Evaluation of the safety and efficacy of tocilizumab (AryoGen ‎Pharmed Co., Iran) in patients with severe COVID-19‎

The evaluation of efficacy and safety of Tocilizumab (AryoGen Pharmed Co.) in patients with severe ‎COVID-19.‎

This is a phase III, open-label, and single-arm study with the sample size of 85 patients.‎

This phase-III, single-arm, open-label, multi-center (8 cities of Iran) clinical trial will be conducted in patients with COVID-19 with a follow-up duration of 14 days. Tocilizumab will be administered to the eligible patients on day 1, and the outcomes will be investigated with the 14-day monitoring of the patients.

َInclusion criteria: Ability to comprehend and willingness to sign the Informed Consent Form for this study by ‎the patient or his/her guardian; Patients aged≥18 years old; Patients with any of the following symptoms: ‎fever (body temperature>37.8°C), shortness of breath, cough, or respiratory rate higher than 30 breaths/min and SpO2≤93%, with the confirmed diagnosis of ‎SARS-CoV-2 infection based on PCR and/or radiography; Serum Interleukin-6 level ≥ 3 times upper limit of normal. Exclusion criteria include hypersensitivity to Tocilizumab or any ‎components of the formulation, hepatic or renal disorders, bone marrow suppression, patients with a high risk of GI ‎perforation, history of tuberculosis, hepatitis B or C, HIV, pregnancy and breastfeeding, and any other active ‎infection.

Intervention group: Subcutaneous (two PFS injections of 162 mg Tocilizumab for ‎patients <100 kg and three PFS injections of 162 mg Tocilizumab for patients >100 kg) in addition to the standard treatment. In case of inadequate response, Tocilizumab would be re-administered with a 12-hour interval between injections.

All-cause mortality rate during the study (date and cause of death, if applicable)

To amend the study design (interventions, study endpoints, inclusion criteria, and sample size): based on the state-of-the-art studies in the field of COVID-19 and the fact that improving patient survival is the ultimate goal in these patients, the primary endpoint is changed to the all-cause mortality rate during the study. Secondary endpoints are updated accordingly. Due to the unavailability of the intravenous form, subcutaneous injection was used for all patients. As a result, the interventions section is updated. According to the definition of severe COVID-19 by WHO, respiratory rate higher than 30 breaths/min is added to the inclusion criteria number 3. Based on the significantly elevated IL-6 levels in patients with severe COVID-19 and the mechanism of action of tocilizumab, the inclusion criteria number 4 is changed to serum Interleukin-6 level ≥ 3 times upper limit of normal. Based on the first version of the protocol, the trial was going to be conducted in 500 patients with the aim of increasing the patient access to the treatment. Yet, in the current version and due to the increased concern on the safety of tocilizumab treatment in patients with COVID-19, the sample size is calculated to be 85, using Fleming’s method (single-arm study) with the statistical power of 90%, alpha level of 5%, and the goal of decreasing the mortality rate by 15% (with the assumption of 60% survival rate with the standard treatment and an increase to 75% by the addition of tocilizumab to the treatment). Moreover, since only severe COVID-19 patients are included in the study, the term "severe" is added to the title. Following the addition of a study center in Semnan and the removal of the centers in Shiraz and Rasht, the total number of cities is changed to 8 in the Summary section.