A two-arm, randomized, controlled, multi-centric, open-label Phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19

Abstract

An uncontrolled increase in cytokine production may lead to systemic hyperinflammation, vascular hypo-responsiveness, increased endothelial permeability, hypercoagulation, multi-organ dysfunction and eventually death in moderate to severely ill COVID-19 patients. Targeting T-cells, an important driver of the hyperinflammatory response, in the treatment of COVID-19, could potentially reduce mortality and improve survival rates. Itolizumab is an anti-CD6 humanized monoclonal antibody with an immunomodulating action on Teffector cells that downregulates T-cell activation, proliferation and subsequent production of various chemokines and cytokines. The efficacy and safety of Itolizumab for the treatment of cytokine release syndrome in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase 2 study. Eligible patients were randomized (2:1) to arm A (best supportive care + Itolizumab) and arm B (best supportive care). The primary outcome of interest was reduction in all-cause mortality 30 days after enrolment. Thirty-six patients were screened, 5 were treated as first dose sentinels and the rest were randomized, whilst 4 patients were considered screen failures. Two patients in the Itolizumab treatment arm discontinued prior to receiving the first dose and were replaced. At the end of 1 month, there were 3 deaths in arm B, and none in arm A (p= 0.0296). At the end of the follow-up period, more patients in Arm A had improved SpO2 without increasing FiO2 (p=0.0296), improved PaO2 (p=0.0296), and reduction in IL-6 (43 pg/ml vs 212 pg/ml; p=0.0296) and tumor necrotic factor-α (9 pg/ml vs 39 pg/ml; p=0.0253) levels. Itolizumab was generally safe and well tolerated, and transient lymphopenia (11 patients in Arm A) and infusion reactions (7 patients) were the commonly reported treatment related safety events. These encouraging results indicate that larger clinical trials are warranted to establish the role of Itolizumab in controlling immune hyperactivation in COVID-19.

Pharmacotherapy of Cytokine Release Syndrome in Severe COVID-19 Patients: A Systematic Review

“…Ultimately, nine studies have assessed the treatment/management of the cytokine release syndrome in severe COVID-19 patients and were included in the current systematic review [Figure 1]. [21][22][23][24][25][26][27][28][29] e systematic review revealed two therapeutic contenders that should be utilized in patients suffering from the cytokine release syndrome. A tocilizumab/corticosteroid combination and the second being a therapeutic plasma exchange (TPE).…”

A Systematic Review Assessing the Underrepresentation of Cancer Patients in COVID-19 Trials

“…Ten trials excluded neutropenic patients, seven of which excluded patients with an absolute neutrophil count (ANC) <500 k/μL and three trials excluded patients with an ANC <1,000 k/μL [19, 25,28,[30][31][32][33]. Seven trials excluded thrombocytopenic patients (platelets <50 k/μL).…”

“…Eleven trials excluded patients that treated with any immunosuppression treatment, most of which did not specify the exact medications [12,14,16,18,19,25,26,28,[31][32][33].…”

Therapeutic Approaches in Modulating the Inflammatory and Immunological Response in Patients With Sepsis, Acute Respiratory Distress Syndrome, and Pancreatitis: An Expert Opinion Review

“…Multiple clinical studies observed positive results with Itolizumab in different levels of COVID-19 disease severity [106][107][108]. In severe ARDS, Kumar et al reported greater mortality and recovery benefits with Itolizumab than control [109]. Carbon monoxide (CO) protects against oxidative stress and cell death and suppresses inflammation.…”