Clinical trial NCT04389840
Conditions: Coronavirus Disease 2019 (COVID-19) Acute Lung Injury Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Keywords: COVID-19 ALI SARS-CoV-2
Sponsor: Chimerix
Start date: 2020-07-08; Completion date: 2021-05-20
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blind, placebo-controlled Phase 2/3 study to evaluate the safety and efficacy of dociparstat sodium in adult patients with acute lung injury (ALI) due to Coronavirus Disease 2019 (COVID-19). This study was designed to determine if dociparstat sodium could accelerate recovery and prevent progression to mechanical ventilation in patients severely affected by COVID-19.

Detailed description:
This was a randomized, double-blind, placebo-controlled, Phase 2/3 trial to evaluate the safety and efficacy of dociparsat sodium in adults patients with severe COVID-19 who were at high risk of respiratory failure. Eligible subjects were with confirmed COVID-19 and required hospitalization and supplemental oxygen therapy. This study was designed to determine if dociparstat sodium could accelerate recovery and prevent progression to mechanical ventilation in patients severely affected by COVID-19.

Arms: arm 1: Subjects received 4 mg/kg of dociparstat administered as an intravenous (IV) bolus on Day 1, followed by 0.25 mg/kg/hr dociparstat by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 \[168 hours\]). arm 2: Placebo IV bolus on Day 1, followed by Placebo by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 \[168 hours\]) arm 3: Subjects received 4 mg/kg of dociparstat administered as an intravenous (IV) bolus on Day 1, followed by 0.325 mg/kg/hr dociparstat by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 \[168 hours\]). arm 4: Subjects received placebo IV bolus on Day 1, followed by placebo by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 \[168 hours\]). arm 5: Subjects received 4 mg/kg of dociparstat administered as an intravenous (IV) bolus on Day 1, followed by 0.325 mg/kg/hr dociparstat by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 \[168 hours\]). arm 6: Subjects received placebo IV bolus on Day 1, followed by placebo by continuous IV infusion for 24 hours daily for up to 7 days (starting on Day 1 and ending on Day 8 \[168 hours\]).
Interventions: intervention 1: Dociparstat sodium intervention 2: Placebo
Intervention descriptions: intervention 1: Dociparstat is a glycosaminoglycan derived from porcine heparin. intervention 2: 0.9% Normal Saline

Protocol documents:
Prot_000.pdf: 
Protocol CMX-DS-004 
 
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Study Title: A Phase 2/3 Study to Evaluate the Safety and Efficacy of Dociparstat 
Sodium for the Treatment of Severe COVID-19 in Adults at High Risk of 
Respiratory Failure 
NCT Number: NCT04389840 
Document Date: 06 November 2020 
 
 
 
 
 
 
 
 
 


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TITLE PAGE 
 
Protocol Title:  
A Phase 2/3 Study to Evaluate the Safety and Efficacy of Dociparstat Sodium 
for the Treatment of Severe COVID-19 in Adults at High Risk of Respiratory 
Failure 
Protocol Number: CMX-DS-004 
 
Compound: Dociparstat sodium (DSTAT; CX-01; 2-O, 3-0 Desulfated Heparin) 
Study Phase: 2/3 
Short Title: Dociparstat for the Treatment of Severe COVID-19 in Adults at High Risk of 
Respiratory Failure 
 
Sponsor Name: Chimerix, Inc 
Legal Registered Address: 2505 Meridian Parkway, Suite 100; Durham, NC USA 27713 
 
Regulatory Agency Identifier Number(s): US IND 149,415 
 
Protocol Version Date: Amendment 3, 06 November 2020 
 
Sponsor Signatory: Allen Melemed, MD, Chief Medical Officer, Chimerix 
 
Medical Monitor Name and Contact Information: Refer to the Study Reference Manual 
 
Document History: 
Version 
Date 
Amendment 3 
06 November 2020 
Amendment 2 
10 August 2020 
Amendment 1 
19 June 2020 
Original Protocol 
30 April 2020 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
PROTOCOL SYNOPSIS .............................................................................................7 
1.1. 
Schedule of Activities .................................................................................................16 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Study Rationale ...........................................................................................................18 
2.2. 
Background .................................................................................................................18 
2.3. 
Benefit/Risk Assessment ............................................................................................21 
2.3.1. 
Risk Assessment .........................................................................................................21 
2.3.2. 
Benefit Assessment .....................................................................................................21 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................21 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................22 
4. 
STUDY DESIGN .......................................................................................................24 
4.1. 
Overall Design ............................................................................................................24 
4.2. 
Scientific Rationale for Study Design ........................................................................24 
4.3. 
Justification for Dose ..................................................................................................25 
4.4. 
End of Study Definition ..............................................................................................26 
5. 
STUDY POPULATION .............................................................................................27 
5.1. 
Inclusion Criteria ........................................................................................................27 
5.2. 
Exclusion Criteria .......................................................................................................27 
5.3. 
Screen Failures ............................................................................................................29 
6. 
STUDY INTERVENTION ........................................................................................30 
6.1. 
Study Intervention(s) Administered ...........................................................................30 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................31 
6.2.1. 
Dose Preparation .........................................................................................................31 
6.2.2. 
Handling, Storage, and Accountability .......................................................................31 
6.3. 
Dose Modification ......................................................................................................32 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................................32 
6.5. 
Study Intervention Compliance ..................................................................................33 
6.6. 
Concomitant Therapy .................................................................................................34 
6.6.1. 
Prohibited Therapies ...................................................................................................34 
6.6.2. 
Permitted Therapies ....................................................................................................35 


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6.7. 
Intervention After the End of the Study .....................................................................35 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................36 
7.1. 
Interruption of Study Intervention ..............................................................................36 
7.2. 
Discontinuation of Study Intervention........................................................................37 
7.3. 
Participant Withdrawal from the Study ......................................................................37 
7.4. 
Lost to Follow-up .......................................................................................................38 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
8.1. 
Screening ....................................................................................................................40 
8.2. 
Efficacy Assessments .................................................................................................40 
8.2.1. 
Clinical Evaluations ....................................................................................................40 
8.2.2. 
Laboratory Assessments .............................................................................................41 
8.3. 
Safety Assessments .....................................................................................................41 
8.3.1. 
Physical Examinations ................................................................................................41 
8.3.2. 
Vital Signs ..................................................................................................................41 
8.3.3. 
Electrocardiograms .....................................................................................................42 
8.3.4. 
Clinical Laboratory Assessments ...............................................................................42 
8.4. 
Adverse Events and Serious Adverse Events .............................................................45 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................45 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................45 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................45 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................46 
8.4.5. 
Death Events ...............................................................................................................46 
8.4.6. 
Adverse Events of Special Interest .............................................................................46 
8.5. 
Treatment of Overdose ...............................................................................................46 
8.6. 
Pharmacokinetics ........................................................................................................47 
8.7. 
Pharmacodynamics .....................................................................................................47 
8.8. 
Biomarkers ..................................................................................................................48 
9. 
STATISTICAL CONSIDERATIONS .......................................................................49 
9.1. 
Statistical Hypotheses .................................................................................................49 
9.2. 
Sample Size Determination ........................................................................................49 
9.3. 
Analysis Sets ...............................................................................................................49 
9.4. 
Statistical Analyses .....................................................................................................50 


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9.4.1. 
Primary Endpoint ........................................................................................................50 
9.4.2. 
Secondary Endpoints ..................................................................................................51 
9.4.3. 
Safety Analyses ..........................................................................................................51 
9.4.3.1. 
Adverse Events ...........................................................................................................51 
9.4.3.2. 
Laboratory Results ......................................................................................................52 
9.4.4. 
Other Analyses ............................................................................................................52 
9.5. 
Phase 3 Interim Futility Analysis ...............................................................................52 
9.6. 
Data Monitoring Committee .......................................................................................52 
10. 
REFERENCES ...........................................................................................................54 
11. 
APPENDICES: SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS .....................................................................60 
11.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................61 
11.1.1. 
Regulatory and Ethical Considerations ......................................................................61 
11.1.2. 
Financial Disclosure ...................................................................................................61 
11.1.3. 
Informed Consent Process ..........................................................................................61 
11.1.4. 
Data Protection ...........................................................................................................63 
11.1.5. 
Data Quality Assurance ..............................................................................................63 
11.1.6. 
Source Documents ......................................................................................................64 
11.1.7. 
Study and Site Start and Closure ................................................................................64 
11.1.8. 
Dissemination of Clinical Study Data ........................................................................65 
11.1.9. 
Publication Policy .......................................................................................................65 
11.2. 
Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................66 
11.2.1. 
Definition of AE .........................................................................................................66 
11.2.2. 
Definition of an SAE ..................................................................................................66 
11.2.3. 
Recording and Follow-Up of AEs, SAEs, and AEs of Special Interest .....................68 
11.2.4. 
Reporting of SAEs and AEOSIs .................................................................................69 
11.3. 
Appendix 3: Contraceptive Guidance and Pregnancy Reporting ...............................70 
11.3.1. 
Definitions ..................................................................................................................70 
11.3.2. 
Contraception Guidance .............................................................................................71 
11.3.3. 
Collection of Pregnancy Information .........................................................................73 
11.4. 
Appendix 4: NIAID Ordinal Scale .............................................................................74 
11.5. 
Appendix 5: Tisdale Risk Score .................................................................................75 


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11.6. 
Appendix 6: Evaluation of Potential Heparin-Induced Thrombocytopenia 
(HIT) ...........................................................................................................................76 
11.7. 
Appendix 7: Drugs Known to Prolong the QTc Interval ............................................78 
11.8. 
Appendix 8: Anticoagulation Considerations for Prevention of Venous 
Thromboembolism ......................................................................................................79 
11.9. 
Appendix 9: Abbreviations .........................................................................................80 
11.10. 
Appendix 10: Protocol Amendment Summary of Changes .......................................82 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities/Assessments ...........................................................................16 
Table 2: 
Dociparstat Details ......................................................................................................30 
Table 3: 
Dosing Regimen: Bolus Dose plus Continuous Infusion ...........................................31 
Table 4: 
Laboratory Assessments .............................................................................................44 
Table 5: 
Risk Score to Identify Patients at Greatest Risk of QTc Interval Prolongation .........75 
Table 6: 
The 4Ts Clinical Pretest Probability of HIT ...............................................................77 
Table 7: 
Prophylactic Anticoagulant Dosing Guidelines for Reference ...................................79 
Table 8: 
Amendment 1 Summary of Changes ..........................................................................82 
Table 9: 
Amendment 2 Summary of Changes ..........................................................................84 
Table 10: Amendment 3 Summary of Changes ..........................................................................85 
 
LIST OF FIGURES 
Figure 1: 
Treatment Algorithm ..................................................................................................15 
Figure 2: 
HIT Evaluation Algorithm ..........................................................................................76 
 
 


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1. 
PROTOCOL SYNOPSIS 
Name of Sponsor:  
Chimerix, Inc; 2505 Meridian Parkway, Suite 100; Durham, NC USA 27713 
Name of Investigational Product: dociparstat sodium (DSTAT; CX-01) 
Name of Active Ingredient: 2-O, 3-O desulfated heparin 
Protocol Number: CMX-DS-004 
Version Date: Amendment 3, 06 November 2020 
Phase: 2/3 
Title of Study: A Phase 2/3 Study to Evaluate the Safety and Efficacy of Dociparstat Sodium for the 
Treatment of Severe COVID-19 in Adults at High Risk of Respiratory Failure 
Short Title: Dociparstat for the Treatment of Severe COVID-19 in Adults at High Risk of 
Respiratory Failure  
Regulatory Agency Identifier Number(s): US IND 149,415 
Study Centers: This study will be conducted in the United States. 
Number of Participants: Approximately 600 potential participants are expected to be screened to 
achieve a total of approximately 75 participants randomized in Phase 2, and 450 participants 
randomized in Phase 3 of the study. 
Rationale: The clinical manifestations of infection with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) range from mild, self-limited respiratory tract illness to severe alveolar 
damage and progressive respiratory failure, multiple organ failure, and death. Generally, coronavirus 
infection may damage the lung epithelium and the capillary endothelium, leading to accumulation of 
cell debris and protein exudates from leaky capillaries in the alveoli. The viral-induced tissue damage 
spurs inflammation, immune cell infiltration, coagulation disorders, and mild to severe respiratory 
distress. Mortality in COVID-19 is associated with severe pulmonary disease (e.g., resting oxygen 
saturation of <94% on room air), disseminated intravascular coagulation (DIC), and venous 
thromboembolism (VTE). 
Dociparstat is a glycosaminoglycan derived from porcine heparin. The pharmacologic activity profile 
of dociparstat retains the polyanionic and anti-inflammatory activities of unfractionated heparin with 
substantially reduced anticoagulant activity. 
Dociparstat may improve outcomes in severe COVID-19 by several mechanisms including: 
• 
Reducing inflammation 
• 
Reducing immune cell infiltration 
• 
Reducing excessive thrombosis 
Dociparstat is a well-characterized compound that is also in clinical development for acute myeloid 
leukemia and has demonstrated a favorable safety profile in clinical studies for acute chronic 
obstructive pulmonary disease exacerbations, pancreatic cancer, and acute myeloid leukemia (AML).  
Overall Design 
This is a randomized, double-blind, placebo-controlled, Phase 2/3 study to determine the safety and 
efficacy of dociparstat in adults with acute lung injury associated with severe COVID-19 who are at 
high risk of respiratory failure. 
Eligible participants hospitalized with laboratory-confirmed SARS-CoV-2, with a resting oxygen 
saturation (by pulse oximetry) of <94% on ambient air will be randomized to receive dociparstat or 
placebo as an initial IV bolus dose followed by a continuous IV infusion for 7 days; both groups will 


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also receive best supportive care (as determined by the investigator) as background therapy. The 
randomization ratio will be 1:1 in Cohort 1 and 2:1 (dociparstat: placebo) in all other cohorts. 
Randomization of participants in Phase 2/Cohort 3 and Phase 3 will be stratified by baseline score on 
the National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale (3 or 4) and by age 
(<60 years or ≥60 years). Randomization of participants in Phase 3 will additionally be stratified by 
baseline BMI (<34 kg/m2 or ≥34 kg/m2). 
Enrollment will be as follows: 
• 
Phase 2 
− Cohort 1: 6 participants randomized to dociparstat, 6 randomized to placebo. Dociparstat 
will be dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.25 mg/kg/hr. 
− Cohort 2: 8 participants randomized to dociparstat, 4 randomized to placebo. Dociparstat 
will be dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.325 mg/kg/hr 
(dose to be confirmed after review of data from Cohort 1). 
− Cohort 3: 34 participants randomized to dociparstat, 17 randomized to placebo. 
Dociparstat will be dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.25 or 
0.325 mg/kg/hr (dose to be determined after review of data from prior cohorts). 
• 
Phase 3: 300 participants randomized to dociparstat, 150 randomized to placebo.  
Dociparstat will be dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.25 or 
0.325 mg/kg/hr (will be the same dose as administered in Cohort 3). 
The primary efficacy endpoint is the proportion of participants who are alive and free of invasive 
mechanical ventilation through Day 28. Secondary endpoints include all-cause mortality, disease 
resolution, time to improvement, number of ventilator-free days, daily average of prednisone-
equivalent corticosteroid dose, and change in potential biomarkers. Safety, including hematology, 
chemistry, and coagulation parameters and the incidence of AEs, severe AEs, and SAEs, will be 
assessed throughout the study. 
After completion or discontinuation of study intervention, all participants will be followed-up 
through Day 28. 
Note: In the setting of a highly-infectious pandemic with resource-constrained investigative sites, all 
protocol-specified assessments are understood to be “whenever practicable/feasible” (considering the 
safety of both the study participant and medical personnel). Many of the protocol-specified 
assessments will be performed and data collected as part of standard care; data relevant to the study 
will be entered into the case report form. Evolving best practices and guidance from the Food and 
Drug Administration and other agencies, professional organizations, and local institutions will be 
consulted as the study progresses. 
 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary – Phase 2 
 
• To select maximally tolerated dose 
for use in Phase 3, and to assess the 
effect of dociparstat on disease 
progression in participants with 
severe COVID-19  
 
 
• Incidence of AEs, severe AEs, and SAEs 
• Proportion of participants who are alive and free of 
invasive mechanical ventilation through Day 28. 


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Primary – Phase 3 
 
• To assess the effect of dociparstat on 
disease progression in participants 
with severe COVID-19  
• Proportion of participants who are alive and free of 
invasive mechanical ventilation through Day 28. 
Key Secondary  
 
• To assess the effect of dociparstat on 
mortality 
• All-cause mortality through Day 28 
Secondary  
 
• To determine additional evidence of 
a therapeutic effect of dociparstat in 
participants with severe COVID-19  
• Time to invasive mechanical ventilation or all-cause 
mortality 
• Time to all-cause mortality 
• Proportion of participants who are alive, discharged from 
the hospital, and not using home oxygen at fixed time 
points (Days 8, 14, and 28) 
• Clinical status assessed by the NIAID ordinal scale at 
fixed time points (Days 8, 14, and 28) 
• Time to clinical improvement, defined as time to at least 
a 2-grade improvement from baseline on the NIAID 
ordinal scale 
• Number of ventilator-free days from baseline through 
Day 28 
• Time to hospital discharge 
• Time to resolution of fever, defined as temperature 
≤99.0°F (≤37.2°C) and no antipyretic use within the 
preceding 48 hours (participants with baseline fever only) 
• Change from baseline in C-reactive protein level 
• Change from baseline in serum ferritin level 
• Change from baseline in lactate dehydrogenase level 
• Change from baseline in d-dimer level 
• Daily average of prednisone-equivalent corticosteroid 
dose through Day 28 
• To determine the safety of 
dociparstat when added to best 
supportive care for the treatment of 
severe COVID-19 
• Incidence of AEs: overall, treatment-related, Grade 3 or 
higher in severity, serious, fatal, and those resulting in 
treatment discontinuation 
• Change from baseline in clinical laboratory parameters 
• Distribution of graded clinical laboratory results 
Exploratory 
 
• To determine the effect of 
dociparstat on viral load and 
biomarkers related to the 
pathophysiology of severe 
COVID-19  
• Change from baseline in levels of high mobility group 
box protein 1 (HMGB1), interleukin-6 (IL-6), tumor 
necrosis factor alpha (TNFα), serum amyloid A (SAA), 
and other biomarkers of inflammation 


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• Change from baseline in SARS-CoV-2 viral load 
(Cohort 3 and Phase 3 only) 
• To evaluate the systemic exposure 
of dociparstat. 
• Dociparstat plasma concentrations and PK parameters as 
data permit. 
Diagnosis and Main Criteria for Inclusion: 
A potential participant must meet all the following criteria to be eligible to participate in the study: 
1. Hospitalized for laboratory-documented COVID-19 disease (e.g., positive for SARS-CoV-2 
via nasopharyngeal swab RT-PCR [or other commercial or public health assay]). 
2. Age ≥18 years and ≤85 years. 
3. Resting oxygen saturation (SaO2) of <94% while breathing ambient air. 
4. Score of 3 or 4 on the NIAID ordinal scale (requires supplemental oxygen or noninvasive 
ventilation). 
5. Provide informed consent to participate in the study (by participant or legally-acceptable 
representative). 
A potential participant who meets any of the following criteria is not eligible to participate in the 
study: 
1. Currently receiving invasive mechanical ventilation (e.g., via an endotracheal tube) (score 
of 2 on NIAID ordinal scale). 
2. Severe chronic respiratory disease, defined by any oxygen requirement prior to incident 
COVID-19. 
3. Active or uncontrolled bleeding at the time of randomization; a bleeding disorder, either 
inherited or caused by disease; history of known arterial-venous malformation, intracranial 
hemorrhage, or suspected or known cerebral aneurysm; or clinically significant (in the 
judgment of the investigator) gastrointestinal bleeding within the 3 weeks prior to 
randomization. 
4. Receiving any other investigational (non-approved) therapy for the treatment of COVID-19 
or participating in the treatment period of any other therapeutic intervention clinical study. 
Participating in the follow-up period of an interventional study may be permitted with prior 
medical monitor approval; participation in an observational study is permitted. Refer to the 
list of prohibited and permitted concomitant therapies. 
5. Receiving systemic corticosteroids for a chronic condition. 
6. Receiving chronic anticoagulation with warfarin or direct oral anticoagulants 
(e.g., rivaroxaban, dabigatran, apixaban, edoxaban).  
7. Receiving or anticipated to require systemic anticoagulation dosing at a therapeutic intensity. 
Prophylaxis of VTE using SC unfractionated heparin or enoxaparin is permitted with 
appropriate monitoring of coagulation status and within the guidelines described in 
Appendix 8. 
8. Receiving antiplatelet therapy, alone or in combination, including aspirin and other 
antiplatelet agents (e.g., clopidogrel, ticagrelor, and prasugrel), unless able to discontinue 
these agents at the time of randomization and to remain off these agents throughout the 
duration of the study intervention infusion period. 
9. Treatment with systemic (nonsteroid) immunomodulators or immunosuppressant 
medications, including but not limited to TNF inhibitors, anti-interleukin-1 agents, and Janus 
kinase (JAK) inhibitors within 5 half-lives or 30 days (whichever is longer) prior to 
randomization. 


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10. A history of congestive heart failure requiring hospitalization. 
11. Active pericarditis (based on clinical assessment). 
12. Malignancy or other irreversible disease or condition for which 6-month mortality is 
estimated ≥50%. 
13. QTc >500 msec (or >530-550 msec in participants with QRS greater than >120 msec).  
(See Section 8.3.3 for details about QTc correction formulas.) 
14. Tisdale risk score ≥11 without the ability to monitor with serial ECGs or telemetry. 
15. Severe renal impairment, as determined by calculated creatinine clearance <30 mL/min or 
estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. 
16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x upper limit of 
normal (ULN). 
17. Activated partial thromboplastin time (aPTT) >42 seconds. 
18. Thrombocytopenia with a platelet count <80,000/mm3. 
19. Severe chronic liver disease (Child-Pugh Score of 10 to 15). 
20. Received dociparstat in a different clinical study. 
21. Woman of childbearing potential who is pregnant, breastfeeding, and/or not using a highly-
effective method of contraception (consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies). 
22. Evidence of clinical improvement in COVID-19 status including, but not limited to, a 
sustained reduction in oxygen requirements over the previous 48 hours, or extubated and/or 
no longer requiring mechanical ventilation following intubation for COVID-19. 
23. Any other condition, including abnormal laboratory values, that, in the judgment of the 
investigator, could put the participant at increased risk, or would interfere with the conduct or 
planned analysis of the study. 
Intervention Groups and Duration: Participants will receive study intervention for 7 days 
(168 hours). Participants who have improved and are eligible for hospital discharge prior to 
completion of the planned 7-day treatment course will discontinue study intervention just prior to 
discharge. 
All participants will be followed-up through Day 28. 
Study Intervention: Participants will receive blinded study intervention consisting of either 
dociparstat or normal saline as a placebo control for 7 days (starting on Day 1 and ending on Day 8 
[168 hours]). Both groups will also receive best supportive care (as determined by the investigator). 
Dociparstat dosing will be as follows: 
• 
Phase 2 
− Cohort 1: 4 mg/kg IV bolus followed by continuous infusion of 0.25 mg/kg/hr. 
− Cohort 2: 4 mg/kg IV bolus followed by continuous infusion of 0.325 mg/kg/hr  
(dose to be confirmed after review of data from Cohort 1). 
− Cohort 3: 4 mg/kg IV bolus followed by continuous infusion of 0.25 or 0.325 mg/kg/hr 
(dose to be determined after review of data from prior cohorts). 
• 
Phase 3: 4 mg/kg IV bolus followed by continuous infusion of 0.25 or 0.325 mg/kg/hr  
(will be the same dose as administered in Cohort 3). 
Dociparstat sodium solution for injection 50 mg/mL is provided by the sponsor in 10-mL vials. Each 
vial will be labeled in accordance with applicable regulatory requirements. Normal saline is sourced 
and provided by the study center. 


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Preparation of dociparstat will be performed by an unblinded pharmacist within the investigational 
pharmacy or other designated entity. Dociparstat will be initially administered as an IV bolus dose 
over 5 minutes, followed by a continuous maintenance infusion of dociparstat administered 24 hours 
daily for 7 days. 
The unblinded pharmacist will prepare each study intervention to the appropriate dose based on the 
individual participant’s body weight. Normal saline will be used to dilute the IV bolus dose and 
continuous maintenance infusion of dociparstat treatment. The dociparstat IV bolus dose will be 
diluted to a total infusion volume of 30 mL. The 24-hour continuous infusion will have the 
appropriate volume of dociparstat added to approximately 250 mL or 500 mL of 0.9% normal saline. 
Study Intervention Dose Interruptions and Modifications: 
Infusion of study intervention (i.e., dociparstat or placebo) will be interrupted in the following 
situations: 
aPTT: If aPTT is >50 seconds, repeat testing as soon as practicable. If aPTT is confirmed >50 
seconds (or when retest and confirmation cannot occur within the same day), reduce the dose of 
unfractionated heparin or enoxaparin (as applicable). If aPTT remains elevated upon repeat testing, 
then interrupt the study intervention infusion. [Note: ensure aPTT samples were not obtained from 
the same line as the study intervention infusion (e.g., collect samples via peripheral venipuncture).] 
• 
Participants in cohorts with dociparstat dosed at 0.25 mg/kg/hr: study intervention dosing 
will not be resumed if interruption criteria are met. 
• 
Participants in cohorts with dociparstat dosed at 0.325 mg/kg/hr: To minimize time that the 
participant is off therapy, perform repeat testing for aPTT approximately 2 to 6 hours after 
interruption (as practicable). When aPTT is <40 seconds, the infusion may be resumed at a 
reduced dose of 0.25 mg/kg/hr. 
Renal function: If the calculated creatinine clearance drops below 30 mL/min or eGFR drops below 
30 mL/min/1.73 m2 prior to or during dosing with study intervention, the infusion will be held until 
the creatinine clearance or eGFR rises to ≥30. 
Thrombocytopenia: If a participant experiences a decrease in platelet count by ≥50% from baseline 
value, or to an absolute platelet count of <50,000/mm3 they are to be evaluated for possible heparin-
induced thrombocytopenia (HIT), per the algorithm in Appendix 6. For participants with a 4Ts score 
≥4 who are receiving concomitant VTE prophylaxis permitted per protocol, discontinue heparin or 
enoxaparin until test results rule out heparin-induced thrombocytopenia. For those participants with a 
4Ts score ≥4 who are not receiving VTE prophylaxis permitted per protocol, study intervention is to 
be interrupted, and may only be resumed if test results rule out HIT, and the 7-day treatment period 
has not ended. 
ECG/QTc: If QTc increases by >60 msec or absolute QTc is >500 msec (or >530-550 msec if QRS 
>120 msec), discontinue and/or reduce the dose of potentially causative medications 
(e.g., azithromycin and hydroxychloroquine; see Appendix 7). Repeat ECG daily. If there is no 
reduction in QTc after modifications to dosing of other medications (e.g., azithromycin and 
hydroxychloroquine), discontinue study intervention. 
Discontinuation of Study Intervention: 
In some instances, it may be necessary for a participant to permanently discontinue study intervention 
before completing the protocol-specified treatment period. Reasons for permanent discontinuation of 
study intervention may include the following: 
• 
Criteria for restarting study intervention after interruption were not met. 
• 
ALT ≥3x ULN (and >2x baseline value) plus bilirubin ≥2x ULN. 
• 
Thrombocytopenia, defined as a platelet count of <30,000/mm3. 


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• 
Hemorrhagic AE of Grade 3 or higher. 
• 
Other treatment-related AE of unacceptable severity. 
• 
Condition has improved and participant is eligible for hospital discharge. 
• 
Participant requests to discontinue study intervention. 
• 
Investigator initiates treatment with a therapeutic anticoagulant dose, a thrombolytic agent, or 
otherwise prohibited therapy that may affect the participant’s safety if study intervention 
were to be continued. 
• 
Investigator determines discontinuation is in the best interests of the participant for safety, 
behavioral, compliance, or administrative reasons. 
Participants who discontinue study intervention early will complete the early discontinuation 
assessments (refer to the Schedule of Assessments) and will continue to be followed-up for outcomes 
through Day 28. 
Criteria for Evaluation 
Efficacy will be evaluated through clinical examinations, oxygen requirements, and laboratory tests. 
Safety will be monitored through collection of AE data and laboratory tests. 
For this study, the following events will be considered AEs of special interest and must be recorded 
and reported to the sponsor (or designee) within 24 hours: 
• 
Bleeding / hemorrhagic AEs. 
• 
Heparin-induced thrombocytopenia (HIT). 
All planned assessments and associated time points are shown in the Schedule of Activities. 
Data Monitoring Committee: An independent unblinded data monitoring committee (DMC) will 
review safety data from Cohort 1 to make a recommendation on dose escalation in Cohort 2 and 
review safety data from both Cohorts 1 and 2 to make a recommendation on dosing in Cohort 3. The 
sponsor will consider the DMC recommendation when determining the actual doses for Cohorts 2 
and 3. Due to the evolving standard of care for COVID-19, the sponsor may decide to unblind and 
review study data following Cohort 1 and/or 2. After completion of Phase 2, all data will be 
unblinded to the DMC and sponsor to determine whether the study should proceed with enrollment of 
Phase 3. 
During Phase 3, the DMC will convene to review safety data after approximately 100, 225, and 
350 participants complete the study. In addition, the DMC will review the pre-specified futility 
interim analysis. 
The DMC will be provided with real-time, expedited safety reports to continue monitoring safety. 
The DMC chair may schedule ad hoc safety review meetings at any time during the study as deemed 
appropriate. 
Statistics: 
The sample size of 12 participants for Cohorts 1 and 2 was selected to assess for any major safety 
signals in a limited number of participants. The sample size of 51 participants for Cohort 3 was 
selected to provide a reasonable level of precision to assess the treatment effect for the primary 
endpoint. For Phase 3, the sample size of 450 participants was selected to detect the difference 
between a control failure rate of 20% and a dociparstat failure rate of 9% at a two-sided 0.05 alpha 
level with >80% power. This also accounts for a futility analysis after 50% of the Phase 3 
participants are enrolled using a Pocock beta spending function. 
The intent-to-treat analysis set will be used to summarize all efficacy endpoints. The per-protocol 
analysis set will be determined prior to unblinding and will be used for supportive primary and key 
secondary efficacy analyses and possibly other selected endpoints to be defined in the Statistical 


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Analysis Plan. The safety analysis set will be used to summarize all safety and other non-efficacy 
(e.g., medical history, medications, exposure) analyses. 
Data from Cohorts 1 and 2 will be analyzed and presented separately. Due to the evolving standard of 
care for COVID-19, the sponsor may decide to unblind and review study data following Cohort 1 
and/or 2; therefore, one of two scenarios will inform the analysis approach for Cohort 3 as follows: 
• 
In the event that Cohort 1 and 2 results remain blinded through Cohort 3 database lock, 
Cohort 3 data will be combined with either Cohort 1 or Cohort 2 data, depending on the 
selected dose.  
• 
In the event that Cohort 1 and/or 2 results are unblinded prior to Cohort 3 database lock, 
Cohort 3 data will be analyzed and presented separately. In addition, Cohort 1, 2, and 3 data 
may be combined to support exploratory analysis.  
Phase 3 analyses will be presented separately (i.e., data from the Phase 2 portion of the study will not 
be used for the final confirmatory inference). 
For Phase 3, the primary analysis will utilize the ITT analysis set and a Cochran-Mantel-Haenszel 
test stratified by each of the actual stratification factors. Participants will be counted as failures once 
they go on a ventilator or die. Number and percentage of failures will be presented for each treatment 
arm. Cochran-Mantel-Haenszel p-values, estimated common odds ratios, estimated common risk 
differences, and corresponding approximate two-sided 95% CIs will be presented. The Breslow-Day 
test will be used to test the homogeneity of the odds ratios across strata. Although missing data are 
expected to be limited, any such cases will be imputed as failure. A supportive analysis using 
multiple imputation will be done in order to assess the sensitivity of the inference to the approach to 
missing data. 
All safety analyses will be presented using the safety analysis set. Inferential analyses will generally 
not be performed for safety endpoints unless specified in the Statistical Analysis Plan. Frequency and 
percentage will be presented for categorical variables. Sample size, mean, standard deviation, 
median, interquartile range, and range will be presented for continuous variables. 
 


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Figure 1: 
Treatment Algorithm 
 
 
Phase 2, Cohort 1
Dociparstat N=6
Placebo N=6
Phase 2, Cohort 2
Dociparstat N=8
Placebo N=4
Phase 2, Cohort 3
Dociparstat N=34
Placebo N=17
Phase 3
Dociparstat N=300
Placebo N=150
DMC 
Review 
All participants:  
• 
Randomized treatment for 7 days 
• 
Follow-up through Day 28 
DMC 
Review 
DMC 
Review 


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1.1. 
Schedule of Activities 
Table 1: 
Schedule of Activities/Assessments 
Study Day: 
Screen 
BL/ 
D1 
D
2 
D
3 
D
4 
D
5 
D
6 
D
7 
D
8 
D  
14±3d 
D  
28±3d 
Early 
Therapy 
DC 
Notes 
Examination / Procedure 
Study day is relative to Day 1= first 
dose of study intervention 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination / vital signs 
X 
 
 
 
 
 
 
 
 
 
 
 
Record abnormal results as medical 
history 
Height / Weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature / antipyretic use  
X 
X 
-----------------------------------------------------→ 
X 
Collect per standard of care through 
hospital discharge 
Electrocardiograma 
X 
 
 
X 
 
 
 
 
 
 
 
 
Monitor per standard of care 
Pregnancy test (as applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
Women of childbearing potential 
Laboratory assessments 
– Hematology, Clinical chemistryb 
– D-dimer, fibrinogen 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Local laboratory – record results in the 
case report form 
– Biomarkers (e.g., HMGB1, IL-6, 
SAA, TNFα) 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Store plasma samples for central 
laboratory analysis 
– PT/INR, aPTT c,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Local Lab. Do not draw from the same 
line used for drug administration c,d 
– Anti-Xa (if applicable) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
To monitor enoxaparin anticoagulation 
Pharmacokinetic samples  
(sites with appropriate capabilities) 
 
Xc 
Xc 
 
Xc 
 
 
 
Xc 
 
 
 
D1 predose and end of bolus dose, D2 
and D4 anytime, D8/end of continuous 
infusion. Do not draw from the same 
line used for drug administration. 
Central laboratory analysis. 
NIAID ordinal scale components 
– Ventilator use 
– Oxygen use 
X 
X 
-------------------------------------------------------→ 
X 
Record date/time for each change in 
individual components of the 
assessmente 
Sample for virology 
 
X 
 
 
 
 
 
 
X 
 
 
 
Cohort 3 and Phase 3 only 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Study Day: 
Screen 
BL/ 
D1 
D
2 
D
3 
D
4 
D
5 
D
6 
D
7 
D
8 
D  
14±3d 
D  
28±3d 
Early 
Therapy 
DC 
Notes 
Examination / Procedure 
Study day is relative to Day 1= first 
dose of study intervention 
Study intervention – bolus dose 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study intervention – continuous 
infusion – start/change IV bag 
 
X 
X 
X 
X 
X 
X 
X 
End 
 
 
 
Begin after bolus dose 
Adverse event assessmentsf 
Procedure-
related SAEs 
X 
-------------------------------------------------------→ 
X 
Record through Day 28 
Concomitant medications 
X 
X 
-------------------------------------------------------→ 
X 
Abbreviations: aPTT=activated partial thromboplastin time; D=day; INR=international normalized ratio; NIAID (ordinal scale)= National Institute of Allergy 
and Infectious Diseases (scale used in Study NCT04280705); PT=prothrombin time; HMGB1=high mobility group box protein 1; IL-6=interleukin-6; 
SAA=serum amyloid A; TNFα=tumor necrosis factor alpha 
 
a Recommend following guidelines of American College of Cardiology. Day 3 ECG not required if participant is on continuous telemetry. Perform unscheduled 
ECG if irregular heart rhythm on exam or telemetry. 
b Refer to Section 8.3.4 and Table 4 for complete list of laboratory tests. Chemistry includes alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, bilirubin (total and direct), blood urea nitrogen, C-reactive protein, creatinine (with calculated creatinine clearance or estimated glomerular 
filtration rate), calcium, ferritin, lactate dehydrogenase, magnesium, potassium, and sodium. Hematology includes platelet count, hemoglobin, absolute 
neutrophil count, and white blood cell count with differential. In the event of thrombocytopenia, refer to the evaluation algorithm in Appendix 6 for additional 
laboratory tests to diagnose/rule out heparin-induced thrombocytopenia. 
c Do not draw blood for aPTT or PK analyses from the same line that is used for study intervention administration. Drawing blood from a heparinized line may 
falsely alter results obtained; therefore, if using an indwelling catheter, draw approximately 5 mL of blood from the line for discard before drawing the aPTT 
and PK samples. 
d Draw blood for aPTT measurements no sooner than 8 hours after the bolus dose. During the continuous infusion, aPTT should be measured a minimum of once 
daily; more frequent monitoring is recommended when feasible based on the clinical status of the participant. 
e Record date AND time for each change in individual components of the assessment: mechanical ventilation start/stop, high flow/mask oxygen start/stop, nasal 
oxygen start/stop, hospital discharge (whether with limitations, or without limitations), and death. 
f All adverse events must be recorded from the time of administration of the first dose of study intervention until the participant has completed the study 
(Day 28). However, any study procedure-related SAE that occurs after the study participant has signed the informed consent form and prior to administration of 
the first dose of study intervention should be recorded as an SAE for the purposes of this protocol.


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2. 
INTRODUCTION 
Dociparstat sodium is being investigated for the treatment of acute lung injury (ALI) associated 
with severe Coronavirus Disease 2019 (COVID-19) in adults. 
2.1. 
Study Rationale 
This Phase 2/3 study of dociparstat in participants with ALI associated with severe COVID-19 is 
being conducted to determine whether dociparstat can be safely and effectively used to mitigate 
respiratory failure, prevent the need for ventilator support, and reduce excessive coagulation. 
Dociparstat is a glycosaminoglycan derived from porcine heparin. The pharmacologic activity 
profile of dociparstat retains the polyanionic and anti-inflammatory activities of unfractionated 
heparin with substantially reduced anticoagulant activity (Rao 2010). 
Dociparstat may improve outcomes in severe COVID-19 by several mechanisms including: 
1. Reducing inflammation 
2. Reducing immune cell infiltration 
3. Reducing excessive thrombosis 
Dociparstat is a well-characterized compound that is also in clinical development for acute 
myeloid leukemia (AML) and has demonstrated a favorable safety profile in clinical studies for 
acute exacerbations of chronic obstructive pulmonary disease (COPD), pancreatic cancer, and 
AML (Kovacsovics 2018). 
The purpose of this study is to test whether use of dociparstat results in clinical benefit in 
patients hospitalized with severe COVID-19. This study is being conducted in accordance with 
the Secretary of the Department of Health and Human Services’ (HHS) Declaration under the 
Public Readiness and Emergency Preparedness (PREP) Act for medical countermeasures against 
COVID-19 (COVID-19 Declaration) effective 04 February 2020. This study is authorized to 
proceed under an approved Investigational New Drug application (IND) in accordance with the 
public health and medical response of the Food and Drug Administration (FDA), an Authority 
Having Jurisdiction as described under the PREP Act, to prescribe, administer, deliver, 
distribute, or dispense this Covered Countermeasure as defined by and following the HHS 
COVID-19 Declaration. 
2.2. 
Background 
The clinical manifestations of infection with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) range from mild, self-limited respiratory tract illness to severe alveolar damage 
and progressive respiratory failure, multiple organ failure, and death (Wang 2020, Wu 2020, 
Xu 2020). Generally, coronavirus infection may damage the lung epithelium and the capillary 
endothelium, leading to accumulation of cell debris and protein exudates in the alveoli 
(Tian 2020). The viral-induced tissue damage spurs inflammation, immune cell infiltration, 
coagulation disorders, and mild to severe respiratory distress. Disease severity and mortality in 
COVID-19 is associated with progressive pulmonary complications (e.g., resting oxygen 
saturation of <94% on room air), high concentrations of proinflammatory cytokines, a high 


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neutrophil to lymphocyte ratio, and disseminated intravascular coagulation (DIC) (Liu 2020, 
Herold 2020, Tang 2020, Zhou 2020). Based on the pulmonary pathophysiology, a critical need 
exists for therapies to manage patients with severe COVID-19 disease who are at risk of 
progressing to intubation. Preventing progression to mechanical ventilation would mitigate 
secondary pathologies associated with ventilator use (e.g., lung injury, infections) and ease the 
burden on a limited supply of mechanical ventilators. 
Nebulized heparin has shown some efficacy in the treatment of ALI which has led to the 
COVID-19 HOPE Trial recently proposed (Dixon 2010, McGinn 2019). IV administration of 
dociparstat may present an advantage by allowing for the systemic administration of a low 
anticoagulant heparin derivative while avoiding the significant risks to healthcare providers 
associated with nebulization in the context of active SARS-CoV-2 infection. The following 
sections provide a summary of the proposed mechanisms of action for dociparstat in COVID-19. 
Dociparstat has the potential to decrease inflammation in the setting of ALI via inhibition 
of high mobility group box protein 1 (HMGB1). 
Dociparstat inhibits activity of HMGB1, a highly regulated (e.g., via oxidation state, acetylation, 
phosphorylation, location) protein that plays a major role in the pathogenesis of immune 
disorders and is often associated with proinflammatory responses to infection and injury. 
HMGB1 is released in active forms from necrotic cells and/or secreted by immune cells such as 
activated macrophages (Harris 2004; Pisetsky 2007), dendritic cells, and natural killer cells 
(Semino 2005). It interacts with multiple proteins, including receptor for advanced glycation end 
products (RAGE) and toll-like receptors, which may upregulate production of interleukin-6 
(IL-6) and tumor necrosis factor alpha (TNFα) by macrophages via activation of nuclear factor 
kappa B (NFκB) (Rao 2010, Pisetsky 2007). 
A variety of cytokines, including IL-6, TNFα, and monocyte chemoattractant protein 1 (MCP-1), 
are elevated in SARS-CoV-2 infected patients (Huang 2020) and patients infected with 
SARS-CoV and MERS-CoV (Channappanavar 2017, Chien 2006, Wang 2005, Wong 2004, 
Zhang 2004). Plasma IL-6 is associated with ALI in COVID-19 patients and has been proposed 
as a biomarker which correlates with disease severity (Herold 2020). Huan et al. demonstrated 
significant reductions in cytokine expression (including IL-6 and TNFα) with HMGB1 inhibition 
in a porcine epidemic diarrhea virus model derived from the genus Alphacoronavirus 
(Huan 2016). 
Inhibition of HMGB1 is an attractive target as it may modulate multiple proinflammatory 
cytokines/chemokines and has been shown to attenuate cytokine-associated lung injury 
(Jia 2016). While trials are underway to specifically inhibit IL-6 activity, no HMGB1 inhibitors 
are in clinical studies. Dociparstat inhibits HMGB1 interaction RAGE and other targets involved 
in inflammation and chemotaxis in sepsis and trauma, suggesting potential to reduce 
inflammation/activation during SARS-CoV-2 associated with cytokines including, but not 
limited to, IL-6 and TNFα (Harris 2004, Pisetsky 2007, Rao 2010, Zeng 2015). 
Dociparstat has the potential to reduce immune cell infiltration in the lungs. 
Infiltration of monocytes and other immune cells into the inflamed lung tissue is a key 
pathogenic driver of ALI (Aggarwal 2014, Thompson 2017, Jiang 2017, Li 1998). Dociparstat 
treatment may inhibit immune cell migration and lung infiltration via HMGB1-mediated 
inhibition of MCP-1 and other ligands. HMGB1 inhibition with inhibitors other than dociparstat 


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has demonstrated downregulation of MCP-1 with subsequent reduction of monocyte chemotaxis 
(Nativel 2013). In addition, dociparstat is a potent inhibitor of P-selectin and Mac-1 (Rao 2010), 
which are required for immune cell attachment to the pulmonary endothelium and subsequent 
transendothelial migration (Gerhardt 2015; Ivetic 2019). Finally, dociparstat may interfere with 
CXCR4/CXCL12 mediated chemotaxis both by direct interaction with CXCL12 and indirectly 
through inhibition of HMGB1 activity which can also induce CXCR4/ CXCL12-mediated 
chemotaxis (Kovacsovics 2018, Yang 2013). These interactions suggest that dociparstat may 
reduce cellular infiltration of immune cells in the lungs via multiple mechanisms. 
In a mouse model of neutrophil elastase induced airway inflammation, dociparstat reduced 
HMGB1 in bronchoalveolar lavage and reduced airway inflammation (Griffin 2014). 
Furthermore, dociparstat demonstrated activity in a mouse model of Pseudomonas aeruginosa 
mediated pneumonia/ALI where treatment reduced the concentration of HMGB1 in 
bronchoalveolar lavage, reduced cell/neutrophil infiltration, and reduced lung damage, resulting 
in increased survival (Sharma 2014). 
Dociparstat has the potential to alleviate coagulation disorders. 
DIC has been demonstrated in patients with infectious diseases such as sepsis. DIC is 
characterized by elevated d-dimers as well as decreased platelet counts and has been linked to 
inferior outcomes in sepsis patients (Milbrandt 2009, Rodelo 2012). Notably, DIC has been 
observed in COVID-19 patients with autopsies identifying clotting in the pulmonary and venous 
systems (Lippi 2020b, Tang 2020, Zhou 2020). In addition, there have been reports of fatal 
pulmonary embolisms in COVID-19 patients (Xie 2020). 
A recent retrospective analysis of 1779 patients with COVID-19 (399 were severe) found that a 
low platelet count was associated with a >5-fold increased risk of severe COVID-19 
(Lippi 2020a). Activated platelets drive inflammation and tissue damage by the release of 
platelet factor 4 (PF4) which has been implicated in endothelial cell toxicity, 
pulmonary/capillary barrier compromise, and recruitment of inflammatory cells into the 
interstitial and bronchoalveolar space, potentially via histone displacement from neutrophil 
extracellular traps (NETs) (Bdeir 2017, Doster 2018, Kowalska 2014, Krauel 2012, Porto 2016, 
Alhamdi 2017). Dociparstat binds to PF4 and can inhibit its activities (Joglekar 2012; 
Krauel 2012). 
HMGB1 may be implicated in DIC via several mechanisms including proinflammatory activity 
and interaction with DNA and histones. In sepsis, the pathogenesis of DIC is triggered by the 
systemic inflammatory response, in which IL-6 and other HMGB1-induced cytokines are 
important mediators (Gando 2016, Levi 1997, Levi 2004). Additionally, HMGB1 promotes the 
formation of NETs during inflammation (Tadie 2013). While NETs are often beneficial in 
trapping and killing pathogens (e.g., bacteria), they can also promote excessive thrombosis by 
providing a substrate for platelet binding and aggregation (Porto 2016; Brinkmann 2004, 
Elaskalani 2018, Fuchs 2010, Fuchs 2012). Inhibition of these PF4 and HMGB1-associated 
activities, in concert with the low-level anti-coagulative activity of dociparstat, may reduce DIC 
and other coagulation disorders in patients with severe COVID-19 without the risk of severe 
bleeding events presented by heparin. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of dociparstat is 
provided in the investigator’s brochure. 


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2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Based on results of dociparstat nonclinical and clinical studies and the relationship of dociparstat 
to heparin, possible risks of particular interest with dociparstat therapy include prolonged aPTT 
(with a potential associated risk of bleeding/hemorrhagic events) and an increase in hepatic 
enzymes. Transient elevation of liver enzymes is considered a class effect for all heparins, 
heparin derivatives, LMWHs, and heparinoids (Harrill 2012). 
Inclusion/exclusion criteria and screening assessments are designed to limit enrollment to 
participants who are less likely to have confounding conditions that could impact their safety 
(see Section 5). Participants will receive dociparstat while inpatients and will be monitored 
throughout the infusion period. Criteria for dose interruption and discontinuation are included in 
Section 7. 
Heparin is not associated with QT prolongation and no cardiac safety signal has been identified 
to date in preclinical and clinical dociparstat studies. However, considering the risk of QT 
prolongation associated with potential concomitant medications (e.g., hydroxychloroquine), it is 
recommended that the investigator monitor participants in accordance with the American 
College of Cardiology (or equivalent) guidelines (Simpson 2020). 
Both unfractionated and low molecular weight heparins have been associated with heparin-
induced thrombocytopenia (HIT). In contrast, dociparstat suppresses heparin-induced 
thrombocytopenia-related platelet activation in vitro and may disrupt formation of heparin/PF4 
multimolecular complexes. 
More detailed information about the known and expected benefits, risks, and reasonably 
expected AEs of dociparstat may be found in the investigator’s brochure. 
2.3.2. 
Benefit Assessment 
Treatment with dociparstat may prevent or mitigate respiratory failure and the need for ventilator 
support in participants with severe COVID-19, which is a newly-identified disease with no 
approved treatment options. 
Results of this study will also contribute to the rapidly evolving knowledgebase regarding the 
natural history of SARS-CoV-2 infection, the progression of COVID-19, and which patients are 
most likely to require and respond to various treatments. 
2.3.3. 
Overall Benefit: Risk Conclusion 
COVID-19 is a serious, life-threatening, novel condition with no approved treatment options. 
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified in association with dociparstat treatment are not greater than the risks of only receiving 
supportive care. 
Thus, the use of dociparstat is justified by the anticipated benefits that may be afforded to 
participants with COVID-19 in this study. 


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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary – Phase 2 
 
• To select maximally tolerated dose 
for use in Phase 3, and to assess the 
effect of dociparstat on disease 
progression in participants with 
severe COVID-19  
• Incidence of AEs, severe AEs, and SAEs 
• Proportion of participants who are alive and free of 
invasive mechanical ventilation through Day 28 
Primary – Phase 3 
 
• To assess the effect of dociparstat on 
disease progression in participants 
with severe COVID-19  
• Proportion of participants who are alive and free of 
invasive mechanical ventilation through Day 28 
Key Secondary  
• To assess the effect of dociparstat on 
mortality 
• All-cause mortality through Day 28 
Secondary 
 
• To determine additional evidence of 
a therapeutic effect of dociparstat in 
participants with severe COVID-19  
• Time to invasive mechanical ventilation or all-cause 
mortality 
• Time to all-cause mortality 
• Proportion of participants who are alive, discharged from 
the hospital, and not using home oxygen at fixed time 
points (Days 8, 14, and 28) 
• Clinical status assessed by the NIAID ordinal scale at 
fixed time points (Days 8, 14, and 28) 
• Time to clinical improvement, defined as time to at least 
a 2-grade improvement from baseline on the NIAID 
ordinal scale 
• Number of ventilator-free days from baseline through 
Day 28 
• Time to hospital discharge 
• Time to resolution of fever, defined as temperature 
≤99.0°F (≤37.2°C) and no antipyretic use within the 
preceding 48 hours (participants with baseline fever only) 
• Change from baseline in C-reactive protein level 
• Change from baseline in serum ferritin level 
• Change from baseline in lactate dehydrogenase level 
• Change from baseline in d-dimer level 
• Daily average of prednisone-equivalent corticosteroid 
dose through Day 28 


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Objectives 
Endpoints 
• To determine the safety of 
dociparstat when added to best 
supportive care for the treatment of 
severe COVID-19 
• Incidence of AEs: overall, treatment-related, Grade 3 or 
higher in severity, serious, fatal, and those resulting in 
treatment discontinuation 
• Change from baseline in clinical laboratory parameters 
• Distribution of graded clinical laboratory results 
Exploratory 
 
• To determine the effect of 
dociparstat on viral load and 
biomarkers related to the 
pathophysiology of severe 
COVID-19 
• Change from baseline in levels of HMGB1, IL-6, TNFα, 
SAA, and other biomarkers of inflammation 
• Change from baseline in SARS-CoV-2 viral load 
(Cohort 3 and Phase 3 only) 
• To evaluate the systemic exposure 
of dociparstat 
• Dociparstat plasma concentrations and PK parameters as 
data permit 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, Phase 2/3 study to determine safety and 
therapeutic effect of dociparstat in adults with severe COVID-19 who are at high risk of 
respiratory failure. 
Eligible participants hospitalized with laboratory-confirmed SARS-CoV-2, with a resting oxygen 
saturation (by pulse oximetry) of <94% on ambient air will be randomized to receive dociparstat 
or placebo for 7 days; both groups will also receive best supportive care (as determined by the 
investigator) as background therapy. The randomization ratio will be 1:1 in Cohort 1 and 2:1 
(dociparstat: placebo) in all other cohorts. Randomization of participants in Phase 2/Cohort 3 and 
Phase 3 will be stratified by baseline score on the National Institute of Allergy and Infectious 
Diseases (NIAID) ordinal scale (3 or 4) and by age (<60 years or ≥60 years). Randomization of 
participants in Phase 3 will additionally be stratified by baseline BMI (<34 kg/m2 or ≥34 kg/m2). 
Enrollment will be as follows: 
• Phase 2 
− Cohort 1: 6 participants randomized to dociparstat, 6 randomized to placebo. 
− Cohort 2: 8 participants randomized to dociparstat, 4 randomized to placebo. 
− Cohort 3: 34 participants randomized to dociparstat, 17 randomized to placebo. 
• Phase 3: 300 participants randomized to dociparstat, 150 randomized to placebo. 
The primary efficacy endpoint is the proportion of participants who are alive and free of invasive 
mechanical ventilation through Day 28. Secondary endpoints include all-cause mortality, disease 
resolution, time to improvement, number of ventilator-free days, daily average of prednisone-
equivalent corticosteroid dose, and change in potential biomarkers. Safety, including 
hematology, chemistry, and coagulation parameters and the incidence of AEs, severe AEs, and 
SAEs, will be assessed throughout the study. 
After completion or discontinuation of study intervention, participants will be followed-up for 
outcomes through Day 28. 
4.2. 
Scientific Rationale for Study Design 
A randomized, double-blind, placebo-controlled study design was selected as the most robust 
design to minimize potential bias and because the efficacy of dociparstat in preventing the 
systemic inflammation and coagulopathy that characterizes severe COVID-19 disease is not 
currently known. Randomization also allows the balancing of the variety of risk factors and 
concomitant diseases across treatment arms. 
Blinding of investigator and participant decreases the potential for differential treatments in the 
2 groups, particularly given that standard therapy is not currently established, and evidence of 
safety and efficacy of potential therapies is evolving rapidly. For example, remdesivir 
demonstrated benefit over placebo in adults hospitalized with COVID-19 (Beigel 2020), while 
the use of hydroxychloroquine, though initially thought to speed viral clearance in one small 


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study (Gautret 2020), has since been found to offer no clinical benefit in hospitalized patients 
with COVID-19 (Oxford University 2020; RECOVERY Trial). 
4.3. 
Justification for Dose 
Dociparstat will be administered as an IV bolus dose of 4 mg/kg on Day 1, followed by a 
continuous IV infusion of 0.25 or 0.325 mg/kg/hr for 7 days (168 hours). 
Selection of the dose of dociparstat for the treatment of COVID-19 was based upon the dual 
requirements to achieve a high enough drug concentration to be effective while also minimizing 
the potential for adverse effects related to prolongation of coagulation time. 
The safety and tolerability of dociparstat has been well-characterized in healthy volunteers and in 
study participants with severe illnesses. Cantex (formerly ParinGenix) conducted 8 clinical 
studies with dociparstat: 3 clinical pharmacology studies, 2 clinical studies in participants 
receiving induction chemotherapy for newly-diagnosed AML, and 3 clinical studies in non-AML 
indications (adults with COPD exacerbations, protein losing enteropathy, and pancreatic cancer). 
Overall, 370 participants (dociparstat and control groups) have been enrolled in a Cantex-
sponsored clinical study and 236 participants have been assigned to receive at least 1 dose of 
dociparstat. 
Serious bleeding is the primary toxicity associated with dociparstat in human studies to date, 
which is both dose and context dependent. A serious event of retroperitoneal hemorrhage 
occurred in the COPD Phase 2 study in a participant who was receiving dociparstat (8 mg/kg 
bolus with 0.375 mg/kg.hr continuous infusion) with concomitant enoxaparin and aspirin. In the 
recently completed Phase 2b study in participants with newly-diagnosed AML, one SAE of 
retroperitoneal bleeding was reported in a participant receiving the highest dose level that was 
originally included in the study (0.325 mg/kg/hr), a dose level that was discontinued as a 
precautionary measure. This event was considered unlikely to be related to dociparstat since the 
participant had a very low platelet count (6,000 K/uL) after systemic chemotherapy, and 
PT/aPTT and anti-Xa were within normal range at the time of the bleeding episode. There was, 
however, no imbalance in serious bleeding events in the AML study in participants treated with 
0.25 mg/kg/hr, despite the universal occurrence of severe thrombocytopenia. 
In the Phase 2 study of dociparstat for COPD (which was administered to 69 participants as an 
8 mg/kg bolus followed by 0.375 mg/kg/hr over 96 hours), there were very few instances of 
minor/moderate bleeding. During continuous IV infusion of dociparstat, the aPTT was prolonged 
in all the participants with a mean of ≤8 seconds from baseline, determined daily. This does not 
seem to impose added risks for bleeding in this population, in accordance with the findings in 
healthy volunteers from the 3 Phase I studies with dociparstat; as discussed above, these effects 
could in fact ameliorate the disseminated intravascular coagulopathy that seems to characterize 
severe cases of COVID-19. The dociparstat effect on ALT (observed in 37% of dociparstat 
recipients vs. 11% of placebo recipients in the COPD study) is a class effect to all heparins, 
heparin derivatives, LMWHs, and heparinoids; this occurs on approximately Day 5 or 7 of 
exposure with return to baseline values by Day 14 after treatment discontinuation. A total of 
50 SAEs were reported during the double-blind portion of the study; of these, 27 SAEs were 
reported in the placebo group by 14 participants and 23 SAEs reported in the dociparstat group 
by 17 participants. Eight deaths occurred during the study; 5 in the placebo group and 3 in the 


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dociparstat group, none of them were considered as related to study intervention by the 
investigators. 
This Phase 2/3 study of dociparstat in participants with severe COVID-19 lung disease seeks to 
determine whether there is evidence that dociparstat can prevent or mitigate respiratory failure 
and the need for ventilator support. Dociparstat given as a bolus of 4 mg/kg followed by a 
continuous infusion for up to 7 days was also generally well tolerated when administered with 
systemic chemotherapy (anthracycline plus cytarabine for AML, and gemcitabine plus 
nab-paclitaxel for pancreatic cancer). 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the Day 28 
follow-up visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 


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5. 
STUDY POPULATION 
The target study population is adults 18 to 85 years old who are hospitalized with positive 
SARS-CoV-2 infection and documented COVID-19 in the presence of resting oxygen saturation 
(SaO2) of <94% while breathing ambient air. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
A potential participant must meet all the following criteria to be included in the study: 
1. Hospitalized for laboratory-documented COVID-19 disease (e.g., positive for 
SARS-CoV-2 via nasopharyngeal swab RT-PCR [or other commercial or public health 
assay]). 
2. Age ≥18 years and ≤85 years. 
3. Resting oxygen saturation (SaO2) of <94% while breathing ambient air. 
4. Score of 3 or 4 on the NIAID ordinal scale (requires supplemental oxygen or noninvasive 
ventilation) (see Appendix 4). 
5. Provide informed consent to participate in the study (by participant or legally-acceptable 
representative). 
5.2. 
Exclusion Criteria 
A potential participant who meets any of the following criteria is not eligible to participate in the 
study: 
1. Currently receiving invasive mechanical ventilation (e.g., via an endotracheal tube) 
(score of 2 on NIAID ordinal scale). 
2. Severe chronic respiratory disease, defined by any oxygen requirement prior to incident 
COVID-19. 
3. Active or uncontrolled bleeding at the time of randomization; a bleeding disorder, either 
inherited or caused by disease; history of known arterial-venous malformation, 
intracranial hemorrhage, or suspected or known cerebral aneurysm; or clinically 
significant (in the judgment of the investigator) gastrointestinal bleeding within the 
3 weeks prior to randomization. 
4. Receiving any other investigational (non-approved) therapy for the treatment of 
COVID-19 or participating in the treatment period of any other therapeutic intervention 
clinical study. Participating in the follow-up period of an interventional study may be 
permitted with prior medical monitor approval; participation in an observational study is 
permitted. Refer to the lists of prohibited and permitted concomitant therapies (see 
Section 6.6). 
5. Receiving systemic corticosteroids for a chronic condition. 


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6. Receiving chronic anticoagulation with warfarin or direct oral anticoagulants 
(e.g., rivaroxaban, dabigatran, apixaban, edoxaban). 
7. Receiving or anticipated to require other systemic anticoagulation dosing at a therapeutic 
intensity. Prophylaxis of venous thromboembolism (VTE) using SC unfractionated 
heparin or enoxaparin is permitted with appropriate monitoring of coagulation status and 
within the guidelines described in Appendix 8.  
8. Receiving antiplatelet therapy, alone or in combination, including aspirin and other 
antiplatelet agents (e.g., clopidogrel, ticagrelor, and prasugrel), unless able to discontinue 
these agents at the time of randomization and to remain off these agents throughout the 
duration of the study intervention infusion period. 
9. Treatment with systemic (nonsteroid) immunomodulators or immunosuppressant 
medications, including but not limited to TNF inhibitors, anti-interleukin-1 agents and 
Janus kinase (JAK) inhibitors within 5 half-lives or 30 days (whichever is longer) prior to 
randomization. 
10. A history of congestive heart failure requiring hospitalization. 
11. Active pericarditis (based on clinical assessment). 
12. Malignancy or other irreversible disease or condition for which 6-month mortality is 
estimated ≥50%. 
13. QTc >500 msec (or >530-550 msec in participants with QRS greater than >120 msec).  
(See Section 8.3.3 for details about QTc correction formulas.) 
14. Tisdale risk score ≥11 (see Appendix 5) without the ability to monitor with serial ECGs 
or telemetry. 
15. Severe renal impairment, as determined by calculated creatinine clearance <30 mL/min 
or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. 
16. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x upper limit of 
normal (ULN). 
17. Activated partial thromboplastin time (aPTT) >42 seconds. 
18. Thrombocytopenia with a platelet count <80,000/mm3. 
19. Severe chronic liver disease (Child-Pugh Score of 10 to 15). 
20. Received dociparstat in a different clinical study. 
21. Woman of childbearing potential who is pregnant, breastfeeding, and/or not using a 
highly-effective method of contraception (consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies). 
22. Evidence of clinical improvement in COVID-19 status including, but not limited to, a 
sustained reduction in oxygen requirements over the previous 48 hours, or extubated 
and/or no longer requiring mechanical ventilation following intubation for COVID-19. 
23. Any other condition, including abnormal laboratory values, that, in the judgment of the 
investigator, could put the participant at increased risk, or would interfere with the 
conduct or planned analysis of the study. 


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5.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study intervention. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. At a minimum, the following information will be entered into the 
electronic case report form (eCRF): demography, reason(s) for screen failure, and any study 
procedure-related SAEs. 
Individuals whose laboratory results initially do not meet the criteria for participation in this 
study may have the test(s) repeated one time within 10 days; if the repeat value is not 
exclusionary, the participant may be eligible for enrollment and randomization. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention, marketed products, or placebo 
intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Details of dociparstat solution for injection are listed in Table 2. 
Table 2: 
Dociparstat Details 
Intervention Name 
Dociparstat sodium 
Type  
Drug 
Dose Formulation 
Solution for injection 
Unit Dose Strength(s) 
50 mg/mL 
Route of Administration 
Intravenous infusion (Bolus then continuous IV infusion) 
Use 
Experimental agent 
IMP and NIMP 
IMP  
Sourcing 
Provided centrally by the sponsor  
Packaging and Labeling 
Provided in 10-mL vials (4 vials/carton). Vials will be supplied to sites 
in a bulk manner. Each carton will contain 4 vials for individual use and 
will be labeled in accordance with applicable regulatory requirements 
Current/ Former Names  
DSTAT, CX-01, ODSH 
Normal saline (sodium chloride 0.9%) will be used to dilute dociparstat solution for injection 
before each infusion. In order to maintain blinding of randomized study intervention, normal 
saline will also be used as the de facto placebo. Commercially-available product will be 
purchased and provided locally by the study site (or subsidiary or designee); packaging and 
labeling will be per local requirements for commercial products. 
Dociparstat sodium solution for injection is supplied in 10-mL vials. Vials will be supplied in a 
bulk manner in a carton containing 4 vials per carton for individual use. Calculate dosing based 
on participant’s screening weight and prepare/dilute the drug product before IV infusion. 
Dociparstat must be administered via a dedicated infusion line. Do not mix with other IV 
medications. 
Dociparstat is administered as an initial IV bolus dose, immediately followed by a continuous IV 
infusion 24 hours daily for 7 days (see Table 3). 


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Table 3: 
Dosing Regimen: Bolus Dose plus Continuous Infusion 
 
Study Intervention Dosing 
All Participants: 
• Dociparstat 4 mg/kg or placebo IV bolus on Day 1, followed by 
• Dociparstat or placebo by continuous IV infusion for 24 hours daily for 7 days 
(starting on Day 1 and ending on Day 8 [168 hours]) 
Dociparstat Continuous Infusion Dose by Cohort 
Phase 2, Cohort 1 
• 0.25 mg/kg/hr 
Phase 2, Cohort 2 
• 0.325 mg/kg/hr  
(dose to be confirmed after DMC review of data from Cohort 1) 
Phase 2, Cohort 3 
• 0.25 or 0.325 mg/kg/hr  
(dose to be confirmed after DMC review of data from prior cohorts) 
Phase 3 
• 0.25 or 0.325 mg/kg/hr 
(dose will be the same as used in Cohort 3) 
 
6.2. 
Preparation, Handling, Storage, and Accountability 
6.2.1. 
Dose Preparation 
Preparation of randomized study intervention (i.e., dociparstat or placebo) will be performed by 
an unblinded pharmacist within the investigational pharmacy. The pharmacist will prepare study 
intervention to the appropriate dose based on the individual participant’s body weight. Normal 
saline will be used to dilute the IV bolus dose and continuous maintenance infusion of 
dociparstat treatment. The dociparstat IV bolus dose will be diluted to a total infusion volume of 
30 mL. The 24-hour continuous infusion will have the appropriate volume of dociparstat added 
to approximately 250 mL or 500 mL of 0.9% normal saline. 
The placebo IV bolus dose will be a total infusion volume of 30 mL of 0.9% normal saline only. 
Placebo for the continuous infusion will be 250 mL or 500 mL of 0.9% normal saline only. 
Sites will follow their own labeling procedures to identify prepared study intervention 
(i.e., dociparstat or placebo) for each participant in a blinded manner. 
6.2.2. 
Handling, Storage, and Accountability 
A sufficient quantity of dociparstat vials will be supplied to the investigator (or qualified 
designee) at each study center. Vials will be shipped in a carton containing 4 vials per carton. 
The vials will be supplied in a bulk manner to allow individual assignment of vials to 
participants. Once received at the study center, vials of dociparstat should be stored in 
accordance with the labeled storage conditions, in a securely locked area, with access limited to 
the unblinded pharmacist and authorized site staff. 
Dociparstat should be stored at controlled room temperature (i.e., 15°C to 25°C [59°F to 77°F]), 
with excursions permitted to 30°C (86°F); protect from freezing. 


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The investigator or qualified designee (e.g., unblinded pharmacist) must confirm appropriate 
temperature conditions have been maintained during transit for all study intervention received 
and must report and resolve any discrepancies before use of the study intervention. 
The investigator’s qualified designee (e.g., unblinded pharmacist) is responsible for ensuring 
adequate accountability of all used and unused study intervention. This includes 
acknowledgment of receipt of the shipment(s) of study intervention (date, quantity, and 
condition), participant dispensing records, and returned or destroyed vials. Dispensing records 
will document the dispensing of the vials to individual participants (including vial number, date 
dispensed, and participant identifier number), the initials of the person(s) dispensing the study 
interventions, and the return and/or disposal of the study intervention. All study intervention 
records must be maintained at the site and copies must be submitted to Chimerix at the end of the 
study. 
After verification of the study intervention records by the unblinded study monitor, all remaining 
study intervention supplies should be destroyed according to directions provided by Chimerix (or 
its designee) and/or any applicable site-specific standard operating procedures. If necessary, 
unused study intervention supplies may also be returned to the appropriate depot with prior 
approval from Chimerix (or its designee). If study intervention is destroyed on site, the 
investigator must maintain accurate records for all study intervention destroyed. Records must 
show the identification and quantity of each unit destroyed, the method of destruction, and 
person who disposed of the drug. 
Only participants randomized in the study may receive study intervention and only authorized 
site staff may prepare, supply, or administer study intervention. It is recommended that 
preparation of each dose of study intervention be confirmed by a second unblinded pharmacist. 
6.3. 
Dose Modification 
Dosing will be calculated on the basis of each participant’s screening weight. 
Criteria for interruption (including resuming dosing at a reduced dose) and discontinuation of 
study intervention are provided in Section 7. 
6.4. 
Measures to Minimize Bias: Randomization and Blinding 
A randomized, double-blind, placebo-controlled study design was selected as the most robust 
design to minimize potential bias. 
Participants who meet all applicable eligibility criteria will be centrally randomized to one of 
2 study intervention groups (dociparstat or placebo) using an automated interactive response 
technology (IRT) system and a computer-generated randomization code provided by the sponsor 
or designee. Randomization of participants in Cohort 3 and in Phase 3 will be stratified based 
upon NIAID score (3 or 4) and age (<60 years vs ≥60 years). Randomization of participants in 
Phase 3 will additionally be stratified by baseline BMI (<34 kg/m2 or ≥34 kg/m2). 
Once a randomization number has been assigned, it will not be re-assigned to any other 
participant in the study. The IRT system will also be used to track study intervention dispensing. 
Investigators and participants will be blinded to each participant’s assigned study intervention 
throughout the course of the study. In order to maintain this blind, an otherwise uninvolved third 


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party (an unblinded study pharmacist) will be responsible for the preparation and dispensation of 
blinded study interventions (i.e., dociparstat and placebo) and will ensure that there are no 
differences in appearance or time taken to dispense study intervention following randomization. 
In addition, the bolus syringe and the IV bags will be masked to obscure any visual differences in 
color between dociparstat and placebo. 
In the event of a regulatory inspection or quality assurance audit, the auditor(s) will be allowed 
access to unblinded study intervention records at the site(s) to verify that randomization and 
dispensing have been done accurately. Additional roles and responsibilities that require 
unblinding of specified sponsor (and/or designated contract research organization) personnel not 
directly involved in the conduct of the study include supply chain, regulatory reporting of 
expedited safety reports, and DMC reviewers. 
Normal saline (sodium chloride 0.9%) will be used as the study intervention placebo for both the 
loading doses and the continuous infusions. Placebo-controlled studies are the gold standard for 
clinical trials, as they reduce bias in care and conduct during the study. Though the efficacy 
endpoints are objective, safety assessments are less biased when treatment allocation is masked. 
Modest effects of dociparstat on aPTT have been observed in previous studies. Although the 
mean aPTT values during the continuous infusion were nominally higher for dociparstat 
0.25 mg/kg than control, the individual participant values were variable and had considerable 
overlap between groups; therefore, individual aPTT measurements are not expected to unblind 
the participant’s treatment assignment. In the current study, potential unblinding will be 
mitigated by obtaining initial aPTT measurements no sooner than 8 hours after the bolus infusion 
(after the time of peak effect) and by instructions to obtain blood for aPTT measurements from a 
location that is separate from the dociparstat infusion. Specifically, blood should be obtained via 
separate venipuncture and/or a catheter separate from the one used to administer study 
intervention. If the specimen is drawn from a heparinized line, first draw 5 mL of blood from the 
line for discard before drawing the aPTT sample. 
The IRT will be used for blind-breaking instructions. In case of an emergency, the investigator 
has the sole responsibility for determining if unblinding of a participant’s intervention 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact the sponsor prior to unblinding a participant’s intervention 
assignment unless this could delay emergency treatment. If a participant’s intervention 
assignment is unblinded, the sponsor must be notified within 24 hours after breaking the blind. 
The date and reason that the blind was broken must be recorded in the source documentation and 
eCRF, as applicable. 
6.5. 
Study Intervention Compliance 
Participants will receive study intervention directly from the investigator or qualified designee, 
under medical supervision. The date and start/stop times of each dose of study intervention 
administered will be recorded in the source documents and in the eCRF. 
Study participant identification will be confirmed at the time of dosing by a member of the site 
staff other than the person administering the study intervention. 


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6.6. 
Concomitant Therapy 
Information about the participant’s concomitant medications/therapies will be collected in the 
eCRF as specified below. 
Collection time periods:  
 
• Prior medications: All medications taken from 14 days prior to the time of signing 
ICF through time of randomization. 
• Concomitant medications: All medications and transfusions from the time of first 
dose of study intervention on Day 1 through Day 28. 
Information to collect: 
• Names (nonproprietary names are preferred) for all prescription medications. 
• Reason for use (indication). 
• Start and end dates of administration. 
• Dosage information, including dose, units, route, and frequency. 
Contact the medical monitor (or designee) if there are any questions regarding concomitant or 
prior therapy. 
6.6.1. 
Prohibited Therapies 
Refer to the exclusion criteria (see Section 5.2) for medications prohibited prior to randomization 
(and the associated time period) in the study. 
The following medications are prohibited through Day 28 (unless otherwise specified): 
• Warfarin or direct oral anticoagulants (e.g., rivaroxaban, dabigatran, apixaban, 
edoxaban). 
• Aspirin and any other antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are 
prohibited from the time of randomization throughout the duration of the study 
intervention infusion period. 
• Thrombolytic agents. 
• Systemic (nonsteroid) immunomodulators or immunosuppressant medications, 
including but not limited to TNF inhibitors, anti-interleukin-1 agents, and JAK 
inhibitors. 
• Investigational (non-approved) therapy for the treatment of COVID-19, including 
(but not limited to) the following: favipiravir, tocilizumab or other agents that 
interfere with IL-6 release/function, or other anti-inflammatory approaches to 
COVID-19 treatment. 
As there is no standard of care or approved treatment options for COVID-19, it is not possible to 
predict all medications that may be considered during the course of treatment. 
Contact the medical monitor for prior approval and to discuss any questions on the use of 
concomitant therapies for the treatment of COVID-19 and associated sequelae not specified in 


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the protocol or pharmacy manual. To ensure interpretability of the data and participant safety, 
administration of concomitant therapies outside of protocol guidelines and without prior 
approval by the medial monitor will be considered a protocol deviation; however, it is 
recognized that use of concomitant therapies is always at the investigator’s discretion with the 
health and safety of the study participant as the priority. 
6.6.2. 
Permitted Therapies 
The following medications are permitted during the study: 
• Medications for acute (e.g., pain, bacterial infection) or chronic (e.g., hypertension, 
diabetes) medical conditions, unless otherwise prohibited. 
• Prophylaxis for venous thromboembolism using SC unfractionated heparin or 
enoxaparin with appropriate monitoring of coagulation status. See Appendix 8 for 
guidelines. 
• Remdesivir, per available data sheets/guidance on dosing and toxicity management. 
• Convalescent plasma. 
For participant’s whose condition declines to a 2 on the NIAID ordinal scale (i.e., requires 
invasive mechanical ventilation or extracorporeal membrane oxygenation), otherwise prohibited 
treatments may be initiated at the investigator’s discretion. In this situation, please contact the 
medical monitor since discontinuation of study intervention may be warranted if use of an 
otherwise prohibited treatment (e.g., therapeutic anticoagulant doses) could affect the 
participant’s safety if study intervention were to be continued. 
6.7. 
Intervention After the End of the Study 
Dociparstat is not intended for continued maintenance treatment; therefore, the study 
intervention will not be provided beyond the protocol-specified treatment period. 
After the end of the treatment period, the participants’ ongoing medical care and treatment in the 
event of a recurrence will be the responsibility of the participants’ physician(s). 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
All reasons for dose interruption, discontinuation, and study withdrawal must be entered into the 
eCRF. 
7.1. 
Interruption of Study Intervention 
Infusion of study intervention (i.e., dociparstat or placebo) will be interrupted in the following 
situations: 
aPTT: If aPTT is >50 seconds, repeat testing as soon as practicable. If aPTT is confirmed 
>50 seconds (or when retest and confirmation cannot occur within the same day), reduce the 
dose of enoxaparin or unfractionated heparin (as applicable). If aPTT remains elevated upon 
repeat testing, then interrupt the study intervention infusion. [Note: ensure aPTT samples were 
not obtained from the same line as the study intervention infusion (e.g., collect samples via 
peripheral venipuncture).] 
• Participants in cohorts with dociparstat dosed at 0.25 mg/kg/hr: study intervention dosing 
will not be resumed if interruption criteria are met. 
• Participants in cohorts with dociparstat dosed at 0.325 mg/kg/hr: To minimize time that 
the participant is off therapy, perform repeat testing for aPTT approximately 2 to 6 hours 
after interruption (as practicable). When aPTT is <40 seconds, the infusion may be 
resumed at a reduced dose of 0.25 mg/kg/hr. 
Renal function: If the calculated creatinine clearance drops below 30 mL/min or eGFR drops 
below 30 mL/min/1.73 m2 prior to or during dosing with study intervention, the infusion will be 
held until the creatinine clearance or eGFR rises to ≥30. 
Thrombocytopenia: If a participant experiences a decrease in platelet count by ≥50% from 
baseline value, or has an absolute platelet count of <50,000/mm3 they are to be evaluated for 
possible HIT, per the algorithm in Appendix 6. 
Consistent with the mechanism of dociparstat, no evidence of HIT has been identified in clinical 
studies. However, considering the risk of HIT associated with potential concomitant medications 
used for venous thromboembolism (VTE) prophylaxis during study participation, it is 
recommended that investigators evaluate participants for HIT if they meet platelet criteria 
described above, starting with assessment of the 4Ts score to determine pretest probability, and 
proceeding with testing per the algorithm for participants who score ≥4 (considered intermediate 
or high pretest risk of HIT). 
For participants with a 4Ts score ≥4 who are receiving concomitant VTE prophylaxis permitted 
per protocol, discontinue heparin or enoxaparin until test results rule out HIT. For those 
participants with a 4Ts score ≥4 who are not receiving VTE prophylaxis permitted per protocol, 
study intervention is to be discontinued, and may only be resumed if test results rule out HIT, 
and the 7-day treatment period has not ended. 
ECG/QTc: Heparin is not associated with QT prolongation and no cardiac safety signal has been 
identified to date in preclinical and clinical dociparstat studies. However, considering the risk of 
QT prolongation associated with potential concomitant medications (e.g., hydroxychloroquine), 


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it is recommended that the investigator monitor participants in accordance with the American 
College of Cardiology (or equivalent) guidelines (Simpson 2020). 
If QTc increases by >60 msec or absolute QTc is >500 msec (or >530-550 msec if QRS 
>120 msec), discontinue and/or reduce the dose of potentially causative medications 
(e.g., azithromycin and hydroxychloroquine; see Appendix 7). Repeat ECG daily. If there is no 
reduction in QTc after modifications to dosing of other medications (e.g., azithromycin and 
hydroxychloroquine), discontinue study intervention. 
7.2. 
Discontinuation of Study Intervention 
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention before completing the protocol-specified treatment period. Reasons for permanent 
discontinuation of study intervention may include the following: 
• Criteria for restarting study intervention after interruption were not met. 
• ALT ≥3x ULN (and >2x baseline value) plus bilirubin ≥2x ULN. 
• Thrombocytopenia defined as a platelet count of <30,000/mm3. 
• Hemorrhagic AE of Grade 3 or higher (graded according to the National Cancer Institute-
Common Terminology Criteria for Adverse Events [NCI-CTCAE]). 
• Other treatment-related AE of unacceptable severity. 
• Condition has improved and participant is eligible for hospital discharge. 
• Participant requests to discontinue study intervention. 
• Investigator initiates treatment with a therapeutic anticoagulant dose, a thrombolytic agent, 
or otherwise prohibited therapy that may affect the participant’s safety if study intervention 
were to be continued. 
• Investigator determines discontinuation is in the best interests of the participant for safety, 
behavioral, compliance, or administrative reasons. 
Participants who discontinue study intervention early will complete the early discontinuation 
assessments (refer to the Schedule of Assessments) and will continue to be followed-up through 
Day 28. 
Note: For participants who are discharged from the hospital prior to Day 8, the next visit will be 
Day 14. 
7.3. 
Participant Withdrawal from the Study 
It is expected that all participants randomized in the study, regardless of completion or 
discontinuation of study intervention, will remain in the study for follow up through Day 28. 


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• Before withdrawing a participant from the study, clarify and document the specific 
expectations of the participant’s request for withdrawal. The following withdrawal scenarios 
may apply: 
− Discontinuation of study intervention, but completes remaining study 
assessments, and agrees to collection of relevant follow-up information 
(i.e., remains in the study; this is the default scenario). 
− Discontinuation of study intervention and/or refuses further study-specific 
assessments, but agrees to collection of relevant follow-up information 
(i.e., remains in the study). 
− Completion or discontinuation of study intervention and/or refuses further 
assessments, AND withdraws consent for any further study communication or 
follow-up from the study center (i.e., withdraws from the study); the investigator 
must document this in the site study records. 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
• At the time of withdrawing from the study, if possible, an early withdrawal visit will be 
conducted. See the Schedule of Assessments for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested; the investigator must document this in the site study records. 
Discontinuation of specific sites or of the study as a whole are discussed in Appendix 1. 
7.4. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and the study center is unable to contact the participant. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 


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• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. The sponsor may retain and continue to use any data collected. 
• The site should also make every effort to verify the participant’s vital status with the 
participant’s regular/non-study physician(s). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Planned time points for all study assessments and procedures are provided in the Schedule of 
Assessments (see Table 1). Adherence to the study design requirements, including those 
specified in the Schedule of Assessments, is essential and required for study conduct. Protocol 
waivers or exemptions are not allowed. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
sample quality. Record results of any unscheduled assessments or visits related to study 
participation in the eCRF. 
8.1. 
Screening 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., SARS-CoV-2, blood counts) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes, provided the procedures meet protocol-specified criteria and 
were performed within the time frame defined in the Schedule of Assessments. Applicable 
results must be entered into the participant’s eCRF. 
The following examinations and procedures will be conducted as part of the screening process: 
• Informed consent. Documentation of completion of the informed consent process 
with the potential participant (and/or legally authorized representative as applicable) 
(see Section 11.1.3). 
• Demographics, medical history (including family medical history), medication 
history, physical examination, vital signs, height, and weight. 
• Cardiac health: ECG (see Section 8.3.3), congestive heart failure history, clinical 
signs of pericarditis, and Tisdale risk score (see Appendix 5) (or plan for serial ECGs 
or continuous telemetry). 
• Laboratory: Clinical chemistry, hematology, and coagulation (fibrinogen, D-dimer, 
aPTT, PT/INR) tests (see Section 8.3.4). 
• Review of all eligibility criteria to determine if participant qualifies for 
randomization. This includes review of results of all screening assessments and a 
final review for any changes in medical history or concomitant medications. 
8.2. 
Efficacy Assessments 
The activity of dociparstat will be assessed by clinical evaluations and routine laboratory tests. 
8.2.1. 
Clinical Evaluations 
The efficacy endpoints primarily rely on the participant’s clinical status with respect to death, 
hospitalization, mechanical ventilation, and supplemental oxygen. The primary efficacy endpoint 
is the proportion of participants who are alive and free of invasive mechanical ventilation 
through Day 28 and the key secondary endpoint is all-cause mortality at Day 28. 


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Two of the secondary endpoints, clinical status and time to clinical improvement, are based on 
the 8-point NIAID ordinal scale (see Appendix 4). In addition to death, hospitalization, 
mechanical ventilation, and supplemental oxygen, components of the ordinal scale also include 
ongoing medical care and limitations on activities. It is important for changes in each of these 
components to be documented with the date and time of change. Participants must be considered 
a 3 or 4 on the scale to be eligible for enrollment, and an improvement of ≥2 grades is considered 
a treatment success. 
8.2.2. 
Laboratory Assessments 
Multiple laboratory assessments will contribute to the evaluation of efficacy. For simplicity, 
these laboratory assessments are included in the list of safety labs in Section 8.3.4. 
Instructions for collection, handling, and shipment of samples is included in the laboratory 
manual. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Assessments (see 
Table 1). 
The investigator will discuss any immediate safety concerns with the sponsor (or designee) upon 
occurrence or awareness to determine if the participant should continue or discontinue receiving 
study intervention. 
Safety data will be monitored by an independent DMC on a routine basis (see Section 9.6). 
8.3.1. 
Physical Examinations 
Measure height and weight at screening. Complete a physical examination at screening as part of 
the review for eligibility for the study. Investigators should pay special attention to clinical signs 
related to the respiratory system and any other previous or ongoing serious illnesses. Record any 
clinically-relevant findings in the eCRF as medical history. 
After the first dose of study intervention, record any clinically-relevant change(s) in physical 
examination (obtained during routine standard of care) findings in the eCRF as an AE(s). 
8.3.2. 
Vital Signs 
Assess all vital signs (temperature, pulse rate, respiratory rate, blood pressure, and oxygen 
saturation) at screening as part of the review for study eligibility. 
Monitor temperature from baseline through hospital discharge. Record date and time of each 
measurement. 
Record any clinically-relevant findings prior to the first dose of study intervention as medical 
history in the eCRF. During the treatment period of the study, record any clinically-relevant 
change(s) in vital sign measurements (obtained during routine standard of care) in the eCRF as 
an AE(s). 


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8.3.3. 
Electrocardiograms 
ECGs will be obtained using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals. 
As specified in the Schedule of Assessments, 12-lead ECGs will be obtained at the following 
time points: 
• Screening 
• Day 3 (±1 day), unless participant is being monitored by continuous telemetry 
• Additional readings may be necessary to monitor AEs and/or changes in ECG 
measurements (e.g., as described in Section 7) 
At screening, 3 individual ECG tracings should be obtained as closely as possible in succession, 
but no more than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes. At subsequent time points, a single ECG tracing will be obtained, with a repeat 
tracing to confirm QTc intervals >450 msec. 
Refer to Section 5.2 for QTc-related criteria for participant exclusion and Section 7 for 
QTc-related criteria for interruption and discontinuation of study intervention. 
At screening, as part of the review for eligibility for the study, record any clinically-relevant 
ECG findings as medical history in the eCRF. During the treatment period of the study, record 
any clinically-relevant change(s) in ECGs (obtained at protocol-specified time points or during 
routine standard of care) in the eCRF as an AE(s). 
It is recommended that QTc be calculated using Fridericia’s formula (QTcF) for all participants. 
If a study center does not have access to an ECG machine capable of calculating QTcF, then 
correction using an alternate formula may be used. All recordings for a single participant must 
use the same correction formula; therefore, if one formula is used at screening to determine 
eligibility for enrollment, that same formula must also be used during treatment to determine if 
criteria have been met for discontinuation of study intervention. 
8.3.4. 
Clinical Laboratory Assessments 
All required laboratory assessments must be conducted in accordance with this protocol and the 
laboratory manual. The timing and frequency of laboratory assessments are specified in the 
Schedule of Assessments (Table 1). 
• The laboratory tests (clinical chemistry, hematology, and coagulation) listed in 
Table 4) will be performed by the study centers’ usual local laboratory, unless 
otherwise specified. 
• All laboratory reports will be filed with the source documents. 
• Site personnel must enter results into the eCRF for the specified laboratory 
parameters (with units and relevant reference ranges) at each specified time point. 
• The investigator must document their review of each laboratory report. 
Clinically-relevant abnormal laboratory findings at screening and before the first dose 
of study intervention will be recorded as medical history. 


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• Clinically significant abnormal changes occurring within 28 days after first dose of 
study intervention will be recorded in the eCRF as an AE(s). 
− These laboratory tests will be repeated (and recorded in the eCRF) until the values 
return to normal or baseline or are no longer considered clinically significant by 
the investigator. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified. 
− The investigator may consult with the medical monitor for any questions. 
Laboratory tests may be performed at additional times during the study as part of standard care, 
as determined necessary by the investigator, or as required by local regulations. Any laboratory 
test(s) performed in response to an AE must be recorded in the participants’ eCRF (as an 
unscheduled visit if not at a protocol-specified time point). 
Refer to Section 5.2 for laboratory-related participant exclusion criteria and Section 7 for 
laboratory-related criteria for interruption and discontinuation of study intervention. 
Study center staff must enter results of all local/institutional laboratory results into the eCRF. 
Instructions for collection, handling, and shipment of samples for central analysis is included in 
the laboratory manual. 


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Table 4: 
Laboratory Assessments 
Laboratory 
Assessments 
Parameters for Routine Monitoring 
Additional Parameters 
Hematology 
(local) 
• Platelet Count 
• Hemoglobin 
• Absolute neutrophil count 
• White blood cell count with differential 
Screening only: 
Hematocrit,  
red blood cell count 
Clinical 
Chemistry 
(local)  
• Alanine aminotransferase 
• Aspartate aminotransferase 
• Total and direct bilirubin 
• Alkaline phosphatase 
• Blood urea nitrogen 
• Creatinine  
(with calculated creatinine clearance or 
estimated glomerular filtration rate) 
• Lactate dehydrogenase 
• Calcium 
• Magnesium 
• Potassium 
• Sodium 
• C-reactive protein 
• Ferritin 
Screening only: 
Chloride, phosphate, albumin, 
total protein, glucose, uric acid, 
gamma-glutamyl transferase  
 
Coagulation 
(local) 
• Activated partial thromboplastin time 
• Prothrombin time and international 
normalized ratio 
• D-dimer 
• Fibrinogen 
• Anti-Xa (to monitor enoxaparin) 
  
Other 
(plasma will 
be stored for 
analysis by 
central lab) 
• HMGB1 
• IL-6 
• TNFα 
• Serum amyloid A (SAA) 
• Other biomarkers of inflammation 
 
HIT 
Evaluationa 
(local) 
 
Only when indicated: 
• Anti-PF4/heparin antibody 
(ELISA) 
• Serotonin release assay (SRA) 
a Refer to HIT evaluation algorithm and guidelines in Appendix 6. 


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8.4. 
Adverse Events and Serious Adverse Events 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for follow-up. 
AEs will be categorized by system organ class and preferred term using the Medical Dictionary 
for Regulatory Activities dictionary and AE severity will be graded according to the National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE). 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Any SAE that is considered related to study procedures will be collected from the time of 
consent until the first dose of study intervention. Any other medical occurrences that begin 
during this time period will be recorded on the medical history/current medical conditions 
section of the eCRF (not as an AE/SAE). 
All AEs will be collected from the time of first dose (Day 1) through Day 28. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 2. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of the data being available. 
Investigators are not obligated to actively seek new onset AEs or SAEs after the protocol-defined 
reporting period; however, if the investigator learns of any SAE and he/she considers the event to 
be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After an initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. It is important for all SAEs, AEs of special interest (as 
defined in Section 8.4.6), AEs considered related to study intervention, and AEs that resulted in 
discontinuation of study intervention to be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.4). 


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8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor is essential so that legal and 
regulatory obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and be forwarded to 
investigators as necessary. An investigator who receives an investigator safety report describing 
an SAE or other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.4.5. 
Death Events 
If a participant dies during participation in the study (at any time from the time of consent 
through follow-up), the investigator will provide the date of death and a determination of cause 
of death (including any supporting information, such as death certificate, pathology or autopsy 
information, as applicable). 
All deaths from events with onset through Day 28 are to be reported as SAEs. 
8.4.6. 
Adverse Events of Special Interest 
For this study, the following events will be considered AEs of special interest: 
• Bleeding / hemorrhagic AEs. 
• Heparin-induced thrombocytopenia (see Appendix 6). 
An AE of special interest must be recorded and reported to the sponsor (or designee) within 
24 hours following the same procedure as for an SAE. 
Hemorrhagic AEs that are Grade 3 or higher in severity (per CTCAE criteria) will be considered 
related to study intervention, unless the cause is clearly not related. 
Additional information about these events will be collected to more fully describe the 
participant’s status and assess potential causes and contributing factors; this includes, at a 
minimum, aPTT values, platelet values, anti-Xa value (if obtained), possible contributory 
medications (e.g., heparin, enoxaparin, or other anticoagulants), and treatment(s) administered. 
8.5. 
Treatment of Overdose 
For this study, any dose of study intervention (i.e., dociparstat or placebo) greater than 8 mg/kg 
as a bolus dose, greater than 0.5 mg/kg/hr infusion, or greater than 20 mg/kg within a 24-hour 
time period will be considered an overdose. 


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In the event of an overdose, the investigator should: 
• Contact the medical monitor immediately. 
• If the continuous infusion is ongoing, adjust the rate to administer the correct dose. 
• Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 48 hours after the overdose. 
• Document the quantity of the excess dose and duration of the overdose in the eCRF. 
Discontinue the study intervention infusion if clinically significant bleeding (e.g., Grade 3 or 
higher hemorrhagic AE) or aPTT >50 seconds occurs after administration of an overdose of 
dociparstat (see Section 7.1). Other decisions regarding dose interruptions will be made by the 
investigator in consultation with the medical monitor based on clinical evaluation of the 
participant. 
At the discretion of the investigator in consultation with the medical monitor, protamine may be 
used to neutralize the anticoagulation effects of dociparstat overdose. Protamine doses should be 
based on activated clotting time or aPTT plasma values and not based on the milligram dosage of 
dociparstat administered. 
8.6. 
Pharmacokinetics 
During the treatment period plasma samples (~2 mL) will be collected for analysis of dociparstat 
concentrations and pharmacokinetic parameters, as data permit. 
Plasma samples will be collected at the following time points: 
• Day 1, predose and at the end of the bolus infusion. 
• Day 2 and Day 4, a single sample will be collected during the infusion (at any time). 
• Day 8 (or the last day of study infusion), ideally within 5 minutes after the end of the 
continuous infusion. 
The date and actual time (24-hour clock time) of each sample must be recorded. 
Note: Do not draw blood for PK analyses from the same line that is used for study intervention 
administration. Drawing blood from a heparinized line may falsely alter the results obtained; 
therefore, if using an indwelling catheter, draw approximately 5 mL of blood for discard before 
drawing the PK sample. Additional information regarding sample collection and handling is 
provided in the laboratory manual. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
PK samples will be collected at study centers with appropriate capabilities (e.g., centrifuge, staff 
experience and availability). Genetic analyses will not be performed on these plasma samples. 
Participant confidentiality will be maintained. 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 


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8.8. 
Biomarkers 
A 10-mL whole blood sample will be collected at designated time points for plasma processing 
and central laboratory analyses. 
Plasma samples will be used to conduct analyses of biomarkers including, but not limited to 
HMGB1, IL-6, TNFα, and SAA to evaluate their association with observed clinical responses 
and gain insight into the mechanism of action of dociparstat in COVID-19 treatment. The 
samples may be retained while research on dociparstat continues, but no longer than 15 years or 
other period as per local requirements. Genetic analyses will not be performed on plasma 
samples. 
PCR of SARS-CoV-2 may be performed on virology samples, but participant DNA will not be 
evaluated. Participant confidentiality will be maintained. 
Details on processes for sample collection, processing, shipment, and destruction is included in 
the laboratory manual. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The null hypothesis is that the effect of dociparstat is equal to the effect of placebo with respect 
to disease progression (proportion of participants who are alive and free of invasive mechanical 
ventilation through Day 28), or: 
H0: Pdstat = Ppbo 
The alternative hypothesis is that the effect of dociparstat is not equal to the effect of placebo 
with respect to disease progression (proportion of participants who are alive and free of invasive 
mechanical ventilation through Day 28), or: 
HA: Pdstat ≠ Ppbo 
9.2. 
Sample Size Determination 
Approximately 600 potential participants are expected to be screened to achieve a total of 
approximately 75 participants randomized in Phase 2, and 450 participants randomized in 
Phase 3 of the study. 
The sample size of 12 participants for Cohorts 1 and 2 was selected to assess for any major 
safety signals in a limited number of participants. 
The sample size for Cohort 3 was selected to provide a reasonable level of precision to assess the 
treatment effect for the primary endpoint, specifically when the sample size is 51 randomized 2:1 
dociparstat: placebo, a two-sided 95% confidence interval for the difference between a control 
failure rate of 20% and a dociparstat failure rate of 9% based on the large sample normal 
approximation will extend 21.3% from the observed difference in proportions.  
For Phase 3, the sample size of 450 participants randomized 2:1 dociparstat: placebo was 
selected to detect the difference between a control failure rate of 20% and a dociparstat failure 
rate of 9% at a two-sided 0.05 alpha level with >80% power. This sample size also accounts for a 
futility analysis after 50% of the Phase 3 participants are enrolled using a Pocock beta spending 
function. 
9.3. 
Analysis Sets 
The following analysis sets are defined: 
Analysis Set 
Description 
Screened 
All participants who sign the ICF. 
Intent to Treat 
(ITT) 
All participants who are randomized. Participants will be analyzed in the group to 
which they were randomized. 
Safety 
All participants who are randomized and receive at least one dose of blinded 
dociparstat or placebo. Participants will be analyzed in the group corresponding to 
the first blinded dose of study intervention received.  


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Analysis Set 
Description 
Per Protocol 
(PP) 
(Phase 3 only) All participants who are randomized to and receive at least one dose 
of blinded dociparstat or placebo, excluding those who have any significant 
inclusion/exclusion criteria violation or noncompliance that would be expected to 
impact the analysis of efficacy. Participants will be analyzed in the group 
corresponding to the first blinded dose of study intervention received. 
The ITT analysis set will be used to summarize all efficacy endpoints. The PP analysis set will 
be determined prior to unblinding and will be used for supportive primary and key secondary 
efficacy analyses and possibly other selected endpoints to be defined in the Statistical Analysis 
Plan (SAP). The safety analysis set will be used to summarize all safety and other non-efficacy 
(e.g., medical history, medications, exposure) analyses. 
9.4. 
Statistical Analyses 
The SAP for Phase 2 will be finalized prior to the Cohort 3 analysis. The SAP for Phase 3 will be 
finalized prior to the first Phase 3 unblinded analysis. The SAPs will include a more technical 
and detailed description of the statistical analyses described in this section. 
Phase 2: Data from Cohorts 1 and 2 will be analyzed and presented separately. Due to the 
evolving standard of care for COVID-19, the sponsor may decide to unblind and review study 
data following Cohort 1 and/or 2; therefore, one of two scenarios will inform the analysis 
approach for Cohort 3 as follows: 
• In the event that Cohort 1 and 2 results remain blinded through Cohort 3 database lock, 
Cohort 3 data will be combined with either Cohort 1 or Cohort 2 data, depending on the 
selected dose. 
• In the event that Cohort 1 and/or 2 results are unblinded prior to Cohort 3 database lock, 
Cohort 3 data will be analyzed and presented separately. In addition, Cohort 1, 2, and 3 
data may be combined to support exploratory analysis.  
Phase 3: Analysis sets will be presented separately (i.e., data from the Phase 2 portion of the 
study will not be used for the final confirmatory inference). 
Descriptive analyses will be used to present Cohort 1 and Cohort 2 data. 
9.4.1. 
Primary Endpoint 
Phase 3: The primary analysis will utilize the ITT analysis set and a Cochran-Mantel-Haenszel 
test stratified by each of the actual stratification factors. Participants will be counted as failures 
once they go on a ventilator or die. Number and percentage of failures will be presented for each 
treatment arm. Cochran-Mantel-Haenszel p-values, estimated common odds ratios, estimated 
common risk differences, and corresponding approximate two-sided 95% CIs will be presented. 
The Breslow-Day test will be used to test the homogeneity of the odds ratios across strata. 
Although missing data are expected to be limited, any such cases will be imputed as failure. A 
supportive analysis using multiple imputation will be done in order to assess the sensitivity of the 
inference to the approach to missing data. 
Phase 2: A similar methodology will be used; however, multiple imputation will not be done. 


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9.4.2. 
Secondary Endpoints 
Phase 3: 
In the event the primary endpoint is met, the key secondary analysis of all-cause mortality at 
Day 28 will be tested sequentially at the 0.05 alpha level. This endpoint and other dichotomous 
secondary endpoints will use the same methods used for the primary endpoint. 
For time-to-event secondary efficacy analyses, stratified log-rank p-values and hazard ratios 
from Cox proportional hazard models with 95% CIs will be presented. Median times to 
success/failure and corresponding 95% CIs will be presented for each group. For each endpoint, 
handling of participants who die during the study will be addressed in detail in the SAP. 
Participants who are lost to follow-up will be censored at date/time of last follow-up. 
The NIAID ordinal scale will be analyzed using the van Elteren test. The number and percentage 
of participants at each level will be summarized. 
Continuous secondary analyses will be analyzed using analysis of variance (ANOVA), including 
stratification factors as independent factors. Treatment effects, corresponding 95% confidence 
intervals, and p-values will be presented. Rank ANOVA will be considered if normality 
assumptions governing use of parametric ANOVA are not supported. Analysis of covariance will 
be used if a baseline measure is available. Repeated measures analyses will be considered as 
appropriate. 
The primary efficacy endpoint will be analyzed by various subgroups, including, but not limited 
to, each of the stratification factors, sex, and race (each race contributing ≥10% of participants 
plus other races grouped). 
Phase 2: Similar methodologies will be used to analyze Phase 2 data. 
9.4.3. 
Safety Analyses 
All safety analyses will be presented using the safety analysis set. Inferential analyses will 
generally not be performed for safety endpoints unless specified in the SAP. Frequency and 
percentage will be presented for categorical variables. Sample size, mean, standard deviation, 
median, interquartile range, and range will be presented for continuous variables. 
9.4.3.1. 
Adverse Events 
Treatment-emergent AEs are those that begin on or after the date of the first dose of 
study intervention. 
Summaries (number and percent of participants) of treatment-emergent AEs (by system organ 
class and preferred term) will be provided as follows: 
• All 
• Severe, life-threatening, and fatal 
• Treatment-related 
• Severe, life-threatening, and fatal treatment-related 
• Serious 


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• Treatment-related serious 
• Those leading to study intervention discontinuation 
• Those leading to study intervention interruption 
• Fatal 
9.4.3.2. 
Laboratory Results 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided for each continuous laboratory test as follows: 
• Baseline values 
• Values at each postbaseline analysis window (to be defined in the SAP) 
• Change from baseline at each postbaseline analysis window 
The minimum, maximum, and last postbaseline value / change from baseline will also be 
summarized. Missing data will not be imputed. 
Laboratory tests will be descriptively analyzed by grade and analysis window using counts and 
percentages. The maximum and last postbaseline grade for each participant will also be 
summarized. Denominators will be the number of participants with a graded (or normal) test 
during the window. Laboratory tests with criteria for both increased and decreased levels will be 
analyzed for each direction (i.e., increased and decreased). This analysis will be generated twice 
to count (1) treatment-emergent increases in laboratory grades (i.e., only those above the baseline 
grade) and (2) any grade regardless of baseline. 
9.4.4. 
Other Analyses 
Other analyses, including but not limited to participant enrollment, analysis sets, demographics, 
baseline characteristics, prior and concomitant medications, study intervention usage, and 
pharmacokinetics will be specified in the SAP or other specific analysis plans. 
9.5. 
Phase 3 Interim Futility Analysis 
A formal Phase 3 interim futility analysis will be conducted after 225 participants complete the 
study. The primary endpoint will be tested using a non-binding Pocock beta spending function 
boundary (futility bound 0.919). The study will not be stopped early for efficacy. 
9.6. 
Data Monitoring Committee 
An independent unblinded DMC will review safety data from Cohort 1 to make a 
recommendation on dose escalation in Cohort 2, and will review safety data from both Cohorts 1 
and 2 to make a recommendation on dosing in Cohort 3. The sponsor will consider the DMC 
recommendation when determining the actual doses for Cohorts 2 and 3. Due to the evolving 
standard of care for COVID-19, the sponsor may decide to unblind and review study data 
following Cohort 1 and/or 2. After completion of Phase 2, all data will be unblinded to the DMC 
and sponsor to determine whether the study should proceed with enrollment into Phase 3. 


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During Phase 3, the DMC will convene to review safety data after approximately 100, 225, and 
350 participants complete the study. In addition, the DMC will review the pre-specified futility 
interim analysis. 
The DMC will be provided with real-time, expedited safety reports to continue monitoring 
safety. The DMC chair may schedule ad hoc safety review meetings at any time during the study 
as deemed appropriate. 
Details of the DMC membership and review procedures will be outlined in a separate charter. 


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10. 
REFERENCES 
Aggarwal NR, King LS, D’Alessio FR. Diverse macrophage populations mediate acute lung 
inflammation and resolution. 2014 Am J Physiol Lung Cell Mol Physiol. 2014;306: L709-L725. 
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11. 
APPENDICES: SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS 


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11.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
11.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable ICH Good Clinical Practice (GCP) Guidelines. 
• Applicable laws and regulations. 
The investigator will submit the protocol, protocol amendments, ICF, and other relevant 
documents (e.g., advertisements) to an IRB/IEC for review and approval by the IRB/IEC before 
the study is initiated. Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study participants. 
The investigator will also be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Oversight of the conduct of the study at the site and adherence to requirements of US 
regulations (21 CFR), ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
• Notify the IRB/IEC of protocol deviations according to the local guidelines and 
maintaining this documentation in the site’s study file. 
11.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with enough accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators and 
subinvestigators are responsible for providing information on financial interests during the study 
and for 1 year after study completion. 
11.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the participant 
and/or legally authorized representative and will answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. The ICF shall contain 
authorization for the use and disclosure of the participant’s protected health information in 
connection with the study. The authorization shall include at a minimum a clear description of 


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the following: the duration of the authorization, the right of access to the information (or any 
suspension thereof during the course of the study), type of information to be used/disclosed in 
the study, names or classes of parties that may use or disclose information, purpose of the 
use/disclosure, extent of the right to revoke the authorization, extent to which participation in the 
study is conditioned on signing the authorization, and potential for redisclosure of protected 
health information. 
When the ICF is amended, the investigator must follow all applicable regulatory requirements 
pertaining to approval of the amended ICF document(s) by the IRB/IEC prior to use. Participants 
must be re-consented to the most current version of the ICF(s) during their participation in the 
study. 
Unless extenuating circumstances permit alternate procedures, the following information applies: 
Participants or their legally authorized representative (as defined by local regulations) will be 
required to sign a statement of informed consent that meets the requirements of US regulations 
(21 CFR Part 50), local regulations, ICH guidelines, and the IRB/IEC. The authorized person 
obtaining the informed consent must also sign the ICF. The medical record must include the date 
written informed consent was obtained and a statement that consent was obtained before the 
participant was enrolled in the study. The investigator must maintain the original and any 
amended signed and dated ICFs. A copy of each signed ICF must be provided to the participant 
and/or the participant’s legally authorized representative. 
If verbal consent is required due to a participant being in isolation or other extenuating 
circumstances related to infection control, the following guide should be followed: 
1. An unsigned consent form is provided to the participant by a healthcare worker who has 
entered the room. 
2. If direct communication with the participant in isolation is not feasible or safe, the 
investigator (or their designee) obtains the participant phone number and arranges a 
three-way call or video conference with the participant, an impartial witness, and if 
desired and feasible, additional people (e.g. next of kin) requested by the participant. 
3. To ensure that participants are approached in a consistent fashion, a standard process 
should be used that will accomplish the following: 
• Identification of who is on the call. 
• Review of the informed consent with the participant by the investigator (or their 
designee) and response to any questions the participant may have. 
• Confirmation by the witness that the participant’s questions have been answered. 
• Confirmation by the investigator that the participant is willing to take part in the study 
and sign the informed consent document while the witness is listening on the phone. 
• Verbal confirmation by the participant that they would like to take part in the study 
and that they have signed and dated the informed consent document that is in their 
possession. 


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If the signed informed consent document cannot be collected from the participant’s location for 
inclusion in the study records, FDA considers the following 2 options acceptable to provide 
documentation that the participant signed the informed consent document: 
Attestations by the witness who was on the call and by the investigator that the 
participant confirmed that they agreed to take part in the study and signed the informed 
consent 
OR 
A photograph of the informed consent document with attestation by the person entering 
the photograph into the study record that states how that photograph was obtained and 
that it is a photograph of the informed consent signed by the participant. 
A copy of the informed consent document signed by the investigator and witness should be 
placed in the participant’s study source documents, with a notation by the investigator of how the 
consent was obtained (e.g., telephone). The study record at the investigational site should 
document how it was confirmed that the participant signed the consent form (i.e., either using 
attestation by the witness and investigator or the photograph of the signed consent). The note 
should include a statement of why the informed consent document signed by the participant was 
not retained (e.g., due to contamination of the document by infectious material). 
11.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will only contain the identifier; any information that 
would make the participant identifiable (e.g., name) will not be transferred. The investigator will 
keep an enrollment and identification log that contains a record of the personal identification data 
linked to each participant’s study identification number. 
Encoded participant data will be transferred to the sponsor (located in the US) and will be stored 
indefinitely. Encoded data will be used by the sponsor for safety reporting, research and 
development, regulatory purposes, and marketing of dociparstat; encoded data may also be 
shared with other companies or individuals for research purposes. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with US Health Insurance Portability and Accountability Act (HIPAA) 
requirements (where applicable) and/or national data protection/privacy laws (outside of the 
USA), including without limitation the General Data Protection Regulation (GDPR) 2016/679 
(in the EU). The participant will be required to give consent for their data to be used as described 
in the informed consent document. 
The participant must be informed about the level of disclosure and that his/her medical records 
may be examined by clinical quality assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
11.1.5. 
Data Quality Assurance 
All observations relating to the study will be recorded by site personnel in source documents. In 
addition, an eCRF must be completed for every participant entered into the study. The eCRF 
must be completed according to the eCRF completion guidelines. After each participant has 


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completed the study, the investigator must review and electronically sign the eCRFs indicating 
that (s)he has reviewed the completed eCRFs and pertinent clinical data for the participant and 
that, to the best of his/her knowledge, all data recorded in the eCRFs accurately reflects the 
participant’s performance in the study. 
Quality controls are incorporated into project management activities conducted by Chimerix (or 
its designee), including the monitoring and verification of clinical and safety data. 
The investigator must permit study-related monitoring, audits, IRB/IEC reviews, and regulatory 
agency inspections and provide direct access to source data documents. Study monitors will 
perform ongoing source data verification to confirm that data entered into the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
Essential documents pertaining to the conduct of the study should be retained for the following 
time period: 
• At least 2 years after approval of the last marketing application. 
OR 
• At least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
These documents should be retained for a longer period (e.g., 15 years or more), however, if 
required by applicable local or country-specific regulatory requirements or by an agreement with 
Chimerix. It is the responsibility of Chimerix to inform the investigator/institution as to when 
these documents no longer need to be retained. If it becomes necessary for Chimerix or any 
regulatory authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
11.1.6. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. Current medical records must be 
available for inspection; the investigator may need to request previous medical records or 
transfer records, depending on the study. 
11.1.7. 
Study and Site Start and Closure 
The study start date is the date on which the first participant randomized signed the ICF (i.e., first 
participant first visit). 
The clinical study will be open for recruitment of participants when the first site has completed 
site initiation, has study intervention onsite, and has been notified by the sponsor (or designee). 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further development of the study intervention. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, IECs/IRBs, regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should ensure 
appropriate participant therapy and/or follow-up. 
11.1.8. 
Dissemination of Clinical Study Data 
Results of the study will be posted on the relevant clinical study registration websites 
(e.g., clinicaltrials.gov). Results of the study will also be submitted for publication in a peer-
reviewed scientific journal, unless the study is terminated prematurely and does not yield 
sufficient data for a publication. 
11.1.9. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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11.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
11.2.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfill the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
11.2.2. 
Definition of an SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study). 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
• 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is an SAE. 
• 
When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 
Exceptions: 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. Hospitalization for protocol therapy administration. 
• 
Hospitalization for diagnostic investigations (e.g., scans, endoscopy, sampling for laboratory tests, 
bone marrow sampling) that are not related to an AE. 
• 
Hospitalization for technical, practical, or social reasons, in absence of an AE. 
• 
Hospitalization for a procedure that was planned prior to study participation (i.e., before consent 
or randomization). 
• 
However, hospitalization or prolonged hospitalization for complications of administration of study 
intervention, diagnostic investigations, planned procedures, or administration of blood or platelet 
transfusion remains reportable as an SAE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 


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11.2.3. 
Recording and Follow-Up of AEs, SAEs, and AEs of Special Interest 
AE, SAE, and AEOSI Recording 
• 
When an AE/SAE/AEOSI occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to 
the event. 
• 
The investigator will then record all relevant AE/SAE/AEOSI information in the eCRF/data 
collection tool, as appropriate. 
• 
The investigator will promptly (preferably within 24 hours) respond to all queries related to 
SAEs/AEOSIs. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records to 
the sponsor in lieu of completion of the AE/SAE/AEOSI eCRF/data collection tool. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
sponsor. In this case, all participant identifiers, with the exception of the participant’s study 
number, will be redacted on the copies of the medical records before submission. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE/AEOSI. 
Assessment of Intensity 
The investigator will assess the intensity for each AE/SAE/AEOSI reported during the study and assign 
an intensity/severity grade based on the National Cancer Institute-Common Terminology Criteria for 
Adverse Events [NCI-CTCAE]) Version 5. 
Note: An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is of severe intensity. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE/AEOSI. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
• 
The investigator will also consult the investigator’s brochure for dociparstat and the Product 
Information for any concomitant medications (as applicable). 
• 
For each AE/SAE/AEOSI, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE/AEOSI and has provided an assessment of causality. 
• 
There may be situations in which an SAE/AEOSI has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assess causality for every event before initial transmission of the SAE/AEOSI 
data to the sponsor. 
• 
The investigator may change his/her opinion of causality after follow-up information is available 
and send an SAE/AEOSI follow-up report with the updated causality assessment. 


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• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs, SAEs, and AEOSIs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature 
and/or causality of the AE/SAE/AEOSI as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
• 
If a participant dies during participation in the study (at any time from randomization through 
Day 28), the investigator will provide the date of death and a determination of cause of death 
(including any supporting information, such as death certificate, pathology or autopsy 
information, as applicable). 
• 
The investigator will submit any updated SAE/AEOSI data to the sponsor within 24 hours of 
receipt of the information. 
11.2.4. 
Reporting of SAEs and AEOSIs 
SAE/AEOSI Reporting to the Sponsor  
• 
The primary mechanism for reporting an SAE to the sponsor is the eCRF/data collection tool. 
• 
If an electronic system is used, but is unavailable, then the site will use the paper SAE data 
collection tool in order to report the event within 24 hours. 
• 
Contacts details for SAE reporting are included in the study reference manual. 
 


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11.3. 
Appendix 3: Contraceptive Guidance and Pregnancy Reporting 
11.3.1. 
Definitions 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered a woman of childbearing potential 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g., Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study eligibility. 
Note: Documentation can come from site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle-stimulating hormone level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, confirm with more than one follicle-stimulating 
hormone measurement. 
• Females on hormone replacement therapy and whose menopausal status is in doubt 
will be required to use one of the nonestrogen hormonal highly-effective 
contraception methods if they wish to continue their hormone therapy during the 
study. Otherwise, they must discontinue hormone therapy to allow confirmation of 
postmenopausal status before study enrollment. 


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11.3.2. 
Contraception Guidance 
Males must 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
OR 
• Agree to use a male condom with spermicide when having sexual intercourse with a 
woman of childbearing potential throughout the study and for at least 30 days after 
the last dose of study intervention. The participants should also be advised of the 
benefit for his female partner to use a highly-effective method of contraception as a 
condom may break or leak. 
Females must: 
• Be of nonchildbearing potential. 
OR 
• Agree to use a highly-effective method of contraception throughout the study and for 
at least 30 days after the last dose of study intervention. 


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Contraceptive Methods Allowed During the Study include the Following:  
Highly-Effective Methods That Have Low User Dependency 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
Vasectomized partner is a highly-effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly-effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days. 
Highly-Effective Methods That Are User Dependent 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 
o oral 
o intravaginal 
o transdermal 
o injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
o oral 
o injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly-effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
Notes: 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
Highly-effective methods have a failure rate of <1% per year when used consistently and correctly.  
Typical use failure rates differ from those when used consistently and correctly. 
 
Contraceptive Methods that are NOT ACCEPTABLE During the Study include the Following: 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods). 
• 
Withdrawal (coitus interruptus). 
• 
Spermicides alone. 
• 
Lactational amenorrhea method. 
• 
Use of both male condom and female condom together, because of the risk of failure with friction. 
 


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11.3.3. 
Collection of Pregnancy Information 
Female participants who become pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant’s pregnancy. 
• The participant will be followed to determine the pregnancy outcome. The 
investigator will collect follow-up information on the participant and neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. A spontaneous abortion (occurring at <22 weeks 
gestational age) or still birth (occurring at >22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor as described in Section 8.4.4. While the 
investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


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11.4. 
Appendix 4: NIAID Ordinal Scale 
 
The ordinal scale is an assessment of the clinical status of the participant at a given time point. 
The scale is as follows: 
1. Death 
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO) 
3. Hospitalized, on noninvasive ventilation or high flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental oxygen; requiring ongoing medical care 
(COVID-19 related or otherwise) 
6. Hospitalized, not requiring supplemental oxygen; no longer requires ongoing medical 
care 
7. Not hospitalized, limitation on activities and/or requiring home oxygen 
8. Not hospitalized, no limitations on activities 
 
 
 
Note: This scale is being used for the primary endpoint in the Adaptive COVID-19 Treatment Trial (ACTT; 
NCT04280705), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). 


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11.5. 
Appendix 5: Tisdale Risk Score 
 
Table 5: 
Risk Score to Identify Patients at Greatest Risk of QTc Interval Prolongation 
Risk Factor 
Points 
Age ≥68 years 
1 
Female 
1 
Loop diuretic 
1 
Serum potassium ≤3.5 mmol/L 
2 
Presenting QTc interval ≥450 msec 
2 
Acute myocardial infarction 
2 
Heart failure with reduced ejection fraction 
3 
1 QTc interval-prolonging drug 
3 
≥2 QTc interval-prolonging drugs  
3a 
Sepsis 
3 
Maximum score 
21 
a Three points in addition to the 3 points for taking 1 QTc interval-prolonging drug (6 points total.) 
Total score <7 = low risk; score 7 to 10 = moderate risk; score ≥11 = high risk 
 
 
Source: Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk 
assessment, prevention and management. Can Pharm J (Ott) 2016;149:139-152. 
 


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11.6. 
Appendix 6: Evaluation of Potential Heparin-Induced 
Thrombocytopenia (HIT) 
If a participant experiences a decrease in platelet count by >50% from baseline, or to an absolute platelet 
count of <50,000/mm3, evaluate for HIT, based on the following algorithm. 
Figure 2: 
HIT Evaluation Algorithm 
 
 


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Table 6: 
The 4Ts Clinical Pretest Probability of HIT 
4Ts 
2 points 
1 point 
0 points 
Thrombocytopenia 
Platelet count fall >50% 
and platelet nadir ≥20 x 
109/L 
Platelet count fall 30% 
to 50% or platelet nadir 
10-19 x 109/L 
Platelet count fall <30% 
or platelet nadir <10 x 
109/L 
Timing of platelet 
count fall 
Clear onset between 
Days 5 to 14 or platelet 
fall ≤1 day (if prior 
heparin exposure within 
30 days) 
Consistent with Days 5 
to 14 fall, but not clear 
(e.g., missing platelet 
counts) or onset after 
Day 14 or fall ≤1 day (if 
prior heparin exposure 
30 to 100 days ago) 
Platelet count fall 
≤4 days without recent 
exposure 
Thrombosis or other 
clinical sequelae  
New thrombosis 
(confirmed); skin 
necrosis at heparin 
injection sites; 
anaphylactoid reaction 
after IV heparin bolus; 
adrenal hemorrhage 
Progressive or recurrent 
thrombosis; 
Nonnecrotizing 
(erythematous) skin 
lesions;  
Suspected thrombosis 
(not confirmed) 
None 
Other causes of 
thrombocytopenia  
None apparent  
Possible (e.g., sepsis) 
Probable/Definite 
(e.g., DIC, medication, 
within 72 hours of 
surgery) 
 
 
 
 
Interpretation 
≤3 points = Low probability (<1%) 
4 to 5 points = Intermediate probability (~10%) 
6 to 8 points = High probability (~50%) 
Source: Pishko AM, Linkins, LA, Warkentin TE, Cuker A. Diagnosis and management of heparin-induced 
thrombocytopenia (HIT). 2018 Dec. Available at: https://www.hematology.org/-
/media/Hematology/Files/Education/Clinicians/Guidelines-Quality/Documents/ASH_VTE_HIT_PocketGuide.pdf 
Adapted from Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4Ts) for the diagnosis of 
heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759. 
 
Missing or inaccurate information may lead to a faulty 4Ts score and inappropriate management 
decisions. Every effort should be made to obtain accurate and complete information necessary to 
calculate the 4Ts score. If key information is missing, it may be prudent to err on the side of a 
higher 4Ts score. Reassess frequently. If there is a change in the clinical picture, the 4Ts score 
should be recalculated. 


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11.7. 
Appendix 7: Drugs Known to Prolong the QTc Interval 
 
The following drugs (list is not exhaustive) are known to prolong the QT interval: 
• amiodarone 
• disopyramide 
• haloperidol 
• posaconazole 
• astemizole 
• dofetilide 
• hydroxychloroquine 
• probucol 
• azithromycin 
• domperidone 
• ibutilide 
• procainamide 
• bepridil 
• droperidol 
• levomethadyl 
• quinidine 
• chloroquine 
• erythromycin 
• mesoridazine 
• sevoflurane 
• chlorpromazine 
• escitalopram 
• methadone 
• sotalol 
• ciprofloxacin 
• flecainide 
• moxifloxacin 
• sparfloxacin 
• cisapride 
• fluconazole 
• ondansetron 
• terfenadine 
• citalopram 
• granisetron 
• pentamidine 
• thioridazine 
• clarithromycin 
• halofantrine 
• pimozide 
• voriconazole 
 
 


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11.8. 
Appendix 8: Anticoagulation Considerations for Prevention of 
Venous Thromboembolism 
Anticoagulation therapy is not required on study. However, you may follow existing local 
institutional guidelines for the utilization of prophylactic anticoagulation therapy for participants 
with COVID-19 who are at risk of VTE. Table 7 represents guidelines derived from several 
institutions for reference; this is not intended to replace clinical judgement. It is recognized that 
specific guidelines within an institution could change as data emerge and may or may not follow 
these considerations. 
Based on clinical evaluation and local institutional guidelines, determine if prophylactic 
treatment is appropriate for an individual participant at the time of screening and randomization.  
The study permits enrollment of participants who are not receiving any prophylactic treatment, 
or who are receiving standard or intermediate intensity prophylactic treatment. Anticoagulant 
dosing at therapeutic intensity is exclusionary for randomization.  
For participants on enoxaparin, monitor anti-Xa peak levels ~4 hours after the second dose; 
adjust or discontinue prophylactic dosing to maintain anti-Xa level < 0.6 IU/mL. For participants 
receiving unfractionated heparin, adjust or discontinue dosing to maintain aPTT within 
prophylactic levels. Refer to Section 7 for the aPTT threshold for interruption and 
discontinuation criteria. 
Table 7: 
Prophylactic Anticoagulant Dosing Guidelines for Reference 
Clinical 
Consideration 
Treatment Intensity 
Standard Prophylaxis 
Intermediate Prophylaxis 
Therapeutic 
Standard BMI 
 
CrCl ≥30 mL/min 
Enoxaparin  
40 mg SC once daily 
Enoxaparin  
40 mg BID 
Anticoagulation 
higher than 
intermediate 
treatment intensity 
CrCl <30 mL/min 
UFH 5000 units SC 
every 8 hours 
UFH 7500 units SC 
every 8 hours 
Obese (BMI >35 kg/m2) 
 
CrCl ≥30 mL/min 
Enoxaparin  
40 mg SC BID 
Enoxaparin 0.5 mg/kg SC 
(maximum dose 100 mg) BID 
Anticoagulation 
higher than 
intermediate 
treatment intensity 
CrCl <30 mL/min 
UFH 7500 units SC 
every 8 hours 
UFH 10,000 units SC 
every 8 hours 
Abbreviations: BID=twice daily; BMI=body mass index; CrCl=creatinine clearance; SC=subcutaneous; 
UFH=unfractionated heparin 
Note: These considerations are based on published guidelines as of 02 August 2020 from the following institutions:  
- Emory Health Care (https://www.emoryhealthcare.org/ui/pdfs/covid/medical-
professionals/COVID%20Emory%20VTE%20Guidelines%20FINAL.pdf)    
- Brigham and Woman’s Hospital (https://covidprotocols.org/protocols/hematology/) 
- University Health Systems (https://www.universityhealthsystem.com/~/media/files/pdf/covid-19/guidelines-for-
anticoagulation-in-hospitalized-covid-19-patients.pdf?la=en).   
- University of Pennsylvania (https://www.med.upenn.edu/uphscovid19education/assets/user-
content/documents/treatment-guidelines/critical-care/anticoagulation-tip-sheet.pdf) 
 


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11.9. 
Appendix 9: Abbreviations 
 
AE 
adverse event 
AEOSI 
adverse event of special interest 
ALI 
acute lung injury  
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANOVA 
analysis of variance 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CX-01 
dociparstat sodium, 2-O, 3-O desulfated heparin 
CXCL12 
chemokine SDF-1, and abbreviation for stromal cell derived factor-1 
CXCR4 
receptor for the chemokine SDF-1  
DIC 
disseminated intravascular coagulation 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF / CRF 
electronic case report form / case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIT 
heparin-induced thrombocytopenia 
HMGB1 
high mobility group box protein 1 
HR 
hazard ratio 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IL-6 
interleukin-6 
IRB/IEC 
institutional (or independent) review board/independent ethics committee 
IRT 
interactive response technology 
ITT 
intent to treat 


Protocol CMX-DS-004  
 
Amendment 3: 06 November 2020
 
 
 
81 
Confidential 
IV 
intravenous  
JAK 
Janus kinase 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NET 
neutrophil extracellular trap 
NIAID 
National Institute of Allergy and Infectious Diseases 
ODSH 
(previously-used abbreviation for) 2-O, 3-O desulfated heparin 
PF4 
platelet factor 4 
PK 
pharmacokinetic 
PTT 
partial thromboplastin time 
RAGE 
receptor for advanced glycation end products 
SAA 
serum amyloid A 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
TNFα 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
VTE 
venous thromboembolism 
 
 


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Amendment 3: 06 November 2020
 
 
 
82 
Confidential 
11.10. 
Appendix 10: Protocol Amendment Summary of Changes 
Key changes from the prior version of the protocol are listed in the tables below. The synopsis 
has been updated to align with all changes in the protocol. Corrections of typographical errors 
and minor clarifications not listed in the summary of changes tables have also been included in 
the amendments. 
Table 8: 
Amendment 1 Summary of Changes 
Section(s) 
Change 
Rationale 
3 
Objectives 
and Endpoints 
Combined the list of exploratory 
biomarkers into a single endpoint and 
added “other biomarkers of 
inflammation.” 
To simplify the list of endpoints and account 
for analysis of other biomarkers that may be 
relevant to dociparstat. 
4.2 
Scientific 
Rationale 
Updates on other potential treatment 
options for COVID-19. 
To acknowledge the evidence regarding 
safety and effectiveness of potential 
treatments for COVID-19 is rapidly 
changing. 
5.1 
Inclusion 
Criteria 
Increased enrollment age limit from 
≤80 years to ≤85 years. 
COVID-19 disproportionately affects elderly 
patients. Increasing the age limit, while 
retaining specific health-related exclusion 
criteria, may increase enrollment of potential 
participants who may benefit from 
dociparstat. 
5.2 
Exclusion 
Criteria 
 
Added to exclusion criterion 4 
(formerly #3) to specify exclusion of 
potential participants who are also 
participating in the treatment period of 
any other therapeutic intervention 
study. Participation in the follow-up 
period of an interventional study may 
be permitted with prior medical 
monitor approval; participation in an 
observational study is permitted. 
Clarification that participants should not be 
participating in the treatment period of other 
therapeutic intervention studies, regardless of 
the therapy’s approval status. Participation in 
the follow-up period of another therapeutic 
intervention study must be approved by the 
medical monitor. 
Revised exclusion criterion 5 
(formerly #4) from excluding all 
current or anticipated use of systemic 
corticosteroids to excluding only 
chronic use of systemic 
corticosteroids. 
It is recognized that some potential 
participants may receive dexamethasone (or 
other corticosteroids) prior to being screened 
for this study, and investigator’s may want to 
treat participants with corticosteroids if their 
condition has deteriorated. 


Protocol CMX-DS-004  
 
Amendment 3: 06 November 2020
 
 
 
83 
Confidential 
Section(s) 
Change 
Rationale 
Added 4 new exclusion criteria: 
3. Active or uncontrolled bleeding… 
8. Receiving antiplatelet therapy… 
22. Evidence of clinical improvement 
in COVID-19 status … 
23. Any other condition, that, in the 
judgment of the investigator, could put 
the participant at increased risk … 
Overall numbering of exclusion 
criteria was also revised. 
To ensure appropriate participants are 
enrolled in the study by: 
(a) preventing enrollment of participants who 
are already showing signs of clinical 
improvement; and 
(b) preventing enrollment of participants 
with pre-existing conditions that increase the 
risk for serious bleeding, thereby improving 
participant safety.  
6.6.1 
Prohibited 
Therapies 
Added prohibition of aspirin and other 
antiplatelet agents during the study 
intervention infusion period. 
Concomitant use of antiplatelet agents with 
dociparstat has the potential to increase the 
risk for serious bleeding, therefore, 
prohibiting use will improve participant 
safety.  
6.6.2 
Permitted 
Therapies 
Deleted specific reference to 
hydroxychloroquine, chloroquine, and 
azithromycin as permitted therapies.  
The Emergency Use Authorization for 
hydroxychloroquine and chloroquine was 
revoked by FDA on 15 June 2020 and 
investigators have indicated the combination 
of hydroxychloroquine and azithromycin is 
no longer frequently used.  
8.2.1 
Clinical 
Evaluations 
Corrected the primary endpoint and 
specified that efficacy endpoints 
primarily rely on clinical status with 
respect to death, hospitalization, 
mechanical ventilation, supplemental 
oxygen. 
Error correction and clarification. 
 
 


Protocol CMX-DS-004  
 
Amendment 3: 06 November 2020
 
 
 
84 
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Table 9: 
Amendment 2 Summary of Changes 
Section(s) 
Change 
Rationale 
Schedule of 
Activities; 
8.3.4 
Clinical 
Laboratory 
Assessments 
Added anti-Xa monitoring of 
enoxaparin levels. 
Added to monitor the coagulation status of 
participants receiving concomitant 
enoxaparin therapy. 
5.2 
Exclusion 
Criteria 
Revised exclusion criterion 7 to 
exclude anticoagulation dosing at a 
therapeutic intensity, and to permit 
prophylactic heparin or enoxaparin 
within the guidelines described in 
Appendix 8. 
 
With the continually evolving guidelines for 
care of patients with COVID-19, 
anticoagulation is becoming standard for 
hospitalized patients. Concomitant use of 
standard or intermediate prophylactic dosing 
of anticoagulants with dociparstat has the 
potential to increase the risk of bleeding; 
therefore, monitoring of anti-Xa levels was 
added to the study to monitor enoxaparin.  
5.2 
Exclusion 
Criteria 
Exclusion criterion 17 was revised to 
exclude “Activated partial 
thromboplastin time (aPTT) 
>42 seconds,” which was changed 
from >40 seconds.  
Potential participants who are receiving 
anticoagulants at a dose higher than 
originally permitted may have an associated 
aPTT at screening that is higher than 
originally expected. 
6.6.1 
Prohibited 
Therapies; 
6.6.2  
Permitted 
Therapies 
Removed “other anticoagulants” from 
list of prohibited therapies. 
Added unfractionated heparin and 
enoxaparin to list of permitted 
therapies, with appropriate monitoring 
of coagulation status. 
Treatment recommendations for the 
management of patients with COVID-19 are 
rapidly evolving, with higher doses (than 
initially permitted) of enoxaparin and 
unfractionated heparin for prophylaxis of 
venous thromboembolism becoming a 
standard of care.  
6.6.2  
Permitted 
Therapies 
Added convalescent plasma.  
Concomitant use of convalescent plasma 
with dociparstat is not expected to adversely 
impact participant safety. 
7.1  
Interruption of 
Study 
Intervention 
Added recommendation to reduce the 
dose of enoxaparin or unfractionated 
heparin (as applicable) as the first step 
in the event of aPTT >50 seconds. 
Holding or reducing the dosing of the known 
anticoagulant is the most appropriate action 
to reduce the risk of bleeding. Any individual 
participant may be receiving either 
dociparstat or placebo; therefore, interrupting 
the dosing of study intervention may not 
have any effect on aPTT. 
9.2  
Sample Size 
Determination 
Sample size calculations were 
adjusted.  
To account for potential unblinding of data 
after Cohort 2, which would decrease the 
sample size for analyses after Cohort 3. 


Protocol CMX-DS-004  
 
Amendment 3: 06 November 2020
 
 
 
85 
Confidential 
Section(s) 
Change 
Rationale 
9.4  
Statistical 
Analyses 
Added 2 scenarios for the analysis 
approach based on whether or not data 
are unblinded after Cohort 2. 
To account for potential unblinding of data 
after Cohort 2. 
9.6  
Data 
Monitoring 
Committee 
Added “Due to the evolving standard 
of care for COVID-19, the sponsor 
may decide to unblind and review 
study data following Cohort 2.” 
Changes in standard of care and use of 
concomitant therapies may impact the 
viability of the study; therefore, the sponsor 
may decide to evaluate the data at an earlier 
timepoint than initially planned. 
Appendix 8 
New appendix included to provide 
“Anticoagulation Considerations for 
Prevention of Venous 
Thromboembolism.” 
Numbering of subsequent appendices 
was updated accordingly. 
To provide updated guidelines on the use of 
prophylactic anticoagulation with respect to 
dosing and monitoring. 
 
 
Table 10: 
Amendment 3 Summary of Changes 
Section(s) 
Change 
Rationale 
4.1 Overall 
Design, 
6.4 Measures 
to Minimize 
Bias, 
9.2 Sample 
Size 
Determination 
Randomization ratio changed from 1:1 
to 2:1 (dociparstat: placebo) for 
Phase 2 Cohorts 2 and 3 and for 
Phase 3. 
Phase 2/Cohort 3 sample size adjusted 
from N=50 to N=51 (34 dociparstat 
and 17 placebo) and Phase 3 adjusted 
from N=452 to N=450 (300 dociparstat 
and 150 placebo). 
To increase the number of participants with 
COVID-19 who are exposed to dociparstat. 
The number of participants was adjusted to 
align with the change in randomization ratio. 
9.4 Statistical 
Analyses,  
9.6 Data 
Monitoring 
Committee 
Modified text to indicate the sponsor 
may decide to unblind and review 
study data following Cohort 1 
and/or 2 (previously only after 
Cohort 2). 
Based on the slower than anticipated study 
enrollment and the rapidly evolving 
COVID-19 landscape, the sponsor wants the 
flexibility to review unblinded dated after 
completion of Cohort 1. This change is being 
included in this amendment from an 
administrative change letter issued 
28 September 2020. 
9.5 Phase 3 
Interim 
Futility 
Analysis,  
9.6 Data 
Monitoring 
Committee 
Timing of futility analysis and DMC 
safety review adjusted from after 226 
participants complete the study to after 
225 participants complete the study.  
To align with change in randomization ratio 
and sample size adjustment. 
 

SAP_001.pdf: 
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Page 1 of 45 
 
 
Study Title: A Phase 2/3 Study to Evaluate the Safety and Efficacy of Dociparstat 
Sodium for the Treatment of Severe COVID-19 in Adults at High Risk of Respiratory 
Failure 
NCT Number: NCT04389840 
Document Date: 06 November 2020 
 
 
 
 


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Page 2 of 45 
 
Post-Cohort 1 or 2 Lock Analyses - Shells 
 
 
 
 
Sponsor Name: 
Chimerix, Inc 
 
Protocol Number and Title: 
CMX-DS-004 
A Phase 2/3 Study to Evaluate the Safety and 
Efficacy of Dociparstat Sodium for Treatment 
of Severe COVID-19 in Adults at High Risk of 
Respiratory Failure 
 
Final Protocol Date: 
Protocol Amendment 3, dated 06 Nov 2020 
 
Syneos Health Project Code: 
7015085 
 
Author(s): 
Roland Wolf, PhD, Lead Biostatistician 
Version 
2.0 
 
Version Date: 
12 March 2021 
 
 
Notice of Confidential and Proprietary Information 
 
 
The information contained in this document is confidential belonging to Chimerix, Inc. Acceptance of 
this document constitutes agreement by the recipient that no information contained herein will be 
published or disclosed without prior written authorization from an official of Chimerix, Inc. However, 
this document may be disclosed to appropriate Institutional Review Board and Ethics Committees or 
duly authorized representatives of a national regulatory authority under the condition that they are 
requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 


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APPROVALS and ACKNOWLEDGEMENT OF REVIEW 
Syneos Health 
Roland Wolf, PhD 
Roland Wolf 
Electronically signed by: Roland Wolf 
Reason: I am the author 
Date: Mar 15, 2021 17:27 GMT+1 
Principal Biostatistician 
Signature 
Date (DD-Mmm-YYYY) 
Andrea Wirth 
Andrea Wirth 
Electronically signed by: Andrea Wirth 
Reason: I am the approver 
Date: Mar 15, 2021 17:35 GMT+1 
Senior Principal Biostatistician 
Signature 
Date (DD-Mmm-YYYY) 
Blake Allman 
Blake Allman 
Electronically signed by: Blake Allman 
Reason: I am the approver 
Date: Mar 16, 2021 08:51 GMT 
Principal Stat Programmer 
Signature 
Date (DD-Mmm-YYYY) 
Chimerix 
Thomas M. Brundage 
Thomas M. 
Brundage 
Digitally signed by Thomas M. 
Brundage 
Date: 2021.03.15 11:30:00 -04'00' 
Executive Director, Biostatistics 
Signature 
Date (DD-Mmm-YYYY) 


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Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
1.0 
17 Sep 2020 
Roland Wolf 
Initial Release Version 
2.0 
12 Mar 2021 
Roland Wolf 
Updated for Protocol Amendment 3. Clarify analysis 
of subjects randomized but not treated. 


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List of Tables 
TABLE OF CONTENTS 
 
Table 1: Demographics and Baseline Characteristics – Safety Set. ....................... 11 
Table 2: Listing of demographics, baseline characteristics, study drug usage and 
disposition – Safety Set ....................................................................... 13 
Table 3: Study drug usage – Safety Set .................................................................. 14 
Table 4: Listing of study drug interruptions / discontinuations – Safety Set ......... 15 
Table 5: Treatment disposition – Safety Set .......................................................... 16 
Table 6: Study disposition – Randomized Subjects ................................................17 
Table 7: Proportion of subjects who go on invasive mechanical ventilation or 
ECMO - Safety Set ............................................................................. 18 
Table 8: Treatment-emergent Adverse Events (TEAEs) – Safety Set .................... 21 
Table 9: Severe, life-threatening or fatal treatment emergent Adverse Events – 
Safety Set ............................................................................................ 22 
Table 10: Treatment emergent Adverse Events leading to study drug 
discontinuation – Safety Set. ............................................................... 22 
Table 11: Serious treatment emergent Adverse Events – Safety Set ..................... 22 
Table 12: Listing of Serious Adverse Events and Adverse Events of Special 
Interest – Safety Set ............................................................................ 23 
Table 13: Overview CTCAE v5.0 Grades ..............................................................24 
Table 14: Distribution of laboratory grade by parameter and visit – Safety Set. ... 25 
Table 15: Listing of laboratory results – Safety Set ............................................... 26 
Table 16: Shift-table of laboratory results – Safety Set ..........................................27 
Table 17: Listing of Prior and Concomitant Medications (only Targeted 
Medications) – Safety Set ................................................................... 30 
Table 18: Proportion of and time to invasive mechanical ventilation or all-cause 
mortality – ITT Set. ............................................................................. 33 
Table 19: Proportion of and time to all-cause mortality – ITT Set .........................35 
Table 20: Proportion of participants who are alive, discharged from the hospital, 
and not using home oxygen – ITT Set .................................................37 


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Table 21: Clinical status assessed by the NIAID ordinal scale at fixed time points – 
ITT Set ................................................................................................ 38 
Table 22: Time to clinical improvement – ITT Set. ............................................... 40 
Table 23: Number of ventilator-free days from baseline through Day 28 – ITT Set 
..............................................................................................................42 
Table 24: Time to last hospital discharge – ITT Set ...............................................43 
Table 25: Time to first hospital discharge – ITT Set ..............................................45 
 
List of Figures 
 
Figure 1: Time to first invasive mechanical ventilation or ECMO (KM-Plot) - 
Safety Set ............................................................................................ 19 
Figure 2: Duration of first invasive mechanical ventilation or ECMO (KM-Plot) - 
Safety Set ............................................................................................ 20 
Figure 3: Selected laboratory parameters over time (Box-Whisker-Plot) - Safety 
Set ....................................................................................................... 28 
Figure 4: Biomarkers during the course of the study – Safety Set ......................... 31 
Figure 5: Time to invasive mechanical ventilation, ECMO or all-cause mortality 
(KM-Plot) – ITT Set ........................................................................... 34 
Figure 6: Time to all-cause mortality (KM-Plot) – ITT Set ................................... 36 
Figure 7: Time to clinical improvement (KM-Plot) – ITT Set .............................. 41 
Figure 8: Time to last hospital discharge (KM-Plot) – ITT Set ..............................44 
Figure 9: Time to first hospital discharge (KM-Plot) – ITT Set .............................45 


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1. 
PURPOSE 
This is a randomized, double-blind, placebo-controlled, Phase 2/3 study to determine the safety and 
efficacy of dociparstat in adults with acute lung injury associated with severe COVID-19 who are at 
high risk of respiratory failure. 
 
An independent unblinded data monitoring committee (DMC) will review safety data from Cohort 1 
to make a recommendation on dose escalation in Cohort 2 and review safety data from both Cohorts 
1 and 2 to make a recommendation on dosing in Cohort 3. The sponsor will consider the DMC 
recommendation when determining the actual doses for Cohorts 2 and 3. 
 
Due to the evolving standard of care for COVID-19, the sponsor may decide to unblind and review 
study data following Cohorts 1 and/or 2. 
 
The purpose of this document is to describe the pre-defined post-Cohort 1 or 2 lock analysis. This 
document specifies the derivations and TFL package and is based on the study protocol amendment 
3, dated 06 November 2020. 


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2. 
INTRODUCTION 
Cohort 1 contains 6 participants randomized to dociparstat, 6 randomized to placebo. Dociparstat 
will be dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.25 mg/kg/hr. 
 
Cohort 2 includes 6 participants randomized to dociparstat, 6 randomized to placebo. Dociparstat 
will be dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.325 mg/kg/hr (dose to be 
confirmed after review of data from Cohort 1). 
 
Based on Protocol Amendment 3, dated 06 November 2020, the randomization ratio (dociparstat: 
placebo) changed from 1:1 in Cohort 1 to 2:1 in the following cohorts. 
 
Both Cohorts 1 and 2 may be unblinded to the entire team following cleaning and database lock of 
Cohort 1/2 data. The full randomization code will remain blinded as is; in this event, only the Cohort 
1/2 assignments will be unblinded. 
 
The first part of the analysis defined in this document will be eqivalent to the statistical output 
delivered to the DMC-members for the 2nd Cohort (see Section 5.1), however with all data collected 
until End of Study (EOS). 


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3. 
DERIVATIONS AND DEFINITIONS 
Kaplan-Meier estimates 
 
Time to xxx (days): Days are calculated as (start date/time – first study drug date/time)/24h). Time 
will be censored at last individual date/time reported. 
 
Worst-case results in 2 scenarios for missing time-values: 
 
1. Missing time for negative events will be imputed with “00:01”, missing time for censored 
observations will be imputed with “23:59”. 
Negative events are: 
- 
Time to first invasive mechanical ventilation or ECMO 
- 
Time to first invasive mechanical ventilation, ECMO or all-cause mortality 
- 
Time to all-cause mortality 
 
2. Missing time for positive events will be imputed with “23:59”, missing time for censored 
observations will be imputed with “00:01”. 
Positive events are: 
- 
Time to clinical improvement 
- 
Time to hospital discharge 
In addition, to avoid bias in the positive events, deaths occurring prior to the positive event 
being observed will censored at Day 28. 
 
Ventilator-free days 
 
Ventilator-free days are only counted from baseline through Day 28 or end of study, whichever comes 
first. They are derived based on the eCRF data collected on the Ventilator/Oxygen/Medical Care 
Status CRF page, Ventilator-free days are all days where Ventilator/Oxygen/Medical Care Status is 
not equal “Invasive Mechanical Ventilation or extracorporeal membrane oxygenation (ECMO)”. 
 
Ventilator days are defined as cumulative rounded number of days with Ventilator/Oxygen/Medical 
Care Status = “Invasive Mechanical Ventilation or extracorporeal membrane oxygenation (ECMO)” 
devided by 24 h. Missing time for start will be imputed with “00:01”, missing time for stop will be 
imputed with “23:59”. 
 
Study duration in days is defined as: Date of study completion (or date of early study 
discontinuation) – date of first study treatment + 1. For subjects randomized but not treated the 
date of randomization will be used instead of first study treatment date. The maximum study 
duration is set to 28 days, even if study completion or study discontinuation is after 28 days. 
 
Ventilator-free days are defined as: study duration - number of ventilator days. For subjects who 
died during the course of the study, the number of ventilator-free days will be defined as 0. 


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Randomized, but not treated subjects: 
 
The following rules will apply for randomized subjects without receiving study treatment, if not stated 
otherwise: 
 
- 
Calculations referring to start of treatment or baseline will be performed with respect to 
randomization date/time. 
 
- 
Study duration in days is calculated as study discontinuation date - randomization date +1. 
- 
In Kaplan-Meier analysis the “time-to” will be censored at 0. 


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4. 
CONVENTIONS FOR SUMMARY TABLES AND LISTINGS 
At the top of each table/listing/figure, the first three title lines should read: 
Chimerix 
CMX-DS-004 
Post-Cohort 1/2 Lock Analysis - FINAL (Unblinded) 
 
Following those titles, the next title should include the output number and a description of the 
table/listing content, including the Analysis Set used. 
The next line is an optional sub-title with description of a subgroup, if applicable. 
Horizontal lines will appear before and after the column heading of the table/listing. Footnotes will be 
put under the main body of text and each new footnote should start with a new line. Very long 
footnotes will be presented only on the very first page of the output. 
At the bottom of each TFL, the following information should be printed: date of the data base cut off, 
date and time of the run of the TFL and name of the program. 
Data Cut-off date: DDMMMYYYY; 
Program name: M:\project-sas\chimerix\7015085\biostat\3-cohort\tables\production\xxxxx.sas 
Run date: DDMMMYYYY HH:MM 
Page X of Y 
 
Outputs will be prepared in landscape layout unless otherwise specified. Blank margins of all tables 
and listings will be a minimum of 1 inch. In general, Courier New 8 point font will be used. 
 
Listings Layout 
 
Listings will contain the data of all subjects except when otherwise specified. The following visit labels 
will be used (shorthand in parentheses), but data will be sorted by assessment date (including the 
Unscheduled Visits): 
 
o 
Screening (SCRN) 
o 
Baseline (D1) 
o 
Day 2 (D2) 
o 
Day 3 (D3) 
o 
Day 4 (D4) 
o 
Day 5 (D5) 
o 
Day 6 (D6) 
o 
Day 7 (D7) 
o 
Day 8 (D8) 
o 
Day 14 (D14) 
o 
Day 28 (D28) 
o 
Early Tx DC (TXDC) 
o 
Unscheduled (UNSCH) 


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5. 
TABLE SHELLS 
5.1. 
DMC – TABLE SHELLS 
 
Table 1: Demographics and Baseline Characteristics – Safety Set 
 
DSTAT 0.25 
N=xxx 
 
Cohort 1 PBO 
N=xxx 
 
DSTAT 0.325 
N=xxx 
 
Cohort 2 PBO 
N=xxx 
 
Total 
N=xxx 
 
 
Gender, n(%) 
Male 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Female 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Unknown/Not Answered 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Race, n(%) 
White 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Black 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Asian 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unknown/Not Answered 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Ethnicity, n(%) 
Hispanic or Latino 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Not Hispanic or Latino 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unknown/Not Answered 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Age (years) 
n 
Xxx 
xxx 
xxx 
xxx 
xxx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
Xx 
xx 
xx 
xx 
xx 
Q1, Q3 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
Age (years), n(%) 
< 60 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
>=60 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Weight (kg) 
N 
xxx 
xxx 
xxx 
xxx 
xxx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx 
xx 
xx 
xx 
xx 
Q1, Q3 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 12 of 45 
 
 
 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Total 
N=xxx 
Height (cm) 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx 
xx 
xx 
xx 
xx 
Q1, Q3 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Body mass index (kg/m2) 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx 
xx 
xx 
xx 
xx 
Q1, Q3 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Temperature (°C) 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx 
xx 
xx 
xx 
xx 
Q1, Q3 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Fever, n(%) 
<= 37.2°C 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
> 37.2°C to 38.2°C 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
> 38.2°C 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
NIAID-Score (IRT), n(%) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
NIAID-Score (actual), n(%) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
SD: Standard deviation; Q1, Q3: First, third quartile; Min: minimum; Max: maximum. 
Baseline is defined as last measurement prior to or on the date of first study treatment. 
NIAID-Score (IRT): directly entered in RAVE by the investigator. 
NIAID-Score (actual): calculated using hospitalization and ventilation status at time of randomization. 
Page X of Y 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 13 of 45 
 
 
 
Table 2: Listing of demographics, baseline characteristics, study drug usage and disposition – Safety Set 
 
 
Subject 
Age/Sex 
Treatment 
Group 
Race 
Ethni- 
city 
Weight 
(kg) 
BMI 
(kg/m2) 
Temp 
(°C) 
NIAID (IRT / 
actual) 
Bolus received 
/ 
# infusion days 
Treatment 
disposition 
Study 
disposition 
Death / 
Date 
999-999 
/70/F 
999-999 
DSTAT 0.25 
Cohort 1 PBO 
Asian 
Other: 
HL 
NHL 
xx.x 
xx.x 
xx.x 
xx.x 
4 / 4 
3 / 3 
Yes / 3 
Yes / 7 
Discontinued: 
AE 
Discontinued: 
Discontinued: 
Progression 
Discontinued: 
xx/xx 
xxxxxx 
Other: xxx 
FUP 
999-999 
xx/xx 
Cohort 1 PBO Other: 
xxxxxx 
NHL 
xx.x 
xx.x 
3 / 3 
Yes / 7 
Completed 
Completed 
Yes / 
ddMMMYYY 
999-999 
xx/xx 
Cohort 1 PBO Other: 
xxxxxx 
NHL 
xx.x 
xx.x 
3 / 4 
Yes / 7 
Unknown 
Ongoing 
 
 
Ethnicity: HL=Hispanic or Latino, NHL=Not Hispanic or Latino 
NIAID-Score (IRT): directly entered in RAVE by the investigator. 
NIAID-Score (actual): calculated using hospitalization and ventilation status at time of randomization. 
 
Page X of Y 
 
 
(Notes for programmer: 
- Sorted by subject number 
- Disposition: Progression=Progression of disease, AE=Adverse Event, Prohibited=Patient requires use of a prohibited therapy, 
Compliance=Non-compliance, FUP=Lost to follow-up, Consent=Patient withdrawal of consent, Physician=Physician decision, 
Sponsor=Sponsor decision, Improvement=Improvement of condition under study, UNK=Unknown/Not answered) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 14 of 45 
 
 
 
 
Table 3: Study drug usage – Safety Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Bolus received, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Infusion (days received), n(%) 
1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
Infusion (days received): Study drug administered at any time during the corresponding study-day (cumulated). 
Page X of Y 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 15 of 45 
 
 
 
 
 
Table 4: Listing of study drug interruptions / discontinuations – Safety Set 
 
 
Subject 
Age/Sex/Race 
Treatment 
Group 
Visit 
Start 
Date / Time 
Stop 
Date / Time 
Bolus / 
Infusion no 
Total Voulume 
Given (mL) 
Interrupted due 
to 
Permanently 
discontinued due to 
999-999 / 
DSTAT 0.25 
Baseline (D1) 
69/F/W 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
Bolus 
999.99 
Adverse Event 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
1 
999.99 
Day 2 (D2) 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
2 
999.99 
Other:xxxxxx 
Day 3 (D3) 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
3 
999.99 
Adverse Event 
Day 4 (D4) 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
4 
999.99 
Other: xxxxxx 
999-999 / 
Cohort 1 PBO Baseline (D1) 
35/M/B 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
Bolus 
999.99 
Adverse Event 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
1 
999.99 
Day 2 (D2) 
ddMMMyy hh:mm 
ddMMMyy hh:mm 
2 
999.99 
Page X of Y 
 
(Note for programmer: Sorted by subject number, start date, start time) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 16 of 45 
 
 
 
Table 5: Treatment disposition – Safety Set 
 
 
Treatment disposition 
Primary reason for treatment discontinuation 
DSTAT 0.25 
N=xxx 
 
Cohort 1 PBO 
N=xxx 
 
DSTAT 0.325 
N=xxx 
 
Cohort 2 PBO 
N=xxx 
Completed treatment, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Treatment disposition unknown, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Discontinued treatment, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Primary reason for treatment discontinuation, n(%) 
Progression of disease 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Adverse Event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Patient requires use of a prohibited therapy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Non-compliance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lost to follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Patient withdrawal of consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Physician decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Sponsor decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Improvement of condition under study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unknown/Not Answered 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death (during treatment period) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
 
Page X of Y 
 
(Note for programmer: Death (during treatment period) to be derived in case death date = date of last treatment start date or stop 
date) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 17 of 45 
 
 
 
Table 6: Study disposition – Randomized Subjects 
 
 
 
Study Disposition 
Primary reason for early termination 
DSTAT 0.25 
N=xxx 
 
Cohort 1 PBO 
N=xxx 
 
DSTAT 0.325 
N=xxx 
 
Cohort 2 PBO 
N=xxx 
Randomized subjects, n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Randomized not treated subjects, n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x 
Treated subjects, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed study, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ongoing, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Discontinued study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Primary reason for study discontinuation, n(%) 
Patient withdrawal of consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Adverse Event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Use of a prohibited therapy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Non-compliance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lost to follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Investigator decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Sponsor decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unknown/Not Answered 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death, n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of randomized subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
 
Page X of Y 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 18 of 45 
 
 
 
Table 7: Proportion of subjects who go on invasive mechanical ventilation or ECMO - Safety Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Number of subjects with any invasive 
mechanical ventilation, ECMO or early 
study discontinuation, n (%) (a) 
Any invasive mechanical ventilation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Early study discontinuation < Day 25 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Kaplan-Meier estimates (b) 
Number of censored subjects, n (%) (b) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Time to first invasive mechanical 
ventilation or ECMO (days) (b) 
25% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Median (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
75% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Number of subjects who stopped invasive 
mechanical ventilation or ECMO, n(%) (c) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Kaplan-Meier estimates (c) 
Number of censored subjects, n (%) (c) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Duration of first invasive mechanical 
ventilation or ECMO (days) (c) 
25% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Median (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
75% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
ECMO: Extracorporeal membrane oxygenation. 
(a) Subjects with any invasive mechanical ventilation, ECMO or early study discontinuation before Day 25 will be counted as 
event. 
(b) Kaplan-Meier estimates: Subjects with any invasive mechanical ventilation or ECMO will be counted as event. All other 
subjects will be censored. Time to first invasive mechanical ventilation or ECMO (days): Days are calculated as (start date/time 
– first study drug date/time)/24h). Time will be censored at last individual date/time reported. If time is not available for 
events “00:01” will be imputed, for censored observations “23:59” will be imputed. 
(c) Kaplan Meier estimates: Duration of first invasive mechanical ventilation or ECMO (days): Only calculated for subjects with 
an invasive mechanical ventilation or ECMO reported. Duration is calculated as (stop date/time – start date/time)/24h). If start 
time is not available “00:01” will be imputed, if end time is missing “23:59” will be imputed. Duration will be censored for 
subjects with ongoing ventilation at last individual date/time reported. 
Page X of Y 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 19 of 45 
 
 
 
Figure 1: Time to first invasive mechanical ventilation or ECMO (KM-Plot) - Safety Set 
Kaplan-Meier Plot: 
 
y-axis: 
range: 0% to 100% by 20% 
label: Event-free Probability 
reference-line: 50% 
x-axis: 
range: 0 to xxx (depending on data), by 7 days 
label: Time to Event (Days) 
Lines: 
solid 
different colors/line styles for the treatment-groups 
starting at (100%/Baseline) 
Censored values marked 
 
 
Please use the following footnote for Figure 1 : 
 
N = Number of subjects in a specific group; (+) = censored values; 
Kaplan-Meier estimates: Subjects with any invasive mechanical ventilation or ECMO will be counted as event. All other subjects will 
be censored. 
Time to first invasive mechanical ventilation or ECMO (days): Days are calculated as (start date/time – first study drug 
date/time)/24h). Time will be censored at last individual date/time reported. If time is not available for events “00:01” will be 
imputed, for censored observations “23:59” will be imputed. 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 20 of 45 
 
 
 
Figure 2: Duration of first invasive mechanical ventilation or ECMO (KM-Plot) - Safety Set 
 
Kaplan-Meier Plot: 
 
y-axis: 
 
 
 
x-axis: 
 
 
Lines: 
range: 0% to 100% by 20% 
label: Event Probability 
reference-line: 50% 
 
range: 0 to xxx (depending on data), by 7 days 
label: Duration (Days) 
 
solid 
different colors/line styles for the treatment-groups 
starting at (0%/Baseline) 
Censored values marked 
 
 
 
Please use the following footnote for Figure 2 : 
 
N = Number of subjects in a specific group; (+) = censored values; 
Kaplan Meier estimates: Duration of first invasive mechanical ventilation or ECMO (days): Only calculated for subjets with an 
invasive mechanical ventilation of ECMO reported. Duration is calculated as (stop date/time – start date/time)/24h. If start time 
is not available “00:01” will be imputed, if end time is missing, “23:59” will be imputed. Duration will be censored for subjects 
with ongoing ventilation at last individual date/time reported. 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 21 of 45 
 
 
 
Table 8: Treatment-emergent Adverse Events (TEAEs) – Safety Set 
 
 
Primary system organ class 
Preferred term 
 
DSTAT 0.25 
N=xxx 
n (%) 
 
Cohort 1 PBO 
N=xxx 
n (%) 
 
DSTAT 0.325 
N=xxx 
n (%) 
 
Cohort 2 PBO 
N=xxx 
n (%) 
Number (%) of subjects with at least 
one such AE 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
SOC 1 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
PT 1 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
PT 2 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
: 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
SOC 2 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
: 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with at least one event in the category; 
Percentages are based on N; Adverse events are coded using MedDRA version 23.0. 
If a subject has multiple occurrences of an AE, the subject is presented only once in the respective subject count (n). 
 
Page X of Y 
 
(Note for programmer: AEs are sorted by decending patients’ frequency of SOC and by decending frequency of PT within the SOC in the 
DSTAT 0.25) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 22 of 45 
 
 
 
 
 
Table 9: Severe, life-threatening or fatal treatment emergent Adverse Events – Safety Set 
For the layout refer to Table 8 
(Notes for programmer: 
- Change first line in the table to “Number (%) of subjects with at least one such AE”. 
- TEAEs with the following AE severity grades are reported: Grade 3 (Severe), Grade 4 (Life-threatening), Grade 5 (Fatal).) 
 
 
Table 10: Treatment emergent Adverse Events leading to study drug discontinuation – Safety Set 
 
 
For the layout refer to Table 8 
(Note for programmer: Change first line in the table to “Number (%) of subjects with at least one such AE”. 
 
 
 
Table 11: Serious treatment emergent Adverse Events – Safety Set 
 
 
For the layout refer to Table 8 
(Note for programmer: Change first line in the table to “Number (%) of subjects with at least one such TEAE”. 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 23 of 45 
 
 
 
Table 12: Listing of Serious Adverse Events and Adverse Events of Special Interest – Safety Set 
 
Subject 
Age/Sex/Race 
 
Treatment 
Group 
 
Preferred term 
Verbatim 
 
Start Date 
(Study Day) 
 
Stop Date 
(Study Day) Severity 
 
Relation- 
ship 
Outcome 
 
Serious 
AE 
 
AE of Special 
Interest 
 
Action taken 
with study drug 
 
 
999-999 / 
70/F/W 
DSTAT 
0.25 
PT1 
xxxxxxxxx 
DdMMMyy (xx) DdMMMyy (xx) 
Mild 
Related 
Fatal 
Yes 
Yes 
Discontinued 
999-999 / 
xx/xx/xx 
Cohort 1 
PBO 
PT1 
xxxxxxxxx 
DdMMMyy (xx) DdMMMyy (xx) 
Mild 
Related 
Recovered 
No 
Yes 
No Change 
 
 
 
Note: Adverse events are coded using MedDRA version 23.0. 
Study Days prior to first treatment date are calculated as (actual date – first treatment date), after first treatment date as (actual 
date – first treatment date) + 1. 
 
Page 1 of x 
 
 
(Notes for programmer: 
- Sorted by subject number, start date, stop date, Preferred term and Verbatim 
- Outcome: Ongoing=Not recovered (Ongoing), Sequelae=Recovered with Sequelae, Unknown=Unknown/Lost to Follow-up 
- Action taken with study drug: Interrupted=Study drug temporarily interrupted, Discontinued=Study drug permanently discontinued 
) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 24 of 45 
 
 
 
Table 13: Overview CTCAE v5.0 Grades 
 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
<LLN - 10.0 g/dL 
<LLN - 6.2 mmol/L 
<LLN - 100 g/L 
<10.0 - 8.0 g/dL 
<6.2 - 4.9 mmol/L 
<100 - 80g/L 
<8.0 g/dL 
<4.9 mmol/L 
<80 g/L 
NA 
Platelets 
<LLN - 75,000/mm3; 
<LLN - 75.0 x 10e9/L 
<75,000 - 50,000/mm3; 
<75.0 - 50.0 x 10e9/L 
<50,000 - 25,000/mm3; 
<50.0 - 25.0 x 10e9/L 
<25,000/mm3; 
<25.0 x 10e9/L 
Activated Partial Thromboplasting Time (aPTT) 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
NA 
Prothrombin Intl. Normalized Ratio (INR) 
>1.2 - 1.5 
>1.5 - 2.5 
>2.5 
NA 
Aspartate Aminotransferase (AST) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Alanine Aminotransferase (ALT) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Total Bilirubin 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Creatinine 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Creatinine Clearance, Estimated 
<LLN - 60 ml/min 
<60 - 30 ml/min 
<30 - 15 ml/min 
<15 ml/min 
 
NA = Not applicable, ULN = Uppler limit of normal, LLN = Lower limit of normal. 
Grade 0 : Any result not graded 1, 2, 3, 4 or Unknown. 
Grade Unkown : Missing result or missing upper limit of normal for parameters requiring ULN for grading. 
 
(Notes for programmer: 
- LLN for creatinine clearance is fixed 90 mL/min 
- Calculation of creatinine clearance (CC) (Cockcroft-Gault): 
(140 – age (years)) 
CC (ml/min) = -------------------------------- * baseline weight (kg) * (0.85 if female) 
0.8143 * serum creatinine (µmol/L) 
) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 25 of 45 
 
 
 
Table 14: Distribution of laboratory grade by parameter and visit – Safety Set 
Parameter: <Hemoglobin> <Platelets> <Activated partial thromboplastin time (aPTT)> <Prothrombin International Normalized Ratio 
(INR)> <Aspartate aminotransferase (AST)> <Alanine aminotransferase (ALT)> <Total bilirubin> <Creatinine> <Creatinine Clearance, 
Estimated > 
 
 
Scheduled Visit 
DSTAT 0.25 
Cohort 1 PBO 
DSTAT 0.325 
Cohort 2 PBO 
Grades (a) 
N=xxx 
N=xxx 
N=xxx 
N=xxx 
Baseline 
Grade 0 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unknown 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Maximum Post-baseline Grade 
Grade 0 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Unknown 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
(a) CTCAE v5.0 grades using absolute thresholds without accounting for baseline. 
Baseline value is defined as the last non-missing measurement prior to, or on the date/time of the first administration of study 
treatment. 
NA = not applicable 
Page X of Y 
 
(Notes for programmer: 
- CTCAE Grades: Unknown: missing result (or missing upper limit of normal for parameters requiring ULN for grading). Grade 0: any 
result not graded 1, 2, 3, 4 or Unknown. 
- display only for visit Baseline and Maxiumum Grade per subject and all 6 categories (Grade 0 – Grade 4 and Unknown), if 
applicable. 
- generate a post-baseline Maximum Grade per subject (incl. unscheduled measurements) 
- for the generation of Maxiumum Grade use the following order: Unknown – Grade 0 – Grade 1,…. Grade 4) 
- Calculation of creatinine clearance (CC) (Cockcroft-Gault): 
(140 – age (years)) 
CC (ml/min) = -------------------------------- * baseline weight (kg) * (0.85 if female) 
0.8143 * serum creatinine (µmol/L) 
) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 26 of 45 
 
 
 
 
Table 15: Listing of laboratory results – Safety Set 
 
 
Subject 
Age/Sex/Race 
Treatment 
Group 
Parameter 
Date/Time 
Visit 
Value $ 
Unit 
Lower 
Limit 
Upper 
Limit 
Grade 
(a) 
999-999 
70/F/W 
DSTAT 0.25 
Hemoglobin 
Ddmmmyy/mm:hh 
Ddmmmyy/mm:hh 
Screening 
Baseline 
99999 H 
99999 L 
NCS 
Unit 
CS 
Unit 
LLL 
LLL 
UUU 
UUU 
1 
4 
 
(a) CTCAE v5.0 grades using absolute thresholds without accounting for baseline. Grade=0 and Grade=Unknown are not displayed. 
$: H = Above upper limit of normal; L = Below lower limit of normal, NCS = Not clinically significant, CS= Clinically significant. 
Visit “Early Tx DC (TXDC)” denotes Early Treatment Discontinuation Visit. 
 
(Notes for programmer: 
- Sorted by subject number, Parameter, date and time 
- The following parameter will be displayed: Hemoglobin, platelets, activated partial thromboplastin time (aPTT), prothrombin time 
(PT), prothrombin international normal ratio (INR), d-dimer, Anti-Xa, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), total bilirubin, creatinine, Creatinine Clearance, Estimated. 
- LLN for creatinine clearance is fixed 90 mL/min 
- CTCAE Grades: reference Table 13.) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 27 of 45 
 
 
 
 
Table 16: Shift-table of laboratory results – Safety Set 
Parameter: <Hemoglobin> <Platelets> <Activated partial thromboplastin time (aPTT)> <prothrombin time (PT)> <Prothrombin 
International Normalized Ratio (INR)> <d-dimer> <Anti-Xa> <Aspartate aminotransferase (AST)> <Alanine aminotransferase (ALT)> 
<Total bilirubin> <Creatinine> <Creatinine Clearance, Estimated> 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
Baseline (D1) 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
<LLN 
Normal 
>ULN 
<LLN 
Normal 
>ULN 
<LLN 
Normal 
>ULN 
<LLN 
Normal 
>ULN 
Post-Baseline 
Minimum, n(%) 
<LLN 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
Normal 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
>ULN 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
Post-Baseline 
Maximum, n(%) 
<LLN 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
Normal 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
>ULN 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
(xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
Normal: Within normal range, LLN: Lower limit of normal, ULN: Upper limit of normal. 
Only subjects with baseline and at least one post-baseline value are considered. 
Baseline value is defined as the last non-missing measurement prior to, or on the date/time of the first administration of study 
treatment. NA = not applicable. 
 
Page X of Y 
 
(Notes for programmer: 
- generate a post-baseline Maximum Value and post-baseline Minimum Value per subject (incl. unscheduled measurements 
- LLN for creatinine clearance is fixed 90 mL/min 
- if ULN (eg CC) available, please display n/a 
) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 28 of 45 
 
 
 
Figure 3: Selected laboratory parameters over time (Box-Whisker-Plot) - Safety Set 
Box-Whisker-Plots: by <Parameter> (<unit>), Cohort X, Reference Ranges xxx – yyyy <unit> 
y-axis: 
range: depending on data 
label: Value 
 
x-axis: 
range: Visits : Screening, D1 to D28 (depending on data) visit. Incl Early Tx DC at the end of the x-axis. 
label: Visit 
Box-Whisker Plots: 
different styles/colors for the treatment-groups 
 
Plots shifted to not overlap 
Default SAS Box-Whisker-Plots – Min, 25%, Median, 75%, Max. Whiskers as 1.5 IQR. Mean included. 
 
Footnotes to be used for the Box-Whisker-Plots : 
Visit “Early Tx DC (TXDC)” denotes Early Treatment Discontinuation Visit. Reference Ranges do not necessarily present “values of 
concern” in this population but will give some context to the results relative to a normal population. 
 
(Notes for programmer: 
- replace <Parameter> <unit>, in label by actual parameter and unit used 
- Adapt Visits as relevant for the different parameters. Not all parameters are reported for all visits, only scheduled visits to 
be included in the Figure 
- display for: Hemoglobin, Platelets, Activated partial thromboplastin time (aPTT), prothrombin time (PT), Prothrombin 
International Normalized Ratio (INR), d-dimer, Anti-Xa, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Total 
bilirubin, Creatinine, Creatinine Clearance, Estimated) 
- Include reference lines for each parameter in the Box-Whisker-Plot based on the table below. Use the last column “Proposed 
Reference Range for Boxplots”. 
 
Given that normal ranges for laboratory values vary from center to center, we propose standard reference lines be added to the 
boxplots based on ranges available from the American Board of Internal Medicine (January 2020). Specifically, we will implement 
this approach according to the ranges noted in the table below without objection. It should be noted that these ranges do not 
necessarily represent “values of concern” in this population but will give some context to the results relative to a normal 
population. 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 29 of 45 
 
 
 
 
 
Test 
ABIM Reference Range 
Proposed Reference 
Range for Boxplots 
Hemoglobin 
Female: 120–160 g/L 
Male: 140–180 g/L 
120-180 g/L 
Platelets 
150-450 10^9/L 
150-450 10^9/L 
aPTT 
25-35 sec 
25-35 sec 
PT 
11-13 sec 
11-13 sec 
PT-INR* 
n/a 
0.8-1.2 
D-dimer 
<0.5 mg/L 
0-0.5 mg/L 
Anti-Xa 
0.3–0.7 IU/mL 
0.3–0.7 IU/mL 
AST 
10-40 U/L 
10-40 U/L 
ALT 
10-40 U/L 
10-40 U/L 
Total Bilirubin 
5.13-17.10 umol/L 
5.13-17.10 umol/L 
Creatinine 
Female: 44.21–97.26 umol/L 
Male: 61.89–114.95 umol/L 
44.21-114.95 umol/L 
Creatinine Clearance 
90–140 mL/min/1.73m2 
90–140 mL/min 
* Upper reference corresponds to lowest CTCAE Grade 1 result; lower reference from Medline 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 30 of 45 
 
 
 
 
Table 17: Listing of Prior and Concomitant Medications (only Targeted Medications) – Safety Set 
 
 
 
Subject 
Age/Sex/Race 
 
Treatment 
Group 
ATC Level 2/ 
Preferred Term/ 
Medication Name 
 
Start Date 
(Study Day) 
 
Stop Date 
(Study Day) 
 
Dose 
[Unit] 
Frequency 
Route Indication 
 
 
 
999-999 / 
70/F/W 
 
999-999 / 
xx/xx/xx 
 
999-999 / 
xx/xx/xx 
DSTAT 
0.25 
 
Cohort 1 
PBO 
 
Cohort 1 
PBO 
ATC Level 2 
Preferred Term 
Medication Name 
 
ATC Level 2 
Preferred Term 
Medication Name 
 
ATC Level 2 
Preferred Term 
Medication Name 
DdMMMyy (xx) DdMMMyy (xx) 40 [mg] BID 
IV 
AE: xxxxxxxxxxxx 
AE: xxxxxxxxxxxxxx 
AE: xxxxxxxxxx 
 
DdMMMyy (xx) 
Ongoing 
PBO 
MH: xxxxxxxxxxxxx 
MH: xxxx 
 
DdMMMyy (xx) 
Ongoing 
PBO 
PR: xxxxxxxx 
 
 
 
 
Note: Medications are coded using WHO-DD Version March 2020. 
Study Days prior to first treatment date are calculated as (actual date – first treatment date), after first treatment date as (actual 
date – first treatment date) + 1. 
AE: Adverse Event, MH: Medical History, PR: Prophylaxis or Other 
 
Page x of y 
 
 
(Notes for programmer: 
- Sorted by subject number, start date, stop date, ATC Level 2, preferred term and Medication Name 
- Target Medications are: 
Remdesvir 
(WHO-DC starting with “142690“) 
Dexamethasone 
(WHO-DC starting with “000160“) 
Anti-XA (enoxaparin) 
(WHO-DC starting with “017082“ or “000277”) 
- Indication: If multiple, concatentate and wrap, drop the AE/MH-Numbers 
) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Page 31 of 45 
 
 
 
5.2. 
ADDITIONAL POST-COHORT 2 LOCK ANALYSES – TABLE SHELLS 
 
Figure 4: Biomarkers during the course of the study – Safety Set 
 
Line-plots 
 
Biomarker: <HMGB1 (SI-unit)> <IL-6 (SI-unit)> <TNF alpha (SI-unit)> <SAA (SI-unit)> - see list of Biomarkers on the next page 
 
y-axis:  
range: depending on data 
label: Value (unit) 
 
x-axis:  
range: Baseline (D1), Day 3 (D3), Day 5 (D5), Day 7 (D7), Day 14 (D14), Day 28 (D28) 
label: Visit 
Line-Plots: different line styles/colors to differentiate cohort/group 
 
Lines:  
one line per subject 
4 different line styles/colors to differentiate cohort/group 
 
(Notes for programmer: 
- one figure per biomarker, 
- additional Biomarkers might be added on short notice of sponsor 
- “(SI-unit) » in sub-title to be replaced by actual SI-unit 
) 
 
See list of Biomarkers provided by Chimerix on 9Dec2020 


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Page 32 of 45 
 
 
 
 
 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
This document is confidential. 
Page 33 of 45 
 
 
 
Table 18: Proportion of and time to invasive mechanical ventilation or all-cause mortality – ITT Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Number of subjects who are alive and free of 
invasive mechanical ventilation or ECMO through 
Day 28 (a) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of subjects with any invasive mechanical 
ventilation, ECMO, all-cause mortality or early 
study discontinuation, whatever comes first, 
n (%) (b) 
Any invasive mechanical ventilation, ECMO 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Early study discontinuation < Day 25 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Kaplan-Meier estimates (c) 
Number of censored subjects, n (%) (c) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Time to first invasive mechanical ventilation, 
ECMO or all-cause mortality (days) (c) 
25% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Median (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
75% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
ECMO: Extracorporeal membrane oxygenation. 
(a) Early study discontinuation before Day 25 are not included. 
(b) Subjects with any invasive mechanical ventilation, ECMO, all-cause mortality or early study discontinuation before Day 25 will 
be counted as event. 
(c) Kaplan-Meier estimates: Subjects with any invasive mechanical ventilation, ECMO or all-cause mortality will be counted as 
event. All other subjects will be censored. Time to first invasive mechanical ventilation, ECMO or all-cause mortality, whatever 
comes first (days): Days are calculated as (start date/time – first study drug date/time)/24h). Time will be censored at last 
individual date/time reported. If time is not available for events “00:01” will be imputed, for censored observations “23:59” will 
be imputed. Randomized untreated subjects will be censored at time = 0. 
Page X of Y 
 
(Notes for programmer: Subjects randomized not treated will be counted in 
a) as failure, and therefore not included in (a) 
b) as event (in the line “Early study discontinuation < Day 25”) in case of early study discontinuation < Day 25 
c) as censored observation (censor time = 0) 
) 


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Page 34 of 45 
 
 
 
Figure 5: Time to invasive mechanical ventilation, ECMO or all-cause mortality (KM-Plot) – ITT Set 
Kaplan-Meier Plot: 
y-axis: 
 
 
 
x-axis: 
 
 
Lines: 
range: 0% to 100% by 20% 
label: Event-free Probability 
reference-line: 50% 
 
range: 0 to xxx (depending on data), by 7 days 
label: Time to Event (Days) 
 
solid 
different colors/line styles for the treatment-groups 
starting at (100%/Baseline) 
Censored values marked 
 
Footnote: 
 
N = Number of subjects in a specific group; (+) = censored values; 
Kaplan-Meier estimates: Subjects with any invasive mechanical ventilation, ECMO or all-cause mortality will be counted as event. 
All other subjects will be censored. 
Time to first invasive mechanical ventilation, ECMO or all-cause mortality, whatever comes first (days): Days are calculated as 
(start date/time – first study drug date/time)/24h). Time will be censored at last individual date/time reported. If time is not 
available for events “00:01” will be imputed, for censored observations “23:59” will be imputed. Randomized untreated subjects will 
be censored at time = 0. 
 
(Notes for programmer: Subjects randomized not treated will be counted as censored observation (censor time = 0) 
) 


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Table 19: Proportion of and time to all-cause mortality – ITT Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Number of subjects with all-cause mortality 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
or early study discontinuation, n (%) (a) 
Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Early study discontinuation < Day 25 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Kaplan-Meier estimates (b) 
Number of censored subjects, n (%) (b) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Time to all-cause mortality (days) (b) 
25% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Median (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
75% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
(a) Subjects with all-cause mortality or early study discontinuation before Day 25 will be counted as event. 
(b) Kaplan-Meier estimates: Subjects who died will be counted as events. All other subjects will be censored. Time to all-cause 
mortality (days): Days are calculated as (start date/time – first study drug date/time)/24h). Time will be censored at last 
individual date/time reported. If time is not available for events “00:01” will be imputed, for censored observations “23:59” 
will be imputed. Randomized untreated subjects will be censored at time = 0. 
 
Page X of Y 
 
(Notes for programmer: Subjects randomized not treated will be counted in 
a) as event (in the line “Early study discontinuation < Day 25”) in case of early study discontinuation < Day 25 
b) as censored observation (censor time = 0) 
) 


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Page 36 of 45 
 
 
 
Figure 6: Time to all-cause mortality (KM-Plot) – ITT Set 
 
Kaplan-Meier Plot: 
 
y-axis: 
 
 
 
x-axis: 
 
 
Lines: 
range: 0% to 100% by 20% 
label: Event-free Probability 
reference-line: 50% 
 
range: 0 to xxx (depending on data), by 7 days 
label: Time to Event (Days) 
 
solid 
different colors/line styles for the treatment-groups 
starting at (100%/Baseline) 
Censored values marked 
 
Footnote: 
 
N = Number of subjects in a specific group; (+) = censored values; 
Kaplan-Meier estimates: Subjects who died will be counted as event. All other subjects will be censored. 
Time to all-cause mortality (days): Days are calculated as (start date/time – first study drug date/time)/24h). Time will be 
censored at last individual date/time reported. If time is not available for events “00:01” will be imputed, for censored 
observations “23:59” will be imputed. Randomized untreated subjects will be censored at time = 0. 
(Notes for programmer: Subjects randomized not treated will be counted as censored observation (censor time = 0) 
) 


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Table 20: Proportion of participants who are alive, discharged from the hospital, and not using home oxygen – ITT Set 
 
Visit 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
n (%) 
n (%) 
n (%) 
n (%) 
Day 8 (D8) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Day 14 (D14) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Day 28 (D28) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; 
Subjects who discontinued study early prior to start of time window (-3 days to -1 day for each visit) will be considered as 
failures even if alive and last records indicate no oxygen and out of hospital. 
If the discontinuation is within the time window for the respective visit the last available status to be considered. 
Page X of Y 
(Notes for programmer: 
Number of subjects who are alive, discharged from the hospital and not using home oxygen are defined based on the 
Ventilator/Oxygen/Medical Care Status and the Hospitalization/Activity Status eCRF pages: 
All subjects who are 
• 
not hospitalized (either with limited activities or not) AND 
• 
do not require oxygen (no matter whether ongoing medical care is required or not) 
at the specific time points will meet this endpoint. 
Use the CDISC study day – for corresponding start and stop date (e.g. hospitalization stop date, or start date of not require 
oxygen) and assign the relevant study days to the corresponding visit (Day 8, Day 14 and Day 28). 
- 
Determine status on particular day with respect to death, hospitalization, and oxygen use. For example, if a subject starts 
oxygen (e.g. Nasal Supplemental Oxygen) on Day -1 and stops on Day 10, subject is using oxygen at Visit Day 8, subject is not 
using oxygen at Day 14 and Day 28. 
- 
If can’t determine one, pick the worst status on that day. For example oxygen stops on Day 8, subject will be considered to be 
on oxygen for Day 8 analysis and subject is not using oxygen at Day 14 and Day 28. 
Subject discharge from the hospital on Day 8, subject will be considered to be in the hospital for Day 8 analysis and to be 
discharged from the hospital on Day 14 and Day 28. 
- 
Subjects who discontinued study early PRIOR to start of time window (-3 days to -1 day for each visit) will be failures even if 
alive and last records indicate no oxygen and out of hospital. Subjects who discontinued study early but within the time window 
of the respective visit, e.g. on Day 7, discharged from hospital earlier and not using home oxygen will be considered with the 
last available status at Day 8 (= no failure), and as failure at Day 14 and Day 28. Subjects who discontinued study early on 
Day 10 will be considered as failure at Day 14 and Day 28. ) 
- 
Subjects randomized not treated will be counted as failure at the respective visit in case of early study discontinuation prior 
to start of the time window (-3 days to -1 day for each visit). 


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Table 21: Clinical status assessed by the NIAID ordinal scale at fixed time points – ITT Set 
 
Visit 
NIAID Score 
DSTAT 0.25 
N=xxx 
n (%) 
Cohort 1 PBO 
N=xxx 
n (%) 
DSTAT 0.325 
N=xxx 
n %) 
Cohort 2 PBO 
N=xxx 
n (%) 
Day 8 (D8) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Missing 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Day 14 (D14) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Missing 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Day 28 (D28) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Missing 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
NIAID scores are derived according to Appendix 4 of the study protocol. Higher values indicates a better outcome. 
For subjects who discontinued study early within the time window (-3 days to – 1 day for each visit), the last available NIAID 
scale will be used at the corresponding visit and a NIAID score = missing to be assigned to all visits after early study 
discontinuation date. 
Page X of Y 
 
(Notes for programmer: 


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Page 39 of 45 
 
 
 
 
Use a skeleton and include all 8 NIAID scores in the table for each visit and include Missing category) 
 
The NIAID ordinal score at the predefined time points will be derived based on the eCRF data collected on the 
Ventilator/Oxygen/Medical Care Status, the Hospitalizations/Activities Status pages and the death date. In the event subjects 
transition from one score to another on a particular Day, the worse score will be used. 
 
Use the CDISC study day – for corresponding start and stop date (e.g. hospitalization stop date, or start date of nasal 
suppplemental oxygen) and assign the relevant study days to the corresponding visit (Day 8, Day 14 and Day 28). 
 
- 
Determine status on particular day with respect to death, hospitalization, and ventilatory care status. For example, if a 
subject starts nasal supplemental oxygen on Day -1 and stops on Day 10, and if the subject is still in hospital at Day 8, a 
NIAID score = 4 to be assigned at Day 8. 
 
- 
If can’t determine one, pick the worst status on that day. 
For example nasal supplemental oxygen stops on Day 8, and subject does not require oxygen but requires ongoing medical are 
starting on Day 8, and the subject is in hospital at Visit Day 8, a NIAID score = 4 to be assigned at Day 8. 
 
- 
For subjects who discontinued study early within the time window (-3 days to – 1 day for each visit), the last available NIAID 
score will be used at the corresponding visit and a NIAID score = missing will be assigned to all visits after early study 
discontinuation date. 
E.g. if a subject withdraw from study on Day 7, his or her last NIAID score will be assigned to Day 8, and NIAID scores at Day 
14 and Day 28 are considered as missing. If subject withdrawal on Day 8, his or her Day 8 NIAID score will be assigned to Day 
8, and NIAID scores at Day 14 and Day 28 are considered as missing. 
 
- 
For subjects who died e.g. prior to or on Day 8 a NIAID score = 1 will be assigned for the visits on and after Day 8 
 
- 
Subjects randomized not treated will be counted as missing at the respective visit in case of early study discontinuation 
prior to start of the time window (-3 days to -1 day for each visit). 
) 


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Table 22: Time to clinical improvement – ITT Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Number of participants with clinical 
improvement, n (%) (a) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Kaplan-Meier estimates (b) 
Number of censored subjects, n (%) (b) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of subjects without improvement 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Time to clinical improvement (days) (b) 
25% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Median (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
75% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
Clinical improvement is defined as at least a 2-grade improvement from baseline on the NIAID ordinal score. 
(a) Subjects with a clinical improvement will be counted as event. 
(b) Kaplan-Meier estimates: Subjects with a clinical improvement will be counted as event. Subjects without a clinical 
improvement or deaths occurring prior to the positive event will be censored. Time to clinical improvement: Days are calculated 
as (start date/time – first study drug date/time)/24h). Time will be censored at last individual date/time reported. If time is 
not available for events “23:59” will be imputed, for censored observations “00:01” will be imputed. Participants who died prior 
to Day 28 without clinical improvement will be censored at Day 28. Randomized untreated subjects will be censored at time = 0. 
 
Page X of Y 
 
(Notes for programmer: Subjects randomized not treated will be counted as censored observation (censor time = 0) 
) 


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Page 41 of 45 
 
 
 
Figure 7: Time to clinical improvement (KM-Plot) – ITT Set 
 
Kaplan-Meier Plot: 
 
y-axis: 
 
 
 
x-axis: 
 
 
Lines: 
range: 0% to 100% by 20% 
label: Event Probability 
reference-line: 50% 
 
range: 0 to xxx (depending on data), by 7 days 
label: Time to Event (Days) 
 
 
solid 
different colors/line styles for the treatment-groups 
starting at (0%/Baseline) 
Censored values marked 
 
Footnote: 
 
N = Number of subjects in a specific group; (+) = censored values; 
Clinical improvement is defined as at least a 2-grade improvement from baseline on the NIAID ordinal score. 
Kaplan-Meier estimates: Subjects with a clinical improvement will be counted as event. Subjects without a clinical improvement or 
deaths occurring prior to the positive event will be censored. 
Time to clinical improvement (days): Days are calculated as (start date/time – first study drug date/time)/24h). Time will be 
censored at last individual date/time reported. If time is not available for events “23:59” will be imputed, for censored 
observations “00:01” will be imputed. Participants who died prior to Day 28 without clinical improvement will be censored at Day 
28. Randomized untreated subjects will be censored at time = 0. 
 
(Notes for programmer: Subjects randomized not treated will be counted as censored observation (censor time = 0) 
) 


Syneos Health #7015085, Chimerix, Inc, Protocol # CMX-DS-004, Post-Cohort 1 or 2 Lock Analysis Shells: Version 2.0, dated 12 Mar 2021 
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Table 23: Number of ventilator-free days from baseline through Day 28 – ITT Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Number of ventilator-free days, n(%) 
0 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
28 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
n 
xxx 
Xxx 
xxx 
xxx 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx 
Xx 
xx 
xx 
Q1, Q3 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
SD: Standard deviation; Q1, Q3: First, third quartile; Min: minimum; Max: maximum. 
Ventilator-free days are only counted through the date of early study discontinuation, study completion date or Day 28, 
whichever comes first. For subjects who die during the course of the study, number of ventilator-free days is defined as 0. 
Page X of Y 
 
(Notes for programmer: 
Include only the categories of Days (0-28) in the table which are available in the data 
) 


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Page 43 of 45 
 
 
 
Table 24: Time to last hospital discharge – ITT Set 
 
DSTAT 0.25 
N=xxx 
Cohort 1 PBO 
N=xxx 
DSTAT 0.325 
N=xxx 
Cohort 2 PBO 
N=xxx 
Number of subjects discharged from hospital, 
n (%) (a) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Kaplan-Meier estimates (b) 
Number of censored subjects, n (%) (b) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of subjects alive and still in hospital 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Time to hospital discharge (days) (b) 
25% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
Median (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
75% Quartile (95% CI) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
x.x (x.xx,x.xx) 
 
N = Number of subjects in a specific group; n = Number of subjects with data available; Percentages are based on N; 
(a) Subjects discharged from hospital will be counted as event. 
(b) Kaplan-Meier estimates: Subjects discharged from hospital will be counted as event. Subjects who are still in the hospital 
or died in the hospital will be censored. 
Time to hospital discharge (days): Days are calculated as (last hospital discharged date/time – first study drug 
date/time)/24h). Time will be censored at last individual date/time reported. If time is not available for events “23:59” will 
be imputed, for censored observations “00:01” will be imputed. Participants who died prior to hospital discharge will be 
censored at Day 28. Randomized untreated subjects will be censored with time to hospital discharge = 0. 
 
Page X of Y 
(Notes for programmer: Subjects randomized not treated will be counted as censored observation (censor time = 0) 
) 


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Page 44 of 45 
 
 
 
 
Figure 8: Time to last hospital discharge (KM-Plot) – ITT Set 
 
Kaplan-Meier Plot: 
 
y-axis: 
 
 
 
x-axis: 
 
 
Lines: 
range: 0% to 100% by 20% 
label: Event Probability 
reference-line: 50% 
 
range: 0 to xxx (depending on data), by 7 days 
label: Time to Event (Days) 
 
 
solid 
different colors/line styles for the treatment-groups 
starting at (0%/Baseline) 
Censored values marked 
 
Footnote: 
 
N = Number of subjects in a specific group; (+) = censored values; 
Kaplan-Meier estimates: Subjects discharged from hospital will be counted as event. Subjects who are still in the hospital or died 
in the hospital will be censored. 
Time to hospital discharge (days): Days are calculated as (last hospital dischared date/time – first study drug date/time)/24h). 
Time will be censored at last individual date/time reported. If time is not available for events “23:59” will be imputed, for 
censored observations “00:01” will be imputed. Participants who died prior to hospital discharge will be censored at Day 28. 
Randomized untreated subjects will be censored with time to hospital discharge = 0. 
 
 
(Notes for programmer: Subjects randomized not treated will be counted as censored observation (censor time = 0) 
) 


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Page 45 of 45 
 
 
 
 
 
Table 25: Time to first hospital discharge – ITT Set 
 
For the layout refer to Table 24 
 
Adapt footnote: 
… Time to hospital discharge (days): Days are calculated as (first hospital discharged date/time – first study drug 
date/time)/24h)... 
 
 
Figure 9: Time to first hospital discharge (KM-Plot) – ITT Set 
 
For the layout refer to Figure 8 
 
Adapt footnote: 
… Time to hospital discharge (days): Days are calculated as (first hospital discharged date/time – first study drug 
date/time)/24h)...