Conditions: Coronavirus Disease 2019 COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 149
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, multi-center trial to evaluate the safety and efficacy of TJ003234 administered as an intravenous (IV) infusion in subjects with severe COVID-19 under supportive care, and to assess the effect of TJ003234 on the levels of cytokines.

Detailed description:

Arms:
arm 1: None arm 2: Part 1 only arm 3: None arm 4: Part 2 Phase 3 only

Interventions: intervention 1: TJ003234 intervention 2: Placebo
Intervention descriptions: intervention 1: patients receive a single infusion intervention 2: patients receive a single infusion

Protocol document:
Prot_000.pdf: 
Cover page: 
 
Clinical Trial Protocol: A Phase 2/3, Randomized, Double-Blind, 
Placebo-Controlled, 
Multi-Center Study to Evaluate the Safety and Efficacy of 
TJ003234 in Subjects with Severe Coronavirus Disease 2019 
(COVID-19)  
(Protocol Number TJ003234COV201) 
 
NCT: NCT04341116  
 
Document Date: 23 Sept 2021 


Clinical Trial Protocol  
 
A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled, 
Multi-Center Study to Evaluate the Safety and Efficacy of 
TJ003234 in Subjects with Severe Coronavirus Disease 2019 
(COVID-19)  
 
 
This study will be conducted according to this protocol, including protocol amendments and in 
compliance with Good Clinical Practice, the ethical principles, and other applicable regulatory 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from I-Mab Biopharma. In the event of any 
actual or suspected breach of this obligation, I-Mab Biopharma must be promptly notified. 
Protocol number:  
TJ003234COV201 
Study drug:  
TJ003234 
Indication:  
Severe Coronavirus Disease 2019 (COVID-
19) 
Sponsor:  
I-Mab Biopharma Co., Ltd.  
Address:  
Suite 802, West Tower, 88 Shangke Road 
Pudong New District 
Shanghai 20120, China 
Protocol version 
9.0 
Date 
23 September 2021 


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These restrictions on disclosure will apply equally to all future information supplied to you that 
is indicated as privileged or confidential. 
 
Sponsor Approval  
 
 
I have read this protocol and approve it:   
 
 
Claire (Cong) Xu, MD, PhD 
US Site Head 
Date 
 
 
9/23/2021 | 3:48:32 PM EDT


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Sponsor Contact Information 
Name  
Title/Role 
Contact Information 
Claire Xu, MD, PhD 
Study Director/Medical 
Monitor 
Phone: 317-755-8242 
Email: claire.xu@i-mabbiopharma.com 
Elizabeth Lindner 
Director, Clinical 
Project Management 
Phone: 856-261-4470 
Email: Elizabeth.lindner@i-
mabbiopharma.us 
Andria White 
Clinical Project 
Manager 
Phone: 631-356-0091 
Email: Andria.White@i-mabbiopharma.us  
 
If any contact information changes during the course of the study, written notification will be 
provided to the Investigator and IRB/IEC, per requirements. A protocol amendment will not be 
required in this case.  
 
 
 
 
 
 
 
 
 
 
 
 


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Investigator Agreement 
I have read the protocol and agree to conduct the study as described herein: 
 
__________________________________________ 
Principal Investigator (Printed) 
 
 
 
 
 
 
 
Principal Investigator (Signature) 
 
Date 
 
 
 
Clinical Site 
 
By my signature, I agree to personally supervise the conduct of this study at my study site and 
to ensure its conduct is in compliance with the protocol, informed consent, Institutional 
Review Board (IRB)/Ethics Committee (EC) procedures, instructions from I-Mab Biopharma 
representatives, the Declaration of Helsinki, ICH Good Clinical Practices Guidelines, and local 
regulations governing the conduct of clinical studies. 
 
 


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Table of Contents 
 
List of Tables ............................................................................................................................... 8 
List of Figures .............................................................................................................................. 8 
Protocol Synopsis ......................................................................................................................... 9 
Schedule of Procedures .............................................................................................................. 19 
Abbreviations ............................................................................................................................. 21 
1. 
Background ..................................................................................................................... 25 
1.1. 
Preclinical Studies ....................................................................................................... 28 
1.1.1 
Toxicological study .................................................................................................. 28 
1.1.1.1 Tissue-cross Reactivity in Human and Cynomolgus Monkey ................................. 29 
1.1.1.2 In vitro Hemolysis Assay ............................................................................................ 29 
1.1.1.3 Immunotoxicity and immunogenicity ........................................................................ 29 
1.1.2 
Pharmacological Studies .......................................................................................... 30 
1.1.2.1 In vitro Pharmacology .......................................................................................... 30 
1.1.2.2   In vivo Pharmacology ...................................................................................... 31 
1.1.3.1  Single-dose Pharmacokinetics ................................................................................. 35 
1.1.3.2  
Repeat-dose Pharmacokinetics............................................................................. 35 
1.2. 
Clinical Study .............................................................................................................. 36 
1.3. 
Benefits and Risks Assessment ................................................................................... 38 
2. 
Objectives and Endpoints................................................................................................ 39 
2.1. 
Objectives .................................................................................................................... 39 
2.1.1. 
Primary Objective .............................................................................................. 39 
2.1.2. 
Secondary Objectives ......................................................................................... 39 
2.2. 
Endpoints ..................................................................................................................... 39 
2.2.1. 
Primary Efficacy Endpoint ............................................................................... 39 
2.2.2. 
Secondary Efficacy Endpoints .......................................................................... 39 
2.2.3. 
Exploratory Efficacy Endpoints ....................................................................... 40 
2.2.4. 
Safety Endpoints ................................................................................................ 40 
3. 
Investigational Plan ......................................................................................................... 41 
3.1. 
Study Design ............................................................................................................... 41 
3.1.1. 
Part 1 ........................................................................................................................ 41 
3.1.2. 
Part 2 ........................................................................................................................ 42 
3.1.2.1. 
Pharmacokinetic (PK) and Anti-Drug Antibody (ADA) Subgroup ..................... 42 


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3.1.3. 
Study Populations and Sample Size ........................................................................ 42 
3.2. 
Scientific Rationale for Study Design ......................................................................... 42 
3.3. 
Justification for Dose ................................................................................................... 44 
3.4. 
Criteria for Termination of Study ................................................................................ 45 
4. 
Selection of Study Populations ....................................................................................... 45 
4.1. 
Inclusion Criteria ......................................................................................................... 45 
4.2. 
Exclusion Criteria ........................................................................................................ 46 
4.3. 
Subject Numbering ...................................................................................................... 47 
4.4. 
Withdrawal Criteria ..................................................................................................... 47 
5. 
Study drug ....................................................................................................................... 47 
5.1. 
Physical and chemical properties, specifications and ingredients of drugs ................ 48 
5.2. 
Drug Packaging, Labelling, and Storage ..................................................................... 48 
5.3. 
Drug Dispensing, Administration and Dosage ............................................................ 48 
5.3.1. 
Randomization and Blinding ............................................................................ 48 
5.3.1.1. Part 1 ................................................................................................................... 49 
5.3.1.2. Part 2 ................................................................................................................... 49 
5.3.2. 
Drug Dispensing ................................................................................................. 49 
5.3.3. 
Drug Administration .......................................................................................... 50 
5.4. 
Compliance Requirements .......................................................................................... 50 
5.4.1. 
Contraceptive requirements .............................................................................. 50 
5.5. 
Concomitant Medication and Therapies ...................................................................... 50 
5.6. 
Prohibited Medications ................................................................................................ 50 
5.7. 
Rescue Therapies ......................................................................................................... 51 
6. 
Study Procedures............................................................................................................. 51 
6.1. 
Description of Study Procedures ................................................................................. 51 
6.1.1. 
Vital signs and Pulse Oximetry ......................................................................... 51 
6.1.2. 
Physical examination ......................................................................................... 52 
6.1.3. 
ECG ..................................................................................................................... 52 
6.1.4. 
Clinical laboratory tests ..................................................................................... 52 
6.1.5. 
Radiographic Lung Imaging ............................................................................. 53 
6.1.6. 
Pregnancy test ..................................................................................................... 53 
6.1.7. 
Adverse Events (AEs) ........................................................................................ 54 
6.2. 
Screening period (Day -3 to Day -1) ........................................................................... 54 
6.3. 
Baseline period (Day 1) ............................................................................................... 55 
6.4. 
Follow-up period: Day 2 ............................................................................................. 56 


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6.5. 
Follow-up period: Day 3 ............................................................................................. 56 
6.6. 
Follow-up period: Day 5 ............................................................................................. 57 
6.7. 
Follow-up period: Day 7 ............................................................................................. 57 
6.8. 
Follow-up period: Day 11 ± 1 ..................................................................................... 58 
6.9. 
Follow-up period: Day 14 ± 2 ..................................................................................... 58 
6.10. 
Follow-up period: Day 30± 2 (End of Study Visit) ................................................. 59 
6.11. 
Discharge from Hospital .......................................................................................... 60 
7. 
Safety and Reporting ....................................................................................................... 60 
7.1. 
Adverse Events ............................................................................................................ 60 
7.1.1. 
Definition of Adverse Events ............................................................................. 60 
7.1.2. 
Collection of Adverse Events ............................................................................. 60 
7.1.3. 
Criteria for severity of adverse events ............................................................. 61 
7.1.4. 
Criteria for determining causality between adverse events and study drug 61 
7.1.5. 
Follow-up of Adverse Events ............................................................................. 62 
7.2. 
Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI) ........ 62 
7.2.1. 
Definition of SAE ............................................................................................... 62 
7.2.2. 
Adverse Event of Special Interest (AESI) ........................................................ 63 
7.2.3. 
Reporting of SAEs and AESIs ........................................................................... 63 
7.3. 
Pregnancy .................................................................................................................... 64 
7.4. 
Emergency Unblinding ................................................................................................ 64 
8. 
Data Handling and Recordkeeping ................................................................................. 64 
8.1. 
Data Record and Management .................................................................................... 65 
8.2. 
Protocol Deviations ..................................................................................................... 65 
8.3. 
Record Retention ......................................................................................................... 65 
9. 
Statistical Considerations ................................................................................................ 67 
9.1. 
Sample Size Determination ......................................................................................... 67 
9.2. 
General Considerations ............................................................................................... 67 
9.3. 
Subject Demographics/Other Baseline Characteristics ............................................... 68 
9.4. 
Safety Analysis ............................................................................................................ 68 
9.5. 
Efficacy Analysis ......................................................................................................... 68 
9.6. 
Independent Data Monitoring Committee ................................................................... 69 
10. 
Regulatory Human Subject Protection and Regulatory Oversight ................................. 70 
10.1. 
Regulatory and Ethical Considerations.................................................................... 70 
10.2. 
Informed Consent Processes and Documentation ................................................... 70 
10.3. 
Confidentiality ......................................................................................................... 71 


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10.4. 
Conflict of Interest ................................................................................................... 71 
11. 
Quality Control and Quality Assurance .......................................................................... 73 
12. 
Confidentiality and Publication of Test Results .............................................................. 73 
13. 
References ....................................................................................................................... 74 
14. 
Appendices ...................................................................................................................... 77 
14.1. 
Appendix 1: Contraceptive requirements ................................................................ 77 
14.2. 
Appendix 2: Cardiac Function Grading of NYHA .................................................. 77 
14.3. 
Appendix 3: Sequential Organ Failure Assessment Score ....................................... 78 
14.4. 
Appendix 4: Inhaled corticosteroid dose guidance .................................................. 79 
 
 List of Tables 
Table 1. Schedule of Procedures ................................................................................................ 19 
Table 2. Results of in vitro pharmacological studies ................................................................. 30 
Table 3. TJ003234RAR101: TJ003234 Serum Pharmacokinetic Parameters following Single 
Ascending Intravenous Dose of TJ003234 in Healthy Subjects (PK Population) ..... 37 
Table 4. Study drug dispensing dose and volume ...................................................................... 50 
Table 5. Laboratory Tests ........................................................................................................... 52 
 
List of Figures 
Figure 1. GM-CSF antibodies inhibited the release of cytokines caused by CAR-T cells. ..... 26 
Figure 2. Infection of SARS-CoV-2 Caused Hyperactivation of T helper cells to Drive Aberrant 
Monocyte Activation .................................................................................................. 26 
Figure 3. In vivo Efficacy of Repeat Dose TJ003234 on Type II Collagen Induced Arthritis (CIA) 
Model in Cynomolgus Monkeys ................................................................................ 32 
Figure 4. Dose response relationship of TJ003234 in monkey CIA Model ............................. 33 
Figure 5: Study Design Schema ............................................................................................... 41 
 
 
 


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Protocol Synopsis 
Protocol Title: 
A Phase 2/3 Randomized, Double-blind, Placebo-Controlled, Multi-Center Study to 
Evaluate the Safety and Efficacy of TJ003234 in Subjects with Severe Coronavirus 
Disease 2019 (COVID-19) 
Objectives: 
Primary Objective: 
To evaluate the efficacy and safety of TJ003234 in subjects with severe COVID-19 with 
supportive care. 
Secondary Objectives: 
 To evaluate the effects of TJ003234 on cytokines in subjects with severe COVID-
19. 
 To assess the pharmacokinetics (PK) and immunogenicity potential of TJ003234 
when administered as a single dose IV infusion in subjects with severe COVID-
19. 
Endpoints: 
Primary Efficacy Endpoints: 
Proportion (%) of subjects who are alive and free of mechanical ventilation at Day 30 
among subjects who are non-mechanical ventilated at baseline.  
Key Secondary Efficacy Endpoints: 
• 
Proportion (%) of subjects recovered by Day 14. Recovery is defined as the 
subject scoring a 3, 2, or 1 on the 8-category ordinal scale below by Day 14 and 
subsequently does not progress to a score ≥ 4 for the remainder of the study. If a 
subject scores 3 at baseline, this subject is considered to be recovered if this 
subject’s score improves to 1 or 2 by Day 14. 
8, death; 7, ventilation in addition to extracorporeal membrane oxygen (ECMO), 
continuous renal replacement therapy (CRRT) or pressors; 6, intubation and mechanical 
ventilation; 5, non-invasive mechanical ventilation (NIV) or high-flow oxygen; 4, 
hospitalization with oxygen by mask or nasal prongs; 3, hospitalization without oxygen 
supplementation; 2, limitation of activities, discharge from hospital; and 1, no limitation 
of activities, discharge from hospital. 
• 
Proportion (%) of subjects recovered by Day 30. Sustained recovery is defined 
as the subject scoring a 3, 2, or 1 on the 8-category ordinal scale as defined in 
the key secondary endpoint by Day 30 and subsequently does not progress to a 
score ≥ 4 for the remainder of the study. If a subject scores 3 at baseline, this 
subject is considered to be recovered if this subject’s score improves to 1 or 2 by 
Day 30. 
• 
All-cause mortality rate on Day 30.  


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Secondary Efficacy Endpoints: 
• 
Time to sustained recovery among subjects alive by Day 30 [Time Frame: Day 
1 through Day 30]: Day of sustained recovery is defined as the first day on 
which the recovered subject scores 3, 2 or 1 and maintains such score through 
Day 30 from the 8-category ordinal scale as defined in the key secondary 
endpoint. If a subject is scored at 3 at baseline, day of recovery is defined as the 
day on which this subject’s score improves to 1 or 2 and maintains such score 
through Day 30. 
• 
Length of hospitalization. 
Exploratory Efficacy Endpoints: 
• 
Improvement in clinical status (Day 7, Day 14 and Day 30) 
• 
Sequential Organ Failure Assessment score (SOFA score) (Day 7 and Day 14 
from the day of dosing) 
• 
Change from baseline in PaO2/ FiO2 (Day 7 and Day 14 from the day of dosing) 
• 
Length of time to normalization of oxygen saturation which is defined as 
SpO2≥94% sustained minimum 24 hours 
• 
Percentage of subjects requiring mechanical ventilation at Day 7 and Day 14 
• 
Change from baseline in serum cytokines, e.g. IL-1RA, IL-1β, IL-2, IL-6, IL-7, 
IL-10, GCSF, GM-CSF, CCL2, CCL3, CCL17, CXCL10, TNF-α and IFN-γ, 
etc. (Day 2, Day 3, Day 5, Day 7, and Day 14 from the day of dosing) 
• 
Change from baseline in D-dimer, cardiac troponin, LDH, and ferritin levels 
(Day 7 and Day 14 from the day of dosing) 
• 
Peripheral blood neutrophils-to-lymphocyte ratio (NLR) 
Safety Endpoints: 
 Treatment-emergent Adverse events evaluated using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events Criteria 
(CTCAE) (version 5.0),  
 Changes from baseline in clinical laboratory parameters, physical examinations, 
vital sign measurements, 12-lead electrocardiograms (ECGs), and radiographic 
lung imaging. 
Pharmacokinetic and Immunogenicity Endpoints: 
• Serum concentration of TJ003234 (Day 1 predose, Day 1 End of Infusion, Day 
7 and Day 14) 
• Incidence and titer of anti-drug antibodies (ADA) (Day 1 predose, Day 14) 
 
Study Design: 
This is a phase 2/3 randomized, double-blind, placebo-controlled, multi-center trial to 
evaluate the safety and efficacy of TJ003234 administered as an intravenous (IV) 


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infusion in subjects with severe COVID-19 under supportive care, and to assess the 
effect of TJ003234 on the levels of cytokines. The study will be conducted in two parts. 
Part 1: 
Part 1 is designed as a randomized, double-blind, placebo-controlled, 3-arm, parallel-
group study to evaluate the safety of TJ003234 in subjects with severe COVID-19. 
Potential subjects will be screened to assess their eligibility to enter the study within 3 
days prior to study drug administration. A total of 24 eligible subjects will be randomized 
at a ratio of 1:1:1 to receive either a single dose of 3 mg/kg TJ003234, a single dose of 
6 mg/kg TJ00324 or placebo, administered by IV infusion. Before and after the 
treatment, all subjects will be allowed to receive supportive care and/or additional 
treatments for COVID-19 and its complications per the Investigator. Up to twenty-four 
subjects will be enrolled in Part 1. If no more than 2 out of 8 subjects experience a Grade 
≥3 treatment-related adverse event (AE) within 7 days of the subjects receiving the study 
drug in either TJ003234 arm and no more than 4 out of 16 subjects experience a Grade 
≥3 treatment-related AE within 7 days of the subjects receiving the study drug in both 
TJ003234 arms combined, Part 2 will be initiated. The end of Part 1 is defined as 30 
days after the last subject is dosed, or until study termination.  
Part 2: 
Part 2 is designed as a randomized, double-blind, placebo-controlled, 2-arm, parallel-
group study to evaluate the safety and efficacy of TJ003234 in subjects with severe 
COVID-19. Part 2 contains two phases, the first phase, Phase 2, will enroll 120 subjects 
and the second phase, Phase 3, will enroll approximately 450 subjects. The data collected 
from Phase 2 will be used to make decision for Phase 3 and may be used to re-estimate 
sample size of Phase 3 portion. Potential subjects will be screened to assess their 
eligibility to enter the study within 3 days prior to the first dose administration. A total 
of 570 eligible subjects will be randomized at a ratio of 2:1 to receive either a single 
dose of TJ003234 or placebo, administered by intravenous infusion. Subjects in Part 2 
Phase 2 will receive either a single dose of 6 mg/kg TJ003234 or placebo. Subjects in 
Part 2 Phase 3 will receive either a single dose of 10 mg/kg TJ003234 or placebo. 
Randomization will be stratified by age and use of remdesivir. Before and after the 
treatment, all subjects will be allowed to receive supportive care and/or additional 
treatments for COVID-19 and its complications per the Investigator.  
Follow-up Period: 
After study drug administration, all subjects will enter a follow-up period and will be 
evaluated for safety and efficacy for 30 days after the last dose of study drug. Subjects 
will be followed for 30 days following the day of dosing (Day 1), or until withdrawal 
of consent, lost to follow-up, or death. 
End of study is defined as Day 30 from the day of enrollment of the last subject, or 
study termination. 
Safety Evaluations: 
All adverse events will be collected from the day of informed consent to Day 30. 
All subjects who received the study drug will be included in the safety analysis. The 
CTCAE Version 5.0 will be used as the criteria for safety evaluation.  
The safety evaluations will be performed at Screening, Day 1 predose (baseline), Day 7, 
Day 14 and Day 30.  


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Safety endpoints will include treatment-emergent adverse events, changes from baseline 
in physical examinations, clinical laboratory parameters, vital sign measurements, pulse 
oximetry, 12-Lead ECG, and radiographic lung imaging. 
Clinical laboratory parameters will include complete blood count (CBC), serum 
chemistry (including Lactate Dehydrogenase (LDH)), coagulation profile, troponin, 
arterial blood gas analysis, C-reactive Protein (CRP), and Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) diagnostic test by polymerase chain reaction 
(PCR) or other commercial or public health assay. 
Radiographic lung imaging will include lung computed tomography (CT) or lung X-ray. 
Efficacy Evaluations: 
The efficacy evaluations in this study will be performed based on clinical status (8-
category ordinal scale), sequential organ failure assessment (SOFA) score, and PaO2/ 
FiO2. They will be evaluated from Day 1 predose (baseline) to Day 30. In addition, the 
subjects will be assessed for all-cause mortality and need for mechanical ventilation. 
Changes from baseline in serum cytokines including IL-1RA, IL-1β, IL-2, IL-6, IL-7, 
IL-10, GCSF, GM-CSF, CCL2, CCL3, CCL17, CXCL10, TNF-α and IFN-γ, etc. will 
be measured on Day 1 pre-dose, and Days 2, 3, 5, 7, and 14 post-dose. 
Sample Size: 
This is a 2-part study. Part 1 will enroll about 24 subjects to establish the safety profile 
of single dose of 3 mg/kg and 6 mg/kg of TJ003234 in subjects with severe COVID-19 
before moving to Part 2. Part 2 plans to enroll 570 subjects. Eligible subjects will be 
randomized to TJ003234 or placebo with a ratio of 2:1. Assuming mechanical ventilation 
free rates by Day 30 are 77% in the control arm and 88% in the treatment arm, with 10% 
drop-out rate, a total of 120 subjects are required based on a 2-sided alpha level of 0.2 
and 80% power in the Phase 2 portion, and a total of 450 subjects are required based on 
a 2-sided alpha level of 5% and 80% power in the Phase 3 portion. 
Scientific Rationale for Study Design: 
GM-CSF, as a key upstream trigger factor in the inflammatory cytokine cascade, can 
enhance the effects of neutrophils and macrophages, produce inflammatory cytokines 
and activate the phagocytosis. In addition, GM-CSF is also an important cytokine that 
induces the polarization of monocytes to the inflammatory M1 phenotype and promotes 
the activation of macrophages, and the macrophages secrete a large number of 
inflammatory cytokines such as IL-6 and TNF-α, to involve in tissue inflammation 
(Hamilton, 1980). The strong proinflammatory effects of GM-CSF make it a promising 
target in acute inflammatory conditions where elevated GM-CSF has been implicated in 
orchestrating a cytokine storm. At least three such syndromes share immunological and 
pathologic features of a cytokine storm: chimeric antigen receptor (CAR)-T cell therapy 
related cytokine release syndrome (CRS), macrophage activation syndrome (MAS) and 
most recently, acute respiratory distress syndrome (ARDS) in severe coronavirus disease 
(COVID-19) cases caused by SARS-CoV-2 (severe acute respiratory syndrome 
coronavirus 2).  
In the recent COVID-19 epidemic caused by the coronavirus SARS-CoV-2 in China, 
approximately 15-30% of severe COVID-19 patients developed ARDS (Wang, 2020; 
Huang, 2020; Chen, 2020; Guan, 2020). Without intervention, the clinical course is 
expected to be dire for severe COVID-19 patients. Therefore, there is a huge unmet 


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medical need of therapy for severe COVID-19 patients. At present, there is no specific 
immune modulating therapy for severe COVID-19 patient. 
The clinical features (Huang, 2020) and immunopathology (Xu, 2020) of patients with 
COVID-19 in China have now been reported, and they remarkably resembled those 
found in SARS (Channappanavar, 2017). Common features among COVID-19 patients, 
particularly those seriously or critically ill, included lymphopenia and significantly 
elevated levels of inflammatory cytokines including IL-1, IL-7, IL-8, IL-9, IL-10, basic 
FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1A, MIP-1B, PDGF, TNF-α, and 
VEGF. (Huang, 2020). Massive production of IL-6, CRP, D-dimer and ferritin were also 
observed, which are all indicative of cytokine storm (Wang, 2020). Importantly, lung 
pathology revealed heavy interstitial lymphocytic infiltrates along with diffuse alveolar 
damage with fibromyxoid exudates, multinucleated giant cells and hyaline membrane 
formation, indicative of ARDS (Xu, 2020). Interestingly, these pathological features and 
lung CT imaging characteristics are also remarkably similar to those reported for a subset 
of Systemic Juvenile Idiopathic Arthritis (JIA) patients that developed MAS that led to 
severe immunopathology and lung disease (Schulert, 2019).  
It seems evident from the recent reports that severe COVID-19 bears all the hallmarks 
of a cytokine storm instigated by exuberant immune cells producing GM-CSF and IL-6. 
They drive aberrant monocyte and T cell activation which in turn produce more 
cytokines and chemokines in a feed forward cycle that culminates in profound tissue 
injury, airway constriction, vascular collapse and organ failure (Zhou, 2020). Peripheral 
blood mononuclear cell (PBMC) immunophenotyping showed an abundance of highly 
active GM-CSF-producing T helper cells and pathogenic monocytes in COVID-19 
patients (Xu, 2020; Zhou, 2020). A recent study published in Blood showed that GM-
CSF antibodies have been demonstrated to effectively inhibit the cytokine storm caused 
by CAR-T cell therapy and reduce the levels of a series of inflammatory factors such as 
IFN-g, IL-6, MCP-1, MIP-1 in preclinical experiments. In addition, it can control the 
infiltration of immune cells such as T cells and macrophages into the central nervous 
system, and effectively inhibit the generation of neurotoxicity (Sterner et al., 2019). 
Compared to tocilizumab that has been widely used to treat cytokine storm caused by 
CAR-T cells, GM-CSF antibodies may have better efficacy, especially in regulating the 
broad spectrum of cytokines and inhibiting neurotoxicity. Therefore, two clinical trials 
will be conducted to evaluate the therapeutic effects of GM-CSF antibodies or GM-CSF 
receptor antibodies on CAR-T cell-induced side effects such as cytokine storm and 
neurotoxicity (Gilead, 2020). Currently, based on the experience of IL-6R antibody 
tocilizumab in managing CAR-T induced CRS, tocilizumab is being tested for reducing 
cytokine storm and its complications in a clinical trial of COVID-19 patients in China 
(Chinese Clinical Trial Registry, n.d.). GM-CSF neutralizing antibody such as TJ003234 
may also have the potential to prevent or curb cytokine storm and immunopathology and 
thus earn more time for viral clearance, which may improve the overall clinical outcome 
of COVID-19 severe patients.  
 
Justification for Dose: 
In this study, the dose of TJ003234 has been predicted based on the results of safety, 
pharmacokinetics and pharmacodynamics from a single ascending dose study in healthy 
subjects, preclinical data, the safety data of similar GM-CSF antibodies in patients with 
rheumatoid arthritis, as well as the data of IL-6R antibody tocilizumab for treatment of 
cytokine storms. For TJ003234, a single dose escalation study in 32 healthy subjects has 


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been completed. No dose limiting toxicity (DLT) was observed in the 0.3 mg/kg, 1 
mg/kg, 3 mg/kg and 10 mg/kg dose groups. The maximum tolerated dose (MTD) was 
not reached. The half-life of TJ003234 was approximately 3 weeks and plasma 
concentrations increased proportionally with the dose over the range 0.3 mg/kg to 10 
mg/kg. Pharmacodynamics showed similar levels of inhibition of ex-vivo GM-CSF-
activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) at 
doses of TJ003234 3 mg/kg and 10 mg/kg. Inhibition of more than 90% was reached at 
4 hours after dosing and was maintained for 2 weeks (full clinical study report submitted 
to FDA in January 2020).  
The dosing regimen of TJ003234 in the Part 2 Phase 3 trial is amended as 10 mg/kg 
TJ003234 or placebo based on the observed efficacy, safety, and PK data in the 
completed Part 2 Phase 2 study. In Part 2 Phase 2 study with patients with Covid-19, 
improved efficacy over the placebo arm was observed with an acceptable toxicity profile 
of TJ003234. At the same time, increased clearance of TJ003234 (0.02 L/hr in patients 
with Covid-19 compared to 0.009 L/hr in healthy subjects) was observed at a single dose 
of 6 mg/kg TJ003234, with a shorter half-life (6 days) than in healthy subjects (3 weeks). 
Therefore, a single dose of 10 mg/kg is expected to further improve the magnitude of 
efficacy improvement by providing higher exposure than that of 6 mg/kg dose in Covid-
19 patients. Based on the observed PK data, the exposure of a single dose of 10 mg/kg 
TJ003234 in patients with Covid-19 is expected to be lower than that in healthy subjects. 
Therefore, an acceptable safety profile is expected to be maintained, as the 10 mg/kg has 
been tested in healthy subjects with excellent safety profile. According to the preclinical 
toxicology study (once weekly (Q1W) for 4 weeks), the No-Observed-Adverse-Effect 
Level (NOAEL) dose in Cynomolgus monkeys was 60 mg/kg. Since molecular weight 
of TJ003234 is >100,000 Da (146KDa) and administered intravenously, according to 
FDA guidance stating that proteins administered intravascularly with molecular 
weight >100 KDa should be normalized to mg/kg as an exception to mg/m2 scaling 
approach (CDER, 2005), the calculated Human equivalent dose (HED) based on 
NOAEL is also 60 mg/kg.  
GM-CSF antibodies have been reported to be well tolerated in clinical trials. Namilumab 
and KB003 are drugs with the same mechanism of action as the study drug and both 
were well tolerated at doses of 5-6 mg/kg (Huizinga et al., 2017). The Phase IIb clinical 
trial of mavrilimumab, which is an antibody of GM-CSF receptor and has a similar 
mechanism of action as the study drug, showed no adverse reactions in the lung 
(Burmester et al., 2017). The autoantibodies of GM-CSF are associated with the 
development of idiopathic autoimmune pulmonary alveolar proteinosis (PAP). There is 
a theoretical risk of developing PAP when therapeutic antibodies targeting GM-CSF are 
used. Non-clinical studies of mavrilimumab, a compound targeting GM-CSF receptor, 
showed that macrophage change in lung tissues was only observed in studies with dosing 
lasting more than 11 weeks (Ryan et al., 2014). Therefore, it is believed that PAP is a 
long-term chronic development process and, the risk of PAP developed from drug 
exposure after a single dose is most likely to be low. In addition, we closely monitored 
pulmonary function up to 90 days and no clinically meaningful changes of pulmonary 
function were observed in the single dose escalation study (full clinical study report 
submitted to FDA in January 2020). Taken together with the safety data in human and 
preclinical studies, we believe that a single dose of 3 mg/kg and 6 mg/kg TJ003234 will 
be safe in the patient population. 
Preclinical pharmacodynamics showed a treatment effect of <50% (as measured by an 
inhibitory effect on the GM-CSF/GM-CSFR signaling pathway) at a single intravenous 


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infusion dose of 3 mg/kg in the CIA (type II collagen-induced arthritis) model in 
cynomolgus monkeys. The results from the in vitro monocyte activation assay to mimic 
the COVID-19 viral stimulation of primary monocytes confirmed that treatment of 10 
μg/ml TJ003234 suppressed the pro-inflammatory cytokine production and activation 
marker expression, indicating that the dose of 3 mg/kg may be efficacious since the 
trough concentration of a single dose of 3 mg/kg exceeds 10 µg/ml in the Phase I clinical 
trial. On theoretical grounds, the GM-CSF levels will further increase in COVID-19 
patients with cytokine storms compared to healthy individuals and patients with 
autoimmune diseases. This hypothesis has been confirmed by the clinical data of 
tocilizumab. The mean peak concentration of tocilizumab in patients with cytokine 
storms caused by CAR-T was 41% lower than that in patients with systemic JIA, 
suggesting that tocilizumab was eliminated more rapidly in patients with cytokine 
storms (Le et al., 2018). Therefore, in order to better assess the dose response of 
TJ003234 in COVID-19 severe patients, and determine an optimal dose for further 
development, we plan to include an additional dose level of 6 mg/kg TJ003234. Based 
on the PK from healthy adults, TJ003234 PK appears to be linear and we expect that a 
single dose of 6mg/kg may produce two-fold of drug exposure following a single dose 
of 3 mg/kg TJ003234, which will remain within the range of drug exposure tested to be 
safe in the first-in-human (FIH).   
Overall, the totality of the data from the non-clinical data and clinical data from the 
single ascending dose escalation study supports 3 mg/kg and 6 mg/kg as a safe dose 
with potential efficacy to be administered in COVID-19 patients. Furthermore, the 
observed efficacy, safety, and PK data in the completed Part 2 Phase 2 study support a 
single dose of 10 mg/kg TJ003234 in the subsequent Part 2 Phase 3 trial as a safe dose 
with further improved efficacy.  
Inclusion and exclusion criteria: 
Inclusion criteria (To be included in the study, subjects must meet all of the 
following criteria): 
1. Age: 18 years or older (including 18 years); male or female 
2. Laboratory-confirmed SARS-CoV-2 or COVID-19 infection as determined by 
polymerase chain reaction (PCR) or other commercial or public health assay.  
3. Bilateral lung infection confirmed by imaging. 
4. Severe disease that meets one of the following conditions: 
i. 
At rest, finger blood oxygen saturation ≤ 93% or PaO2/FiO2 ≤ 300 
mmHg; OR 
ii. 
Requiring high flow oxygen ≥15L/min  
 
5. Subjects or legally authorized representatives (LARs) who are willing to 
participate in this study and sign the informed consent voluntarily. 
6. Be willing to follow the contraception guidelines in Appendix 1 
7. Subject has been hospitalized for no more than 5 calendar days at the time of 
screening. 


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Exclusion Criteria (Subjects who meet any of the following criteria will be excluded 
from the study): 
1. Any previous and/or current clinically significant disease or condition that has not 
been stable within 3 months prior to enrollment, or acute illness, planned medical/ 
surgical procedure, or any trauma that occurred within 2 weeks prior to enrollment, 
which, in the opinion of the investigator, may place the subject at risk if participating 
in the study, or may interfere with the assessment of the study drug or confound 
interpretation of the study results, or affect the patient's ability to participate in the 
study independently. 
2. Applies to Part 1 Only: Chronic obstructive pulmonary disease (COPD) and 
moderate/severe asthmatic patients requiring inhaled corticosteroid, long-acting 
beta-adrenergic agonists, long-acting anticholinergics, or long-term oxygen therapy. 
Mild asthmatic patients treated with short-acting beta-adrenergic agonists and/or low 
dose of inhaled corticosteroid and/or long-acting beta-adrenergic agonists are 
considered eligible. Please refer to Appendix 4 for inhaled cortiscoteroids dose 
guidance. 
3. Pulmonary interstitial disease, pulmonary alveolar proteinosis, and pulmonary 
granulomatosis. 
4. Cardiovascular event in the 3 months prior to study drug administration: acute 
myocardial infarction or unstable angina pectoris, severe arrhythmia (multiple 
sources of frequent ventricular premature beat, ventricular tachycardia and 
ventricular fibrillation); New York Heart Association Classification (NYHA): Class 
III-Class IV. 
5. Severe renal impairment: e.g. eGFR ≤30 ml/min estimated by MDRD equation or 
have received treatments such as kidney transplantation and dialysis. 
6. Subjects that cannot adhere to protocol requirements due to neuropsychiatric 
disorders. 
7. Severe liver disease: e.g. Child-Pugh Score for Cirrhosis as Grade C, elevated 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 × upper 
limit of normal. 
8. Known active or chronic hepatitis B or C infection or human immunodeficiency 
virus (HIV). 
9. Known active tuberculosis (TB), history of incompletely treated TB, suspected or 
known extrapulmonary TB, suspected or known systemic bacterial or fungal 
infections. 
10. Blood system disorders or routine blood analysis test abnormalities: 
 Hemoglobin < 8 g/dL; 
 Absolute neutrophil count (ANC) <1500 × 109/L; 
 Platelets < 50 × 109/L. 
11. Dependence on glucocorticoid treatment equivalent to methylprednisolone 2 mg/kg/ 
day or more or long-term use of anti-rejection or immunomodulatory drugs. 


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12. Subjects that require invasive mechanical ventilation or ECMO. 
13. Pregnant or breastfeeding females. 
14. Have received any live vaccination within 30 days before dosing. 
15. Subjects who, in the opinion of the investigator, are not suitable for participation in 
this clinical study or will not agree to follow the institution’s supportive care 
protocol. Any condition that, in the opinion of the investigator, may increase the risk 
associated with the subject's participation in the study or may interfere with the 
assessment of the study drug or confound the interpretation of the study results. 
 
Criteria for study termination 
During the conduct of the study, if the investigator or the sponsor finds that continuation 
of the trial may cause potential harm to subjects, the decision may be made to terminate 
the trial after consultation between the investigator, medical monitor and the sponsor. 
Statistical Considerations: 
Analysis Populations: 
Intent-to-treat (ITT) Population: All randomized subjects. This population will be used 
for the primary analysis for Part 1 and Part 2 phase 2 portion, and sensitivity analysis of 
primary analysis for Part 2 phase 3 portion. 
Modified Intent-to-treat (mITT) Population: All randomized subjects who are non-
mechanical ventilated at baseline. This population will be used for the primary analysis 
for Part 2 phase 3 portion. 
Safety Population: Includes all subjects who receive the study drug. This safety 
population will be used for the analysis of demographic data, baseline characteristics, 
and safety. 
Efficacy-evaluable Population: All subjects in the safety population with at least one 
post-dose efficacy evaluation.  
General Methods: 
All data will be summarized by treatment group using descriptive statistics based on the 
data types. Unless otherwise specified, descriptive statistics for continuous variables will 
include number of subjects, mean, standard deviation (SD), median, and range. For 
categorical variables, descriptive statistics including counts and percentages will be 
reported. Data from Part 1 and Part 2 will be analyzed separately.  
Safety Analysis: 
Safety and tolerability evaluations will be performed for all subjects in the safety 
population. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Summary statistics and listings of all the safety data will be provided by 
treatment group and time points as specified in the schedule of procedures.  
Efficacy Analysis: 
For each part, efficacy endpoints will be summarized by treatment group with 


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descriptive statistics based on the ITT / mITT / efficacy-evaluable population. Treatment 
difference along with the 95% CI will be reported. Subgroup analysis by  age at 
randomization (<60 years, ≥60 years) and use of remdesivir (yes/no) might be performed 
where data permits. 
For the efficacy endpoints in Part 2, the primary endpoint will be analyzed using the 
exact method. Difference between two arms will be tested by a stratified Cochran–
Mantel–Haenszel test (CMH) test using the stratification factors at randomization. 
Recovery rates by Day 14, recovery rates by Day 30 , and all-cause mortality rate, will 
be analyzed similarly. Time to recovery among subjects alive by Day 30 will be analyzed 
by a stratified log-rank test for p-value, and the HR ratio between two arms will be 
estimated by a stratified Cox proportional hazard model using the stratification factors 
at randomization. 
For the Phase 3 portion,  multiplicity will be adjusted by a gatekeeping procedure. If 
the null hypothesis for the primary endpoint is rejected, then the key secondary endpoints 
will be tested in the order of: recovery rate by Day 14, recovery rate by Day 30, and all-
cause mortality rate by Day 30.  
 
The trial will be considered as successful if the primary endpoint in Phase 3 portion 
shows a statistically significant improvement in the treatment arm and, as a safety 
measurement, the all-cause mortality rate in the treatment arm is numerically not higher 
than that in the control arm. 
Independent Data Monitoring Committee (IDMC):  
The IDMC is responsible for monitoring safety. The IDMC will be made up entirely of 
members external to I-Mab. The IDMC charter will contain membership information 
and a further delineation of responsibilities. 
The IDMC may recommend continuing enrollment in one dose arm or to terminate the 
study for accumulated safety evaluations. The IDMC will provide a recommendation 
that is made without known bias. I-Mab staff involved in the conduct of the study will 
be kept blinded before a portion of the study is completed, and the members of the IDMC 
will not have involvement with the conduct of the study. 


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Schedule of Procedures  
Table 1. Schedule of Procedures   
Procedure 
Screening 
period* 
Baseline 
period* 
Follow-up period 
-D3-D1 
D1 
D2 D3 D5 
D7** 
D11** 
±1 
D14** 
±2 
D30**
±2 
Informed Consent 
√ 
 
 
 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
 
 
Body weight 
√ 
 
 
 
 
 
 
 
 
Medical history, smoking 
history and medication history, 
and baseline respiratory support 
requirements 
√ 
√ 
 
 
 
 
 
 
 
Pregnancy test or FSH test [1] 
√ 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test [2] 
√ 
 
 
 
 
(√) 
 
(√) 
(√) 
Radiographic lung imaging [3] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
Arterial blood gas analysis [4, 16] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
PaO2/FiO2[16] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
Physical Examination 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Pulse Oximetry [5] 
√ 
Clinical status [6] 
 
√ 
 
 
 
√ 
 
√ 
√ 
Vital signs 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
12-lead ECG [7] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
Routine complete blood count, 
blood biochemistry test, 
coagulation assessment [8] 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Urinalysis [9] 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Troponin  
 
√ 
 
 
 
√ 
 
√ 
 
C-reactive protein, LDH, serum 
ferritin 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Cytokine levels [10] 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
SOFA (Sequential Organ Failure 
Assessment score) [11, 16] 
 
√ 
 
 
 
√ 
 
√ 
√ 
Review subject eligibility 
√ 
√ 
 
 
 
 
 
 
 
Randomization 
 
√ 
 
 
 
 
 
 
 
Dosing [12]  
 
√ 
 
 
 
 
 
 
 
Pharmacokinetic Sampling [13] 
 
√ 
 
 
 
√ 
 
√ 
√ 
Anti-drug Antibody Sampling 
[14] 
 
√ 
 
 
 
 
 
√ 
√ 
Concomitant 
medication/treatment [15]  
√ 
Adverse events  
√ 
 
[1] Pregnancy test is required for women of childbearing potential and follicle stimulating hormone (FSH) is required if 
confirmation of postmenopausal status is needed. 
[2] SARS-CoV-2 diagnostic test by polymerase chain reaction (PCR) or other commercial or public health assay: If a 


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subject has a positive test within the 14 days prior to study drug administration, an additional test at screening does 
not need to be performed. Tests during follow-up are requested, but if missed or done out of window, this will not be 
considered a protocol deviation.  
[3] Radiographic lung imaging examination: Including lung CT or chest X-ray. If this procedure was performed as 
standard of care in the 14 days prior to study drug administration and radiographic infiltrates are present, this may be 
used, and imaging is not required at Screening or Day 1.   
[4] Arterial blood gas analysis, finger blood oxygen saturation: arterial blood gas analysis: PH, partial pressure of oxygen, 
partial pressure of carbon dioxide, total carbon dioxide, oxygen saturation, actual bicarbonate, standard bicarbonate, 
base excess, anion gap. If the interval between arterial blood gas analysis performed during screening and dosing is 
less than 24 hours, a repeated test is not required on Day 1 predose. If Day 7 and/or 14 visits are conducted as 
outpatient visits, it is not necessary to perform an this procedure. 
[5] Pulse oximetry should be recorded on a daily basis while the subject is hospitalized. The lowest registered level from 
each day should be recorded. 
[6] Clinical status evaluation: 8-category ordinal scale score: 8, Death; 7, ventilation in addition to ECMO, CRRT or 
pressors; 6, Intubation and mechanical ventilation; 5, NIV or high-flow oxygen; 4, Hospitalization with oxygen by 
mask or nasal prongs; 3, Hospitalization without oxygen supplementation; 2, Limitation of activities, discharge from 
the hospital; and 1, No limitation of activities, discharge from hospital.   
[7] ECG: Including but not limited to heart rate, QT, QTc, QTcF and P-R interval.  
[8] Routine CBC: White blood cells, red blood cells, hemoglobin, hematocrit, mean cell volume, platelets, absolute 
neutrophil count and percentage, absolute lymphocyte count and percentage, absolute monocyte count and percentage, 
absolute eosinophil count and percentage, absolute basophil count and percentage. Blood biochemistry test: blood 
glucose; liver and kidney functions: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein , 
albumin, total bilirubin, direct bilirubin, alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), creatinine, blood 
urea nitrogen (BUN), uric acid; serum electrolytes: potassium, sodium, chlorine, calcium, magnesium, inorganic 
phosphorus. Coagulation function: prothrombin time (PT), activated partial thromboplastin time (aPTT), international 
normalized ratio (INR), D-dimer. For screening, labs drawn before informed consent may be used if they are collected 
within 72 hours of study drug administration. Please see Section 6.2 for details. 
[9] Dipstick is acceptable. Microscopic analyses if dipstick abnormal. 
[10] Cytokines such as IL-1RA, IL-1β, IL-2, IL-6, IL-7, IL-10, GCSF, GM-CSF, CCL2, CCL3, CCL17, CXCL10, TNF-
α and IFN-γ in serum.  
[11] SOFA (Sequential Organ Failure Assessment score): see Appendix 3.  
[12] Dosing: intravenous infusion. On Day 1, all corresponding assessments will be completed before dosing.   
[13] Only applies to subjects in Part 2 randomized to the PK/ADA subgroup. Pharmacokinetic Samples will be collected 
on Day 1 predose, Day 1 end of infusion (±15 minutes), Day 7, Day 14, and Day 30. The Day 30 sample only must 
be collected if the subject is still hospitalized or is able to come in for an outpatient blood draw. 
[14] Only applies to subjects in Part 2 randomized to the PK/ADA subgroup. The Day 30 sample only must be collected 
if the subject is still hospitalized or is able to come in for an outpatient blood draw. 
[15] Recording concomitant medication/treatment: The concomitant medication mainly includes antiviral drugs, 
antibiotics, Glucocorticoid, and circulatory support drugs. Concomitant treatment mainly includes oxygen therapy, 
non-invasive/invasive mechanical ventilation, ECMO, and continuous renal replacement therapy (CRRT). Any 
SARS-CoV-2 vaccine history will be collected. For subjects who report they have received the SARS-CoV-2 vaccine, 
the following will be collected: Number of doses, date of dose(s) and brand name. 
[16] If subject is discharged from the hospital during the study, complete an unscheduled SOFA score, ABG and 
PaO2/FiO2 ratio based on the last arterial blood gas analysis performed while the subject was hospitalized. 
*If dosing occurs within 24 hours of screening, any Predose procedures done during screening do not need 
to be repeated. SOFA, troponin, clinical status assessment must be collected prior to dosing. Please see 
Section 6 for details. 
**If subject is discharged prior to these visits, they may occur as outpatient or telephone visits. Please see 
Section 6 for details. 
 
 


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Abbreviations 
ANC 
Absolute neutrophil count 
AE 
Adverse Event 
ARDS 
Acute Respiratory Distress Syndrome 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AB 
Actual bicarbonate 
AESI 
Adverse Event of Special Interest, AESI 
AG 
Anion gap 
AUC 
Area Under the Curve 
APTT 
Activated partial thromboplastin time 
ADA 
Anti-Drug Antibody 
AST 
Aspartate aminotransferase 
ALT 
alanine aminotransferase 
ALP 
Alkaline phosphatase 
CIA 
Collagen-Induced Arthritis 
CRP 
C-Reactive Protein 
CL 
Clearance 
CSF2 
Colony-Stimulating Factor 2 
CAR-T 
Chimeric antigen receptor 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cmax 
Maximum concentration 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CDC 
complement dependent cytotoxicity 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
COVID-19 
Coronavirus Disease 2019 
CRS 
Cytokine Release Syndrome 
CRRT 
Continuous renal replacement therapy 


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CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CRO 
Clinical Research Organization 
COPD 
Chronic obstructive pulmonary disease 
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EOI 
End of Infusion 
EC 
Ethic Committee 
ECMO 
Extracorporeal membrane oxygenation 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle Stimulating Hormone 
GGT 
Gamma-glutamyltransferase 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
HIV 
Human Immunodeficiency Virus 
HED 
Human Equivalent Dose 
ICH 
International Committee on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IRR 
Infusion Related Reaction  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous  
INR 
International normalized ratio 
JIA 
Juvenile Idiopathic Arthritis 
LAR 
Legally Authorized Representative  
LDH 
Lactate Dehydrogenase  
MAS 
Macrophage Activation Syndrome 


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MedDRA 
Medical Dictionary for Regulatory Activities  
MTD 
Maximum Tolerated Dose 
MAD 
Maximum Administered Dose 
NIV 
Non-Invasive Mechanical Ventilation 
NCI 
National Cancer Institute 
NLR 
Neutrophil to lymphocyte ratio 
NYHA 
New York Heart Association 
NOAEL 
No Observed Adverse Effect Level 
PBMC 
Peripheral Blood Mononuclear Cell 
PAP 
Pulmonary Alveolar Proteinosis 
PD 
Pharmacodynamics 
PIP 
Proximal Interphalangeal Joint 
pSTAT5 
Phosphorylated Signal transducer and activator of 
transcription 5  
PK 
Pharmacokinetics 
PaO2 
Partial Pressure of Oxygen 
PT 
Prothombin time 
PCR 
Polymerase chain reaction 
Q1W 
Once weekly 
RTSM 
Randomization and trial supply management  
RBC 
Red Blood Cell 
SOFA 
Sequential Organ Failure Assessment 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SARS-COV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SRC 
Safety Review Committee 
SaO2 
Oxygen Saturation  
SC 
Subcutaneous  
SAP 
Statistical Analysis Plan 
Tmax 
Time reach the peak concentration 
T1/2 
Elimination half-life 


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TCR 
Tissue-cross Reactivity 
TK 
Toxicokinetic 
TCO2 
Total Carbon Dioxide 
TEAE 
Treatment Emergent Adverse Event 
TB 
Tuberculosis  
Vss 
Volume of Distribution at Steady State 
Vz 
Volume of distribution 


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1. 
Background  
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), also known as Colony-
Stimulating Factor 2 (CSF2), is a member of the colony-stimulating factor family of 
hematopoietic growth factors. It was first known as an in vitro inducer for bone marrow 
progenitor cells to differentiate and proliferate into a single colony. GM-CSF is a monomeric 
glycoprotein cytokine, which may be produced by many cells including myeloid cells, dendritic 
cells, T cells, B cells, non-hematopoietic cells (such as endothelial cells, chondrocytes and 
alveolar epithelial cells) and even tumor cells (Avci et al., 2016). GM-CSF binds to heterodimeric 
receptors on bone marrow cells and neutrophils and activates GM-CSF receptors to initiate a 
variety of downstream signaling pathways, including Janus kinase signal transducer 
transcription- suppressor of cytokine signaling (JAKSTAT-SOCS), mitogen-activated protein 
kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), and nuclear factor ĸB signaling pathway 
(NF-ĸB) (Hansen et al., 2008; Jenkins et al., 1998; Sato et al., 1993; Broughton et al., 2015; 
Hercus et al., 2017).     
GM-CSF, as a key upstream trigger factor in the inflammatory cytokine cascade, can enhance 
the effects of neutrophils and macrophages, to increase the expression of adhesion molecules, 
produce inflammatory cytokines and activate the phagocytosis. In addition, GM-CSF is also an 
important cytokine that induces the polarization of monocytes to the inflammatory M1 
phenotype and promotes the activation of macrophages, and the macrophages secrete a large 
number of inflammatory cytokines such as IL-6, TNF-α, etc., to involve in tissue inflammation 
(Hamilton, 1980). 
Indeed, the strong proinflammatory effects of GM-CSF make it a prime target in acute 
inflammatory conditions where elevated GM-CSF has been implicated in orchestrating a 
cytokine storm. At least three such syndromes share immunological and pathologic features of a 
cytokine storm: chimeric antigen receptor (CAR)-T cell therapy related cytokine release 
syndrome (CRS) and neurotoxicity, macrophage activation syndrome (MAS) and most recently, 
acute respiratory distress syndrome (ARDS) in severe coronavirus disease (COVID-19) cases 
caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).  
CAR-T therapy is revolutionizing cancer treatment, but its application is limited by life-
threatening toxicities such as CRS and neurotoxicity (Gust, 2019) attributable to hyperactive T 
cells and monocytes/macrophages. It has been reported that GM-CSF neutralizing antibody 
during CAR-T therapy prevented CRS and neuroinflammation and both GM-CSF neutralization 
and GM-CSF knockout in CAR-T cells enhanced antitumor activities in a mouse ALL xenograft 
model (Figure 1, Sterner et al., 2019). In addition, GM-CSF inactivation in this setting abolished 
macrophage-dependent secretion of factors, including monocyte chemoattractant protein 1 
(MCP-1), IL-6, and IL-8 (Sachdeva M, 2019). Compared to tocilizumab that has been widely 
used to treat cytokine storm caused by CAR-T cells, GM-CSF antibodies can achieve better 
treatment effect, especially in regulating the broad spectrum of cytokines and inhibiting 
neurotoxicity. Based on these findings, a clinical trial of GM-CSF antibody lenzilumab in CAR-
T therapy is planned (Sterner et al., 2019). 


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Figure 1. GM-CSF antibodies inhibited the release of cytokines caused by CAR-T cells (Sterner et al., 2019).  
 
Figure 2. Infection of SARS-CoV-2 Caused Hyperactivation of T helper cells to Drive Aberrant 
Monocyte Activation 
 
Both T cells and monocytes produce large amounts of cytokines and chemokines which feed 
forward on the immune cells to precipitate a cytokine storm and tissue damage ensues. GM-CSF 
neutralization could stop this cycle. (Figure 2 from Zhou Y, 2020; caption added). 
In the recent COVID-19 epidemic caused by the coronavirus SARS-CoV-2 in China, 10-20% of 
the pneumonia patients developed severe or critical conditions that required intensive care. These 


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complications included ARDS, multiple organ failure and sometimes death. The clinical features 
(Huang, 2020) and immunopathology (Xu, 2020) of patients with COVID-19 in China have now 
been reported, and they remarkably resembled those found in SARS (Channappanavar, 2017). 
Common features among COVID-19 patients particularly those seriously or critically ill 
included lymphopenia and significantly higher than normal levels of inflammatory cytokines 
(IL-1, IL-7, IL-8, IL-9, IL-10, basic FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1A, 
MIP-1B, PDGF, TNF-α, and VEGF) (Huang, 2020). Most studies also reported massive 
production of IL-6, CRP, D-dimer and ferritin – all consistent with cytokine storm (Wang, 2020). 
Importantly, lung pathology revealed heavy interstitial lymphocytic infiltrates along with diffuse 
alveolar damage with fibromyxoid exudates, multinucleated giant cells and hyaline membrane 
formation, indicative of ARDS (Xu, 2020). Interestingly, these pathological features and lung 
CT imaging characteristics are also remarkably similar to those reported for a subset of systemic 
Juvenile Idiopathic Arthritis (JIA) patients that developed MAS that led to severe 
immunopathology and lung disease (Schulert, 2019). Finally, peripheral blood mononuclear cell 
(PBMC) immunophenotyping showed an abundance of highly active GM-CSF-producing T 
helper cells and pathogenic monocytes in COVID-19 patients (Xu, 2020; Zhou, 2020).  
It seems clear from these recent reports that severe COVID-19 bears all the hallmarks of a 
cytokine storm instigated by exuberant immune cells producing GM-CSF and IL-6. They drive 
aberrant monocyte and T cell activation which in turn produce more cytokines and chemokines 
in a feed forward cycle that culminates in profound tissue injury, airway constriction, vascular 
collapse and organ failure. Without intervention, the clinical course is expected to be dire for 
COVID-19 patients in severe or critical conditions. Currently, based on the experience of IL-6R 
antibody tocilizumab in managing CAR-T induced CRS, tocilizumab is being tested for reducing 
cytokine storm and its complications in a clinical trial of COVID-19 patients. Based on the 
analysis above and progress made in CAR-T therapy with the introduction of GM-CSF inhibition, 
GM-CSF neutralizing antibodies such as TJ003234 may prevent or curb cytokine storm and 
immunopathology in COVID-19 and consequently buy more time for viral clearance. 
TJ003234 is a recombinant anti-GM-CSF humanized monoclonal antibody independently 
developed by I-Mab Biopharma Co., Ltd. At present, a number of preclinical studies have been 
conducted on TJ003234, demonstrating that TJ003234 is a specific and effective antagonist of 
human GM-CSF/GM-CSFR pathway. TJ003234 has shown significant inhibitory effect on GM-
CSF mediating GM-CFSR signaling in vitro and in vivo. Blocking the biological activity of GM-
CSF suppresses the activation of pro-inflammatory monocytes, leading to the potential clinical 
benefits to patients with cytokine storms.  
In December 2018, the US Food and Drug Administration (FDA) approved the first study of 
TJ003234 for human use in healthy volunteers. The phase I study was expected to obtain safe 
tolerated doses and pharmacokinetic characteristics of TJ003234 in humans, and currently the 
study has been completed. In this first human study, a single dose of TJ003234 up to 10 mg/kg 
in healthy subjects was well tolerated. The maximum tolerated dose was not reached. The 
increased TJ003234 exposure (Cmax and AUC) was roughly proportional to the increase in dose. 
The T1/2 was about 3 weeks within the test dose range of 0.3mg/kg to 10mg/kg. The clearance 
rate of TJ003234 decreased with increasing dose. The volume of distribution decreased slightly 
with the increasing dose. In the subjects in 3 mg/kg and 10 mg/kg cohorts, TJ003234 inhibited 


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GM-CSF-stimulated pSTAT5 levels by more than 90% for up to 2 weeks in 4 hours after dosing 
(full clinical study report submitted to FDA in January 2020).  
1.1. 
Preclinical Studies  
For information on TJ003234 preclinical studies, refer to the Investigator’s Brochure. It is 
summarized as follows.    
1.1.1 Toxicological study  
The toxicology studies of TJ003234 include toxicity pre-test in cynomolgus monkeys, 
toxicology and toxicokinetic tests in cynomolgus monkeys after being given TJ003234 by 
repeated intravenous injection for 4 weeks and recovery for 30 days, potential cross-reactions of 
TJ003234 to human and monkey tissues and in vitro hemolysis testing of TJ003234 in rabbit 
blood erythrocytes.  
In the toxicity pre-test in cynomolgus monkeys, a control group and test groups (TJ003234 
Solution for Injection at doses of 20.65, 61.95, 216.2 mg/kg respectively) were established. 
Animals were treated once a week for 3 consecutive weeks (3 times in total). No mortality 
occurred in the study, and all animals survived to the planned necropsy. No obvious TJ003234-
related clinical symptoms, changes in body weights, food intake, and related hematological or 
coagulation parameters and clinical biochemical parameters were observed.  
In a pivotal Good Laboratory Practice (GLP)-compliant toxicity study, 40 cynomolgus monkeys 
were randomly divided into 4 groups (5 animals/sex/group). On Days 1, 8, 15, 22, and 29 (4-
week exposure), animals were administered by intravenous injection of the solvent control or 
test article (TJ003234 of 20, 60 or 200 mg/kg, 5 times in total). No Antidrug Antibody (ADA) 
formation was detected for all animals when the systemic exposure was reached, and no 
TJ003234-related deaths or morbidity occurred.  
During a post-mortem recovery examination, a male animal had minimal congestion and 
multifocal alveolar protein in the lungs in the 20 mg/kg dose group. The alveolar protein was 
characterized by eosinophilic fibers and fluids in the alveoli, with a minimal increase in the 
number of alveolar macrophages with normal morphology. The animal’s lung tissues showed 
negative by oil red O and PAS staining. Lung tissue SP-A and SP-D showed no interalveolar 
staining, and SP-B showed slight staining in a small number of alveoli, which was considered 
non-specific and believed not to be related to PAP (pulmonary alveolar proteinosis). This animal 
was normal by clinical observation and had normal respiratory functions throughout this study. 
The lung changes in male monkey were acute in nature and were considered to be caused by 
stress before or during euthanasia. Similar changes were not observed at higher dose levels or 
final necropsy. These data suggested that the animal’s alveolar staining was not related to PAP.   
During the terminal necropsy, a male animal in the 200 mg/kg group was found to have focal 
neuronal degeneration, edema, and a glial scar under microscopy. Given the low incidence of 
this change, these lesions were likely to be incidental and were not related to the test substance. 
During the terminal necropsy, a male animal in the 200 mg/kg group was found to have 
pulmonary granulomas, and the gross observations showed multifocal yellowing of the lung's 
head lobe, middle lobe and caudate lobe and yellow lumps near the lung hilus. Since oil red O 
and PAS stains showed negative and SP-A, SP-B and SP-D in the alveoli were not specifically 


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stained, the animal's lung findings were not much related to the PAP. Although these lung 
changes occasionally occurred in background lesions of non-human primates, the effect of the 
test substance on the immune system that may affect the original lesions could not be completely 
ruled out.  
Based on the above results, the No-Observed-Adverse-Effect Level (NOAEL) dose of TJ003234 
in cynomolgus monkeys was 60 mg/kg. 
1.1.1.1 Tissue-cross Reactivity in Human and Cynomolgus Monkey  
In this GLP-complaint tissue-cross reactivity (TCR) study, Biotin-TJ003234 (2.5, 5 and 10 
µg/mL), with cryo-sections from histologically normal frozen human and cynomolgus monkey 
tissues (panels of 40 tissues for human and cynomolgus monkey; 3 donors/panel) was assessed 
in this study. All tissues were validated by staining method. The positive control of the study was 
GM-CSF protein. 
Specific positive staining was observed with biotin-TJ003234 in secretory cells within tissues of 
the gastrointestinal tract in the human and cynomolgus money tissues panels examined. 
Additional specific positive staining was observed with biotin-TJ003234 in epithelial cells in 
cynomolgus monkey lung and parotid. The specific positive staining observed is consistent with 
GM-CSF expression, no tissue cross-reactivity was observed. 
1.1.1.2 In vitro Hemolysis Assay 
In this GLP-complaint hemolysis study, approximately 15 mL of blood was collected from a 
male New Zealand white rabbit via a jugular vein. Red blood cells (RBC) were suspended in 
0.9% sodium chloride injection solution to a final concentration of 2%. The hemolytic potential 
of TJ003234 at concentration of 105.5 mg/mL was tested. After TJ003234 was added to the 
samples, the tubes were placed into a water bath set at 37 ℃ ± 0.5 ℃ for 3 hours and observed 
once every 15 minutes during the first hour and every hour during the last two hours for 
hemolytic potential. 
There was no hemolysis noted in RBC incubated with TJ003234 (105.5 mg/mL). There was also 
no RBC coagulation noted. TJ003234 at concentration of 105.5 mg/mL had no hemolytic 
potential. 
1.1.1.3 Immunotoxicity and immunogenicity 
The immunotoxicity study was carried out together with the 4-week toxicology study in 
cynomolgus monkeys. The cytokines are one of important immune function parameters. No 
changes in cytokines were found after intravenous injection of TJ003234. The concentration and 
change of cytokine levels at all time points during the dosing period on Day 1 and Day 22 in the 
TJ003234 group were similar to those in the control group, and the values were within the 
historical variation range, without any toxicological significance. In addition, TJ003234 
specifically bound and neutralized the secreted cytokine GM-CSF, which was not a cell target. 
Therefore, TJ003234 was expected to have a very low risk of inducing cytokine release 


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syndrome in human bodies, so human whole blood or PBMCs was not used for cytokine release 
analysis. All samples were negative for anti-drug antibodies during the dosing and recovery 
periods; therefore, no anti-drug antibody (ADA) formation was detected, which proved that 
TJ003234 had low preclinical immunogenicity. 
1.1.2 Pharmacological Studies  
Pharmacological studies included in vitro and in vivo pharmacological studies. Studies have 
shown that TJ003234 can block the GM-CSF/GM-CSFR interaction, prevent GM-CSFR-
induced signaling pathways, and thereby neutralize the biological activity of GM-CSF. By 
inhibiting the functions of macrophages, TJ003234 can reduce the autoimmune responses. 
TJ003234 did not show antibody-dependent cell-mediated cytotoxicity (ADCC) effect on human 
monocytes and complement dependent cytotoxicity (CDC) effect on human PBMC. The 
evaluation of the effects of TJ003234 on the in vitro monocyte activation to mimic the viral RNA 
stimulation demonstrated that TJ003234 treatment could suppress the activation of as well as 
cytokine production by proinflammatory monocytes. 
1.1.2.1 In vitro Pharmacology 
As shown in Table 2, TJ003234 was characterized through a series of in vitro studies to describe 
1) cross reactivity with GM-CSF from various species; 2) binding specificity to human GM-CSF 
over its structurally and functionally close related proteins; 3) ability to block the interaction of 
GM-CSF with GM-CSF receptor (CD116 or GM-CSFR); 4) ability to inhibit GM-CSF mediated 
STAT5 phosphorylation in PBMCs and whole blood; 5) binding profiles to FcRn, Fcγ receptors 
and C1q; 6) ADCC and CDC study; 7) inhibition of in vitro monocyte activation which is used 
to mimic the COVID-19 viral RNA stimulation of primary monocytes. 
Table 2. Results of in vitro pharmacological studies 
Test Item  
Test 
System  
Test Results  
 Cross-reactivity of TJ003234 against different 
species of antigens 
ELISA 
The EC50s of TJ003234 against human and monkey GM-
CSF antigens were 13.22 ng/mL and 8.44 ng/mL, 
respectively, with similar binding effect. TJ003234 did 
not bind to mouse and rat GM-CSF antigens.  
Antibody specificity of TJ003234  
ELISA 
TJ003234 could bind human or monkey GM-CSF, with 
EC50 of 6.435-6.722 ng/mL and 6.536 ng/mL, 
respectively. TJ003234 could not bind to human G-CSF, 
M-CSF, IL-3 or IL-5.    
Antibody receptor ligand blocking detection of 
TJ003234 
ELISA 
Two independent tests showed that the half-maximum 
blocking concentrations (IC50) of TJ003234  block the 
binding of human GM-CSF to its receptor CD116 were 
112.4 ng/mL and 122.1 ng/mL, respectively, indicating 
that TJ003234 could  effectively block the binding of 
human GM-CSF to CD116.  
Effect of TJ003234 on GM-CSF-mediated 
FACS 
TJ003234 
could 
effectively 
block 
STAT5 
phosphorylation in recombinant human-derived or 


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Test Item  
Test 
System  
Test Results  
STAT5 phosphorylation signals  
cynomolgus monkey GM-CSF-mediated PBMCs. The 
IC50 of its inhibition of human-derived GM-CSF-
mediated STAT5 phosphorylation was 0.34-1.70 ng/mL, 
and its IC90 was 4.15-12.76 ng/mL. The IC50 of its 
inhibition of cynomolgus monkey GM-CSF-mediated 
STAT5 phosphorylation was 0.11-4.54 ng/mL, an its IC90 
was 0.62-22.07 ng/mL.  
Roles of TJ003234 on STAT5 phosphorylation 
induced by GM-CSF activation in human whole 
blood  
FACS 
Antibodies could neutralize the activation of the GM-
CSF-induced STAT5 phosphorylation pathway in a dose-
dependent manner. IC50s of donors 1, 2 and 3 were 0.35 
μg/mL, 1.81 μg/mL, 0.44 μg/mL, respectively; and the 
IC90 of donors 1, 2 and 3 were 3.18 μg/mL, 4.67 μg/mL, 
1.55 μg/mL, respectively. 
Affinity of TJ003234 
antibody to human 
GM-CSF antigen 
 
    
Biacore 
The three batches of antibodies had strong affinity to the 
human antigen GM-CSF, and there was no significant 
difference between the three batches of antibodies.  
ADCC 
and 
CDC 
Effects of TJ003234 
 
     
ELISA 
TJ003234 did not show antibody-dependent cell-
mediated cytotoxicity (ADCC) effect on human 
monocytes and complement dependent cytotoxicity 
(CDC) effect on human PBMC. 
Binding affinity of TJ003234 antibody to FcRn, 
Fcγ receptor and C1q 
Biacore 
The affinity between the antibody and each Fc receptor 
and complement C1qB was as follows (in descending 
order):  CD64, C1qB, CD16a (176Val), CD16a 
(176Phe), FcRn, CD32a, CD16b, CD32b.  IgG1 had a 
high affinity to CD64, but had a relatively low affinity to 
CD32. The above test results were consistent with the 
typical characteristics of IgG1, and there was no 
significant difference between the three batches of 
antibodies.   
Inhibition of in vitro monocyte activation by 
TJ003234 
Luminex 
TJ003234 
treatment 
significantly 
decreased 
the 
production 
of 
proinflammatory 
cytokines 
and 
chemokines by activated monocytes including IL-5, IL-7, 
IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, bFGF and 
Eotaxin.  
 
1.1.2.2   In vivo Pharmacology 
1.1.2.2.1  In vivo Efficacy of Repeat Dose TJ003234 on Type II Collagen Induced Arthritis 
(CIA) Model in Cynomolgus Monkeys 
The in vivo therapeutic efficacy of TJ003234 for type II collagen induced arthritis was evaluated 
in cynomolgus monkeys with overt arthritic symptoms. Seventeen female cynomolgus monkeys 
were randomly assigned to 3 groups and received either no immunization and no administration 


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(n=1), or immunization and vehicle (n=8) or test article (n=8, TJ003234 at 40 mg/kg). 
Animals that developed arthritis were randomly assigned to 2 groups (8F/group) and 
administered vehicle or 40 mg/kg TJ003234 by intravenous (IV) injection once a week for 4 
doses. Arthritis severity was quantified by joint incidence (# of inflamed joints over the total # 
of joints analyzed) and arthritis score. Proximal interphalangeal (PIP) area was also applied to 
quantify joint swelling of arthritis. Additionally, phosphorylation of STAT5 downstream of GM-
CSFR activation was used as a proximal pharmacodynamic (PD) marker reflecting the TJ003234 
mediated blockade of GM-CSF signaling, and was evaluated using PBMCs isolated from 
monkeys before or 24 hours after TJ003234 administration by FACS.  
Figure 3. In vivo Efficacy of Repeat Dose TJ003234 on Type II Collagen Induced Arthritis (CIA) 
Model in Cynomolgus Monkeys 
Joint Incidence
-1
0
1
2
3
4
5
0
10
20
30
40
Vehicle
TJ-M2(40mg/kg)
weeks after treatment
Joint Incidence (%)
Score
-1
0
1
2
3
4
5
0
20
40
60
80
Vehicle
TJ-M2(40mg/kg)
weeks after treatment
Arthritis Score
 
a 
b 
PIP Incidence
-1
0
1
2
3
4
5
0
20
40
60
Vehicle
TJ-M2(40mg/kg)
weeks after treatment
Incidence (%)
PIP Area
-5
-4
-3
-2
-1
0
1
2
3
4
5
0
20
40
60
80
Vehicle
TJ-M2(40mg/kg)
weeks after treatment
Area(cm2)
 
c 
d 


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chang of PIP
-1
0
1
2
3
4
5
-15
-10
-5
0
5
10
15
Vehicle
TJ-M2(40mg/kg)
weeks after treatment
Change percentage  (%)
0
20
40
60
80
Pre
Post
Pre
Post
Vehicle
(n=8)
TJ-M2
(n=7)
p = 0.19
p = 0.004
% of pSTAT5 positive
 
e 
f 
Comments: Joint incidence (a), arthritis score (b), PIP incidence (c), PIP Area (d), PIP area 
change percentage (e) and % of pSTAT5 positive cells in PBMCs (f) in CIA monkey model 
As shown in Figure 3, the treatment at 40 mg/kg of TJ003234 could significantly reduce the 
severity of CIA, indicating that TJ003234 is effective in treating CIA in this model.  
1.1.2.2.2   Dose response relationship of TJ003234 in monkey CIA Model  
Using the same CIA monkey model, a dose-response study was conducted to establish the PK/PD 
relationship of TJ003234. Twenty-eight female cynomolgus monkeys were randomly assigned 
to 4 groups and received immunization and 0, 3, 10 and 30 mg/kg TJ003234 once via IV injection. 
Similar clinical endpoints (joint incidence, arthritis score, PIP incidence, PIP Area, PIP area 
change percentage) and proximal PD marker (phosphorylation of STAT5) were used in this study 
to evaluate the in vivo efficacy. As shown in Figure 4. Dose response relationship of TJ003234 
in monkey CIA Model, the joint incidence was not affected by treatment with TJ003234; the 
mean arthritis scores were progressed in a decreased fashion after the TJ003234 treatment in all 
test groups compared to control group, yet no dose-response was found; no consistent difference 
in PIP incidence and PIP area between vehicle control and TJ003234 treatment; the treatment at 
30 mg/kg of TJ003234 significantly reduced the PIP area in week 2 compared with week 1; 
treatment with TJ003234 (3, 10, or and 30 mg/kg once via IV injection) reduced pSTAT5 levels 
when compared to the vehicle control group. 
Figure 4. Dose response relationship of TJ003234 in monkey CIA Model 
 


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a 
b 
 
c 
PIP area
week -3*
week 0*
week 1*
week 2*
20
25
30
35
40
Vehicle n=5
TJ-M2 3mpk n=6
TJ-M2 10mpk n=6
TJ-M2 30mpk n=6
weeks after treatment
PIP area(cm2)
 
d 
0
3
10
30
0
50
100
150
Week 1*
Week 2*
*
Tj-M2 dose (mpk)
PIP Area change (%)
PIP Area change(%)
 
e 
pSTAT5 in cyno CIA model
Pre
Post
Pre
Post
Pre
Post
Pre
Post
0
20
40
60
vehicle
TJ-M2
(3 mg/kg)
TJ-M2
(10 mg/kg)
TJ-M2
(30 mg/kg)
% of pSTAT5 positive
 
f 
Comments: Joint incidence (a), arthritis score (b), PIP incidence (c), PIP Area (d), PIP area 
change percentage (e) and % of pSTAT5 positive cells in PBMCs (f) following 0, 3, 10, 30 
TJ003234 single IV injection in CIA monkey model   
A systematic exposure study was conducted for all animals. After a single intravenous injection 
of TJ003234 into CIA model monkeys, the mean peak concentrations (Cmax) at 3, 10, and 30 
mg/kg were 76.137, 236.313, and 572.236 μg/mL, respectively; the mean areas under 
concentration-time curve were 2143.691, 9361.553, and 14134.021 μg • hr/mL, respectively. 
Based on the mean Cmax and AUClast, TJ003234 exposure rose with proportionally increased dose 
levels from 3 mg/kg to 30 mg/kg.      


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In summary, a single dose of TJ003234 within the range of 3 to 30 mg/kg can inhibit the 
development of arthritis symptoms without exhibiting a significant dose-dependence: the 
systemic exposures (Cmax and AUC) within the dose range increase proportionally with the dose.   
1.1.3 Pharmacokinetic study  
1.1.3.1  Single-dose Pharmacokinetics  
Based on the cross-reaction of TJ003234 with cynomolgus GM-CSF antigen and no affinity with 
rodent GM-CSF antigen and the fact that TJ003234 can block the GM-CSF-mediated STATS5 
phosphorylation signals in the cynomolgus monkey-derived PBMCs, cynomolgus monkeys 
were selected as the sole animal species. In a single-dose pharmacokinetic study, cynomolgus 
monkeys (3 animals/sex/group) were given 5, 25, and 50 mg/kg of TJ003234 by intravenous 
injection respectively. No sex-specific difference in systemic exposure were observed, and Cmax 
and AUC0-last increased proportionally in the last dose with the range of 5-50 mg/kg. The 
Cmax/dose and AUC0-last/dose in all dose groups were similar within the dose range of 5.0 mg/kg 
to 50 mg/kg, indicating that TJ003234 met the linear pharmacokinetic behaviors within the dose 
range. With the entire dose levels, the mean elimination half-life (T1/2) ranged from 9.0 to 10.0 
days, the clearance (CL) ranged from 0.332 to 0.406 mL/h/kg, the apparent volume of 
distribution (Vz) ranged from 114 to 126 mL/kg, Cmax was 112-1220μg/mL and AUC0-last was 
14800-124000 μg · h/mL.  
The bioavailability of TJ003234 following subcutaneous injection was studied in cynomolgus 
monkeys following a single intravenous injection at 5 mg/kg and a single subcutaneous injection 
at 5 mg/kg, 25 mg/kg and 50 mg/kg, respectively. A linear subcutaneous pharmacokinetic profile 
was observed across three subcutaneous (SC) dose levels, with bioavailability of 77.4%, 78.8%, 
72.6%, respectively. The rate of elimination was similar following IV and SC routes, indicating 
elimination of TJ003234 was independent of the route of administration in cynomolgus monkeys. 
No ADA was detected throughout the study.  
1.1.3.2  Repeat-dose Pharmacokinetics 
The toxicokinetic (TK) profile of TJ003234 across repeated IV doses were determined in 
conjunction with a GLP-compliant repeat-dose toxicology study in cynomolgus monkeys. In this 
study, 40 cynomolgus monkeys were randomly assigned into 4 groups (5/sex/group) and 
administered TJ003234 at 0, 20, 60 or 200 mg/kg via IV injection once weekly (Q1W) for a total 
of 5 doses. 
No significant gender differences in systemic exposure (Cmax and AUC0-t) following the 1st and 
4th doses were observed. The systemic exposure increased dose proportionally after the 1st dose 
from 20 to 200 mg/kg. There were no significant differences in the concentration-time curves 
among individual animals within each dose level. Following the 4th dose, toxicokinetic 
parameters, including time of maximum concentration (Tmax), Cmax, AUC0-t, and clearance (CL) 
were similar to those following the first dose. Exposure did not decrease significantly following 
the 4th dose when compared to the 1st dose, indicating the absence of an increased clearance due 
to potential neutralizing ADA formation. The immunogenicity results confirmed that all samples 


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were detected as anti-TJ003234 antibody negative in the dosing phase. Mild accumulation was 
noticed in AUC0-t and Cmax at all dose levels: for the 4th vs 1st dose, the ratio of Cmax was 1.27, 
1.29, 1.15, and the ratio of AUC0-t was 1.49, 1.41, 1.35, for 20, 60, 200 mg/kg dose levels, 
respectively. 
1.2. 
Clinical Study  
The US FDA approved the Investigational New Drug (IND) of TJ003234 in healthy volunteers 
in December 2018. The phase I trial was designed as a single-center, randomized, double-blind, 
placebo-controlled, single-dose escalation study. 
The study objectives were to evaluate safety, tolerability, PK, PD, and immunogenicity of 
TJ003234 following a single dose. This study enrolled 32 healthy subjects at the dose levels of 
0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg. Eight subjects were randomized at a ratio of 3:1 in 
each dose cohort to receive either TJ003234 or placebo. In the first cohort, to mitigate any 
unforeseen safety issues, the first 4 of the 8 subjects were individually dosed at intervals that 
were, by protocol, at least 24 hours apart. In each study cohort, subjects were screened within 27 
days prior to admission to the site. Subjects were admitted to the site on the day prior to dosing 
(Day -1) for pre-dose study procedures and randomization. On dosing day (Day 1), a single dose 
of TJ003234 was administered IV over a maximum 2-hour period. Subjects were observed 
overnight. On Day 2, after completion of the study procedures and assessments, subjects were 
discharged from the site. The 7-day dose-limiting toxicity (DLT) observational period started at 
the completion of dosing (end of infusion [EOI]). The study period was defined as the time of 
dosing through the end of the study (a duration of 90 days). Subjects returned to the site for 
outpatient visits on Days 3, 5, 8 (week 1), 15 (week 2), 29 (week 4), 43 (week 6), 57 (week 8), 
71 (week 10) and 90 (week 13). Day 90 was considered the end of study (EOS) visit. 
Dose escalation occurred sequentially after review of safety data for each dosing cohort by the 
safety review committee (SRC). Dose escalation to the next dose level proceeded uninterrupted 
as long as no pre-defined DLT or stopping criteria were met. According to the protocol, if the 
maximum tolerated dose (MTD) was not reached during dose escalation, the maximum 
administered dose (MAD) was defined as 10 mg/kg. 
As of January 2020, the study has been completed and a clinical study report has been issued. 
Thirty-two (32) subjects enrolled into and completed TJ003234RAR101. There were no 
interruptions in dosing or early withdrawals. The Safety, PK, and PD Populations each include 
all 32 subjects. All treatment groups included both males and females as well as both black 
(43.8%) and white subjects (43.8%). There were no observable differences between the treatment 
groups that were anticipated to affect assessment of outcome. All major protocol deviations were 
reviewed by the medical monitor and determined to have no medical impact on the study. 
Safety Results: 
TJ003234 is well tolerated following a single IV dose up to 10 mg/kg in healthy subjects with 


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no maximum tolerated dose reached. The majority of adverse events (AEs) were mild to 
moderate. No serious adverse events were reported during the study. Overall, 8 of the 24 subjects 
who received TJ003234 and 3 of the 8 subjects who were on placebo reported treatment-related 
treatment-emergent adverse events (TEAEs). The most common AEs experienced by subjects 
dosed with TJ003234 were headache (25%, grade 1/2) and protein urine (25%, grade 1). These 
AEs were also the most common AEs reported by subjects received placebo (37.5%, grade 1/2 
and 37.5%, grade 1, respectively). Two pulmonary AEs (Grade 1 cough and shortness of breath) 
were reported in one subject at Cohort 3 and were considered to be drug related. Two subjects 
from Cohort 1 and one subject from the Cohort 2 reported more than 20% decrease in FEV1 or 
FVC but the values were still within normal ranges, the changes were not observed in higher 
dose level cohorts. No clinically meaningful changes were observed in the dyspnea score.  
Pharmacokinetic Results: 
A summary of TJ003234 PK parameters following a single ascending dose of 0.3 to 10-mg/kg 
of TJ003234 administered to healthy subjects is presented below.  
Table 3. TJ003234RAR101: TJ003234 Serum Pharmacokinetic Parameters following Single 
Ascending Intravenous Dose of TJ003234 in Healthy Subjects (PK Population) 
Dose level  
Cmax 
(µg/mL)  
Tmax 
(h) 
AUClast 
(day*µg/mL)  
AUC0-∞ 
(day*µg/mL)  
t1/2 
(day)  
CL 
(mL/day)  
Vss 
(L)  
Vz 
(L)  
0.3 
mg/kg(n=6)  
5.24 
(56.2) 
1.26 
(1.00, 1.38)  
80.3  
(63.0) 
85.7 
(66.0) 
22.5 
(5.91) 
290 
(68.2) 
8.26 
(54.8) 
9.15 
(62.5) 
1 mg/kg(n=6)  
24.7 
(19.4) 
1.29 
(1.27, 1.30)  
289 
(25.2) 
298* 
(30.1) 
20.5* 
(4.96) 
258* 
(39.4) 
5.71 
(34.0) 
7.41* 
(17.9) 
3 mg/kg(n=6)  
71.7 
(10.3) 
1.70 
(1.70, 48.6) 
1100 
(27.1) 
1250* 
(22.3) 
20.1* 
(3.20) 
200* 
(12.9) 
5.26 
(4.76) 
5.75* 
(5.60) 
10 mg/kg(n=6)  
258 
(13.6) 
3.58 
(1.77, 25.2)  
3680 
(27.2) 
3860 
(29.9) 
20.6 
(3.49) 
178 
(37.1) 
4.63 
(20.7) 
5.23 
(20.9) 
Cmax, AUClast, AUC0-∞,, CL, Vss, and Vz are presented as geometric mean (%CV). t1/2 is presented as mean (SD). Tmax is 
presented as median (min, max). 
*At the 1 mg/kg and 3 mg/kg dose levels, the sample size reported for AUC0-∞, t1/2, CL, and Vz is 5 subjects not 6 because 
each had too much variability in their concentration-time data and thus too low an r2 to be acceptable for using the data in 
calculating these parameters. 
Pharmacodynamic Results:  
Four hours after dosing, the induction of pSTAT5 by ex vivo GM-CSF stimulation in the 
monocyte population was inhibited by at least 70% compared to the placebo following a single 
dose of TJ003234 for all dose groups. The induction of pSTAT5 by GM-CSF stimulation was 
inhibited by 94.1% at 4h postdose and 92.6% at 336h postdose following a single dose of 3mg/kg 
TJ003234. A comparable inhibitory effect was observed at 10mg/kg cohort, i.e. 95.3% inhibition 


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at 4hour postdose and 91.7% at 336 hour postdose. The inhibition was sustained for 2 weeks at 
3 mg/kg and 10 mg/kg cohorts, suggesting the saturation of the pSTAT5 inhibition by the 
treatment at a 3 mg/kg dose and above.   
Immunogenicity Results: 
Two subjects in the 3 mg/kg TJ003234 cohort and one placebo subject were positive for ADA. 
The placebo subject was positive on Day 57 but negative on Day 90. One subject in the 3 mg/kg 
TJ003234 cohort developed a positive response at the Day 57 timepoint and maintained it when 
tested on Day 90. The other subject in the 3 mg/kg TJ003234 cohort was positive only on Day 
90. No subject in the 10 mg/kg dose level was positive for ADA. 
1.3. Benefits and Risks Assessment  
1.3.1 Benefits 
Based on the anti-inflammatory action mechanism of GM-CSF antibody, preclinical study results 
of TJ003234 and inhibition of in vitro monocyte activation by TJ003234, we believe that 
TJ003234 has potential benefits for the treatment of severe COVID-19.  
1.3.2 Risks 
Based on the results of preclinical studies conducted by I-Mab Biopharma and with reference to 
the published data in clinical studies of antibody with same/similar mechanism, the important 
potential risks of TJ003234 include:     
 
Pulmonary alveolar proteinosis  
 
Infections  
 
Infusion-related reactions  
Pulmonary alveolar proteinosis (PAP) 
GM-CSF promotes alveolar macrophage proliferation, which plays a critical role in lung 
defenses and surfactant homeostasis through catabolism of surfactant lipids and proteins. 
Autoantibodies against GM-CSF have been associated with the development of idiopathic 
autoimmune PAP, in which abnormal accumulation of pulmonary surfactant protein occurs 
within the alveoli due to insufficient clearance by GM-CSF-starved macrophages. Due to this 
association, there is a theoretical risk of developing PAP when long-term using therapeutic 
antibodies that target GM-CSF. No PAP has been indicated in TJ003234 non-clinical studies 
and the completed TJ003234 first-in-human (FIH) study (TJ003234RAR101). No clinically 
significant findings were identified in terms of pulmonary function tests and respiratory related 
signs/symptoms in this FIH study.  
Infections 
 
Due to the biological mechanism of TJ003234, blocking the GM-CSF may inhibit the functions 


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of macrophage and neutrophils, thus potentially may lead to risk of infections, especially long-
term using. No infections were reported from TJ003234 animal studies. In the completed 
TJ003234 study in healthy adults, 24 adults received TJ003234, there was one adult experienced 
nasopharyngitis, and one adult experienced vulvovaginal mycotic infection. One of 8 adults who 
received placebo developed otitis media.   
Infusion related reactions (IRR) 
All therapeutic monoclonal antibodies used for oncology and immunologic therapies have the 
potential to cause infusion related reactions (IRRs). Symptoms vary with a wide spectrum of 
severity, ranging from mild fever and chills to life-threatening anaphylaxis with bronchospasm, 
and hypotension. Typically, IRRs to monoclonal antibodies develop within 30-120 minutes after 
the initiation of drug infusion, although symptoms may not show up until 24 hours. Most 
common symptoms of IRRs are fever, chills, nausea, vomiting, diarrhea, itching, flushing, rash, 
changes in blood pressure and heart rate, dyspnea, chest discomfort, back and abdominal pain. 
The risk of IRR declines with each subsequent course of therapy. Although premedication can 
help to prevent and/or reduce the severity of infusion reactions, anaphylaxis generally cannot be 
prevented by premedication. No IRR was identified in TJ003234 previous completed FIH study.  
2. 
Objectives and Endpoints  
2.1. Objectives 
2.1.1. 
Primary Objective 
To evaluate the efficacy and safety of TJ003234 in subjects with severe novel Coronavirus 
pneumonia (COVID-19) with supportive care.  
2.1.2. 
Secondary Objectives 
 To evaluate the effects of TJ003234 on cytokines in subjects with severe COVID-19.  
 To assess the pharmacokinetics (PK) and immunogenicity potential of TJ003234 when 
administered as a single dose IV infusion in subjects with severe COVID-19. 
2.2. Endpoints  
2.2.1. 
Primary Efficacy Endpoint 
Proportion (%) of subjects who are alive and free of mechanical ventilation at Day 30 among 
subjects who are non-mechanical ventilated at baseline. 
2.2.2. 
Secondary Efficacy Endpoints 
Key Secondary Efficacy Endpoints: 
 
Proportion (%) of subjects recovered by Day 14. Recovery is defined as the subject scoring 
a 3, 2, or 1 on the 8-category ordinal scale as defined below by Day 14 and subsequently 
does not progress to a score ≥ 4 for the remainder of the study. If a subject scores 3 at 
baseline,  this subject is considered to be recovered if this subject’s score improves to 1 


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or 2 by Day 14. 
8, death; 7, ventilation in addition to extracorporeal membrane oxygen (ECMO), continuous 
renal replacement therapy (CRRT) or pressors; 6, intubation and mechanical ventilation; 5, 
non-invasive mechanical ventilation (NIV) or high-flow oxygen; 4, hospitalization with oxygen 
by mask or nasal prongs; 3, hospitalization without oxygen supplementation; 2, limitation of 
activities, discharge from hospital; and 1, no limitation of activities, discharge from hospital. 
• 
Proportion (%) of subjects recovered by Day 30. Sustained recovery is defined as the 
subject scoring a 3, 2, or 1 on the 8-category ordinal scale as defined in the key secondary 
endpoint by Day 30 and subsequently does not progress to a score ≥ 4 for the remainder 
of the study. If a subject scores 3 at baseline, this subject is considered to be recovered if 
this subject’s score improves to 1 or 2 by Day 30. 
 
All-cause mortality rate on Day 30.  
Other Secondary Efficacy Endpoints: 
 
Time to sustained recovery among subjects alive by Day 30 [Time Frame: Day 1 through 
Day 30]: Day of sustained recovery is defined as the first day on which the recovered 
subject scores 3, 2 or 1 and maintains such score through Day 30 from the 8-category 
ordinal scale as defined in the key secondary endpoint. If a subject is scored at 3 at 
baseline, day of recovery is defined as the day on which this subject’s score improves to 
1 or 2 and maintains such score through Day 30. 
 
Length of hospitalization. 
2.2.3. 
Exploratory Efficacy Endpoints 
• 
Improvement in clinical status (Day 7, Day 14 and Day 30) 
• 
Sequential Organ Failure Assessment score (SOFA score) (Day 7 and Day 14 from the 
day of dosing) 
• 
Change from baseline in PaO2/ FiO2 (Day 7 and Day 14 from the day of dosing) 
• 
Length of time to normalization of oxygen saturation which is defined as SpO2≥94% 
sustained minimum 24 hours 
• 
Percentage of subjects requiring mechanical ventilation at Day 7 and Day 14 from the 
day of dosing. 
• 
Change from baseline in serum cytokines, e.g. IL-1RA, IL-1β, IL-2, IL-6, IL-7, IL-10, 
GCSF, GM-CSF, CCL2, CCL3, CCL17, CXCL10, TNF-α and IFN-γ, etc. (Day 2, Day 
3, Day 5, Day 7, and Day 14 from the day of dosing) 
• 
Change from baseline in D-dimer, cardiac troponin, LDH, and ferritin levels (Day 7 and 
Day 14 from the day of dosing) 
• 
Peripheral blood neutrophils-to-lymphocyte ratio (NLR) 


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2.2.4. 
Safety Endpoints 
 Treatment-emergent Adverse events evaluated using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events Criteria (CTCAE) (version 5.0),  
 Changes from baseline in clinical laboratory parameters, physical examinations, vital 
sign measurements, 12-lead electrocardiograms (ECGs), and radiographic lung imaging. 
3. 
Investigational Plan 
3.1. Study Design 
This trial is designed as a two-part study to evaluate the efficacy and safety of TJ003234 
administered by an IV infusion in subjects with severe COVID-19 with supportive care, and to 
assess the effect of cytokine elevations on the disease as well as the effect of TJ003234 on the 
levels of cytokines.  
Figure 5: Study Design Schema 
 
 
3.1.1. Part 1  
Part 1 is designed as a randomized, double-blind, placebo-controlled, 3-arm, parallel-group study 
to evaluate the safety of TJ003234 in subjects with severe COVID-19. Potential subjects will be 
screened to assess their eligibility to enter the study within 3 days prior to study drug 
administration. A total of 24 eligible subjects will be randomized at a ratio of 1:1:1 to receive 
either a single dose of 3 mg/kg TJ003234, a single dose of 6 mg/kg TJ00324 or placebo, 
administered by IV infusion. Before and after the treatment, all subjects will be allowed to 
receive supportive care and/or additional treatments for COVID-19 and its complications per the 
Investigator. Up to twenty-four subjects will be enrolled in Part 1. If no more than 2 out of 8 
subjects experience a Grade ≥3 treatment-related AE within 7 days of the subjects receiving the 
study drug in either TJ003234 arm and no more than 4 out of 16 subjects experience a Grade ≥3 


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treatment-related AE within 7 days of the subjects receiving the study drug in both TJ003234 
arms combined, Part 2 will be initiated. The end of Part 1 is defined as 30 days after the last 
subject is dosed, or until study termination. 
Enrolled subjects will complete follow-up visits for 30 days after dosing to assess the safety and 
efficacy of the study drug. Subjects will be followed until the complete all study visits, the subject 
(or their legally authorized representative (LAR)) withdraws consent, the subject is lost to 
follow-up or the subject dies. 
3.1.2. Part 2  
Part 2 is designed as a randomized, double-blind, placebo-controlled, 2-arm, parallel-group study 
to evaluate the efficacy and safety of TJ003234 in subjects with severe COVID-19. Part 2 
contains two phases, the first phase, Phase 2, will enroll 120 subjects and the second phase, Phase 
3, will enroll approximately 450 subjects. The data collected from Phase 2 will be used to make 
decision for Phase 3 and may be used to re-estimate sample size of Phase 3 portion. Potential 
subjects will be screened to assess their eligibility to enter the study within 3 days prior to the 
first dose administration. A total of 570 eligible subjects will be randomized at a ratio of 2:1 to 
receive either a single dose of TJ003234 or placebo, administered by intravenous infusion. 
Randomization will be stratified by age at randomization (<60 years versus ≥ 60 years) and use 
of remdesivir (yes versus no). Before and after the treatment, all subjects will be allowed to 
receive supportive care and/or additional treatments for COVID-19 and its complications per the 
Investigator.  
Enrolled subjects will complete follow-up visits for 30 days after dosing to assess the safety and 
efficacy of the study drug. Subjects will be followed until they complete all study visits, the 
subject meets the withdrawal criteria in Section 4.4 or the subject dies. 
3.1.2.1. Pharmacokinetic (PK) and Anti-Drug Antibody (ADA) Subgroup 
In Part 2 Phase 2 stage, 40 subjects will be randomly assigned to a subgroup to collect PK and 
ADA samples. PK samples will be collected on Day 1 (predose and at End of Infusion), Day 7 
and Day 14. ADA samples will be collected on Day 1 predose and Day 14. Of these 40 subjects, 
30 will be from the 6 mg/kg TJ003234 treatment arm and 10 will be from the placebo arm. 
In Part 2 Phase 3 stage, 40 subjects will be randomly assigned to a subgroup to collect PK and 
ADA samples. PK samples will be collected on Day 1 (predose and at End of Infusion), Day 7 
and Day 14. ADA samples will be collected on Day 1 predose and Day 14. Of these 40 subjects, 
30 will be from the 10 mg/kg TJ003234 treatment arm and 10 will be from the placebo arm. 
3.1.3. 
Study Populations and Sample Size 
Part 1 of the study will enroll up to 24 subjects at a 1:1:1 ratio (3 mg/kg TJ003234 to 6 mg/kg 
TJ003234 to placebo). Part 2 of the study will enroll up to 570 subjects at a 2:1 ratio (TJ003234 
to placebo).  


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3.2. 
Scientific Rationale for Study Design  
GM-CSF, as a key upstream trigger factor in the inflammatory cytokine cascade, can enhance 
the effects of neutrophils and macrophages, produce inflammatory cytokines and activate the 
phagocytosis. In addition, GM-CSF is also an important cytokine that induces the polarization 
of monocytes to the inflammatory M1 phenotype and promotes the activation of macrophages, 
and the macrophages secrete a large number of inflammatory cytokines such as IL-6 and TNF-
α, to involve in tissue inflammation (Hamilton, 1980). The strong proinflammatory effects of 
GM-CSF make it a promising target in acute inflammatory conditions where elevated GM-CSF 
has been implicated in orchestrating a cytokine storm. At least three such syndromes share 
immunological and pathologic features of a cytokine storm: chimeric antigen receptor (CAR)-T 
cell therapy related cytokine release syndrome (CRS), macrophage activation syndrome (MAS) 
and most recently, acute respiratory distress syndrome (ARDS) in severe coronavirus disease 
(COVID-19) cases caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).  
In the recent COVID-19 epidemic caused by the coronavirus SARS-CoV-2 in China, 
approximately 15-30% of severe COVID-19 patients developed ARDS (Wang, 2020; Huang, 
2020; Chen, 2020; Guan, 2020). Without intervention, the clinical course is expected to be dire 
for severe COVID-19 patients. Therefore, there is a huge unmet medical need of therapy for 
severe COVID-19 patients. At present, there is no specific immune modulating therapy for 
severe COVID-19 patient. 
The clinical features (Huang, 2020) and immunopathology (Xu, 2020) of patients with COVID-
19 in China have now been reported, and they remarkably resembled those found in SARS 
(Channappanavar, 2017). Common features among COVID-19 patients, particularly those 
seriously or critically ill, included lymphopenia and significantly elevated levels of inflammatory 
cytokines including IL-1, IL-7, IL-8, IL-9, IL-10, basic FGF, G-CSF, GM-CSF, IFN-γ, IP-10, 
MCP-1, MIP-1A, MIP-1B, PDGF, TNF-α, and VEGF. (Huang, 2020). Massive production of 
IL-6, CRP, D-dimer and ferritin were also observed, which are all indicative of cytokine storm 
(Wang, 2020). Importantly, lung pathology revealed heavy interstitial lymphocytic infiltrates 
along with diffuse alveolar damage with fibromyxoid exudates, multinucleated giant cells and 
hyaline membrane formation, indicative of ARDS (Xu Z, 2020). Interestingly, these pathological 
features and lung CT imaging characteristics are also remarkably similar to those reported for a 
subset of JIA patients that developed MAS that led to severe immunopathology and lung disease 
(Schulert, 2019).  
It seems evident from the recent reports that severe COVID-19 bears all the hallmarks of a 
cytokine storm instigated by exuberant immune cells producing GM-CSF and IL-6. They drive 
aberrant monocyte and T cell activation which in turn produce more cytokines and chemokines 
in a feed forward cycle that culminates in profound tissue injury, airway constriction, vascular 
collapse and organ failure (Zhou, 2020). Peripheral blood mononuclear cell (PBMC) 
immunophenotyping showed an abundance of highly active GM-CSF-producing T helper cells 
and pathogenic monocytes in COVID-19 patients (Xu, 2020; Zhou, 2020). A recent study 
published in Blood showed that GM-CSF antibodies have been demonstrated to effectively 
inhibit the cytokine storm caused by CAR-T cell therapy and reduce the levels of a series of 
inflammatory factors such as IFN-g, IL-6, MCP-1, MIP-1 in preclinical experiments. In addition, 


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it can control the infiltration of immune cells such as T cells and macrophages into the central 
nervous system, and effectively inhibit the generation of neurotoxicity. Compared to tocilizumab 
that has been widely used to treat cytokine storm caused by CAR-T cells, GM-CSF antibodies 
may have better efficacy, especially in regulating the broad spectrum of cytokines and inhibiting 
neurotoxicity. Therefore, two clinical trials will be conducted to evaluate the therapeutic effects 
of GM-CSF antibodies or GM-CSF receptor antibodies on CAR-T cell-induced side effects such 
as cytokine storm and neurotoxicity (Gilead, 2020). Currently, based on the experience of IL-6R 
antibody tocilizumab in managing CAR-T induced CRS, tocilizumab is being tested for reducing 
cytokine storm and its complications in a clinical trial of COVID-19 patients in China (Chinese 
Clinical Trial Registry, n.d.). GM-CSF neutralizing antibody such as TJ003234 may also has the 
potential to prevent or curb cytokine storm and immunopathology and thus earn more time for 
viral clearance, which may improve the overall clinical outcome of COVID-19 severe patients. 
 
3.3. 
Justification for Dose  
In this study, the dose of TJ003234 has been predicted based on the results of safety, 
pharmacokinetics and pharmacodynamics from a single ascending dose study in healthy subjects, 
preclinical data, the safety data of similar GM-CSF antibodies in patients with rheumatoid 
arthritis, as well as the data of IL-6 antibody tocilizumab for treatment of cytokine storms. For 
TJ003234, a single dose escalation study in 32 healthy subjects has been completed. No dose 
limiting toxicity (DLT) was observed in the 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg dose 
groups. The maximum tolerated dose (MTD) was not reached. The half-life of TJ003234 was 
approximately 3 weeks and plasma concentrations increased proportionally with the dose over 
the range 0.3 mg/kg to 10 mg/kg. Pharmacodynamics showed similar levels of inhibition of ex-
vivo GM-CSF-activated pSTAT5 at doses of TJ003234 3 mg/kg and 10 mg/kg. Inhibition of 
more than 90% was reached at 4 hours after dosing and was maintained for 2 weeks (full clinical 
study report submitted to FDA in January 2020). 
The dosing regimen of TJ003234 in the Part 2 Phase 3 trial is amended as 10 mg/kg TJ003234 
or placebo based on the observed efficacy, safety, and PK data in the completed Part 2 Phase 2 
study. In Part 2 Phase 2 study with patients with Covid-19, improved efficacy over the placebo 
arm was observed with an acceptable toxicity profile of TJ003234. At the same time, increased 
clearance of TJ003234 (0.02 L/hr in patients with Covid-19 compared to 0.009 L/hr in healthy 
subjects) was observed at a single dose of 6 mg/kg TJ003234, with a shorter half-life (6 days) 
than in healthy subjects (3 weeks). Therefore, a single dose of 10 mg/kg is expected to further 
improve the magnitude of efficacy improvement by providing higher exposure than that of 6 
mg/kg dose in Covid-19 patients. Based on the observed PK data, the exposure of a single dose 
of 10 mg/kg TJ003234 in patients with Covid-19 is expected to be lower than that in healthy 
subjects. Therefore, an acceptable safety profile is expected to be maintained, as the 10 mg/kg 
has been tested in healthy subjects with excellent safety profile. The dosing regimen of TJ003234 
in the Part 2 Phase 3 trial is amended as 10 mg/kg TJ003234 or placebo based on the observed 
efficacy, safety, and PK data in the completed Part 2 Phase 2 study. 
According to the preclinical toxicology study (Q1W for 4 weeks), the No-Observed-Adverse-
Effect Level (NOAEL) dose in Cynomolgus monkeys was 60 mg/kg. Since molecular weight of 


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TJ003234 is >100,000 Da (146KDa) and administered intravenously, according to FDA 
guidance stating that proteins administered intravascularly with molecular weight >100 KDa 
should be normalized to mg/kg as an exception to mg/m2 scaling approach (CDER, 2005), the 
calculated Human equivalent dose (HED) based on NOAEL is also 60 mg/kg.  
GM-CSF antibodies have been reported to be well tolerated in clinical trials. Namilumab and 
KB003 are drugs with the same mechanism of action as the study drug and both were well 
tolerated at doses of 5-6 mg/kg (Huizinga, et al., 2017). The Phase IIb clinical trial of 
mavrilimumab, which is an antibody of GM-CSF receptor and has a similar mechanism of action 
as the study drug, showed no adverse reactions in the lung (Burmester et al., 2017). The 
autoantibodies of GM-CSF are associated with the development of idiopathic autoimmune 
pulmonary alveolar proteinosis (PAP). There is a theoretical risk of developing PAP when 
therapeutic antibodies targeting GM-CSF are used. Non-clinical studies of mavrilimumab, a 
compound targeting GM-CSF receptor, showed that macrophage change in lung tissues was only 
observed in studies with dosing lasting more than 11 weeks (Ryan et al., 2014). Therefore, it is 
believed that the PAP is a long-term chronic development process and, the risk of PAP developed 
from drug exposure after a single dose is most likely to be low. In addition, we closely monitored 
pulmonary function up to 90 days and no clinical meaningful changes of pulmonary function 
was observed in the single dose escalation study (full clinical study report submitted to FDA in 
January 2020), Taken together with the safety data in human and preclinical studies, we believe 
that a single dose of 3 mg/kg and 6 mg/kg TJ003234 will be safe in the patient population. 
Preclinical pharmacodynamics showed a treatment effect of <50% (as measured by an inhibitory 
effect on the GM-CSF/GM-CSFR signaling pathway) at a single intravenous infusion dose of 3 
mg/kg in the CIA (type II collagen-induced arthritis) model in cynomolgus monkeys. The results 
from the in vitro monocyte activation assay to mimic the COVID-19 viral stimulation of primary 
monocytes confirmed that treatment of 10 μg/ml TJ003234 suppressed the pro-inflammatory 
cytokine production and activation marker expression, indicating that the dose of 3 mg/kg may 
be efficacious since the trough concentration of a single dose of 3 mg/kg exceeds 10 µg/ml in 
the Phase I clinical trial. On theoretical grounds, the GM-CSF levels will further increase in 
COVID-19 patients with cytokine storms compared to healthy individuals and patients with 
autoimmune diseases. This hypothesis has been verified by the clinical data of tocilizumab. The 
mean peak concentration of tocilizumab in patients with cytokine storms caused by CAR-T was 
41% lower than that in patients with systemic JIA, suggesting that tocilizumab was eliminated 
more rapidly in patients with cytokine storms (Le et al., 2018). Therefore, sufficient exposure of 
TJ003234 will be required to effectively reduce GM-CSF levels and thus their downstream 
cytokine levels. Therefore, in order to better assess the dose response of TJ003234 in COVID-
19 severe patients, and determine an optimal dose for further development, we plan to include 
an additional dose level of 6 mg/kg TJ003234. Based on the PK from healthy adults, TJ003234 
PK appears to be linear and we expect that a single dose of 6 mg/kg may produce two-fold of 
drug exposure following a single dose of 3 mg/kg TJ003234, which will remain within the range 
of drug exposure tested to be safe in the FIH.  
Overall, the totality of the data from the non-clinical data and clinical data from the single 
ascending dose escalation study supports 3 mg/kg and 6 mg/kg as safe doses with potential 
efficacy to be administered in COVID-19 patients. Furthermore, the observed efficacy, safety, 


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and PK data in the completed Part 2 Phase 2 study support a single dose of 10 mg/kg TJ003234 
in the subsequent Part 2 Phase 3 trial as a safe dose with potentially further improved efficacy. 
3.4. 
Criteria for Termination of Study  
During the conduct of the study, if the investigator or the sponsor finds that continuation of the 
trial may cause potential harm to subjects, or the study is futile per IDMC’s assessment, the 
decision may be made to terminate the trial after consultation between the investigator, medical 
monitor and the sponsor. 
4. 
Selection of Study Populations  
4.1.  Inclusion Criteria  
1. Age: 18 years or older (including 18 years); male or female 
2. Laboratory-confirmed SARS-COV-2 or COVID-19 infection as determined by polymerase 
chain reaction (PCR) or other commercial or public health assay.  
3. Bilateral lung infection confirmed by imaging 
4. Severe disease that meets one of the following conditions: 
i. 
At rest, finger blood oxygen saturation ≤ 93% or PaO2/FiO2 ≤ 300 mmHg; OR 
ii. 
Requiring high flow oxygen ≥ 15L/min 
5. Subjects or LARs who are willing to participate in this study and sign the informed consent 
voluntarily. 
6. Be willing to follow the contraception guidelines in Appendix 1 
7. Subject has been hospitalized for no more than 5 calendar days at the time of screening. 
4.2. Exclusion Criteria  
1. Any previous and/or current clinically significant disease or condition that has not been stable 
within 3 months prior to enrollment, or acute illness, planned medical/ surgical procedure, or 
any trauma that occurred within 2 weeks prior to enrollment, which, in the opinion of the 
investigator, may place the subject at risk if participating in the study, or may interfere with 
the assessment of the study drug or confound interpretation of the study results, or affect the 
patient's ability to participate in the study independently. 
2. Applies to Part 1 only: Chronic obstructive pulmonary disease (COPD) and moderate/severe 
asthmatic patients requiring inhaled corticosteroid, long-acting beta-adrenergic agonists, 
long-acting anticholinergics, or long-term oxygen therapy. Mild asthmatic patients treated 
with short-acting beta-adrenergic agonists and/or low dose of inhaled corticosteroid and/or 
long-acting beta-adrenergic agonists are considered eligible. Please refer to Appendix 4 for 
inhaled cortiscoteroids dose guidance. 
3. Pulmonary interstitial disease, pulmonary alveolar proteinosis, and pulmonary 
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4. Cardiovascular event in the 3 months prior to study drug administration: acute myocardial 
infarction or unstable angina pectoris, severe arrhythmia (multiple sources of frequent 
ventricular premature beat, ventricular tachycardia and ventricular fibrillation); New York 
Heart Association Classification (NYHA): Class III-Class IV. 
5. Severe renal impairment: e.g. eGFR ≤30 ml/min estimated by MDRD equation or have 
received treatments such as kidney transplantation and dialysis. 
6. Subjects that cannot adhere to protocol requirements due to neuropsychiatric disorders. 
7. Severe liver disease: e.g. Child-Pugh Score for Cirrhosis as (Grade C, elevated aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) (> 5 × upper limit of normal. 
8. Known active or chronic hepatitis B or C infection or human immunodeficiency virus (HIV). 
9. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known 
extrapulmonary TB, suspected or known systemic bacterial or fungal infections. 
10. Blood system disorders or routine blood analysis test abnormalities: 
 Hemoglobin < 8 g/dL; 
 ANC <1500 × 109/L; 
 Platelets < 50 × 109/L. 
11. Dependence on glucocorticoid treatment equivalent to methylprednisolone 2 mg/kg/ day or 
more or long-term use of anti-rejection or immunomodulatory drugs. 
12. Subjects that require invasive mechanical ventilation or ECMO. 
13. Pregnant or breastfeeding females. 
14. Have received any live vaccination within 30 days before dosing. 
15. Subjects who, in the opinion of the investigator, are not suitable for participation in this 
clinical study or will not agree to follow the institution’s supportive care protocol. Any 
condition that, in the opinion of the investigator, may increase the risk associated with the 
subject's participation in the study or may interfere with the assessment of the study drug or 
confound the interpretation of the study results.  
4.3. Subject Numbering  
Three-digit subject numbers will be allocated as all subjects consent to take part in the study. 
Subject numbers in Part 1 will follow the pattern “1yy”. Subject numbers in Part 2 will follow 
the pattern with “2yy” and “3yy”. Within each study site, this number will be allocated to subjects 
according to the sequence of presentation for trial participation. The subject number will be 
combined with the 4-digit site number (“xxxx”) to form the unique 7-digit subject identifier 
(“xxxx-1yy” for subjects in Part 1 and “xxxx-2yy” for subjects in Part 2 Phase 2 and “xxxx-3yy” 
for subjects in Part 2 Phase 3) for the study. This subject ID number will also be used as a unique 
identifier for the subject throughout the study for lab reports, source, safety reporting forms, case 


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report forms (CRFs), etc. 
4.4. Withdrawal Criteria   
A subject is free to withdraw from the study at any time. In addition, a subject will be withdrawn 
if any of the following criteria are met: 
1) Subject withdraws informed consent  
2) Subject is lost to follow-up after the investigator or designee has made multiple 
documented attempts to regain contact with the subject, including at least two attempts 
by telephone and a final attempt by certified or traceable mail. 
Prior to withdrawal, subjects should be encouraged to complete all follow-up assessments if 
possible. Subjects with ongoing adverse events at the time of withdrawal should be followed in 
accordance with Section 7.1.5.   
5. 
Study drug 
The study drug, TJ003234, is provided by I-Mab Biopharma Co., Ltd., and should only be used 
for this study according to the study protocol and Pharmacy Manual. Placebo will be 0.9% 
sodium chloride injection (normal saline) and must be provided by the site. 
5.1. Physical and chemical properties, specifications and ingredients of drugs    
TJ003234 is a recombinant anti-GM-CSF humanized monoclonal antibody, consisting of two 
heavy chains and two light chains of IgG1. Each heavy chain contains 450 amino acids and each 
light chain contains 214 amino acids. Its theoretical molecular weight is about 146 kDa.  
TJ003234 is a brown-yellow sterile liquid, with a specification of 200 mg/2 ml/ vial. Its 
ingredients contain 100 mg/ml TJ003234, 0.96 mg/ml L-histidine, and 2.89 mg/ml L-histidine 
hydrochloride, 75.31 mg/ml sucrose, 0.2 mg/ml polysorbate 80 (pH 5.8).  
The drug TJ003234 should be stored and transported at 2-8°C, protected from light.  
5.2. Drug Packaging, Labelling, and Storage  
TJ003234 drug product is packaged in a 2 ml type I glass vial, stoppered with 13 mm bromobutyl 
rubber stopper (Aptar Stelmi) and capped with aluminum cap. Vials of TJ003234 will be 
packaged in cartons. Each vial and carton will contain a label stating the study number, lot 
number, date of manufacture, drug type, storage conditions, and appropriate precautionary 
statements. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
All study treatments must be stored in a secure, environmentally controlled area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized 
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5.3. 
Drug Dispensing, Administration and Dosage  
5.3.1. Randomization and Blinding 
Both parts of this study are randomized, double-blind, and placebo controlled. 
Most study personnel will remain blinded for the duration of each Part of the study (i.e., Part 1 
will remain blinded until the completion of Part 1, at which point it will be unblinded for 
exploratory analyses; Part 2 phase 2 will remain blinded until completion of Part 2 phase 2; and 
Part 2 phase 3will remain blinded until database lock). To allow for the execution of clinical 
trial-related services, the following individuals will be unblinded during the study: 
 External randomization and trial supply management (RTSM) vendor 
 Independent Statistician 
 External clinical supply distribution vendor 
 Bioanalytical laboratory analyst 
 Sponsor Drug Supply Management Representative 
 Site pharmacy staff 
 Unblinded study nurse (if needed for site operations to administer study drug) 
5.3.1.1. Part 1 
There will be approximately 24 subjects randomized 1:1:1 (eight 3 mg/kg TJ003234: eight 6 
mg/kg TJ003234: eight placebo) to the following treatment arms: 
 Treatment 1A: TJ003234 3 mg/kg (initial dose assignment based on weight at screening); 
single dose. 
 Treatment 1B: TJ003234 6 mg/kg (initial dose assignment based on weight at screening); 
single dose. 
 Treatment 1C: Placebo (administered as normal saline); single dose. 
Randomization will not be stratified. Each investigational site will randomize subjects to 
treatment groups using a randomization scheme generated by an RTSM system. Treatment 
allocation will be blinded per Section 5.3.1.  
After the safety evaluation and decision has been made to continue to Part 2, the data from Part 
1 will be analyzed for exploratory analysis. 
5.3.1.2. Part 2 
There will be approximately 570 subjects randomized 2:1 (380 TJ003234: 190 placebo) to the 
following treatments arms: 
 Treatment 2A: TJ003234 6 mg/kg (phase 2) or 10 mg/kg (phase 3), with initial dose 


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assignment based on weight at screening; single dose. 
 Treatment 2B: Placebo, administered as normal saline; single dose. 
Randomization will be stratified by age at randomization (<60 years versus ≥ 60 years) use of 
remdesivir (yes versus no). Each investigational site will randomize subjects to treatment groups 
using a randomization scheme generated by an RTSM system. For more information, please refer 
to the Pharmacy Manual. Treatment allocation will be blinded per Section 5.3.1. 
5.3.2. Drug Dispensing  
Once the treatment assignment has been confirmed per Section 5.3.1.1 or Section 5.3.1.2, if the 
subjects is assigned to a TJ003234 treatment arm, the study drug dose will be calculated 
according to the body weight of subjects at screening when dispensing. The study drug is diluted 
to appropriate volume and concentration with 0.9% sodium chloride injection (normal saline) 
(see Table 4). After dilution with normal saline in the infusion bag, diluted study drug should be 
fully infused within 4 hours if stored at room temperature, or within 24 hours if stored at 2-8℃. 
If the subject is assigned to a placebo arm, normal saline will be administered per the Pharmacy 
Manual. 
Table 4. Study drug dispensing dose and volume 
 
For specific instructions on the preparation and management of the study drug, refer to the 
Pharmacy Manual.  
5.3.3. 
Drug Administration  
After pre-dose procedures have been conducted on Day 1, eligible subjects will receive a single 
dose of their assigned treatment, diluted using normal saline (0.9% NaCl) to the appropriate 
volume and concentration per Table 4 and the subject’s body weight at screening. Administer 
using a low-protein-binding 0.22 μm in-line filter and an infusion pump. The infusion line should 
be flushed with 0.9% sodium chloride injection after TJ003234 administration to ensure that the 
subject receives the full dose. All doses should be administered over 1 hour. Further instructions 
with details on handling and administration of study drug is described in the separate Pharmacy 
Manual. 
5.4. 
Compliance Requirements  
5.4.1. 
Contraceptive requirements 
Females of childbearing potential and males should agree to take appropriate contraceptive 
Subject weight 
Dosing mode  
Infusion bag  
Specification and total 
volume of infusion bag  
≤ 100 kg 
Intravenous drip 
Infusion bags 
100 mL 
100.1 to 250 kg 
Intravenous drip 
Infusion bags 
250mL 


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measures during the trial period and for 4 months after the final dose of study drug. For detailed 
instructions and definitions, please refer to Appendix 1.  
5.5. 
Concomitant Medication and Therapies  
The investigator should record all concomitant medications (including any investigational 
therapies), indications, daily doses, starting and ending dates of dosing throughout the study.  
Medications and therapies administered within 3 days of the first dose of study drug (with the 
exception of SARS-CoV-2 vaccine history) should be recorded as prior medications or therapies. 
Medications or therapies received after the first dosing of the study drug should be recorded as 
concomitant medications or therapies.  
5.6. 
Prohibited Medications 
The following prior or concomitant medications are not allowed during the trial:  
1. Immunomodulatory/immunosuppressive drugs, including biologics and JAK inhibitors 
except when administered as a rescue therapy as described in Section 5.7  (Note: 
recommended drugs for standard treatment are allowed, such as Glucocorticoid). 
2. Drugs that may aggravate the subjects’ conditions per the investigator’s judgement.  
3. Any vaccine during the trial or any live vaccine within 30 days prior to dosing, with the 
exception of the SARS-CoV-2 vaccine.     
5.7. 
Rescue Therapies 
Rescue therapies are considered to be any otherwise prohibited medications given for COVID-
19 (e.g. convalescent plasma, tocilizumab, etc.) that are administered after the subject has 
received the study drug and experiences deterioration in their clinical condition. Rescue therapies 
are permitted  after study drug administration at the Investigator’s discretion and a deterioration 
of clinical status must be documented. Prior to administering a rescue therapy, perform the 
following procedures as an unscheduled visit: 
 Clinical Status Assessment 
 Arterial Blood Gas Analysis 
 SOFA Score 
 PaO2/FiO2 ratio 
 Physical Examination 
 Pulse Oximetry 
 Vital Signs 
 Clinical Laboratory Tests: CBC, Serum Biochemistry, Troponin, CRP, LDH, Ferritin, 
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6. 
Study Procedures   
This trial will use a 2-part randomized, double-blind, placebo-controlled design and observation 
for 30 days after a single dose of study drug. The study procedures are described below.  
6.1. 
Description of Study Procedures  
6.1.1. 
Vital signs and Pulse Oximetry 
The following vital signs will be measured according to the schedule of procedures: temperature, 
pulse, respiratory rate and blood pressure.  
Vital signs should be monitored and recorded within 30 min before drug infusion, 30 min ± 5 
min after the start of infusion, at the end of infusion ± 5 min, and 60 min ± 5 min after infusion.  
The measurement of blood pressure and pulse should occur according to institutional practices.  
Pulse oximetry should be recorded daily while hospitalized. The lowest registered level from 
each day should be collected. 
6.1.2. 
Physical examination 
A general physical examination should include the overall appearance, head and face, ear, nose, 
throat, mouth, skin, lymph nodes, respiratory, cardiovascular, abdomen, urogenital (when 
necessary), musculoskeletal and nervous, and neurological systems. Missed body systems will 
not be considered a protocol deviation, unless there are ongoing Adverse Events that are not 
assessed as a result of missed body systems. 
6.1.3. 
ECG   
ECGs will be performed as specified in the schedule of procedures according to institutional 
practices.  
During visits where both ECGs and blood draws are scheduled, the ECG should take place before 
the blood draws.  
6.1.4. 
Clinical laboratory tests  
Blood samples will be collected for serum biochemical and hematological analysis. Urine 
samples will be collected for urinalysis. The investigator shall review the laboratory test results 
and record laboratory test results with clinical significance as judged by the investigator as an 
adverse event.  
Table 5. Laboratory Tests 


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Serum 
biochemical 
test  
• Blood glucose 
• Liver and kidney functions: Alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, γ-glutamyltransferase, total protein, albumin, total bilirubin, 
direct bilirubin, creatinine, eGFRa, BUN, uric acid.  
• Serum electrolytes: potassium, sodium, chlorine, calcium, magnesium, inorganic 
phosphorus.  
CBC 
• White blood cells, absolute neutrophil count and percentage, absolute lymphocyte 
count and percentage, absolute monocyte count and percentage, absolute eosinophil 
count and percentage, absolute basophil count and percentage. 
• Red blood cells, hemoglobin, hematocrit, mean cell volume  
• Platelets 
Coagulation 
assessment 
• Prothrombin time, International Normalized Ratio 
• Activated partial thromboplastin time 
• D-dimer 
Urinalysis 
• Bilirubin, Blood, Color and appearance, Glucose, Ketones, Leukocyte esterase, Nitrite, 
pH, Protein, Specific gravity, Urobilinogen 
• Microscopic examination (if protein, leukocyte esterase, nitrite, or blood is positive) 
Other  
• β-human chorionic gonadotropin b 
• Follicle-stimulating Hormone (FSH) test c 
• Inflammation-related indicators: troponin, C-reactive protein, LDH, serum ferritin 
• Arterial blood gas analysis: pH, partial pressure of oxygen, partial pressure of carbon 
dioxide, total carbon dioxide, oxygen saturation, actual bicarbonate, standard 
bicarbonate, base excess, anion gap  
• SARS-CoV-2 diagnostic test by PCR or other commercial or public health assay. Note 
that a standardized method should be used for collection of nasopharyngeal samples. 
Please use the same nostril for collections if only one nostril will be sampled. 
• Cytokines, such as IL-1RA, IL-1β, IL-2, IL-6, IL-7, IL-10, GCSF, GM-CSF, CCL2, 
CCL3, CCL17, CXCL10, TNF-α and IFN-γ 
• Pharmacokinetic Sampling (for those in the PK/ADA subgroup in Part 2) 
• ADA Sampling (for those in the PK/ADA subgroup in Part 2) 
a. 
eGFR(ml/min×1.73m2) =175×creatinine ([Scr(mg/dL)])-1.154×age-0.203×gender ( male=1, female =0.742)×1.212 (if black) ; 
b. 
Serum pregnancy test for women of childbearing potential at the time of screening.  
c. 
If needed to confirm menopausal status. 
6.1.5. 
Radiographic Lung Imaging 
Radiographic lung imaging includes lung CT or chest X-ray. If this procedure was performed as 
standard of care in the 14 days prior to Day 1 and radiographic infiltrates are present, this may 
be used, and imaging is not required at Screening or Day 1.      
6.1.6. 
Pregnancy test 
A blood pregnancy test will be performed for women of childbearing potential at screening. 
Pregnant women are not eligible to participate in this study and will be considered ineligible for 
screening.    


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6.1.7. 
Adverse Events (AEs)  
The investigator should collect and record AEs for each subject from the signing of the informed 
consent to 30 days after the last dose. The investigator is responsible for observation, recording 
and follow-up of all AEs that occur during the study, regardless of any cause. Serious adverse 
events (SAEs) that occur within 30 days after the last dose should also be collected and reported 
if considered as related to TJ003234 by investigator (see Section 7.2.3 for the reporting process). 
The investigator will follow up AEs as specified in Section 7.  
6.2. 
Screening period (Day -3 to Day -1)  
Subjects (or LAR) should sign a written or electronic ICF on a voluntary basis before screening. 
The screening is performed within Day -3 to Day -1, to identify if they meet the 
inclusion/exclusion criteria. Those subjects who meet all inclusion criteria and do not meet any 
one of the exclusion criteria are eligible to participate in this trial. The screening procedures 
include the following:  
 
Demographic data (including gender, age, ethnicity, date of birth); 
 
Height and body weight;  
 
Medical history from previous 5 years, including smoking history. Ensure that the date 
of onset of COVID-19 symptoms is recorded as part of the Medical History;  
 
SARS-CoV-2 vaccine history (not restrictive to within 3 days before dosing); 
o 
Number of doses 
o 
Date of dose(s) 
o 
Brand name 
 
Collecting a complete history of prescription or over-the-counter drugs, dietary 
supplements and herbal medicines used within 3 days before dosing;  
 
Physical examination; 
 
12-lead ECG; 
 
Vital signs; 
 
PaO2/FiO2 ratio; 
 
Radiographic lung imaging (chest x-ray or CT) (see section 6.1.5);  
 
Biological samples are collected for the following tests. If any of these labs were drawn 
prior to subject signing consent, but within 72 hours of dosing, they may be used for the 
purposes of this visit and they do not need to be repeated:  
o 
Safety laboratory tests (CBC, blood biochemistry test, urinalysis); 
o 
Coagulation function test (prothrombin time (PT), activated partial prothrombin 
time (APTT), international normalized ratio, D-dimer);   
o 
Blood β-HCG testing (required for female subjects of childbearing potential only);  


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o 
FSH test (to confirm menopausal status, if applicable) 
o 
Testing of C-Reactive Protein (CRP), Lactate Dehydrogenase (LDH) and serum 
ferritin;  
o 
SARS-CoV-2 diagnostic test by PCR or other commercial or public health assay. 
If a subject has a positive test within the 14 days prior to study drug administration, 
this may be used to assess eligibility, and an additional test at screening does not 
need to be performed. Note that a standardized method should be used for collection 
of nasopharyngeal samples. Please use the same nostril for collections if only one 
nostril will be sampled. 
o 
Arterial blood gas analysis; 
o 
Testing of cytokine levels.  
 
Pulse oximetry;  
 
Collection/evaluation of adverse events at baseline. 
 
Review subject eligibility 
6.3. 
Baseline period (Day 1)  
Subjects will complete the following procedures before dosing: 
 
Review any changes in subject’s status since screening to confirm eligibility;  
 
Physical examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Arterial blood gas analysis (may be omitted if screening test was done within 24 
hours); 
o 
Troponin test;  
o 
Testing of CRP, LDH and serum ferritin; 
o 
Testing of cytokine levels. 
o 
PK and ADA sampling (if included in the PK/ADA subgroup in Part 2) 
 
Vital signs; 
 
PaO2/FiO2 ratio; 
 
12-lead ECG; 
 
Pulse oximetry; 
 
Record baseline respiratory support requirements (e.g., oxygen requirements) 
 
Clinical status assessment; 


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 
SOFA score. 
If dosing occurs within 24 hours of screening, pre-dose procedures do not need to be repeated, 
unless the labs are from within >24 hours of dosing. The following procedures must be 
completed Predose, as they were not completed as screening assessments: 
 SOFA score 
 Clinical Assessment 
 Troponin test 
After completing the above procedures, subjects will be randomized and receive their assigned 
study drug by IV infusion.  
During the infusion, vital signs will be measured in accordance with Section 6.1.1. After end of 
infusion, the following procedures will be performed:  
 
Vital signs;  
 
12-lead ECG; 
 
Collection/evaluation of adverse events; 
 
Monitoring concomitant medication/treatment. 
After the infusion, the following procedure will be performed within 15 minutes of end of 
infusion: 
 
PK sampling (for those subjects in the PK/ADA subgroup in Part 2) 
6.4. 
Follow-up period: Day 2  
The following procedures will be performed:  
 
Vital signs;  
 
Physical Examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Testing of CRP, LDH and serum ferritin; 
o 
Testing of cytokine levels. 
 
Pulse oximetry 
 
Collection/evaluation of adverse events; 
 
Monitoring concomitant medication/treatment. 
6.5. 
Follow-up period: Day 3 
The following procedures will be performed  
 
Vital signs; 


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 
Physical Examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Testing of CRP, LDH and serum ferritin; 
o 
Testing of cytokine levels. 
 
Pulse oximetry 
 
Collection/evaluation of adverse events 
 
Monitoring concomitant medication/treatment 
6.6. 
Follow-up period: Day 5  
The following procedures will be performed:  
 
Vital signs; 
 
Physical Examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Testing of CRP, LDH and serum ferritin; 
o 
Testing of cytokine levels. 
 
Pulse oximetry 
 
Collection/evaluation of adverse events 
 
Monitoring concomitant medication/treatment 
6.7. 
Follow-up period: Day 7  
If subjects are discharged prior to this visit, the visit may occur as an outpatient or 
telephone visit. If the visit occurs via telephone, only collection/evaluation of adverse 
events, clinical status assessment (including whether subject is still on supplemental 
oxygen support), and monitoring concomitant medication and treatment must occur. The 
following procedures will be performed: 
 
Vital signs; 
 
Physical Examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Arterial blood gas analysis (not needed if conducted as an outpatient visit); 


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o 
Troponin test; 
o 
Testing of CRP, LDH and serum ferritin; 
o 
SARS-CoV-2 diagnostic test by PCR or other commercial or public health assay 
o 
Testing of cytokine level. 
o 
PK sampling (for those subjects in the PK/ADA subgroup in Part 2) 
 
12-lead ECG; 
 
PaO2/FiO2 ratio (not needed if conducted as an outpatient visit) 
 
Pulse oximetry 
 
Radiographic Lung Imaging;  
 
Clinical status assessment; 
 
SOFA score (not needed if conducted as an outpatient visit); 
 
Collection/evaluation of adverse events; 
 
Monitoring concomitant medication/treatment. 
6.8. 
Follow-up period: Day 11 ± 1  
If subjects are discharged prior to this visit, this visit may occur via telephone. If the visit 
occurs via telephone, only collection/evaluation of adverse events, and monitoring 
concomitant medication and treatment must occur. Otherwise, the following procedures 
will be performed:  
 
Vital signs; 
 
Pulse oximetry; 
 
Collection/evaluation of adverse event 
 
Monitoring concomitant medication/treatment 
6.9. 
Follow-up period: Day 14 ± 2  
If subjects are discharged prior to this visit, the visit may occur as an outpatient or telephone 
visit. If the visit occurs via telephone, only collection/evaluation of adverse events, clinical 
status assessment (including whether subject is still on supplemental oxygen support), and 
monitoring concomitant medication and treatment must occur. The following procedures 
will be performed: 
 
Vital signs; 
 
Physical Examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Arterial blood gas analysis; (not needed if performed as an outpatient visit); 


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o 
Troponin test; 
o 
Testing of CRP, LDH and serum ferritin; 
o 
SARS-CoV-2 diagnostic test by PCR or other commercial or public health assay 
o 
Testing of cytokine levels 
o 
PK and ADA sampling (if included in the PK/ADA subgroup in Part 2) 
 
12-lead ECG; 
 
PaO2/FiO2 ratio (not needed if conducted as an outpatient visit) 
 
Pulse oximetry 
 
Radiographic lung imaging;  
 
Clinical status assessment; 
 
SOFA score (not needed if conducted as an outpatient visit); 
 
Collection/evaluation of adverse events; 
 
Monitoring concomitant medication/treatment. 
6.10. Follow-up period: Day 30± 2 (End of Study Visit)  
If subjects are discharged prior to this visit, this visit may occur as an outpatient visit or via 
telephone. If the visit occurs via telephone, only collection/evaluation of adverse events, clinical 
status assessment (including whether subject is still on supplemental oxygen support), and 
monitoring concomitant medication and treatment must occur. Otherwise, the following 
procedures will be performed: 
 
Vital signs; 
 
Physical Examination; 
 
Biological samples are collected for the following tests:    
o 
Safety laboratory tests (routine blood analysis, blood biochemistry test, urinalysis); 
o 
Coagulation function test (PT, aPTT, INR, D-dimer); 
o 
Arterial blood gas analysis (not needed if conducted as an outpatient visit); 
o 
Testing of CRP, LDH and serum ferritin; 
o 
SARS-CoV-2 diagnostic test by PCR or other commercial or public health assay 
o 
Testing of cytokine levels. 
 
12-lead ECG; 
 
PaO2/FiO2 ratio (not needed if conducted as an outpatient visit); 
 
Pulse oximetry; 
 
Radiographic lung imaging;  
 
Clinical status assessment; 


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 
SOFA score (not needed if conducted as an outpatient visit); 
 
Collection/evaluation of adverse events; 
 
Monitoring concomitant medication/treatment. 
6.11. Discharge from Hospital 
If a subject is discharged from the hospital prior to the end of study visit, an unscheduled arterial 
blood gas analysis, PaO2/FiO2 ratio, and a SOFA score should be completed based on the last 
arterial blood gas analysis performed while the subject was hospitalized. 
7. 
Safety and Reporting 
7.1. Adverse Events  
Adverse events observed or discovered by the Investigator or those reported by subjects, 
regardless of having a suspicious causal relationship with the study drug or not, must be recorded 
according to the following requirements.  
7.1.1. 
Definition of Adverse Events 
An adverse event (AE) is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial whether or not the event is considered related to the study 
drug. Disease progression or deterioration must also be recorded as an AE/SAE, regardless of 
whether the Investigator assesses that it is related to the study drug. Additionally, signs and 
symptoms from the following may be considered AEs: drug overdose, withdrawal or misuse, 
drug interactions, extravasations, exposure during pregnancy/breastfeeding. 
7.1.2. 
Collection of Adverse Events  
The Investigator should report all adverse events using concise medical terminologies. Disease 
diagnosis should be given as much as possible rather than listing symptoms and signs only.  
The Investigator should collect and record adverse events for all subjects from the signing of the 
informed consent to 30 days after the last dose or the subject meets the withdrawal criteria in 
Section 4.4. The Investigator is responsible for observation, recording and follow-up of all 
adverse events that occur during the study, regardless of any cause. SAEs that occur after 30 days 
of the last dose or after a withdrawal criteria is met should also be collected and reported (see 
7.2.4 for the reporting process) if judged to be possibly related to the study drug by the 
investigator.   
For any adverse event that occurs during this trial, regardless of seriousness and relatedness, the 
Investigator should record them in the CRF, including the occurrence date, symptoms, severity 
(CTCAE), even start and stop dates, action taken with the study drug (no action taken, stopped 
temporarily, permanently discontinued or N/A), treatment methods and outcomes (resolved, 
resolved with sequelae, not resolved, resolving, fatal, or unknown), etc. In addition, based on a 
comprehensive consideration of the disease itself, comorbidities, and concomitant 


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medications/therapies, its causal relationship with the study drug should be evaluated.  
The Investigator should determine whether the abnormal laboratory test result is clinically 
significant or not. If the abnormal laboratory test value is clinically significant, it should be 
recorded as an adverse event on the original medical records and CRFs.   
If unexplainable, abnormal laboratory test results occur, repeated tests or follow up should be 
performed until the test results are within the normal range or at the baseline level and/or the 
abnormal results are reasonably and adequately explained and recorded on the original medical 
records and CRFs.  
If any new infections occur regardless of the infection agent (i.e., viral or non-viral), they should 
be recorded as AEs. Additionally, in the CRF, the site of infection and source of culture 
(bronchoalveolar lavage, tracheal aspirate, sputum, blood, urine, etc.,) should also be recorded.  
7.1.3. 
Criteria for severity of adverse events 
The severity of adverse events is judged per CTCAE version 5.0 standard, divided into the 
following 5 grades:  
 
Grade 1- Mild, requiring no treatment or requiring minimal, non-invasive treatment 
only. 
 
Grade 2- Moderate, requiring a general degree of non-invasive treatment. 
 
Grade 3- Serious, resulting in limited daily activities. 
 
Grade 4- Symptoms that may be life-threatening, leading to limited daily activities, or 
permanent injury and disability. 
 
Grade 5- Death.  
7.1.4. 
Criteria for determining causality between adverse events and study drug  
The investigator will determine the causality between adverse events and the study drug 
according to the correlation between them, and divide them into five categories, they are 
“definitely related, probably related, possibly related, unlikely related, definitely unrelated”. 
“Definitely related, probably related, and possibly related” are classified into related to the study 
drug, and “unlikely related, definitely unrelated” are classified into unrelated to the study drug.   
 
Definitely unrelated   
AE is definitely not related to the use of study drug.  
  Unlikely related 
AE is more likely to be caused by other factors such as concomitant medications or concomitant 
disease, or the temporal relationship indicates that it is unlikely to be causally related to the study 
drug.   
 
Possibly related  


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AE may be related to the study drug. Other factors such as concomitant medications or 
concomitant disease have not been identified yet. There is a reasonable temporal relationship 
between the AE and study drug; therefore, a causal relationship is not ruled out.  
 
Probably related  
AE may be related to the drug use. There is indicative temporal relationship (for example, 
determined by study drug discontinuance). It is unlikely to be caused by other factors such as 
concomitant medications or concomitant disease.   
 
Definitely related 
AE is a possible adverse reaction and cannot be explained by other reasons, such as concomitant 
medications and concomitant disease. There is an obvious temporal relationship between the AE 
and the study drug (for example, it can be determined by study drug discontinuance and 
rechallenge).    
7.1.5. 
Follow-up of Adverse Events 
All adverse events (including abnormal laboratory test results) must be followed up until the end 
of the study or any one of the following conditions has been achieved, whichever occurs later: 
 The event has resolved;  
 The event is stable;  
 The event returns to the baseline level; 
 The event is judged as not treatment-related by investigator;  
 When more information is not available (subject withdrew consent and/or refuses to 
provide more information, is lost to follow up or dies);  
 The investigator determines that further follow-up is not warranted.   
7.2. Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI)  
7.2.1. 
Definition of SAE  
An AE that meets any one of the following conditions, regardless of whether related to study 
drug or not, should be considered a serious adverse event:  
1) Results in death; 
2) Is life-threatening (i.e., the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death);  
      3) Causes inpatient hospitalization or prolongation of existing hospitalization;  
4) Results in persistent or significant disability/incapacity; 
5) Is a congenital anomaly or birth defect (in the child of a subject who was exposed to the 
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Other important medical events that may not be immediately life-threatening or result in death 
or hospitalization but, when based on appropriate medical judgment, may jeopardize the subject 
or may require intervention to prevent one of the outcomes in the definition of SAE listed above 
should also be considered SAEs.  Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations.   
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalized: 
 Hospitalizations for respite care 
 Planned hospitalizations required by the protocol 
 Hospitalizations planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
 Hospitalization for routine maintenance of a device (e.g., battery replacement) that was 
in place before study entry 
7.2.2. 
Adverse Event of Special Interest (AESI)  
This study will consider the following AEs to be AESIs:  
 Infusion-related reactions at grade 3 or higher 
 Grade 3 or higher infections 
 Pulmonary alveolar proteinosis.  
These AESIs may not meet the criteria of an SAE, but the investigator shall report them 
according to the reporting requirements and timeframe of SAEs (i.e., the investigator shall fill 
out the Serious Adverse Event Report Form as soon as possible (within 24 hours) after becoming 
aware of the AESI, and follow up the outcome of the event. If the IRB has any reporting 
requirements for the AESI, the investigator shall report them in accordance with relevant IRB 
requirements (if applicable).    
7.2.3. 
Reporting of SAEs and AESIs  
Any SAE or AESI, which occurs to any subject participating in this study must be reported by 
investigator to the sponsor within 24 hours (and IRB as required) of first becoming aware of the 
event. The study sponsor will be responsible for notifying the FDA of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible, but in no later than 7 calendar 
days after the sponsor's initial receipt of the information. In addition, the sponsor must notify 
FDA and all participating investigators in an IND safety report of potential serious risks, from 
clinical trials or any other source, as soon as possible, but in no later than 15 calendar days after 
the sponsor determines that the information qualifies for reporting. 
SAEs will be collected by the investigator from the time of consent through 30 days after the last 
dose of study drug or the subject meets the withdrawal criteria in Section 4.4. Any SAE that is 
judged by the investigator to be related to the study drug must be reported regardless of the 
amount of time since the last dose received. Follow-up information collected for any initial report 
of an SAE must also be reported to the sponsor (or its designee) within 24 hours of receipt by 


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the investigator.  
In the event of death, regardless of cause, all attempts should be made to obtain the death 
certificate and any autopsy report, if performed. These records should be reviewed in detail, and 
the investigator should comment on any event, lab abnormality, or any other finding, noting 
whether it should be considered a serious or non-serious AE, or whether it should be considered 
as part of the subject’s history. In addition, all events or other findings determined to be SAEs 
should be identified on the follow-up SAE form and the investigator should consider whether 
the event is related or not related to study drug. 
7.3. Pregnancy  
A pregnancy event refers to pregnancy of a female subject or a male subject’s partner during the 
trial. After becoming aware of the pregnancy, the investigator shall immediately fill out the 
Pregnancy Report Form, and promptly (within 24 hours after becoming aware of the pregnancy) 
report them to the sponsor or designee (and the IRB, if required). Pregnancy outcomes will be 
followed by the Sponsor. In addition, the investigator must report to the sponsor or designee 
follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome.  
7.4. Emergency Unblinding  
As a double-blind, placebo-controlled study, both the subjects and Investigators are blinded to 
the study treatment assignment. In addition, it is anticipated that all clinical research personnel, 
laboratory personnel, except for personnel needed to prepare the study drug, are blinded to the 
treatment assignment and will remain blinded through the completion of the study.  
In the event emergency unblinding of study treatment is necessary, the Investigator shall utilize 
the RTSM system to obtain subject dose details. The individual subject dose details should be 
revealed only in case of an emergency where the further treatment of the subject is dependent on 
knowing the study medication he or she has received. The date and time of breaking the blind as 
well as the reason must be recorded on the subject study medication record. The subject will be 
automatically discontinued from the study in the event emergency unblinding of study treatment 
takes place. If a blind is broken due to an adverse event, a corresponding adverse event entry 
must be completed in the CRF. Any ongoing AEs will be followed in accordance with Section 
7.1.5 of the protocol. 
It is strongly encouraged that unblinding only be completed after consultation with the medical 
monitor, provided this does not compromise subject safety. If unblinding should occur (either by 
accident or for a medical emergency), the Investigator must promptly and immediately notify 
the Sponsor, study medical monitor, and IRB/IEC, and document the circumstances surrounding 
this action in a memorandum to the study file. 
8. 
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8.1. 
Data Record and Management  
As used in this protocol, the term CRF should be understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each subject. The completed original CRFs are 
the sole property of I-Mab Biopharma and should not be made available in any form to third 
parties, except for authorized representatives of I-Mab Biopharma or appropriate regulatory 
authorities, without written permission from I-Mab Biopharma. 
The Investigator has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 
and ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, 
timely (contemporaneous), enduring, and available when required. The CRFs must be signed by 
the Investigator or by an authorized staff member to attest that the data contained on the CRFs 
are true. Any corrections to entries made in the CRFs or source documents must be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. In most cases, 
the source documents are the hospital's or the physician's patient chart. In these cases, data 
collected on the CRFs must match the data in those charts. Discrepancies in the data will be 
brought to the attention of the clinical team, and investigational site personnel, if necessary. 
Resolutions to these issues will be reflected in the database. An audit trail within the system will 
track all changes made to the data.  
8.2. 
Protocol Deviations  
The Investigator must adhere to the protocol as detailed in this document. The Investigator will 
be responsible for enrolling only those subjects who have met protocol eligibility criteria. The 
Investigators will be required to sign an Investigator Agreement to confirm acceptance and 
willingness to comply with the study protocol. The Investigator should document and explain 
any protocol deviations in source. The Investigator should promptly report any deviations to 
the Sponsor or designee, and to the IRB/EC in accordance with established IRB/EC policies 
and procedures. The Sponsor or designee will review all protocol deviations and conduct 
impact assessments as needed. As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility criteria, 
are not allowed and will not be granted. 
8.3. 
Record Retention  
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval 
of 
a 
marketing 
application 
in 
an 
International 
Conference 
on 
Harmonisation/International Council for Harmonisation (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product. 
The Investigator must retain these documents for the time period described above or according 
to local laws or requirements, whichever is longer. Essential documents include, but are not 
limited to, the following:  signed informed consent documents for all subjects; subject 
identification code list, screening log (if applicable), and enrollment log; record of all 


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communications between the Investigator and the IRB; composition of the IRB; record of all 
communications between the Investigator, Sponsor, and their authorized representative(s); list of 
Sub investigators and other appropriately qualified persons to whom the Investigator has 
delegated significant study-related duties, together with their roles in the study, curriculum vitae, 
and their signatures; copies of CRFs (if paper) and of documentation of corrections for all 
subjects; investigational product accountability records; record of any body fluids or tissue 
samples retained; and all other source documents (subject records, hospital records, laboratory 
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9. 
Statistical Considerations  
The details of the statistical methods and data presentation, PK and ADA analysis will be 
provided in the Statistical Analysis Plan (SAP).   
 
9.1. 
Sample Size Determination 
This is a 2-part study. Part 1 will enroll about 24 subjects to establish the safety of TJ003234 in 
subjects with severe COVID-19 before initiating Part 2.  
The estimated rate of mechanical ventilation free subjects in the control arm is based on recent 
observations in COVID-19 studies.  
The sample size of Part 2 Phase 2 portion is calculated based on the following assumptions: 
 Randomization ratio of 2:1 (TJ003234 6 mg/kg : placebo);  
 Rate of mechanical ventilations free subjects by Day 30: 88% in the TJ003234 arm and 
77% in the placebo arm; 
 2-sided alpha of 0.20 and 80% power. 
 10% drop out rate 
The sample size of Part 2 Phase 3 portion is calculated based on the following assumptions: 
 Randomization ratio of 2:1 (TJ003234 10 mg/kg : placebo);  
 Rate of mechanical ventilations free subjects by Day 30: 88% in the TJ003234 arm and 
77% in the placebo arm; 
 2-sided alpha of 0.05 and 80% power. 
 10% drop out rate 
Part 2 plans to enroll of 570 subjects with 120 in the Phase 2 portion and 450 in the Phase 3 
portion. The results of Phase 2 portion may be used to re-estimate the sample size for Phase 3 
portion.  
 
9.2. 
General Considerations 
Analysis Populations:  
Intent-to-treat (ITT) Population: All randomized subjects. This population will be used for the 
primary analysis for Part 1 and Part 2 phase 2 portion, and sensitivity analysis of primary analysis 
for Part 2 phase 3 portion. 


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Modified Intent-to-treat (mITT) Population: All randomized subjects who are non- mechanical 
ventilated at baseline. This population will be used for the primary analysis of Phase 2 phase 3 
portion.  
Safety Population: Includes all subjects who receive the study drug. This safety population will 
be used for the analysis of demographic data, baseline characteristics, and safety.  
Efficacy-evaluable Population: All subjects in the safety population with at least one post-dose 
efficacy evaluation.   
Methods for Statistical Analysis  
All data will be summarized by treatment group using descriptive statistics based on the data 
types by timepoint if applicable. Unless otherwise specified, descriptive statistics for continuous 
variables will include number of subjects, mean, standard deviation (SD), median, and range. 
For categorical variables, descriptive statistics including counts and percentages will be reported. 
All statistical analysis will be performed using SAS 9.4 (or above version) statistical analysis 
software. The specific statistical method will be detailed in the Statistical Analysis Plan (SAP).  
9.3. 
Subject Demographics/Other Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, and some other baseline 
disease characteristics) will be summarized for the Safety Population. Descriptive statistics will 
be presented in addition to data listings.  
9.4. 
Safety Analysis 
Safety and tolerability evaluations will be performed for all subjects in the safety population.   
Unless otherwise specified, the last evaluation before dosing will be used as the baseline. AEs 
will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Summary statistics and listings of all the safety data will be provided by treatment group and 
time points as specified in the schedule of procedures. 
9.5. 
Efficacy Analysis  
All efficacy endpoints will be summarized by treatment group with descriptive statistics based 
on the ITT / mITT / efficacy-evaluable population. 95% CI of the estimates will be provided 
where appropriate. Treatment difference along with 95% CI will also be reported for Part 2 of 
the study. Subgroup analysis by stratification factors, i.e. age (<60 year vs. ≥60 years) and use 
of remdesivir (yes vs. no) might be performed where data permits.  
For the efficacy endpoints in Part 2, the primary endpoint will be analyzed using the exact 
method. Difference between two arms will be tested by a stratified Cochran–Mantel–Haenszel 
test (CMH) test using the stratification factors at randomization. Recovery rate by Day 14, 
recovery rate by Day 30, and all-cause mortality rate will be analyzed similarly. Time to 
recovery among subjects alive by Day 30 will be analyzed by a stratified log-rank test for p-


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value, and the HR ratio between two arms will be estimated by a stratified Cox proportional 
hazard model using the stratification factors at randomization. For the phase 2 portion the 
primary analysis will be based on the ITT population. For the phase 3 portion the primary 
analysis will be based on the mITT population, and sensititivy analyses will be conducted 
based on the ITT population.  
For the Part 2 phase 3 portion, multiplicity will be adjusted by a gatekeeping procedure. If the 
null hypothesis for the primary endpoint is rejected, then the key secondary endpoints will be 
tested in the order of: proportion of recovered subjects by Day 14, proportion of recovered 
subjects by Day 30, and all-cause mortality rate by Day 30.  
 
The primary clinical question of interest for the primary objective is whether there is a 
difference in proportion of subjects who are alive and free of mechanical ventilation after 30 
days comparing TJ003234 10 mg/kg versus placebo in COVID-19 subjects who have low 
blood oxygen or requires high flow oxygen regardless of initiation of additional medication or 
change in background medication (remdesivir and/or steroids). The clinical question of interest 
for the secondary objectives are similar, which is whether there is a difference in proportion of 
subjects who will recover after 14 or 30 days comparing TJ003234 10 mg/kg versus placebo in 
iCOVID-19 subjects who have low blood oxygen or requires high flow oxygen regardless of 
initiation of additional medication or change in background medication (remdesivir and/or 
steroids). 
 
The estimand is described by the following attributes: 
 Population: severe hospitalized COVID-19 subjects who require non mv oxygen supply 
at baseline.  
 Endpoint: proportion of subjects who are non-mechanical ventilated at baseline by Day 
30.  
 Treatment condition: TJ003234 10 mg/kg and placebo with or without background 
medication (remdesivir and/or steroids). 
 Intercurrent events and strategies: The intercurrent events “change in background 
medication (remdesivir and/or steroids)” are addressed by the treatment condition of 
interest attribute following the treatment policy strategy. Other relevant intercurrent 
events are not anticipated at this point in time. 
 Population-level summary: difference in proportions between treatment conditions 
 
The trial will be considered as successful if the primary endpoint in Phase 3 portion shows a 
statistically significant improvement in the treatment arm and, as a safety measurement, the all-
cause mortality rate in the treatment arm is numerically not higher than that in the control 
arm.Sensitivity analyses and subgroup analysis will be performed to investigate the robustness 
of the primary efficacy outcome. Details will be provided in the statistical analysis plan (SAP).  
 


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9.6. 
Independent Data Monitoring Committee  
The Independent Data Monitoring Committee (IDMC) is responsible for monitoring safety. The 
IDMC will be made up entirely of members external to I-Mab. The IDMC charter will contain 
membership information and a further delineation of responsibilities. 
The IDMC may recommend continuing enrollment in one dose arm or to terminate the study 
for accumulated safety evaluations. The IDMC will provide a recommendation that is made 
without known bias. I-Mab staff involved in the conduct of the study will be kept blinded to 
before a portion of the study is completed, and the members of the IDMC will not have 
involvement with the conduct of the study. 
 


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10. Regulatory Human Subject Protection and Regulatory Oversight 
10.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
 Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator’s Brochure, 
and other relevant documents (e.g., advertisements) must be submitted to an Institutional 
Review Board (IRB) by the Investigator and reviewed and approved by the IRB before the 
study is initiated.  
Any amendments to the protocol will require IRB and regulatory authority (as locally required) 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB. 
 Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.2. Informed Consent Processes and Documentation 
In obtaining and documenting informed consent, the Investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should 
adhere to ICH GCP. Prior to the beginning of the trial, the Investigator should have the IRB’s 
written approval for the protocol and the written ICF and any other written information to be 
provided to the participants. Participants will be asked to read and review the IRB-approved ICF 
and other written information.  The ICF should include a detailed description of study 
procedures, risk and benefits, directions, participant’s rights, compensation (if applicable), and 


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contact of Human Subject Protection Services.  Additionally, the Investigator will explain the 
research study to the participant in terms suited to the participant’s comprehension and answer 
any questions that may arise. The Investigator should explain their rights as research participants, 
study procedures, risk and benefits, and anticipated adverse effects.  Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. ICF 
should be signed prior to any interventions are performed for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. Participant will be given a copy of the signed consent form and the original 
consent form will be kept as a permanent record. 
10.3. Confidentiality  
Participant confidentiality and privacy is strictly held in trust by the participating Investigator(s), 
their staff, and the Sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the Investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
Sponsor requirements. 
Research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the data management group at the designated CRO. This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by CRO staff will be secured, 
and password protected. At the end of the study, all study databases will be de-identified and 
archived at the CRO or Sponsor until further data integration with future studies of TJ003234. 
10.4. Conflict of Interest  
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 


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design and conduct of this trial. 


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11. Quality Control and Quality Assurance  
Sponsor or designee will conduct periodic monitoring visits to ensure that the protocol and 
current Good Clinical Practices within standard operating procedures are being followed. 
The monitors may review source documents to confirm that the data recorded on CRFs are 
accurate. The Investigator and institution will allow the Sponsor’s medical monitors or its 
agents and appropriate regulatory authorities direct access to source documents to perform 
this verification. Accuracy will be checked by performing source data verification that is a 
direct comparison of the entries made onto the CRFs against the appropriate source 
documentation. Any resulting discrepancies will be reviewed with the Investigator and/or 
his/her staff. Any necessary corrections will be made directly to the electronic CRFs or via 
queries by the Investigator and/or his/her staff. Monitoring procedures require that informed 
consents, adherence to inclusion/exclusion criteria, and documentation of SAEs and their 
proper recording be verified. Additional monitoring activities may be outlined in a study 
specific monitoring plan. 
12. Confidentiality and Publication of Test Results 
All information about this trial (including but not limited to the following documents: 
protocols, investigator’s brochure) must be kept strictly confidential. Investigators shall be 
aware that the scientific or medical information derived from this trial may be of commercial 
value to the sponsor. Investigators should keep the information and data related to the trial 
confidential. If Investigators are intended to publicly release information or conclusions 
obtained from the trial, they shall consult with the sponsor in advance and obtain the written 
consent of the sponsor. In order to protect rights and interest, the sponsor may require 
investigators not to publish information about the trial until the trial product is approved for 
marketing.   
The sponsor has the right to publish or release information or data related to the trial, or 
report them to the regulatory authorities.  
 
 


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13. References   
Avci, A.B., Feist, E. and Burmester, G.R. (2016). Targeting GM-CSF in Rheumatoid 
Arthritis. Clin Exp Rheumatol, 34 (4 Suppl 98):39–44. 
Beigel, J.H., Tomashek, K.M., Dodd, L.E., Mehta, A.K., Zingman, B.S., Kalil, A.C.,… 
Lane, H.C. for the ACTT-1 Study Group Members (2020). Remdesivir for the Treatment 
of Covid-19 — Preliminary Report. New England Journal of Medicine, Published Online 
2020 May 22; NEJMoa2007764. doi: 10.1056/NEJMoa2007764. 
Broughton, S. E., Nero, T. L., Dhagat, U., Kan, W. L., Hercus, T. R., Tvorogov, D., … 
Parker, M. W. (2015). The βc receptor family – Structural insights and their functional 
implications. Cytokine, 74(2), 247–258. doi: 10.1016/j.cyto.2015.02.005 
Burmester, G. R., Mcinnes, I. B., Kremer, J., Miranda, P., Korkosz, M., Vencovsky, J., … 
Weinblatt, M. E. (2017). A randomised phase IIb study of mavrilimumab, a novel GM–
CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Annals 
of the Rheumatic Diseases, 76(6), 1020–1030. doi: 10.1136/annrheumdis-2016-210624  
Channappanavar, Rudragouda, and Stanley Perlman. “Pathogenic Human Coronavirus 
Infections: 
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Consequences 
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Immunopathology.” Seminars in Immunopathology, vol. 39, no. 5, Feb. 2017, pp. 529–
539., doi:10.1007/s00281-017-0629-x. 
Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., … Zhang, L. (2020). 
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus 
pneumonia in Wuhan, China: a descriptive study. The Lancet, 395(10223), 507–513. doi: 
10.1016/s0140-6736(20)30211-7 
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De Luca, G., Cavalli, C., Campochiaro, C., Della-Torre, E., Angelillo, P., Tomelleri, A.,… 
Dagna. L. (2020). GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia 
and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet 
Rheumatol, Published Online June 16, 2020 doi: https://doi.org/10.1016/S2665-
9913(20)30170-3 
FDA Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers, July 2005 
Gilead. 
Press 
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https://www.gilead.com/news-and-press/press-room/press-
releases. Accessed March 8, 2020. 
Goldman, J.D., Lye, D.C.B., Hui, D.S., Marks, K.M., Bruno, R., Montejano, R, … and 


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CONFIDENTIAL 
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Subramanian, A. (2020). Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 
New England Journal of Medicine, Published Online May 27, 2020, DOI: 
10.1056/NEJMoa2015301 
Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., … Zhong, N.-S. (2020). 
Clinical characteristics of 2019 novel coronavirus infection in China. doi: 
10.1101/2020.02.06.20020974 
Gust J, Finney O, Li D, Brakke HM, Hicks RM et al. (2019). Glial injury in neurotoxicity 
after pediatric CD19-directed chimeric antigen receptor T cell therapy. Ann Neurol. 
86(1):42-54. 
Hamilton, J. A. (1980). Macrophage stimulation and the inflammatory response to 
asbestos. Environmental Health Perspectives, 34, 69–74. doi: 10.1289/ehp.803469 
Hansen, G., Hercus, T., Woodcock, J., Mcclure, B., Stomski, F., Xu, Y., … Parker, M. 
(2008). Structure of the GM-CSF Receptor Complex. doi: 10.2210/pdb3cxe/pdb 
Hercus, T. R., Kan, W. L. T., Broughton, S. E., Tvorogov, D., Ramshaw, H. S., Sandow, J. 
J., … Lopez, A. F. (2017). Role of the β Common (βc) Family of Cytokines in Health and 
Disease. Cold 
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Perspectives 
in 
Biology, 10(6). 
doi: 
10.1101/cshperspect.a028514 
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., … Cao, B. (2020). Clinical features 
of 
patients 
infected 
with 
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novel 
coronavirus 
in 
Wuhan, 
China. The 
Lancet, 395(10223), 497–506. doi: 10.1016/s0140-6736(20)30183-5 
Huizinga, T. W. J., Batalov, A., Stoilov, R., Lloyd, E., Wagner, T., Saurigny, D., … 
Esfandiari, E. (2017). Phase 1b randomized, double-blind study of namilumab, an anti-
granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-
moderate rheumatoid arthritis. Arthritis Research & Therapy, 19(1). doi: 10.1186/s13075-
017-1267-3 
I-Mab Biopharma. TJ003234RAR101 Clinical Study Report. (Version 1.0). 03 January 
2020. 
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Jenkins, B. J., Blake, T. J., & Gonda, T. J. (1998). Saturation Mutagenesis of the β Subunit 
of the Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor Shows 
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10.1182/blood.v92.6.1989.418k18_1989_2002 
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based treatments in COVID-19: reconciling opposing therapeutic approaches. Nat Rev 
Immunol. 2020 Jun 23;1-8. doi: 10.1038/s41577-020-0357-7. 
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(2018). Tocilizumab for Treatment of Severe or Life-Threatening Chimeric Antigen 
Receptor T Cell-Induced Cytokine Release Syndrome—FDA Approval Summary. Biology 
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in cynomolgus monkeys: Relevance for human safety. Toxicology and Applied 
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Inactivation in CAR T-Cells Prevents Monocyte-Dependent Release of Key Cytokine 
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14. Appendices   
14.1. Appendix 1: Contraceptive requirements 
Definition of women of childbearing potential:  
Non-fertile women are defined as post-menopausal women and pre-menopausal women 
who have undergone surgical sterilization. Postmenopausal is defined as menopause ≥ 12 
months without alternative medical measures. Follicle Stimulating Hormone (FSH) test 
should be performed for subjects who are not sure of their menopausal status, and if FSH>40 
MlU/mL, it can be confirmed as menopause. Sterilization operations include bilateral 
fallopian tube ligation or bilateral ovariectomy or hysterectomy. 
Women of childbearing age are defined as those who are anatomically and physiologically 
able to get pregnant.   
Contraceptive requirements  
Women of childbearing potential must have a negative pregnancy test during the screening 
period. If of childbearing potential, women must agree to one of the following methods of 
contraception beginning at screening and continuing for a period of 4 months after the final 
dose of IP: 
 
Hormonal contraception (e.g., oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive)  
 
Double-barrier birth control (e.g., condom plus intrauterine device, diaphragm plus 
spermicide or condom plus spermicide)  
 
Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy  
 
Abstinence 
Male subjects who are sexually active must agree to use a double-barrier method of 
contraception (condom with spermicide) from the first dose of randomized study drug until 
4 months after their last dose and must not donate sperm during their study participation 
period. 
  
14.2. Appendix 2: Cardiac Function Grading of NYHA  
Grade I: A patient has a heart disease, but his/her daily activity is not limited. General 
physical activity will not cause excessive fatigue, palpitations, asthma or angina. 
Grade II: a patient with heart disease has slightly limited physical activity. He/she has no 
conscious symptoms at rest, and general physical activity may cause excessive fatigue, 
palpitations, asthma or angina. 


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Grade III: a patient with heart disease has obviously limited physical activity. He/she has no 
symptoms at rest, but physical activity lower than normal level may cause excessive fatigue, 
palpitations, asthma or angina. 
Grade IV: a patient with heart disease cannot engage in any physical activity, and heart 
failure symptoms also occur during rest, which worsens after physical activities.  
 
14.3. Appendix 3: Sequential Organ Failure Assessment Score 
System  
Test Item  
0 
1 
2 
3 
4 
Score  
Respiratory 
system 
PaO2/FiO2, 
mmHg (kPa) 
>400 
(>53.33) 
301-400 
(≤53.33 
and >40) 
201-300 
(≤40 
and >26.6
7) 
101-200 
(≤26.67) 
≤100 
(<13.33
) 
 
Respiratory 
support 
(yes/no) 
 
 
 
Yes  
Yes 
 
Coagulation 
system 
Platelets, 109/L  >150 
101-150 
51-100 
21-50 
<21 
 
Liver  
Bilirubin, 
mg/dL 
(umol/L)  
<1.2 
(<20) 
1.2-1.9 
(20-32) 
2.0-5.9 
(33-101) 
6.0-11.9 
(102-
204) 
>12.0 
(>204) 
 
Circulatory 
system 
Mean arterial 
pressure 
(mmHg)  
≥70 
<70 
 
 
 
 
Dopamine 
dose 
(ug/kg/min)  
 
 
≤5 or  
>5 or 
>15 or 
Adrenaline 
dose 
(ug/kg/min)  
 
 
 
≤0.1 or 
>0.1 or 
Norepinephrin
e dose 
(ug/kg/min) 
 
 
 
≤0.1 
>0.1 
Dobutamine 
(yes / no) 
 
 
Yes  
 
 
Nervous 
system 
GCS score 
15 
13-14 
10-12 
6-9 
<6 
 
Kidneys  
Creatinine, 
mg/dL 
(umol/L)  
<1.2 
(<110) 
1.2-1.9 
(110-
170) 
2.0-3.4 
(171-299) 
3.5-4.9 
(300-
440) 
>5.0 
(>440) 
 
24-hour urine 
output 
(ml/24h)  
 
 
 
201-500 
<200 
Remarks: 
1. The worst daily value should be taken for daily assessment;  
2. The higher the score, the worse the prognosis. 


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3. For the respiratory system score, to receive a score of 3 or 4 points, the patient 
needs to be mechanically ventilated. If the patient has a PaO2/FiO2 value of ≤40 
kPa and the patient is not on mechanical ventilation, the score will be 2, regardless 
if the value is lower than 26.67.  
 
14.4. Appendix 4: Inhaled corticosteroid dose guidance 
Adapted from Global Strategy for Asthma Management and Prevention – GINA 2019.  
This is not a table of equivalence, but of estimated clinical comparability based on available 
studies and product information.  
Doses are in mcg. CFC: chlorofluorocarbon propellant. DPI: dry powder inhaler. HFA: 
hydrofluoroalkane propellant. 
 
Inhaled corticosteroid 
Adults and adolescents 
Low 
Medium 
High 
Beclometasone dipropionate (CFC) 
200-500 
>500-1000 
>1000 
Beclometasone dipropionat 
100-200 
>200-400 
>400 
Budesonide (DPI) 
200-400 
>200-400 
>400 
Ciclesonide (HFA) 
80-160 
>160-320 
>320 
Fluticasone furoate (DPI) 
100 
n.a. 
200 
Fluticasone priopionate (DPI) 
100-250 
>250-500 
>500 
Fluticasone priopionate (HFA) 
100-250 
>250-500 
>500 
Mometasone furoate 
110-220 
>220-440 
>440 
Triamcinolone acetonide 
400-1000 >1000-2000 
>2000 
 
 


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SAP_001.pdf: 
Cover page: 
 
Clinical Trial Protocol: A Phase 2/3, Randomized, Double-Blind, 
Placebo-Controlled, 
Multi-Center Study to Evaluate the Safety and Efficacy of 
TJ003234 in Subjects with Severe Coronavirus Disease 2019 
(COVID-19)  
(Protocol Number TJ003234COV201) 
 
NCT: NCT04341116  
 
Document Date: 21 April 2022 


 
 
 
 STATISTICAL ANALYSIS PLAN 
STUDY SPONSOR: 
I-Mab Biopharma Co., Ltd. 
Suite 802, West Tower, 88 Shangke Road 
Pudong New District 
Shanghai 20120, China 
SPONSOR REPRESENTATIVES: 
Erin Relunia 
Associate Director, Clinical Project Management 
 
Elizabeth Lindner 
Director, Clinical Project Management 
 
Claire Xu, MD, PhD 
Study Director/Medical Monitor 
 
Vivian Yuan 
Statistician 
PROTOCOL TITLE: 
A Phase 2/3 Randomized, Double-blind, Placebo-
Controlled, Multi-Center Study to Evaluate the Safety 
and Efficacy of TJ003234 in Subjects with Severe 
Coronavirus Disease 2019 (COVID-19) 
PROTOCOL NUMBER: 
TJ003234COV201 
PROTOCOL VERSION AND DATE: 
Version 9: 23 September 2021 
NAME OF TEST DRUG: 
TJ003234 
PHASE: 
Phase 2/3 
METHODOLOGY: 
Randomized, Double-Blind, Placebo-Control 
ANALYSIS PLAN DATE: 
21 April 2022 
ANALYSIS PLAN VERSION: 
Final Version 2.0 
AUTHOR: 
Rodney Sleith 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of I-Mab 
Biopharma Co., Ltd. (I-Mab) and any unauthorized use or disclosure of such 
information without the prior written authorization of I-Mab is expressly prohibited. 


 
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Statistical Analysis Plan; Effective 21 April 2022, Vers 2.0 
 
TMP-BS-001 Statistical Analysis Plan Template 
Version 3.0 
Effective: 17 Aug 2020 
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CONFIDENTIAL 
Page 2 of 34 
 
APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Phase 2/3 Randomized, Double-blind, 
Placebo-Controlled, Multi-Center Study to 
Evaluate the Safety and Efficacy of TJ003234 
in Subjects with Severe Coronavirus Disease 
2019 (COVID-19) 
Sponsor: 
I-Mab Biopharma Co., Ltd. (I-Mab) 
Suite 802, West Tower, 88 Shangke Road 
Pudong New District 
Shanghai 20120, China 
Protocol Number: 
TJ003234COV201 
Document Date / Version: 
21 April 2022 / Final Version 2.0 
Veristat, Inc. Author: 
Rodney Sleith 
134 Turnpike Road, Suite 200 
Southborough, MA  01772 
Approval Signature 
Job Title 
 
 
 
 
Principal Biostatistician


 
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Page 3 of 34 
 
Sponsor Signatory: 
I-Mab Biopharma Co., Ltd. (I-Mab) 
Suite 802, West Tower, 88 Shangke Road 
Pudong New District 
Shanghai 20120, China 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report. 
Approval Signature 
Job Title 
 
 
 
 
 
 
 
 
Associate Director, Clinical Project Mgmt.
Director, Clinical Project Management, I-Mab
Vice President, Medical, I-Mab
Director, Statistics, I-Mab


 
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CONFIDENTIAL 
Page 4 of 34 
 
TABLE OF CONTENTS 
Section 
Page 
1. 
Information From the Study Protocol.........................................................................9 
1.1. 
Introduction and Objectives.............................................................................9 
1.1.1. 
Introduction ..........................................................................................9 
1.1.2. 
Study Objectives ................................................................................11 
1.2. 
Study Design ....................................................................................................11 
1.2.1. 
Synopsis of Study Design ..................................................................11 
1.2.1.1. Part 1 ...................................................................................11 
1.2.1.2. Part 2 ...................................................................................12 
1.2.2. 
Randomization Methodology .............................................................12 
1.2.2.1. Part 1 ...................................................................................12 
1.2.2.2. Part 2 Phase 2 ......................................................................13 
1.2.2.3. Part 2 Phase 3 ......................................................................13 
1.2.3. 
Stopping Rules and Unblinding .........................................................13 
1.2.4. 
Study Procedures ...............................................................................14 
1.2.5. 
Efficacy, Pharmacokinetic, and Safety Parameters ...........................18 
1.2.5.1. Efficacy Parameters (Part 2 only) .......................................18 
1.2.5.2. Exploratory Efficacy Parameters ........................................19 
1.2.5.3. Pharmacokinetic and Anti-Drug Antibody Parameters.......19 
1.2.5.4. Safety Parameters ................................................................20 
2. 
Subject Population ......................................................................................................21 
2.1. 
Population Definitions ....................................................................................21 
2.2. 
Protocol Violations ..........................................................................................21 
3. 
General Statistical Methods .......................................................................................22 
3.1. 
Sample Size Justification ................................................................................22 
3.2. 
General Methods .............................................................................................22 
3.3. 
Computing Environment ................................................................................23 
3.4. 
Baseline Definitions .........................................................................................23 
3.5. 
Methods of Pooling Data ................................................................................23 
3.6. 
Adjustments for Covariates ...........................................................................23 
3.7. 
Multiple Comparisons/Multiplicity ...............................................................23 


 
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Page 5 of 34 
 
Section 
Page 
3.8. 
Subpopulations ................................................................................................24 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ..................................................24 
3.10. Missing, Unused, and Spurious Data ............................................................24 
3.11. Visit Windows ..................................................................................................24 
4. 
Study Analyses .............................................................................................................25 
4.1. 
Subject Disposition ..........................................................................................25 
4.2. 
Demographics and Baseline Characteristics ................................................25 
4.3. 
Efficacy Evaluation .........................................................................................25 
4.3.1. 
Primary Efficacy Endpoint ................................................................25 
4.3.2. 
Key Secondary Efficacy Endpoints ...................................................26 
4.3.3. 
Secondary Efficacy Endpoints ...........................................................26 
4.3.3.1. Time to recovery among subjects alive by Day 30 .............26 
4.3.3.2. Length of hospitalization.....................................................27 
4.3.4. 
Exploratory Efficacy Endpoints .........................................................27 
4.4. 
Safety Analyses ................................................................................................28 
4.4.1. 
Study Drug Administration ................................................................28 
4.4.2. 
Adverse Events ..................................................................................28 
4.4.3. 
Laboratory Data .................................................................................29 
4.4.4. 
Vital Signs and Physical Examination ...............................................29 
4.4.5. 
Electrocardiogram ..............................................................................29 
4.4.6. 
Concomitant Medications ..................................................................29 
4.4.7. 
Radiographic Lung Imaging ..............................................................30 
5. 
Changes to Planned Analyses .....................................................................................31 
6. 
References ....................................................................................................................32 
7. 
Clinical Study Report Appendices .............................................................................34 
7.1. 
Statistical Tables to be Generated .................................................................34 
 


 
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TABLES INCLUDED IN THE TEXT 
 
Page 
Table 1 
Schedule of Procedures ................................................................................................... 15 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ARDS 
Acute respiratory distress syndrome 
CAR 
Chimeric antigen receptor 
CCL 
Chronic Lymphocytic Leukemia  
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel test 
COVID-19 
Novel coronavirus 2019 
CRF 
Case report form 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
EE 
Efficacy Evaluable 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
IFN 
Interferon  
IL 
Interleukin  
ITT 
Intent-to-treat 
IV 
Intravenous 
LDH 
Lactic dehydrogenase 
MAS 
Macrophage activation syndrome 
MCP-1 
Monocyte chemoattractant protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIP 
Macrophage inflammatory protein 
NLR 
Neutrophils-to-lymphocyte ratio  
NMLR 
Neutrophils-to-(monocyte + lymphocyte) ratio  
PK 
Pharmacokinetic(s) 
PR 
Interval between P wave and QRS complex 
QT 
Interval between Q and T waves 
QTc 
Corrected interval between Q and T waves 
RTSM 
Randomization and trial supply management system 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SI 
International System of Units 
SOC 
System organ class 
SOFA 
Sequential Organ Failure Assessment 


 
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Abbreviation 
Definition 
SpO2 
Oxygen saturation 
TEAE 
Treatment-emergent adverse event 
TNFα 
Tumor necrosis factor alpha 
WHO 
World Health Organization 
 
 
 
 


 
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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), also known as Colony-
Stimulating Factor 2 (CSF2), is a member of the colony-stimulating factor family of 
hematopoietic growth factors. It was first known as an in vitro inducer for bone marrow 
progenitor cells to differentiate and proliferate into a single colony. GM-CSF is a monomeric 
glycoprotein cytokine, which may be produced by many cells including myeloid cells, dendritic 
cells, T cells, B cells, non-hematopoietic cells (such as endothelial cells, chondrocytes and 
alveolar epithelial cells) and even tumor cells (Avci et al., 2016). GM-CSF binds to 
heterodimeric receptors on bone marrow cells and neutrophils and activates GM-CSF receptors 
to initiate a variety of downstream signaling pathways, including Janus kinase signal transducer 
transcription-suppressor of cytokine signaling (JAKSTAT-SOCS), mitogen-activated protein 
kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), and nuclear factor ĸB signaling pathway 
(NF-ĸB) (Hansen et al., 2008; Jenkins et al., 1998; Sato et al., 1993; Broughton et al., 2015; 
Hercus et al., 2017). 
GM-CSF, as a key upstream trigger factor in the inflammatory cytokine cascade, can enhance 
the effects of neutrophils and macrophages, to increase the expression of adhesion molecules, 
produce inflammatory cytokines and activate the phagocytosis. In addition, GM-CSF is also an 
important cytokine that induces the polarization of monocytes to the inflammatory M1 
phenotype and promotes the activation of macrophages, and the macrophages secrete a large 
number of inflammatory cytokines such as IL-6, TNF-α, etc., to involve in tissue inflammation 
(Hamilton, 1980). 
Indeed, the strong proinflammatory effects of GM-CSF make it a prime target in acute 
inflammatory conditions where elevated GM-CSF has been implicated in orchestrating a 
cytokine storm. At least three such syndromes share immunological and pathologic features of a 
cytokine storm: chimeric antigen receptor (CAR)-T cell therapy related cytokine release 
syndrome (CRS) and neurotoxicity, macrophage activation syndrome (MAS) and most recently, 
acute respiratory distress syndrome (ARDS) in severe coronavirus disease (COVID-19) cases 
caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).  
CAR-T therapy is revolutionizing cancer treatment, but its application is limited by 
life-threatening toxicities such as CRS and neurotoxicity (Gust, 2019) attributable to 
hyperactive T cells and monocytes/macrophages. It has been reported that GM-CSF neutralizing 
antibody during CAR-T therapy prevented CRS and neuroinflammation and both GM-CSF 
neutralization and GM-CSF knockout in CAR-T cells enhanced antitumor activities in a mouse 
ALL xenograft model (Sterner et al., 2019). In addition, GM-CSF inactivation in this setting 
abolished macrophage-dependent secretion of factors, including monocyte chemoattractant 
protein 1 (MCP-1), interleukin 6 (IL-6), and IL-8 (Sachdeva M, 2019). Compared to 
tocilizumab that has been widely used to treat cytokine storm caused by CAR-T cells, GM-CSF 
antibodies can achieve better treatment effect, especially in regulating the broad spectrum of 
cytokines and inhibiting neurotoxicity. Based on these findings, a clinical trial of GM-CSF 
antibody lenzilumab in CAR-T therapy is planned (Sterner et al., 2019). 


 
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Both T cells and monocytes produce large amounts of cytokines and chemokines which feed 
forward on the immune cells to precipitate a cytokine storm and tissue damage ensues. GM-CSF 
neutralization could stop this cycle. 
In the recent COVID-19 epidemic caused by the coronavirus SARS-CoV-2 in China, 10-20% of 
patients with pneumonia developed severe or critical conditions that required intensive care. 
These complications included ARDS, multiple organ failure, and sometimes death. The clinical 
features (Huang, 2020) and immunopathology (Xu, 2020) of patients with COVID-19 in China 
have now been reported, and they remarkably resembled those found in SARS 
(Channappanavar, 2017). Common features among COVID-19 patients particularly those 
seriously or critically ill included lymphopenia and significantly higher than normal levels of 
inflammatory cytokines (IL-1, IL-7, IL-8, IL-9, IL-10, basic fibroblast growth factor [FGF], 
granulocyte colony stimulating factor [G-CSF], GM-CSF, interferon [IFN]-γ, interferon 
gamma-inducible protein [IP]-10, MCP-1, macrophage inflammatory protein [MIP]-1A, 
MIP-1B, platelet-derived growth factor [PDGF], TNFα, and vascular endothelial growth factor 
[VEGF]) (Huang, 2020). Most studies also reported massive production of IL-6, C-reactive 
protein (CRP), D-dimer, and ferritin – all consistent with cytokine storm (Wang, 2020). 
Importantly, lung pathology revealed heavy interstitial lymphocytic infiltrates along with diffuse 
alveolar damage with fibromyxoid exudates, multinucleated giant cells and hyaline membrane 
formation, indicative of ARDS (Xu, 2020). Interestingly, these pathological features and lung 
CT imaging characteristics are also remarkably similar to those reported for a subset of systemic 
Juvenile Idiopathic Arthritis (JIA) patients that developed MAS that led to severe 
immunopathology and lung disease (Schulert, 2019). Finally, peripheral blood mononuclear cell 
(PBMC) immunophenotyping showed an abundance of highly active GM-CSF-producing T 
helper cells and pathogenic monocytes in COVID-19 patients (Xu, 2020; Zhou, 2020).  
It seems clear from these recent reports that severe COVID-19 bears all the hallmarks of a 
cytokine storm instigated by exuberant immune cells producing GM-CSF and IL-6. They drive 
aberrant monocyte and T cell activation which in turn produce more cytokines and chemokines 
in a feed forward cycle that culminates in profound tissue injury, airway constriction, vascular 
collapse and organ failure. Without intervention, the clinical course is expected to be dire for 
COVID-19 patients in severe or critical conditions. Currently, based on the experience of IL-6R 
antibody tocilizumab in managing CAR-T induced CRS, tocilizumab is being tested for 
reducing cytokine storm and its complications in a clinical trial of COVID-19 patients. Based on 
the analysis above and progress made in CAR-T therapy with the introduction of GM-CSF 
inhibition, GM-CSF neutralizing antibodies such as TJ003234 may prevent or curb cytokine 
storm and immunopathology in COVID-19 and consequently buy more time for viral clearance. 
TJ003234 is a recombinant anti-GM-CSF humanized monoclonal antibody independently 
developed by I-Mab Biopharma Co., Ltd. At present, a number of preclinical studies have been 
conducted with TJ003234, demonstrating that TJ003234 is a specific and effective antagonist of 
human GM-CSF/GM-CSFR pathway. TJ003234 has shown significant inhibitory effect on 
GM-CSF mediating GM-CFSR signaling in vitro and in vivo. Blocking the biological activity of 
GM-CSF suppresses the activation of pro-inflammatory monocytes, leading to the potential 
clinical benefits to patients with cytokine storms. 
In December 2018, the US Food and Drug Administration (FDA) approved the first study of 
TJ003234 for human use in healthy volunteers. The phase I study was expected to obtain safe 


 
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tolerated doses and pharmacokinetic characteristics of TJ003234 in humans, and currently the 
study has been completed. In this first human study, a single dose of TJ003234 up to 10 mg/kg 
in healthy subjects was well tolerated. The maximum tolerated dose was not reached. The 
increased TJ003234 exposure (Cmax and AUC) was roughly proportional to the increase in 
dose. The T1/2 was about 3 weeks within the test dose range of 0.3mg/kg to 10mg/kg. The 
clearance rate of TJ003234 decreased with increasing dose. The volume of distribution 
decreased slightly with the increasing dose. In the subjects in 3 mg/kg and 10 mg/kg cohorts, 
TJ003234 inhibited GM-CSF-stimulated pSTAT5 levels by more than 90% for up to 2 weeks in 
4 hours after dosing (full clinical study report submitted to FDA in January 2020). 
1.1.2. 
Study Objectives 
The primary study objective is to evaluate the efficacy and safety of TJ003234 in subjects with 
severe COVID-19 with supportive care. 
Secondary objectives are as follows: 
 To evaluate the effects of TJ003234 on cytokines in subjects with severe COVID-19  
 To assess the pharmacokinetics (PK) and immunogenicity potential of TJ003234 when 
administered as a single dose intravenous (IV) infusion in subjects with severe COVID-19 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This trial is designed as a two-part study to evaluate the efficacy and safety of TJ003234 
administered by an IV infusion in subjects with severe COVID-19 with supportive care, and to 
assess the effect of cytokine elevations on the disease as well as the effect of TJ003234 on the 
levels of cytokines. 
1.2.1.1. 
Part 1 
Part 1 is designed as a randomized, double-blind, placebo-controlled, 3-arm, parallel-group 
study to evaluate the safety of TJ003234 in subjects with severe COVID-19. Potential subjects 
will be screened to assess their eligibility to enter the study within 3 days prior to study drug 
administration. A total of 24 eligible subjects will be enrolled and randomized at a ratio of 1:1:1 
to receive either a single dose of 3 mg/kg TJ003234, a single dose of 6 mg/kg TJ00324, or 
placebo administered by IV infusion. Before and after the treatment, all subjects will be allowed 


 
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to receive supportive care and/or additional treatments for COVID-19 and its complications per 
the Investigator. Up to twenty-four subjects will be enrolled in Part 1. If no more than 2 out of 8 
subjects experience a Grade ≥3 treatment-related adverse event (AE) within 7 days of the 
subjects receiving the study drug in either TJ003234 arm, and no more than 4 out of 16 subjects 
experience a Grade ≥3 treatment-related AE within 7 days of the subjects receiving the study 
drug in both TJ003234 arms combined, Part 2 will be initiated. The end of Part 1 is defined as 
30 days after the last subject is dosed or until study termination. 
Enrolled subjects will complete the follow-up visits for 30 days after dosing to assess the safety 
and efficacy of the study drug. Subjects will be followed until they complete all study visits, the 
subject (or their legally authorized representative [LAR]) withdraws consent, the subject is lost 
to follow-up, or the subject dies. 
1.2.1.2. 
Part 2 
Part 2 is designed as a randomized, double-blind, placebo-controlled, 2-arm, parallel-group 
study to evaluate the efficacy and safety of TJ003234 in subjects with severe COVID-19. Part 2 
contains two phases; in the first phase, Phase 2, 120 subjects will be enrolled, and in the second 
phase, Phase 3, approximately 450 subjects will be enrolled. The data collected from Phase 2 
will be used to make decisions for Phase 3 and may be used to re-estimate the sample size of the 
Phase 3 portion. Potential subjects will be screened to assess their eligibility to enter the study 
within 3 days prior to the first dose administration. A total of 570 eligible subjects will be 
enrolled and randomized at a ratio of 2:1 to receive either a single dose of TJ003234 or placebo, 
administered by IV infusion. Randomization will be stratified by age at randomization (< 60 
years versus ≥ 60 years) and use of remdesivir (yes versus no). Before and after the treatment, 
all subjects will be allowed to receive supportive care and/or additional treatments for COVID-
19 and its complications per the Investigator.  
Enrolled subjects will complete the follow-up visits for 30 days after dosing to assess the safety 
and efficacy of the study drug. Subjects will be followed until they complete all study visits, the 
subject meets the withdrawal criteria in protocol Section 4.4, or the subject dies. 
1.2.2. 
Randomization Methodology 
Both parts of this study are randomized, double-blind, and placebo controlled. 
1.2.2.1. 
Part 1 
There will be approximately 24 subjects randomized 1:1:1 (eight subjects each) to the following 
treatment arms: 
 Treatment 1A: TJ003234 3 mg/kg (initial dose assignment based on weight at screening); 
single dose. 
 Treatment 1B: TJ003234 6 mg/kg (initial dose assignment based on weight at screening); 
single dose. 
 Treatment 1C: placebo (administered as normal saline); single dose. 


 
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Randomization will not be stratified. Each investigational site will randomize subjects to 
treatment groups using a randomization scheme generated by a randomization and trial supply 
management (RTSM) system. 
1.2.2.2. 
Part 2 Phase 2 
There will be approximately 120 subjects randomized 2:1 (80 TJ003234:40 placebo) to the 
following treatments arms: 
 Treatment 2A: TJ003234 6 mg/kg (initial dose assignment based on weight at screening); 
single dose. 
 Treatment 2B: placebo (administered as normal saline); single dose. 
Randomization will be stratified by age (< 60 years versus ≥ 60 years) and use of remdesivir 
(yes versus no). Each investigational site will randomize subjects to treatment groups using a 
randomization scheme generated by an RTSM system. 
1.2.2.3. 
Part 2 Phase 3 
There will be approximately 450 subjects randomized 2:1 (300 TJ003234:150 placebo) to the 
following treatments arms: 
 Treatment 3A: TJ003234 10 mg/kg (initial dose assignment based on weight at screening); 
single dose. 
 Treatment 3B: placebo (administered as normal saline); single dose. 
Randomization will be stratified by age (< 60 years versus ≥ 60 years) and use of remdesivir 
(yes versus no). Each investigational site will randomize subjects to treatment groups using a 
randomization scheme generated by an RTSM system. 
1.2.3. 
Stopping Rules and Unblinding 
Stopping rules for Part 1 are detailed in Section 1.2.1.1.  
As a double-blind, placebo-controlled study, both the subjects and Investigators are blinded to 
the study treatment assignment. In addition, it is anticipated that all clinical research personnel, 
laboratory personnel, except for personnel needed to prepare the study drug, are blinded to the 
treatment assignment and will remain blinded through the completion of the study.  
In the event emergency unblinding of study treatment is necessary, the Investigator shall utilize 
the RTSM system to obtain subject dose details. The individual subject dose details should be 
revealed only in case of an emergency where further treatment of the subject is dependent on 
knowing the study medication he or she has received. The date and time of breaking the blind as 
well as the reason must be recorded on the subject study medication record. The subject will be 
automatically discontinued from the study in the event emergency unblinding of study treatment 
takes place. If a blind is broken due to an AE, a corresponding AE entry must be completed in 


 
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the case report form (CRF). Any ongoing AEs will be followed in accordance with Section 7.1.5 
of the protocol. 
It is strongly encouraged that unblinding only be completed after consultation with the medical 
monitor, provided this does not compromise subject safety. If unblinding should occur (either by 
accident or for a medical emergency), the Investigator must promptly and immediately notify 
the Sponsor, study medical monitor, and Institutional Review Board/Independent Ethics 
Committee, and document the circumstances surrounding this action in a memorandum to the 
study file. 
1.2.4. 
Study Procedures 
The schedule of procedures, as outlined in the study protocol, is provided in Table 1. 


 
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Table 1 
Schedule of Procedures 
Procedure 
Screening 
period* 
Baseline 
period* 
Follow-up period 
-D3-D1 
D1 
D2 
D3 
D5 
D7** 
D11** 
±1 
D14** 
±2 
D30**±2 
Informed Consent 
√ 
 
 
 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
 
 
Body weight 
√ 
 
 
 
 
 
 
 
 
Medical history, smoking history and 
medication history, and baseline 
respiratory support requirements 
√ 
√ 
 
 
 
 
 
 
 
Pregnancy test or FSH test [1] 
√ 
 
 
 
 
 
 
 
 
SARS-CoV-2 diagnostic test [2] 
√ 
 
 
 
 
(√) 
 
(√) 
(√) 
Radiographic lung imaging [3] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
Arterial blood gas analysis [4, 16] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
PaO2/FiO2[16] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
Physical Examination 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Pulse Oximetry [5] 
√ 
Clinical status [6] 
 
√ 
 
 
 
√ 
 
√ 
√ 
Vital signs 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
12-lead ECG [7] 
√ 
√ 
 
 
 
√ 
 
√ 
√ 
Routine complete blood count, blood 
biochemistry test, coagulation assessment 
[8] 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 


 
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Procedure 
Screening 
period* 
Baseline 
period* 
Follow-up period 
-D3-D1 
D1 
D2 
D3 
D5 
D7** 
D11** 
±1 
D14** 
±2 
D30**±2 
Urinalysis [9] 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Troponin  
 
√ 
 
 
 
√ 
 
√ 
 
C-reactive protein, LDH, serum ferritin 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Cytokine levels [10] 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
SOFA (Sequential Organ Failure 
Assessment score) [11, 16] 
 
√ 
 
 
 
√ 
 
√ 
√ 
Review subject eligibility 
√ 
√ 
 
 
 
 
 
 
 
Randomization 
 
√ 
 
 
 
 
 
 
 
Dosing [12]  
 
√ 
 
 
 
 
 
 
 
Pharmacokinetic Sampling [13] 
 
√ 
 
 
 
√ 
 
√ 
√ 
Anti-drug Antibody Sampling [14] 
 
√ 
 
 
 
 
 
√ 
√ 
Concomitant medication/treatment [15]  
√ 
Adverse events  
√ 
[1]  
Pregnancy test is required for women of childbearing potential and follicle stimulating hormone (FSH) is required if confirmation of 
postmenopausal status is needed. 
[2] 
SARS-CoV-2 diagnostic test by polymerase chain reaction (PCR) or other commercial or public health assay: If a subject has a positive test within 
the 14 days prior to study drug administration, an additional test at screening does not need to be performed. Tests during follow-up are requested, 
but if missed or done out of window, this will not be considered a protocol deviation.  
[3]  
Radiographic lung imaging examination: Including lung CT or chest X-ray. If this procedure was performed as standard of care in the 14 days 
prior to study drug administration and radiographic infiltrates are present, this may be used, and imaging is not required at Screening or Day 1.   
[4] 
Arterial blood gas analysis, finger blood oxygen saturation: arterial blood gas analysis: PH, partial pressure of oxygen, partial pressure of carbon 
dioxide, total carbon dioxide, oxygen saturation, actual bicarbonate, standard bicarbonate, base excess, anion gap. If the interval between arterial 
blood gas analysis performed during screening and dosing is less than 24 hours, a repeated test is not required on Day 1 predose. If Day 7 and/or 


 
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14 visits are conducted as outpatient visits, it is not necessary to perform any of these procedures. 
[5]  
Pulse oximetry should be recorded on a daily basis while the subject is hospitalized. The lowest registered level from each day should be recorded. 
[6] 
 Clinical status evaluation: 8-category ordinal scale score: 8, Death; 7, ventilation in addition to ECMO, CRRT or pressors; 6, Intubation and 
mechanical ventilation; 5, NIV or high-flow oxygen; 4, Hospitalization with oxygen by mask or nasal prongs; 3, Hospitalization without oxygen 
supplementation; 2, Limitation of activities, discharge from the hospital; and 1, No limitation of activities, discharge from hospital.   
[7]  
ECG: Including but not limited to heart rate, QT, QTc, QTcF and P-R interval.  
[8]  
Routine CBC: White blood cells, red blood cells, hemoglobin, hematocrit, mean cell volume, platelets, absolute neutrophil count and percentage, 
absolute lymphocyte count and percentage, absolute monocyte count and percentage, absolute eosinophil count and percentage, absolute basophil 
count and percentage. Blood biochemistry test: blood glucose; liver and kidney functions: alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total protein, albumin, total bilirubin, direct bilirubin, alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), 
creatinine, blood urea nitrogen (BUN), uric acid; serum electrolytes: potassium, sodium, chlorine, calcium, magnesium, inorganic phosphorus. 
Coagulation function: prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), D-dimer. For 
screening, labs drawn before informed consent may be used if they are collected within 72 hours of study drug administration. Please see Section 
6.2 for details. 
[9] 
 Dipstick is acceptable. Microscopic analyses if dipstick abnormal. 
[10] 
 Cytokines such as IL-1RA, IL-1β, IL-2, IL-6, IL-7, IL-10, GCSF, GM-CSF, CCL2, CCL3, CCL17, CXCL10, TNF-α and IFN-γ in serum.  
[11]  
SOFA (Sequential Organ Failure Assessment score): see Appendix 3.  
[12]  
Dosing: intravenous infusion. On Day 1, all corresponding assessments will be completed before dosing.   
[13] 
 Only applies to subjects in Part 2 randomized to the PK/ADA subgroup. Pharmacokinetic Samples will be collected on Day 1 predose, Day 1 end 
of infusion (±15 minutes), Day 7, Day 14, and Day 30. The Day 30 sample only must be collected if the subject is still hospitalized or is able to 
come in for an outpatient blood draw. 
[14]  
Only applies to subjects in Part 2 randomized to the PK/ADA subgroup. The Day 30 sample only must be collected if the subject is still hospitalized 
or is able to come in for an outpatient blood draw. 
[15] 
 Recording concomitant medication/treatment: The concomitant medication mainly includes antiviral drugs, antibiotics, Glucocorticoid, and 
circulatory support drugs. Concomitant treatment mainly includes oxygen therapy, non-invasive/invasive mechanical ventilation, ECMO, and 
continuous renal replacement therapy (CRRT). Any SARS-CoV-2 vaccine history will be collected. For subjects who report they have received 
the SARS-CoV-2 vaccine, the following will be collected: Number of doses, date of dose(s) and brand name. 
[16]  
If subject is discharged from the hospital during the study, complete an unscheduled SOFA score, ABG and PaO2/FiO2 ratio based on the last 
arterial blood gas analysis performed while the subject was hospitalized. 
*If dosing occurs within 24 hours of screening, any Predose procedures done during screening do not need to be repeated. SOFA, troponin, clinical status 
assessment must be collected prior to dosing. Please see Section 6 of protocol for details. 
**If subject is discharged prior to these visits, they may occur as outpatient or telephone visits. Please see Section 6 of protocol for details. 
 


 
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1.2.5. 
Efficacy, Pharmacokinetic, and Safety Parameters 
1.2.5.1. 
Efficacy Parameters (Part 2 only) 
The primary efficacy endpoint is the proportion (%) of subjects who are alive and free of 
mechanical ventilation by Day 30, among subjects who are free of mechanical ventilation at 
baseline. Free of mechanical ventilation by Day 30 is defined as subjects who are discharged 
from the hospital or have a score of 1 to 5 in the following 8-category ordinal scale by Day 30:  
1. Discharged from hospital, with no limitation of activities 
2.   Discharged from hospital, with limitation of activities 
3. Hospitalization without oxygen supplementation  
4. Hospitalization with oxygen by mask or nasal prongs 
5. Noninvasive mechanical ventilation (NIV) or high-flow oxygen 
6. Intubation and mechanical ventilation 
7. Ventilation in addition to extracorporeal membrane oxygen (ECMO), continuous renal 
replacement therapy (CRRT), or pressors 
8.  Death 
Key secondary efficacy endpoints include the following: 
 The proportion (%) of subjects recovered by Day 14. Sustained recovery in clinical status is 
defined as a score of 1, 2, or 3 on the 8-category ordinal scale defined in the primary 
endpoint by Day 14, without subsequently progressing to a score ≥ 4 for the remainder of 
the study. If a subject has a baseline score of 3, then recovery is defined as a score of 1 or 2 
by Day 14. 
 The proportion (%) of subjects recovered by Day 30. Sustained recovery in clinical status is 
defined as a score of 1, 2, or 3 on the 8-category ordinal scale defined in the primary 
endpoint by Day 30, without subsequently progressing to a score ≥ 4 for the remainder of 
the study. If a subject has a baseline score of 3, then recovery is defined as a score of 1 or 2 
by Day 30. 
 All-cause mortality rate on Day 30.  
Other secondary efficacy endpoints include the following: 
 Time to sustained recovery among subjects alive by Day 30 (Time Frame: Day 1 through 
Day 30). Day of sustained recovery is defined as the first day on which a subject scores 1, 2, 
or 3 on the 8-category ordinal scale defined in the primary endpoint and maintains such 
score through Day 30. If a subject has a baseline score of 3, then day of recovery is defined 


 
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as the day on which the subject has a score of 1 or 2 and maintains such score through Day 
30. 
 Length of hospitalization  
1.2.5.2. 
Exploratory Efficacy Parameters 
Exploratory efficacy endpoints include the following: 
 Improvement in clinical status (Day 7, Day 14, and Day 30 from the day of dosing) 
 Sequential Organ Failure Assessment (SOFA) score (Day 7 and Day 14 from the day of 
dosing)  
 Change from baseline in the ratio of arterial oxygen partial pressure (PaO2) to fractional 
inspired oxygen (FiO2) (Day 7 and Day 14 from the day of dosing) 
 Length of time to normalization of oxygen saturation (SpO2) which is defined as SpO2 ≥ 
94% sustained minimum 24 hours 
 Proportion of subjects requiring mechanical ventilation (Day 7 and Day 14 from the day of 
dosing)  
 Changes from baseline in serum cytokines including IL-1RA, IL-1β, IL-2, IL-6, IL-7, IL-10, 
GCSF, GM-CSF, CCL2, CCL3, CXCL10, TNF-α, and IFN-γ (Day 2, Day 3, Day 5, Day 7, 
and Day 14 from the day of dosing)  
 Change from baseline in D-dimer, cardiac troponin, lactate dehydrogenase (LDH), and 
ferritin levels (Day 7 and Day 14 from the day of dosing) 
 Peripheral blood neutrophils-to-lymphocyte ratio (NLR)  
1.2.5.3. 
Pharmacokinetic and Anti-Drug Antibody Parameters 
In Part 2 Phase 2 stage, 40 subjects will be randomly assigned to a subgroup to collect PK and 
ADA samples. PK samples will be collected on Day 1 (predose and at End of Infusion), Day 7 
and Day 14. ADA samples will be collected on Day 1 predose and Day 14. Of these 40 subjects, 
30 will be from the 6 mg/kg TJ003234 treatment arm and 10 will be from the placebo arm. 
In Part 2 Phase 3 stage, 40 subjects will be randomly assigned to a subgroup to collect PK and 
ADA samples. PK samples will be collected on Day 1 (predose and at End of Infusion), Day 7 
and Day 14. ADA samples will be collected on Day 1 predose and Day 14. Of these 40 subjects, 
30 will be from the 10 mg/kg TJ003234 treatment arm and 10 will be from the placebo arm. 
The PK endpoint includes serum concentration of TJ003234. Anti-drug antibody parameters 
include incidence and titer of ADAs. 
Planned analyses of PK and ADA parameters will be described in a separate analysis plan. 


 
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1.2.5.4. 
Safety Parameters 
Safety evaluations performed during the study included physical examinations, measurement of 
vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory evaluations including 
hematology, serum chemistry, and urinalysis, radiographic lung imaging, and monitoring of 
AEs and concomitant medications. 


 
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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
 Modified Intent-to-Treat (mITT) Population:  All subjects randomized to treatment who 
were mechanical ventilation free at baseline. Subjects in the mITT population will be 
analyzed based on the treatment to which they were randomized, regardless of what 
treatment they actually received. The mITT population will be used for the analysis of the 
primary efficacy endpoint of Part 2. 
 Intent-to-Treat (ITT) Population:  All subjects randomized to treatment. Subjects in the ITT 
population will be analyzed based on the treatment to which they were randomized, 
regardless of what treatment they actually received. The ITT population will be used for the 
primary analysis for Part 1, and for Part 2 secondary and exploratory efficacy endpoints. 
 Efficacy-Evaluable (EE) Population:  All randomized and treated subjects with at least one 
post baseline efficacy evaluation. Subjects in the EE population will be analyzed based on 
the treatment actually received. The EE population may be used for supportive analyses of 
Part 2. 
 Safety Population:  All subjects randomized to treatment and who received study drug. 
Subjects in the Safety population will be analyzed based on the treatment actually received. 
This safety population will be used for the analysis of demographic data, baseline 
characteristics, and safety. 
2.2. 
Protocol Violations 
At the discretion of the Sponsor, major protocol violations, as determined by a review of the 
data prior to unblinding of the study results and the conduct of statistical analyses, may result in 
the removal of a subject’s data from the EE population. The Sponsor or designee will be 
responsible for producing the final protocol violation file (formatted as a Microsoft Excel file), 
in collaboration with Veristat and the data monitoring group as applicable; this file will include 
a description of the protocol violation and clearly identify whether the violation warrants 
exclusion from the EE population. This file will be finalized prior to hard database lock. 
All protocol violations will be presented in a data listing. 


 
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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
This is a 2-part study. Part 1 will enroll about 24 subjects to establish the safety of TJ003234 in 
subjects with severe COVID-19 before initiating Part 2. 
The estimated rate of mechanical ventilation free subjects in the control arm is based on recent 
observations in COVID-19 studies.  
The sample size for Part 2 Phase 2 is calculated based on the following assumptions: 
 Randomization ratio of 2:1 (TJ003234 6 mg/kg : placebo);  
 Rate of mechanical ventilation free subjects by Day 30: 88% in the TJ003234 arm and 
77% in the placebo arm; 
 2-sided alpha of 0.20 and 80% power; 
 10% drop out rate. 
The sample size for Part 2 Phase 3 is calculated based on the following assumptions: 
 Randomization ratio of 2:1 (TJ003234 10 mg/kg : placebo);  
 Rate of mechanical ventilation free subjects by Day 30: 88% in the TJ003234 arm and 
77% in the placebo arm; 
 2-sided alpha of 0.05 and 80% power; 
 10% drop out rate. 
The planned enrollment for Part 2 is 714 subjects, with 264 in Phase 2 and 450 in Phase 3. The 
results of Phase 2 may be used to re-estimate the sample size for Phase 3.  
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day).  Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication which is designated as Day 1.  The preceding day is Day -1, the day before that is 
Day -2, etc.   
All output will be incorporated into Microsoft Word or Excel files, or Adobe Acrobat PDF files, 
sorted and labeled according to the International Council for Harmonisation (ICH) 
recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, PK, and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 


 
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presented.  For continuous variables, the number of subjects, mean, median, standard deviation 
(SD), minimum, and maximum values will be presented.  Time-to-event data will be 
summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles 
with associated 2-sided 95% confidence intervals (CIs), as well as percentage of censored 
observations.   
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4, 
unless otherwise noted. Medical history and adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 23.0. Concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary Global Version B3 
March 1, 2020. 
3.4. 
Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. 
3.5. 
Methods of Pooling Data 
Data from Part 1 will not be included in summaries and analyses of Part 2. 
For the primary analysis of pooled Phase 2 and Phase 3, a single TJ003234 arm will be 
compared to placebo, i.e., the 6 mg/kg and 10 mg/kg dose groups will be combined. A 
supportive analysis will compare each planned dose group (TJ003234 6 mg/kg and TJ003234 
10 mg/kg) with placebo. For this analysis, subjects enrolled in Phase 3 with a planned dose of 
6 mg/kg will be included in the 6 mg/kg group. 
Demographics and baseline characteristics, and all summaries of safety, will be presented by 
planned dose group, i.e., TJ003234 6 mg/kg, TJ003234 10 mg/kg, or placebo, and overall. For 
these summaries, subjects enrolled in Phase 3 with a planned dose of 6 mg/kg will be included 
in the 6 mg/kg group. 
3.6. 
Adjustments for Covariates 
The primary efficacy endpoint will be analyzed using an exact method. The difference in 
proportions between the two arms will be tested by a stratified logistic regression model, using 
the randomization stratification factors as strata. An exact p-value is obtained using the EXACT 
statement in PROC LOGISTIC. This is equivalent to a Cochran–Mantel–Haenszel (CMH) test; 
however, only an asymptotic p-value is available using the CMH option in PROC FREQ. 
3.7. 
Multiple Comparisons/Multiplicity 
For Part 2, multiplicity will be adjusted by a gatekeeping procedure. If the null hypothesis for 
the primary endpoint is rejected, then the key secondary endpoints will be tested in the 
following order: proportion of recovered subjects by Day 14, proportion of recovered subjects 
by Day 30, and all-cause mortality rate by Day 30. If at any point in the gatekeeping procedure 


 
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the null hypothesis is not rejected, no further hypothesis testing will be performed, and analyses 
of any remaining endpoints will be descriptive only. The gatekeeping procedure applies only to 
the primary analyses of pooled TJ003234 versus placebo. Analyses of the individual dose levels 
versus placebo are considered supportive and are not subject to the gatekeeping procedure. 
3.8. 
Subpopulations 
The following subgroups will be analyzed for the primary and key secondary endpoints: 
 age (< 65 years versus ≥ 65 years)  
 use of remdesivir (yes versus no)  
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who are withdrawn or discontinue from the study will not be replaced. 
3.10. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the CRF will be included in data listings that will accompany the CSR. 
When tabulating AE data, partial dates will be handled as follows:  
 If the day of the month is missing, the onset day will be set to the first day of the month 
unless it is the same month and year as study treatment. In this case, to conservatively report 
the event as treatment-emergent, the onset date will be assumed to be the date of treatment.  
 If the onset day and month are both missing, the day and month will be assumed to be 
January 1, unless the event occurred in the same year as the study treatment. In this case, the 
event onset will be imputed as the day of treatment in order to conservatively report the 
event as treatment-emergent.  
A missing onset date will be imputed as the day of treatment. Any imputed start date that is after 
a reported end date will be imputed as the end date. Imputed start dates are used only to 
determine treatment emergence. Partial dates as recorded in the eCRF will be presented in 
subject listings. 
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the CRF even if the assessment is outside of the 
visit window.  In data listings, the relative day of all dates will be presented. 


 
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4. 
STUDY ANALYSES 
Unblinded summaries of data from Part 1 were performed in July 2020. Summaries included 
descriptive statistics of patient disposition, demographic characteristics, the 8-category clinical 
status scale, adverse events, pulse oximetry, serum cytokines, and neutrophils-to-lymphocyte 
ratio. No analyses of efficacy data were performed in Part 1. All efficacy analyses are exclusive 
to Part 2. 
4.1. 
Subject Disposition 
Subject disposition will be tabulated and include the number screened, the number randomized 
by treatment group and overall, the number in each subject population for analysis, the number 
who withdrew prior to completing the study and reason(s) for withdrawal. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented by treatment 
group and overall. Summaries will be provided for the ITT, mITT, EE, and Safety populations. 
Age, height, weight, and body mass index will be summarized using descriptive statistics 
(number of subjects, mean, SD, median, minimum, and maximum). The numbers and 
percentages of subjects in each sex, ethnicity and race category also will be presented. Age 
group (< 60, ≥ 60) and remdesivir use (Yes/No) will be based on the randomization 
stratification factors from the RTSM system. Dexamethasome use (Yes/No) and an additional 
age group summary (< 40, 40 – 65, > 65) will be included. Supplemental oxygen use (Yes/No), 
non-invasive ventilation use, and mechanical ventilation use (as reported on the Baseline 
Respiratory Support Requirements CRF) will be summarized. No formal statistical comparisons 
will be performed. 
Medical history will be summarized by treatment group and overall for the ITT population. 
Summaries will be provided by MedDRA system organ class (SOC) and preferred term. 
Demographic and baseline data for each subject will be provided in data listings. Listings will 
include smoking history, baseline respiratory support requirements, and results from the 
Screening SARS-CoV-2 diagnostic test.  
4.3. 
Efficacy Evaluation 
4.3.1. 
Primary Efficacy Endpoint 
The primary analysis of the primary efficacy endpoint will be based on the mITT population. 
Supportive analyses will be based on the EE population. 
The primary efficacy endpoint is the proportion (%) of subjects who are alive and free of 
mechanical ventilation at Day 30, among subjects who were mechanical ventilation free at 
baseline. Mechanical ventilation free by Day 30 is defined as subjects who are discharged from 


 
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hospital or score 1 to 5 on the 8-category ordinal clinical status scale by Day 30. The numbers 
and percentages of subjects who are alive and ventilation free will be presented along with exact 
(Clopper-Pearson) 95% CIs. The risk difference, i.e., the difference in ventilation-free rates, will 
be calculated for the active treatment arm versus placebo. The risk difference will be presented 
along with a 95% CI based on the score statistic (Miettinen and Nurminen 1985). The risk 
difference will be calculated as active minus placebo (thus a positive difference suggests a 
benefit from active treatment). The significance of the risk difference will be assessed using the 
CMH test, stratified by randomization stratification factors. An exact p-value will be presented. 
The above analysis will be based on observed cases. For the primary analysis of the primary and 
key secondary efficacy endpoints, the pooled TJ003234 dose groups will be compared to 
placebo. As a supportive analysis, each individual active dose group (i.e., combined 6 mg/kg 
and 10 mg/kg) will be compared to placebo. See Section 3.5 for additional information on 
pooling of data. 
4.3.2. 
Key Secondary Efficacy Endpoints 
The primary analysis of the key secondary efficacy endpoints will be based on the ITT 
population. Supportive analyses will be based on the EE population. 
Key Secondary endpoints are: 
 The proportion (%) of subjects recovered by Day 14. Sustained recovery in clinical status is 
defined as a score of 1, 2, or 3 on the 8-category ordinal scale defined in the primary 
endpoint by Day 14, without subsequently progressing to a score ≥ 4 for the remainder of 
the study. If a subject has a baseline score of 3, then recovery is defined as a score of 1 or 2 
by Day 14. 
 The proportion (%) of subjects recovered by Day 30. Sustained recovery in clinical status is 
defined as a score of 1, 2, or 3 on the 8-category ordinal scale defined in the primary 
endpoint by Day 30, without subsequently progressing to a score ≥ 4 for the remainder of 
the study. If a subject has a baseline score of 3, then recovery is defined as a score of 1 or 2 
by Day 30. 
 All-cause mortality rate on Day 30.  
Key secondary endpoints will be analyzed similarly to the primary endpoint.  
4.3.3. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed based on the ITT population. 
4.3.3.1. 
Time to recovery among subjects alive by Day 30 
Day of recovery is defined per protocol as the first day on which the subject scores 3, 2 or 1 
from the 8-category ordinal scale as defined in the primary endpoint. If a subject is scored at 3 at 
baseline, day of recovery is defined as the day on which the subject's score improves to 1 or 2. 
Day of recovery may also be determined by hospital discharge or removal from oxygen support. 


 
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Therefore, time to recovery shall be defined as the number of days from randomization to the 
earliest of (1) date removed from oxygen support, (2) date of discharge from hospital, or (3) 
date of recovery as assessed at the Day 14 or Day 30 visit. 
A proportional hazards model will be used to estimate the hazard ratio and associated 95% CI. 
The model will include treatment group as the sole independent variable, with randomization 
factors as strata variables. 
Median time to recovery and associated 95% CI will be estimated from the product-limit 
(Kaplan-Meier) method. Estimates of the 25th and 75th percentiles will also be presented. 
Differences in time to recovery between treatment groups will be tested by a stratified log-rank 
test, with randomization factors as strata. Kaplan-Meier plots of the survivor function will be 
presented. A summary of recovery events and censored observations will be included. Subjects 
will be censored for the following: 
 Not recovered: subjects alive and not recovered by Day 30 will be censored at Day 31 
 Death prior to Day 30: subjects will be censored on Day 31.  
 Lost to follow-up: subjects will be censored at their last clinical status assessment date 
4.3.3.2. 
Length of hospitalization 
Length of hospitalization, defined as the number of days from randomization to hospital 
discharge, will be analyzed similarly to time to recovery. Subjects who are not hospitalized at 
baseline will be excluded from the analysis. Subjects will be censored for the following: 
 Not discharged: subjects alive and not discharged by Day 30 will be censored at Day 30 
 Death prior to Day 30: subjects will be censored on Day 31.  
 Lost to follow-up: subjects will be censored at their last assessment date 
4.3.4. 
Exploratory Efficacy Endpoints 
Analyses of exploratory efficacy endpoints will be based on the ITT population. 
 Clinical status will be summarized by presenting the numbers and percentages of subjects in 
each treatment group within each of the 8-point ordinal scale categories. Change from 
baseline in clinical status, categorized as Improved, Stable, or Deteriorated, will be 
summarized as well. Median values will be plotted by treatment group over time. “Error” 
bars will be included, represented by the 25th and 75th percentiles (i.e., first and third 
quartiles). 
 Observed values and change from baseline in the SOFA score will be summarized using 
descriptive statistics, including quartiles.  
 Observed values, change from baseline, and percent from baseline in NLR will be 
summarized using descriptive statistics, including quartiles. Changes from baseline with 


 
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standard error bars will be plotted over time. Spaghetti plots of individual patient values 
over time will be presented separately by treatment group.  
 Observed values and change from baseline in pulse oximetry will be summarized using 
descriptive statistics, including quartiles.  
 By-subject listings will be provided for D-dimer, cardiac troponin, LDH, and ferritin levels 
(Day 7 and Day 14 from the day of dosing). 
4.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population. 
4.4.1. 
Study Drug Administration 
The number of subjects who experienced dose interruptions will be tabulated, as well as the 
reason for the interruption (AE, any reason). 
Dosing information for each subject will be presented in a data listing. 
4.4.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system and displayed in tables and data 
listings by SOC and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset after the administration of study 
medication through 30 days after the date of infusion, or any event that was present at baseline 
but worsened in intensity or was subsequently considered drug-related by the Investigator 
through the end of the study. Serious AEs that occur after 30 days post-infusion will be 
considered treatment-emergent, if judged by the Investigator to be at least possibly related to the 
study drug. 
Adverse events are summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given AE (SOC or preferred term). 
The numbers and percentages of subjects with any treatment-emergent AE (TEAE), any related 
TEAE, any Grade ≥3 AE, any related Grade ≥3 AE, any infusion related reaction, any AE of 
special interest (AESI), any infection adverse event, any serious AE, any related serious AE, 
any AE leading to study treatment discontinuation and any AE leading to death will be 
summarized by treatment group and overall. In these tabulations, each subject will contribute 
only once (i.e., the most related occurrence or the greatest severity grade) to each of the 
incidence rates in the descriptive analysis, regardless of the number of episodes. 
No formal hypothesis-testing analysis of adverse event incidence rates will be performed. 
All AEs occurring on-study will be listed in subject data listings. 


 
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By-subject listings also will be provided for the following: subject deaths, serious AEs, AEs 
leading to discontinuation of study drug, and Grade ≥ 3 adverse events. In addition, separate 
listings will be provided for AESIs and infection AEs. 
4.4.3. 
Laboratory Data 
Clinical laboratory values will be expressed using the International System of Units (SI units). 
The actual value and change from baseline to each on-study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry. In the event of 
repeat values, the last non-missing value per study day/time will be used. Select laboratory 
parameters will be graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.3. Shifts from baseline to the worst value and shifts to the last value will be 
presented. Box plots of change from baseline over time will be presented for hematology and 
clinical chemistry parameters. 
All laboratory data will be provided in data listings. A subset listing will be presented for all 
abnormal laboratory values. 
4.4.4. 
Vital Signs and Physical Examination 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and temperature. The actual value and change from baseline to each on-study 
evaluation will be summarized for vital signs. Vital sign measurements will be presented for 
each subject in a data listing. 
All abnormal physical examination findings will be presented in a data listing. 
4.4.5. 
Electrocardiogram 
The actual value and change from baseline to each on-study evaluation will be summarized for 
ECG interval data (PR, QRS, QTc). Electrocardiogram overall interpretation will be 
summarized, including the number and percentage of subjects with normal, abnormal, and 
clinically significant abnormal results at baseline and each study visit. 
Electrocardiogram data for each subject will be provided in a data listing. 
4.4.6. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary. Results will be 
tabulated by anatomic therapeutic class (ATC) and preferred term. 
Concomitant medications will be tabulated by treatment group, where any medications that did 
not end prior to administration of study drug will be included. If an end date is missing or the 
medication is ongoing, the medication will be included in the summary table. Partial end dates 
will be compared to the date of infusion; a medication will be considered concomitant unless the 
partial end date shows unequivocally that the medication ended prior to the date of infusion. 


 
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The use of concomitant medications will be provided in a by-subject data listing. 
4.4.7. 
Radiographic Lung Imaging 
Lung imaging results at each time point will be summarized by presenting the numbers and 
percentages of subjects with findings, for each of the findings specified on the eCRF. 
All lung imaging findings will be presented in a data listing. 


 
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5. 
CHANGES TO PLANNED ANALYSES 
 Per protocol, the following exploratory efficacy endpoints are noted in Section 1.2.5.2 but 
will not be included in the analysis of Part 2: 
 Change from baseline in the ratio of arterial oxygen partial pressure (PaO2) to fractional 
inspired oxygen (FiO2) (Day 7 and Day 14 from the day of dosing) 
 Length of time to normalization of oxygen saturation (SpO2) which is defined as SpO2 ≥ 
94% sustained minimum 24 hours 
 Proportion of subjects requiring mechanical ventilation (Day 7 and Day 14 from the day 
of dosing)  
 Changes from baseline in serum cytokines including IL-1RA, IL-1β, IL-2, IL-6, IL-7, 
IL-10, GCSF, GM-CSF, CCL2, CCL3, CXCL10, TNF-α, and IFN-γ (Day 2, Day 3, Day 
5, Day 7, and Day 14 from the day of dosing)  
 The protocol states that for the Part 2 Phase 3 portion, multiplicity will be adjusted by a 
gatekeeping procedure. However, due to the small number of subjects enrolled into Phase 3, 
data from Phase 2 and Phase 3 will be pooled, and the primary treatment group comparison 
will be based on combined TJ003234 6 mg/kg and TJ003234 10 mg/kg versus placebo. The 
gatekeeping procedure will be applied to the primary and key secondary endpoints based on 
the pooled treatment group comparisons. Supportive analyses will compare each dose level 
versus placebo, but will not be subject to the gatekeeping procedure. 
 


 
I-Mab Biopharma Co., Ltd. 
Statistical Analysis Plan; Effective 21 April 2022, Vers 2.0 
 
TMP-BS-001 Statistical Analysis Plan Template 
Version 3.0 
Effective: 17 Aug 2020  
TMP-CC-012 v1.0 Plan Template Effective 29Oct2019  
CONFIDENTIAL 
Page 32 of 34 
 
6. 
REFERENCES 
Avci, A.B., Feist, E. and Burmester, G.R. (2016). Targeting GM-CSF in Rheumatoid Arthritis. 
Clin Exp Rheumatol, 34 (4 Suppl 98):39–44. 
Broughton, S. E., Nero, T. L., Dhagat, U., Kan, W. L., Hercus, T. R., Tvorogov, D., … Parker, 
M. W. (2015). The βc receptor family – Structural insights and their functional implications. 
Cytokine, 74(2), 247–258. doi: 10.1016/j.cyto.2015.02.005 
Channappanavar, Rudragouda, and Stanley Perlman. “Pathogenic Human Coronavirus 
Infections: Causes and Consequences of Cytokine Storm and Immunopathology.” Seminars in 
Immunopathology, vol. 39, no. 5, Feb. 2017, pp. 529– 539., doi:10.1007/s00281-017-0629-x. 
Gust J, Finney O, Li D, Brakke HM, Hicks RM et al. (2019). Glial injury in neurotoxicity after 
pediatric CD19-directed chimeric antigen receptor T cell therapy. Ann Neurol. 86(1):42-54. 
Hamilton, J. A. (1980). Macrophage stimulation and the inflammatory response to asbestos. 
Environmental Health Perspectives, 34, 69–74. doi: 10.1289/ehp.803469 
Hansen, G., Hercus, T., Woodcock, J., Mcclure, B., Stomski, F., Xu, Y., … Parker, M. (2008). 
Structure of the GM-CSF Receptor Complex. doi: 10.2210/pdb3cxe/pdb 
Hercus, T. R., Kan, W. L. T., Broughton, S. E., Tvorogov, D., Ramshaw, H. S., Sandow, J. J., 
… Lopez, A. F. (2017). Role of the β Common (βc) Family of Cytokines in Health and 
Disease. Cold Spring Harbor Perspectives in Biology, 10(6). doi: 10.1101/cshperspect.a028514 
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., … Cao, B. (2020). Clinical features of 
patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497–
506. doi: 10.1016/s0140-6736(20)30183-5 
Jenkins, B. J., Blake, T. J., & Gonda, T. J. (1998). Saturation Mutagenesis of the β Subunit of 
the Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor Shows Clustering of 
Constitutive Mutations, Activation of ERK MAP Kinase and STAT Pathways, and Differential 
β Subunit Tyrosine Phosphorylation. Blood, 92(6), 1989–2002. doi: 
10.1182/blood.v92.6.1989.418k18_1989_2002 
Miettinen, O.S., and Nurminen, M.M. (1985). “Comparative Analysis of Two Rates.” Statistics 
in Medicine 4:213-226 
Sachdeva, Mohit, et al. “Granulocyte–Macrophage Colony-Stimulating Factor Inactivation in 
CAR T-Cells Prevents Monocyte-Dependent Release of Key Cytokine Release Syndrome 
Mediators.” Journal of Biological Chemistry, vol. 294, no. 14, 2019, pp. 5430–5437., 
doi:10.1074/jbc.ac119.007558. 
Sato, N., Sakamaki, K., Terada, N., Arai, K., & Miyajima, A. (1993). Signal transduction by the 
high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit 
responsible for different signaling. The EMBO Journal, 12(11), 4181–4189. doi: 
10.1002/j.1460-2075.1993.tb06102.x 


 
I-Mab Biopharma Co., Ltd. 
Statistical Analysis Plan; Effective 21 April 2022, Vers 2.0 
 
TMP-BS-001 Statistical Analysis Plan Template 
Version 3.0 
Effective: 17 Aug 2020  
TMP-CC-012 v1.0 Plan Template Effective 29Oct2019  
CONFIDENTIAL 
Page 33 of 34 
 
Schulert, Grant S., et al. “Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: 
Characterization and Risk Factors.” Arthritis & Rheumatology, vol. 71, no. 11, 2019, pp. 1943–
1954., doi:10.1002/art.41073. 
Sterner, RM, et al. GM-CSF inhibition reduces cytokine release syndrome and 
neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697-
709 
Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., … Peng, Z. (2020). Clinical 
Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia 
in Wuhan, China. Jama. doi: 10.1001/jama.2020.1585 
Xu Z, Shi L, Wang Y, Zhang J, Huang J, et al. (2020). Pathological findings of COVID-19 
associated with acute respiratory distress syndrome. Lancet Respir Med. doi: 10.1016/S2213-
2600(20)30076-X. 
Zhou, Yonggang, et al. “Aberrant Pathogenic GM-CSF T Cells and Inflammatory CD14 CD16 
Monocytes in Severe Pulmonary Syndrome Patients of a New Coronavirus.” 2020, 
doi:10.1101/2020.02.12.945576. 
 
 
 


 
I-Mab Biopharma Co., Ltd. 
Statistical Analysis Plan; Effective 21 April 2022, Vers 2.0 
 
TMP-BS-001 Statistical Analysis Plan Template 
Version 3.0 
Effective: 17 Aug 2020  
TMP-CC-012 v1.0 Plan Template Effective 29Oct2019  
CONFIDENTIAL 
Page 34 of 34 
 
7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables to be Generated 
A list of tables, listings, and figures to be generated, and table and listing shells are provided as 
a separate document. 


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