Pre-emptive tocilizumab in hypoxic COVID-19 patients, a prospective randomized trial

Patients who develop respiratory failure with COVID-19 have a small chance
(20%; with 8x IC capacity overload) to be eligible for invasive ventilation
(capacity problem). This group of patients with respiratory failure who is not
given invasive ventilation is likely to have very high (> 95%) mortality.
However, the mortality of patients undergoing invasive ventilation is also high
(approximately 50-60%) [Weiss et al. Lancet 2020, March 17].People who get
respiratory problems do not get into trouble because they cannot clear the
virus, but get into trouble because of the (uncontrolled) inflammatory response
(see figure) [Mehta et al. Lancet 2020 March 13; Hasan et al. J Heart & Lung
transpl. 2020 March]. The recently published clinical study, showing no effect
of anti-viral therapy (Lopinavir * Ritonavir) in admitted patients with severe
COVID-19, is in line with the belief that in the later stages of the disease,
not the virus, but hyper- inflammation is the problem [A Trial of Lopinavir *
Ritonavir in Adults Hospitalized with Severe Covid-19. Bin Cao, MD, et al. NEJM
2020]. This clinical picture is very similar to the cytokine release syndrome
(CRS) as seen in cancer immunotherapy (eg, in the context of chimeric antigen
receptor (CAR) T cell therapy and bi-specific antibody therapy).NB Experiences
with UMCG patients with status after lung and liver transplantation who
completed the SARS-CoV-2 virus and had a mild clinical picture fit this
observation.

The aim of the study is to assess whether early administration of the drug
tocilizumab in SARS-CoV-2 infection (COVID19 - coronavirus) can prevent the
risk of death and mechanical ventilation (assisted respiration by a
ventilator).

This is a randomized open label phase II study.

Eligible patients will be randomized (after written informed consent) to
standard care or intravenous tocilizumab.
Eligible patients who are randomized will receive intravenous tocilizumab 8
mg/kg (maximum dose 800 mg), infused over 1 hour. This dose can be repeated
after 8 hours if the hypoxia is not resolved (still at dyspneu grade II
according to CRS scale). Patients that are not randomized for intervention
using tocilizumab will receive standard care.

Patients in this study are treated with intravenous tociluzumab: 8 mg/kg
(maximum dose 800 mg), which can be repeated at the same dose after 8 hours if
the hypoxia has not improved

Allergic reactions during or after infusion can occur

Very common (incidence > 10%)
* upper respiratory tract infections with typical symptoms such as cough,
blocked nose, runny nose, sore throat and headache * high blood fat
(cholesterol) levels.

Common (incidence 1-10 %)
* lung infection (pneumonia) * shingles (herpes zoster) * cold sores (oral
herpes simplex), blisters * skin infection (cellulitis) sometimes with fever
and chills * rash and itching, hives * allergic (hypersensitivity) reactions *
eye infection (conjunctivitis) * headache, dizziness, high blood pressure *
mouth ulcers, stomach pain * fluid retention (oedema) in the lower legs, weight
increase * cough, shortness of breath * low white blood cell counts shown by
blood tests (neutropenia, leucopenia) * abnormal liver function tests
(increased transaminases) * increased bilirubin shown by blood tests * low
fibrinogen levels in the blood (a protein involved in blood clotting).

Uncommon (< 1%)
* diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain) * red
swollen areas in the mouth * high blood fat (triglycerides) * stomach ulcer *
kidney stones * underactive thyroid.