Intravenous Tocilizumab versus Standard of Care in the Treatment of Severe and Critical COVID-19-related Pneumonia: A Single Center, Double-blind, Placebo Controlled, Phase 3 Trial

Eric Jason B. Amante, MD; Aileen S. David-Wang, MD; Michael L.  Tee, MD; Felix Eduardo R.  Punzalan, MD; John C.  Añonuevo, MD; Lenora C.  Fernandez, MD; Albert B. Albay Jr., MD; John Carlo M.  Malabad, MD, PhD; Fresthel Monica M.  Climacosa, MD, PhD; A. Nico Nahar I.  Pajes, MD; Patricia Maria Gregoria M. Cuaño, MD; Marissa M.  Alejandria, MD, MSc

doi:10.47895/amp.vi0.6175

Eric Jason B. Amante, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila https://orcid.org/0009-0006-8729-5383
Aileen S. David-Wang, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
Michael L. Tee, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
Felix Eduardo R. Punzalan, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
John C. Añonuevo, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
Lenora C. Fernandez, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
Albert B. Albay Jr., MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
John Carlo M. Malabad, MD, PhD College of Medicine, University of the Philippines Manila
Fresthel Monica M. Climacosa, MD, PhD Department of Medical Microbiology, College of Public Health, University of the Philippines Manila
A. Nico Nahar I. Pajes, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
Patricia Maria Gregoria M. Cuaño, MD Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila
Marissa M. Alejandria, MD, MSc Department of Medicine, Philippine General Hospital, University of the Philippines Manila; College of Medicine, University of the Philippines Manila

DOI: https://doi.org/10.47895/amp.vi0.6175

Keywords: COVID-19, Tocilizumab, IL-6, randomized trial

Abstract

Background. Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors.

Objectives. This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease.

Methods. This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner.

Results. Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups.

There was no significant difference between groups in terms of treatment success in both the intention-to-treat
analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21).
There was no significant difference in time to improvement of at least two categories relative to baseline on the
7-point Ordinal Scale of clinical status.

Conclusion. The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.