Clinical trial NCT04412668
Conditions: SARS-CoV-2 (COVID-19) Severe Pneumonia
Keywords: SARS-CoV-2 CoV-2 ATYR1923 (efzofitimod) acute respiratory distress syndrome ARDS SARS-CoV-2 Infection COVID-19 Severe Pneumonia
Sponsor: aTyr Pharma, Inc.
Start date: 2020-06-04; Completion date: 2020-10-23
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and preliminary efficacy of efzofitimod, compared to placebo matched to efzofitimod, in hospitalized participants with SARS-CoV-2 (COVID-19) severe pneumonia not requiring mechanical ventilation.

Detailed description:

Arms: arm 1: Participants will receive single dose of efzofitimod 1 milligrams/kilograms (mg/kg) IV infusion on Day 1. arm 2: Participants will receive single dose of efzofitimod 3 mg/kg IV infusion on Day 1. arm 3: Participants will receive placebo matched to efzofitimod IV infusion on Day 1.
Interventions: intervention 1: Efzofitimod 1 mg/kg intervention 2: Efzofitimod 3 mg/kg intervention 3: Placebo
Intervention descriptions: intervention 1: Concentrate for solution for infusion intervention 2: Concentrate for solution for infusion intervention 3: Concentrate for solution for infusion

Protocol documents:
Prot_000.pdf: 
aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1923-C-003 
13 November 2020 
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aTyr Pharma, Inc.
A Randomized Double-blind Placebo-controlled Study to Evaluate the Safety and Efficacy of 
ATYR1923 In Adult Patients With Severe Pneumonia Related To SARS-CoV-2 Infection 
(COVID-19) 
Protocol Number: ATYR1923-C-003 
This study will be conducted according to the protocol and in compliance with  
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki, 
and other applicable regulatory requirements. 
Study Sponsor: 
aTyr Pharma, Inc. 
3545 John Hopkins Court 
Suite #250 
San Diego, CA 92121, USA 
IND Number: 
148398 
Document Date (Version): 
13 November 2020 (Version 5.0; Amendment 4) 
Previous Versions: 
24 July 2020 (Version 4.0; Amendment 3) 
19 May 2020 (Version 3.0; Amendment 2) 
28 April 2020 (Version 2.0; Amendment 1) 
08 April 2020 (Version 1.0; Original) 
NCT #NCT04412668


aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1923-C-003 
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SPONSOR SIGNATORY 
aTyr Pharma, Inc. 
 
 
Date 
13 November 2020


aTyr Pharma, Inc. 
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INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by aTyr Pharma, Inc. (aTyr), or its 
designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
investigator brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB). No changes will be made to the study protocol without 
the prior written approval of aTyr and the IRB, except where necessary to eliminate an 
immediate hazard to a patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained 
in this protocol. 
 
Investigator Signature 
Date 
 
Printed Name 
 
 


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CLINICAL STUDY SYNOPSIS 
Title 
A Randomized Double-blind Placebo-controlled Study to Evaluate the 
Safety and Efficacy of ATYR1923 In Adult Patients With Severe 
Pneumonia Related To SARS-CoV-2 Infection (COVID-19) 
Sponsor 
aTyr Pharma, Inc. 
Clinical Phase 
2 
Indication 
Treatment of severe pneumonia due to SARS-CoV-2 infection. 
Objectives and 
Endpoints 
The objective of this study is to evaluate the safety and preliminary 
efficacy of ATYR1923, compared to placebo, in subjects with SARS-
CoV2-related severe pneumonia not requiring mechanical ventilation. 
Primary 
• 
To assess the safety of a single intravenous (IV) dose of 
ATYR1923. Safety will be assessed by: 
- Incidence of treatment-emergent adverse events (TEAEs), 
including serious and severe TEAEs, overall and by severity. 
Secondary 
• 
To assess the preliminary effects of ATYR1923 on clinical 
outcome measures of SARS-CoV-2 infection, including: 
- Time to hospital discharge. 
- Time to recovery (World Health Organization [WHO] Ordinal 
Scale score ≤3). 
- Proportion of patients achieving recovery by Day 14 and 
Day 28. 
- Duration of supplemental oxygen (O2) requirement. 
- Number of days with fever (temperature >100.4ºF [38.0ºC]). 
- Change from baseline in WHO Ordinal Scale score on Days 5, 
7, 14, 28, and 60. 
- Time to improvement from inpatient hospital admission based 
on at least a 1 point reduction in WHO Ordinal Scale score. 
- All-cause mortality at Days 14, 28, and 60. 


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Exploratory:  
• 
To explore the preliminary efficacy of ATYR1923 for SARS-CoV-
2 infection by evaluating effects on the following: 
- Change from baseline in supplemental oxygen requirement at 
Days 3, 5, 10, 14 and discharge. 
- Proportion of patients requiring intubation, and among those 
patients, number of days of intubation. 
• 
To assess the pharmacodynamics (PD) of a single IV dose of 
ATYR1923 by measuring inflammatory biomarkers and cytokines 
including: C-reactive protein (CRP), interferon gamma (INF-γ), 
interleukin (IL)-6, IL-2, IL-7, IL-10, tumor necrosis factor-alpha 
(TNFα), macrophage inflammatory protein-1 (MIP1), C-X-C motif 
chemokine 10 (CXC-10), and monocyte chemoattractant protein-1 
(MCP-1). 
• 
To assess the impact of a single IV dose of ATYR1923 by 
measuring potential markers of COVID-19 disease, including 
serum ferritin and D-dimer. 
Study Design 
This is a randomized, double-blind, placebo-controlled study to evaluate 
the safety, PD, and efficacy of ATYR1923 in hospitalized patients with 
SARS-CoV-2-related severe pneumonia not requiring mechanical 
ventilation. SARS-CoV-2 infection will be confirmed using a polymerase 
chain reaction (PCR) based test during Screening. 
Eligible patients will be randomized 1:1:1 to a single IV dose of 
ATYR1923 1 mg/kg, ATYR1923 3 mg/kg, or placebo. Study drug will be 
added to standard of care (SOC) per institutional standard for treating 
SARS-CoV2 infection. 
A single dose of study drug will be administered on Day 1. All study drug 
will be administered in the hospital setting; patients who are intubated after 
randomization but prior to study drug administration are no longer eligible 
to receive study drug. As this is a single-dose study, the treatment period is 
1 day. Thereafter, all patients will be followed for 60 days post-treatment. 
The schedule of study assessments over this period is dependent on the 
duration of hospitalization and whether or not the patient requires 
intubation (ie, non-intubated and intubated patients).  
• 
While hospitalized, non-intubated patients will have study 
assessments performed while hospitalized on Days 2, 3, 4, 5, 6, 7, 
10, and Day 14 and/or Discharge.  
- If the non-intubated patient is discharged prior to Day 14, the 
assessments scheduled for Day 14 and/or Discharge will be 
completed at the time of discharge. If discharge occurs on 
another scheduled study assessment day (ie, any day between 
Day 2 and 10), the Day 14 and/or Discharge assessments 


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supersede that study assessment day and the patient then will 
proceed to outpatient telephone contact (TC) follow-up visits. 
- If the patient is discharged prior to Day 14, then outpatient TC 
follow-up visits are to be conducted on Day 7 (as applicable) 
and Day 14. 
- If the non-intubated patient is discharged after Day 14, the 
patient is to have the assessments scheduled for Day 14 and/or 
Discharge performed on the day of discharge. If the patient is 
hospitalized for ≥21 days, the Day 14 assessments are to be 
performed weekly (Days 21, 28, 35, etc.) until discharge (with 
the exception of PK, which is to be done only at Day 28). After 
discharge, the patient will proceed to the next scheduled 
outpatient TC follow-up visit. (Thus, if a patient remains 
hospitalized on Day 28, the Day 28 TC follow-up visit need not 
be conducted.) 
• 
In the event a patient is intubated, SOC assessments and 
interventions will supersede study assessments while intubated and 
for the duration of intubation1, with clinical assessments collected 
as available per the institution’s electronic medical records. 
- Patients will resume the study assessment schedule upon 
extubation. (Thus, for example, if an intubated patient is 
extubated on Day 7, they will resume the study assessment 
schedule on Day 7). 
- Extubated patients will have the assessments scheduled for 
Day 14 and/or Discharge performed at the time of hospital 
discharge and will attend Day 28 and 60 TC follow-up visits. 
- If the patient is hospitalized for ≥21 days, assessments 
(outlined in Section 4.1.1), are to be performed weekly 
(Days 21, 28, 35, etc.) until discharge (with the exception of 
PK, which is to be done only at Day 28). After discharge, the 
patient will proceed to the next scheduled outpatient TC 
follow-up visit. (Thus, if a patient remains hospitalized on 
Day 28, the Day 28 TC follow-up visit need not be conducted.) 
An independent Data Safety Monitoring Board (DSMB) will review the 
progress of the study and perform interim reviews of safety data at regular 
intervals beginning after the 6th patient has been dosed, and at a frequency 
guided by the enrollment rate and DSMB recommendation.  
Number of Subjects 
Approximately 30 patients. 
                                                     
1 
With the exception of the WHO Scale and sample collection for ADA and Jo-1 Ab, which will continue to be collected as 
per the Schedule of Assessments. 


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Number of Study 
Centers 
Approximately 15 study centers in the United States. 
Target Population 
Inclusion Criteria 
1. Age 18 to 75 years. 
2. Confirmation of SARS-CoV2 infection by PCR. 
3. Severe pneumonia related to SARS-CoV2 infection, defined as 
fever or suspected respiratory infection with radiographic 
abnormalities suggestive of viral pneumonia, plus at least one of 
the following: 
- Respiratory rate >30 breaths/min; or 
- Severe respiratory distress, as determined by the Investigator; 
or; 
- Oxygen saturation (SpO2) ≤93% on room air. 
4. Female patients of childbearing potential must be willing to use 
adequate contraception or refrain from heterosexual intercourse 
from Screening until 30 days after the last follow-up visit. Male 
patients, if not infertile or surgically sterilized, must agree to use 
adequate contraception and not donate sperm or refrain from 
heterosexual intercourse from Day -1 until 30 days after the last 
follow-up visit. (Refer to Section 7.1.6.2 for details regarding 
adequate contraception.) 
5. Signed informed consent by patient or designated legal 
representative.  
Exclusion Criteria  
1. Patient is intubated/mechanically ventilated. 
2. In the opinion of the Investigator, patient’s progression to death is 
imminent. 
3. Treatment with immunosuppressant/immunotherapy drugs, 
including but not limited to IL-6 inhibitors, TNF-α inhibitors, anti-
IL-1 agents and janus kinase inhibitors within 5 half-lives or 
30 days (whichever is longer) prior to Day 1. 
4. Use of chronic (>30 days) oral corticosteroids for a 
non-COVID-19-related condition in a dose higher than prednisone 
10 mg or equivalent per day. 
5. Weight >165 kg or <40 kg. 
6. Class III or IV congestive heart failure as defined by the New York 
Heart Association (NYHA) or any recent onset of heart failure 
resulting in NYHA Class III/IV symptoms. 
7. Acute coronary syndrome (eg, myocardial infarction, unstable 
angina pectoris) and/or any history of significant cardiovascular 


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disease within the last 30 days. (Controlled hypertension is not a 
criterion for exclusion.) 
8. Hospitalization for respiratory disease within 1 year before 
screening, or a history of chronic obstructive or restrictive 
respiratory disease that limits activity and requires treatment to 
manage symptoms, including but not limited to, severe asthma, 
chronic obstructive pulmonary disease (GOLD Stage 2 or higher) 
bronchiectasis, interstitial lung disease, pulmonary hypertension, or 
any other respiratory diseases requiring long-term daily oxygen 
therapy. 
9. Renal failure requiring renal replacement therapy. 
10. Patient has a chronic infection such as hepatitis B virus (HBV), 
hepatitis C virus (HCV), or human immunodeficiency virus (HIV), 
or known active tuberculosis or history of untreated tuberculosis. 
11. History of anti-synthetase syndrome or known Jo-1 positivity prior 
to Screening. 
12. Pregnancy (negative pregnancy test required for women of child-
bearing potential). 
13. Participation in another clinical study of an investigational agent 
within 3 months (small molecules), 6 months (biologics) or 5 half-
lives of the agent, whichever is longer. 
14. Any physical examination findings and/or history of any illness 
that, in the opinion of the study Investigator, might confound the 
results of the study or pose an additional risk to the patient by their 
participation in the study. 
Length of Study  
~ 63 days: 
• 
Screening over Days – 7 to -1. 
• 
A single-dose of study drug on Day 1. 
• 
Post-treatment monitoring during inpatient hospitalization through 
hospital discharge.  
• 
TC follow-up visits after hospital discharge on Days 28 and 60. (If 
discharged prior to Day 14, TC follow-up visits also will be 
conducted on Day 7, as applicable, and Day 14.) 
Investigational Medical 
Product(S) 
Dose/ Route/ Regimen 
Single dose of ATYR1923 administered via IV infusion at a dose of 
1 mg/kg, 3 mg/kg, or placebo. The study drug dose will be calculated using 
the patient’s weight. No patient will receive an absolute dose >800 mg. 
Non-Investigational 
Medical Product(s) 
SOC, per standard institutional practice 
Reference Therapy 
Placebo (0.9% sterile sodium chloride solution, USP) 


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Statistical Methods 
Sample size 
30 subjects randomized 1:1:1 to ATYR1923 1 mg/kg, 3 mg/kg, or placebo, 
respectively. 
Analysis populations 
• 
Modified intent-to-treat population: all subjects randomized who 
have received any amount of study drug. Subjects will be analyzed 
as randomized. 
• 
Safety population: all subjects who have received any amount of 
study drug. Subjects will be analyzed as treated. 
Efficacy analyses 
Descriptive summary statistics: Continuous variables will be summarized 
using descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum). Categorical variables will be summarized showing the 
number and percentage (n, %) of patients within each classification. 
Safety analyses 
Safety and tolerability will be assessed through documentation of TEAEs 
and vital signs and, as available, clinical laboratory and physical 
examination findings, and any other parameters relevant to safety.  
 


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Table 1: 
Schedule of Assessments 
Assessment 
Screening 
Treatment 
Post-Treatment Monitoring During Hospitalization1 
Out-
patient 
Follow 
Up1 
Day -7 to -1 
D1 
(pre-
dose) 
baseline 
D1 
(post-
dose) 
D2 
D3 
D4 
D5 
D6 
D7 
D10 
D14/ 
Dis-
charge1 
D7, 14, 
28, 60 
TC1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
 
Radiographic studies 
X2 
X4 
 
Electrocardiograms 
X3 
X4 
 
SARs-CoV-2 Testing5 
X 
X4 
 
Serology (HBsAg, anti-HCV, and anti-
HIV 1/2 tests) 
X6 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical History, COVID-
19 Symptom History7 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test8 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X9 
X4 
 
Vital signs 
X 
X10 
X10 
X11 
 
SpO2 
X12 
X13 
X13 
X11 
 
Temperature 
X 
X13 
X13 
X11 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Height14 and weight 
X 
X15 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
WHO Ordinal Scale score16 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen utilization17 
X 
X 
X 
X11 
 
Safety laboratory testing (hematology, 
clinical chemistry), Urinalysis 
X18 
X18 
 
X11 
 
Blood sampling (serum) for ATYR1923 
PK19 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Blood sampling for Jo-1 Ab and ADA 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
Blood sampling for cytokines/chemokines 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Blood sampling for cardiac troponins, D-
dimers, ferritin, NT-proBNP 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Tryptase 
 
X20 
 
 
 
 
 
 
 
 
 
 


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Assessment 
Screening 
Treatment 
Post-Treatment Monitoring During Hospitalization1 
Out-
patient 
Follow 
Up1 
Day -7 to -1 
D1 
(pre-
dose) 
baseline 
D1 
(post-
dose) 
D2 
D3 
D4 
D5 
D6 
D7 
D10 
D14/ 
Dis-
charge1 
D7, 14, 
28, 60 
TC1 
Adverse events21 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intensive care unit utilization /  
Ventilation status23 
 
 
X 
1. 
This schedule applies for hospitalized, non-intubated patients. Refer to Footnote 2 and Section 4.1.1 for assessments to be performed while intubated. 
If a patient is discharged prior to Day 14, then outpatient TC follow-up visits are to be conducted on Day 7 (as applicable) and Day 14. The assessments to be conducted at the 
D7 and D14 TC follow-up visits are the same as those indicated for the Day 28 and Day 60 TC follow-up visits. 
2. 
A radiologic study performed within 7 days prior to Day 1 is acceptable to determine study eligibility. If the radiologic study was performed >7 days before Day 1, a repeat 
radiologic study is to be performed during Screening. 
3. 
ECG is to be collected during Screening if it was performed per SOC. 
4. 
After Screening, findings from any radiographic studies, electrocardiograms, SARs-CoV-2 testing, or abnormal physical examination findings performed per SOC are to be 
recorded in the eCRF. Furthermore, radiographic images may be collected and submitted to a central reader for review. 
5. 
Confirmation of SARS-CoV-2 infection by PCR is to be performed during Screening. However, if the test was performed at the study center/institution within 7 days before 
Day 1 and results are available in the medical record, then this test may be used as the confirmatory screening test. If the SARs-CoV-2 test results are older than 7 days or the 
test was performed at a different location, a repeat test is to be performed. 
6. 
Blood samples for serology may be collected within 7 days before Day 1. 
7. 
COVID-19 symptom history is to include date of onset of symptoms, list of symptoms, radiological test results, and date of initial SARS-CoV-2 positivity.  
8. 
Urine pregnancy test for women of child-bearing potential. 
9. 
If performed at the study center/institution within 7 days before Day 1 and results are available in the medical record, any abnormal physical examination findings are to be 
documented in the eCRF. Any abnormal physical examination findings from examinations performed per SOC through discharge also are to be recorded in the eCRF. 
Respiratory findings supportive of severe respiratory distress, if present, are to be documented on the Physical Examination eCRF if not otherwise captured as part of the 
patients recent COVID-19-related medical history.  
10. Day1 vital signs are to be obtained pre-infusion and at 15 and 30 minutes (±5 minutes) and at 1, 2, and 4 hours (±15 minutes) after the start of infusion (SOI). Vital signs will 
include blood pressure (systolic and diastolic), heart rate, and respiratory rate, recorded after resting for 5 min. 
11. After Day 1, temperature, SpO2, oxygen utilization, vital signs, and safety laboratory tests are to be measured per SOC and recorded in the eCRF. 
12. To assess eligibility, one measurement of SpO2 without supplemental oxygen should be attempted. If not clinically feasible, obtain the measurement with supplemental 
oxygen. The corresponding level of supplemental O2 use is to be recorded in the eCRF at screening to confirm eligibility. 
13. Day 1 temperature and SpO2 (by pulse oximetry) readings will be recorded pre-dose then at 1 and 4 hours (±15 minutes) after the SOI. 
14. Height may be collected via patient report. 
15. Weight is to be measured within 3 days prior to Day 1. If there is a weight change >10% between Day -3 and Day 1, the dose should be recalculated. 
16. The WHO Ordinal Scale score is to be determined between 06:00 and 10:00 hours at each designated time point, or per local SOC, and the score closest to 08:00 hours 
recorded. 
17. Supplemental oxygen is to be captured as a concomitant medication. 


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18. Note that if Screening safety laboratory assessments are performed within 2 days of Day 1, then the pre-dose Day 1 safety laboratory assessments need not be repeated. 
19. On Day 1, blood will be drawn for the PK analysis per the following schedule:  end of infusion (EOI), and then at any single time point between 4 and 12 hrs after start of 
infusion (SOI). Samples will then be drawn once daily on Days 5, 7, 10, and 14. A Day 28 sample will be collected from patients who remain hospitalized. 
20. To be repeated within 2 hours for any patient experiencing a suspected infusion-related reaction or anaphylaxis. 
21. Any new infections are to be documented as AEs. The new infection site and source of culture are to be recorded in the eCRF. 
22. Any ongoing medications are to be documented during Screening. 
23. In the event that a patient requires intubation, SOC assessments and interventions will supersede study assessments for the duration of intubation; refer to Section 4.1 and 
Section 4.1.1 for details. 
NOTE: Any patient experiencing a suspected infusion-related reaction or anaphylaxis is to be managed as described in Section 9.9. 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
Antibody 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BNP 
B-type natriuretic peptide 
COVID-19 
SARS-CoV-2 Infection 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CXC-10 
C-X-C motif chemokine 10 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
Gamma-GT 
Gamma glutamyl transferase  
GCP 
Good Clinical Practice 
HARS 
Histidyl-tRNA synthetase 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon gamma 
IgG1 
Immunoglobulin G1 


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Abbreviation 
Definition 
IL 
Interleukin 
ILD 
Interstitial lung disease 
iMod 
Human 59 amino acid protein 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
MCP-1 
Monocyte chemoattractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIP1 
Macrophage inflammatory protein-1 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NRP2 
Neuropilin 2 
NYHA 
New York Heart Association 
O2 
Oxygen 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SOC 
Standard of care 
SOI 
Start of infusion 
SOP 
Standard operating procedure 
SpO2 
Oxygen saturation 
SUSAR 
Serious unexpected suspected adverse reaction 
TC 
Telephone contact 


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Abbreviation 
Definition 
TEAE 
Treatment-emergent adverse event 
TNF-α 
Tumor necrosis factor-alpha 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATORY ........................................................................................................... 2 
INVESTIGATOR STATEMENT .............................................................................................. 3 
CLINICAL STUDY SYNOPSIS ................................................................................................ 4 
LIST OF ABBREVIATIONS ................................................................................................... 13 
TABLE OF CONTENTS .......................................................................................................... 16 
LIST OF TABLES IN THE TEXT .......................................................................................... 20 
1. 
Study Personnel and Administrative Structure .......................................................... 21 
2. 
Introduction .................................................................................................................... 22 
2.1. 
ATYR1923 .......................................................................................................... 22 
2.1.1. 
Clinical Experience with ATYR1923 ................................................... 22 
2.2. 
Rationale for ATYR1923 for the Treatment of Severe Pneumonia Related to 
SARS-CoV-2 Infection (COVID-19) ................................................................ 23 
3. 
Study Objectives and Endpoints................................................................................... 25 
3.1. 
Primary ............................................................................................................... 25 
3.2. 
Secondary............................................................................................................ 25 
3.3. 
Exploratory ......................................................................................................... 25 
4. 
Investigational Plan ....................................................................................................... 27 
4.1. 
Overall Study Design and Plan ......................................................................... 27 
4.1.1. 
Assessments During Intubation ............................................................ 28 
4.1.2. 
Study Completion ................................................................................. 29 
4.2. 
Discussion of Study Design ................................................................................ 29 
5. 
Study Population ............................................................................................................ 31 
5.1. 
Inclusion Criteria ............................................................................................... 31 
5.2. 
Exclusion Criteria .............................................................................................. 31 
5.3. 
Source of Patients ............................................................................................... 32 
6. 
Study Conduct ................................................................................................................ 33 
6.1. 
Patient Identification, Enrollment, and Randomization ................................ 33 
6.2. 
Patient Management .......................................................................................... 33 
6.3. 
Patient Adherence .............................................................................................. 33 
6.4. 
Withdrawal and Replacement of Patients ....................................................... 34 
6.4.1. 
Study Drug Discontinuation Criteria .................................................... 34 


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6.4.2. 
Replacement of Patients........................................................................ 34 
6.4.3. 
Study Withdrawal Criteria .................................................................... 35 
6.5. 
Study Completion............................................................................................... 35 
6.6. 
Study Termination ............................................................................................. 35 
6.7. 
Investigator Compliance ................................................................................... 35 
6.8. 
Data Safety Monitoring Board ......................................................................... 35 
7. 
Study Drug ...................................................................................................................... 37 
7.1. 
Study Drug Dose and Administration .............................................................. 37 
7.1.1. 
Treatments Administered ...................................................................... 37 
7.1.2. 
Identity of Investigational Products ...................................................... 37 
7.1.3. 
Method of Assigning Patients to Treatment Groups ............................ 37 
7.1.4. 
Selection of Doses in the Study ............................................................ 38 
7.1.5. 
Blinding ................................................................................................ 39 
7.1.6. 
Concomitant Medication and Other Restrictions During the Study ..... 39 
7.1.7. 
Treatment Compliance .......................................................................... 40 
8. 
Study Visits and Assessments ....................................................................................... 41 
8.1. 
Schedule of Assessments .................................................................................... 41 
8.2. 
Screening and Baseline Measurements ............................................................ 41 
8.2.1. 
Informed Consent ................................................................................. 41 
8.2.2. 
Demographics ....................................................................................... 41 
8.2.3. 
Medical History and History of COVID-19 Symptoms ....................... 41 
8.2.4. 
SARS-CoV-2 Testing ........................................................................... 41 
8.2.5. 
Serology ................................................................................................ 41 
8.2.6. 
Height and Weight ................................................................................ 42 
8.3. 
Efficacy and Exploratory Assessments ............................................................ 42 
8.3.1. 
Hospitalization Status ........................................................................... 42 
8.3.2. 
WHO Ordinal Scale of Clinical Status ................................................. 42 
8.3.3. 
Pulse Oximetry ..................................................................................... 42 
8.3.4. 
Vital Signs and Temperature ................................................................ 43 
8.4. 
Pharmacokinetic Measurements and Variables ............................................. 43 


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8.5. 
Pharmacodynamic/Exploratory Measurements and Variables .................... 43 
8.5.1. 
Blood for Cytokines/Chemokines ......................................................... 43 
8.6. 
Safety and Tolerability Measurements ............................................................ 43 
8.6.1. 
Physical Examination ........................................................................... 43 
8.6.2. 
Immunogenicity Measurements ............................................................ 43 
8.6.3. 
Adverse Events ..................................................................................... 44 
8.6.4. 
Concomitant Medications ..................................................................... 45 
8.6.5. 
Safety Laboratory Tests ........................................................................ 45 
8.6.6. 
Radiographic Studies and Electrocardiograms ..................................... 46 
8.6.7. 
Pregnancy Testing................................................................................. 46 
8.6.8. 
Appropriateness of Measurements........................................................ 46 
9. 
Adverse Events ............................................................................................................... 47 
9.1. 
Definitions ........................................................................................................... 47 
9.1.1. 
Adverse Event ....................................................................................... 47 
9.1.2. 
Suspected Adverse Reaction ................................................................. 47 
9.1.3. 
Serious Adverse Event .......................................................................... 47 
9.1.4. 
Unexpected Adverse Event ................................................................... 48 
9.1.5. 
Serious and Unexpected Suspected Adverse Reaction ......................... 48 
9.2. 
Adverse Event Assessment ................................................................................ 48 
9.2.1. 
Serious/Non-Serious ............................................................................. 49 
9.2.2. 
Relationship to Study Drug................................................................... 49 
9.2.3. 
Relationship to SARS-CoV2 infection: ................................................ 50 
9.2.4. 
Intensity ................................................................................................ 50 
9.2.5. 
Outcome ................................................................................................ 51 
9.2.6. 
Study Drug Action ................................................................................ 51 
9.3. 
Recording Adverse Events ................................................................................ 51 
9.4. 
Reporting Serious Adverse Events ................................................................... 52 
9.5. 
Follow-Up of Adverse Events ............................................................................ 53 
9.6. 
Reporting Safety Information ........................................................................... 53 
9.7. 
Protocol Deviations Due to an Emergency or Adverse Event........................ 53 


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9.8. 
Pregnancy ........................................................................................................... 53 
9.9. 
Management of Potential Infusion Related Reactions, Including Anaphylaxis
.............................................................................................................................. 54 
9.9.1. 
Anaphylaxis .......................................................................................... 55 
10. 
Statistical Analyses......................................................................................................... 56 
10.1. Statistical Procedures and Determination of Sample Size ............................. 56 
10.1.1. 
Analysis Sets ......................................................................................... 56 
10.1.2. 
Statistical and Analytical Plan for Pharmacokinetic, Pharmacodynamic, 
Safety and Exploratory Evaluation ....................................................... 56 
10.1.3. 
Determination of Sample Size .............................................................. 57 
10.2. Data Quality Assurance ..................................................................................... 57 
10.2.1. 
Interim Analyses ................................................................................... 58 
10.3. Changes to the Planned Statistical Methods ................................................... 58 
11. 
Ethical, Legal, and Administrative Considerations .................................................... 59 
11.1. Good Clinical Practice ....................................................................................... 59 
11.2. Informed Consent .............................................................................................. 59 
11.3. Institutional Review Board/Independent Ethics Committee ......................... 59 
11.4. Amending the Protocol ...................................................................................... 60 
11.5. Confidentiality/Data Protection ........................................................................ 60 
11.6. Publication Policy............................................................................................... 60 
12. 
Study Management ........................................................................................................ 62 
12.1. Data Quality Assurance ..................................................................................... 62 
12.2. Case Report Forms and Source Documentation ............................................. 62 
12.3. Monitoring .......................................................................................................... 62 
12.4. Inspections .......................................................................................................... 62 
12.5. Financial Disclosure Reporting Obligations .................................................... 63 
12.6. Archiving Study Records .................................................................................. 63 
13. 
REFERENCES ............................................................................................................... 64 
14. 
Appendices ...................................................................................................................... 65 
 


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LIST OF TABLES IN THE TEXT 
Table 1: 
Schedule of Assessments ..................................................................................... 10 
Table 2: 
Criteria for Determination of Adverse Event Relationship to Study Drug .......... 49 
Table 3: 
Criteria for Determination of Adverse Event Intensity ........................................ 50 
Table 4: 
Criteria for Determination of Adverse Event Outcome ....................................... 51 
Table 5: 
Study Drug Action Taken as a Result of Adverse Events ................................... 51 
 
 


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1. 
STUDY PERSONNEL AND ADMINISTRATIVE STRUCTURE 
Study Sponsor: 
aTyr Pharma, Inc. 
3545 John Hopkins Court, Suite #250 
San Diego, CA 92121 
USA 
Primary Sponsor Contact: 
 
Telephone:  
 
Email:  
 
aTyr Pharma, Inc. 
Sponsor Signatory: 
 
 
aTyr Pharma, Inc. 


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2. 
INTRODUCTION 
2.1. 
ATYR1923 
ATYR1923 is a novel molecular entity that acts as an extracellular immunomodulator and is 
under development for treatment of interstitial lung disease (ILD). ATYR1923 comprises a 
human 59 amino acid protein (iMod) fused to the Fc region of human immunoglobulin 1 (IgG1). 
The amino acid sequence of the 59 amino acid iMod domain in ATYR1923 corresponds 
identically to the extracellularly active iMod domain of histidyl-tRNA synthetase (HARS) amino 
acids 2 to 60 (HARS 2-60). In solution, the ATYR1923 molecule forms a homodimer, similar to 
other Fc fusion proteins.  
ATYR1923 may provide a naturally occurring human immunomodulatory function to 
therapeutically control or balance the human immune system. The mechanism of action of 
ATYR1923 in T-cells overlaps with the cellular pathology observed in lung sarcoidosis. In 
nonclinical studies, ATYR1923 has been shown to inhibit cytokines involved in regulation of 
inflammatory and immune responses and attenuate T-cell activation (Mertsching et al., 2018) As 
Neuropilin-2 (NRP-2) was recently discovered to bind ATYR1923, and innate immune cells 
such as dendritic cells and macrophages are known to express NRP-2 (Roy et al., 2017; 
Schellenburg et al., 2017), further research into the interaction between ATYR1923 and NRP-2 
on these cells could potentially elucidate an additional mechanism through which ATYR1923 
modulates the immune system. 
2.1.1. 
Clinical Experience with ATYR1923 
To-date, ATYR1923 has been evaluated in 1 completed study in normal healthy volunteers 
(ATYR1923-C-001) and 1 ongoing, blinded placebo-controlled study in patients with active 
pulmonary sarcoidosis (ATYR1923-C-002); data from this latter study remain blinded.  
In Study ATYR1923-C-001, 25 healthy adult subjects were exposed to single doses of 
ATYR1923 ranging from 0.03 to 5.0 mg/kg. ATYR1923 pharmacokinetics (PK) was dose-
proportional over the range of 0.03 mg/kg to 5.0 mg/kg. Terminal elimination phases were 
parallel, and the mean t1/2 was consistent from the 0.1 mg/kg dose onwards, with mean values 
ranging from 167 to 242 hours, supporting the potential for once-monthly dosing. ATYR1923 
was generally well tolerated at all doses tested. No severe treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), or TEAEs leading to study drug modification (dose 
reduction or discontinuation) were reported. No apparent dose relationship was seen across the 
range of doses studied with regard to the incidence of TEAEs. Adverse reactions reported were 
headache, dizziness, and back pain.  
The safety profile of ATYR1923 in patients with pulmonary sarcoidosis in Study ATYR1923-C-
002 was consistent with that seen in healthy volunteers. No deaths or treatment-related SAEs 
were reported. Adverse reactions included dizziness, headache, and productive cough (each 
2 patients) and back pain, Candida infection (considered related to Symbicort), diarrhea, 
migraine, rash pruritic, sinus congestion, and urticaria (each 1 patient).  


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Three (13%) patients experienced a severe (Grade 3) TEAE; no Grade 4 TEAEs were reported. 
Grade 3 TEAEs included cholecystitis acute, depression, and urticaria, each in 1 (4%) patient. 
No ATYR1923-treated subject in Study ATYR1923-C-001 experienced a definitive infusion-
related reaction (IRR). However, the occurrence of an IRR could not be ruled out for subject, 
who experienced mild, transient symptoms of dizziness, abdominal pain, and “feeling cold” 
followed by back pain. A patient with pulmonary sarcoidosis in Study ATYR1923-C-002 also 
experienced events considered representative of an IRR, with this patient similarly experiencing 
mild transient symptoms of dizziness as well as back pain. Other symptoms included a 
generalized warm sensation and tingling. As data from this study remain blinded, it is unknown 
whether this patient was exposed to ATYR1923.  
To-date, no patient participating in an ATYR1923 clinical study has developed a persistent anti-
drug antibody (ADA) response, or has been positive for Jo-1 antibodies (Ab) after ATYR1923 
exposure. 
2.2. Rationale for ATYR1923 for the Treatment of Severe Pneumonia 
Related to SARS-CoV-2 Infection (COVID-19) 
Emergent data gathered from patients with COVID-19 infection indicate that significant 
inflammatory infiltration of the lungs and concurrent elevations in pro-inflammatory 
cytokines/chemokines (ie, cytokine storms) are prominent factors in severe cases that have 
progressed to acute respiratory distress syndrome (ARDS) (Zhou et al., 2020). Severely ill 
patients have significant increases in plasma concentrations of several pro-inflammatory 
cytokines: interleukins (IL)-2, -7, -6 and 10, granulocyte-colony stimulating factor, interferon-
monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 alpha 
(MIP1A), and tumor necrosis factor-alpha (TNF-α), indicative of a cytokine storm (Wang et al., 
2020). Consistent with this acute inflammatory insult, serial computed tomography scans of 
patients with COVID-19 infection illustrate the rapid development of diffuse interstitial lung 
injury, which tracks with clinical disease progression (Shi et al., 2020). It has been hypothesized 
that rapid activation of CD4+T lymphocytes leads to the acute elevations these pro-inflammatory 
cytokines, resulting in aberrant lung inflammation and leading to potentially fatal lung damage 
(Zhou et al., 2020). 
ATYR1923 decreases the release of inflammatory cytokines, including IL-2, TNF-α, and IL-13 
from human T cells activated in vitro, substantiating that ATYR1923 directly modulates T-cell 
responses. Anti-inflammatory and anti-fibrotic effects of ATYR1923 have also been shown in 
various animal models of immune-mediated acute lung injury. In the bleomycin-induced lung 
fibrosis mouse and rat models, ATYR1923 significantly reduced inflammation-dependent 
pulmonary fibrosis and improved respiratory function parameters. 
Significant anti-fibrotic activity has also been demonstrated with ATYR1923 treatment in a 
sclerodermatous chronic graft-vs-host mouse model. In two granuloma-forming, highly 
inflammatory mouse models of interstitial lung disease, S. rectivirgula-induced chronic 


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hypersensitivity pneumonitis and P. acnes-induced sarcoidosis, ATYR1923 treatment led to the 
reduction of several pro-inflammatory cytokines, including IL-6, MCP-1 and IFN-γ (Burkart et 
al., 2019). The immunomodulatory activity of ATYR1923 is likely exerted through interaction 
with the cell-surface receptor NRP-2, which is present on multiple immune cell types and 
upregulated on alveolar macrophages and inflammatory monocytes in response to inflammatory 
conditions in the lung. A potential therapeutic effect of ATYR1923 was also investigated in a 
murine acute lung injury model that reproduces key features of human ARDS. Treatment with 
ATYR1923 at 3.0 and 10 mg/kg led to a dose-dependent reduction of total neutrophil and 
alveolar macrophage counts in the lung at 24h post insult.  
Thus, a strong scientific rationale exists to investigate ATYR1923 as a treatment for severe 
respiratory complications related to COVID-19 infection. aTyr is conducting the current study to 
evaluate ATYR1923 1 mg/kg and 3 mg/kg in adults with severe respiratory complications 
related to SARS-CoV2 infection. Eligible patients will be adults aged 18 to 75 years, who 
present with SARS-CoV2-related severe pneumonia not requiring mechanical ventilation. The 
patient or designated legal representative is required to provide informed consent before the 
performance of any study-related procedures. The primary objective is determination of the 
safety of ATYR1923 in this patient population. The effects of ATYR1923 on efficacy outcomes, 
including oxygen saturation levels, fever and clinical status, is a secondary objective. The effect 
of ATYR1923 on other outcome measures in this patient population also will be explored. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
The objective of this study is to evaluate the safety and preliminary efficacy of ATYR1923, 
compared to placebo, in subjects with SARS-CoV2-related severe pneumonia not requiring 
mechanical ventilation. 
3.1. 
Primary 
The primary objective is: 
• To assess the safety of a single intravenous (IV) dose of ATYR1923. Safety will be assessed 
by: 
- Incidence of TEAEs, including serious and severe TEAEs, overall and by severity. 
3.2. 
Secondary 
Secondary objective is: 
• To assess the preliminary effects of ATYR1923 on clinical outcome measures of SARS-
CoV-2 infection, including: 
- Time to hospital discharge. 
- Time to recovery (World Health Organization [WHO] Ordinal Scale score ≤3). 
- Proportion of patients achieving recovery by Day 14 and Day 28. 
- Duration of supplemental oxygen (O2) requirement. 
- Number of days with fever (temperature >100.4ºF [38.0ºC]). 
- Change from baseline in WHO Ordinal Scale score on Days 5, 7, 14, 28, and 60. 
- Time to improvement from inpatient hospital admission based on at least a 1 point 
reduction in WHO Ordinal Scale score. 
- All-cause mortality at Days 14, 28, and 60. 
3.3. 
Exploratory 
The exploratory objectives are: 
• To explore the preliminary efficacy of ATYR1923 for SARS-CoV-2 infection by evaluating 
effects on the following: 
- Change from baseline in supplemental oxygen requirement at Days 3, 5, 10, 14 and 
discharge. 
- Proportion of patients requiring intubation, and among those patients, number of days of 
intubation. 
• To assess the pharmacodynamics (PD) of a single IV dose of ATYR1923 by measuring 
inflammatory biomarkers and cytokines including: C-reactive protein (CRP), interferon 


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gamma (INF-γ), interleukin (IL)-6, IL-2, IL-7, IL-10, tumor necrosis factor-alpha (TNFα), 
macrophage inflammatory protein-1 (MIP1), C-X-C motif chemokine 10 (CXC-10), and 
monocyte chemoattractant protein-1 (MCP-1). 
• To assess the impact of a single IV dose of ATYR1923 by measuring potential markers of 
COVID-19 disease, including serum ferritin and D-dimer. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
Study ATYR1923-C-003 is a randomized, double-blind, placebo-controlled study to evaluate the 
safety, PD and efficacy of ATYR1923 in subjects with SARS-CoV-2 related severe pneumonia. 
SARS-CoV-2 infection will be confirmed using a polymerase chain reaction (PCR) based test 
during Screening. The Investigator, Sponsor, and patient will be blinded to treatment assignment; 
study center pharmacy personnel will be unblinded. 
Eligible patients will be randomized 1:1:1 to a single IV dose of ATYR1923 1 mg/kg, 
ATYR1923 3 mg/kg, or placebo. Study drug (ATYR1923 or placebo) will be added onto 
institutional standard of care (SOC) for treating SARS-CoV2 infection.  
A single dose of study drug will be administered on Day 1. All study drug will be administered 
in the hospital setting; patients who are intubated after randomization but prior to study drug 
administration are no longer eligible to receive study drug. As this is a single-dose study, the 
treatment period is 1 day. Thereafter, all patients will be followed for 60 days post-treatment. 
The schedule of study assessments over this period is dependent on the duration of 
hospitalization and whether or not the patient requires intubation.  
• While hospitalized, non-intubated patients will have study assessments performed on Days 2, 
3, 4, 5, 6, 7, 10, and Day 14 and/or Discharge.  
- If the non-intubated patient is discharged prior to Day 14, the assessments scheduled for 
Day 14 and/or Discharge will be completed at the time of discharge. If discharge occurs 
on another scheduled study assessment day (ie, any day between Day 2 and 10), the 
Day 14 and/or Discharge assessments supersede that study assessment day and the patient 
then will proceed to outpatient telephone contact (TC) follow-up visits. 
- If a patient is discharged prior to Day 14, then outpatient TC follow-up visits are to be 
conducted on Day 7 (as applicable) and Day 14.  
- If the non-intubated patient is discharged on Day 15-20, the patient is to have the 
assessments scheduled for Day 14 and/or Discharge performed on the day of discharge. If 
the patient is hospitalized for ≥21 days, the Day 14 assessments are to be performed 
weekly (Days 21, 28, 35, etc.) until discharge (with the exception of PK, which is to be 
done only at Day 28). After discharge, the patient will proceed to the next scheduled 
outpatient TC follow-up visit. (Thus, if a patient remains hospitalized on Day 28, the 
Day 28 TC follow-up visit need not be conducted.) 


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• In the event a patient is intubated, SOC assessments and interventions will supersede study 
assessments for the duration of their intubation2, with clinical assessments collected as 
available per the institution's electronic medical records (see Section 4.1.1). 
- Intubated patients will resume the study assessment schedule upon extubation. (Thus, for 
example, if an intubated patient is extubated, they will resume the study assessment 
schedule on Day 7). 
- Extubated patients will have the assessments scheduled for Day 14 and/or Discharge 
performed at the time of hospital discharge and will attend Day 28 and 60 TC follow-up 
visits. 
- If the patient is hospitalized for ≥21 days, assessments (outlined in Section 4.1.1), are to 
be performed weekly (Days 21, 28, 35, etc.) until discharge (with the exception of PK, 
which is to be done only at Day 28). After discharge, the patient will proceed to the next 
scheduled outpatient TC follow-up visit. (Thus, if a patient remains hospitalized on 
Day 28, the Day 28 TC follow-up visit need not be conducted.) 
An independent Data Safety Monitoring Board (DSMB) will review the progress of the study 
and perform interim reviews of safety data at regular intervals beginning after the 6th patient has 
been dosed, and at a frequency guided by the enrollment rate and DSMB recommendation.  
4.1.1. 
Assessments During Intubation 
In the event that a patient requires intubation, SOC assessments and interventions will supersede 
study assessments for the duration of intubation, with the exception of the WHO Scale and 
sample collection for ADA and Jo-1 Ab, which will continue to be collected as per the Schedule 
of Assessments (Table 1) on Days 5, 7, 10, 14 and weekly thereafter. The following clinical 
assessments will be collected and analyzed as available per the institution's electronic medical 
records.  
• Date and time of intubation and extubation. 
• Adverse events (AEs) (including new infections). In the case of new infections, the site and 
source of culture are to be recorded. 
• Concomitant medications. 
Patients requiring intubation will have the assessments scheduled for Day 14 and/or Discharge 
performed at the time of hospital discharge and will attend Day 28 and 60 TC follow-up visits. 
                                                     
2 
With the exception of the WHO Scale and sample collection for ADA and Jo-1 Ab, which will continue to be collected as 
per the Schedule of Assessments. 


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If the patient is hospitalized for ≥21 days, the Day 14 and/or Discharge assessments are to be 
performed weekly (Days 21, 28, 35, etc.) until discharge (with the exception of PK, which is to 
be done only at Day 28). 
After discharge, the patient will proceed to the next scheduled outpatient TC follow-up visit. 
(Thus, if a patient remains hospitalized on Day 28, the Day 28 TC follow-up visit need not be 
conducted.) 
4.1.2. 
Study Completion 
The study will be considered complete when the last patient completes the Day 60 TC Follow-up 
visit and any necessary follow-up for Jo-1 Ab positivity or ongoing study drug-related TEAEs 
has been completed. 
4.2. 
Discussion of Study Design 
Single and repeated doses of ATYR1923 were found to be safe and well tolerated in a in healthy 
volunteers and patients with pulmonary sarcoidosis. No significant immunogenic responses 
(induction of ADAs or Jo-1 Ab positivity) were observed following the administration of single 
or repeated doses of ATYR1923. The PK of a single dose of ATYR1923 was well characterized 
and demonstrated dose-proportional exposures over the range of doses from 0.03 to 5 mg/kg 
following IV drug administration. Terminal elimination phases were parallel, and the mean half-
life was consistent from the 0.1 mg/kg onwards, with mean values ranging from 167 to 
242 hours.  
These data support the continued clinical evaluation of ATYR1923, a novel molecular entity that 
acts as an extracellular immunomodulator and is under development for treatment of ILD. A 
strong scientific rationale exists to investigate ATYR1923 as a treatment for patients with severe 
pneumonia related to SARS-CoV-2 infection (COVID-19), a heavily compromised patient 
population representing a significant unmet medical need. 
Several design features have been employed in the current study in an effort to minimize bias, 
including a double-blind design, with patients randomized to treatment with ATYR1923 1 
mg/kg, 3 mg/kg, or placebo. Random assignment of patients avoids bias and helps ensure that 
both known and unknown risk factors are distributed evenly between treatment groups. The use 
of placebo control permits prospective comparison between the ATYR1923 groups and the 
control group.  
This study will be conducted at multiple-study centers. This multi-center design is needed not 
only for efficient enrollment of the required number of patients, allowing for a more efficient 
evaluation of ATYR1923, but it provides a better basis for the subsequent generalization of study 
findings (ICH, 1998). 


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The current study is specifically designed, with the inclusion of detailed safety measures, to 
evaluate these parameters in patients with severe pneumonia related to SARS-CoV-2 infection 
(COVID-19).  
Patients will be evaluated for 60 days after study drug exposure.  
The development of humoral immune responses (formation of Ab) to exogenously administered 
proteins occurs commonly. ATYR1923 is a protein-based therapeutic; specifically, it is a human 
59-amino acid protein (ie, iMod) directly fused to the C-terminus Fc region of human IgG1, and 
exists as an Fc fusion dimer. The immunogenicity assessments in clinical ATYR1923 studies 
include assessment of both ADA and Jo-1 Ab, the Ab that recognizes HARS, with loss of 
immune tolerance to HARS being associated with anti-synthetase syndrome. No significant 
immunogenic responses (persistent induction of ADAs or Jo-1 Ab positivity) have been observed 
in patients participating in an ATYR1923 clinical study to date. However, ADA have occurred 
infrequently in nonclinical studies with ATYR1923 in the rat and non-human primate. ADA did 
not affect the PK of the drug. Thus, ADAs may be observed in the current clinical study. 
Accordingly, the study design includes ADA and Jo-1 Ab testing, detailed clinical monitoring 
for adverse immunological events, extended safety follow-up if indicated to follow-up on 
serological findings, and a specific plan to assist Investigators in the clinical management of 
patients in whom immunogenicity occurs (see Section 9.9).  
The Investigator will take all the usual medical safety precautions necessary for studies at an 
early stage in the development of a new drug and has full discretion to stop study drug infusion 
at any time, if clinically warranted, or otherwise in the patient’s best interest (Section 6.4). 


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5. 
STUDY POPULATION 
Approximately 30 patients with severe pneumonia related to SARS-CoV-2 infection (COVID-
19) are planned to be enrolled in this study.  
5.1. 
Inclusion Criteria 
The following inclusion criteria must be met for a patient to be eligible for inclusion in the study: 
1. Age 18 to 75 years. 
2. Confirmation of SARS-CoV2 infection by PCR. 
3. Severe pneumonia related to SARS-CoV2 infection, defined as fever or suspected 
respiratory infection with radiographic abnormalities suggestive of viral pneumonia, plus 
at least one of the following: 
• Respiratory rate >30 breaths/min; or 
• Severe respiratory distress, as determined by the Investigator; or; 
• Oxygen saturation (SpO2) ≤93% on room air. 
4. Female patients of childbearing potential must be willing to use adequate contraception 
from Screening until 30 days after the last follow-up visit. Male patients, if not infertile 
or surgically sterilized, must agree to use adequate contraception and not donate sperm 
from Day -1 until 30 days after the last follow-up visit. (Refer to Section 7.1.6.2 for 
details regarding adequate contraception.) 
5. Signed informed consent by patient or designated representative.  
5.2. 
Exclusion Criteria 
A patient who meets any of the following exclusion criteria will not be eligible for inclusion in 
the study: 
1. Patient is intubated/mechanically ventilated. 
2. In the opinion of the Investigator, patient’s progression to death is imminent. 
3. Treatment with immunosuppressant/immunotherapy drugs, including but not limited to 
IL-6 inhibitors, TNF-α inhibitors, anti-IL-1 agents and janus kinase inhibitors within 
5 half-lives or 30 days (whichever is longer) prior to Day 1. 
4. Use of chronic (>30 days) oral corticosteroids for a non-COVID-19-related condition in a 
dose higher than prednisone 10 mg or equivalent per day. 
5. Weight >165 kg or <40 kg. 
6. Class III or IV congestive heart failure as defined by the New York Heart Association 
(NYHA) or any recent onset of heart failure resulting in NYHA Class III/IV symptoms. 


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7. Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and/or 
any history of significant cardiovascular disease within the last 30 days. (Controlled 
hypertension is not a criterion for exclusion.) 
8. Hospitalization for respiratory disease within 1 year before screening, or a history of 
chronic obstructive or restrictive respiratory disease that limits activity and requires 
treatment to manage symptoms, including but not limited to, severe asthma, chronic 
obstructive pulmonary disease (GOLD Stage 2 or higher) bronchiectasis, interstitial lung 
disease, pulmonary hypertension, or any other respiratory diseases requiring long-term 
daily oxygen therapy. 
9. Renal failure requiring renal replacement therapy. 
10. Patient has a chronic infection such as hepatitis B virus (HBV), hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV), or known active tuberculosis or history of 
untreated tuberculosis. 
11. History of anti-synthetase syndrome or known Jo-1 positivity prior to Screening. 
12. Pregnancy (negative pregnancy test required for women of child-bearing potential).  
13. Participation in another clinical study of an investigational agent within 3 months (small 
molecules), 6 months (biologics) or 5 half-lives of the agent whichever is longer. 
14. Any physical examination findings and/or history of any illness that, in the opinion of the 
study Investigator, might confound the results of the study or pose an additional risk to 
the patient by their participation in the study. 
5.3. 
Source of Patients 
This will be a multi-center study. Each study center is required to obtain Institutional Review 
Board (IRB) and regulatory approval to conduct the study before enrollment of patients may 
commence. Patients meeting the study entry criteria will be eligible for enrollment. 


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6. 
STUDY CONDUCT 
6.1. 
Patient Identification, Enrollment, and Randomization 
After obtaining informed consent, patients will be screened according to the inclusion and 
exclusion criteria. Patients will be randomized to one of the three treatment arms based on their 
availability. Patients who have met all eligibility criteria will receive a unique Screening number 
according to the Screening order. Then, prior to dosing, each patient will be allocated a 
randomization number according to their chronological order of inclusion in the study. This 
number will correspond to a treatment (ATYR1923 or placebo) as specified on the pre-
determined randomization schedule.  
The master randomization schedule will be made of randomly permuted blocks of appropriate 
sizes, as determined by the unblinded study team member producing the schedule. The schedule 
will be generated electronically. 
For patients who are replaced, the replacements should take the same treatment assignment as 
the original patient to ensure that the treatment groups stay balanced. 
The randomization code will be produced within the interactive web response system (IWRS). 
The study center pharmacist or designated unblinded study team member will be provided access 
to the randomization code within the IWRS. The laboratory where the PK samples are to be 
analyzed will also be provided access to distinguish between samples of patients dosed with 
ATYR1923 versus placebo. 
Patients who withdraw for any reason without completing all Screening evaluations successfully, 
will be considered “screen failures”. Such patients will have a limited number of electronic case 
report forms (eCRFs) completed.  
6.2. 
Patient Management 
All patients or their designated legal representatives must provide informed consent before the 
performance of any study-related procedure. Patients eligible for the study will be randomized 
within 24 hours before study drug administration on Day 1 and will receive a single dose of 
study drug (either ATYR1923 or placebo), according to their treatment assignment on a double-
blind basis. Patients will have post-treatment follow-up visit assessments performed for 60 days 
after completion of dosing. 
6.3. 
Patient Adherence 
All patients are required to adhere to the protocol-specified dosing and visit schedules. If a 
patient misses a scheduled visit, attempts should be made to reschedule the visit within the visit 
windows specified in Table 1.  


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6.4. 
Withdrawal and Replacement of Patients 
6.4.1. 
Study Drug Discontinuation Criteria 
Study drug administration must be permanently discontinued for a patient if any of the following 
events occur: 
• A SAE that has a reasonable possibility of a causal relationship with the study drug. 
• A severe IRR that includes cardiac and/or respiratory observations (see Section 9.9 for 
Management of IRRs). 
• Patient request to discontinue study drug dosing for any reason. 
• Other findings that, at the discretion of the Investigator and/or Sponsor, indicate that study 
drug administration should be discontinued. 
The Investigator has full discretion to stop study drug infusion at any time, if clinically warranted 
or in the patient’s best interest. 
All patients who have been dosed with any amount of study drug will continue to be followed for 
safety. Patients who discontinue study drug dosing at any time during the treatment period 
should return to the study center for the post treatment follow-up visits and as clinically 
indicated. 
Patients who withdraw their consent will not receive any further study drug, but will be offered 
all follow-up safety assessments.  
If a subject fails to attend scheduled study assessments, the Investigator must determine and 
document the reasons and the circumstances as completely and accurately as possible. 
6.4.2. 
Replacement of Patients 
If a patient is withdrawn from the study for any reason, whether related to the study drug or not, 
or if a patient voluntarily withdraws before or after receiving the study drug, such patient will be 
considered an early-termination patient.  
Investigator will make every effort to ensure that early-termination patients who have received 
study drug complete the safety follow up assessments. 
Patients who are randomized and do not receive study drug will be replaced at the Sponsor’s 
discretion. The decision regarding the replacement of patients will be documented. 


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6.4.3. 
Study Withdrawal Criteria 
Patients will be informed that they have the right to discontinue from the study and withdraw 
consent at any time for any reason, without prejudice to their medical care. The Investigator also 
has the right to withdraw patients from the study for any of the following reasons: 
• Patient non-adherence to study drug or protocol requirements. 
• Patient unwillingness to continue in the study. 
• Any other reason, based upon the medical judgment of the Investigator. 
The reason for study withdrawal is to be documented in the patient’s source documents and 
electronic case report form (eCRF). 
At the time of discontinuation from the study, patients are to have all the assessments planned for 
the final follow-up visit performed after the last study drug dose, if feasible.  
6.5. 
Study Completion 
A patient is considered to have completed the study if they completed all dosing and all follow-
up visits. 
6.6. 
Study Termination 
If the Sponsor or Investigator discovers conditions arising during the study that suggest the study 
should be halted, then this can happen only after appropriate consultation between the Sponsor 
and Investigator. Conditions that may warrant study termination include, but are not limited to: 
• The discovery of any unexpected, significant, or unacceptable risk to the patients enrolled in 
the study. 
• Insufficient adherence to the protocol requirements. 
• A decision on the part of the Sponsor to discontinue the Study 
• A decision on the part of the Sponsor to suspend or discontinue development of ATYR1923. 
6.7. 
Investigator Compliance 
If the study center deviates significantly from the protocol, the center may be discontinued from 
the study. The Investigator is responsible for ensuring the accuracy and completeness of all 
research records, the accountability of Study Drug, and the conduct of clinical and laboratory 
evaluations as outlined in the protocol. The Investigator is responsible for ensuring that the 
clinical study is performed in accordance with the Declaration of Helsinki and the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidance documents. 
6.8. 
Data Safety Monitoring Board 
Ongoing review of safety and tolerability data will be performed by the Medical Monitor and 
aTyr Pharma personnel. (The Investigator, Sponsor, and patient will be blinded to treatment 
assignment). 


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An independent DSMB will review the progress of the study and perform interim reviews of 
safety data at regular intervals beginning after the 6th patient has been dosed, and at a frequency 
guided by the enrollment rate and DSMB recommendation.  
The Food and Drug Administration will be notified if any patient is withdrawn for safety reasons 
and of any decision to pause enrollment or terminate the study. 


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7. 
STUDY DRUG 
7.1. 
Study Drug Dose and Administration 
7.1.1. 
Treatments Administered 
Patients will be randomly assigned via computer-generated randomization list to 1 of 3 treatment 
groups at a 1:1:1 ratio as follows: 
• Single dose of ATYR1923 1 mg/kg 
• Single dose of ATYR1923 3 mg/kg 
• Single dose of placebo. 
It is planned that study drug will be administered as an IV infusion. 
The patient’s weight will be used to calculate the ATYR1923 dose. No patient will receive an 
absolute dose >800 mg. If there is a weight change >10% between Day -3 and Day 1, the dose 
should be recalculated. 
7.1.2. 
Identity of Investigational Products 
7.1.2.1. 
ATYR1923 
The ATYR1923 Drug Product is a sterile, clear to slightly opalescent, colorless to slightly 
yellow, preservative-free liquid concentrate for IV administration. ATYR1923 Drug Product 
(3.8 mL fill volume) is supplied in a single-use borosilicate glass vial, stoppered with 
bromobutyl rubber stopper (with FluroTec coating), and sealed with aluminum Flip-off® seal. 
The formulation of ATYR1923 Drug Product contains 25 mg/mL ATYR1923, 20 mM 
L-histidine, 125 mM sodium chloride, 3% sucrose, 10 mM L-methionine, and 0.02% polysorbate 
20 at pH 6.9.  
ATYR1923 will be administered to patients by IV infusion after appropriate dilution in 0.9% 
sterile sodium chloride solution, United States Pharmacopeia (USP), as outlined in the study 
Pharmacy Manual. 
7.1.2.2. 
Placebo 
Placebo used in this study will be 0.9% sterile sodium chloride solution, USP.  
Placebo will be administered to patients by IV infusion as outlined in the study Pharmacy 
Manual. 
7.1.3. 
Method of Assigning Patients to Treatment Groups 
After obtaining informed consent, patients will be screened according to the inclusion and 
exclusion criteria. Patients who are determined to be eligible, based on Screening assessments, 
will be randomized on a 1:1:1 basis in a blinded fashion to 1 of 3 treatment groups (ATYR1923 


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1 mg/kg, ATYR1923 3 mg/kg, or placebo) via the computer-generated randomization list. 
Patients who are randomized are considered enrolled in the study.  
7.1.3.1. 
Criteria for Pausing Enrollment 
In the event that a serious unexpected suspected adverse reaction (SUSAR) has occurred, the 
enrollment and initiation of study drug administration to new patients will be paused and the 
Sponsor will request an unblinded review by the DSMB, who will provide its recommendation to 
aTyr Pharma. Such recommendation may include, but is not limited to, stopping enrollment, 
continuing the study as planned, or continuing the study with modifications. 
In addition, if unexpected, clinically significant trends or changes in other safety assessments are 
identified during routine safety reviews the Sponsor may request the DSMB to similarly perform 
a review and provide recommendations.  
7.1.4. 
Selection of Doses in the Study 
To date, 25 healthy adult subjects have been exposed to ATYR1923 at doses ranging from 0.03 
to 5.0 mg/kg in a first-in-human clinical study. In addition, 24 patients with pulmonary 
sarcoidosis have participated in an ongoing multiple-dose study. At the time of this document, 
enrollment in Cohorts 1 and 2 (ATYR1923 1 and 3 mg/kg) has been complete, with DSMB 
review of blinded data performed. (As the data remain blinded, the number of patients exposed 
to ATYR1923 is unknown, but, based on the randomization scheme, is assumed to be 
approximately 16). Doses of 1 and 3 mg/kg are estimated to be pharmacologically active. 
To date, no deaths or study drug-related SAEs have been reported with ATYR1923. No apparent 
dose relationship was seen across the range of doses studied with regard to the incidence of 
TEAEs. Adverse reactions reported to date include back pain, Candida infection, diarrhea, 
dizziness, headache, migraine, productive cough, rash pruritic, sinus congestion, and urticaria.  
No ATYR1923-treated subject in Study ATYR1923-C-001 experienced a definitive IRR. 
However, the occurrence of an IRR could not be ruled out for one subject, who experienced 
mild, transient symptoms of dizziness, abdominal pain, and “feeling cold” followed by back 
pain. A patient with pulmonary sarcoidosis in Study ATYR1923-C-002 also experienced events 
considered representative of an IRR, with this patient similarly experiencing mild transient 
symptoms of dizziness as well as back pain. Other symptoms included a generalized warm 
sensation and tingling. As data from this study remain blinded, it is unknown whether this patient 
was exposed to ATYR1923. 
No patient participating in an ATYR1923 clinical study was positive for ADA or Jo-1 Ab after 
study drug exposure. 
Given that doses of 1 and 3 mg/kg have been tolerable in both healthy volunteers and patients 
with pulmonary sarcoidosis and are predicted to be pharmacologically active, these dose levels 
were selected for use in the current study.  


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7.1.5. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The infusion solution for patients assigned to active drug and placebo will be 
indistinguishable in appearance. 
• The study center pharmacist or designated unblinded study team member will have 
access to random treatment assignments via IWRS for dispensing purposes; treatment 
assignments will be accessible only to the pharmacist or designated unblinded study team 
member and will be maintained in a blinded fashion. The study drug infusion will be 
labeled by the unblinded pharmacist or designated unblinded study team in a blinded 
manner. 
To manage the patient’s condition in case of a medical emergency, the Investigator (or delegate) 
is allowed to break the code in order to identify whether a patient received ATYR1923 or 
placebo. If the blind is broken for an individual patient, the name of the person who broke the 
blind and the date and time of and the reason for breaking the blind must be documented. The 
Sponsor will be informed in case of unblinding. There are no specific antidotes for ATYR1923. 
Knowledge of whether the patient received ATYR1923 or placebo, may not necessarily help in 
the care of an individual patient. The need to break the blind must therefore be carefully 
considered. 
The laboratory where the PK samples are to be analyzed will also be provided access to the 
randomization code within the IWRS to distinguish between samples of patients dosed with 
ATYR1923 versus placebo. 
7.1.6. 
Concomitant Medication and Other Restrictions During the Study 
7.1.6.1. 
Prohibited or Restricted Concomitant Medications and Substances 
The following treatments and procedures are prohibited prior to and/or during study 
participation, as indicated below: 
• All investigational agents or devices (other than ATYR1923) within 3 months for small 
molecules and 6 months for biologics, or 5 half-lives (if known) of the agent, whichever is 
longer, before the first study drug dose and through the duration of study drug treatment.  
• Use of chronic (>30 days) oral corticosteroids for a non-COVID-19-related condition in a 
dose higher than prednisone 10 mg or equivalent per day. 
• Use of immunosuppressive medications/immunotherapy including but not limited to 
sarilumab and tocilizumab. 
• Off-label use of commercially-available medications for the treatment of SARS-CoV-2. 
All other concomitant medications and procedures (including remdesivir) are allowed. 


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Concomitant medications, including supplemental oxygen, are to be recorded in the source 
documents and in the eCRF.  
7.1.6.2. 
Contraception 
Female patients of childbearing potential must be non-pregnant and non-lactating, and have a 
negative urine pregnancy test at Screening.  
Male patients who are not surgically sterilized and female patients of childbearing potential are 
required to use adequate contraception from first entry into the clinical research center until 
30 days after the last follow-up visit. Male patients who are not surgically sterilized are required 
to use condoms. Adequate contraception for females of childbearing potential is defined as using 
hormonal contraceptives, levonorgestrel implants, injectable progestogen, or an intrauterine 
device combined with at least 1 of the following forms of barrier contraception: a diaphragm or 
cervical cap, or a condom.  
Total abstinence, in accordance with the lifestyle of the patient, is acceptable. 
7.1.7. 
Treatment Compliance 
Study drug will be administered at the study center. To ensure treatment compliance, 
administration of the study drug will be supervised by the Investigator or authorized designee. 
Compliance will be further confirmed by bioanalytical assessment of ATYR1923 in serum 
samples (see Section 8.4). 


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8. 
STUDY VISITS AND ASSESSMENTS 
8.1. 
Schedule of Assessments 
The Schedule of Assessments is presented in Table 1. 
8.2. 
Screening and Baseline Measurements 
8.2.1. 
Informed Consent 
All patients or their designated legal representatives must provide informed consent, based on 
local age of majority, before any samples are collected or evaluations performed in this study 
that are not part of standard patient care.  
8.2.2. 
Demographics 
Patient demographics, including age, sex, and race, are to be documented during Screening. 
8.2.3. 
Medical History and History of COVID-19 Symptoms 
A complete medical history, including respiratory history, is to be documented during Screening. 
Smoking history of use of any inhalation products (eg, nicotine-containing products including e-
cigarettes or e-vaporizers) is to be documented. 
COVID-19 symptom history is to include date of onset of symptoms, list of symptoms (eg, fever, 
fatigue cough [with or without sputum production], anorexia, malaise, muscle pain, sore throat, 
dyspnea, nasal congestion, headache, diarrhea, nausea, vomiting, pneumonia, loss of taste and/or 
smell), and radiological test results.  
The date of initial SARS-CoV-2 positivity also is to be documented, if available.  
8.2.4. 
SARS-CoV-2 Testing 
Confirmation of SARS-CoV-2 infection by PCR is to be performed during Screening. However, 
if the test was performed at the study center/institution within 7 days before Day 1 and results are 
available in the medical record, then this test may be used as the confirmatory screening test. If 
the SARs-CoV-2 test results are older than 7 days from Day 1 or the test was performed at a 
different location, a repeat test is to be performed. 
After Screening, nasopharyngeal swab results are to be recorded in the eCRF per SOC until 
discharge. If quantitative testing is performed, the results also are to be recorded in the eCRF. 
8.2.5. 
Serology 
A blood sample for serology, including HIV1 and 2, HBsAg, and anti-HCV, is to be collected 
during Screening within 7 days before Day 1 and tested locally. If serology is positive for HCV, 
the Investigator may elect to measure HCV ribonucleic acid to confirm the absence of infection.  
Patients with positive results are not eligible for study participation.  


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8.2.6. 
Height and Weight 
Height is to be documented during Screening; height may be documented via patient report. 
Weight is to be measured within 3 days predose; weight is to be used to calculate the study drug 
dose.  
If there is a weight change >10% between Day -3 and Day 1, the dose should be recalculated. 
8.3. 
Efficacy and Exploratory Assessments 
8.3.1. 
Hospitalization Status 
The date, time and reason of initial hospitalization and discharge are to be documented in the 
eCRF. During hospitalization, the date and time of any change in the patient’s hospitalization 
status, specifically admittance and discharge to the intensive care unit are also to be recorded. If, 
in the Investigator’s opinion, the patient required a higher level of care (ie, admittance to the 
intensive care unit) but did not receive due to resource availability, this should be documented.  
8.3.2. 
WHO Ordinal Scale of Clinical Status 
The patient’s clinical status is to be assessed using the WHO Ordinal Scale (see Appendix 1) at 
the time points designated in Table 1. The WHO Ordinal Scale score is to be determined 
between 06:00 and 10:00 hours each day, or per local SOC, and the score closest to 8:00 hours 
recorded.  
The date and time of any change in the components of clinical status are to be documented in the 
patient’s eCRF, including: 
• Change in ambulatory status. 
• Requirement for oxygen (yes/no), and if yes, method of oxygenation (mask/nasal prongs, 
non-invasive ventilation, or high-flow oxygen; intubation and mechanical ventilation). 
The volume of oxygen administered is to be captured as a concomitant medication (see 
Section 7.1.6). If, in the Investigator’s opinion, a patient required a higher level of 
oxygenation, but did not receive due to resource availability, this should be documented. 
8.3.3. 
Pulse Oximetry 
To assess eligibility, one measurement of SpO2 without supplemental oxygen should be 
attempted. If not clinically feasible, obtain the measurement with supplemental oxygen. The 
corresponding level of supplemental O2 use is to be recorded in the eCRF at screening to confirm 
eligibility. 
On Day 1, SpO2 readings will be recorded pre-dose then at 1 and 4 hours (±15 minutes) after the 
start of infusion (SOI). 
After Day 1, SpO2 is to be measured per SOC and recorded in the eCRF, as per Table 1.  


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8.3.4. 
Vital Signs and Temperature 
Vital signs include blood pressure, heart rate, and respiration rate, and temperature. 
Day1 vital signs are to be obtained pre-infusion and at 15 and 30 minutes (±5 minutes) and at 1, 
2, and 4 hours (±15 minutes) after the start of infusion (SOI). Vital signs will include blood 
pressure (systolic and diastolic), heart rate, and respiratory rate, recorded after resting for 5 min. 
After Day 1, temperature and vital signs are to be measured per SOC and recorded in the eCRF, 
as per Table 1. 
8.4. 
Pharmacokinetic Measurements and Variables 
At the time points defined in the Schedule of Assessments (Table 1), blood samples will be taken 
for the PK analysis of ATYR1923 in serum samples and analyzed at a central laboratory. The 
exact times of blood sampling will be recorded in the eCRF.  
Details on sample collection, handling, storage and shipping of blood samples for PK analysis of 
ATYR1923 will be described in the Laboratory Manual. 
8.5. 
Pharmacodynamic/Exploratory Measurements and Variables 
8.5.1. 
Blood for Cytokines/Chemokines 
Blood samples for the analysis of cytokines/chemokines, including C-reactive protein, INF-γ, IL-
6, IL-2, IL-7, IL-10, TNFα, MIP1, CXC-10, and MCP-1 will be taken at the time points 
designated in Table 1 and analyzed at a Central Laboratory. 
Details on sample collection, handling, storage and shipping of blood samples for 
cytokines/chemokines analysis will be described in the Laboratory Manual.  
8.6. 
Safety and Tolerability Measurements 
Safety assessments will be performed in accordance with the Schedule of Assessments. 
8.6.1. 
Physical Examination 
If performed at the study center/institution within 7 days before Day 1 and results are available in 
the medical record, any abnormal physical examination findings are to be documented in the 
eCRF. Any abnormal physical examination findings from examinations performed per SOC 
through discharge are to be recorded in the eCRF.   
Respiratory findings supportive of severe respiratory distress, if present, are to be documented on 
the Physical Examination eCRF if not otherwise captured as part of the patients recent 
COVID-19-related medical history. 
8.6.2. 
Immunogenicity Measurements 
Blood samples for determination of Jo-1 Ab levels in serum will be collected at the time points 
designated in Table 1 and processed at the local laboratory. Any patient who develops positive 
Jo-1 antibodies will be monitored clinically for signs/symptoms of anti-synthetase syndrome. 


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Blood samples for determination of ADAs against ATYR1923 in serum will be collected at the 
time points designated in Table 1 and analyzed at a central laboratory.  
In addition, blood samples for ADAs and Jo-1 Ab levels in serum will be repeated if the patient 
experiences a suspected IRR or anaphylaxis per Section 9.9. 
Blood samples will be collected and processed as described in the Laboratory Manual. The exact 
times of blood sampling will be recorded in the eCRF. 
8.6.3. 
Adverse Events 
AEs will be recorded from the time of initiation of study drug administration through the last 
visit for a patient. Any clinically significant observations in results of clinical laboratory, 12-lead 
electrocardiograms (ECGs) (if performed per SOC), vital signs, pulse oximetry, or physical 
examinations are to be recorded as part of the patient’s medical history if occurring prior to start 
of dosing and as an AE if occurring after the start of study drug administration at Day 1, where 
the finding represents a change from Baseline. 
A TEAE is defined as any event not present prior to (the first) administration of the study drug or 
any event already present that worsens in either intensity or frequency following exposure to the 
study drug.  
An AE which occurs prior to (the first) administration of the study drug will be considered a pre-
treatment AE. 
AEs that occur during or within 24 hours after study drug injection should be captured as 
individual signs and symptoms (eg, dyspnea, rash, flushing) rather than a diagnosis of allergic 
reaction or IRR.  
Patients will be asked non-leading questions and evaluated to determine the occurrence of AEs. 
All AEs reported or observed spontaneously during the course of the study will be recorded. 
The intensity of each AE will be rated by the Investigator using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 (available at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf).  
AEs not listed on the NCI CTCAE V5.0 are to be rated by the Investigator as “mild (Grade 1)”, 
“moderate (Grade 2)”, “severe” (Grade 3), “life-threatening”(Grade 4), or “fatal” (Grade 5).  
The relationship between the AEs and the study drug will be indicated as “not related”, “unlikely 
related”, “possibly related”, or “related”. AEs assessed as “possibly related” or “related” will be 
considered to be related to the study drug whereas AEs assessed as “not related” or “unlikely 
related” will be considered not to be related to the study drug.  
Details on the rating of the severity of the AEs and relationship to the study treatment are given 
in Section 9.2. 


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8.6.3.1. 
Infections 
Any new infections are to be documented as AEs. The new infection site and source of culture 
are to be recorded in the eCRF. 
8.6.4. 
Concomitant Medications 
Medications that are ongoing at Screening are to be documented. Furthermore, all medications 
and supplements, including supplemental oxygen, the patient receives during their course of 
hospitalization as part of their standard of care as well as during the study are to be documented 
in the source documents and in the eCRF. 
8.6.5. 
Safety Laboratory Tests 
Blood and urine samples for clinical safety laboratory assessments will be collected at the time 
points designated in Table 1 at Screening and Day 1. After Day 1, clinical safety laboratory 
assessments are to be collected per SOC. Note that if screening safety laboratory assessments are 
performed within 2 days of Day 1, then the pre-dose Day 1 safety laboratory assessments need not be 
repeated.  
These samples will be analyzed at the local laboratory following their laboratory standard 
operating procedures (SOPs). 
The following parameters may be collected and documented in the eCRF, as available per SOC: 
• Clinical chemistry (serum quantitatively): 
• Total bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), lactate dehydrogenase (LDH), creatine phosphokinase, albumin, 
creatinine, blood urea nitrogen, total protein, glucose, , sodium, potassium, calcium and 
chloride,.  
• Hematology (blood quantitatively): 
- 
Leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes, partial automated 
differentiation (lymphocytes, monocytes, eosinophils, basophils, neutrophils), mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration 
• Coagulation (blood quantitatively): 
- 
Prothrombin time (reported in seconds and as international normalized ratio) and 
partial thromboplastin time 
• Urinalysis (semi-quantitative by dipstick): 
- 
Hemoglobin, urobilinogen, ketones, glucose, protein 
- 
Microscopy is to be performed if indicated by an abnormal and clinically significant 
result. Culture results, if conducted per SOC, are to be documented. 


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• Cardiac troponins, ferritin, B-type natriuretic peptide (BNP) or N-terminal-pro-BNP, and 
D-dimer. 
In case of unexplained or unexpected clinical laboratory test values, the tests will be repeated as 
soon as possible and followed up until the results have returned to the normal range, baseline 
level and/or an adequate explanation for the abnormality is found. The clinical laboratory will 
clearly mark all laboratory test values that are outside the normal range and the Investigator will 
indicate which of these deviations are clinically significant. These clinically significant deviating 
laboratory results will then be recorded as AEs and the relationship to the treatment will be 
indicated (see also Section 9.2).  
8.6.6. 
Radiographic Studies and Electrocardiograms 
A radiologic study performed within 7 days prior to Day 1 is acceptable to determine study 
eligibility. If the radiologic study was performed >7 days before Day 1, a repeat radiologic study 
is to be performed during Screening. 
An ECG is to be collected during Screening if it was performed per SOC. 
Findings from any radiographic studies or ECGs performed during inpatient hospitalization are 
to be recorded in the eCRF. Radiographic images may be collected and may be submitted to a 
central reader for review. 
8.6.7. 
Pregnancy Testing 
Female patients of childbearing potential must have a urine pregnancy test performed during 
Screening. Any patient with a positive pregnancy test result is not eligible for study participation. 
Pregnancy test results are to be obtained and confirmed to be negative prior to randomization and 
study drug infusion. 
8.6.8. 
Appropriateness of Measurements 
The assessments, which will be made in this study are standard, and generally recognized as 
reliable, accurate, and relevant. Efficacy assessments are consistent with the WHO, COVID-19 
Therapeutic Trial Synopsis. 


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9. 
ADVERSE EVENTS 
9.1. 
Definitions 
9.1.1. 
Adverse Event 
An AE is defined in the ICH Guideline for GCP as “any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment” (ICH E6:1.2). 
Worsening of a pre-existing medical condition, (ie, diabetes, migraine headaches, gout) is to 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. 
Interventions for pretreatment conditions (ie, elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered AEs. 
In the case of death, only record “Fatal” for the event causing death. AEs that are ongoing at the 
end of the study or time of death are to be noted as “continuing.”  
The Investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual patient represents a significant change from baseline. In general, 
abnormal laboratory findings without clinical significance (based on the Investigator’s judgment) 
should not be recorded as AEs; however, laboratory value changes requiring therapy or 
adjustment in prior therapy are considered AEs. 
9.1.2. 
Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of Investigational New Drug Application (IND) safety 
reporting, “reasonable possibility” and/or at least possibly related means there is evidence to 
suggest a causal relationship between the drug 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 drug. 
9.1.3. 
Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• is fatal. 
For the purposes of this study, death due to SARS-CoV2 infection is not considered an 
SAE. 
• is life-threatening (ie, places the patient at immediate risk of death). 


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• requires in-patient hospitalization (overnight stay) or prolongation of existing 
hospitalization. 
As all patients are required to be hospitalized as inpatients to be eligible for this study, 
any event other than SARS-CoV2 infection requiring prolonging of inpatient 
hospitalization and/or rehospitalization after discharge will be considered an SAE. 
Hospitalization due to SARS-CoV2 infection is not considered an SAE, provided that it 
did not deteriorate in an unexpected manner during the study. 
• results in persistent or significant disability/incapacity. 
• is a congenital anomaly/birth defect. 
• is an important medical event; an important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
9.1.4. 
Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or intensity that has been previously 
observed; or, if an Investigator’s Brochure is not required or available, is not consistent with the 
risk information described in the General Investigational Plan or elsewhere in the current 
application, as amended.  
9.1.5. 
Serious and Unexpected Suspected Adverse Reaction 
A SUSAR is any event that meets all 3 of the following definitions: 
1) suspected adverse reaction (Section 9.1.2); 
2) serious (Section 9.1.3); and  
3) unexpected (Section 9.1.4). 
9.2. 
Adverse Event Assessment 
All AEs will be collected and recorded in this study from the time of initiation of study drug 
administration through the last visit for a patient. This includes AEs the patient reports 
spontaneously, those observed by the Investigator, and those elicited by the Investigator in 
response to open-ended questions during scheduled study center visits. 
AEs that occur during or within 24 hours after study drug infusion are to be captured as 
individual signs and symptoms rather than a diagnosis of allergic reaction or IRR. 


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Each AE is to be assessed by the Investigator with regard to the following categories. 
9.2.1. 
Serious/Non-Serious 
AEs that meet the criteria specified in Section 9.1.3 are to be considered serious. 
9.2.2. 
Relationship to Study Drug 
This determination is based on the Investigator’s clinical judgment regarding the likelihood that 
the study drug caused the AE and may include consideration of some or all of the following 
factors:  
• Alternative possible causes of the AE, including the patient’s underlying disease or 
co-morbid conditions, other drugs, other host and environmental factors; 
• The chronological relationship between the exposure to study drug and the AE;  
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or toxicity of the study drug;  
• Whether the AE resolved or improved with decreasing the dose or stopping the study 
drug (ie, dechallenge);  
Whether the AE recurred or worsened with re-exposure to the drug (ie, rechallenge).  
The relationship between the study drug and the AE will be described using one of the following 
categories Table 2. 
Table 2: 
Criteria for Determination of Adverse Event Relationship to Study Drug 
Relationship 
Definition 
Related  
The study drug is more likely the cause of the AE than other factors 
Possibly Related 
There is a reasonable possibility that the study drug is the cause of the AE, 
including that the study drug and another factor(s) are equally likely as causes 
of the AE 
Unlikely Related  
Another factor is considered more likely the cause of the AE than the study 
drug 
Not related  
Another factor is considered to be the cause of the AE 
 


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9.2.3. 
Relationship to SARS-CoV2 infection: 
The relationship between each AE and SARS-CoV2 infection (related/unrelated) is to be 
documented. 
9.2.4. 
Intensity 
The intensity of each AE is to be assessed by the Investigator using the NCI CTCAE, version 5.0 
(available at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf).  
AEs not listed on the NCI CTCAE V5.0 are to be rated by the Investigator according to the 
categories in Table 3. 
Table 3: 
Criteria for Determination of Adverse Event Intensity 
Intensity 
Definition 
Mild (Grade 1):  
Asymptomatic or mild symptoms: clinical or diagnostic observations only; 
intervention not indicated. 
Moderate (Grade 2) 
Minimal, local, or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
Severe (Grade 3):  
Severe or medically significant but not immediately life threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living; incapacitating with inability to work or 
perform normal daily activity. 
Life-threatening (Grade 4):  
Consequences: urgent intervention indicated. 
Fatal (Grade 5) 
AE resulted in death 
 


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9.2.5. 
Outcome 
The outcome of each AE will be described using the categories in Table 4. 
Table 4: 
Criteria for Determination of Adverse Event Outcome 
Outcome 
Definition 
Resolved without sequelae: 
The event resolved and patient returned to baseline 
Resolved with sequelae: 
The event resolved but the patient is left with residual problems (eg, 
functional deficits, pain) 
Resolving 
At the last observation, the event was improving 
Not Resolved 
At the last observation, the event was unchanged 
Death (Fatal) 
To be used for the one AE which, in the judgment of the Investigator, was the 
primary cause of death 
Unknown 
There were no observations after the onset (initial observation or report) of the 
event 
 
9.2.6. 
Study Drug Action 
For each AE, the Investigator will indicate the action taken regarding the administration of study 
drug per the categories in Table 5. 
Table 5: 
Study Drug Action Taken as a Result of Adverse Events 
Action 
Definition 
Discontinued (withdrawn) 
Study drug was stopped permanently due to the AE 
Dosing Interrupted 
Study drug regimen was modified by being temporarily halted, but drug was 
not stopped permanently 
Dose Decreased 
Study drug regimen was modified by subtraction, ie, by decreasing the 
strength or amount 
Dose Increased 
Study drug regimen was modified by addition, ie, by increasing the strength or 
amount 
None 
No change in the administration of study drug 
 
9.3. 
Recording Adverse Events 
All AEs occurring from the time of initiation of study drug administration through the last 
follow-up visit, or after the end of the study, if thought to be related to study drug, are to be 
recorded in the source documents and in the eCRF. All AE reports are to contain the following 
details regarding the AE:  a brief description, onset date and time, resolution date and time, 
intensity, treatment required, relationship to study drug, action taken with study drug, outcome, 
and whether the event is classified as serious. 


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AEs that occur during or within 24 hours after study drug injection should be captured as 
individual signs and symptoms (eg, dyspnea, rash, flushing) rather than a diagnosis of allergic 
reaction or IRR.  
9.4. 
Reporting Serious Adverse Events 
SAEs will be collected and recorded throughout the study period, beginning with the signing of 
the informed consent form (ICF) through the last follow-up visit, or after the end of the study if 
thought to be related to study drug. 
The Investigator must report all SAEs within 24 hours of discovery to the Contract Research 
Organization (CRO) Safety Team. 
SAE reporting, including supporting materials, will be performed by the study center personnel 
using a system approved by the Sponsor. Detailed training will be provided by the CRO. Contact 
information for guidance and assistance with SAE reporting is provided in the Study Reference 
Manual. A completed SAE report is to be entered into the system approved by the Sponsor 
within 24 hours of discovering the event. Upon entry into the system, the responsible parties 
(including Medical Monitor and Safety Reporting Specialist) will be immediately notified. 
The Study Reference Manual will include an emergency back-up paper based reporting system, 
to be used if needed. 
The CRO Safety Team will immediately (within one business day of receipt) forward the SAE 
report to the Sponsor. The initial report should include at least the following information:  
• Patient’s identification number; 
• Description and date of the event; 
• Criterion for serious; and 
• Preliminary assignment of causality to study drug.  
The Medical Monitor may contact the Investigator via telephone for urgent follow-up 
information regarding the SAE, as appropriate. 
The Investigator, or designated party, should notify the appropriate IRB of SAEs occurring at the 
study center and other AE reports received from aTyr, in accordance with local procedures and 
statutes. 
SAEs that are considered as possibly or definitely related to the investigational product, and as 
unexpected (ie, SUSARs), will be reported to the National Regulatory Authority(ies) and IRB by 
the Sponsor or Sponsor’s designee as required by applicable local regulations. Per regulation, 
any fatal or life-threatening SUSAR will be reported to the National Regulatory 
Authority(ies)/IRB within 7 calendar days, and additional information within an additional 
8 calendar days. The Sponsor or Sponsor’s designee is required to submit any other SUSAR to 
the National Regulatory Authority(ies)/IRB within 15 calendar days of notification. The Sponsor 
or its designee is also responsible for notifying the investigational sites of all expedited SAEs, in 


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accordance with local requirements. The Investigator must keep copies of all expedited SAE 
information including correspondence with the Sponsor on file.  
9.5. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all study drug-related TEAEs either until resolution or 
the Investigator assesses them as chronic or stable. This follow-up may extend after the end of 
the study and may be conducted by telephone contact or unscheduled visit. 
9.6. 
Reporting Safety Information 
The Investigator must promptly report to his or her IRB all unanticipated problems involving 
risks to patients, in accordance with local requirements. This may include death from any cause 
and all SAEs reasonably or possibly associated with the use of study drug according to the IRB’s 
procedures.  
9.7. 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and only in 
the event of an emergency. The Investigator or other physician in attendance in such an 
emergency must contact the Medical Monitor as soon as possible to discuss the circumstances of 
the emergency. 
The Medical Monitor, in conjunction with the Investigator, will decide whether the patient 
should continue to participate in the study. All protocol deviations and reasons for such 
deviations must be noted in the eCRF. 
9.8. 
Pregnancy 
Pregnancies occurring while the patient is receiving study drug or within 30 days after the 
patient’s last dose of ATYR1923 will not be considered serious, but are to be reported using the 
same procedures as for SAEs described in Section 9.4. 
In the event of a pregnancy, the patient should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the patient until completion of the pregnancy, and must notify the 
Medical Monitor of the outcome within 5 days. The Investigator will provide this information as 
a follow-up to the initial report. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should report it as such. 
Furthermore, all neonatal deaths that occur within 30 days of birth are to be reported, without 
regard to causality, as SAEs. In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to the study drug should also be reported. 


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9.9. 
Management of Potential Infusion Related Reactions, Including 
Anaphylaxis 
ATYR1923 is a biologic and as with all biologics there is a risk for IRRs. These reactions 
typically occur in close temporal relationship with the infusion. They may be related to cytokine 
release or immune mediated.  
A generalized IRR could be occurring when any symptoms begin during the study drug infusion 
or during the post-infusion observation period. While these symptoms may be self-limiting, such 
symptoms may signal the possibility of a severe reaction that could escalate into a life-
threatening situation.  
Should a patient develop an IRR the subsequent management will depend on the nature of the 
IRR. Where the IRR symptoms are not cardiorespiratory in nature i.e. they comprise cutaneous 
rash, flushing, burning sensation etc. and are mild to moderate in intensity – the patient may 
complete the infusion and receive subsequent doses. The patient will need to be observed until 
all symptoms resolve or for 6 hours after the end of the infusion.  
If the IRR symptoms constitute a cardiorespiratory risk (hypotension, dyspnea, hypoxia etc.) or 
any severe AE then all further dosing should be stopped for the patient. If necessary, the patient 
should be transferred to an acute care facility.  
Vital signs, pulse oximetry, and ECGs are to be performed to gather clinical information as soon 
as possible after the onset of clinical symptoms of a generalized IRR (for instance, immediately 
after cessation of the study drug infusion if such a reaction is seen) and monitored as medically 
indicated. ECGs should be repeated as medically indicated. 
The following tests and procedures are to be performed 1 to 2 hours after the onset of symptoms: 
• ATYR1923 serum concentrations. 
• Jo-1 and ADA. 
• Tryptase. 
• Complete safety laboratory panel, including urine analysis and urine microscopy. 
• Cytokines/chemokines. 
The Investigator must inform the study Medical Monitor promptly regarding any patient who 
experiences a generalized IRR for additional instruction. 
Patients who experience generalized IRRs will continue to be monitored / have repeat 
assessments performed at a schedule determined by the Investigator in consultation with the 
Medical Monitor and Sponsor. Appropriate follow up for the patient must occur to ensure that 
there are no late-occurring sequelae. 
Note that in the eCRF, AEs that occur during or within 24 hours after study drug injection should 
be captured as individual signs and symptoms rather than a diagnosis of allergic reaction or IRR.  


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9.9.1. 
Anaphylaxis 
IRRs meeting the definition of anaphylaxis are to be reported in the eCRF as such (Sampson et 
al., 2006):   
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula). 
And at least one of the following: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia). 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence). 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula). 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia). 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence). 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting). 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours): 
a. Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease in systolic blood pressure*. 
b. Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease 
from that person’s baseline. 
Patients who experience anaphylaxis are to be managed as described in Section 9.9. 


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10. 
STATISTICAL ANALYSES 
10.1. 
Statistical Procedures and Determination of Sample Size 
10.1.1. 
Analysis Sets 
10.1.1.1. 
Intent-to-Treat Set 
The Modified Intent-to-treat Set will comprise all patients randomized who have received any 
amount of study drug. Patients will be analyzed as randomized. 
10.1.1.2. 
Safety Set 
The Safety Set will comprise all patients who have received any amount of study drug. Patients 
will be analyzed as treated. 
10.1.2. 
Statistical and Analytical Plan for Pharmacokinetic, Pharmacodynamic, Safety 
and Exploratory Evaluation 
A Statistical Analysis Plan (SAP) will be generated by the CRO Biostatistics Department; the 
SAP will be finalized prior to database lock or interim analysis if applicable and subsequent 
unblinding of study treatment codes. Full details of the analysis to be performed will be included 
in the SAP. 
Any deviation from the SAP will be reported in the section “Changes in Planned Analysis” in the 
CSR. 
10.1.2.1. 
Pharmacokinetic Evaluation 
The PK parameters and their statistical evaluation will be included in the Clinical Study Report 
(CSR) for this study. 
All data will be summarized using descriptive statistics and will be listed and summarized in 
tabular and/or graphical form. Any additional analyses will be specified in the SAP. 
10.1.2.2. 
Efficacy Evaluation 
The efficacy parameters and their statistical evaluation will be included in the CSR of this study. 
All data will be summarized using descriptive statistics and will be listed and summarized in 
tabular and/or graphical form. 
10.1.2.3. 
Evaluation of Safety and Tolerability 
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, ECGs and 
physical examination findings, and any other parameter that is relevant for safety assessment. 


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10.1.2.3.1. Adverse Events 
A listing of all individual AEs will be provided. Summary tables of TEAEs will be presented by 
system organ class based on the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology list (preferred terms): 1 containing the number of TEAEs (frequency of occurrence, 
number of patients experiencing the event) by treatment and 1 containing the number of 
drug-related TEAEs (frequency of occurrence, number of patients experiencing the event) per 
treatment. Additional tables of total counts by treatment and relationship and by treatment and 
intensity will be given. 
10.1.2.3.2. Clinical Laboratory 
Clinical laboratory data will be listed, and will also be flagged if the parameter is outside the 
reference range. A summary of all data outside the reference range of the clinical laboratory will 
be provided. Clinical laboratory data will be presented descriptively, where applicable. 
10.1.2.3.3. Immunogenicity 
The presence of ADAs and Jo-1 antibodies in serum will be listed and presented descriptively, 
where applicable. 
10.1.2.4. 
Evaluation of Efficacy and Exploratory Variables 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). Categorical variables will be summarized showing 
the number and percentage (n, %) of patients within each classification. Details regarding 
efficacy and exploratory analyses, including the handling of missing variables, will be detailed in 
the SAP. 
10.1.3. 
Determination of Sample Size 
For this study, no prospective calculations of statistical power have been made. The sample size 
has been selected to provide information on safety, tolerability, PK and efficacy following single 
doses of ATYR1923. Any p-values to be calculated according to the SAP will be interpreted in 
the perspective of the explorative character of this study. 
10.2. 
Data Quality Assurance 
The study may be audited to assess adherence to the clinical study protocol and Quality System. 
During the conduct of the study, process-related audits may be performed. An audit certificate 
will be provided in the appendices of the final CSR outlining any audits and other related 
activities performed.  
The clinical research site will be monitored by the study monitor to ensure correct performance 
of the study procedures and assure that the study will be conducted according to the relevant 


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regulatory requirements. The eCRF entries will be verified with the source documentation, if 
applicable (in some cases there are no source pages, therefore verification is not necessary). 
Regulatory authorities, the IRB and/or the Sponsor’s clinical quality assurance group may 
request access to all source documents, eCRFs, and other study documentation for on-site audit 
or inspection. Direct access to these documents must be guaranteed by the Investigator, who 
must provide support at all times for these activities. 
Quality control principles will be applied throughout the performance of this study. Review 
procedures will be followed by the Sponsor and designees for all documents that are generated in 
relation with the study. Essential study activities of personnel will be checked by colleagues 
during execution, and each of them will sign off the documentation for execution or checking of 
the activities. 
An explanation will be given for all missing, unused and spurious data in the relevant sections of 
the CSR. 
10.2.1. 
Interim Analyses 
Details of any interim analyses will be provided in the SAP. 
10.3. 
Changes to the Planned Statistical Methods 
Changes to the planned statistical methods will be documented in the CSR. 


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11. 
ETHICAL, LEGAL, AND ADMINISTRATIVE 
CONSIDERATIONS 
11.1. 
Good Clinical Practice 
This study will be conducted according to the protocol and in compliance with ICH GCP, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory 
requirements. 
The Investigator confirms this by signing the protocol. 
11.2. 
Informed Consent 
Informed consent, based on age of majority, in compliance with 21 Code of Federal Regulations 
§ 50 and/or ICH regulations will be obtained from each patient or their designated legal 
representative prior to undergoing any protocol-specific tests or procedures that are not part of 
routine care. 
The Sponsor or designee will provide an ICF template to the Investigator for use in developing a 
study center-specific consent document. Prior to submission of the study center-specific ICF 
form to the IRB, these documents must be reviewed and approved by the Sponsor or designee. 
Any changes requested by the IRB must also be approved by the Sponsor or designee. The final 
IRB-approved ICF must be provided to the Sponsor or designee. Revisions to the ICF required 
during the study must be approved by the Sponsor or designee, and a copy of the revised ICF 
provided to the Sponsor or designee. 
Before recruitment and enrollment, each prospective patient or their designated legal 
representative will be given a full explanation of the study and be allowed to read the ICF in a 
language they understand. After the Investigator or designee is assured that the patient/patient’s 
designated legal representative understands the commitments of participating in the study, the 
patient/patient’s designated legal representative, as appropriate, will be asked to provide consent.  
If able, a signed and dated ICF will be maintained in the patient’s medical record. However, due 
to the nature of SARS-CoV-2 infection, specific site informed consent policies will be followed 
and a physical copy of the signed consent form may not be retained.  
11.3. 
Institutional Review Board/Independent Ethics Committee 
Federal regulations and ICH require that approval be obtained from an IRB prior to participation 
of patients in research studies. Prior to the study onset, the protocol, any protocol amendments, 
ICFs, advertisements to be used for patient recruitment and any other written information 
regarding this study to be provided to a patient must be approved by the IRB. 
All IRB approvals must be dated and signed by the IRB Chairperson or designee and must 
identify the IRB by name and address, the clinical protocol by title and/or protocol number, and 
the date approval or favorable opinion was granted for the clinical research. 


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No drug will be released to the site to dose a patient until written IRB authorization has been 
received by the Sponsor or designee. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB. The Investigator must supply the Sponsor or 
designee with written documentation of the approval of the continued clinical research. 
The Investigator, sponsor, or designee as applicable, will make all attempts to ensure that the 
IRB is constituted and operates in accordance with Federal and ICH GCP and any local 
regulations. 
11.4. 
Amending the Protocol 
Any changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor or designee and the IRB that 
approved the study. Amendments to the protocol must be submitted in writing to the 
Investigator’s IRB for approval prior to patients being enrolled into the amended protocol. 
The Sponsor may make administrative changes (ie, changes that do not significantly affect 
patient safety or the study’s scope or scientific quality) without any further approvals.  
All amendments will be distributed to all protocol recipients. 
11.5. 
Confidentiality/Data Protection 
All study findings and documents will be regarded as confidential. The Investigator and other 
study personnel must not disclose such information without prior written approval from the 
Sponsor. 
Patients will be assigned a unique identifier by the Sponsor. Any participant records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information which would make the participant identifiable will not be transferred. 
The patient 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 patient. 
The patient 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 
members, and by inspectors from regulatory authorities. 
11.6. 
Publication Policy 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. The initial planned publication will be 
a multi-center report of the study outcome. Additional publications from a given center can only 
occur after the publication of the multi-center results. A prepublication manuscript is to be 
provided to the Sponsor at least 30 days prior to the submission of the manuscript to a publisher. 


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Similarly, the Sponsor will provide any company-prepared manuscript to the Investigators for 
review at least 30 days prior to submission to a publisher. 


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12. 
STUDY MANAGEMENT 
12.1. 
Data Quality Assurance 
 The Sponsor or its designated legal representative will conduct a study center visit to verify the 
qualifications of each Investigator, inspect study center facilities, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
12.2. 
Case Report Forms and Source Documentation 
The Investigator and designees agree to maintain accurate eCRFs and source documentation as 
part of case histories. Source documents are the originals of any documents used by the 
Investigator or subinvestigator or hospital/institution that allow verification of the existence of 
the patient and substantiate the integrity of the data collected during the study. 
The Sponsor or designee will provide eCRF access to the study center. eCRFs will be completed 
for each patient. It is the Investigator’s responsibility to ensure the accuracy, completeness, and 
timeliness of the data reported in the patient’s eCRF. Source documentation supporting the eCRF 
data should indicate the patient’s participation in the study and should document the dates and 
details of informed consent, study procedures, AEs, and patient status.  
The Investigator, or designated legal representative, should complete the eCRF as soon as 
possible after information is collected / data are available, preferably on the same day that a 
patient is seen for an examination, treatment, or any other study procedure. Any outstanding 
entries must be completed immediately after the final examination. An explanation should be 
given for all missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the eCRF to 
endorse the recorded data.  
12.3. 
Monitoring 
A clinical research associate (CRA) or other representative of the Sponsor or designee will verify 
the qualifications of each Investigator, confirm the appropriateness of study center facilities, and 
inform the Investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
During the course of the study, the CRA will review protocol compliance, compare eCRFs and 
individual patient medical records, assess drug accountability, and ensure that the study is being 
conducted according to pertinent regulatory requirements in respect to GCP. eCRFs will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. 
12.4. 
Inspections 
Regulatory authorities and/or quality assurance personnel from the Sponsor or its designated 
representative may wish to carry out such source data checks and/or in-center audit inspections. 
The Investigator assures the Sponsor of the necessary support at all times. In the event of an 


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audit, the Investigator agrees to allow the Sponsor’s representatives and any regulatory agencies 
access to all study records. 
12.5. 
Financial Disclosure Reporting Obligations 
Investigators and subinvestigators are required to provide financial disclosure information to the 
sponsor to permit the sponsor to fulfill its regulatory obligation. Investigators and 
subinvestigators must commit to promptly updating the information if any relevant changes 
occur during the study and for a period of one year after the completion of the study. 
12.6. 
Archiving Study Records 
Essential documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. However, these documents should be 
retained for a longer period if required by the applicable local requirements. 
ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
 


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Version 5.0 
13. 
REFERENCES 
Burkart, C., Seikkula, M., Eide, L., Paz, S., Chu, D., Polizzi, C., . . . Ogilvie, K. (2019, 2019). 
ATYR1923 Modulates the Inflammatory Response in Experimental Models of Interstitial Lung 
Disease. 
ICH. (1998). Statistical Principles for Clinical Trials, E9. Federal Register 
Mertsching, E. C., Ampudia, J., Adams, R., Rosengren, S., Nangle, L., Mendlein, J., . . . King, D. 
(2018). Identification of a T cell immunomodulatory domain in histidyl-tRNA synthetase. In: 
Am Assoc Immnol. 
Roy, S., Bag, A. K., Singh, R. K., Talmadge, J. E., Batra, S. K., & Datta, K. (2017). Multifaceted 
Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy. Front 
Immunol, 8, 1228. doi:10.3389/fimmu.2017.01228 
Sampson, H. A., Muñoz-Furlong, A., Campbell, R. L., Adkinson Jr, N. F., Bock, S. A., Branum, 
A., . . . Galli, S. (2006). Second symposium on the definition and management of anaphylaxis: 
summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. Journal of Allergy Clinical Immunology, 117(2), 391-397.  
Schellenburg, S., Schulz, A., Poitz, D. M., & Muders, M. H. (2017). Role of neuropilin-2 in the 
immune system. Mol Immunol, 90, 239-244. doi:10.1016/j.molimm.2017.08.010 
Shi, H., Han, X., Jiang, N., Cao, Y., Alwalid, O., Gu, J., . . . Zheng, C. (2020). Radiological 
findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. The 
Lancet Infectious Diseases, 20(4), 425-434. doi:10.1016/s1473-3099(20)30086-4 
Wang, Z., Yang, B., Li, Q., Wen, L., & Zhang, R. (2020). Clinical Features of 69 Cases with 
Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. doi:10.1093/cid/ciaa272 
Zhou, Y., Fu, B., Zheng, X., Wang, D., Zhao, C., qi, Y., . . . Wei, H. (2020). Aberrant pathogenic 
GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome 
patients of a new coronavirus. bioRxiv, 2020.2002.2012.945576. doi:10.1101/2020.02.12.945576 


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14. 
APPENDICES 


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Appendix 1: WHO Ordinal Scale for Clinical Improvement 
 
Source:  WHO R&D Blueprint novel Coronavirus. COVID-19 Therapeutic Trial Synopsis.  
Available at:  https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf 
 

SAP_001.pdf: 
PAREXEL International 
aTyr Pharma, Inc 
ATYR1923-C-003  
   Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
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aTyr Pharma, Inc 
ATYR1923-C-003 
A Randomized Double-blind Placebo-controlled Study to Evaluate the Safety and Efficacy of 
ATYR1923 In Adult Patients With Severe Pneumonia Related To SARS-CoV-2 Infection 
(COVID-19) 
Statistical Analysis Plan 
Version: 3.0 
PAREXEL Project Number: 252361 
NCT #NCT04412668


PAREXEL International 
aTyr Pharma, Inc 
 
ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
Project Document Effective Date: Date of last signature 
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SPONSOR SIGNATURE PAGE 
 
Signature(s) below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signatory 
Approver 
 
Project Role: 
 aTyr Pharma, Inc. 
Approver 
 
Project Role: 
 aTyr Pharma, Inc. 


PAREXEL International 
aTyr Pharma, Inc 
 
ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 3 of 39 
 
 
 
PAREXEL SIGNATURE PAGE 
 
Signature(s) below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
 
 
 
Signatory 
Author 
 
Project Role:  Biostatistics Lead 


PAREXEL International 
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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
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Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
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Page 4 of 39 
 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ....................................................................................................... 9 
2 
STUDY OBJECTIVES ............................................................................................... 9 
2.1 
Primary .................................................................................................................... 9 
2.2 
Secondary ................................................................................................................ 9 
2.3 
Exploratory .............................................................................................................. 9 
3 
INVESTIGATIONAL PLAN ..................................................................................... 9 
3.1 
Overall Study Design and Plan ............................................................................... 9 
3.1.1 Hospitalized, Non-intubated Patients .................................................................... 10 
3.1.2 Hospitalized, Intubated Patients ............................................................................ 10 
3.1.3 Independent Data Safety Monitoring Board ......................................................... 11 
3.1.4 Determination of Sample Size .............................................................................. 11 
3.1.5 Planned Interim Analysis ...................................................................................... 11 
3.2 
Changes in the Conduct of Planned Analyses....................................................... 11 
3.3 
Final Database Lock .............................................................................................. 12 
3.4 
Endpoints .............................................................................................................. 12 
3.4.1 Primary .................................................................................................................. 12 
3.4.2 Secondary .............................................................................................................. 12 
3.4.3 Exploratory ............................................................................................................ 12 
4 
STATISTICAL METHODS ..................................................................................... 13 
4.1 
Data Quality Assurance......................................................................................... 13 
4.2 
General Presentation Considerations .................................................................... 13 
4.3 
Missing Data ......................................................................................................... 15 
4.3.1 Imputation of Non-Date Missing Data .................................................................. 15 
4.3.2 Imputation of Partial Dates ................................................................................... 16 
4.4 
Software ................................................................................................................ 17 
4.5 
Analysis Sets ......................................................................................................... 17 
4.6 
Study Patients ........................................................................................................ 18 
4.6.1 Disposition of Patients .......................................................................................... 18 
4.6.2 Protocol Deviations ............................................................................................... 18 
4.7 
Demographic and Other Baseline Characteristics................................................. 19 
4.8 
Concomitant Medications and Procedures ............................................................ 20 
4.9 
Efficacy Evaluation ............................................................................................... 21 
4.9.1 Differences from Interim Analysis........................................................................ 21 
4.9.2 Multiple Comparisons and Multiplicity ................................................................ 21 
4.9.3 Primary Efficacy Analyses .................................................................................... 21 
4.9.4 Key Secondary and Exploratory Efficacy Analyses ............................................. 21 
4.9.4.1 Secondary Efficacy Analyses ................................................................................ 22 
4.9.4.2 Exploratory Efficacy Analyses ............................................................................. 26 
4.9.4.2.1 Subgroup Secondary Efficacy Analyses ...........................................................27 
4.10 
Safety Evaluation .................................................................................................. 27 
4.10.1 Extent of Exposure ................................................................................................ 27 
4.10.2 Adverse Events...................................................................................................... 27 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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4.10.2.1 Adverse Event Summaries by System Organ Class and Preferred Term ......... 28 
4.10.2.2 Adverse Event Listings .................................................................................... 29 
4.10.3 Clinical Laboratory Evaluation ............................................................................. 29 
4.10.4 Vital Signs and Physical Findings ........................................................................ 31 
4.10.5 Electrocardiogram Measurements ......................................................................... 31 
4.11 
Other Analyses ...................................................................................................... 31 
4.11.1 Pharmacokinetics .................................................................................................. 31 
4.11.2 Immunogenicity .................................................................................................... 31 
4.11.3 Biomarker .............................................................................................................. 33 
5 
REFERENCES .......................................................................................................... 34 
6 
APPENDICES ........................................................................................................... 35 
6.1 
Schedule of Assessments ...................................................................................... 36 
6.2 
WHO Ordinal Scale for Clinical Improvement .................................................... 38 
6.3 
Urinalysis Grading Rules ...................................................................................... 39 
 


PAREXEL International 
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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Project Document Version No. 3.0 
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REVISION HISTORY 
 
 
Version No. 
Effective Date Summary of Change(s) 
1.0 
09 Dec 2020 
New document 
2.0 
05 Mar 2021 
Correction of typographic errors 
Post-unblinding Modifications after sponsor review: 
• New definition and analysis of Time to recovery with 
WHO scale score ≤ 3 without supplemental oxygen 
added, see Section 4.9.4.1 
• additional baseline categories, see Section 4.7 
• additional concomitant medication of special interest, 
see Section 4.8  
• Grading added for Urinalysis, see Section 6.3 
• Efficacy Evaluation Analysis Set added, see Section 
4.5  
3.0 
24 Mar 2021 
Minor Post-unblinding Modifications after sponsor review: 
• Update Time to recovery with WHO scale score ≤ 3 
without supplemental oxygen  
 
 
 


PAREXEL International 
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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
Ab 
Antibody 
ADA 
Anti-drug antibody 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BILI 
Total bilirubin 
BMI 
Body Mass Index 
BP 
Blood pressure 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CXC-10 
C-X-C motif chemokine 10 
DBP 
Diastolic blood pressure 
DILI 
Drug-induced liver injury 
DoD 
Day-of-Discharge 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
EOS 
End-of-Study 
ET 
Early Termination 
HR 
Heart rate 
IFN-γ 
Interferon gamma 
IL 
Interleukin 
ISOC 
Institutional standard of care 
ITT 
Intent-to-treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LOCF 
Last Observation Carried Forward 
MCP-1 
Monocyte chemoattractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIP-1 
Macrophage inflammatory protein-1 
MIP-1α 
Macrophage inflammatory protein-1 alpha 
MMRP 
Mixed Model with Repeated Measurements 
NRP2 
Neuropilin 2 
O2 
Oxygen 


PAREXEL International 
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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Abbreviation 
Definition 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOC 
System organ class 
SPO2 
Oxygen saturation 
TC 
Telephone contact 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, listings, and figures 
TNF-α 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 


PAREXEL International 
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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
TP-GDO-WW-016-07.a 
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Project Document Version No. 3.0 
Effective Date:  30 Jan 19 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a detailed description of the statistical methods and 
analyses to be carried out for the Clinical Study Report (CSR) in support for study ATYR1923-
C-003. 
The analyses described in this SAP are based upon the following study documents: 
• Study Protocol, Version 5.0 (dated 13 Nov 2020), 
• Electronic Case Report Form (eCRF) v5.0 (dated 15 Aug 2020). 
2 
STUDY OBJECTIVES 
2.1 
Primary 
• To assess the safety of a single intravenous (IV) dose of ATYR1923. 
2.2 
Secondary 
• To assess the preliminary effects of ATYR1923 on clinical outcome measures of SARS-
CoV-2 infection. 
2.3 
Exploratory 
The exploratory objectives are: 
• To explore the preliminary efficacy of ATYR1923 for SARS-CoV-2 infection. 
• To assess the PD of a single IV dose of ATYR1923. 
• To assess the impact of a single IV dose of ATYR1923 by measuring potential biomarkers of 
COVID-19 disease. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
Study ATYR1923-C-003 is a randomized, double-blind, placebo-controlled study to evaluate the 
safety, PD, and efficacy of ATYR1923 in hospitalized subjects with SARS-CoV-2 related severe 
pneumonia not requiring mechanical ventilation.  
Eligible patients will be randomized 1:1:1 to a single IV dose of ATYR1923 1 mg/kg, 
ATYR1923 3 mg/kg, or placebo. Study drug (ATYR1923 or placebo) will be added onto 
institutional standard of care (ISOC) for treating SARS-CoV2 infection. 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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A single dose of study drug will be administered on Day 1. All study drug will be administered in 
the hospital setting; patients who are intubated after randomization but prior to study drug 
administration are no longer eligible to receive study drug. As this is a single-dose study, the 
treatment period is 1 day. Thereafter, all patients will be followed for 60 days post-treatment. The 
schedule of study assessments over this period is dependent on the duration of hospitalization and 
whether or not the patient requires intubation. 
3.1.1 Hospitalized, Non-intubated Patients 
While hospitalized, non-intubated patients will have study assessments performed on Days 2, 3, 
4, 5, 6, 7, 10, and 14 and/or Discharge. 
If the non-intubated patient is discharged prior to Day 14, the assessments scheduled for Day 14 
and/or discharge will be completed at the time of discharge. If discharge occurs on another 
scheduled study assessment day (ie, any day between Days 2 and 10), the Day 14 and/or 
discharge assessments supersede that study assessment day and the patient then will proceed to 
outpatient telephone contact (TC) follow-up visits. If a patient is discharged prior to Day 14, then 
outpatient TC follow-up visits are to be conducted on Day 7 (as applicable) and Day 14. 
If the non-intubated patient is discharged on Days 15-20, the patient is to have the assessments 
scheduled for Day 14 and/or discharge performed on the day of discharge. If the patient is 
hospitalized for ≥21 days, the Day 14 assessments are to be performed weekly (Days 21, 28, 35, 
etc.) until discharge (with the exception of pharmacokinetics [PK], which is to be done only at 
Day 28). After discharge, the patient will proceed to the next scheduled outpatient TC follow-up 
visit. (Thus, if a patient remains hospitalized on Day 28, the Day 28 TC follow-up visit need not 
be conducted.) 
3.1.2 Hospitalized, Intubated Patients 
In the event that a patient requires intubation while hospitalized, ISOC assessments and 
interventions will supersede study assessments for the duration of intubation, with the exception 
of the World Health Organization (WHO) Scale and sample collection for anti-drug antibody 
(ADA) and Jo-1 antibody (Ab), which will continue to be collected as per the Schedule of 
Assessments (Appendix 6.1) on Days 5, 7, 10, 14 and weekly thereafter. The following clinical 
assessments will be collected and analyzed as available per the institution's electronic medical 
records. 
• Date and time of intubation and extubation. 
• Adverse events (AEs) (including new infections). In the case of new infections, the site and 
source of culture are to be recorded. 
• Concomitant medications. 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Patients will resume the study assessment schedule upon extubation. (Thus, for example, if an 
intubated patient is extubated on Day 7, they will resume the study assessment schedule on Day 
7). 
Extubated patients will have the assessments scheduled for Day 14 and/or discharge performed at 
the time of hospital discharge and will attend Days 28 and 60 TC follow-up visits. 
If the patient is hospitalized for ≥21 days, assessments are to be performed weekly (Days 21, 28, 
35, etc.) until discharge (with the exception of PK, which is to be done only at Day 28). After 
discharge, the patient will proceed to the next scheduled outpatient TC follow-up visit. (Thus, if a 
patient remains hospitalized on Day 28, the Day 28 TC follow-up visit need not be conducted.) 
3.1.3 
Independent Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will review the progress of the study and 
perform interim reviews of safety data at regular intervals beginning after the sixth patient has 
been dosed, and at a frequency guided by the enrollment rate and DSMB recommendation. 
Details will be documented within the DSMB Charter. 
3.1.4 
Determination of Sample Size 
For this study, no prospective calculations of statistical power have been made. The sample size 
has been selected to provide information on safety, tolerability, PK, and efficacy following single 
doses of ATYR1923. There will be 30 patients randomized 1:1:1 to ATYR1923 1 mg/kg, 
3 mg/kg, or placebo, respectively. 
3.1.5 
Planned Interim Analysis 
A soft-lock of the data base is planned for an ad hoc safety Interim Analysis (IA). The IA will be 
reviewed by an designated sponsor team unblinded to treatment group to determine the 
continuation of the trial. Timing of the IA rests with the sponsor. A separate IA SAP and separate 
IA TFL Shells will be developed. 
 
3.2 
Changes in the Conduct of Planned Analyses 
Changes not mentioned in the CSP or SAP will be clearly indicated in the Clinical Study Report. 
Any post hoc analyses after database lock will clearly be labelled as post hoc. 
Table 1 Changes in the Conduct of Planned Analyses 
CSP V5.0 
Changes 
Secondary Endpoint:  
“Time to improvement from inpatient hospital 
admission based on at least a 1 point 
reduction in WHO Ordinal Scale score. ” 
Patients are hospitalized prior study start and 
therefore first WHO Scale score to be 
collected during Screening. Secondary 
Endpoint definition to be changed to:  


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CSP V5.0 
Changes 
“Time to improvement from baseline on at 
least a 1 point reduction in WHO Ordinal 
Scale score. ” 
 
3.3 
Final Database Lock 
The study database will be finally locked when all patients completed the study. The study will 
be considered complete when the last patient completes the Day 60 TC follow-up visit and any 
necessary follow-up for Jo-1 Ab positivity or ongoing study drug-related treatment-emergent 
AEs (TEAEs) has been completed and cleaned. 
3.4 
Endpoints 
3.4.1 Primary 
• Incidence of TEAEs, including serious and severe TEAEs, overall and by severity. 
3.4.2 Secondary 
• Time to hospital discharge, 
• Time to recovery (WHO score ≤3), 
• Proportion of patients achieving recovery by Day 14 and Day 28, 
• Duration of supplemental oxygen (O2) requirement, 
• Number of days with fever (temperature >100.4ºF [38.0ºC]), 
• Change from baseline in WHO Ordinal Scale score on Days 5, 7, 14, 28, and 60, 
• Time to improvement from baseline based on at least a 1 point reduction in WHO Ordinal 
Scale score, 
• All-cause mortality at Days 14, 28, and 60. 
 
3.4.3 Exploratory 
• Change from baseline in supplemental oxygen requirement at Days 3, 5, 10, 14, and 
discharge. 
• Proportion of patients requiring intubation, and among those patients, number of days in 
intubation. 


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• Change from baseline in inflammatory biomarkers and cytokines including: C-reactive 
protein (CRP), interferon gamma (INF γ), interleukin (IL)-6, IL-2, IL-7, IL-10, tumor 
necrosis factor-alpha (TNFα), macrophage inflammatory protein-1 (MIP1), C-X-C motif 
chemokine 10 (CXC-10), and monocyte chemoattractant protein-1 (MCP-1).  
• Change from baseline in potential markers of COVID-19, including serum ferritin and D-
dimer. 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with PAREXEL standard procedures. 
4.2 
General Presentation Considerations 
Baseline: the last available pre-treatment assessment, unless otherwise specify. All assessments 
should have time collected. If time is not collected and date of assessment is the same as study 
drug administration date then assessment will be assumed to be collected prior to treatment 
unless schedule of assessments and protocol indicate planned collection is always after dosing.  
For baseline of oxygen use, total oxygen use in 24 hours before drug administration date.  
Day-of-Discharge (DoD): day when patient is discharged from the hospital. 
Date of discharge: date patient is discharged from the hospital. 
Early Termination (ET): day when patient withdraws from the study before completion. 
End-of-Study (EOS): the EOS assessment is at Day 60 for patients who complete the study. 
End of study date: date of EOS assessment (Day 60) if patient completes the study or date of 
early withdrawal if patient discontinues early, or date of death. 
Study Day: <Assessment Date> - study drug administration date+ 1 if <Assessment Date> is on 
or after study drug administration date. <Assessment Date> - study drug administration date, if 
<Assessment Date> is before study drug administration date. 
Durations are generally calculated as the stop date - start date +1, if not otherwise stated. 
For elapsed time (eg, time since the initial diagnosis) is calculated as reference date - event date. 
If more than one laboratory value is available for a given study day, the last valid observation 
will be used in summaries, unless otherwise stated. If it is not possible to determine which is the 
last measurement due to missing times, then the average of all measurements for that study day 
will be used as the value for that study day. All observations will be presented in listings. 
Laboratory data will be presented in standard units. 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum and number of observations, unless otherwise stated. Continuous data that 
are expected to be skewed will be presented in terms of the maximum, upper quartile, median, 
lower quartile, minimum and number of observations. The minimum and maximum will be 
reported to the same number of decimal places as the raw data recorded in the database. The 
mean, median, lower quartile and upper quartile will be reported to one more decimal place than 
the raw data recorded in the database. The SD will be reported to two more decimal places than 
the raw data recorded in the database. In general, the maximum number of decimal places 
reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of patients providing data at the 
relevant time point (n), frequency counts and percentages. Any planned collapsing of categories 
will be detailed in the SAP text and the data displays. 
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentages will be calculated using N as the denominator, unless otherwise stated. If 
sample sizes are small, the data displays will show the percentages, but any textual report will 
describe frequencies only. Changes from baseline in categorical data will be summarized using 
shift tables where appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. 
P-values less than 0.001 will be presented as “<0.001”. Confidence intervals (CIs) will be 
presented to one more decimal place than the raw data. 
Analysis Visit Window:  
By visit summaries will be based on the nominal/scheduled visit as reported in eCRF and will be 
grouped by Day 1, 2, 3, 4, 5, 6, 7, 10, 14, 28 and 60. 
For (telephone contact) TC follow up visits and unscheduled Discharge visits, analysis visit 
windows will be applied as in Table 2 and Table 3 below. Note, analysis visit windows are only 
used for by visit summaries, not for time to event calculation which will based on actual date of 
data collected. TC follow up visits and Discharge visits that are not in any of the analysis visit 
windows, will be excluded from summaries and only presented in listings. 
 
Table 2 Analysis Visit Window for TC follow up visits 
mapped to 
Visit Window  
Day 7 
Day 7 ± 2 days 
Day 14 
Day 14 ± 2 days 
Day 28 
Day 28 ± 5 days 
Day 60 
Day 60 ± 5 days 
 
 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Table 3 Analysis Visit Window for unscheduled Discharge visits 
mapped to 
Visit Window  
Day 7 
Day 8 
Day 10  
Day 10 ± 1 days 
Day 14 
Day 14 ± 2 days 
Day 28 
Day 28 ± 5 days 
Day 60 
Day 60 ± 5 days 
 
In case several outcomes are available for the nominal/scheduled analysis visits, the latest non-
missing result will be used for summaries. 
 
Treatment Descriptors 
Displayed columns will be labelled and ordered: 
• Placebo, 
• ATYR1923 1 mg/kg, 
• ATYR1923 3 mg/kg, 
• ATYR1923 Total, 
• All Patients. 
4.3 
Missing Data 
4.3.1 Imputation of Non-Date Missing Data 
Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” in subject listing 
displays. Answers such as “Not applicable” and “Not evaluable” are not considered to be missing 
data and should be displayed as such. 
Subjects with the designation of treatment relationship for AEs and SAEs missing will have the 
worst realistic case assumed to impute the relationship: if relationship is missing and the AE 
started on or after study drug administration it will be assumed to be “related” (worst case). If the 
AE with missing relationship started before study drug administration (eg, during Screening 
Period), it will be considered as “not related” (realistic case). Missing Severity will be assumed to 
be “Life-threatening” (worst case). In listings these imputed relationships and causalities will be 
flagged. 
For variables which determine the proportion of events, all subjects in the respective analysis set 
will be included in the denominator when calculating the percentages irrespective of whether 
their outcome may be missing. 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Handling of complete or partial missing dates for Adverse Events or reported Concomitant 
Medication will be given in the following Section. 
All other missing data will not be imputed. 
4.3.2 Imputation of Partial Dates 
Imputed dates will be used only to assign reported AEs and Medications to the different study 
Periods: Screening Period, Treatment Period, FU Period; for determining the category for 
reported Medication as ‘PRIOR ONLY’, ‘PRIOR and CONCOMITANT’ or ‘CONCOMITANT 
ONLY’ and to determine if an AE is treatment emergent. 
Both observed and imputed dates will be included into the analysis datasets. Dates will be 
displayed in listings with only the information available in the database. 
Partial date imputation will follow ADaM conventions. The ADaM approach is to populate the 
numeric date variables with the imputed date and add a flag variable to the dataset that indicates 
the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y' with 
blank: indicates that no imputation was done, 
D = 'Day': indicates that the day portion of the date is imputed, 
M = 'Month': indicates that the month and day portions of the date are imputed, 
Y = 'Year': indicates that the entire date (year, month, and day) is imputed. 
Table 4 Partial Date Imputation Rules for AEs and Medications 
Date 
Missing Element 
Rule 
Start Date 
 
 
day, month, and year 
Do not impute completely missing start dates 
day, month only 
Set to January 1st of the year the event started. 
day only 
Set start date to the 1st of the month the event started.  
End Date 
day, month, and year 
No imputation for completely missing end dates; report the event as 
ongoing if not already documented as ‘ongoing’ 
day, month only 
If the partial end date contains year only, set end date to December 31st or 
last study visit, whichever occurs first.  
day only 
If the partial end date contains month and year, set the end date to the 
last day of the end month or last study visit, whichever occurs first.  
Thus, AEs will be assumed to be treatment-emergent, unless there is clear evidence to suggest 
that the AE started prior to treatment. 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Table 5 Partial Date Imputation Rules for Death and Hospitalization 
Missing Element 
Rule 
month and/or year 
Do not impute. 
day only 
Set start date to the 1st of the month.  
If imputing the first day of the month results in a negative overall 
survival time, the patient will be censored for overall survival at the 
reference date. 
 
4.4 
Software 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure and 
validated environment. 
4.5 
Analysis Sets 
All Screened consists of all subjects who provide written informed consent. 
Randomized Set comprises all patients randomized regardless of whether they received study 
treatment. Patients will be summarized and analyzed ‘as randomized,’ ie, by randomized 
treatment group. 
Modified Intention-to-Treat Set (mITT Set) comprises all patients randomized who have 
received any amount of study drug. Patients will be summarized and analyzed ‘as randomized,’ 
ie, by randomized treatment group.  
Safety Set is defined as all randomized patients who received any amount of study drug. Patients 
will be summarized and analyzed ‘as treated,’ ie, by actual treatment group. 
Pharmacokinetic Set (PK Set) is defined as patients that receive at least one dose of study drug 
and have at least 1 evaluable post-dose PK sample. 
A by-patient listing of analysis set details including patient identifier, inclusion/exclusion flag for 
each set, and reason for exclusion from each set. 
Efficacy Evaluation Set (EE Set) comprises all patients randomized and dosed who do not have 
any major violations or other findings upon medical review that the Sponsor determines might 
impact the efficacy evaluation.  
Technical Note: The sponsor will provide a CSV file containing a list of all subjects and a flag if 
that subject will be included or exclude from EE Set. 
 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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4.6 
Study Patients 
4.6.1 Disposition of Patients 
A clear accounting of the disposition of all patients who enter the study will be provided, from 
screening to study completion. Summaries will include: 
• number of patients screened, 
• number of patients randomized, 
• number of patients dosed, 
• number of patients in each analysis sets, 
• number of patients who completed study (Day 60 assessment), 
• number of patients who withdrew early from the study (including reasons for early 
withdrawal). 
By-patient listings of eligibility details, randomization details, visit dates and withdrawal/study 
completion details (including reason for discontinuation and duration of treatment prior to 
discontinuation) will be provided. Disposition data will be listed and summarized for All 
Screened, and also summarized for mITT set. 
4.6.2 Protocol Deviations 
All identified protocol deviations throughout the study will be listed prior to database lock. 
Protocol deviations will be identified and classified into major or minor. Major protocol 
deviations are defined as those that could have a significant effect on the subject’s safety, rights, 
or welfare and/or on the integrity of the study data.  
During the blinded data review meeting (BDRM), the subject’s assignment to or exclusion from 
any analysis set will be discussed in detail. The decisions made during the BDRM will be 
documented in the BDRM minutes and agreed upon prior to database lock and unblinding for 
final analysis. 
The following summaries will be provided for mITT set: 
• all major protocol deviations related to inclusion and exclusion criteria, 
• all other major protocol deviations. 
A by-subject listings will be provided for all reported protocol deviations. 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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4.7 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by treatment group, for both 
treatment groups combined (Total) and All Patients using the mITT set. The summaries provided 
will include the following: 
• Demographic variables: 
- Age (continuous and categorical [<65 years; ≥ 65 years]), 
- Sex, 
- Race, 
- Ethnicity, 
- Baseline height, 
- Baseline weight, 
- Baseline Body Mass Index (BMI) continuous and categorized (<30, ≥30) and (<35, ≥35). 
Age will be calculated based on date of randomization. BMI will be calculated based on baseline 
height and weight as weight (kg) / height2 (m2). 
 
• Baseline disease characteristics: 
- Baseline WHO Ordinal Scale, 
- Baseline maximum temperature measurements, 
- Baseline oxygen utilization (yes, no), if yes method of Oxygen delivery, 
- Baseline oxygen saturation ≤86%, 
- Days since onset of COVID-19 related symptoms, 
- Days hospitalized prior Day 1. 
Technical Note: Onset of COVID-19 related symptoms are documented on the Medical History 
Form. Use the earliest MH record related to COVID-19 and derive as: date of study drug 
administration – date of start of first MH record related to COVID-19. 
 
• Risk Factors at Baseline: 
- subjects with Age ≥65 years, 
- subjects with Obesity (BMI ≥ 30), 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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- subjects with Morbid Obesity (BMI ≥ 35), 
- subjects with Diabetes (MH PT: type 2 diabetes mellitus, diabetes mellitus), 
- subjects with Hypertension (MH PT: hypertension), 
- subjects with Coronary Artery Disease (MH PT: coronary artery disease), 
- subjects with  Chronic Kidney Disease (MH PT: chronic kidney disease), 
- subjects with Chronic Respiratory Disease (MH PT: Asthma; Chronic obstructive pulmonary 
disease; Sleep apnoea syndrome), 
- subjects with Cardiovascular Disease (MH SOC: Cardiac Disorders), 
- subjects with 1, 2, 3, 4, 5, 6, or 7 risk factors present at baseline. 
Technical Note: Medical History Terms that are related to COVID-19 will not be considered for 
risk factors. The risk BMI ≥ 30 and/or ≥ 35 will be counted as only one risk factor per subject 
and further, risk of coronary artery disease and/or cardiovascular disease will only be counted as 
one risk factor per subject. 
 
• Medical history will be reported by system organ class (SOC) and preferred term (PT) as 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0 or 
higher. Two summaries will be provided 1) non-COVID-19 related and 2) COVID-19 
related. 
 
By-patient listings of demographic data, other baseline characteristics (as summarized above) and 
medical history will be provided. Reproductive system findings including child-bearing potential 
and pregnancy test results will be listed only. 
4.8 
Concomitant Medications and Procedures 
Medications will be coded using Anatomical Therapeutic Chemical (ATC) Classification codes 
by WHO Drug Global version Mar 2019 Format C3. Prior and concomitant medications will be 
summarized by ATC class level II, and Preferred Term, using the Safety Set.  
Medication start and stop dates will be compared to study drug administration date to allow 
medications to be classified as either prior only, both prior and concomitant, or concomitant only. 
Missing or partial start dates will be imputed as described in Section 4.3.  
Medications that start and stop prior to study drug administration will be classified as prior only. 
If a medication starts before study drug administration and stops on or after study drug 
administration or stop date is missing, then the medication will be classified as both prior and 
concomitant. Medications will be classified as concomitant only if they have a start date on or 
after study drug administration. 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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In the summary of prior and concomitant medications, each subject will be counted once within 
each unique term. For example, if a subject takes amoxycillin on 2 separate occasions, the subject 
is counted only once under the corresponding ATC class. 
Summaries and by-subject listings will be given for Safety Set. The summary will group the 
medication by Prior only, Prior and Concomitant and Concomitant only. 
Listings will include medication/therapy start and end date:time or ongoing status, dose, route, 
frequency, primary indication for the medication, AE term if applicable, medical history term if 
applicable and concomitant medication flag (Prior only, Prior and Concomitant, Concomitant 
only). 
Additionally, number of patients taking Remdesivir (ATC Level 2 code “J05”) and/or 
Dexamethasone or other glucocorticosteroids (ATC Level 2 code  “H02”) and/or Convalescent 
Plasma (ATC Level 2 code ‘J06) flagged as “Prior and Concomitant” or “Concomitant only” will 
be provided by treatment group for the Safety Analysis Set. 
 
4.9 
Efficacy Evaluation 
4.9.1 Differences from Interim Analysis 
No changes from Interim Analysis. 
 
4.9.2 Multiple Comparisons and Multiplicity 
Given the exploratory nature of this study, all comparisons of treatment groups versus placebo 
will be interpreted in an exploratory manner and thus no adjustments for multiplicity will be 
performed. P-values provided are deemed to be exploratory. 
4.9.3 Primary Efficacy Analyses 
See Section 4.10.2. 
4.9.4 Key Secondary and Exploratory Efficacy Analyses 
 
Secondary and exploratory endpoints will be analyzed according to the type of endpoint as 
described below. If data are sparse for any of the exploratory endpoints, summaries may be 
limited to descriptive statistics of available data or listings only as appropriate. 
 
Time to event endpoints will be analyzed using Kaplan Meier method. The total number of 
patients with an event, the total number censored and Kaplan-Meier survival estimates with 
associated 95% CI (25% percentile, median, and 75% percentile) will be presented by treatment 
group. Further, crude proportions for having the event at timepoints with events observed 
(derived as: cumulative number of subjects with events / number of subjects in treatment group at 
baseline) along with 95% Wilson Score intervals with continuity correction will be provided.  
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Further, Kaplan-Meier estimates at 5, 6, 7, 10, 14 and 28 days from first study drug 
administration will be provided with associated 95% CI.  
A survival plot will be produced with the probability of an event (0% to 100%) along the Y-axis 
and time in days along the X-axis.  
 
The hazard ratio of ATYR1923 1 mg/kg versus Placebo, ATYR1923 3 mg/kg versus Placebo, 
and ATYR1923 Total versus Placebo with corresponding 95% CI and p-values will be estimated 
from a single Cox Proportional Hazards model. 
 
All efficacy summaries and analyses will be based on mITT Set, unless otherwise stated.   
 
4.9.4.1 Secondary Efficacy Analyses 
 
Time to hospital discharge  
Time to hospital discharge will be calculated as:  
discharge date – study drug administration date.  
Patients who die in hospital will be censored at death date. Patients still in hospital at EOS will 
be censored at EOS visit. 
 
For imputation of partial missing dates for death or discharge from hospitalization see Section 
4.3.2. 
 
Additionally, time to hospital discharge will be analyzed using an adapted derivation:  
discharge date – randomization date. The same rules for handling of hospitalized or discontinued 
patients and partial missing data applies as mentioned above. Related output will be noted as 
sensitivity analysis. 
 
Time to hospital discharge will be analyzed based on mITT and EE Set. Sensitivity analysis for 
time to hospital discharge will be analyzed based on mITT only. 
 
Time to recovery   
Time to recovery is calculated as: 
date of first time WHO scale score ≤ 3 - study drug administration date; or date of 
discharge from hospital - study drug administration date, whichever occurs first. 
In the case that a patient does not reach WHO scale score ≤ 3 criteria, the patient will be censored 
at EOS visit.  
Additionally, time to recovery will be analyzed using an adapted derivation:  


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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date of first time WHO scale score ≤ 3 – randomization date or date of discharge from hospital 
≤ 3 – randomization date, whichever occurs first. Related output will be noted as sensitivity 
analysis. 
 
Time to recovery will be analyzed based on mITT and EE Set. Sensitivity analysis for time to 
recovery will be analyzed based on mITT only. 
 
Time to recovery with WHO scale score ≤ 3 without supplemental oxygen   
Some patients were discharged from hospital while still using supplemental oxygen and so an 
additional sensitivity analysis will be performed to evaluate the impact for time to recovery. The 
following Pseudo-Code will be applied in the given order to derive time to recovery without 
supplemental oxygen: 
1. Derive time to event ‘T’ as date of first time WHO scale score ≤ 3 - study drug 
administration date; or date of discharge from hospital - study drug administration 
date, whichever occurs first. 
2. For subjects who discharged earlier than reporting an WHO scale score ≤ 3 apply 
the following checks: 
a. If an supplemental oxygen dose of ‘0’ is reported at day of discharge keep 
T. 
b. If an supplemental oxygen dose of ‘0’ is already reported one day prior 
day of discharge use T-1. 
c. If an supplemental oxygen dose of >0 is reported at day of discharge and 
discharge reason indicate that the subject in not on oxygen (e.g. “On Room 
Air” or “Weaned off O2”) keep T. 
d. If an WHO scale score ≥ 4 is reported at day of discharge and an WHO scale 
score ≤3 is reported one day after discharge use T+1. 
e. If an WHO scale score ≥ 4 is reported at day of discharge and an WHO scale 
score ≤3 is reported two days after discharge use T+2. 
f. If an WHO scale score ≥ 4 is reported at day of discharge and none of the 
criteria above are met use T+2. 
3. In the case that a patient does not reach WHO scale score ≤ 3 criteria or has no 
discharge event, the patient will be censored at EOS visit. 
 
Time to recovery with WHO Scale score ≤ 3 and without supplemental oxygen will be analyzed 
based on mITT and EE Set. 
 
 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Proportion of patients achieving recovery by Day 14 and by Day 28  
Number and percentage of patients achieving recovery (WHO scale score ≤ 3 or discharge from 
hospital, whichever occurs first) by Day 14 and by Day 28 will be presented. 
 
Duration of supplemental oxygen (O2) requirement : 
The number of days with supplemental oxygen (O2) will be calculated as: 
stop date of supplemental oxygen – start date of supplemental oxygen +1; if supplemental 
oxygen started after study drug administration; otherwise supplemental oxygen – date of 
study drug administration +1. 
If there are multiple periods of supplemental oxygen (O2), total days will be the sum of each 
period. Patients who die or withdraw from the study with ongoing supplemental oxygen at the 
last contact date, days will be (earliest of [date of death, EOS date] – start date of supplemental 
oxygen +1). Standard descriptive statistics (mean, SD, median, minimum, maximum) will be 
used. Standard descriptive statistics will also be presented for mITT Set excluding withdrawals 
and deaths. 
Days of supplemental oxygen (O2) up to Day 14 will be used as a sensitivity analysis. Days will 
be calculated as below: 
• For patients who Die or Withdraw before Day 14, their total will be factored-up to an 
equivalent 14 day period. For example, if a patient withdraws on Day 5 having already 
received 3 days of supplemental oxygen between Day 1 and Day 5, then their endpoint 
value will be 8.4 days i.e. (3/5)*14 . 
• For patients who do not withdraw or die before Day 14, count the actual days on 
supplemental oxygen (O2) up to Day 14. 
 
Number of days with fever (temperature >100.4oF [38.0oC]): 
The Number of days with fever are calculated as: 
stop date of fever – start date of fever +1, if fever started after study drug administration; 
otherwise stop date of fever – date of study drug administration +1.  
If there are multiple periods of fever, Total days will be the sum of each period. Standard 
descriptive statistics (mean, SD, median, minimum, maximum) will be used. Standard descriptive 
statistics will also be presented for mITT Set excluding withdrawals and deaths. 
Days with fever up to Day 14 will be used as a sensitivity analysis. Days will be calculated the 
same as described for Days of supplemental oxygen (O2) up to Day 14.  
 


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Change from baseline in WHO Ordinal Scale score 
The description of the WHO Ordinal Scale score is shown in Section 6.2. The Number and 
percentage of patients on WHO Scale scores and change from baseline (-7, -6, -5, -4, -3, -1, 0, 1, 
2, 3, 4) will be presented by visit. Shift table will be presented by visit as well.  
Simple Ordinal logistic regression on the WHO Scale score at each visit (Days 5, 7, 14, 28, and 
60) will be performed to compare ATYR1923 1 mg/kg versus Placebo and ATYR1923 3 mg/kg 
versus Placebo. Firth logistic regression (Firth, 1993) on the collapsed WHO Ordinal Scale (0-3 
versus 4-8) at each visit (Days 5, 7, 14, 28, and 60) will be performed as well. 
Distribution of WHO Ordinal Scale at 1, 2, 3, 4, 5, 6, 7, 10, 14, 28 and 60 days will be visualized 
by treatment group using an stacked bar chart. These figures will only consider scheduled 
assessments and in case the scheduled assessment is not available the mapped unscheduled TC 
follow up assessments as defined in Section 4.2.  
 
Time to Improvement in Clinical Status 
Time to improvement in days is the time in which the patient sees a decrease after study 
treatment in the WHO Ordinal Scale score from baseline by at least 1 point, derived as: 
date of decrease in WHO scale compared to baseline by at least 1 point - study drug 
administration date; or date of discharge from hospital - study drug administration date, 
whichever occurs first.  
In the case that a patient has not decreased in the WHO scale or withdraws from the study, they 
will be censored at EOS date. Time to improvement will be analyzed using the Kaplan-Meier 
methods and Cox Proportional Hazards model as described in the above. 
 
Repeat analysis above for improvement of WHO Ordinal Scale score by at least 2 points.  
 
Additionally, time to improvement will be analyzed using an adapted derivation: date of decrease 
in WHO scale compared to baseline by at least 1 point - randomization date; or date of discharge 
from hospital - randomization date, whichever occurs first.  
Related output will be noted as sensitivity analysis. 
 
Time to improvement (by at least 1 and 2 points) will be analyzed based on mITT and EE Set. 
Sensitivity analysis for time to improvement will be analyzed based on mITT only. 
 
 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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All-cause mortality 
Number and percentage of patients who died will be summarized by day 14, 28 and 60 by 
treatment group. If the total number ≤ 3, only listing will be presented.   
4.9.4.2 Exploratory Efficacy Analyses 
 
Unless specified, standard descriptive statistics (mean, standard deviation, median, minimum, 
maximum) will be used to summarize continuous variables below. Number and percentage will be 
presented for categorical variable below. For the number of days, will count the actual days not 
considering discontinuation or death.    
 
Change from baseline in supplemental oxygen requirement at day 3, 5, 10, 14 and discharge 
Subject´s status of supplemental oxygen requirement (none, low flow: face mask or nasal canula, 
high flow: high-flow oxygen or non-invasive ventilation) will be summarized at each scheduled 
visit. Shift to baseline table will be provided for each scheduled visit as well. 
By-patient listings of all supplemental oxygen use including unscheduled assessments will be 
provided. 
 
Proportion of patients requiring intubation, and among those patients, number of days of 
intubation. 
Proportion of patients requiring intubation, and among those patients, number of days of 
intubation derived as: 
date of extubating or EOS, whichever occurs first – date of intubation + 1, if intubation 
happened after study drug administration. 
By-patient listings of all respiratory support including unscheduled assessments will be provided. 
 
Pharmacodynamics (PD) biomarkers and potential COVID-19 disease biomarkers   
See Section 4.11.3. 
 
 
 
 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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4.9.4.2.1 Subgroup Secondary Efficacy Analyses 
 
Subgroups: 
• BMI (<30, ≥30) at Baseline; 
• WHO Score at Baseline (<5, ≥5); 
• Concomitant Medication: Remdesivir (yes, no), see Section 4.8, 
• Concomitant Medication Dexamethasone (yes, no), see Section 4.8. 
Secondary Efficacy Analysis to be repeated by subgroups mentioned above are 
• Time to Hospital Discharge and proportion of patients achieving recovery (WHO scale 
score ≤ 3) by Day 14 and by Day 28, 
• Summary of WHO ordinal scale score by visit, 
• Time to recovery (WHO scale score ≤ 3). 
 
Subgroup analyses will be only produced if the categories contain at least 5 subjects.  
 
4.10 Safety Evaluation 
All safety summaries and analyses will be based on the Safety Set.  
4.10.1 Extent of Exposure  
A by-patient listing of exposure data will be provided. 
4.10.2 Adverse Events 
Adverse events will be coded using the MedDRA Version 23.0 or higher. 
Treatment-emergent AEs (TEAE) are defined as AEs that either start or worsen in severity on or 
after the date/time of study drug administration and through the end of study. Partial date 
imputation was specified in Section 4.3. Imputed dates will only be used for TEAE definition.  
An overall summary table of TEAEs will be provided with the number and percentage of patients 
(incidence) reporting an event along with the total number of events presented for the following 
categories: 
• All TEAEs, 
• TEAEs related to Study Drug,  
• TEAEs by severity, 
• Severity grade 3 and higher TEAEs,  
• Severity grade 3 and higher TEAEs related to Study Drug, 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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• Serious TEAEs, 
• Study drug-related serious AEs (SAEs), 
• Fatal TEAEs, 
• TEAEs leading to study discontinuation, 
• SAEs related to COVID-19, 
• TEAEs suspected as infusion-related reactions. 
4.10.2.1 Adverse Event Summaries by System Organ Class and Preferred Term 
The incidence and total number of events for the following will be summarized by SOC and PT, 
unless otherwise specify: 
• All TEAEs, 
• TEAEs related to Study Drug,  
• TEAEs by maximum severity, 
• TEAEs by maximum causality, 
• TEAEs related to Study Drug by maximum severity, 
• Severity grade 3 or higher TEAEs, 
• Study drug related grade 3 or higher TEAEs, 
• Serious TEAEs, 
• SAEs related to Study Drug, 
• Fatal TEAEs, 
• TEAEs leading to study discontinuation,  
• TEAEs suspected as infusion-related reactions, 
• SAEs related to COVID-19. 
Adverse event summaries will be ordered by decreasing incidence for SOC, and PT within SOC, 
in the ATYR1923 Total treatment group. In case of equal number of subjects sorting will be done 
alphabetically. Additionally all TEAEs will be summarized by PT only and will be ordered by 
decreasing incidence for PT in the ATYR1923 Total treatment group. 
For each patient and each adverse event, the worst severity recorded will be attributed and used 
in the by-maximum-severity summaries. Similarly, the worst causality (most related to treatment) 
will be attributed and used in the by-maximum-causality summaries. If missing severity or 
causality will be imputed as stated in Section 4.3.1. 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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4.10.2.2 Adverse Event Listings 
By-patient listings of all AEs will be provided. The following listings will be provided: 
• All AEs, 
• All drug-related AEs, 
• All grade 3-5 AEs, 
• All SAEs, 
• All fatal AEs, 
• All AEs leading to study discontinuation.  
4.10.3 Clinical Laboratory Evaluation 
Local laboratories will be used for laboratory safety evaluations in this study. Table 6 shows the 
list of laboratory parameters. Laboratory results will be graded as low, normal, or high comparing 
to the normal range provided by the local laboratories .   
All laboratory values will be reported in local units and in alphabetical order.    
For by-visit summaries, the first non-missing assessment (including repeat assessments) recorded 
at each visit will be used. Optional laboratory parameters (Creatine Phosphokinase, Lactate 
Dehydrogenase (LDH)) will not be summarized by treatment group, only listed. Separate 
summaries for Hematology, Clinical Chemistry, Coagulation, Urinalysis and Serology (Baseline 
only) to be produced will be: 
• for laboratory values reported as a character value, such as ‘negative’, number and 
percentage of subjects for each outcome by scheduled visit 
• for continuous laboratory values, number and percentage of subjects with values outside 
normal range by scheduled visit, 
• for continuous laboratory values, shifts from baseline in relation to normal range at all 
scheduled visits. 
 
By-patient listings of all laboratory data, with abnormal values flagged, will be provided for 
Serology, Hematology, Clinical Chemistry, Coagulation and Urinalysis test results. Further 
marker of anaphylaxis: Tryptase will be listed by subject. 
 
 


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ATYR1923-C-003                                                                                                                      Statistical Analysis Plan 
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Table 6 List of Laboratory Parameters 
Hematology 
RBC 
WBC 
Basophils (absolute and %) 
Eosinophils (absolute and %) 
Lymphocytes (absolute and %) 
Monocytes (absolute and %) 
Neutrophils (absolute and %) 
Platelets 
Hematocrit 
Hemoglobin 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Clinical Chemistry 
Total bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Lactate dehydrogenase (LDH) 
Creatine phosphokinase 
Albumin 
Creatinine 
BUN 
Total Protein 
Glucose  
Sodium 
Potassium 
Calcium 
Chloride 
Coagulation 
Prothrombin time (PT) 
activated Partial thromboplastin time (PTT) 
International normalized ratio (INR) 
Urinalysis 
Hemoglobin 
Urobilinogen 
Glucose 
Ketones 
Protein 
Leukocyte Esterase 
Microscopy results: Urine RBC, Urine Squamous cell,  
                                 Urine WBC 
Serology 
(Baseline only) 
Hepatitis B Virus Core Antibody 
Hepatitis B surface antigen (HBsAg) 
HIV-1 Antibody 


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HIV-2 Antibody 
Hepatitis C antibody 
Hepatitis C Virus RNA  
Marker of anaphylaxis 
Tryptase 
4.10.4 Vital Signs and Physical Findings  
Vital Signs will be presented in standard units and in alphabetical order including weight, height, 
BMI, systolic and diastolic blood pressure, respiratory rate, heart rate and temperature. Absolute 
value, change and percent change from baseline will be summarized at each visit.  
A by-patient listing of all vital signs data will be provided by treatment group.   
Physical examination results will be listed only. 
4.10.5 Electrocardiogram Measurements 
All abnormal findings including ECG date and time, clinically significant status (Yes, No) and 
detailed findings will be summarized by visit and listed by subject. 
Observed values and change from baseline for ECG values such as Single RR Heart Rate, RR 
Interval, PR Interval, QRS Duration, QT Interval, QTcA Interval will be listed by subject and 
summarized presenting the number of observations, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum at each visit. 
4.11 Other Analyses 
4.11.1 Pharmacokinetics 
PK analysis will be performed on the PK Set.  
On Day 1, blood will be drawn for the PK analysis per the following schedule: end of infusion 
(EOI), and then at any single time point between 4 and 12 h after start of infusion (SOI). Further, 
samples will then be drawn once daily on Day 5, 7, 10, and 14. A Day 28 sample will be 
collected from patients who remain hospitalized. 
Concentrations of Tyr1923 will be listed by individual subject, including actual sampling date 
and time and time from start of drug administration.  
Pharmacokinetic data analysis will not be performed until after unblinding as it is potentially 
unblinding. 
 
4.11.2 Immunogenicity 
Anti-Drug Antibody (ADA) and Jo-1 Ab data will be summarized by treatment group for the 
Safety Set.  


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The following will be summarized for ADA: 
•  At Baseline 
o ADA incidence and incidence rate for Screened Positive, Confirmed Positive, 
o ADA titer value for positive results categorized (1:30 to <1:90, 1:90 to <1:270, 
≥1:270). 
• By Visit (after study drug administration) 
o ADA incidence and incidence rate for Screened Positive, Confirmed Positive, 
o ADA titer value or positive results categorized (1:30 to <1:90, 1:90 to <1:270, 
≥1:270). 
• At Any Visit (after study drug administration) 
o ADA incidence and incidence rate for at least one Confirmed Positive result, 
o Maximum ADA titer value or positive results categorized (1:30 to <1:90, 1:90 to 
<1:270, ≥1:270); 
o Baseline ADA Incidence (The proportion of pre-dose ADA-positive subjects as a 
percentage of total number of subjects (ATYR1923 and placebo subjects)) 
o Treatment-induced ADA Incidence (The proportion of individuals with 
Confirmed Positive ADA any time after ATYR1923 treatment that were ADA 
negative at baseline), 
o Treatment-boosted ADA Incidence (The proportion of individuals that were ADA 
positive at baseline who had an greater value in ADA after ATYR1923 treatment 
compared to baseline). 
 
The following will be summarized for Jo-1 Ab: 
• incidence and incidence rate of results that were above ‘high’ compared to local normal 
range by visit and at any visit, 
• incidence and incidence rate of results that were abnormal (above ‘high’ or below ‘low’ 
compared to local normal range) by visit and at any visit. 
 
ADA and serum Jo-1 Ab will be listed separately by subject including nominal/planned visits and 
actual time after start of study drug administration. 
 
 


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4.11.3 Biomarker 
Continuous biomarker values and change from baseline will be summarized descriptively per 
assessment time point using only values from scheduled visits for Safety Analysis Set.  
• inflammatory biomarkers and cytokines: C-reactive protein (CRP), interferon gamma 
(INF-γ), interleukin (IL)-6, IL-2, IL-7, IL-10, tumor necrosis factor-alpha (TNFα), 
macrophage inflammatory protein-1 (MIP1), C-X-C motif chemokine 10 (CXC-10), and 
monocyte chemoattractant protein-1 (MCP-1), if available. 
• potential markers of COVID-19 disease: Troponin I, Troponin T, NT-proBNP, BNP,  
Ferritin and D-dimer. 
By-patient listings of all biomarker results including unscheduled assessments will be provided. 


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5 
REFERENCES 
1. Burkart C, Seikkula M, Eide L, et al. ATYR1923 modulates the inflammatory response in 
experimental models of interstitial lung disease. Am J Respir Crit Care Med. 
2020;201:A2421. 
2. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 
pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434. 
3. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical Features of 69 Cases with Coronavirus 
Disease 2019 in Wuhan, China. Clin Infect Dis. 2020;ciaa272. 
4. Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory 
CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. 
bioRxiv. 2020.2002.2012.945576. 
5.  Firth, D. 1993. “Bias reduction of maximum likelihood estimates.” Biometrika, 80: 27-38. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1 
Schedule of Assessments 
 
  
  


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PAREXEL International 
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ATYR1923-C-003                                                                                                                       Statistical Analysis Plan 
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CONFIDENTIAL                                Project Document Version No. 3.0 
Effective Date:  30 Jan 19                                                       Project Document Effective Date: Date of last signature 
Related to: SOP-GDO-WW-019                                                                                                                   Page 38 of 39 
 
6.2 
WHO Ordinal Scale for Clinical Improvement 
 
 
 
 
 
 
 
 
 
 


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ATYR1923-C-003                                                                                                                       Statistical Analysis Plan 
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6.3 
Urinalysis Grading Rules 
Parameter 
Rules 
Hemoglobin 
ABNORMAL IF PRESENT 
  
NORMAL IF NOT PRESENT 
Urobilinogen 
ABNORMAL IF 2 OR GREATER 
  
NORMAL IF LESS THAN 2 
Glucose 
ABNORMAL IF POSITIVE 
  
NORMAL IF NEGATIVE 
Ketones 
ABNORMAL IF >=0.6 
  
NORMAL IF <0.6 
Protein 
ABNORMAL IF >14 
  
NORMAL IF <=14 
Leukocyte Esterase 
ABNORMAL IS POSITIVE 
  
NORMAL IS NEGATIVE 
Urine RBC 
ABNORMAL IF >4 
Technical Note:  include subjects with results reported as range value of 3-10 
  
NORMAL IF <=4 
Urine WBC 
ABNORMAL IF >5 
Technical Note:  include subjects with results reported as range value of 0-6 
  
NORMAL IF <=5 
Urine Squamous cell 
ABNORMAL IF >5 
  
NORMAL IF <=5 
 
 
 
 


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