no conflict of interest or financial relationships relevant to the submitted work to disclose.

Ethics Approval Statement: The trial was approved by the Committee for Biomedical Research Ethics of the Reina Sofía University Hospital and was conducted in accordance with the International Conference on Harmonization E6 Guideline for Good Clinical Practice and ethical principles of the Declaration of Helsinki. Authorization was also obtained from the Spanish Agency of Medicines and Medical Products (AEMPS, 20-0262).