A Phase II Trial to Evaluate the Safety and Tolerability of Clazakizumab® (Anti-IL-6 Monoclonal) Compared to Placebo for the Treatment of COVID-19 Infection
Phase: PHASE2
Conditions: COVID-19
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
 
 
 
 
Official Title: A Phase II Trial to Evaluate the Safety and Tolerability of Clazakizumab® 
(Anti IL-6 monoclonal) compared to placebo for the treatment of COVID-19 infection 
NCT #: NCT04348500 
Document Date: May 05, 2020 

Page 1  
 
PROTOCOL 
 
STUDY TITLE: 
A Phase II Trial to Evaluate the Safety and Tolerability of Clazakizumab® (Anti-IL-
6 monoclonal) compared to placebo for the treatment of COVID-19 infection  
 
Study Drug 
Clazakizumab (Anti-IL-6 monoclonal) 
 
Support Provided By 
Vitaeris Inc. 
Vancouver, BC Canada 
Contact: Edward Chong, MD 
eddie.chong@vitaerisbio.com 
    
Sponsor Investigator 
Name:  Stanley C. Jordan, M.D. 
Institution/Organization: Cedars-Sinai Medical Center 
Address: 8900 Beverly Blvd.  
L.A., CA. 90048 
Phone: 310-423-8282 
Fax: 310-423-8208 
Email: sjordan@cshs.org 
NCT: NCT04348500 
FDA IND: 149531 
 
Co-Investigator(s) and Research Coordinators 
Ashley Vo, Pharm.D. 
Director, Transplant Immunotherapy Program 
Institution/Organization: Cedars-Sinai Medical Center 
Address: 8900 Beverly Blvd. 
L.A., CA. 90048 
Phone: 310-423-2641 
 
Nori Ammerman, PharmD 
8900 Beverly Blvd. L.A., CA.90048 
Phone: 310-248-8186  
 
 
Coordinating Institution 
Cedars-Sinai Medical Center 
8700 Beverly Blvd., L.A., CA. 90048 
 
Version 1.4 May 5, 2020 
 
 
 
 
 

 
 
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Abbreviations 
ABMR 
Antibody-mediated rejection 
AE 
Adverse Event/Adverse Experience 
ARDS 
Acute Respiratory Distress Syndrome 
BNP 
B-type Natriuretic Peptide 
CBC with diff 
Complete blood count with differential  
CLS 
Cytokine release syndrome 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRP 
C-reactive protein 
DSMB 
Data and Safety Monitoring Board 
ECMO 
Extra-corporeal membrane oxygenation 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GVHD 
Graft versus Host Disease 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board 
IV 
Intravenous  
IB 
Investigator’s Brochure 
LDH 
Lactate dehydrogenase  
PI 
Principal Investigator 
PsA 
Psoriatic arthritis 
Q4W 
Once every 4 weeks 
QA 
Quality Assurance 
QC 
Quality Control 
RA 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous  
SOC 
Standard of care  
SOP 
Standard Operating Procedure 
TB 
Tuberculosis  
US 
United States 
WOCP 
Women of Child Bearing Potential  
 
 
 

 
 
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Table of Contents 
Section 
Description 
Page 
1 
Background & Rationale 
4 
1.1  
IL-6 as a Target for Treatment of COVID-19 
4 
1.2 
Tocilizumab for Treatment of COVID-19 
5 
1.2.1 
Tocilizumab (anti-IL-6R) for Treatment of COVID-19 
(Cedars-Sinai Experience) 
7 
1.3 
Clazakizumab (anti-IL-6) as a Potential Agent to 
Treat COVID-19 
8 
2 
Study Hypothesis 
12 
3 
Primary Objectives 
12 
3.1 
Major Secondary Objectives 
12 
3.2 
Inclusion Criteria 
12 
3.3 
Exclusion Criteria 
12 
3.4 
Subject Screening and Enrollment 
13 
3.5  
Subject Recruitment 
13 
3.6 
Informed Consent Considerations 
13 
4 
Study Design & Methods 
14 
4.1 
Study Analysis  
15 
4.2 
Statistical considerations 
15 
4.3 
Study Schedule  
16 
4.4  
Monitoring for AE/SAEs  
16 
4.5 
Safety Reporting of Adverse Events 
16 
4.5.1 
Reporting of Serious Adverse Events Associated with 
Clazakizumab 
18 
4.5.2 
Pregnancy Reporting  
19 
4.5.3 
Data Safety Monitoring Board 
21 
5 
Dosing of Clazakizumab 
22 
5.1 
Storage and Handling 
22 
5.1.1 
Clazakizumab Overdosage 
22 
5.2 
Dose Modification/Toxicity Management  
22 
5.3  
Adverse Drug Reactions 
21 
5.4 
Concomitant Medications 
23 
5.5  
Latent TB Treatment 
23 
5.6 
IP Orders 
23 
6 
Therapy Stopping Points 
23 
7 
References 
24 
Appendix A 
Visit Schedule 
25 
Appendix B 
Labs 
26 
Appendix C 
FDA Guidance for Clinical Trial Sponsors 
DSMB Charter 
26 
Appendix D 
Statistical Calculations 
26 
Appendix E 
Safety Reporting Form 
27 
 
 
 

 
 
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1.0 
Background & Rationale  
 
The COVID-19 epidemic is rapidly consuming the world. As of 3/24/20, there are now 
414,050 cases worldwide with 18,543 deaths. In the United States, the epidemic is 
rapidly spreading with increased confirmed cases and deaths. Today, there are 
51,134 reported cases with ~ 700 deaths. There have been 7400 new cases in the past 
24 hours and 105 deaths. To understand the nature of the pandemic, the graphs below 
show how rapidly COVID-19 is spreading worldwide.1 
 
Figure 1 shows the total cases world wide and total deaths. In two days, 3/22/20->3/24/20, 
the numbers have increased above 414,000 cases and 18,543 deaths.(source: 
https://www.worldometers.info/coronavirus/) 
 
The COVID-19 epidemic has shut down most of the world and is decimating the world 
economies with no relief in sighte. Vaccines are being developed but are more than 
12-18 months away. There is a clear and prescient need for new drug development to 
address this deadly epidemic. Drug companies, researchers are trying to move 
promising agents into clinical trials but most studies to date are anecdotal and of 
unclear benefit. There is a desperate need for these agents to help save human 
lives and our economies. 
 
1.1 Interleukin 6 (IL-6) as a Target for Treatment of COVID-19  
 
Interleukin-6 is an important mediator of inflammation and the development, 
maturation, and activation of T-cells, B-cells and plasma cells.2 Excessive IL-6 
production has been linked to a number of human diseases characterized by excessive 
and unregulated antibody production and autoimmunity, and recently severe capillary 
leak or cytokine storm seen in CART-cell therapy.3  
Recent data has demonstrated the importance of IL-6 in mediating the severity of 
COVID-19 and SARS-CoV-2 pneumonia. Investigators examined the role of clinical 

 
 
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laboratory data in the differential diagnosis of the severe forms of COVID-19 as 
they had not  been definitely established. They aimed to examine laboratory factors 
that would distinguish severe from mild cases of COVID-19.  They examined forty-
three adult patients with COVID-19. The patients were classified into mild group(28 
patients)and severe group(15  patients). Here, significant differences in IL-6, 
D-Dimer, GLU, TT, FIB and CRP (P <0.05)were found. The optimal threshold and area 
under the ROC curve for  IL-6 were 24.3 pg/mL and 0.795 respectively. The area 
under the ROC curve (AUC) of IL-6 combined with D-Dimer was 0.840. The specificity 
of predicting the severity of COVID-19 during IL-6 and D-Dimer tandem testing was 
up to 93.3%, while the sensitivity of IL-6 and D-Dimer by parallel test in the 
severe COVID-19 was 96.4%. The authors conclude that IL-6 and D-Dimer were closely 
related to the occurrence of severe COVID-19 and their combined detection had the 
highest specificity and sensitivity for early prediction of the severity of COVID-
19 patients. The authors conclude this is of important clinical value in 
determining those likely to progress.4 See Figure 2 below: 
 
 
Figure 2 
Figure 2: This figure shows the ROC curves for various lab parameters and their predictive 
value for discriminating severe COVID 19 infections from milder cases. CRP,DD and IL-6 showed 
significant benefits (a). However, the most robust predictors were IL-6 levels >24 + D-dimer 
level elevations.4 
 
1.2 Tocilizumab (anti-IL-6R) for Treatment of COVID-19  
 
Tocilizumab (Actemra®, Roche/Genentech, CA, USA) is the first in class humanized 
monoclonal aimed at the IL-6 receptor (IL-6R). Tocilizumab binds to both soluble 
and membrane bound forms of the IL-6R receptor. Tocilizumab was recently approved 
by the FDA for treatment of rheumatoid arthritis (RA) and juvenile idiopathic 
arthritis and cytokine release syndrome (CRS).5 In patients with CRS after CAR 
T-cell therapy, elevations of IL-6 and C-reactive protein (CRP) can be seen that 
have benefit in predicting severity of disease. Tocilizumab has had an important 
and significant benefit in treating patients with CRS. The question is whether this 
benefit would translate to other diseases where extreme elevations of IL-6 are 
seen, such as COVID-19. 
 

 
 
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Recent data is available to address this. Xu et al recently reported on an open 
label trial of tocilizumab for treatment of severely ill COVID-19, SARS CoV-2 
pneumonia patients.6 In December 2019, severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2) was identified in Wuhan, China, which spread rapidly and has become 
a world-wide public epidemic. These investigators aimed to assess the efficacy of 
tocilizumab (anti-IL-6R) in patients with severe COVID-19. The patients were 
diagnosed as severe or critical COVID-19 in China. All patients were given 
tocilizumab (400mg X 1) in addition to standard of care therapy from February 5-
February 14, 2020. Assessments included change in clinical manifestations, CT scan 
image, and laboratory examinations. Analysis of therapeutic efficacy showed that 
fever returned to normal within 1-2 days and all other symptoms improved rapidly. 
Fifteen of the 20 patients (75.0%) showed decrements in FiO2 and one patient no 
longer required oxygen. Sequential CT scans demonstrated an improvement in  
pulmonary infiltrates  in 19 patients (90.5%). Lymphocytes in peripheral blood, 
were decreased in 85.0% of patients (17/20) before treatment and returned to normal 
in 52.6% patients (10/19) on day 5 post-tocilizumab treatment. Elevated CRP levels  
decreased significantly post-tocilizumab in 84.2% patients (16/19). No adverse 
reactions were observed. Nineteen patients (90.5%) were discharged on average 13.5 
days after the tocilizumab. The authors conclude that tocilizumab may represent a 
novel therapeutic strategy for this often fatal infectious disease. Data from this 
paper is shown below:  
 
 
Figure 3: this figure details the improvements in pulmonary infiltrates pre- and post-
tocilizumab infusion in 3 patients. These findings correlated with improvements in O2 
saturation and decrements in O2 requirements.  

 
 
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Figure 4: Figure 4 shows the improvements in clinical and laboratory parameters post-
tocilizumab therapy. Here rapid improvements in temperature, CRP and oxygen requirements were 
seen in most patients treated with tocilizumab.  
 
1.2.1 Tocilizumab (anti-IL-6R) for Treatment of COVID-19 (Cedars-Sinai Experience) 
 
From 3/13/2020-3/22/2020, 9 patients with COVID-19,SARS-CoV-2 pneumonia admitted to 
Cedars-Sinai Medical Center and intubated due to severe hypoxia and pneumonia were 
treated with tocilizumab 400 mg X 1. Although early, some important indicators have 
emerged from this open label trial. To date, all patients are alive with one being 
extubated and home. The other patients have all shown decreasing FiO2 requirements 
but are still intubated. Some patients have shown improvements in CXR while others 
are stable, but all have shown dramatic reductions in CRP values and temperatures 
similar to that seen in the study of Xu et al.6 Data are summarized below: 
 
  
 
 
 
Figure 5: This figure shows the O2 saturation in the patients’ blood Pre-, at and Post-
Tocilizumab 400mg X 1 dose. All patients have shown reductions in FiO2 requirements, but 8/9 
remain intubated.  
0
20
40
60
80
100
1
2
3
4
5
6
7
8
9
10
Pre-Toci
Rx-Toci
Days Post-Tocilizumab 
O2 Saturation 
(%)

 
 
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Figure 6: This figure shows pre- & post-tocilizumab CXR in a patient with COVID-19+ with 
SARS-CoV-2 pneumonia. Patient showed rapid clinic improvement clinically consistent with 
improvements in his CXR. 
 
 
Pre-Tocilizumab 
 
 
48-72hrs Post-Tocilizumab 
Figure 7: This figure shows rapid improvement in CRP levels in all patients with COVID-19, 
SARS-CoV-2 pneumonia (NL: 0-5 mg/L). This indicates effective blockade of the IL-6/IL-6R 
classic and trans signaling pathway, thus reducing inflammation. Mean IL-6 levels in this 
group were 262.7 pg/ml (NL: 0-5 pg/ml) prior to tocilizumab treatment. 
 
1.3 Clazakizumab (anti-IL-6) as a Potential Agent to Treat COVID-19 
 
Clazakizumab (Vitaeris Inc., Vancouver, BC Canada) is a humanized monoclonal 
antibody aimed at the cytokine IL-6 ligand. Clazakizumab has been evaluated 
extensively in patients with RA, but has not yet been approved by the FDA for any 
condition. Since the introduction of IL-6/IL-6R blocking drugs, reports indicate 
that inhibition of the IL-6/IL-6R pathway may have significant benefits in Systemic 
Lupus Erythematosus and other vasculitic disorders and reduces antibody producing 
cells in treated patients.  
 
Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) 
antibody that binds to human IL-6 with an affinity of 4 pM. Using multiple assays 
0
50
100
150
200
250
300
350
C-Reactive Protein mg/L 

 
 
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for signaling and cellular functions in response to IL-6 alone (to measure 
classical signaling) and a combination of IL-6 and sIL-6R (to measure trans-
signaling), it was demonstrated that clazakizumab is a potent and full antagonist 
of IL-6-induced signaling as measured by phosphorylation of signal transducer and 
activator of transcription 3 (STAT3), as well as cellular functions such as cell 
proliferation, differentiation, activation, B-cell production of immunoglobulins, 
and hepatocyte production of acute phase proteins (CRP and fibrinogen). In 
addition, clazakizumab is shown to be a competitive antagonist of IL-6-induced cell 
proliferation. This in vitro pharmacological profile supports the potential of 
clazakizumab to impact multiple immune and non-immune cellular processes that are 
central to disease pathogenesis, and thus, to offer a new therapeutic modality in 
the treatment of autoimmune diseases and other IL-6 mediated diseases.  
The clazakizumab development program includes a comprehensive nonclinical 
development program and completed clinical studies conducted in healthy subjects 
and in subjects with RA, psoriatic arthritis (PsA), Crohn’s disease, graft-versus-
host disease (GVHD), and oncology. Ongoing studies include a pivotal Phase 3 study 
in kidney transplant recipients with chronic active antibody-mediated rejection 
(CABMR)(Study VKTX01) and 3 Investigator-initiated trials (IITs) in the kidney 
transplant setting including highly- sensitized subjects awaiting a kidney 
transplant, subjects with CABMR, and subjects with late, active antibody-mediated 
rejection (ABMR). 
Nonclinical Studies 
A comprehensive nonclinical development program has been completed. Clazakizumab 
was shown to be a potent inhibitor of IL-6-induced acute phase proteins. In 
pharmacokinetic (PK)/pharmacodynamic (PD) studies, a single dose of clazakizumab 
resulted in full inhibition of IL-6 activity as measured by the inhibition of IL-6-
induced phosphorylated STAT3 (pSTAT3) activity in whole blood treated ex vivo with 
IL-6. The results of this functional PD assay correlated with drug exposures where 
full inhibition of pSTAT3 activity was observed when drug levels exceeded 50 ng/mL 
(approximately 0.3 nM). In a tissue cross-reactivity study, tissue binding of 
clazakizumab was observed in multiple tissues in both human and cynomolgus monkey, 
was generally cytoplasmic in nature, and was consistent with the known expression 
of IL-6 by cells and tissues. Results from both single- and repeat-dose nonclinical 
toxicology studies of up to 6 months in cynomolgus monkeys demonstrated an 
acceptable safety profile for clazakizumab. In a preliminary enhanced pre- and 
post-natal development (ePPND) study conducted in cynomolgus monkeys, an increase 
in the number of monkeys with retention of the placenta at parturition was observed 
at clazakizumab doses of 3 mg/kg (n=2) and 30 mg/kg (n=3), corresponding to doses 
17 and 170 times a human dose of 25 mg (based on a 70 kg adult). These doses are 
expected to generate exposures (AUCs) approximately 24 and 240 times higher, 
respectively, than a human dose of 25 mg once every 4 weeks (Q4W). There were no 
other safety findings of clinical concern. 
Clinical studies 
Clinical studies have been conducted in healthy subjects and in the following 
patient populations: RA, PsA, Crohn’s Disease, GVHD, and oncology. These clinical 
studies include a total of 1,223 subjects, of which 1,056 subjects were exposed to 
clazakizumab with doses ranging from 1 mg to 640 mg given by either intravenous 
(IV) or subcutaneous (SC) injection for up to 175 weeks.  
Clinical Pharmacology 
Following the administration of clazakizumab as a 1-hour IV infusion, the PK of 
clazakizumab were linear over the dose ranges of 30 mg to 640 mg in healthy 
subjects and 80 mg to 320 mg in subjects with RA as indicated by consistent 
clearance at these dose levels. The T-half of clazakizumab at all doses was very 
similar in healthy male subjects and in subjects with RA and was consistent with 

 
 
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that expected for a humanized IgG1 antibody. Across the doses studied, the mean T-
half of clazakizumab ranged from 19.5 to 31.0 days in healthy male subjects and 
from 26.4 to 30.9 days in subjects with RA. The T-half of clazakizumab after SC 
administration in healthy male subjects was similar to the IV administration. In a 
Phase 1 study comparing IV and SC dosing in healthy male subjects, the mean T-half 
of clazakizumab was 30.7 days after a single IV dose and, 31.1 to 33.6 days after 
SC administration. The bioavailability of clazakizumab after SC administration was 
60% of the IV formulation. As expected, Cmax was lower and Tmax was longer for the 
SC administration relative to IV administration. 
Population PK analysis of the data from clinical studies in RA, PsA and healthy 
subjects have indicated that body weight affects the PK of clazakizumab such that 
both clearance and central volume of distribution increase with increasing body 
weight. Therefore, heavier subjects will have lower drug exposure compared with 
less heavy subjects. 
Clinical Efficacy and Safety Studies 
Efficacy and safety data for clazakizumab is available from clinical studies 
conducted in RA, PsA, and oncology. Preliminary safety data are also available from 
the ongoing Study VKTX01 and IITs in the kidney transplant setting. Studies 
conducted in GVRD and Crohn’s disease were prematurely terminated due to safety 
concerns and therefore no efficacy conclusions are available for these studies. 
In Phase 2 studies in RA and PsA, doses from 5 mg SC Q4W up to 320 mg IV once every 
8 weeks were significantly effective with clinical response evident as early as 
12 weeks post treatment. One study in RA also demonstrated that the efficacy of 
clazakizumab is comparable or may be better than the standard of care treatment 
(adalimumab + methotrexate (MTX)) in RA. 
 
Efficacy with clazakizumab was not shown in the 2 Phase 2 studies in oncology (head 
and neck cancer and non-small cell lung cancer). 
 
Two studies were terminated prematurely due to safety concerns. A Phase 2 study in 
Crohn’s was terminated early because of gastrointestinal (GI) perforation in 3 
subjects who had received clazakizumab and this indication is no longer being 
studied. Although these subjects had multiple confounding medical issues, and the 
disease itself has an inherent risk of mucosal perforation, cases of perforated 
diverticulitis were also observed in 1 patient with head and neck cancer and in 2 
kidney transplant patients with antibody-mediated rejection. Gastrointestinal 
perforations were also observed during the clinical studies with tocilizumab in 
patients with RA. Gastrointestinal perforation is a recognized risk of anti-IL-6 
mAbs. After only 3 subjects were enrolled, a study in subjects with GVHD was also 
prematurely terminated due to 2 subjects experiencing similar serious adverse 
events (SAEs) (i.e., acute renal failure) which led to death. Both subjects had 
severe GVHD disease at the time of death. 
Overall, the safety findings from the clinical studies conducted with clazakizumab 
to date are consistent with the known effects of blocking the IL-6 pathway (see 
Actemra® prescribing information). Identified risks associated with clazakizumab 
administration include the following: infections, liver function test 
abnormalities, changes in hematology parameters (i.e., neutropenia and 
thrombocytopenia), dyslipidemia (i.e., hypercholesterolemia and 
hypertriglyceridemia), and GI perforations. Mild or moderate injection site 
reactions have been reported with SC administration.  Infusion reactions including 
hypersensitivity type reactions have the potential to occur with IV administration 
of antibody products, although this type of reaction has not been observed to date 
with clazakizumab.  
 

 
 
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For further details regarding clinical studies with clazakizumab, please consult 
the Investigator’s Brochure. 
 
Rationale for Dosing 
 
The dose chosen for this study (25 mg IV)is based on the results of nonclinical 
studies, and the pharmacodynamic  efficacy and safety profile seen in repeat-dose 
clinical studies conducted with clazakizumab in RA and PsA, as well as preliminary 
safety data from the ongoing pivotal study (VKTX01) and IITs in which clazakizumab 
is being investigated in the kidney transplant setting at doses of up to 25 mg SC 
Q4W. Selection of the proposed dose also takes into consideration the comparability 
of doses of clazakizumab and tocilizumab used in RA, as well as preliminary 
evidence of the efficacy of IL-6R blockade and acceptable toxicity of tocilizumab 
in the treatment of patients with severe COVID-19 infections (see Sections 1.2 and 
1.2.1, respectively).  
 
In RA, PsA, and in healthy subjects, rapid and durable suppression of CRP has been 
demonstrated at clazakizumab doses bracketing the proposed investigational dose of 
25 mg. In RA studies, the observed level of CRP suppression at clazakizumab doses 
≥5 mg SC Q4W was similar to that seen for tocilizumab 8 mg/kg IV injection Q4W 
+methotrexate. In efficacy analyses in RA, clazakizumab doses of 5 mg, 25 mg, and 
100 mg SC injection Q4W were comparable to tocilizumab doses of 4 mg/kg and 8 mg/kg 
IV Q4W. In Chinese patients( Xu et al) and in Cedars-Sinai patients with 
severe/critical COVID-19 infection, rapid suppression of CRP was observed with a 
tocilizumab dose of 400 mg IV (corresponding to 5.6 mg/kg for a 70 kg adult). Based 
on the data from the aforementioned clinical trials, a 25 mg dose of clazakizumab 
would be expected to show similar suppression of CRP in this patient population. 
 
In our current kidney transplant study for ABMR treatment, clazakizumab has been 
administered 25 mg SC monthly for the first year, followed by 25 mg SC every other 
month for years 2 and 3. Our kidney transplant desensitization study uses 
clazakizumab 25 mg SC monthly x 6 months pre-transplant, followed by 25 mg SC 
monthly for 1 year post-transplant.  
 
The completed and ongoing clinical trials provide an extensive drug exposure 
experience to define the safety profile of clazakizumab, which is primarily 
associated with its IL-6 blocking effects. The AEs observed with clazakizumab have 
been described with other mAbs that block IL-6 signaling, such as tocilizumab and 
sarilumab. Clinically significant AEs were mainly seen at higher clazakizumab doses 
(i.e., ≥100 mg), whereas doses 25 mg or less were well tolerated.  
 
For the route of administration, trials of both the SC and IV routes have been 
performed. Apart from the bioavailability being about 40% less by the SC route vs 
IV, the most notable difference between the two routes is the median time to Tmax.  
Tmax was achieved after 1 week in patients a receiving SC dose, compared to at the 
end of infusion for patients receiving an IV dose. Given that the study subjects 
enrolled here are acutely ill, any beneficial effect of the clazakizumab will need 
to be seen immediately.  
 
2.0 
Study Hypothesis 
 
Based on data of efficacy of tocilizumab in capillary leak syndrome, data obtained 
from  the tocilizumab trial in China and data from our institution,  we strongly 
believe the evidence supports the use of anti-IL-6/IL-6R therapies as possible 
treatments for prevention and treatment of COVID-19 disease and SARS-CoV-2 
pneumonia. Unfortunately, tocilizumab is in short supply and not available for 
purchase at this time. Due to our experience with clazakizumab (anti-IL-6) which 

 
 
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shows potent efficacy in inhibiting both classic and trans-signaling pathways, we 
would propose a study to investigate efficacy in COVID-19+ patients who have not 
yet progressed to SARS-CoV-2 pneumonia in an effort to interrupt the severe 
pulmonary pathology induced by COVID-19 and high mortality. Thus, we proposed a 
randomized placebo controlled trial to evaluate the utility of clazakizumab as a 
treatment that is likely to benefit COVID-19+ patients and will significantly 
reduce or eliminate their progression to SARS-CoV-2 pneumonia with attendant 
improvements in mortality and morbidity. This treatment is likely to reduce the 
numbers of patients needing respiratory therapy, reduce hospital length of stay and 
costs to the health care system. 
 
3.0 
Primary Objectives 
 
The primary objective of the study is to evaluate the safety of clazakizumab for 
the treatment of patients  with COVID-19 disease and signs of pulmonary 
involvement.  
 
3.1 Major Secondary Objectives 
 
The administration of  clazakizumab is hypothesized to reduce the risk of 
progression of COVID-19 disease to ARDS  requiring mechanical ventilation and/or 
extra-corporeal membrane oxygenation(ECMO). The secondary endpoints will be the 
need for mechanical ventilation and/or ECMO at 14 days after the first administered 
dose in comparison to placebo, patient survival at 28 and 60 days, the number of 
patients requiring the dose of open-label clazakizumab, and the ability of 
clazakizumab to reduce the duration of intensive care unit stay and hospital stay, 
in comparison to placebo. 
 
3.2 
Inclusion Criteria 
 
 Age >18 at the time of screening. 
 Subject must be able to understand and provide informed consent or have a 
surrogate decisions maker available to provide consent 
 Subject must be able to comply with the protocol and willing to fully 
participate in the requirements of the study 
 Hospitalized with COVID19+ disease (confirmed by PCR assay from any specimen 
within 72 hours of screening e.g. respiratory, blood, urine, stool, other) 
 Not on mechanical ventilation and/or ECMO 
 Evidence of pulmonary involvement with at least 2 of the following: 
- oxygen saturation at rest in ambient air with SpO2 ≤ 94% 
- tachypnea with resting respiration rate (RR) > 25 breaths/minute 
- PaO2/FiO2 ≤ 300 mmHg 
- Chest imaging (radiograph, CT scan, or lung ultrasound) with abnormalities 
consistent COVID-19 pneumonia  
- 
CRP >35 mg/L 
 
3.3 
Exclusion Criteria 
 
 Previous hypersensitivity or allergic reactions to  clazakizumab 
 Lactating or pregnant females. 
 Known, active: inflammatory bowel disease, untreated diverticulitis or GI 
perforation 
 Known, active infection  
 Subjects with latent TB and who are not receiving treatment.  
 Subjects with active TB 

 
 
Page 13  
 A significantly abnormal screening lab result defined as a WBC < 3.0 X 103/ml, 
a Hgb < 8.0 g/dL, a platelet count < 50 X 103/ml, an SGOT or SGPT > 5X upper 
limit normal 
 Participation in another clinical trial investigating COVID-19 aimed agents 
 
3.4 
Subject Screening and Enrollment  
 
The patients eligible for the study and who may benefit from the administration of 
clazakizumab will be identified by the members of the inpatient team and referred 
to the study team. A member of the study team will then review the medical record 
to assess eligibility (minimum 17 variables assessed). If the patient is eligible, 
the PI or Co-Investigator will discuss the study with the patient.  
 
3.5 
Subject Recruitment 
 
Hospital leadership is closely monitoring the COVID-19 cases and are in 
communication with investigators running COVID-19 trials. Treating physicians of 
COVID-19 patients will be made aware of the research offering. If they have 
capacity to consent for themselves, treating physicians will ask patients if they 
are willing to be approached about research options. Researchers may approach 
potential subjects who indicate they are interested.  
 
Note: patients may be in isolation units. Therefore, this contact may be made over 
the phone into the patient’s room with visualization from the treating physician 
and research from the window outside the room to minimize contact 
 
 
The population of patients being admitted with COVID-19 disease does include a 
large component of older patients with some degree of diminished cognitive 
function. If patients do not have the capacity to consent for themselves, treating 
physicians will work with researchers to identify an appropriate surrogate and 
connect researchers with surrogate decision makers to determine if a research 
option is appropriate for the patient. 
 
The research relates to life-threatening diseases and conditions of the 
participants and holds out the prospect of direct benefit. The consenting co-
investigators (MDs) will determine the patient’s capacity to provide consent. 
Subjects who lack capacity will be given the opportunity to dissent where 
appropriate. An individual who has Power of Attorney or who is otherwise authorized 
to make health care decisions for a potential research subject may not provide 
consent on behalf of the potential subject if the potential subject has the 
cognitive capacity to provide consent for themselves. The research will not enroll 
persons under psychiatric conservatorship or persons on a voluntary or involuntary 
psychiatric hold. The surrogates will not be paid for providing informed consent. 
If a subject should regain capacity during their participation, they will be 
informed of the nature of their participation and given the opportunity to consent 
to continue to participate in the research or refuse to continue to take part in 
the study. The study team will document the surrogate decision makers who are 
involved and available to provide informed consent for the subject, their 
relationship to the subject, and their respective decisions. 
 
REDCap or DocuSign may be used for remote consent of surrogate decision makers, as 
there are restrictions in place that preclude in-person visitors. The remote 
consent process may take place over the phone or via a video visit to allow the 
consent conversation and process, and signature may be obtained either through 
REDCap or DocuSign, or the surrogate may scan/email their signed copy for the 

 
 
Page 14  
investigator to either print and sign, or add an Adobe digital signature. If need 
be, the surrogate could fax their signature page instead of scanning/emailing. 
 
 
3.6 
Informed Consent Considerations 
 
Given limited supplies of personal protective equipment and isolation requirements, 
consent may be provided over the phone and, when feasible, with direct 
visualization through the patient room window or using a video platform to minimize 
entry into the room. A picture of the consent form with patient signature may be 
utilized as documentation of informed consent. The signed consent in these 
circumstances will be photographed and saved electronically. The consenting 
physician and witness (when the patient is a non-English speaker) will sign a 
second full copy of the consent and print/attach the photographed patient’s 
signature page.  
 
Given isolation precaution for this population, potential subjects who have 
capacity to consent and who have access to a smartphone, tablet, or computer with 
them in their room may be provided a link to a digital version of the consent form 
using REDCap or DocuSign to avoid the use of paper, which cannot be removed from 
the containment unit. If the potential subject does not have access to a 
smartphone/online consent form, then a paper copy will be used. While patients may 
be approached soon after their visit and/or admission begins, they can take time to 
consider and discuss participation with others before deciding. All questions will 
be answered by an investigator prior to signing the consent form. If the above 
process to obtain consent with the subject are not possible in an individual case, 
as a last resort, the study team can treat this as a case where the subject cannot 
physically sign and have a witness (e.g., clinical nurse) to the consent discussion 
sign to document that the patient agreed to participate.  This will be a last 
resort option and the study team will make every effort first to get a signature 
from the patient.  The process followed will be fully documented with a consent 
progress note.  
 
For the enrollment of non-English speaking subjects, certified medical interpreters 
will be used with the short form consent. A certified medical interpreter will be 
present (over the phone) to translate the document and interpret the consent 
discussion following IRB policy. A witness to the consent process must sign the 
consent form and short form, but the witness does not need to be fluent in both 
languages. If the interpreter is unable to sign as witness, a chart note should 
document the identity and involvement of the interpreter.  
 
4. Study Design & Methods 
 
This is a single center, randomized, double-blind, placebo-controlled, exploratory 
phase II study. We propose the administration of a blinded dose of an 
investigational product (IP) (clazakizumab or placebo[0.9% saline]) in patients 
with COVID-19 disease and signs of pulmonary involvement who have not yet required 
mechanical ventilation and/or ECMO. If a patient progresses to mechanical 
ventilation and/or ECMO or develops clinical signs of deteriorating COVID-19 
disease, and there are no treatment related serious adverse events(SAEs), within 
the initial 14 day period after the first dose of the IP, at the discretion of the 
investigator or treating physician, open-label clazakizumab 25mg IV X 1 dose may be 
administered (open label dose may be given within the first 14 days of the initial 
blinded IP dose). A minimum of 24 hours should elapse between the first dose of IP 
and this dose of open-label clazakizumab. The patient will remain blinded as to the 
identity of the IP administered in the first dose.  

 
 
Page 15  
 
The trial will primarily examine the safety and tolerability of clazakizumab  given 
to patients with COVID-19 disease. All patients will be recruited at Cedars-Sinai 
Medical Center, unless otherwise designated by sponsor. The patients eligible for 
the study and who may benefit from the administration of clazakizumab will be 
identified by the members of the inpatient team. The study protocol is below: 
 
Figure 8 shows the protocol to be followed. Briefly, Patients admitted to hospital with 
COVID-19 disease with signs of pulmonary involvement will be randomized to receive the anti-
IL-6 drug clazakizumab 25mg IV or placebo. Patients will be followed for improvements in 
clinical symptoms and laboratory parameters which are part of our COVID-19 lab panel 
described below. Patients will receive SOC supportive treatment and will be followed for 14 
days. If a patient from either group progresses to the need for mechanical ventilation and/or 
ECMO, or develops clinical signs of deteriorating COVID-19 disease, and there are no serious 
treatment related SAEs, at the discretion of the investigator or treating physician, the 
patient may receive a single dose of open-label clazakizumab 25mg IV. A minimum of 24 hours 
should elapse between the first dose of IP and this dose of open-label clazakizumab.  
 
Enrolled patients will receive clazakizumab 25 mg or placebo (0.9% saline) given by 
IV infusion over 30 minutes. Clazakizumab will be administered in 50 mL of 0.9% 
saline on Day 1.   
 
COVID19 positivity will be assessed by RT-PCR assay (A*STAR Fortitude 2.0 assay 
from Singapore) and the Abbott ID NOW rapid PCR assay for detection of COVID-19 RNA 
in nasopharyngeal samples, as per SOC. COVID-19 lab panel and clinical parameters 
will be monitored  to determine if patients are progressing towards need for 
ventilation and/or ECMO. The parameters below will be monitored and patient status 
will be assessed by the clinical team. Signs of ARDS that will be considered 
include tachypnea, RR>25 breaths/minute OR SpO2 < 90% on 4L OR increasing O2 
requirements over 24 hours, PLUS 2 or more of the following predictors for severe 
disease: 
• 
IL-6 > 10 pg/mL 
• 
CRP > 35 mg/L 
• 
Ferritin > 500-600 ng/mL 
• 
D-dimer > 1 mcg/L 
• 
Neutrophil-Lymphocyte Ratio > 4 
• 
LDH > 200 U/L 

 
 
Page 16  
• 
↑ troponin in patient w/out known cardiac Disease 
 
If patients do develop these criteria, open-label clazakizumab 25 mg IV may be 
administered as discussed above. A minimum of 24 hours should elapse between the 
first dose of IP and this dose of open-label clazakizumab. Patients ventilated with 
or without ECMO will continue to be monitored post-treatment for signs of 
improvement, (i.e., decreasing FiO2 requirements, CXR improvements, CRP reductions, 
extubation and discharge home) or death.  
 
4.1 Study Analysis  
 
This single-center, randomized, double-blind, placebo-controlled, Phase II, trial 
is designed to examine the safety, tolerability and  efficacy of clazakizumab  vs  
placebo  in subjects with  COVID-19 disease, who have not yet progressed to 
mechanical ventilation and/or ECMO.  
 
4.2 Statistical Considerations 
 
To create a reasonable trial, it is important to understand the risk for 
progression from COVID-19 disease to ventilation with or without ECMO. In our 
institution, initial estimates from our infectious disease specialist suggests ~25% 
will progress to need for ventilation.  This is also consistent with unpublished 
reports from the Chinese experience. Data from a recent report in JAMA indicated 
that up to 41.8% of patients with COVID-19 disease progressed to ARDS and 33.3% 
received mechanical ventilation.7 Based on these observations, we performed the 
following calculations to estimate the number of patients needed to see a 
statistical difference between clazakizumab vs. placebo treated patients. Using the 
Fisher exact test, a significance level of 0.10 α(p-value) and 70% power (rather 
than 80%), assuming the expected rate of 1/30 (0.033), the SAS power analysis gives 
an estimated sample size of 30 per group. Estimated sample sizes:  N =  60. N per 
group = 30. (See Appendix D for Statistical Calculations) In summary, when we 
assume a  rate of 25% for placebo treated patients to progress to ARDS with 
ventilation and/or ECMO, and a 1% rate for clazakizumab, 60 patients are needed to 
see a statistical difference. Thus we propose to use 30 patients per group to 
assess this model. Due to the exploratory nature of this study that involves safety 
endpoints only and the small sample size that is not powered for efficacy end 
points, our primary objective will be to assess safety.   
 
The statistical analysis for the primary objective of safety will utilize the chi-
square test to compare the proportion of severe adverse events (SAE's) between the 
clazakizumab and placebo groups.  The analysis will be performed on an intent-to-
treat basis of the entire study population. For analysis of the secondary objective 
comparing the proportion of patients who required mechanical ventilation in the 
clazakizumab and placebo groups, statistical comparison will be made with the 
Fisher's exact test (given a low anticipated event rate in the treatment group). 
 
4.3 Study Schedule 
Screening: 
• 
Inclusion and exclusion criteria verified 
• 
Medical history and physical exam documented by a member of the treating team 
• 
Concomitant medications documented 
• 
Quantiferon Gold test prior to administration of clazakizumab (does not have 
to be resulted prior to dose; can be within the past 30 days) 
• 
Pregnancy test for women of child bearing potential (WOCBP) 
 

 
 
Page 17  
Day 1 (may be combined with screening visit) 
• 
Informed consent signed 
• 
Physical examination documented by a member of the treating team 
• 
Baseline COVID-19 panel (See Appendix A for lab list) and Treg profile drawn 
• 
Infusion of IP (25 mg clazakizumab or placebo) 
 
Day 3:  
• 
Collection of information: CMP, COVID-19 panel labs obtained through SOC 
 
Day 7 +/- 1: 
• 
COVID-19 panel and Treg profile drawn 
 
Day 14 +/- 2 (Or at discharge, whichever occurs first) 
• 
Physical examination documented by a member of the treating team 
• 
Collect clinical data (hemodynamic parameters, respiratory parameters) 
• 
Collect information: CMP, COVID-19 panel labs obtained through SOC 
• 
Review of Chest X-ray collected per SOC 
• 
Concomitant medications documented 
• 
If the patient progresses to ventilation, use and duration of proning 
• 
Collect clinical data: Any new infections (infection site, culture source) 
 
Additional clinical data to be collected: 
• 
Date of ICU transfer (if occurs) 
• 
Date of ventilation and/or ECMO  (if occurs) 
• 
Date of hospital discharge (if occurs) 
• 
Day 28 and 60 survival status 
• 
Number of days between onset of symptoms and initiation of treatment 
• 
Investigational antiviral agents administered during hospitalization (up to 
Day 60) 
 
4.4 
Monitoring for AE/SAEs   
 
Adverse events (AEs) and serious adverse events will be monitored post IP 
treatment. These include careful attention to infectious complications potentially 
associated with the IP.  
 
Safety oversight will consist of direct communication between the inpatient team 
caring for the patient and the PI/Co-Is.  Safety concerns raised by the clinical 
care team or Co-Is of adverse events that are unexpected or unusual, assessed to be 
connected to the administration of the IP will be directed to the PI.   
 
4.5 
Safety Reporting of Adverse Events  
Assessment of Safety 
Specification of Safety Variables:  
Safety assessments will consist of monitoring and reporting all AEs and SAEs, 
including all life threatening events & events of death, and any study specific 
issue of concern. We will use the Common Terminology Criteria for Adverse Events 
(CTCAE) to grade AEs.  
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational product (IP) or other protocol-
imposed intervention, regardless of attribution. 
This includes the following: 

 
 
Page 18  
• 
AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
blinded IP infusion or open-label Clazakizumab infusion that were not present 
prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions. 
• 
If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other protocol-
mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places 
the subject at immediate risk of death. It does not include an AE that, had 
it occurred in a more severe form, might have caused death.). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the subject’s ability to conduct normal 
life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
• 
It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
Methods and Timing for Assessing AND Recording Safety variables 
The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study, are collected and reported to the FDA, IRB, 
and Vitaeris Inc. in accordance with CFR 312.32 (IND Safety Reports). Only events 
that meet the criteria of serious, unexpected, suspected adverse reactions that 
occur with clazakizumab should be reported to the FDA as an IND safety report  
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained, initiation of study treatment and ends at Day 60.  
4.5.1 Reporting of Serious Adverse Events Associated with Clazakizumab 
 
All serious adverse events (SAEs) including follow ups that are unusual and/or 
unexpected (Version 6.0 of the clazakizumab Investigator’s Brochure will be used to 
assess expectedness of reported SAEs) for which there is a reasonable suspicion the 
experience may have been caused by clazakizumab should be recorded on a MedWatch 
3500A Form and faxed or e-mailed to: 
 
SAE Reporting  
Contact Information  
Vitaeris Drug Safety: Dr Edward Chong  This must 
be reported to Vitaeris within 24 hours.  (Please 
use the safety reporting form attached in 
Appendix E and also submit to 
Drug.Safety@bionical-emas.com) 
Tel: 604 638 1582 (0ffice),  
            250 216 6371 
(cell) 
email: 
eddie.chong@vitaerisbio.com 
Study Coordination Center/Principal Investigator: 
Stanley C. Jordan, M.D. 
Tel: 310-423-2641 
Fax: 310-423-6369 

 
 
Page 19  
IRB Contact information. Online submission of 
MedWatch via Cedars-Sinai IRB portal 
Keren Dunn 
Cedars-Sinai Medical Center 
Executive Director, Research Compliance 
Tel: 310-423-4148 
 
 
 
AND: 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to the IP 
• 
Investigator’s assessment of the expectedness of the adverse event as assessed 
against the current version of IB’s Section 7.3.3. 
 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch 3500A report; submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form.  
• 
Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and 
number, if assigned, suspect drug, brief adverse event description, and notation 
that additional or follow-up information is being submitted (the patient 
identifiers are important so that the new information is added to the correct 
initial report) 
Occasionally Vitaeris may contact the reporter for additional information, 
clarification, or current status of the subject for whom the AE was reported.   
 
Study Drug Relationship: 
The investigator will determine which events are associated with the use of the 
study drugs.  The causality assessment is the determination of whether there exists 
a reasonable possibility that the Study treatment caused or contributed to an 
adverse event: 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, 
and other possible contributing factors can be ruled out. The clinical event, 
including an abnormal laboratory test result, occurs in a plausible time 
relationship to drug administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an 
abnormal laboratory test result, occurs within a reasonable time after 
administration of the drug, is unlikely to be attributed to concurrent disease 
or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill 
this definition. 

 
 
Page 20  
• 
Possibly Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of the 
trial medication). However, other factors may have contributed to the event 
(e.g., the participant’s clinical condition, other concomitant events). Although 
an AE may rate only as “possibly related” soon after discovery, it can be 
flagged as requiring more information and later be upgraded to “probably 
related” or “definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time 
after administration of the trial medication) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug administration, 
and/or evidence exists that the event is definitely related to another etiology. 
There must be an alternative, definitive etiology documented by the clinician. 
 
4.5.2. Pregnancy Reporting 
 
Any pregnancy occurring in a female subject during the study will be reported to 
the FDA and Vitaeris within 72 hours. In the event of a pregnancy, study treatment 
will be stopped. The outcome of all such pregnancies (including normal births) 
shall be followed up and documented. Every effort should be made to gather 
information regarding the pregnancy outcome until 90 days (or otherwise as 
appropriate) post-partum. It is the responsibility of the Investigator, together 
with the appropriate support from Vitaeris, to obtain this information. 
 
Pregnancy in and of itself is not an SAE. However, complications of pregnancy such 
as abortion (spontaneous or induced), premature birth, or congenital abnormality 
are considered SAEs and will be reported. 
 
4.5.3 Data Safety Monitoring Board (DSMB) 
 
Safety oversight will be under the direction of a DSMB. This DSMB committee 
for this study will be comprised of individuals with expertise across the 
broad range of disciplines (such as internal medicine, infectious diseases, 
nephrology). The DSMB Charter is attached in Appendix C. 
The DSMB will be notified of all AEs and SAEs. It will be the responsibility of 
the DSMB to evaluate cumulative participant safety data and make 
recommendations regarding the safe continuation of the study. The DSMB will 
convene a planned meeting after the first 10 patients have enrolled. Subsequent 
meetings will be at the discretion of the DSMB chair and the PI. 
The DSMB will hold emergency meetings in the event of patient deaths to discuss 
whether unblinding is warranted or if the DSMB chair deems this is warranted based 
on any reported AE or SAE. Emergency meetings will occur within 2 business days 
of the precipitating event occurring or being recognized. Any event that prompts 
an emergency DSMB-study team meeting will be reported to the IRB and to Vitaeris 
within 24 hours of the event occurring or being recognized. 
There are no pre-defined stopping rules for this study. The study team will defer 
to the judgement of the DSMB whether safety concerns warrant early stopping of 
the study. There will not be a planned interim unblinded analysis. 
 
5 
Dosing of Clazakizumab   

 
 
Page 21  
 
Clazakizumab will be administered at a dose of  25mg IV infusion over 30 minutes in 
50mL of 0.9% saline.  
 
Product Description, Storage and Administration Instructions  
 
Clazakizumab will be provided by Vitaeris Inc. 
Generic name: 
Clazakizumab 
Active ingredient: 
Genetically engineered humanized anti-IL-6 monoclonal 
antibody 
Strength:  
25 mg/mL or 12.5 mg/mL  
Excipients: 
L-histidine, L-histidine monohydrochloride, sorbitol, polysorbate-
80, and water for injection 
Appearance: 
Clear to slightly opaque, colorless to dark yellow-colored solution 
Dosage form: 
Single-dose vials (25 mg/mL or 12.5 mg/mL) for injection. 
Manufacturer: 
Ajinomoto Althea, San Diego CA 
Clazakizumab vials should be stored at ≤-20°C (-4°F). Protect from light. 
Prepared infusion  may be stored for up to 12 hours in a refrigerator, 2°-8°C (36°-
46°F), and at room temperature, 15°-25°C (59°-77°F). The prepared infusion should 
be protected from light.  
 
5.1 
Storage and Handling  
Clazakizumab will not be used after the expiry date shown on the kit or vial. 
 
5.1.1 Clazakizumab Overdose   
There are no specific antidotes or measures to take in the event of an overdose of 
clazakizumab. Subjects should be treated with the appropriate supportive care. 
 
5.2 
Dose Modification/Toxicity Management 
A number of measures will be taken to ensure the safety of patients participating 
in this study.  These measures will be addressed through exclusion criteria (see 
Section 3.3) and routine monitoring as follows:   
 
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of adverse events, 
physical examinations, blood pressure, and laboratory measurements.  Subjects will 
be evaluated for AEs (all grades), SAEs, and AEs requiring study drug interruption 
or discontinuation at each study visit for the duration of study participation.  
  
5.3 
 Adverse Drug Reactions 
Opportunistic Infections and Serious Infections  
Physicians should exercise caution when considering the use of clazakizumab in 
patients with a history of recurring infection or with underlying conditions (eg, 
diabetes) which may predispose patients to infections.  
 
Vigilance for timely detection of serious infection is recommended for patients 
receiving biologic agents for treatment of moderate to severe RA as signs and 
symptoms of acute inflammation may be lessened due to suppression of the acute 
phase reaction. Patients must be instructed to contact their physician immediately 
when any symptoms suggesting infection appear, in order to assure rapid evaluation 
and appropriate treatment.  If a patient develops a serious infection, 

 
 
Page 22  
administration of clazakizumab is to be interrupted until the infection is 
controlled. The clinician should consider the benefit-risk before resuming 
treatment with clazakizumab. 
 
Gastrointestinal Perforations   
Timely diagnosis and appropriate treatment may reduce the potential for 
complications of diverticulitis and thus reduce the risk of GI perforations. 
Therefore, patients should be made aware of the symptomatology potentially 
indicative of diverticular disease, and they should be instructed to alert their 
healthcare provider as soon as possible if these symptoms arise. In patients with a 
history of symptomatic diverticulosis, diverticulitis or chronic ulcerative lower 
GI disease such as Crohn’s disease, ulcerative colitis or other chronic lower GI 
conditions that might predispose to perforations, the clinician should consider the 
benefit-risk before using clazakizumab.  Discontinuation of clazakizumab is 
recommended for patients who develop GI perforations. 
 
Demyelinating Disorders  
The impact of treatment with clazakizumab on demyelinating disorders is not known; 
events were rarely reported.  Patients should be closely monitored for signs and 
symptoms potentially indicative of central demyelinating disorders.  Physicians 
should exercise caution in considering the use of clazakizumab in patients with 
pre-existing or recent onset demyelinating disorders. Treatment with clazakizumab 
should be interrupted during assessment of a potential demyelination.  
  
Hematologic Abnormalities and Bleeding Events 
Decreases in neutrophil and platelet counts have been observed following treatment 
with clazakizumab in combination with MTX. In addition, there may be an increased 
risk of neutropenia in patients who have previously been treated with a TNF 
antagonist.  For patients with concomitant medications associated with hematologic 
toxicity, the reduction or interruption of the suspected medication is recommended 
prior to modifying clazakizumab. For Absolute neutrophil count (ANC, cells/mm3)< 500 
or platelet count (cells/mm3) < 50,000, discontinue clazakizumab 
 
Elevated Liver Enzymes and Hepatic Events 
Elevations in ALT and AST have been observed during treatment with the study 
medications. For ALT or AST > 5n ULN, discontinue clazakizumab  
 
Cardiovascular Events and Elevated Lipids 
Patients with RA have an increased risk for cardiovascular disorders, therefore, 
risk factors for cardiovascular disease (eg, hypertension, hyperlipidemia) should 
be managed as part of their standard of care.  .   
 
Malignancies 
The impact of immunosuppression on the development of malignancies is not known, 
however an increased rate of some malignancies, notably lymphoma, has been observed 
in RA patients. Although no imbalance of malignancies was observed in clinical 
trials of clazakizumab, malignancies have been identified as a concern for other 
biologics.  It is recognized that identification of such events in clazakizumab-
treated patients may require a longer period of surveillance.  Clazakizumab should 
be discontinued in patients with malignancies (with the exception of local basal or 
squamous cell carcinoma of the skin that is completely excised with free margins). 
 
Hypersensitivity or Anaphylaxis: 
An infusion/dose reaction is defined as an adverse event occurring during and 
within 24 hours after the infusion or subcutaneous injection of clazakizumab. This 
may include hypersensitivity reactions or anaphylactic reactions. Signs of a 
possible hypersensitivity reaction include but are not limited to:  

 
 
Page 23  
• 
fever, chills, pruritus, urticaria, angioedema, and skin rash. 
• 
cardiopulmonary reactions, including chest pain, dyspnea, hypotension or 
hypertension. 
 
Healthcare professionals administering clazakizumab should be trained in the 
appropriate administrative procedures, be able to recognize the symptoms associated 
with potential anaphylactic or hypersensitivity reactions, and have the appropriate 
medication available for immediate use in case of anaphylaxis or hypersensitivity 
reaction during or after administration of clazakizumab.  If a patient has symptoms 
of anaphylaxis or serious hypersensitivity, or requires an interruption of the 
study drug because of symptoms of anaphylaxis or hypersensitivity, administration 
of clazakizumab must be discontinued permanently.  The patient should be treated 
according to the standard of care for management of the hypersensitivity reaction.   
To date, no infusion reactions have been associated with clazakizumab administered 
by IV infusion. Injection site reactions have been reported with SC administration. 
Reactions have been mild or moderate and have resolved without treatment. Both 
allergic reactions and injection site reactions should be treated with standard of 
care. Subjects who have developed significant allergic reaction to study drugs 
should not be re-challenged. 
 
Viral Reactivation 
Though rarely reported within the clazakizumab program due to exclusion criteria at 
study entry, reactivation of viral and other serious infections (e.g. EBV or TB) 
has been observed with biologic therapies. 
 
Pregnancies and Women of Child Bearing Potential 
There are no adequate well-controlled studies in pregnant or lactating women. In 
nonclinical studies, an increase in the number of monkeys with retention of the 
placenta at parturition was observed at clazakizumab doses corresponding to 11 and 
110 times the planned human dose of 50 mg. In 3 of the 5 monkeys with retained 
placentas, the resulting excessive uterine hemorrhage led to moribund status in the 
mothers. Three pregnancies have been reported to date in subjects taking 
clazakizumab. The outcomes included one spontaneous abortion (outcome unknown for 
the other 2 pregnancies). 
 
Under no circumstances shall clazakizumab injection be administered to women known 
to be pregnant or lactating.  
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy. Investigators shall advise these subjects on the use of 
highly effective methods of contraception. Subjects must agree to use adequate 
contraception during the study and for 5 months after the last dose of IP.  
5.4 
Concomitant Medications 
Participation in another study using COVID19 aimed agents will not be permitted 
during this study. Patients may receive SOC supportive care and off-label COVID19 
therapies.  
 
5.5 
Latent TB Treatment  
If an enrolled patient is found to have latent TB, the treatment for latent TB will 
not be initiated immediately. Treatment will be initiated 1-2 months after IP 
administration per the discretion of the investigator and treating team.  
 
5.6 
IP Orders 

 
 
Page 24  
Blinded MD (PI/Co-Is) and pharmacist Co-Is may submit the initial blinded IP order 
(and if needed, the open-label clazakizumab order) to the unblinded IDS pharmacist. 
When the pharmacist Co-I submits the order, this order may be placed via scope of 
practice as allowed by the Pharmacy and Therapeutics Committee.  
 
6 
Therapy Stopping Points 
As indicated previously, the study will be halted and re-evaluated by the PI along 
with the IRB if any patient in the study group develops SAEs or evidence of severe 
infusion related or infectious complications that are deemed to be associated with 
the clazakizumab. In addition the study will be re-evaluated if a patient develops 
worsening COVID-19 while on treatment, possibly indicating lack of efficacy of 
clazakizumab.  

 
 
Page 25  
7 References 
 
1. 
Gao Y, Li T, Han M, et al. Diagnostic Utility of Clinical Laboratory Data Determinations for Patients with the 
Severe COVID-19. J Med Virol 2020. 
2. 
Shirota Y, Yarboro C, Fischer R, Pham TH, Lipsky P, Illei GG. Impact of anti-interleukin-6 receptor blockade 
on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann Rheum Dis 2013;72:118-
28. 
3. 
Tanaka T, Kishimoto T. Targeting interleukin-6: all the way to treat autoimmune and inflammatory 
diseases. Int J Biol Sci 2012;8:1227-36. 
4. 
Uciechowski P, Dempke WCM. Interleukin-6: A Masterplayer in the Cytokine Network. Oncology 
2020;98:131-7. 
5. 
Le RQ, Li L, Yuan W, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen 
Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist 2018;23:943-7. 
6. 
Xiaoling Xu M, Ha TL, Wei Sun, Dongsheng Wang, Binqing Fu, Yonggang Zhou, Xiaohu, Zheng YY, Xiuyong 
Li, Xiaohua Zhang, Aijun Pan, Haiming Wei.   Effective Treatment of Severe COVID-19 Patients 
with Tocilizumab. chinaXiv:202003.00026v12020. 
7. 
Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death 
in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020. 

 
 
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Appendix A   Study/Protocol: A Phase II Trial to Evaluate the Safety and Tolerability of Clazakizumab® 
(Anti-IL-6 monoclonal) As an Agent to Treat COVID-19 Disease 
1) 
At or within one month prior to screening date   2) May be combined (Screening Day and Day 1). Any duplicate items will be collected once. Blood test: comprehensive 
metabolic panel [CMP] performed per standard of care will be assessed.  3) Or at discharge, whichever occurs first.  4) Patients who decompensate before Day 14 can 
receive open label clazakizumab (minimum 24 hours from first IP infusion). CBC and CMP will be assessed prior to clazakizumab dose.    5) during hospitalization only; up to 
study day 60   6) At or within one week of screening 
Study  visit 
Screening2 
Day 12 
Day 3  
Day 7± 1 day3 
Day 14 ± 2 days 3 
Day 28 ± 7 days 
Day 60 -7 days, +30 days (EOS) 
Medical History 
X 
 
 
 
X 
 
 
Complete Physical Exam 
X 
X 
 
 
X 
 
 
Hemodynamic and respiratory parameters  
X 
X 
X 
 
X 
 
 
Informed Consent   
 
X 
 
 
 
 
 
Inclusion/Exclusion criteria review  
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
TB testing [Quantiferon TB Gold]1 
X 
 
 
 
 
 
 
COVID-19 PANEL  
IL-6 
CRP 
Ferritin 
D-dimer 
Troponin 
Procalcitonin 
LDH 
BNP  
CBC with differential 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Lab test: Treg profile 
 
X 
 
X 
 
 
 
Review Chest X-Ray (collected by SOC) 
 
 
 
 
X 
 
 
Concomitant Med Review  
X 
 
 
 
X 
 
 
Clazakizumab or placebo infusion  
 
X 
 
 
 
 
 
Adverse Event Monitoring 
 
X 
 
 
X 
 
X 
Assess CMP, COVID-19 panel labs collected by SOC 
 
 
X 
 
X 
 
 
Assess Survival Status 
 
 
 
 
 
X 
X 
Open label clazakizumab infusion4  
 
 
X 
 
 
 
 
Assess use and duration of proning 
 
 
 
 
X 
 
 
Pregnancy test for WOCBP  (ages 18--55)6 
X 
 
 
 
 
 
 
Assess new infections 
 
 
 
 
X 
 
 
Assess investigational antivirals administered  
 
 
 
 
 
 
X5 

 
 
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Appendix B: Labs 
 
Lab 
Address  
Transplant Immunology Lab  
Cedars-Sinai Transplant Immunology Lab 
8723 Alden Drive, Steven Spielberg Building, Room 336 
Los Angeles, CA 90048 
Reference Lab  
Cedars-Sinai Medical Center Dept of Pathology and Lab Medicine  
8700 Beverly Blvd, Room 3719  
Los Angeles, CA 90048  
 
 
Appendix C: FDA Guidance for Clinical Trial Sponsors, FDA Guidance for COVID19 Pandemic, WHO COVID-19 Trial 
Synopsis 
      
FDA Guidance for 
Clinical Trial Sponso
     
 
 
 
Appendix D: Statistical Calculations 
 
 
Appendix E: Safety Reporting Forms  

 
 
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