A RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED, MULTICENTER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF TOCILIZUMAB IN PATIENTS WITH SEVERE COVID-19 PNEUMONIA

Coronaviruses (CoV) are positive-stranded RNA viruses with a crown-like
appearance under an electron microscope due to the presence of spike
glycoproteins on the envelope. They are a large family of viruses that cause
illness ranging from the common cold to more severe diseases such as Middle
East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome
(SARS-CoV).

COVID-19, which is the acronym of "coronavirus disease 2019," is caused by a
new coronavirus strain that has not been previously identified in humans and
was newly named on 11 February 2020 by the World Health Organization (WHO). An
epidemic of cases with unexplained lower respiratory tract infections was first
detected in Wuhan, the largest metropolitan area in China's Hubei province, and
was reported to the WHO
Country Office in China on December 31, 2019. A pandemic was subsequently
declared by the WHO on 11 March 2020.

According to the WHO, as of 17 March 2020 over 179,000 cases of COVID-19 were
reported in over 100 countries worldwide, with over 7400 deaths. Up to ~20% of
infected patients experienced complications related to a severe form of
interstitial pneumonia, which may progress towards acute respiratory distress
syndrome (ARDS) and/or multi organ failure (MOF) and death.

To date, there is no vaccine and no specific antiviral medicine shown to be
effective in preventing or treating COVID-19. Most patients with mild disease
recover with symptomatic treatment and supportive care.

This study will evaluate the efficacy, safety, pharmacodynamics, and
pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in
combination with standard of care (SOC) in hospitalized patients with severe
COVID-19 pneumonia. Specific objectives and corresponding endpoints for the
study are outlined below.

Overview of Study Design
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter
study to assess
the efficacy and safety of TCZ in combination with SOC compared with matching
placebo in
combination with SOC in hospitalized adult patients with severe COVID-19
pneumonia. The
Sponsor intends to enroll approximately 330 patients that have been diagnosed
with COVID-19
pneumonia and meet the entry criteria in centers globally.
Patients must be at least 18 years of age with confirmed COVID-19 infection per
WHO criteria,
including a positive PCR of any specimen (e.g., respiratory, blood, urine,
stool, other bodily
fluid). At the time of enrollment, patients must have SpO2 * 93% or PaO2/FiO2 *
300 mmHg)
despite being on SOC, which may include anti-viral treatment, low dose
steroids, and supportive
care.

Patients in whom, in the opinion of the treating physician, progression to
death is imminent and
inevitable within the next 24 hours, irrespective of the provision of
treatments, will be excluded
from the study. Patients with active tuberculosis (TB) or suspected active
bacterial, fungal, viral,
or other infection (besides COVID-19) will be excluded from the study.
Patients will be randomized as soon as possible after screening at a 2:1 ratio
to receive blinded
treatment of either TCZ or a matching placebo, respectively. Study treatment
must be given in
combination with SOC. The randomization will be stratified by geographic region
(North
America, Europe, and other) and mechanical ventilation (yes, no).
Patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg, with
a maximum
dose of 800 mg, and patients assigned to the placebo arm will receive one
infusion of placebo,
both in addition to SOC.

For both arms, if the clinical signs or symptoms worsen or do not improve
(reflected by
sustained fever or at least a one-category worsening on the 7-category ordinal
scale of clinical
status), one additional infusion of blinded treatment of TCZ or placebo can be
given, 8*12 hours
after the initial infusion.

Patients who do not meet the criteria for participation in this study (screen
failure) may qualify
for one re-screening opportunity (for a total of 2 screenings per participant)
at the investigator*s
discretion. Patients are not required to re-sign the consent form if they are
re-screened within 7
days after previously signing the consent form. .
The study assessments to be conducted include the following: physical
examination, vital signs,
oxygen saturation, assessment of consciousness, presence and absence of
respiratory support,
adverse events, concomitant therapies, clinical laboratory tests, and
nasopharyngeal swabs.

After Day 28
Patients will be followed up for a total of 60 days after first dose of study
medication.
For patients who are discharged between Day 28 and study completion, visits may
be
conducted via telephone.
During the study, standard supportive care will be given according to clinical
practice.

Patients assigned to the TCZ arm will receive one infusion of TCZ 8 mg/kg, with
a maximum dose of 800 mg, and patients assigned to the placebo arm will receive
one infusion of placebo, both in addition to SOC.

For both arms, if the clinical signs or symptoms worsen or do not improve
(reflected by sustained fever or at least a one-category worsening on the
7-category ordinal scale of clinical status), one additional infusion of
blinded treatment of TCZ or placebo can be given, 8*12 hours after the initial
infusion.

- We will perform a physical examination - at 1 timepoint
- We will measure your vital signs - at 33 timepoints
- We will perform an electrocardiogram (ECG) - at 1 timepoint
- We will perform a pregnancy test - at the screening day
- We will collect blood - at 36 timepoints, 4,5-39mL XX tubes at a time.
This is to monitor your response to the study drug and also to measure the
amount of study drug that is in your body and how your body breaks it down
- We will perform a chest X-ray at a maximum of 7 timepoints. CT scans can be
performed as alternative for the chest X-ray
- We will give you one or two infusions with study drug or placebo