Clinical trial NCT04415073
Conditions: Coronavirus COVID ARDS Cytokine Storm Cytokine Release Syndrome
Sponsor: Syndax Pharmaceuticals
Start date: 2020-05-30; Completion date: 2020-07-13
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blind, placebo-controlled, 29-day study to assess the efficacy and safety of axatilimab plus standard of care (SOC), compared with placebo plus SOC, in participants with respiratory signs and symptoms secondary to COVID-19.

Detailed description:
Axatilimab (SNDX-6352) is a humanized immunoglobin G4 monoclonal antibody with high affinity against colony stimulating factor-1 receptor (CSF-1R) under investigation for the prevention or treatment of respiratory signs and symptoms secondary to COVID-19.

This was a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety and tolerability of axatilimab as an add-on to SOC therapy in hospitalized participants with respiratory signs and symptoms secondary to COVID-19 compared to SOC treatment.

Eligible participants were to be randomized in a 1:1 ratio to 1 of 2 treatment groups, active or control. All participants were to receive axatilimab or matching placebo intravenously (IV) as an add-on to SOC on Day 1, within 8 hours of randomization and on Day 15. Participants were to be followed for at least 28 days (+3 days) after the first dose of study intervention (Day 29).

The primary objective of the study was to assess the proportion of participants alive and free of respiratory failure at Day 29.

Arms: arm 1: Axatilimab on Days 1 and 15, IV + SOC arm 2: Matching placebo on Days 1 and 15, IV + SOC
Interventions: intervention 1: SNDX-6352 intervention 2: Placebo
Intervention descriptions: intervention 1: SNDX-6352 intervention 2: Placebo comparator

Protocol documents:
Prot_SAP_000.pdf: 
Product: SNDX-6352 
Protocol Number: SNDX-6352-0505 
Version 3.0, Amendment 2.0, 23 April 2020 
Page 1 of 83 
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Confidentiality Notice 
This document contains confidential information of Syndax Pharmaceuticals, Inc., the contents 
of which must not be disclosed to anyone other than the study staff and members of the 
respective Institutional Review Board/Ethics Committee. 
The information in this document cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Syndax 
Pharmaceuticals, Inc. 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title: 
A Phase 2, randomized, double-blind, placebo-controlled study 
to evaluate the efficacy and safety of axatilimab for the 
treatment of hospitalized patients with respiratory signs and 
symptoms secondary to novel coronavirus disease (COVID-19) 
Protocol Number: 
SNDX-6352-0505 
Study Intervention: 
Axatilimab (SNDX-6352) 
Study Phase: 
Phase 2 
Clinical Site: 
Up to 10 US sites 
Sponsor Name: 
Syndax Pharmaceuticals, Inc. 
Legal Registered 
Address: 
35 Gatehouse Drive 
Building D, Floor 3 
Waltham, MA 02451 
Regulatory Agency 
Identifier Number(s): 
IND: 149316 
Version: 
3.0, Amendment 2.0 
Approval Date: 
23 April 2020 
NCT #NCT04415073


Product: SNDX-6352 
Protocol Number: SNDX-6352-0505 
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SPONSOR SIGNATORY 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Medical Monitor Name and Contact Information: 
 
Tel: 
 
Email: 
 


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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol (SNDX-6352-0505) entitled “A Phase 2, randomized, double- 
blind, placebo-controlled study to evaluate the efficacy and safety of axatilimab for the treatment 
of hospitalized patients with respiratory signs and symptoms secondary to novel coronavirus 
disease (COVID-19),” dated 23 April 2020 version 3.0, and agree to abide by all provisions set 
forth therein. 
I agree to comply with the International Council for Harmonisation Tripartite E6 Guideline on 
Good Clinical Practice applicable regulations of the Food and Drug Administration and other 
applicable regulations. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me 
• 
my sub-investigators 
at the start of the study, at study completion, and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Syndax. 
 
 
 
 
Signature 
Name of Principal Investigator 
Date 


Product: SNDX-6352 
Protocol Number: SNDX-6352-0505 
Version 3.0, Amendment 2.0, 23 April 2020 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date 
Protocol V3.0, Amendment 2 
23 April 2020 
Protocol V2.0, Amendment 1 
22 April 2020 
Original Protocol V1 
16 April 2020 
Amendment 2, 23 April 2020 
 
Overall Rationale for the Amendment: 
 
Syndax has introduced the following modifications to protocol V3.0, these changes are presented 
in order of appearance: 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 9.1 Statistical Rationale 
and Determination of Sample 
Size 
Section 9.2 Operating 
Characteristics 
• 
Added clarification for the 
primary analysis by 
providing a three-category 
decision guideline. 
• 
Revised assumptions 
concerning the success rate 
in the control arm from 70% 
to 76% as consistent with 
the Agency’s feedback. 
• 
Added operating 
characteristics for a three- 
category decision guideline. 
Upon further consideration of 
the Agency’s feedback, Syndax 
sought advice from 
 
 As a result of his 
advice, Syndax has clarified the 
statistical considerations. 
Section 9.3 Population for 
Analyses 
• 
Revised ITT population 
description to include that 
the ITT set will be used in 
the analyses of the primary 
and secondary endpoints. 
For further clarity. 
Section 9.4.1 Efficacy Analysis 
• 
Revised language to specify 
that rather than considering 
all subjects with missing 
data on Day 29 as failures, 
subjects who cannot be 
documented to be alive or 
free of respiratory failure on 
Day 29 will be imputed 
Per advice of 
. 


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Version 3.0, Amendment 2.0, 23 April 2020 
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using the overall experience 
from placebo patients who 
are assessed at Day 29. 
Section 9.5 Interim Analysis 
• 
Revised language to specify 
that the interim analysis will 
occur at 50% of information 
rather than at 40% of 
information. 
• 
Updated an O-Brien- 
Fleming monitoring 
boundaries. 
Per advice of 
 
 given that this is set up 
as a screening trial with a 
modest sample size, the interim 
analysis will be conducted at 
50% of information. 
Section 9.5.1 Independent Data 
Monitoring Committee (IDMC) 
• 
Revised language to 
highlight that the mission of 
the IDMC to safeguard the 
interests of study 
participants and to enhance 
trial integrity. 
Clarification in language. 
General 
• 
Corrected styles, 
formatting, links and 
checked spelling 
• 
Other minor terminology 
updates 
• 
Update references 
For consistency throughout 
protocol. 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ....................................................................................... 1 
TITLE PAGE ....................................................................................................................... 1 
SPONSOR SIGNATORY .................................................................................................... 2 
INVESTIGATOR’S AGREEMENT ................................................................................... 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................ 4 
TABLE OF CONTENTS ...................................................................................................... 6 
LIST OF TABLES ............................................................................................................... 9 
LIST OF FIGURES ............................................................................................................ 10 
1. 
PROTOCOL SUMMARY ............................................................................... 11 
1.1. 
Synopsis .......................................................................................................... 11 
1.2. 
Schedule of Activities ...................................................................................... 14 
2. 
INTRODUCTION........................................................................................... 19 
2.1. 
Study Rationale and Hypothesis ..................................................................... 19 
2.2. 
Background ..................................................................................................... 20 
2.2.1. 
Clinical Experience with Axatilimab ............................................................... 21 
2.3. 
Benefit and Risk Analysis ................................................................................ 24 
3. 
OBJECTIVES AND ENDPOINTS ................................................................ 26 
4. 
STUDY DESIGN ............................................................................................ 29 
4.1. 
Overall Study Design ...................................................................................... 29 
4.2. 
Scientific Rationale for Study Design ............................................................. 29 
4.3. 
Dose Justification ............................................................................................ 29 
4.4. 
Study Duration ................................................................................................ 31 
4.5. 
End of Study Definition .................................................................................. 31 
5. 
ELIGIBILITY CRITERIA .............................................................................. 32 
5.1. 
Inclusion Criteria ............................................................................................. 32 
5.2. 
Exclusion Criteria ........................................................................................... 33 
5.3. 
Screen Failures ................................................................................................ 34 
6. 
STUDY INTERVENTION .............................................................................. 35 
6.1. 
Study Intervention(s) Administered ................................................................ 35 
6.2. 
Standard of Care .............................................................................................. 36 


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6.3. 
Preparation/Handling/Storage/Accountability ................................................. 36 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ............................ 37 
6.5. 
Study Intervention Compliance ....................................................................... 37 
6.6. 
Dose Modifications ......................................................................................... 37 
6.6.1. 
Dose Modifications for AST, ALT, Bilirubin, Creatine Kinase (CK), 
Amylase and Lipase Elevation ........................................................................ 38 
6.6.2. 
Dose Modifications for Other Non-hematologic Toxicity .............................. 39 
6.6.3. 
Dose Modifications for Hematologic Toxicity ............................................... 39 
6.6.4. 
Axatilimab Infusion-Related Reaction ............................................................ 40 
6.7. 
Concomitant Medication ................................................................................. 40 
6.7.1. 
Prohibited Medications ................................................................................... 41 
6.8. 
Treatment of Overdose .................................................................................... 41 
6.9. 
Intervention after the End of the Study ........................................................... 42 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ....................................................... 43 
7.1. 
Stopping Rules ................................................................................................ 43 
7.1.1. 
Pregnancy ........................................................................................................ 43 
7.2. 
Discontinuation of Study Intervention ............................................................ 43 
7.3. 
Withdrawal from the Study ............................................................................. 44 
7.4. 
Lost to Follow up ............................................................................................ 44 
8. 
STUDY ASSESSMENTS ............................................................................... 45 
8.1. 
Efficacy Assessments ...................................................................................... 45 
8.1.1. 
Measure of Clinical Benefit ............................................................................ 45 
8.1.2. 
Clinical Status Ordinal Score .......................................................................... 45 
8.1.3. 
National Early Warning Score (NEWS) ......................................................... 46 
8.1.4. 
Hospital Discharge Readiness Criteria............................................................ 47 
8.1.5. 
Oxygenation Measures .................................................................................... 47 
8.1.6. 
Viral Clearance................................................................................................ 48 
8.2. 
Safety Assessments ......................................................................................... 48 
8.2.1. 
Physical Examinations .................................................................................... 48 
8.2.2. 
Vital Signs ....................................................................................................... 49 
8.2.3. 
Electrocardiograms .......................................................................................... 49 
8.2.4. 
Clinical Safety Laboratory Assessments ......................................................... 49 


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8.3. 
Adverse Events and Serious Adverse Events.................................................. 50 
8.3.1. 
Time Period and Frequency for Collecting AE, AE of Special Interest and 
SAE Information ............................................................................................. 50 
8.3.2. 
Method of Detecting AEs and SAEs ............................................................... 51 
8.3.3. 
Follow-up of AEs and SAEs ........................................................................... 51 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................................... 51 
8.3.5. 
Pregnancy ........................................................................................................ 52 
8.4. 
Pharmacokinetics ............................................................................................ 52 
8.5. 
Pharmacodynamics and 
 Endpoints ............................................. 52 
8.6. 
Biomarkers ...................................................................................................... 53 
9. 
STATISTICAL CONSIDERATION .............................................................. 54 
9.1. 
Statistical Rationale and Determination of Sample Size ................................. 54 
9.2. 
Operating Characteristics ................................................................................ 54 
9.3. 
Population for Analyses .................................................................................. 55 
9.4. 
Statistical Methods .......................................................................................... 55 
9.4.1. 
Efficacy Analysis ............................................................................................ 56 
9.4.2. 
Safety and Tolerability Analysis ..................................................................... 60 
9.4.3. 
Other Analyses ................................................................................................ 61 
9.5. 
Interim Analysis .............................................................................................. 61 
9.5.1. 
Independent Data Monitoring Committee (IDMC) ........................................ 61 
10. 
APPENDICES ................................................................................................ 62 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ......... 62 
10.1.1. 
Regulatory and Ethical Considerations ........................................................... 62 
10.1.2. 
Informed Consent Process .............................................................................. 62 
10.1.3. 
Data Protection ................................................................................................ 63 
10.1.4. 
Dissemination of Clinical Study Data ............................................................. 63 
10.1.5. 
Data Quality Assurance................................................................................... 63 
10.1.6. 
Source Documents .......................................................................................... 64 
10.1.7. 
Study and Site Closure .................................................................................... 65 
10.1.8. 
Publication Policy ........................................................................................... 65 
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................... 66 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................ 67 


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10.3.1. 
Definition of AE ............................................................................................. 67 
10.3.2. 
Definition of SAE ........................................................................................... 68 
10.3.3. 
Definition of Adverse Events of Special Interest ............................................ 68 
10.3.4. 
Definition of Suspected and Unsuspected Adverse Reaction ......................... 69 
10.3.5. 
Recording and Follow-Up of AE and/or SAE ................................................ 69 
10.3.6. 
Reporting of SAEs .......................................................................................... 71 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ...................................................................................................... 72 
10.5. 
Appendix 5: Glossary ...................................................................................... 75 
10.6. 
Protocol Amendment History ......................................................................... 78 
11. 
REFERENCES ................................................................................................ 80 
 
 
 
LIST OF TABLES 
Table 1: 
Treatment Groups ........................................................................................... 13 
Table 2: 
Schedule of Activities ..................................................................................... 14 
Table 3: 
Treatment Groups ........................................................................................... 29 
Table 4: 
Study Intervention ........................................................................................... 35 
Table 5: 
AST, ALT Bilirubin, CK, Amylase and Lipase: Dose Modification 
Guidelines for Axatilimab for Day 15 dose .................................................... 38 
Table 6: 
Other Non-hematologic Toxicity: Dose Modification Guidelines for 
SNDX-6352 (Day 15) ..................................................................................... 39 
Table 7: 
Hematologic Toxicity: Dose Modification Guidelines for SNDX-6352 (Day 
15) ................................................................................................................... 39 
Table 8: 
Infusion-related Reactions for Study Intervention .......................................... 40 
Table 9: 
A 7-Point Ordinal Score for Assessing Clinical Status ................................... 46 
Table 10: 
NEW Score ...................................................................................................... 47 
Table 11: 
A 4-Point Oxygen Ordinal Scale for Severity Categories by SpO2/FiO2 Ratio 
........................................................................................................................48 
Table 12: 
Adverse Event Observation Periods ............................................................... 50 
Table 13: 
Protocol-Required Laboratory Assessments ................................................... 66 
Table 14: 
Highly Effective methods of contraception (<1% failure rate) ....................... 73 


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LIST OF FIGURES 
Figure 1 
Dynamics of non-classical and intermediate monocytes in plasma of healthy 
volunteers following treatment with axatilimab ............................................. 22 
Figure 2 
Dynamics of non-classical and intermediate monocytes in plasma of solid 
tumor patients following treatment with Axatilimab ...................................... 23 
Figure 3: 
Concentration of Axatilimab in Plasma in Healthy Volunteers and Cancer 
Patients ............................................................................................................ 30 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 2, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of axatilimab for the treatment of hospitalized patients with respiratory 
signs and symptoms secondary to novel coronavirus disease (COVID-19) 
Rationale 
Axatilimab (mAb 969.g2; SNDX-6352) is a humanized IgG4 monoclonal antibody (mAb) 
with high affinity against colony stimulating factor-1 receptor (CSF-1R) under investigation for 
the prevention or treatment of respiratory signs and symptoms secondary to novel coronavirus 
disease (COVID-19). 
A review of clinical outcomes in patients infected with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) indicates the presence of acute respiratory distress syndrome 
(ARDS) in a significant proportion of patients with severe disease (Wang, 2020; Wu, 2020). 
ARDS has been identified as a leading cause of death due to SARS-CoV-2 infection and 
results from excessive inflammatory cytokines, known as a cytokine storm, generated by the 
immune response to the virus (Liao, 2020). Immunopathological characteristics of patients 
with SARS-CoV-2 confirm a significant increase in pro-inflammatory cytokines such as IL-6, 
with the likely source of these pro-inflammatory cytokines being activated macrophages 
(Mehta, 2020; Ruan, 2020; Shi, 2020). In addition, a separate study (Zhang, 2020) supports 
association of elevated numbers of circulating intermediate and pro-inflammatory 
CD14+CD16+ monocytes in SARS-CoV-2 patients with increased severity, admission into 
intensive care units (ICU), and longer recovery time. Interleukin (IL)-6, IL-1b, and other 
cytokines that constitute the cytokine storm are produced by proinflammatory monocyte- 
derived macrophages, and depletion of these cells has been shown to prevent and reduce the 
cytokine release syndrome in preclinical disease models (Giavridis, 2018; Norelli, 2018). 
Depletion of pro-inflammatory monocyte-derived macrophages may ameliorate the 
SARS-CoV-2 associated inflammation in the lungs, thereby preserving lung function and 
reducing the virus-associated mortality. Proliferation and maturation of circulating pro- 
inflammatory monocyte-derived macrophages is regulated through activation of the CSF-1R 
by its ligands colony stimulating factor-1 (CSF-1) and IL-34. In addition, signaling through 
CSF-1R leads to increased tissue-resident macrophage proliferation secondary to 
inflammation. Two independent approaches to understanding the role of myeloid cell 
populations in lung inflammation have demonstrated that CSF-1R blockade can reduce the 
number and function of pro-inflammatory monocytes / macrophages (Anthony, 2014; Joshi, 
2020), suggesting that an anti-CSF-1R approach may be particularly active in preventing or 
reducing SARS-CoV-2 associated inflammation and its consequences. 
Axatilimab has been shown to be extremely effective in rapidly depleting circulating 
pro-inflammatory monocytes in healthy subjects, cancer patients and patients with chronic 
graft versus host disease (cGVHD) at doses that have been tolerated well. Depleting 
circulating pro-inflammatory monocytes with axatilimab may provide a broader and more 
complete dampening of the overactive immune response seen in SARS-CoV-2 patients than 


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merely targeting individual cytokine signaling pathways, thus providing additional 
therapeutic benefit. The ability of axatilimab to rapidly deplete circulating pro-inflammatory 
monocytes in humans is expected to lead to reduction of cytokine storm and subsequent 
prevention or treatment of respiratory signs and symptoms secondary to COVID-19. 
 
Objectives and Endpoints (Primary and Secondary) 
 
Objectives 
Endpoints 
Primary 
• To assess important measures of 
subject benefit (Section 8.1.1) 
• Proportion of subjects alive and free of 
respiratory failure (need for mechanical 
ventilation, extracorporeal membrane 
oxygenation (ECMO), non-invasive 
ventilation >6L oxygen/minute, or clinical 
diagnosis of respiratory failure with 
initiation of none of these measures only 
when clinical decision-making driven is 
driven solely by resource limitation) at 
Day 29 
Secondary 
• Secondary clinical improvement 
outcomes 
• Proportion of subjects achieving a ≥ 2 
category improvement on 7-point ordinal 
score relative to the baseline on Day 28 as 
collected on Day 29 (Section 8.1.2) 
• Time to clinical improvement (TTCI), 
defined as national early warning score 
(NEWS) of ≤2 maintained for 24 hours 
• To evaluate improvement in 
oxygenation in hospitalized adults 
with respiratory signs and 
symptoms secondary to 
COVID-19 treated with 
axatilimab 
• Change from baseline to Day 29 or 
hospital discharge or death, if sooner, in 
the ratio of peripheral hemoglobin oxygen 
saturation to fraction of inspired oxygen 
(SpO2/FiO2) 
• To evaluate changes in 
biomarkers following treatment 
with axatilimab 
• Change from baseline to Day 15 or 
hospital discharge or death, if sooner, in 
serum concentrations of IL-6, and 
c-reactive protein (CRP) 
• To evaluate the safety and 
tolerability of axatilimab in the 
same population 
• Frequency and severity of adverse events 
(AEs) and serious adverse events (SAEs) 


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Overall Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy, safety and tolerability of axatilimab as an add-on to standard of care (SOC) 
therapy in hospitalized subjects with respiratory signs and symptoms secondary to COVID-19 
compared to SOC treatment. 
The study will be comprised of 2 periods: Screening and Treatment. Throughout the study, 
subjects will be evaluated as specified in the Schedule of Activities (SoA) in Section 1.2. 
After signing informed consent form (ICF), potential candidates, who are hospitalized and 
have documented/confirmed infection with SARS-CoV-2 by RNA polymerase chain reaction 
(PCR) test performed <72 hours before randomization, will undergo additional screening 
procedures. 
On Day 1, eligible subjects will be randomized in a 1:1 ratio to one of 2 treatment groups, 
active or control, as shown in Table 3. Screening and randomization may occur on the same 
day; if so, study assessments conducted at Screening do not need to be repeated on Day 1, 
unless drug is not administered within 4 hours of randomization. Randomization will be 
stratified by severity at study entry (Section 6.4). In addition, time from onset of symptoms 
(fever, cough, etc.) to study entry will be collected and analyzed prospectively. All subjects 
will receive study intervention intravenously (IV) as an add-on to SOC on Day 1, within 8 
hours of randomization and on Day 15. Subjects will be followed for at least 28 days (+3 
days) after the first dose of study intervention (Day 29)/end of study (EOS). Subjects who 
experience an AE should be followed for at least 30 days after last dose or until resolution of 
the AE. 
Subjects will be monitored post-study per standard of care for as long as they continue to 
shed viral RNA in nasopharyngeal and stool samples. 
Number of Subjects and Intervention Groups 
Table 1: 
Treatment Groups 
Treatment 
Group 
Dose Level, Schedule and Route of 
administration f 
Number of 
subjects 
Active 
Axatilimab 150 mg on Days 1 and 15, IV + SOC 
93 
Control 
Matching placebo + SOC 
93 
 
Duration 
For each subject, the study is expected to last as follows: 
 
Screening period: 
Up to 3 days 
Treatment period: 
29 days (+3 days) 
Post study follow-up 
TBD, subjects will be monitored per standard of care for as long as 
they continue to shed viral RNA in nasopharyngeal and stool samples 
Independent Data Monitoring Committee: Yes 


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1.2. 
Schedule of Activities 
Table 2: 
Schedule of Activities 
General Notes: 
• 
Some visits/study procedures post-discharge can be done via virtual visits or at home visits. Refer to study reference manual for more details. 
• 
Assessments completed as part of standard of care within the protocol defined windows, will not need to be repeated specifically for the protocol. 
Study Procedures 
Screeninga 
Treatment Period 
Notes 
Baselinea 
Daily until hospital 
discharge 
Daily 
until 
hospital 
discharge 
EOS 
a Screening and Baseline may occur on the 
same day; if so, study assessments 
conducted at Screening do not need to be 
repeated on Day 1, unless drug is not 
administered within 4 hours of 
randomization. 
Early termination (ET); End of Study (EOS) 
Day in study 
-3 to -1 
1 
2-7 
8b 
9-14 
15 b 
16-28c 
29 b /ET 
b Required out-patient visit if previously 
discharged 
c If a subject is discharged from hospital 
prior to Day 22, an out-patient clinic visit or 
telehealth visit for follow up should occur on 
Day 22 
Visit Window (Days) 
NA 
NA 
±1 
±1 
±1 
±1 
+3 
Informed consent 
X 
Demographics d 
X 
d. Includes age, race, and ethnicity. 
Eligibility criteria 
X 
Documented/confirmed 
SAR-CoV-2 by RNA PCR 
Xe 
e. <72 hours before randomization. 
Polymerase chain reaction (PCR) must be an 
FDA approved test. 
Medical & disease historyf 
& prior medications 
 
X 
f. Including time from onset of symptoms 
(fever, cough, etc.) to study entry, COVID- 
19 severity, reason for hospital admission, 
and any instances if care decisions are made 
based on resource limitations. 
Complete physical 
examination 
X 
X 


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Study Procedures 
Screeninga 
Treatment Period 
Notes 
Baselinea 
Daily until hospital 
discharge 
Daily 
until 
hospital 
discharge 
EOS 
a Screening and Baseline may occur on the 
same day; if so, study assessments 
conducted at Screening do not need to be 
repeated on Day 1, unless drug is not 
administered within 4 hours of 
randomization. 
Early termination (ET); End of Study (EOS) 
Day in study 
-3 to -1 
1 
2-7 
8b 
9-14 
15 b 
16-28c 
29 b /ET 
b Required out-patient visit if previously 
discharged 
c If a subject is discharged from hospital 
prior to Day 22, an out-patient clinic visit or 
telehealth visit for follow up should occur on 
Day 22 
Visit Window (Days) 
NA 
NA 
±1 
±1 
±1 
±1 
+3 
Height and weight 
X 
Xg 
g, Weight to be collected at hospital 
discharge. 
Symptoms-directed 
physical exam 
Xh 
X 
X 
X 
X 
X 
h. Not required to be conducted if screening 
and baseline occur on the same day. 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
i. Vital signs should also be obtained during 
or after the infusion, if clinically indicated. 
Same method for temperature measurement 
should be used throughout the study. 
SpO2%j 
 
 
X 
X 
X 
X 
X 
X/ 
X 
X 
j. Peripheral capillary oxygen saturation 
(SpO2) or O2 by arterial blood gas 
The lowest ratio for each day should be 
collected, with the following exceptions. 
The ratio immediately prior to study entry 
will be entered. The last ratio before hospital 
discharge or death (prior to onset of 
cardiopulmonary arrest) will be entered. 
k 
Record FiO2 
 
X 
X 
X 
X 
X 
X 
X 
X 
k. Fraction of inspired oxygen (FiO2). If 
Fi02 not directly obtainable, use method of 
delivery (e.g. nasal canula, simple mask, 
rebreather mask) and oxygen flow rate in 
L/minute. 


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Study Procedures 
Screeninga 
Treatment Period 
Notes 
Baselinea 
Daily until hospital 
discharge 
Daily 
until 
hospital 
discharge 
EOS 
a Screening and Baseline may occur on the 
same day; if so, study assessments 
conducted at Screening do not need to be 
repeated on Day 1, unless drug is not 
administered within 4 hours of 
randomization. 
Early termination (ET); End of Study (EOS) 
Day in study 
-3 to -1 
1 
2-7 
8b 
9-14 
15 b 
16-28c 
29 b /ET 
b Required out-patient visit if previously 
discharged 
c If a subject is discharged from hospital 
prior to Day 22, an out-patient clinic visit or 
telehealth visit for follow up should occur on 
Day 22 
Visit Window (Days) 
NA 
NA 
±1 
±1 
±1 
±1 
+3 
Hospital discharge 
readiness assessment 
Xl 
Refer to Section 8.1.4. 
l. To be collected only on day subject is 
expected to be assessed as discharge ready 
(anytime during the study) or ET/EOS. 
Chest x-ray or CT scan of 
lungsm 
X 
Xn 
Computed tomography (CT) 
m. Same modality to be used throughout the 
study, where possible. 
n. as clinically indicated. 
Nasopharyngeal swab for 
or stool analysis SARS- 
CoV-2 PCRo 
Days 
3, & 
5 
X 
Day 
11 
X 
X 
o. For any given subject, the same technique 
for nasopharyngeal swabbing and nostril (if 
both nostrils are not sampled) should be 
used throughout the study (Refer to 
Section 8.1.6). 
NEWSq 
X 
X 
X 
X 
X 
X 
X 
X 
q. Refer to Section 8.1.3 
National early warning score (NEWS) 
State of consciousness 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogramr 
X 
X 
r. As clinically indicated. 


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Study Procedures 
Screeninga 
Treatment Period 
Notes 
Baselinea 
Daily until hospital 
discharge 
Daily 
until 
hospital 
discharge 
EOS 
a Screening and Baseline may occur on the 
same day; if so, study assessments 
conducted at Screening do not need to be 
repeated on Day 1, unless drug is not 
administered within 4 hours of 
randomization. 
Early termination (ET); End of Study (EOS) 
Day in study 
-3 to -1 
1 
2-7 
8b 
9-14 
15 b 
16-28c 
29 b /ET 
b Required out-patient visit if previously 
discharged 
c If a subject is discharged from hospital 
prior to Day 22, an out-patient clinic visit or 
telehealth visit for follow up should occur on 
Day 22 
Visit Window (Days) 
NA 
NA 
±1 
±1 
±1 
±1 
+3 
Safety Laboratory 
(hematology, & 
biochemistry) 
 
 
 
X 
Xs 
Xt 
X 
X t 
Xu 
X t 
X 
s. Not required to be repeated if screening 
and baseline occur on the same day. 
t. Frequency of safety laboratory to be done 
per standard of care during hospitalization 
and on Day 3, Day 5 and Day 11. 
Refer to Appendix 2 (Section 10.2) for full 
list of clinical laboratory tests. 
u. Safety laboratory values and results to be 
obtained prior to dosing 
Coagulation factorsv 
X 
v. Frequency per standard of care during 
hospitalization. 
Refer to Appendix 2 (Section 10.2) 
Serum Pregnancy test 
(WOCBP only) 
X 
X 
Women of childbearing potential (WOCBP) 
Randomization 
X 
Study intervention 
administration 
Xw 
X 
w. On Day 1, study intervention to be 
administered within 8 hours of 
randomization. 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Procedures 
Screeninga 
Treatment Period 
Notes 
Baselinea 
Daily until hospital 
discharge 
Daily 
until 
hospital 
discharge 
EOS 
a Screening and Baseline may occur on the 
same day; if so, study assessments 
conducted at Screening do not need to be 
repeated on Day 1, unless drug is not 
administered within 4 hours of 
randomization. 
Early termination (ET); End of Study (EOS) 
Day in study 
-3 to -1 
1 
2-7 
8b 
9-14 
15 b 
16-28c 
29 b /ET 
b Required out-patient visit if previously 
discharged 
c If a subject is discharged from hospital 
prior to Day 22, an out-patient clinic visit or 
telehealth visit for follow up should occur on 
Day 22 
Visit Window (Days) 
NA 
NA 
±1 
±1 
±1 
±1 
+3 
Pharmacokineticsx, y 
X 
Day 3 
X 
x. Sampling time: 
Day 1: at 30 min (end of infusion) 
Day 3: if hospitalized, any time 
Day 15/ET: predose and at 30 min (end of 
infusion) 
y. PK samples may be used for anti-drug 
antibody evaluation. 
Pharmacodynamics 
(cytokines)z 
X 
Day 3 
X 
X 
X 
Plasma levels of a cytokine panel will be 
collected predose. 
Pharmacodynamics 
(monocytes) 
X 
z. Plasma levels circulating monocyte 
number and phenotype (CD14/16) will be 
collected predose. 
Serum CRP and ferritin 
X 
X 
X 
X 
C-reactive protein (CRP) 
IL-6 
X 
X 
X 
X 
Interleukin-6 (IL-6) 
Post-study follow-up 
Xaa 
aa. Subjects will be monitored per standard 
of care for as long as they continue to shed 
viral RNA in nasopharyngeal and stool 
samples. 


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2. 
INTRODUCTION 
2.1. 
Study Rationale and Hypothesis 
Axatilimab (mAb 969.g2; SNDX-6352) is a humanized IgG4 monoclonal antibody (mAb) with 
high affinity against colony stimulating factor-1 receptor (CSF-1R). It was derived from a rat 
antibody with humanization achieved by grafting complementary determination region 
sequences, together with key framework region residues, from the parental rat antibody onto 
appropriate human germline variable region framework sequences. 
 
 
 
 
 
Axatilimab is currently under investigation for the prevention or treatment of respiratory signs and 
symptoms secondary to novel coronavirus disease (COVID-19). 
A review of clinical outcomes in patients infected with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) indicates the presence of acute respiratory distress syndrome 
(ARDS) in a significant proportion of patients with severe disease (Wang, 2020; Wu, 2020). 
ARDS has been identified as a leading cause of death due to SARS-CoV-2 infection and results 
from excessive inflammatory cytokines, known as a cytokine storm, generated by the immune 
response to the virus (Liao, 2020). Immunopathological characteristics of patients with 
SARS-CoV-2 confirm a significant increase in pro-inflammatory cytokines such as IL-6, with 
the likely source of these pro-inflammatory cytokines being activated macrophages 
(Mehta, 2020; Ruan, 2020; Shi, 2020). In addition, a separate study (Zhang, 2020) supports 
association of elevated numbers of circulating intermediate and pro-inflammatory CD14+CD16+ 
monocytes in SARS-CoV-2 patients with increased severity, admission into intensive care units 
(ICU), and longer recovery time. Interleukin (IL)-6, IL-1b, and other cytokines that constitute the 
cytokine storm are produced by proinflammatory monocyte-derived macrophages, and depletion 
of these cells has been shown to prevent and reduce the cytokine release syndrome in preclinical 
disease models (Giavridis, 2018; Norelli, 2018). 
Depletion of pro-inflammatory monocyte-derived macrophages may ameliorate the 
SARS-CoV-2 associated inflammation in the lungs, thereby preserving lung function and 
reducing the virus-associated mortality. Proliferation and maturation of circulating pro- 
inflammatory monocyte-derived macrophages is regulated through activation of the CSF-1R by 
its ligands colony stimulating factor-1 (CSF-1) and IL-34. In addition, signaling through CSF-1R 
leads to increased tissue-resident macrophage proliferation secondary to inflammation. Two 
independent approaches to understanding the role of myeloid cell populations in lung 
inflammation have demonstrated that CSF-1R blockade can reduce the number and function of 
pro-inflammatory monocytes / macrophages (Anthony, 2014; Joshi, 2020), suggesting that an 
anti-CSF-1R approach may be particularly active in preventing or reducing SARS-CoV-2 
associated inflammation and its consequences. 


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Axatilimab has been shown to be extremely effective in rapidly depleting circulating 
pro-inflammatory monocytes in healthy subjects, cancer patients and patients with chronic graft 
versus host disease (cGVHD) at doses that have been tolerated well. Depleting circulating 
pro-inflammatory monocytes with axatilimab may provide a broader and more complete 
dampening of the overactive immune response seen in SARS-CoV-2 patients than merely 
targeting individual cytokine signaling pathways, thus providing additional therapeutic benefit. 
The ability of axatilimab to rapidly deplete circulating pro-inflammatory monocytes in humans is 
expected to lead to reduction of cytokine storm and subsequent prevention or treatment of 
respiratory signs and symptoms secondary to COVID-19. 
 
2.2. 
Background 
SARS-CoV-2, a positive-sense single-stranded RNA virus of zoonotic origin, is highly 
contagious in humans and is the cause of the ongoing worldwide pandemic of COVID-19. As of 
April 16, 2020, the SARS-CoV-2 has been responsible for more than 2 million infections and 
139,000 deaths worldwide (data from https://coronavirus.jhu.edu/). 
SARS-CoV-2 is transmitted via respiratory droplets (fomites infectious particles) within a range 
of about 2 meters and direct contact with contaminated surfaces. The median incubation period 
was estimated to be 4-5 days, and the majority (97.5%) developed symptoms within 11.5 days 
(CI, 8.2 to 15.6 days) of infection (Guan, 2020; Lauer, 2020). Higher viral loads are detected 
soon after symptom onset, with higher viral loads detected in the nose than in the throat (Zou, 
2020). The mean viral load of severe cases was around 60 times higher than that of mild cases, 
suggesting that higher viral loads might be associated with severe clinical outcomes (Liu, 2020). 
Initially, SARS-CoV-2 predominantly infects lower airways and binds to angiotensin converting 
enzyme (ACE)-2 on alveolar epithelial cells (Guo, 2020; Kuba, 2010). It is a potent inducer of 
inflammatory cytokines. The “cytokine storm” or “cytokine cascade” is the postulated 
mechanism for organ damage. The virus activates immune cells and induces the secretion of 
inflammatory cytokines and chemokines into pulmonary vascular endothelial cells (Jiang, 2020). 
Clinical symptoms of COVID-19 include fever, cough, and dyspnea (Guan, 2020; Jiang, 2020; 
Rodriguez-Morales, 2020; Rothan, 2020); a small population of patients also may suffer from 
gastrointestinal symptoms (Guan, 2020; Guo, 2020). Radiologic features in the lungs include 
bilateral ground glass opacities on chest x-ray or computed tomography (CT) (Guan, 2020). 
COVID-19 appears to be more prevalent in males than females (Adhikari, 2020). 
There are no approved treatments for COVID-19 or vaccines against SARS-CoV-2. Clinical 
management is mainly focused on symptomatic and respiratory support. There are few specific 
antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under 
urgent investigation (Guo, 2020). Chloroquine phosphate, a drug for treatment of malaria, was 
shown to have apparent efficacy against COVID-19 associated pneumonia in multicenter clinical 
studies conducted in China (Gao, 2020). In addition, IL-6 or IL-6-receptor blocking antibodies 
like tocilizumab (Actemra, Roche-Genentech), sarilumab (Kevzara, Regeneron), and siltuximab 
(Sylvant, EUSA Pharma) which are FDA-approved for various conditions, including cytokine 
release syndrome (CRS), are being investigated in critically ill patients with COVID-19-induced 
hypoxia (Ascierto, 2020; Conti, 2020). Other treatments and therapies include antibiotics, 


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corticosteroids, mechanical ventilation, oxygen therapy, and continuous renal replacement 
techniques (CRRT) (Jiang, 2020). 
Infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from 
asymptomatic, mild, moderate to severe. The population at greatest risk for severe disease are 
immune-compromised patients such as the elderly, and subjects with co-morbid diseases (e.g., 
diabetes, cardiovascular, cancer). The severe cases usually present with pneumonia, which can 
progress to ARDS and cytokine storm (Adhikari, 2020; Guo, 2020). ARDS is defined by the 
acute onset of noncardiogenic pulmonary edema, hypoxemia, and the need for mechanical 
ventilation. Management principles of COVID-19-induced ARDS are mainly supportive and do 
not differ from the management of ARDS from other causes. Treatment of severe ARDS 
associated with COVID-19 is an ongoing challenge. Currently, treatment focuses on lung- 
protective ventilation; no specific pharmacotherapies have been identified (ARDS Definition 
Task Force, 2012; Goh, 2020; Matthay, 2019; Matthay, 2020). Approximately 14% 
(95%CI 6.2-21.5%) of hospitalized patients had fatal outcomes (case fatality rate, CFR) 
(Rodriguez-Morales, 2020). Risk factors associated with the development of ARDS and 
progression from ARDS to death included older age, neutrophilia, and organ and coagulation 
dysfunction (Wu, 2020). 
2.2.1. 
Clinical Experience with Axatilimab 
The clinical development program for axatilimab includes 3 studies: 
• 
 
• 
An ongoing Phase 1 multiple ascending dose study in subjects with solid tumors 
(SNDX-6352-0502) 
• 
An ongoing Phase 1/2, dose finding and dose expansion study in subjects with 
cGVHD (SNDX-6352-0503) 
A brief description of the pharmacology and safety of axatilimab is provided below. 


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SNDX-6352-0502 (ongoing) 
SNDX-6352-0502, is an open label, multi-center Phase 1 study evaluating the safety, tolerability, 
PK and PD activity of axatilimab monotherapy (Phase 1a) and axatilimab in combination with 
durvalumab (Phase 1b) in subjects with unresectable, recurrent, locally-advanced or metastatic 
solid tumors (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) that are not 
amenable to standard therapy. 
 


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SNDX-6352-0503 (ongoing) 
SNDX-6352-0503 is a Phase 1 dose finding and Phase 2 dose expansion study evaluating the 
safety, tolerability, PK/pharmacodynamic (PD), and efficacy of axatilimab in subjects with 
active cGVHD whose disease has progressed despite at least 2 prior lines of therapy. 
 
 


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2.3. 
Benefit and Risk Analysis 
The available nonclinical data and safety clinical data with axatilimab to date support clinical 
investigation in subjects with respiratory signs and symptoms secondary to COVID-19. Please 
refer to the axatilimab Investigator’s brochure (IB) for known and expected benefits and risks 
and reasonably expected adverse events of axatilimab. 
Expected AEs that may be predicted to occur based on the pharmacologic and toxicology 
properties of axatilimab, even if not yet observed with axatilimab include periorbital edema, 
facial swelling, and infusion reactions. 
Due to its mechanism of action (pharmacological inhibition of CSF-1R), axatilimab may induce 
dose-dependent and reversible increases in circulating levels of creatine kinase (CK), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), 
amylase and lipase (see IB for details). Kupffer cells in the liver (which are involved in the 
clearance of these enzymes) are in the macrophage lineage and susceptible to axatilimab 
inhibition of CSF-1R. The expected increases in these enzyme levels are related to decreased 
clearance from the blood, rather than from drug-induced liver injury and are not associated with 


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any histopathological changes. Administration of axatilimab has not been associated with 
clinical manifestations of hepatitis or pancreatitis, or rhabdomyolysis. Furthermore, these 
laboratory abnormalities were not observed in patients treated at a doses equivalent to those 
being proposed in the current study. Laboratory assessments (i.e., clinical chemistries, including 
tests for liver function) will be performed as specified in protocol to monitor subject’s safety. 
A priori mechanistic considerations highlight a number of potential risks, which will be 
monitored in a clinical study setting. On the basis of the information currently available, the risk- 
benefit of axatilimab is considered acceptable for COVID-19. 
Given the underlying scientific basis for testing CSF-1R targeted therapy in respiratory signs and 
symptoms secondary to COVID-19, the lack of treatment options in COVID-19 population, the 
conservative dosing strategy and preliminary PK, PD, safety and preliminary evidence of clinical 
activity seen in prior completed and ongoing studies, the risk of axatilimab in the proposed 
patient population is justified. 


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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• To assess important measures of 
subject benefit (Section 8.1.1) 
• Proportion of subjects alive and free of 
respiratory failure (need for mechanical 
ventilation, extracorporeal membrane 
oxygenation (ECMO), non-invasive 
ventilation >6L oxygen/minute, or clinical 
diagnosis of respiratory failure with 
initiation of none of these measures only 
when clinical decision-making driven is 
driven solely by resource limitation) at 
Day 29 
Secondary 
• Secondary clinical improvement 
outcomes 
• Proportion of subjects achieving a ≥ 2 
category improvement on 7-point ordinal 
score relative to the baseline on Day 28 as 
collected on Day 29 (Section 8.1.2) 
• Time to clinical improvement (TTCI), 
defined as national early warning score 
(NEWS) of ≤2 maintained for 24 hours 
• To evaluate improvement in 
oxygenation in hospitalized adults 
with respiratory signs and 
symptoms secondary to 
COVID-19 treated with 
axatilimab 
• Change from baseline to Day 29 or 
hospital discharge or death, if sooner, in 
the ratio of peripheral hemoglobin oxygen 
saturation to fraction of inspired oxygen 
(SpO2/FiO2) 
• To evaluate changes in 
biomarkers following treatment 
with axatilimab 
• Change from baseline to Day 15 or 
hospital discharge or death, if sooner, in 
serum concentrations of IL-6, and c- 
reactive protein (CRP) 
• To evaluate the safety and 
tolerability of axatilimab in the 
same population 
• Frequency and severity of AEs and SAEs 


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Objectives 
Endpoints 


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Objectives 
Endpoints 


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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy, safety and tolerability of axatilimab as an add-on to standard of care (SOC) therapy 
in hospitalized subjects with respiratory signs and symptoms secondary to COVID-19 compared 
to SOC treatment. 
The study will be comprised of 2 periods: Screening and Treatment. Throughout the study, 
subjects will be evaluated as specified in the Schedule of Activities (SoA) in Section 1.2. 
After signing informed consent form (ICF), potential candidates, who are hospitalized and have 
documented/confirmed infection with SARS-CoV-2 by RNA polymerase chain reaction (PCR) 
test performed <72 hours before randomization, will undergo additional screening procedures. 
On Day 1, eligible subjects will be randomized in a 1:1 ratio to one of 2 treatment groups, active 
or control, as shown in Table 3. Screening and randomization may occur on the same day; if so, 
study assessments conducted at Screening do not need to be repeated on Day 1, unless drug is 
not administered within 4 hours of randomization. Randomization will be stratified by severity at 
study entry (Section 6.4). In addition, time from onset of symptoms (fever, cough, etc.) to study 
entry will be collected and analyzed prospectively. All subjects will receive study intervention 
IV as an add-on to SOC on Day 1, within 8 hours of randomization and on Day 15. Subjects will 
be followed for at least 28 days (+3 days) after the first dose of study intervention (Day 29)/end 
of study (EOS)). Subjects who do not receive a Day 15 dose will also be followed for this period 
of time. Subjects who experience an AE should be followed for at least 30 days after last dose or 
until resolution of the AE. 
Subjects will be monitored post-study per standard of care for as long as they continue to shed 
viral RNA in nasopharyngeal and stool samples. 
Table 3: 
Treatment Groups 
 
Treatment 
Group 
Dose Level, Schedule and Route of 
administration f 
Number of 
subjects 
Active 
Axatilimab 150 mg on Days 1 and 15, IV + SOC 
93 
Control 
Matching placebo + SOC 
93 
 
4.2. 
Scientific Rationale for Study Design 
This Phase 2, randomized, double-blind, placebo-controlled study compares 2 treatment groups, 
active and placebo control. The study intervention will be administered as an add-on therapy to 
SOC as currently there are no approved treatments for this potentially lethal disease. 
 
4.3. 
Dose Justification 
All subjects will receive axatilimab 150 mg or matching placebo, IV as an add-on to SOC on 
Day 1, within 8 hours of randomization, and on Day 15. 


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A flat dose of axatilimab of 150 mg, regardless of body weight, was selected based on 
nonclinical studies and clinical PK and PD data from healthy volunteers, subjects with solid 
tumors, and subjects with cGVHD. Although all prior clinical data were obtained with weight- 
based dosing, review of clinical PK data from those studies showed that a fixed dose (e.g. 
150 mg regardless of body weight) gave equally consistent exposure as a weight-based (mg/kg) 
dose. Therefore, a 150-mg fixed dose will be used both for consistency of exposure (AUC) and 
to facilitate treatment in this acute care setting, especially if medical resources are strained by 
surge. 


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4.4. 
Study Duration 
For each subject, the study is expected to last as follows: 
 
Screening period: 
Up to 3 days 
Treatment period: 
29 days (+3 days) 
Post study follow-up 
TBD, subjects will be monitored per standard of care for as long as 
they continue to shed viral RNA in nasopharyngeal and stool 
samples 
 
4.5. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed Day 29 visit (or 
Early termination [ET] visit) or the last scheduled procedure shown in the SoA (Section 1.2). 
The end of the study is defined as the date of the last post-study assessment (Day 29 + 3 days) of 
the last subject in the study. 


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5. 
ELIGIBILITY CRITERIA 
5.1. 
Inclusion Criteria 
To be eligible for participation in this study, participants must meet the following: 
 
Age 
1. At least 18 years of age at the time of signing the ICF. 
Type of Subject and Disease Characteristics 
2. Documented or confirmed SARS-CoV-2 infection by an FDA-approved PCR test of 
nasopharyngeal swab or stool <72 hours before randomization. 
3. Hospitalized for COVID-19. 
4. Illness of any duration with at least one of the following 
a. Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on 
room air, or 
b. Requiring mechanical ventilation and/or supplemental oxygen, or 
c. Radiographic evidence (chest x-ray or CT scan) of one of the following: 
− Ground-glass opacities, or 
− Local or bilateral patchy infiltrates, or 
− Interstitial pulmonary infiltrates 
5. If the subject is intubated, must have been intubated less than 24 hours prior to 
randomization. 
Sex and Contraception Guidelines 
6. Male and/or female subjects. 
7. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
8. All subjects (male or female) who are of childbearing potential must agree to use 
highly effective contraception during the study. Female subjects and male partners of 
female subjects must continue to use highly effective contraception for 30 days after 
the last dose of study intervention. Female subjects should not donate oocytes during 
this time. Male subjects and female partners of male subjects must continue to use 
highly effective contraception for 90 days. Male subjects must agree not to donate 
sperm during this time. 
9. Women of childbearing potential must have a negative serum pregnancy test at 
Screening within 72 hours prior to first administration of study intervention. 
10. Women not of childbearing potential must be postmenopausal (defined as cessation of 
regular menstrual periods for at least 1 year. 


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Informed Consent 
11. Capable of giving signed informed consent or by a designated representative as 
described in Appendix 1 (Section 10.1.2) which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
 
Medical Conditions 
1. Active bacterial pneumonia defined: based on either lobar consolidation on x-ray, 
positive sputum cultures, or leukocytosis with a left shift. 
2. Known active tuberculosis (TB). 
3. Subjects with acquired immune deficiency syndrome (AIDS). 
4. It is not in the best interest of the subjects to participate, in the opinion of the treating 
Investigator. 
5. In the opinion of the investigator, progression to death is imminent and inevitable 
within the next 24 hours, irrespective of the provision of treatments. 
6. Female subjects who are pregnant or breastfeeding or expecting to conceive within 
the projected duration of the study, starting with the screening visit through 90 days 
after the last dose of study intervention. 
 
Diagnostic Assessments 
7. The following laboratory parameters are excluded: 
• 
Hemoglobin <9 g/dL; 
• 
Absolute neutrophil count <1.5 × 109/L; 
• 
Platelet count < 50 × 109/L; 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper 
limit of normal (ULN); 
• 
Total bilirubin >ULN; 
• 
Serum creatinine >1.5 mg/dL AND creatinine clearance (CrCl) < 45 
mL/min/1.73 m2 based on the Cockcroft-Gault formula. 
Excluded Prior/Concomitant Therapy 
8. Prior treatment with other agents with actual or possible direct acting 
anti-inflammatory activity against SARS-CoV-2 in the past 30 days (e.g. chloroquine, 
hydroxychloroquine). 
9. Treatment with convalescent plasma. 


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10. Treatment with high doses of corticosteroids (>20 mg daily, prednisone equivalent) 
prior to randomization. 
11. Treatment with immunomodulators including anti-IL 6, anti-IL-6 receptor 
antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to 
receive during the study period. 
12. Previous exposure to study intervention or any other agent targeting CSF-1 or 
CSF-1R or known allergy/sensitivity to study intervention. 
Note: subjects on long-term immunosuppressive therapies for pre-existing conditions, such as 
solid organ transplant, can continue such therapies as long as on stable dose for 1 week prior to 
study entry. 
Note: subjects with cancer who have recently received anti-cancer medications (including 
immune checkpoint inhibitors) are eligible. 
 
Prior/Concurrent Clinical Study Experience 
13. Current participation or have participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study 
intervention. 
Note: Subjects participating in an observational study are an exception to this criterion and may 
qualify for the study with Sponsor approval. 
Note: Subjects who have entered the follow-up phase of an investigational study may participate 
as long as it has been 4 weeks after the last dose of the previous investigational agent. 
 
5.3. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) maybe 
rescreened. Rescreened subjects should be assigned the same subject number as for the initial 
screening. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to the 
study protocol. 
 
6.1. 
Study Intervention(s) Administered 
Table 4: 
Study Intervention 
 
Intervention 
Name 
Axatilimab (SNDX-6352) 
Placebo 
Type 
Biologic 
Not applicable 
Dose Formulation 
Solution for infusion 
Saline solution for infusion 
Unit Dose 
Strength(s) 
50 mg/mL 
Not applicable 
Dosage Level(s) 
Day 1: 150 mg 
Day 15: 150 mg 
Not applicable 
Route of 
Administration 
IV infusion over 30 minutes; time windows of -5 minutes to +10 minutes are 
permitted (i.e., infusion time is 25 to 40 minutes). 
On Day 1, study intervention to be administered within 8 hours of randomization 
IMP definition 
A new drug or biological drug that is used in a 
clinical investigation (FDA) 
Not applicable 
Sourcing 
Axatilimab is manufactured by 
 
Study intervention will be provided to the site 
centrally by the Sponsor or designated 
representative. 
Saline solution for infusion 
will be provided by the clinical 
site 
Packaging and 
Labeling 
Axatilimab is supplied as a 1.3 mL (1.0 mL 
extractable volume) sterile, preservative free 
solution in 2 mL, colorless, Type I glass vials 
closed with bromobutyl stoppers and sealed 
with an aluminum overseals and flip-off caps. 
The vials are single use only and contain no 
preservatives. 
Label text for the axatilimab vial will at a 
minimum include the protocol number, the 
contents of the vial (e.g., axatilimab 
50 mg/mL), lot number, storage conditions, and 
Sponsor name. Labels comply with regulatory 
requirements for investigational products. 
Not applicable 


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Former Name(s) 
or Alias(es)] 
UCB-6352 
 
 
If the subject has previously been discharged from the hospital, for the Day 15 study intervention 
dose administration, will be required to attend an out-patient clinic follow-up visit as specified in 
the SoA (Table 2). The required Day 15 laboratory tests should be obtained prior to Day 15 
dosing. Before administering the Day 15 dose, refer to the Dose Modifications Section 6.6. Study 
intervention will be administered as an IV infusion over 30 minutes; time windows of 5 minutes 
to +10 minutes are permitted (i.e., infusion time is 25 to 40 minutes). Medical interventions for 
subjects who have experienced or experience an infusion reaction are addressed in Section 6.6.4. 
6.2. 
Standard of Care 
In both study groups, subjects should receive appropriate supportive care measures as deemed 
necessary by the treating Investigator. 
Site-specific standard of care will be captured under the concomitant medication electronic case 
report form (eCRF page). 
Refer to Section 6.7 for guidelines on allowed and prohibited medications. 
 
6.3. 
Preparation/Handling/Storage/Accountability 
• 
The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only subjects enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
• 
Axatilimab drug product must be diluted with 0.9% saline solution (sodium chloride 
injection) supplied in an infusion bag and a 50 mL infusion given. No other drugs 
should be added to the solution for infusion containing axatilimab. 
• 
For a subject receiving a 150 mg dose a total of 4 vials are required. Infusion solution 
preparation is described in the Pharmacy Manual. The infusion solution can be stored 
for up to 4 hours at ambient temperature. 
• 
The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual. 


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6.4. 
Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally assigned to randomized study intervention using an Interactive 
Response Technology (IRT). Before the study is initiated, the log in information & directions for 
the IRT will be provided to each site. 
Randomization will be stratified by severity of illness at enrollment: 
• 
Critical disease: requiring mechanical ventilation or ECMO 
• 
Severe disease: oxygen requirement of ≥ 4 L/minute, or a SpO2 ≤ 94% or tachypnoea 
(respiratory rate ≥ 24 breaths/minute) 
• 
Moderate disease: Oxygen requirement of < 4 L/minute with SpO2 ≥ 94% and 
respiratory rate <24 breaths/minute 
• 
Mild disease: SpO2 ≥ 94% on room air and respiratory rate < 24 breaths/minute 
without supplemental oxygen. 
Study intervention will be dispensed by the unblinded pharmacy staff to the study staff/research 
nurse in a blinded manner per the schedule summarized in the SoA (Section 1.2). 
The IRT will be programmed with blind-breaking instructions. Subject safety must always be the 
first consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Sponsor prior to unblinding a 
subject’s study intervention assignment unless this could delay emergency treatment of the 
subject. If a subject’s drug assignment is unblinded, the Sponsor must be notified within 24 
hours after breaking the blind. The date and reason that the blind was broken must be recorded in 
the source documentation and case report form, as applicable. 
6.5. 
Study Intervention Compliance 
Administration of study intervention will be supervised by the Investigator or sub Investigator. 
Any delegation of this responsibility must follow the standard procedures. Records of treatment 
administration for each subject will be kept during the study. Clinical research associates will 
review study intervention administration records and verify compliance with the Pharmacy 
Manual during site visits and at the completion of the study. Deviation(s) from the prescribed 
dosage regimen should be recorded in the electronic case report form (eCRF). 
For all study intervention infusions, a mandatory 2-hour observation period for potential infusion- 
related reactions is required. For subsequent infusion and per the discretion of the investigator, no 
observation period is required for subjects with no infusion reactions. Subjects who experience an 
infusion-related reaction at any time, must continue to undergo the mandatory 2-hour observation 
period after each infusion. 
6.6. 
Dose Modifications 
Dose delays for the Day 15 dose but not reductions are allowed in this study. 
All dose modifications should be based on toxicity described in the sections below and should be 
properly documented in source documents. Investigators may take a more conservative approach 


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than the guidelines outlined in the protocol on the basis of clinical judgment that is in the best 
interest of the subject. Such instances should be reported to the Sponsor’s Medical Monitor. 
6.6.1. 
Dose Modifications for AST, ALT, Bilirubin, Creatine Kinase (CK), Amylase 
and Lipase Elevation 
Dose modification guidelines for study intervention due to AST, ALT, bilirubin, CK, amylase or 
lipase elevation are specified in Table 5. 
Table 5: 
AST, ALT Bilirubin, CK, Amylase and Lipase: Dose Modification Guidelines 
for Axatilimab for Day 15 dose 
 
Lab abnormality 
Dose modifications 
Isolated asymptomatic Grade 3 
AST or ALT (> 10x ULN but 
≤ 20 x ULN) 
AND total bilirubin Grade ≤1 
Hold study intervention until < 10 times ULN; 
if resolves to < 10 times ULN within 7 days, resume study 
intervention at the same dose at Investigator’s discretion. (only if 
subject remains hospitalized). 
if does not resolve within 7 days to < 10 times ULN, permanently 
discontinue study intervention. 
Grade 3 AST or ALT with 
evidence of end organ damage 
Permanently discontinue study intervention. 
ALT or AST ≥3 x ULN and 
simultaneous total bilirubin 
≥2 x ULN in the absence of 
cholestasis or hemolysis 
Permanently discontinue study intervention. 
Grade 4 AST or ALT 
(>20 x ULN) 
Permanently discontinue study intervention. 
Grade 2 total bilirubin 
Rule out cholestasis. If ruled out, hold study intervention until 
recovery to Grade 1, then resume. If evidence of cholestasis, study 
intervention may be continued without delay after consultation 
with Sponsor’s Medical Monitor. 
Grade 3 total bilirubin 
Rule out cholestasis. If ruled out, permanently discontinue study 
intervention. If evidence of cholestasis, study intervention may be 
resumed after recovery to Grade 1 and consultation with Sponsor’s 
Medical Monitor. 
Grade 4 total bilirubin 
Permanently discontinue study intervention. 
Grade 3 CK, amylase, or lipase 
in the absence of any clinical 
symptoms directly attributed to 
study intervention 
Before administering study intervention, conduct diagnostic 
evaluation, e.g., serum and urine myoglobin, or CK-MB, BUN, 
creatinine, ECG, troponin (I or T). 
If results show either no evidence of end organ damage attributable 
to study intervention OR if end organ damage is attributed to the 
underlying disease, continue study intervention without delay. 


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Lab abnormality 
Dose modifications 
Grade 4 or symptomatic Grade 3 
CK, amylase or lipase or Grade 4 
CK, amylase, or lipase 
Permanently discontinue study intervention. 
 
6.6.2. 
Dose Modifications for Other Non-hematologic Toxicity 
The rules for the management of other non-hematologic toxicities are outlined as follows in 
Table 6 with toxicities graded by the Investigator according to the NCI CTCAE, version 5.0. 
Table 6: 
Other Non-hematologic Toxicity: Dose Modification Guidelines for 
SNDX-6352 (Day 15) 
 
Toxicity 
Dose modifications 
Grade 4 
Administer symptomatic remedies/start prophylaxis. 
Any Grade 4 events require permanent treatment discontinuation from 
study intervention. 
Grade 3 
Administer symptomatic remedies/ start prophylaxis. Hold study 
intervention dose until recovery to Grade 1 or baseline under the 
following directions: 
1. If recovered by Day 22, resume study intervention without 
dose reduction 
2. If not recovered by Day 22, permanently discontinue study 
intervention. 
Grade 2 
Administer symptomatic remedies / start prophylaxis. 
 
 
6.6.3. 
Dose Modifications for Hematologic Toxicity 
The guidelines in Table 7 will be followed for determining the dose modifications based on 
hematologic status at the time of planned dosing. 
Table 7: 
Hematologic Toxicity: Dose Modification Guidelines for SNDX-6352 (Day 
15) 
 
Toxicity 
Dose modifications 
Grade 3 to 4 neutropenia, 
Febrile neutropenia or 
neutropenic infection; 
Grade 3 to 4 
uncomplicated 
thrombocytopenia, or 
Hold study intervention dose until recovery to Grade 1 or study baseline 
under the following directions. 
1. If recovered by Day 22, resume study intervention without dose 
reduction. 


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Toxicity 
Dose modifications 
Grade 2 complicated 
thrombocytopenia 
2. If not recovered by Day 22, permanently discontinue study 
intervention. 
 
 
6.6.4. 
Axatilimab Infusion-Related Reaction 
If a subject experiences a Grade 1 or 2 axatilimab infusion-related reaction, they may continue 
on study intervention treatment per guidance presented in Table 8. Subjects who previously 
experienced an infusion-related reaction will receive a premedication regimen of 25 to 50 mg IV 
or oral equivalent and diphenhydramine and 650 mg IV or oral equivalent 
acetaminophen/paracetamol approximately 30 to 60 minutes prior to each subsequent dose of 
axatilimab. 
Treatment modifications for study intervention infusion-related reactions are outlined in Table 8. 
Table 8: 
Infusion-related Reactions for Study Intervention 
 
NCI-CTCAE Grade 
Treatment Modification for study intervention 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease study intervention infusion rate by 50% 
being given at the time of event onset and monitor 
closely for any worsening. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, nonsteroidal anti- 
inflammatory drug [NSAIDs], narcotics, IV 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Temporarily discontinue study intervention 
infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity and monitor closely 
for any worsening. At next cycle, administer oral 
premedication with antihistamine and anti-pyretic 
and monitor closely for infusion reaction. 
Grade 3 or Grade 4 – severe or life- 
threatening Grade 3: Prolonged (e.g., not 
rapidly responsive to symptomatic medication 
and/or brief interruption of infusion); recurrence 
of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
Grade 4: Life-threatening consequences – urgent 
intervention is indicated. 
Stop the study intervention infusion immediately 
and disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
study intervention treatment and must not receive 
any further study intervention. 
NSAIDs = nonsteroidal anti-inflammatory drugs 
 
 
6.7. 
Concomitant Medication 
All treatments that the Investigator considers necessary for a subject’s plan of care may be 
administered concomitantly with study intervention at the Investigator’s discretion per standard 


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of care. Other supportive medications in accordance with standard clinical practice (such as for 
prophylaxis for encapsulated bacteria, viral and fungal infections) are permitted per institutional 
policy. 
Azithromycin is allowed prior and or after study initiation either as an anti-inflammatory agent 
or as prophylaxis or treatment for bacterial infection. 
Anti-viral agents, with the exception of prohibited medications (Section 6.7.1), may be started 
after the first dose of study intervention and high dose corticosteroids (>20 mg per day, 
prednisone equivalent) may be initiated in case of clinical deterioration or evidence of adrenal 
insufficiency while on study intervention. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
6.7.1. 
Prohibited Medications 
Below is a list of medications that are prohibited during the study. 
• 
Chloroquine, hydroxychloroquine 
• 
Convalescent plasma 
• 
Anti-IL 6, anti-IL-6 receptor antagonists, or JAKi 
• 
Systemic anti-cancer treatment including immune checkpoint inhibitors such as 
cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death 1 (PD-1), 
and programmed death-ligand 1 (PD-L1) agents 
• 
Agents targeting CSF-1 or CSF-1R 
• 
Investigational agents, other than axatilimab and anti-viral agents 
6.8. 
Treatment of Overdose 
For this study, any dose of study intervention greater than the prescribed dose will be considered 
an overdose. There is no specific treatment recommended to treat an overdose of study 
intervention and the subject should receive treatment directed towards any symptoms manifested. 
In the event of an overdose, the Investigator should: 
• 
Contact the Medical Monitor as soon as possible 
• 
Closely monitor the subject for any AE/SAE and laboratory abnormalities 
• 
Document the quantity of the excess dose as well as the duration of the overdose 


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Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 
6.9. 
Intervention after the End of the Study 
No additional intervention is planned beyond the end of the study. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Stopping Rules 
The study will be paused to enrollment if there is a greater than 20% absolute difference in 
serious adverse reactions (SARs) between the two arms at the interim analysis (Section 9.5). 
Based on unblinded review of data, the independent data monitoring committee (IDMC) may 
recommend permanent stopping of the study. 
There will be close oversight by the Sponsor and IDMC reviews for safety as specified in 
Section 9.5.1. Additional ad hoc analyses may be convened to ensure patient safety. 
7.1.1. 
Pregnancy 
A subject must permanently discontinue study intervention if she is discovered to be pregnant. 
7.2. 
Discontinuation of Study Intervention 
In some instances, it may be necessary for a subject to permanently discontinue study 
intervention. Please also refer to stopping rules described in Section 7.1. 
Permanent discontinuation of study intervention does not mean withdrawal from the study, and 
the subject will be encouraged to remain in the study and continue to complete all study visits. 
See the SoA (Section 1.2) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Subjects may discontinue or be discontinued from study intervention at any time. A subject may 
discontinue study intervention for reasons including but not limited to: 
• 
Adverse event 
• 
Death 
• 
Lost to follow-up 
• 
Non-compliance with study drug 
• 
Physician decision 
• 
Pregnancy 
• 
Lack of efficacy 
• 
Protocol deviation 
• 
Study terminated by Sponsor 
• 
Withdrawal by subject* (*only for discontinuing study intervention, but will remain 
in study) 
The reason for subject discontinuation from study intervention will be recorded in the eCRF. At 
the time of treatment completion or study intervention discontinuation, the Day 15/ET visit 


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should be completed as shown in the SoA (Section 1.2). Subjects should continue to be followed 
for safety even if they discontinue study intervention prematurely unless they withdraw consent. 
Pregnancy is a mandatory criterion for permanent discontinuation of study intervention (see 
Section 7.1.1). 
7.3. 
Withdrawal from the Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the Investigator or at the institution. A subject may 
withdraw from the study for reasons including but not limited to: 
• 
Death 
• 
Withdrawal by subject 
• 
Lost to follow-up 
• 
Study terminated by Sponsor 
The reason for subject withdrawal from the study will be recorded in the eCRF. 
At the time of withdrawal from the study, the Day 15/ET visit should be completed, as shown in 
the SoA (Section 1.2). 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
7.4. 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to engage for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• 
Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 in 
Section 10.1. 


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8. 
STUDY ASSESSMENTS 
• 
Study procedures and their timing are summarized in the SoA (Section 1.2). Protocol 
waivers or exemptions are not allowed. Assessments completed as part of standard of 
care within the protocol defined windows, will not need to be repeated specifically for 
the protocol. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain screening 
information including details of all subjects screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
• 
Missed visits should be avoided if at all possible; if a visit is missed and cannot be 
rescheduled, the subject should resume their original visit schedule at the next 
scheduled visit. Some visits/study procedures can be done via virtual visits or at home 
visits after hospital discharge. The Day 22 visit may be a remote or an in-clinic visit if 
subject was discharge from the hospital per SoA (Table 2). Refer to study reference 
manual for more details. 
8.1. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Table 2). 
 
8.1.1. 
Measure of Clinical Benefit 
At each study day while hospitalized, the following measure of clinical support should be 
assessed: 
• 
Oxygen requirement (yes / no) 
• 
Non-invasive mechanical ventilation (via CPAP/BiPAP mask) (yes / no) 
• 
Mechanical ventilator requirement (via endotracheal tube or tracheostomy tube) or 
Extracorporeal membrane oxygenation (ECMO) requirement (yes / no) 
• 
Level of consciousness: alert vs. (arousable only to voice or pain or unresponsive) 
In addition, date of hospital discharge readiness or date of hospital discharge (if different) will be 
collected. 
8.1.2. 
Clinical Status Ordinal Score 
Clinical status will be assessed using the 7-point ordinal score (Table 9). The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. Each day, the worse 
score for the previous day will be recorded (i.e. on Day 3, Day 2 score is obtained and recorded 


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as Day 2). This scale has been used successfully as an endpoint for evaluation of treatments for 
severe influenza requiring hospitalization (Peterson, 2017). 
Table 9: 
A 7-Point Ordinal Score for Assessing Clinical Status 
 
Score 
Description 
1 
Not hospitalized, no limitations on activities 
2 
Not hospitalized, limitation on activities 
3 
Hospitalized, not requiring supplemental oxygen 
4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6 
Hospitalized, on invasive mechanical ventilation or ECMO 
7 
Death 
 
8.1.3. 
National Early Warning Score (NEWS) 
The NEWS score has demonstrated an ability to discriminate subjects at risk of poor outcomes. 
(Smith, 2016; Williams, 2019). This score is based on 7 clinical parameters, vital signs 
(respiratory rate, temperature, blood pressure, and heart rate), SpO2, breathing room air or 
supplemental oxygen, and consciousness (Table 10). The NEWS score is being used as an 
efficacy measure. 
This should be evaluated at the first assessment of a given study day. These parameters can be 
obtained from the hospital chart using the last measurement prior to the time of assessment. This 
is recorded for the day obtained. 


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Table 10: 
NEW Score 
 
Level of consciousness: alert (A), arousable only to voice (V), or pain (P) and unresponsive (U) 
 
8.1.4. 
Hospital Discharge Readiness Criteria 
The subject’s readiness for hospital discharge will be evaluated based on the following criteria 
(must meet all): 
• 
Normal O2 saturation on room air or a return to pre-morbid status 
• Afebrile 
• Able to ambulate (or use commode) without assistance or a return to pre-morbid mobility 
(for non-ambulatory subjects) 
• Able to dress self or a return to pre-morbid status 
• Eating pre-morbid full diet or a return to pre-morbid status 
Date of actual hospital discharge and date of any readmission during the study period should be 
captured. Subjects’ oxygen supplementation status at hospital discharge will also be captured 
(with vs. without oxygen supplementation). 
8.1.5. 
Oxygenation Measures 
Peripheral capillary oxygen saturation (SpO2) with pulse oximeter may be used as surrogate for 
arterial blood oxygen saturation or arterial blood gas may be measured. Measurement to be done 
with the subject laying in prone position, unless indicated otherwise; same position should be 
used throughout the study; subject position will be captured in the eCRF. 
Peripheral hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2) will also be 
measured. 


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The lowest ratio for each day should be collected, with the following exceptions. The ratio 
immediately prior to study entry will be entered. The last ratio before hospital discharge or death 
(prior to onset of cardiopulmonary arrest) will be entered. 
The FiO2 at the time of the above measurement should also be collected. If the FiO2 cannot be 
directly measured via the used oxygen delivery apparatus (e.g., nasal canula, simple mask, 
rebreather mask), the apparatus used, and flow rate of oxygen in liters/min should be collected. 
The ratio of peripheral hemoglobin oxygen saturation to inspired oxygen fraction (SpO2/FiO2) 
will be calculated based on the values obtained above. In case, values are obtained via analysis of 
arterial blood gases, the following equation will be used for purposes of conversion: SpO2/FiO2 = 
64 + 0.84 x (PaO2/FiO2). 
The lowest ratio for each day should be entered into the eCRF with the following exceptions. 
The ratio immediately prior to study entry will be entered. The last ratio before hospital 
discharge or death (prior to onset of cardiopulmonary arrest) will be entered. 
Oxygenation will be assessed using the categories in Table 11. 
Table 11: 
A 4-Point Oxygen Ordinal Scale for Severity Categories by SpO2/FiO2 Ratio 
 
Score 
Severity 
SpO2/FiO2 (mmHg) 
0 
None 
> 315 
1 
Mild 
> 235 to 315 
2 
Moderate 
> 150 to 235 
3 
Severe 
≤ 150 
 
8.1.6. 
Viral Clearance 
Quantitative viral load will be assessed using nasopharyngeal swab SARS-CoV-2 PCR to 
monitor disease status during the study. Quantitative assessment of viral RNA load in blood and 
stool will also be performed as per site specific standard of care. 
For any given subject, the same technique for nasopharyngeal swabbing and nostril (if both 
nostrils are not sampled) should be used throughout the study. 
Subjects will be monitored post-study per standard of care as long as they continue to shed viral 
RNA in nasopharyngeal or stool samples. 
For more details refer to the laboratory manual. 
 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 2 in Section 1.2). 
 
8.2.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
head, ears, eyes, nose and throat (HEENT), dermatological, respiratory, 


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cardiovascular, gastrointestinal, neurological, and lymphatic, and musculoskeletal 
systems. Height will also be measured and recorded. 
• 
Symptom-directed physical examination will be conducted as clinically indicated. 
• 
Weight will be measured when complete or symptom-directed physical examinations 
are performed. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
8.2.2. 
Vital Signs 
• 
Systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), 
respiration rate (breaths per minute), and temperature (°F or C; oral, rectal, forehead, 
aural), will be measured as per standard practice. 
• 
The same units and mode should be used for a subject across all measurements. 
• 
Vital signs will be measured prior to any blood draw that occurs at the same 
timepoint 
8.2.3. 
Electrocardiograms 
• 
12-lead ECG will be obtained while subject is in supine position using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, and QT 
(QTcF), intervals. Subject to be resting for at least 2 minutes prior to ECG. 
• 
An ECG may be repeated anytime, as clinically indicated. 
 
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency. For the Day 15 dose, safety laboratory 
values and results to be obtained prior to dosing even in subjects who were 
discharged previously. 
• 
The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the subject's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 


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− All protocol-required laboratory assessments, as defined in Section 10.2 
(Appendix 2), must be conducted in accordance with the laboratory manual and 
the SoA. 
− If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the Investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE, adverse events of special interest (AESIs) or SAE can be found in 
Appendix 3 (Section 10.3). 
AE severity will be evaluated by the Investigator in accordance with the NCI CTCAE v5.0. 
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the subject to discontinue the study intervention and/or the study (see Section 7). 
 
8.3.1. 
Time Period and Frequency for Collecting AE, AE of Special Interest and SAE 
Information 
All AEs, AESIs and SAEs will be collected at the time points specified in the SoA (Section 1.2). 
Table 12 below summarizes the different observation periods for AEs and SAEs. 
Table 12: 
Adverse Event Observation Periods 
 
Type of 
Event 
Adverse Event/Adverse 
Events of Special Interest 
Serious Adverse Event 
Reporting 
period 
From consent until Day 29/EOS 
visit (+ 3 day). Subjects who 
experience AE should be 
followed for at least 30 days 
after last dose of study 
intervention or until resolution 
of AE. 
From consent until Day 29/EOS visit (+ 3 day) for 
all SAEs, and any time after the end of study for 
SAEs believed to be related to study intervention. 
Subjects who experience SAE should be followed 
for at least 30 days after last dose of study 
intervention or until resolution of SAE. 
Reporting 
Timelines to 
the Sponsor 
Entered into the clinical 
database on an ongoing basis 
Within 24 hours 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 


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The Investigator is responsible for ensuring that all AEs observed by the Investigator or reported 
by subjects are properly captured in the subject’s medical records and reported in the eCRF. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). Further 
information on follow-up procedures is given in Appendix 3 (Section 10.3). 
 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subject and the 
safety of a study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary. 
• 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 


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8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female subjects, and female partners of a male subject, 
will be collected after the start of study intervention and until 90 days after the last 
dose of study intervention. 
• 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• 
All female subjects, and female partners of male subjects, becoming pregnant must be 
followed to completion/termination of the pregnancy. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.4. 
Pharmacokinetics 
• 
Whole blood samples of approximately 3.5 mL will be collected for measurement of 
serum concentrations of axatilimab as specified in the SoA (Section 1.2) Instructions 
for the collection and handling of biological samples will be provided by the Sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded. 
• 
Samples will be used to evaluate the PK of axatilimab. Samples collected for analyses 
of axatilimab serum concentration may also be used to evaluate safety, efficacy, 
ADA, and/or pharmacodynamic aspects related to concerns or questions arising 
during or after the study. 
• 
Subject confidentiality will be maintained. At visits during which blood samples for 
the determination of PK, and PD related to axatilimab will be taken, 1 sample of 
sufficient volume can be used. 
• 
Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member 
and then archived in the Sponsor and site study files but will not constitute a protocol 
amendment. The IRB/IEC will be informed of any safety issues that require alteration 
of the safety monitoring scheme or amendment of the ICF. 
8.5. 
Pharmacodynamics and 
 Endpoints 
Blood samples will be collected and analyzed for biomarker analysis as specified in the SoA 
(Section 1.2) including IL-6. Additional plasma/serum sample for future biomarker analyses will 
also be collected and stored. 
The Sponsor or designee will supply complete written instructions for handling, processing, 
storage, and shipping of biomarker samples in the Laboratory Manual. 
Samples may be stored for a maximum of 15 years after the last subject’s last visit for the study, 
at a facility selected by the Sponsor, to enable further analysis of biomarker responses to 
axatilimab. 


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8.6. 
Biomarkers 
Collection of samples for other biomarker research is also part of this study. The following blood 
samples for immune correlate analyses biomarker research may be performed and will be 
collected from all subjects in this study as specified in the SoA (Section 1.2): 
• 
Levels of blood cytokine levels that may include IFN-gamma, IL-1beta, IL-4, IL-5, 
IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and change from baseline compared to PK, 
safety endpoints 
Refer to the Study Laboratory Manual for instructions on sample collection and shipment. 
Samples will be tested for axatilimab-related activities to evaluate their association with the 
observed clinical responses. 
• 
In addition, samples will be stored, and analysis may be performed on biomarker 
variants thought to play a role in immune-modulation including, but not limited to, 
emergent candidate genes/genome-wide analysis for RNA, serum analytes, or tissue 
biomarkers to evaluate their association with observed clinical responses to 
axatilimab. 
• 
Refer to the Study Laboratory Manual for instructions on sample collection and 
shipment to the central laboratories. 
Other samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to immune modulation, disease processes and pathways 
associated with disease state, and/or mechanism of action of axatilimab. 
Samples may be stored for a maximum of 10 years (or according to local regulations) following 
the last subject’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to axatilimab. 


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9. 
STATISTICAL CONSIDERATION 
9.1. 
Statistical Rationale and Determination of Sample Size 
This is a placebo controlled randomized Phase 2 trial is designed to evaluate the study 
intervention (axatilimab 150 mg), using screening trial methodology presented in Fleming and 
Richardson (2004). The primary endpoint is the proportion of subjects alive and free of 
respiratory failure at Day 29; treatment effect will be assessed using a Chi-square statistic. 
A total of 186 subjects will be engaged in a 1:1 randomization. The primary analysis of this Phase 
2 trial comparing axatilimab vs placebo is formally based on a three-category decision guideline: 
1. If the estimated increase in the proportion of subjects alive and free of respiratory failure 
at Day 29 is less than 1.282 standard errors, (i.e., corresponding approximately to 
improving a 76% success rate on placebo to less than 83% on axatilimab), then the utility 
of this regimen in this indication should be reconsidered. 
2. If the estimated increase in the proportion of subjects alive and free of respiratory failure 
at Day 29 is between 1.282 and 1.96 standard errors, (i.e., corresponding approximately to 
improving a 76% success rate on placebo to between 83% and 88% on axatilimab), then 
axatilimab quite plausibly is meaningfully more efficacious than placebo and should be 
evaluated in a confirmatory Phase 3 clinical trial. 
3. If the estimated increase in the proportion of subjects alive and free of respiratory failure 
at Day 29 is at least 1.96 standard errors (i.e., corresponding approximately to improving 
a 76% success rate on placebo to at least 88% on axatilimab), then axatilimab would be 
statistically significantly more effective than the placebo control; consideration would be 
given to the need for a confirmatory Phase 3 clinical trial. 
 
9.2. 
Operating Characteristics 
The operating characteristics for this three-category decision guideline are: 
1. The false-positive error rate of the screening procedure is low. In particular, if the 
axatilimab 150 mg regimen truly provides no improvement in the proportion of subjects 
alive and free of respiratory failure at Day 29, then there is only a 10% probability of 
bringing that regimen forward to a Phase 3 trial, and only a 2.5% probability of reaching 
the false positive conclusion that that regimen provides a statistically significant 
improvement in efficacy relative to placebo. 
The false-negative error rate is low. If axatilimab 150 mg truly provides a 76% vs 90% increase 
in proportion of subjects alive and free of respiratory failure at Day 29, then there is only a 10% 
chance that that regimen would be discarded, and thus a 90% probability that it would be 
evaluated in a subsequent confirmatory Phase 3 trial, and there is a 72% probability that that 
regimen would have a statistically significant improvement in efficacy (at one-sided p<0.025) 
relative to placebo. 
The first key secondary endpoint will be tested hierarchically if the primary endpoint achieves 
statistical significance. A sample size of 186 (93 per group) will provide approximately 80% 
power to detect a 30% vs 50% increase in the proportion of subjects achieving a ≥ 2 category 


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improvement on 7-point ordinal score relative to the baseline at Day 28, based on Chi-Square 
test with a (one-sided) 2.5% false positive error rate. Statistical significance at two-sided 0.05 
level would be achieved with an estimated increase of 30% vs. 44% in the proportion of 
responders. 
 
 
9.3. 
Population for Analyses 
For purposes of analysis, the following populations are defined: 
 
Population 
Description 
Intent-to-treat Set 
(ITT) 
ITT set consists of all subjects who are randomized in study 
intervention by following intent to treat principle. The ITT set will be 
used in the analyses of the primary and secondary endpoints. 
Modified Intent to 
Treat (MITT) 
MITT consists of all randomized subjects who receive at least one dose 
of study intervention and on post baseline assessment of SpO2/FiO2 
ratio. 
Per Protocol 
Analysis Set 
Per Protocol Analysis Set consists of all randomized subjects who 
receive at least one dose of study intervention without any major 
protocol violations that would impact the assessment of the primary 
efficacy endpoint. 
Safety Analysis 
Set 
Safety Analysis Set consists of all randomized subjects who received at 
least one dose of study intervention 
PK Analysis Set 
All subjects who receive at least one dose of axatilimab and have at 
least one valid plasma concentration of axatilimab determined. 
Pharmacodynamic 
Subjects who are exposed to axatilimab and have sufficient samples 
collected to permit pharmacodynamic analyses. 
 
9.4. 
Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be maintained by the Sponsor. The 
SAP may modify the plans outlined in the protocol; however, any major modifications will also 
be reflected in a protocol amendment. The SAP will be finalized before database lock and will 
describe the analysis populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. 
The statistical analyses will be performed using SAS® version 9.4 or later (SAS Institute Inc, 
Cary NC). Programming specifications will be prepared that describe the datasets and variables 
created for this study. The datasets will be prepared using the most recent version of CDISC’s 
Study Data Tabulation Model (SDTM) and Analysis Dataset Model (ADaM). The source SDTM 


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and ADaM datasets from which a statistical analysis is performed (including interim reviews) 
will be archived with the Sponsor 
 
9.4.1. 
Efficacy Analysis 
The primary efficacy endpoint the proportion of subjects alive and free of respiratory failure, 
defined as need for mechanical ventilation, ECMO, non-invasive ventilation >6L oxygen/minute, 
or clinical diagnosis of respiratory failure with initiation of none of these measures only when 
clinical decision-making driven is driven solely by resource limitation at Day 29 will be analyzed 
using a Cochran-Mantel-Haenszel (CMH) test stratified by baseline severity (mild, moderate, 
severe, critical). Site will be included in the model. The ITT analysis set will be used. 
For the purposes of the primary efficacy endpoint analysis: 
• 
Subjects who are discharged any time prior to Day 29 who are documented to be 
alive and free of respiratory failure on Day 29 will be considered as success. 
• 
Subjects who cannot be documented to be alive or free of respiratory failure on 
Day 29 will be imputed using the overall experience from placebo patients who are 
assessed at Day 29. 
To assess the robustness of the primary efficacy analysis, the following additional analyses will 
be performed for the primary endpoint. 
• 
A logistic regression model with the proportion of subject alive and free of 
respiratory failure as the response variable and treatment group, baseline 7-point 
ordinal scale assessments and stratification factor (baseline severity: mild, moderate, 
severe, and critical) and site as independent variables will be used using the ITT 
analysis set 
• 
CMH will be performed with subjects who have baseline measurement and at Day 29 
post-baseline assessment using the ITT analysis set (completers) 
• 
CMH will be performed using the per protocol analysis set 
 
 
Endpoints 
Analysis Method 
Primary 
• Proportion of subjects alive and free 
of respiratory failure (need for 
mechanical ventilation, ECMO, 
non-invasive ventilation >6L 
oxygen/minute, or clinical diagnosis 
of respiratory failure with initiation 
of none of these measures only when 
clinical decision-making driven is 
driven solely by resource limitation) 
at Day 29 
• Proportion of subjects alive and free of 
respiratory failure at Day 29 will be 
analyzed using CMH stratified by 
baseline disease severity (mild, 
moderate, severe and critical) and site, 
including the absolute treatment 
difference (%) from placebo and 95% 
CIs. 


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Endpoints 
Analysis Method 
Secondary 
• Proportion of subjects achieving a 
≥ 2 category improvement on 7-piont 
ordinal score relative to the baseline 
on Day 28 as collected on Day 29 
(Section 8.1.2) 
• 
Proportion of subjects achieving a 
≥ 2 category improvement on 7-piont 
ordinal score relative to the baseline on 
Day 29 will be analyzed using CMH 
stratified by baseline severity (mild, 
moderate, severe and critical) and site, 
including the absolute treatment 
difference (%) from placebo and 95% 
CIs. 
• TTCI, defined as NEWS of ≤2 
maintained for 24 hours 
• TTCI, defined as NEWS of ≤2 
maintained for 24 hours will be 
analyzed using the Kaplan-Meier 
method and comparison between 
treatment groups will be made using 
log-rank test stratified by baseline 
severity score (mild-moderate vs 
severe). Subjects will be censored at 
Day 15 or sooner, if they discontinue 
the study prior to observing the event. 
• Change from baseline to Day 29 or 
hospital discharge or death, if 
sooner, in the ratio of SpO2/FiO2 
• Change from baseline to Day 29 or 
hospital discharge or death, if sooner, in 
the ratio of SpO2/FiO2 will be analyzed 
using an analysis of covariance 
(ANCOVA) model, with treatment as a 
fixed effect and site as a covariate. 
• Change from baseline to Day 15 or 
hospital discharge or death, if 
sooner, in serum concentrations of 
IL-6 and CRP 
• Change from baseline to Days 15 or 
hospital discharge, if sooner, in serum 
concentrations of IL-6, ferritin, CRP 
will be analyzed using an ANCOVA 
model, with treatment as a fixed effect 
and site as a covariate. 


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Endpoints 
Analysis Method 


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Endpoints 
Analysis Method 


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Endpoints 
Analysis Method 
 
 
9.4.2. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the Safety Analysis Set. Safety will be assessed by 
clinical review of all relevant parameters including vital signs measurements, AEs, SAEs, 
physical, ECG results, and laboratory values. Summary tables and listings will be provided for 
all reported TEAEs, defined as AEs that start on or after the first administration of study 
treatment. The reported AE term will be assigned a standardized preferred term using the current 
version of the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
adverse event will be summarized based on the number and percentage of subjects experiencing 
the event by MedDRA system organ class and preferred term. In the event a subject experiences 
repeat episodes of the same AE, then the event with the highest severity grade and strongest 
causal relationship to study treatment will be used for purposes of incidence tabulations. 
Tabular summaries will be provided for the following: 


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• 
All treatment-emergent adverse events 
• 
Treatment-emergent adverse events by relationship to study intervention treatment 
and maximum severity grade 
• 
Treatment-emergent adverse events with action of study intervention treatment 
• 
Treatment-emergent adverse events with action of study treatment discontinued 
• 
SAEs 
• 
Changes in chemistry and hematology parameters 
• 
Changes in vital signs, weight and ECGs 
 
9.4.3. 
Other Analyses 
Pharmacokinetic and other correlative studies will be summarized and displayed graphically. 
Additional details for PK, PD, and biomarker exploratory analyses will be described in the 
statistical analysis plan finalized before database lock. 
9.5. 
Interim Analysis 
There will be close oversight of safety by the Sponsor and ongoing reviews by the IDMC. If 
there is a greater than 20% absolute difference in SARs between the two arms at the interim 
analysis, the IDMC may recommend the study be stopped. 
An interim safety/lack of benefit analysis will occur at approximately 50% of total information. 
For the lack of benefit analysis regarding the primary endpoint, the IDMC will be guided by the 
Lan-DeMets spending function analog of the O’Brien-Fleming boundary. At the 50% total 
information, (i.e., with 93 primary endpoints), an O-Brien-Fleming monitoring boundary for lack 
of benefit that protects a 10% false negative error rate against the alternative hypothesis of 76% 
vs. 90% would terminate when the data are 1.9 standard errors from that alternative, (i.e., 
corresponding approximately to a 76% success rate on placebo and less than a 72.5% success 
rate on axatilimab). Further details will be provided in the SAP. 
The unblinded statistical team will prepare the IDMC closed reports for IDMC review and 
recommendations. An additional document on statistical issues related to monitoring will be 
provided to the prior to interim analyses. 
9.5.1. 
Independent Data Monitoring Committee (IDMC) 
The mission of the IDMC will be to safeguard the interests of study participants and to enhance 
trial integrity. The IDMC will meet on a frequent basis and will review unblinded efficacy and 
safety data. The IDMC may recommend stopping the study if at any time during trial conduct if 
there are unacceptable AEs or safety concerns. The members of the IDMC will be listed in a 
separate IDMC Charter, the governing document that will supersede this section of the protocol. 


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10. 
APPENDICES 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
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 ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC 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/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
 
10.1.2. 
Informed Consent Process 
• 
The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding 
the study. 
• 
Subjects must be informed that their participation is voluntary. Subjects or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 


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• 
The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
(28) days from the previous ICF signature date. 
The ICF will contain a separate section that addresses the use of blood samples for optional 
future research. The Investigator or authorized designee will explain to each subject the 
objectives of the future research. Subjects will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a subject's agreement to allow any remaining 
specimens to be used for future research. Subjects who decline to participate in this optional 
research will not provide this separate signature. 
10.1.3. 
Data Protection 
• 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
• 
The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the Subject. 
• 
The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
 
10.1.4. 
Dissemination of Clinical Study Data 
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines. 
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
10.1.5. 
Data Quality Assurance 
• 
All subject data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 


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Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk- 
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH-GCP, and all applicable 
regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator per ICH-GCP and local regulations or 
institutional policies. No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
10.1.6. 
Source Documents 
• 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
site. 
• 
Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained. These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 


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10.1.7. 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or ICH-GCP guidelines 
• 
Inadequate recruitment of subjects by the Investigator 
• 
Discontinuation of further study intervention development 
 
10.1.8. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The clinical laboratory tests detailed in Table 13 will be performed by a local 
laboratory, except where specified below, at the timing/frequency detailed in the SoA. 
• 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.2 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations 
• 
Investigators must document their review of each laboratory safety report. 
Table 13: 
Protocol-Required Laboratory Assessments 
 
Hematology 
White blood cell count (WBC) with absolute 
differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils) 
Red blood cell (RBC) with indices (mean 
corpuscular volume [MCV] and mean corpuscular 
hemoglobin [MCH]) 
Hemoglobin 
Hematocrit 
Platelet count 
Clinical Chemistries 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase 
Gamma-glutamyl transferase (GGT) 
Total and direct bilirubin (fractionated) 
Blood urea nitrogen (BUN) 
Albumin 
Lactate dehydrogenase (LDH) 
Calcium 
Creatinine 
Sodium 
Potassium 
Glucose 
Total protein 
Chloride 
Creatine kinase 
Bicarbonate 
Amylase 
Lipase 
Other Laboratory Assessments 
• 
Coagulation panel: International normalized ratio (INR) 
• 
IL-6 
• 
D-dimer 
• 
Serum ferritin 
• 
Serum C-reactive protein (CRP) 
• 
Serum pregnancy test 
• 
SARS-COV-2 (COVID-19) test (RT-PCR via nasopharyngeal swab). Quantitative 
assessment of viral RNA load in blood and stool will also be performed as per site 
specific standard of care. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
 
AE Definition 
• 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment (ICH E6:1.2). 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention. 
 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (i.e., not related to progression of underlying disease). 
• 
Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, gout) 
should be considered an AE if there is either an increase in severity, frequency, or duration of 
the condition or an association with significantly worse outcomes. 
• 
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 


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10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
1.  Results in death 
2.  Is life-threatening (i.e., places the subject at immediate risk of death) 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
3.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or 
was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
4. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
5.  Is a congenital anomaly/birth defect 
6. Is an important medical event that although may not result in death, be life-threatening, or 
require hospitalization, may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
 
10.3.3. 
Definition of Adverse Events of Special Interest 
 
Adverse Events of Special Interest for Axatilimab are by the Sponsor defined as: 
• 
Any new infection that occurs on study, regardless of infectious agent (e.g., viral or non- 
viral). The site of infection and source of culture (BAL, tracheal aspirate, sputum, blood, 
urine etc.) should be recorded. 


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10.3.4. 
Definition of Suspected and Unsuspected Adverse Reaction 
 
Suspected adverse reactions are defined as: 
• 
any AE for which there is a reasonable possibility that the study intervention caused the AE. 
For the purposes of Sponsor regulatory safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the study intervention and the AE. 
A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any AE caused by a study intervention 
Unexpected Adverse events are defined as: 
• 
AE which is not listed in the IB of the study intervention or is not listed at the specificity or 
severity that has been observed 
 
 
10.3.5. 
Recording and Follow-Up of AE and/or SAE 
 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records 
to the Medical Monitor/ PPD in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
Medical Monitor/ PPD. In this case, all subject identifiers, with the exception of the subject 
number, will be redacted on the copies of the medical records before submission to the 
Medical Monitor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
AE severity will be evaluated by the Investigator in accordance with the NCI CTCAE v5.01. For 
AEs that are not adequately addressed in the NCI CTCAE, the Investigator should classify the 
intensity of the AE using the following guidelines: 
• 
Grade 1: Mild: Aware of sign or symptom, but easily tolerated; no intervention needed 
• 
Grade 2: Moderate: Discomfort enough to cause interference with usual activity, 
minimal non-invasive intervention indicated (e.g., short course of antibiotics) 
 
 
 
 
 
1 Please refer to the CTCAE v5 published on November 2017 at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference 
_5x7.pdf. 


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AE and SAE Recording 
• 
Grade 3: Severe: Medically significant but not immediately life-threatening; 
incapacitation with inability to work or do usual activity 
• 
Grade 4: Life-threatening: Refers to an event in which the subject was at risk of death at 
the time of the event, as judged by the Investigator; urgent/emergent intervention 
indicated. This category should not be used for an event that hypothetically might have 
caused death if it were more severe. 
• 
Grade 5: Fatal outcome. 
It will be left to the Investigator’s clinical judgment to determine whether an AE is of sufficient 
severity to require the subject’s removal from treatment or from the study. A subject may also 
voluntarily withdraw consent from treatment due to what she/he perceives as an intolerable AE. If 
either of these situations arises, the subject should be strongly encouraged to undergo an end-of- 
study assessment and be under medical supervision until symptoms cease or the condition 
becomes stable. An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
(investigational drug and/or study procedures) each occurrence of each AE/SAE 
according to the categories below. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality in terms of whether 
the AE/SAE may be related to study intervention and/or study procedures. 
• 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always assess causality for every event before the initial 
transmission of the SAE data to the Sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Causality Categories: 
• 
Related: An event is considered related if there is a reasonable possibility of causal 
association between the study intervention and the event. This means there is evidence to 


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Assessment of Causality 
suggest a causal relationship between the study intervention and the AE. The AE follows 
a reasonable temporal sequence from the time of study intervention administration and 
follows a known response to the study intervention and cannot be reasonably explained 
by other factors such as the subject's clinical state or other therapeutic interventions, or 
concomitant drugs administered to the subject. 
• 
Not related: The available evidence support that the event is related to other factors such 
as the subject’s clinical state, therapeutic interventions or concomitant drugs administered 
to the subject. 
 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Medical 
Monitor/PPD to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide Medical Monitor/PPD with a copy of any post--mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
10.3.6. 
Reporting of SAEs 
 
 
SAE and AESI Reporting to PPD via email or facsimile 
• 
On discovery, all SAEs and AESIs, regardless of seriousness, should be immediately 
reported (latest within 24 hours of knowledge of the event) to PPD by completing the SAE 
report form and email the documents to: 
 
Please note that this email address is for the reporting of SAE and pregnancy information 
only. 
Back-up reporting method: 
• 
Back-up reporting method to PPD is fax of SAE form to 
 
• 
Contacts for SAE reporting can be found in Investigational Site File 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, or complete 
hysterectomy). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
Women will be considered postmenopausal if they have been amenorrheic for 12 months without 
an alternative medical cause. The following age-specific requirements apply: 
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution. 
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago. 
Note: Females on hormone replacement therapy (HRT) and whose menopausal status is 
in doubt will be required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
Other conditions: 
A. Premenarchal 
B. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should 
be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview. 


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Contraception Guidance: 
Female subjects of childbearing potential should be informed that taking study intervention may 
involve unknown risks to the fetus (unborn baby) if a pregnancy were to occur during the study. 
Specifically, the study intervention may have adverse effects on a fetus in utero. 
See inclusion criteria in Section 5.1 for study contraception requirements for female and male 
subjects. 
Subjects with childbearing potential should use highly effective methods of contraception, 
defined as one that results in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly are described in Table 14. These contraceptive methods must be used 
for at least 90 days after the last dose of study intervention. Subjects must adhere to the 
contraception requirement for the duration of the study and during the follow-up period to 
participate in the study. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
Note that some contraception methods are not considered highly effective (e.g. male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 
Table 14: 
Highly Effective methods of contraception (<1% failure rate) 
 
Barrier/Intrauterine methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine system 
(e.g., Mirena®)a 
• 
Implants: Etonogestrel-releasing implants: 
e.g. Implanon® or Norplan® 
• 
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g. NuvaRing® 
• 
Injection: Medroxyprogesterone injection: 
e.g. Depo-Provera® 
• 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol- 
releasing transdermal system: e.g. Ortho 
Evra® 
• 
Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone-based pill 
a This is also considered a hormonal method 


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Collection of Pregnancy Information in female subjects who become pregnant, and female 
partners of male subjects 
• 
Please refer to the Study Manual for details on the pregnancy reporting procedure and 
associated report form 
• 
The Investigator will collect pregnancy information on any female subject or partner 
of a male subject who becomes pregnant while participating in this study. Information 
will be recorded on the appropriate form and submitted to the Sponsor within 24 
hours of learning of a subject's pregnancy. 
• 
The subject will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information 
in former study subjects, he or she may learn of an SAE through spontaneous 
reporting. 
• 
Any female subject who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 


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10.5. 
Appendix 5: Glossary 
Abbreviation Term 
Description 
ACE 
Angiotensin converting enzyme 
ADA 
Anti-drug antibody 
ADaM 
Analysis Dataset Model 
AE 
Adverse events 
AESI 
Adverse events of interest 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
cGVHD 
Chronic graft versus host disease 
CFR (clinic) 
Case fatality rate 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CrCl 
Creatinine clearance 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Corona virus disease 2019 
CR 
Complete response 
CRP 
C-reactive protein 
CRRT 
Continuous renal replacement techniques 
CRS 
Cytokine release syndrome 
CSF-1 
Colony stimulating factor-1 
CSF-1R 
Colony stimulating factor-1 receptor 
CT 
Computed tomography 
CTLA4 
Cytotoxic T-lymphocyte antigen 4 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 


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Abbreviation Term 
Description 
eCRF 
Electronic case report form 
EOS 
End of Study 
ET 
Early termination 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
HEENT 
Head ears eyes nose and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone replacement therapy 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICU 
Intensive care units 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committees 
IHC 
Immunohistochemistry 
IL-6 
Interleukin 6 
INR 
International normalized ratio 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat Set 
IV 
Intravenous 
JAKi 
Janus kinase inhibitors 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent to Treat 
NSAID 
Non-steroidal anti-inflammatory drug 
NEWS 
National Early Warning Score 
NK 
Natural killer 
PaO2 
Partial pressure of oxygen 
PCR 
Polymerase chain reaction 


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Abbreviation Term 
Description 
PD 
Pharmacodynamic 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed death-ligand 1 
PK 
Pharmacokinetic 
PR 
Partial response 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT-PCR 
Reverse-Transcriptase Polymerase Chain Reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SDTM 
Study Data Tabulation Model 
SoA 
Schedule of Activities 
SNP 
Single nucleotide polymorphism 
SOC 
Standard of care 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Known active tuberculosis 
TEAE 
Treatment-emergent adverse event 
TTCI 
Time to clinical improvement 
ULN 
upper limit of normal 
WBC 
White blood cell count 
WOCBP 
Women of childbearing potential 


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10.6. 
Protocol Amendment History 
Prior Amendments 
Syndax has introduced the following modifications to Protocol Version 3.0. These changes are 
presented in sequential order: 
 
Amendment 1, 22 April 2020 
Overall Rationale for the Amendment: 
Syndax has introduced the following modifications to protocol V1.0, these changes are presented 
in order of appearance: 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
4.1 Overall Study Design 
8.3.1 Time Period and 
Frequency of Collecting 
AE, AESI and SAE 
• 
Clarified collection periods for AEs 
for subjects who experience an AE 
• 
Per FDA request 
1.2 Schedule of Activities 
6.1 Study Intervention(s) 
Administered 
8.2.4 Clinical Safety 
Laboratory Assessments 
• 
Clarified that dosing to be done as 
out-patient for subjects who were 
discharged prior to Day 15 
• 
Clarified procedures for Day 15 
dosing in hospitalized and non- 
hospitalized subjects 
• 
Per FDA request 
1.2 Schedule of Activities 
• 
Reorganized SoA notes to use 
letters (vs. symbols) 
• 
Clarified footnotes relating to 
assessments to be done as out- 
patient for subjects who are 
discharged prior to Day 15 
• 
Clarified that safety laboratory 
results are to be obtained prior to 
dosing 
• 
For clarity purposes 
• 
Per FDA request 
Section 6.6. Dose 
Modifications 
• 
Added dose modifications for non- 
hematologic and hematologic 
toxicities 
• 
Removed the exception for dose 
interruption for increased bilirubin 
due to hemolysis independent of the 
underlying cause of hemolysis in 
Table 5 
• 
Per FDA request 
Section 6.7 Concomitant 
Medication 
• 
Clarified use of azithromycin 
• 
Per FDA request 


Product: SNDX-6352 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 Stopping Rules 
• 
Specified that the study will be 
paused to enrollment if there is a 
greater than 20% absolute 
difference in SARs between the two 
arms at the interim analysis 
• 
Per FDA request 
Section 8.1.4 Hospital 
Discharge Readiness 
Criteria 
• 
Clarified normal oxygen criteria and 
added that oxygen supplementation 
status will be captured 
• 
Per input from 
Investigator 
Appendix 2 
• 
Add laboratory parameters 
mentioned in the SoA (e.g., CK, 
amylase and lipase) 
• 
For consistency 
throughout protocol 
General 
• 
Corrected styles, formatting and 
check spelling 
• 
Other minor terminology updates 
• 
Update glossary 
• 
For consistency 
throughout protocol 


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