Efficacy and Safety of Tocilizumab in Severe Covid-19 Infection in Second and Third Wave of Epidemics in Myanmar: Multicenter Randomized Controlled Trial

Abstract

Background: Coronavirus disease 2019 (COVID-19), emerged in China at the end of 2019, became a major threat to health around the world as it caused significant morbidity and mortality. SARS-CoV-2 infection induces a cytokine storm due to dose-dependent production of IL-6 from bronchial epithelial cells; therefore, Tocilizumab, a monoclonal antibody against the interleukin-6 receptor, is one of the recommended drugs for treatment of COVID-19 infection. It may result in better outcomes in patients with severe Covid-19 infection. The efficacy and timing of Tocilizumab therapy in severe COVID-19 infection in Myanmar was not known clearly. Methods: A hospital based interventional study design (Randomized controlled trial) was conducted in COVID-19 treatment centers in Myanmar -Yangon and Nay Pyi Taw, from February 2020 to August 2021. Supervised treatment was done; and, both clinical and laboratory data were collected by using standardized forms and analysis was done. We conducted a double-blind, randomized, placebo-controlled trial of intravenous Tocilizumab in adults who were hospitalized with severe COVID-19 infection. Patients were randomly assigned to receive either Tocilizumab or placebo for within 5 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results: A total of 105 patients (55 in Tocilizumab group and 50 in Standard treatment group) with severe COVID-19 infection were included. Baseline characteristics in Tocilizumab group and Standard treatment group were as follows: (1) mean age 64.4 ± 11.9 years and 59.9 ± 15.8 years; (2) BMI 24.3 ± 3.0 and 23.9 ± 5.0; (3) mean duration of symptom onset to hospital admission was 9.5 ± 4.4 days and 6.5 ± 3.8; (4) mean duration of symptom onset to treatment was 12.8 ± 3.8 days and 7.1 ± 3.8 days; (6) mean duration of hospital stay was 20.1 ± 16.5 days and 11.4 ± 4.8 days; (7) associated co-morbidities was 88% and 70%; and, (8) mean CXR severity score by Braxia was 12.0 ± 2.0 and 9.6 ± 3.4 respectively. The survival rate in early treatment receiving group was 80% in Tocilizumab group and 65.5% in Standard treatment group; that of median treatment receiving group was 40% and 62.5% respectively. The survival rate in late treatment receiving group reduced to 36% in Tocilizumab group; however, no one survived in Standard treatment group. Inflammatory markers (Ferritin, LDH, D dimer and CRP) dropped significantly at 24 hours and 72 hours after Tocilizumab treatment; the difference was noticeable between survivors and non-survivors. Absolute lymphocyte count, liver enzymes (AST and ALT) and procalcitonin levels became normal by 2 weeks. No significant changes were seen in serum creatinine and blood urea level. Both clinical observation and questioning on experienced side effects from patients on recovery revealed that Tocilizumab therapy was tolerable and safe. Conclusions: Tocilizumab treatment was associated with a lower risk of mortality than Standard treatment group among patients with severe COVID-19 infection. The chance of survival was 36% if Tocilizumab treatment was given late- more than 15 days of symptom onset unlike Standard treatment. The significant inflammatory markers which could predict survival within 24 to 72 hours were serum ferritin, LDH, D dimer and CRP. Tocilizumab treatment in severe COVID-19 infection was safe and effective particularly it was given early.