Clinical trial NCT01598831
Conditions: Severe Sepsis Coagulopathy
Keywords: sepsis
Sponsor: Asahi Kasei Pharma America Corporation
Start date: 2012-10-29; Completion date: 2019-02-28
Enrollment: 816 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate if ART-123 given to patients who have severe sepsis can decrease mortality.

Detailed description:
Study is to evaluate if ART-123 given to patients who have severe sepsis complicated by at least one organ dysfunction and coagulopathy can decrease mortality.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: ART-123 intervention 2: Placebo
Intervention descriptions: intervention 1: Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days intervention 2: Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days.

Protocol documents:
Prot_000.pdf: 


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Synopsis
Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to 
Assess the Safety and Efficacy of ART-123 in Subjects with Severe Sepsis and 
Coagulopathy
Name of Sponsor/Company:  
Asahi Kasei Pharma America Corporation
Name of Investigational Product:  
ART-123
Name of Active Ingredient: thrombomodulin alpha
Objectives 
Primary:
x
To evaluate whether ART-123, when administered to subjects with bacterial 
infection complicated by at least one organ dysfunction and coagulopathy, can 
reduce mortality.
x
To evaluate the safety of ART-123 in this population.
Secondary:
x
Assessment of the efficacy of ART-123 in resolution of organ dysfunction in this 
population.
x
Assessment of anti-drug antibody development in subjects with coagulopathy 
due to bacterial infection treated with ART-123.
Study Center(s): 
Global study, up to 350 study centers 
Phase of Development:
Phase 3
Study Period: 
Estimated time of first subject enrollment: 3Q 2012
Estimated time of last subject enrollment: 3Q 2018
Number of Subjects (planned): 
Approximately 800 randomized subjects.


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Diagnosis and Main Criteria for Inclusion of Study Subjects:
This study targets critically ill subjects with severe sepsis requiring the level of care that 
is normally associated with treatment in an intensive care unit (ICU) setting. The 
inclusion criteria for organ dysfunction and coagulopathy must be met within a 24 hour 
period.
1. Subjects must be receiving treatment in an ICU or in an acute care setting (e.g., 
Emergency Room, Recovery Room).
2. Subjects with:
a.
Clinical objective evidence of bacterial infection and a known site of 
infection (Refer to Appendix C, Section 15.3).
b. Current treatment with intravenous antibiotics.
c.
White Blood Cell (WBC) count greater than (>) 12,000/mm3 or less than (<) 
4,000/mm3 or Bandemia greater than (>) 10%.
d. Temperature of < 36ºC or fever > 38ºC. For hypothermia, a core reading is 
preferred.
Note 1: If a subject has a Gram stain consistent with bacterial infection, positive
culture from blood or an otherwise sterile body fluid, observed peritonitis, positive 
urinary antigen, clinical presentation of meningococcemia, or otherwise 
compelling evidence of infection as determined by the CCC, only one of the two 
inclusion criteria # 2c (WBC) or 2d (temperature) is required. 
Note 2: The presence of concurrent fungal or viral infection is allowed for the 
study entry, provided that the primary reason for treatment is bacterial infection.
3. Subjects with sepsis-associated organ dysfunction defined by at least one of the 
following:
a. Cardiovascular Dysfunction defined as requiring both adequate fluid 
resuscitation and vasopressors* to maintain Mean Arterial Pressure (MAP) 
greater than or equal to (>) 65 mmHg (implies fluid resuscitation alone does 
not raise MAP to > 65 mmHg). Adequate fluid resuscitation is defined as:
o
Intravenous administration of at least 20 mL/kg crystalloid or 
10 mL/kg colloid infusion within 6 hours.
OR


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o
Central Venous Pressure (CVP) of greater than (>) 8 mmHg or 
Pulmonary Artery Wedge Pressure (PAWP) of greater than ( >) 
12 mmHg.
* If dopamine is the only vasopressor used, the infusion rate must be greater 
than (>) 5 μg/kg/min (i.e., must be prescribed to support cardio-pulmonary 
perfusion). If vasopressin is used, it must be given in conjunction with another 
vasopressor.
b. Respiratory Dysfunction is defined as the acute need for mechanical 
ventilation and PaO2/FiO2 ratio of <250 (or < 200 when lung is the site of 
infection). For the purposes of this protocol, mechanical ventilation is defined 
as any type of ventilation administered via an endotracheal tube or 
nasotracheal intubation. A simple administration of supplemental oxygen is 
NOT considered to be mechanical ventilation for the purposes of this study.
4. Subjects with coagulopathy characterized by an INR >1.40 without other known 
etiology (e.g., anticoagulant therapy, chronic liver disease)
5. Subjects with coagulopathy characterized by platelet count in the range of greater 
than (>) 30,000/mm3 to less than (<) 150,000/mm3 OR a greater than 30% decrease 
in platelets in 24 hours 23, 24, 25, 26, 27, 28.
Investigational Product, Dosage and Mode of Administration: 
ART-123 - thrombomodulin alpha:
ART-123 or Placebo, are administered at the equivalent dose of 0.06 mg/kg/day up to a 
maximum dose of 6.0 mg/day for six days.  ART-123 is given by intravenous bolus or 
rapid IV infusion, in which case 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day is 
diluted in 50 mL of Normal Saline (NS) and given over a period of 15 minutes.  ART-
123 must not be administered concurrently with any other medications or in the same IV 
line that is used for administering other medications. If the same IV line that is used for 
delivery of other medications must be used for administering study drug or placebo then 
the line must be flushed with at least 5 mL of 0.9% Saline solution both prior to and 
following the administration of study drug or placebo.
ART-123 is supplied as individual glass ampules containing 6.0 mg of formulated drug 
in 1 mL of total volume, with an overfill of 0.1 mL*. Ampules must be refrigerated at 2ºC-
8ºC and protected from light during storage.
*Refer to Section 3.1 for complete information about ART-123 drug product.


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Duration of Treatment: 
Six (6) days.
Reference Therapy, Dosage and Mode of Administration: 
Placebo:
Placebo for this study is supplied as identically labeled, individual glass ampules in 1 mL
of total volume, with an overfill of 0.1 mL.  Placebo will also be required to be maintained
refrigerated at 2°C-8°C and protected from light during storage.  Placebo must be 
administered according to the same procedures and guidelines as ART-123 (i.e., must not 
be administered concurrently with any other medications and if the same IV line that is 
used for delivery of other medications must be used, the IV line that is used for 
administering study drug or placebo must be flushed with at least 5 mL of 0.9% NS
solution both prior to and following administration of study drug or placebo).
Criteria for Evaluation:
Efficacy 
Primary Efficacy Endpoint:
x
28 day all-cause mortality
Secondary Efficacy Endpoints:
x
Follow-up of all-cause mortality at 3 months
x
Resolution of Organ Dysfunction through Day 28 as measured by
o
Shock free and alive days
o
Ventilator free and alive days
o
Dialysis free and alive days
Tertiary Efficacy Endpoints:
x
Follow-up of all-cause mortality at 6 and 12 months
x
Organ Dysfunction (Hepatic, Renal, Respiratory and Cardiac (Septic Shock) at 
Baseline, Day 3, Day 7, Day 14 and Day 28
x
ICU free and alive days through Day 28
x
Hospitalization free and alive days through Day 28
x
INR at Baseline, Day 3, Day 7, Day 14 and Day 28


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Safety
Primary Safety Endpoints:
x
Serious Adverse Events
x
Major Bleeding Events
x
Adverse Events
Secondary Safety Endpoint:
x
Anti-drug antibodies
Statistical Methods:
The total sample size is 800 randomized subjects. This sample size is allocated to 
treatment arms in a 1 to 1 ratio. The Primary Objective will be tested using a stratified 
Cochran-Mantel-Haenszel test. For sample size and power calculations an un-stratified 
Cochran-Mantel-Haenszel test has been used. This sample size provides 80% power if 
the following assumptions are made:
1)
5% two-sided Alpha level
2)
8% treatment effect (24% placebo mortality rate vs. 16% ART-123 mortality rate).
The assumed treatment effect of 8% is based upon the results of post-hoc analyses from 
the Phase IIb study.
Informed Consent:
Fully informed consent will be obtained before any study specific procedures are 
performed in accordance with all applicable ethical and regulatory requirements. It is 
anticipated, by the very nature of the study that many subjects who will be eligible for 
this protocol will not be able to give fully informed consent themselves due to various 
reasons including sedation, unconscious state, etc. and at no time will medical treatment 
be delayed to secure authorized informed consent for study participation. Therefore, the 
following will be applied as long as your local laws allow:
x
Consent from an Authorized or Legally Authorized Representative (AR / LAR) /
next of kin / legally appointed individual in person;
x
Verbal consent from an AR/LAR / next of kin / legally appointed individual via
telephone, confirmed by signed consent form sent by fax or email (at least 
2 people from the study site are required, one to administer the informed consent 
and the second as a witness);


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x
Consent from a judge or specifically appointed lawyer for this purpose – if 
required by local regulations; 
x
In extreme and urgent circumstances when emergent action is required to mitigate 
the risk of death, it is understood that the presumed will of the subject will be 
determined by a physician and documented based on his/her knowledge of the 
study subject. As appropriate, an independent physician, who is a qualified 
medical doctor with at least one year’s experience in intensive care medicine but 
must be from another department and/or hospital than the investigator, may sign 
the informed consent for the subject if the local laws, regulations and ethics 
committees approve this process. In countries where permissible, this independent 
physician may be from the same department. The study subject must be presented 
with the informed consent as soon as it is possible and reasonable, and informed 
consent obtained for continued study participation. The AR/LAR may act as an 
agent on the subject’s behalf once they are available to provide informed consent. 
In addition, where local regulatory and/or ethics committees allow, advance consent may 
be obtained prior to study entry in an attempt to obtain personal consent from the subject 
themselves. Should a subject who is enrolled in the study on the basis of advance consent 
subsequently become unable to make medical decisions for him/herself, then the subject's 
legally acceptable AR/LAR independent physician should be informed of the subject's 
participation in the trial.


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SIGNATURE PAGE
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
PROTOCOL NUMBER: 3-001
IND #:   100334
EudraCT No. 2012-002251-42
PRODUCT NAME: ART-123
STUDY TITLE:
A RANDOMIZED, DOUBLE–BLIND, PLACEBO–CONTROLLED, PHASE 3 STUDY TO 
ASSESS THE SAFETY AND EFFICACY OF ART-123 IN SUBJECTS WITH SEVERE 
SEPSIS AND COAGULOPATHY
VERSION: 4.1
FINAL: 28APRIL2017
PROTOCOL APPROVAL
The signature of the Principal Investigator constitutes an agreement that this study will be 
conducted according to all stipulations, clinically and administratively, as stated in the 
protocol, including all statements as to confidentiality.  It is agreed that the conduct and 
results of this study will be kept confidential and that the case report forms and other pertinent 
data will become the property of Asahi Kasei Pharma America Corporation. 
It is agreed that the protocol contains all necessary information required to conduct the study 
as outlined in the protocol, and that the study will not be initiated without the approval of an 
appropriate Institutional Review Board or Ethics Review Committee.
It is agreed that all participants in this study will provide written informed consent in 
accordance with ICH Guidelines for Good Clinical Practice and the requirements specified 
in the Code of Federal Regulations (21 CFR Parts 50, 56, 312).  All participants will also be 
informed that their medical records will be kept confidential except for review by authorized 
representatives of Asahi Kasei Pharma America Corporation and its associates, the U.S. Food 
and Drug Administration or other regulatory agencies.
PRINT
PRINCIPALINVESTIGATOR
SIGNATURE
DATE
By signing the above I agree to perform the study in accordance with the protocol, ICH 
Good Clinical Practice (GCP) guidelines, and all applicable regulations.


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Table of Contents
1 
INTRODUCTION··································································································17 
1.1 
Overview........................................................................................................................................17 
1.1.1 
Sepsis ·····································································································17 
1.1.2 
Coagulopathy ····························································································17 
1.2 
Mechanism of Action.....................................................................................................................18 
1.3 
Previous Clinical Experience for ART-123....................................................................................18 
2 
INVESTIGATIONAL PLAN ·····················································································19 
2.1 
Overall Study Design.....................................................................................................................19 
2.2 
Study Objectives ............................................................................................................................20 
2.3 
Rationale for Study Design............................................................................................................20 
2.4 
Appropriateness of Outcome Measures .........................................................................................21 
2.5 
Study Population............................................................................................................................21 
2.6 
Subject Eligibility Criteria .............................................................................................................21 
2.6.1 
Inclusion Criteria ························································································21 
2.6.2 
Exclusion Criteria ·······················································································25 
2.6.3 
Post-surgical Subjects···················································································28 
2.7 
Criteria for Discontinuation from Study Drug or Study Participation ...........................................28 
2.7.1 
Withdrawal from receiving study drug ·······························································28 
2.7.2 
Discontinuation from study participation ····························································29 
2.8 
Data Monitoring Committee (DMC) .............................................................................................31 
2.9 
Clinical Coordinating Centers (CCCs)...........................................................................................31 
3 
TREATMENTS ·····································································································31 
3.1 
Investigational Product, Dosage and Mode of Administration ......................................................32 
3.1.1 
ART-123 ( thrombomodulin alpha)···································································32 
3.2 
Reference Therapy, Dosage and Mode of Administration .............................................................33 
3.2.1 
Placebo for ART-123····················································································33 
3.3 
Blinding .........................................................................................................................................33 
4 
LABORATORY SAMPLES ······················································································34 
4.1 
Central Laboratory Tests:...............................................................................................................34 
4.2 
Local Laboratory Tests: .................................................................................................................35 


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5 
VISIT SCHEDULE AND ASSESSMENTS····································································35 
5.1 
Screening Visit...............................................................................................................................35 
5.2 
Consent and Randomization Process .............................................................................................36 
5.3 
Baseline Visit (prior to dosing) ......................................................................................................36 
5.4 
Dosing Visit (Day 1) ......................................................................................................................39 
5.5 
Day 2 Visit .....................................................................................................................................39 
5.6 
Day 3 Visit (Pre-dose)....................................................................................................................40 
5.7 
Day 3 Visit (Post-dose) ..................................................................................................................41 
5.8 
Days 4-6 Visits...............................................................................................................................42 
5.9 
Day 7 Visit .....................................................................................................................................43 
5.10 
Early Treatment Termination (ETT) Visit....................................................................................44 
5.11 
Days 8-13.....................................................................................................................................46 
5.12 
Day 14 (+ 3 days).........................................................................................................................47 
5.13 
Days 15-27...................................................................................................................................48 
5.14 
Hospital Discharge.......................................................................................................................48 
5.15 
Day 28 (+3 days) or End of Study Visit.......................................................................................50 
5.16 
Survival Status at Day 28 (+3 day) Visit......................................................................................51 
5.17 
3 Month, 6 Month and 12 Month Follow-Up Visits.....................................................................51 
5.18 
Follow-Up Visits for Subjects who have an anti-ART-123 antibody...........................................51 
5.19 
Schedule of Activities ..................................................................................................................53 
6 
EFFICACY ASSESSMENTS·····················································································56 
7 
SAFETY ASSESSMENTS AND REPORTING ·······························································56 
7.1 
Adverse Events ..............................................................................................................................56 
7.1.1 
Severity of Adverse Events ············································································58 
7.1.2 
Relationship of AE to Study Drug ····································································59 
7.2 
Serious Adverse Events..................................................................................................................59 
7.3 
Expected Adverse Events...............................................................................................................61 
7.4 
Expedited Reporting ......................................................................................................................61 
7.5 
Assessment of Risk Burden ...........................................................................................................61 
7.6 
Clinical Laboratory Evaluations ....................................................................................................62 
7.6.1 
Central Laboratory Tests:···············································································62 
7.6.2 
Local Laboratory Tests:·················································································63 
7.6.3 
Laboratory Sample Categories ········································································63 


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7.7 
Physical Examination.....................................................................................................................64 
7.7.1 
Vital Signs································································································64 
7.8 
Electrocardiogram (ECG) ..............................................................................................................65 
8 
PROTOCOL AMENDMENTS ···················································································65 
8.1 
Protocol Amendments....................................................................................................................65 
9 
DATA MANAGEMENT···························································································65 
9.1 
Documentation...............................................................................................................................65 
9.2 
Data Collection ..............................................................................................................................66 
9.3 
Database Management ..................................................................................................................66 
10 
STATISTICAL CONSIDERATIONS ··········································································66 
10.1 
Sample Size and Power Considerations.......................................................................................66 
10.1.1 
Decision Guidelines ···················································································67 
10.2 
Analysis Populations....................................................................................................................67 
10.3 
Study Stopping Rules / Interim Analyses.....................................................................................68 
10.3.1 
Stopping for Safety ····················································································68 
10.3.2 
Stopping for Efficacy··················································································68 
10.3.3 
Stopping Due to Lack of Clinically Meaningful Benefit/Futility ·······························68 
10.4 
Handling of Missing Data............................................................................................................68 
10.5 
Efficacy Analysis .........................................................................................................................69 
10.5.1 
Primary Analysis·······················································································69 
10.5.2 
Secondary Analyses ···················································································69 
10.6 
Safety Analysis.............................................................................................................................69 
10.6.1 
Extent of Exposure ····················································································69 
10.6.2 
Concomitant Medications·············································································69 
10.6.3 
Adverse Events·························································································70 
10.6.4 
Major Bleeding Events················································································70 
10.6.5 
Clinical Laboratory Results ··········································································70 
10.6.6 
Vital Signs and ECG···················································································70 
11 
PROCEDURES AND INSTRUCTIONS ······································································70 
11.1 
Safety-Related Procedures ...........................................................................................................70 
11.1.1 
Reporting Responsibility··············································································70 
11.1.2 
Reporting Procedures··················································································71 


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12 
ADMINISTRATIVE PROCEDURES ·········································································71 
12.1 
Monitoring Procedures.................................................................................................................71 
12.2 
Recording of Data and Retention of Documents .........................................................................71 
12.3 
Study Organization ......................................................................................................................72 
12.3.1 
Data Monitoring Committee ·········································································72 
12.3.2 
Publication of Results ·················································································72 
13 
ETHICS AND GOOD CLINICAL PRACTICE······························································72 
13.1 
Institutional Review Board/Research Ethics Board/ Independent Ethics Committee..................73 
13.2 
Informed Consent.........................................................................................................................73 
14 
REFERENCES ····································································································75 
15 
APPENDICES·····································································································78 
15.1 
Appendix A: Serious Adverse Events ..........................................................................................78 
15.2 
Appendix B: Key Study Definitions ............................................................................................79 
15.3 
Appendix C: Definitions of Infection in the ICU.........................................................................80 
15.4 
Appendix D: Organ Dysfunction Scale 22....................................................................................81 
15.5 
Appendix E: Child-Pugh Scoring.................................................................................................82 
15.6 
Appendix F: West Haven Criteria for Grading of Mental Status in Hepatic Encephalopathy 21 .83 
15.7 
Appendix G: Prohibited Medications...........................................................................................84 
15.8 
Appendix H: Chemotherapeutic Agents Known To Cause Myeloablation..................................85 
15.9 
Appendix I: Toxicity/Adverse Event Grading Table....................................................................86 
I. 
Instructions and Clarifications ·············································································86 
II. 
Definitions of terms used in the Table: ··································································88 
15.10 
Appendix J: Conversions for PaO2/FiO2 calculations ............................................................114 
15.11 
Appendix K: The APACHE II Severity of Disease Classification System29............................115 
15.12 
Appendix L: Glasgow Coma Scale30 .......................................................................................116 


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LIST OF ABBREVIATIONS
ABBREVIATION/TERM
DEFINITION
ABG
Arterial Blood Gas
ADA
Anti-drug Antibody
AE
Adverse Event
AIDS
Acquired Immune Deficiency Syndrome
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine Aminotransferase 
AML
Acute Myelogenous Leukemia
ANOVA
Analysis of Variance
APACHE II
Acute Physiology and Chronic Health Evaluation II
APC
Activated Protein C
AR
Authorized Representative
ARDSNet
Acute Respiratory Distress Syndrome Clinical Network
AST
Aspartate Aminotransferase 
AUC
Area Under the Curve
AVM
Arteriovenous Malformation
bid
Twice daily
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CCC
Clinical Coordinating Center
CFR
Code of Federal Regulations 
CMH
Cochran-Mantel-Haenszel Test
CRO
Contract Research Organization
CRP
C-reactive Protein
CSF
Cerebrospinal Fluid 


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LIST OF ABBREVIATIONS
ABBREVIATION/TERM
DEFINITION
CVP
Central Venous Pressure
DIC
Disseminated Intravascular Coagulation
dL
Deciliter
DVT
Deep Vein Thrombosis
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ESRD
End-Stage Renal Disease
eCRF
Electronic Case Report Form
EP2
Early Phase II
EPCR
Endothelial Protein C Receptor
ER
Emergency Room
F1.2
Prothrombin Fragment 1+2
FAP
Full Analysis Population
FDA
Food and Drug Administration
FiO2
Fraction of Inspired Oxygen
GCP
Good Clinical Practices
GI
Gastrointestinal 
H
Hour
hCG
Human Chorionic Gonadotropin
h
Hour
HEENT
Head, Eyes, Ears, Nose, and Throat
HMGB1
High Mobility Group Box 1
ICH
International Conference on Harmonisation
ICU
Intensive Care Unit


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LIST OF ABBREVIATIONS
ABBREVIATION/TERM
DEFINITION
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product (also known as study drug)
INR
International Normalized Ratio
ISTH
International Society on Thrombosis and Haemostasis
IRB
Institutional Review Board 
ITT
Intention-to-treat
IV
Intravenous
LAR
Legally Authorized Representative
LMWH
Low Molecular Weight Heparin
LP2
Late Phase 2
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MIC
Minimum Inhibitory Concentration
mL
Milliliters
mm3
Cubic Millimeters 
NS
0.9% Normal Saline
OD
Organ Dysfunction
PAI-1
Plasminogen Activator Inhibitor Type-1
PaO2
Partial Pressure of Oxygen in Arterial Blood
PAWP
Pulmonary Artery Wedge Pressure
PI
Principal Investigator
PICD
Patient Informed Consent Document
PK
Pharmacokinetic
PMD
Primary Medical Doctor


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LIST OF ABBREVIATIONS
ABBREVIATION/TERM
DEFINITION
p.o.
By Mouth
PP
Per Protocol
PT
Prothrombin Time
PSV
Pressure Support Ventilation
Q
Every
qd
Once a Day
RBC
Red Blood Cells
RR
Recovery Room
RRT
Renal Replacement Therapy
SAE
Serious Adverse Event
SIRS
Systemic Inflammatory Response Syndrome
SOC
Standard of Care
SOFA 
Sepsis related Organ Failure Assessment
SOP
Standard Operating Procedure
SQ
Subcutaneous
TNF
Tumor Necrosis Factor
US
United States
VAV
Volume Assist Ventilation
VC
Volume Control Ventilation
ȝg/kg/min
Micrograms per kilogram per minute
WBC
White Blood Cell


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1
INTRODUCTION
1.1
Overview
Despite significant advances over the past several decades, mortality from sepsis remains 
unacceptably high. The risk of death is related to the severity of the sepsis, which is 
characterized in terms of the presence of organ dysfunctions and coagulopathy.
1.1.1
Sepsis
Sepsis has been defined as infection complicated by a systemic inflammatory response 
syndrome (SIRS).1,3 A reassessment of sepsis raised concerns that the SIRS criteria were too 
sensitive, and that the approach to sepsis continued to need refinement.2,3 Surviving Sepsis 
Campaign Guidelines provide diagnostic criteria for sepsis as well as a definition of severe 
sepsis in which the diagnostic criteria for sepsis includes the necessity for infection and 
inflammatory response, and that severe sepsis is characterized by evidence of organ 
dysfunction3.
Numerous therapies intended to target the various biological pathways of sepsis have been 
tested in large randomized studies, and all but one, Drotrecogin alfa (recombinant human 
activated protein C, Xigris®), have failed to show evidence of efficacy,4,5,6 Xigris, which 
showed evidence of efficacy in early clinical trials, was withdrawn from the market by the 
manufacturer (Eli Lilly and Co.) on October 25, 2011.
In contrast, mortality has been reduced by improving the technique of mechanical ventilation7
or the introduction of bundles of treatments that target various physiologic manifestations of 
sepsis.8
1.1.2
Coagulopathy
It has been known for a long time that coagulopathy is associated with increased mortality in 
sepsis.9 While thrombocytopenia is an independent risk factor, its role in increased mortality 
is less clear, and may not be a result of coagulopathy.10 Disseminated Intravascular 
Coagulation (DIC) has been well-described as an important risk factor for mortality in sepsis.11
Coagulation and inflammatory pathways are intricately linked12 and thrombomodulin appears 
to play a key role both as a scavenger and modulator of thrombin activity, and in its role as an 
endothelial cell surface protein.13,14


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Some data suggest that anticoagulation may improve survival in sepsis,15 while some clinical 
trials of sepsis therapies may have been confounded by concurrent anticoagulation.16
Irrespective of these findings, modulation of coagulation is a credible approach towards the 
realization of improved prognosis for subjects with sepsis and coagulopathy.  
1.2
Mechanism of Action
ART-123 is a recombinant human soluble thrombomodulin (thrombomodulin alpha).
Endothelial membrane bound and soluble forms of thrombomodulin are part of a network of 
endogenous anti-coagulant proteins that also possess potent anti-inflammatory activities in the 
presence of sepsis.17 The primary mechanism of protection afforded by human recombinant 
soluble thrombomodulin is derived from its capacity to bind circulating thrombin molecules 
and serve as an activation complex to convert protein C to activated protein C (APC).
Soluble thrombomodulin possesses an array of activities which are also relevant in its 
mechanism of protection in sepsis. Soluble thrombomodulin avidly binds thrombin and the 
thrombin: thrombomodulin complex can no longer bind to fibrinogen substrates to generate 
fibrin clots. Additionally, thrombin-soluble thrombomodulin complexes activate a plasma 
procarboxypeptidase B species known as TAFI (thrombin activatable fibrinolysis inhibitor). 
Furthermore, soluble thrombomodulin has intrinsic anti-inflammatory properties separate from
its ability to inactivate thrombin and generate APC.  In experimental models of sepsis soluble
thrombomodulin reduces the expression of pro-inflammatory cytokines and chemokines, 
attenuates endothelial cell adhesion molecule expression, limits neutrophil-endothelial 
interactions and lowers circulating levels of the late acting mediator of sepsis High Mobility 
Group Box (HMGB) – 1.18
1.3
Previous Clinical Experience for ART-123
Endothelial expression of thrombomodulin is down regulated in sepsis.19 Phase III studies 
conducted in Japan, in subjects with DIC due to either infection or hematologic malignancy, 
showed that ART-123 statistically significantly outperformed heparin in the resolution of DIC, 
and it appeared to reduce mortality in a prospective subset of subjects with infection.
In a global Phase IIb trial in subjects with sepsis and suspected DIC ART-123 treated subjects
had a positive trend of reduced mortality as compared to placebo subjects. Post-hoc analysis 
of these data indicated that reduced mortality from ART-123 is best predicted when three 


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factors are present: infection, at least one organ dysfunction, and coagulopathy indicated by 
prolongation of the INR. 
Patients requiring Renal Replacement Therapy (RRT) for chronic or acute renal failure, were 
prohibited from being included in the previous Phase IIb trial and the current Phase III trial 
because the clearance of ART-123 in humans is mainly renal and because of the lack of clinical 
information such as the pharmacokinetics (PK) and safety in this population. In addition, 
subjects who required RRT post study enrollment were required by protocol to discontinue the 
study drug administration. A Phase I trial studying the safety and PK of ART-123 subjects with 
impaired renal function and in healthy subjects with normal renal function was completed. This 
study included the collection of PK and safety data of ART-123 in end-stage renal disease 
(ESRD) subjects undergoing hemodialysis. Based on the data from this study the Sponsor has 
modified the exclusion criteria related to RRT thereby allowing the enrollment of such subjects 
without any dose adjustment to the study drug.
Over 120,000 subjects have been treated with ART-123 worldwide. Results from pre- and post-
marketing studies indicate that ART-123 is safe and well tolerated. Details on all previous 
investigations using ART-123 can be found in the current version of the Investigator’s 
Brochure.
2
INVESTIGATIONAL PLAN
2.1
Overall Study Design
This is a randomized, double-blind, placebo-controlled, multi-center, parallel-group study of 
ART-123 in subjects with coagulopathy due to severe sepsis and a concurrent diagnosis of 
shock and/or respiratory dysfunction that requires mechanical ventilation for hypoxemia. At 
randomization, subjects who meet all inclusion criteria and no exclusion criteria will be 
randomly assigned, in a 1:1 ratio, to receive ART-123 in a dose of 0.06 mg/kg/day up to a 
maximum dose of 6 mg/day or a matching placebo for 6 consecutive days. These doses will be 
administered as an intravenous bolus injection or diluted in 50 mL of NS and infused over the 
period of 15 minutes. Blood samples for assessing coagulation and inflammation parameters, 
ART-123 concentration, organ dysfunction and safety laboratory tests will be obtained 
between baseline assessments and the end of the study procedures. Safety-related assessments 
will include reports of adverse events, monitoring for the degree of burden and risk threshold, 
and assessing continuation of treatment with ART-123/placebo during the dosing period Day 
1-6, ECGs and clinical laboratory test results. 


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2.2
Study Objectives
The primary objectives of this study are:
x
To evaluate whether ART-123, when administered to subjects with bacterial infection 
complicated by at least one organ dysfunction and coagulopathy, can reduce mortality.
x
To evaluate the safety of ART-123 in this patient population. 
Secondary objectives include:
x Assessment of the efficacy of ART-123 in resolution of organ dysfunction in this 
population.
x Assessment of antidrug antibody development in subjects with coagulopathy due to 
bacterial infection treated with ART-123.
2.3
Rationale for Study Design
ART-123 treated subjects with infection and coagulopathy have shown reduced mortality in a 
Phase III clinical trial conducted in Japan and a positive trend of reduced mortality in a Phase 
IIb clinical trial conducted globally. These earlier studies used various criteria for DIC to 
identify subjects with coagulopathy. This DIC based approach was not fully successful in 
selecting subjects most likely to respond to ART-123, perhaps because of changes in the 
methods of identifying subjects with DIC. These studies did not require organ dysfunction 
other than DIC.  Analysis of data from the global Phase IIb trial showed that subjects with 
cardiac or respiratory organ dysfunctions and coagulopathy at study entry had better response 
to treatment than subjects without these conditions and it was not always feasible to identify 
the cause of renal or hepatic dysfunction as sepsis or “other”.
The population for the present study will be limited to subjects with cardiovascular and/or 
respiratory dysfunction, plus coagulopathy in addition to infection characterized by a known 
site of the infection, fever/hypothermia and the typical WBC response to infection 
(leukocytosis, leukopenia, or left shifted differential count).
For clarity, both cardiovascular and respiratory dysfunction have been defined using well-
established criteria, including vasopressor requirement after fluid resuscitation for 
cardiovascular dysfunction, and mechanical ventilation requiring intubation for hypoxemia 
(PaO2/FIO2<250 or PaO2/FIO2<200 for subjects with a lung infection) for respiratory 
dysfunction.


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Women of child-bearing potential will be allowed into the study if they have a negative 
pregnancy test (serum or urine hCG) obtained during the current admission to the hospital. The 
active drug ART-123 has a half-life of approximately 20 hours. Study drug is administered for 
up to 6 days to subjects who are either in shock and/or on a ventilator. Ten half-lives will have 
passed 8 days after the last dose; therefore, there is no reasonable likelihood that such study 
subjects will become pregnant during the period that drug is present in the patient.
The dose and duration of treatment have been established in preclinical and clinical trials.
ART-123 is not expected to affect the underlying condition, i.e., infection, so use of best 
treatment is ethically mandated and randomization should balance any impact of specific 
treatments.
Twenty-eight (28) day mortality is the most commonly used measure by scientific and 
regulatory authorities to assess efficacy of treatment of sepsis, and that will be the primary end 
point of the study. Secondary end points will evaluate response to treatment in shock, 
respiratory failure and the use of dialysis. 
2.4
Appropriateness of Outcome Measures
Twenty-eight (28) day all-cause mortality is the generally accepted primary efficacy outcome 
for sepsis treatments. Because ART-123 acts on the coagulation pathway, major bleeding 
events will be considered as a safety endpoint, together with adverse events and other serious 
adverse events.
2.5
Study Population
Approximately 800 subjects will be randomized globally.
2.6
Subject Eligibility Criteria
2.6.1
Inclusion Criteria
This study targets critically ill subjects with severe sepsis requiring the level of care that is normally 
associated with treatment in an ICU setting. The inclusion criteria for organ dysfunction and 
coagulopathy must be met within a 24 hour period.
1) Subjects must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, RR)


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2) Subjects with:
a.
Clinical objective evidence of bacterial infection and a known site of infection
(Refer to Appendix C, Section 15.3).
b. Current treatment with intravenous antibiotics.
c.
White Blood Cell (WBC) count greater than (>) 12,000/mm3 or less than (<) 
4,000/mm3 or Bandemia greater than (>) 10%.
d. Temperature of <36ºC or fever >38ºC. For hypothermia, a core reading is 
preferred. 
Note 1: If a subject has a Gram stain consistent with bacterial infection, positive 
culture from blood or an otherwise sterile body fluid, observed peritonitis, positive 
urinary antigen, clinical presentation of meningococcemia, or otherwise compelling 
evidence of infection as determined by the CCC, only one of the two inclusion criteria 
# 2c (WBC) or 2d (temperature) is required. 
Note 2: The presence of concurrent fungal or viral infection is allowed for the study 
entry, provided that the primary reason for treatment is bacterial infection.
3) Subjects with sepsis associated organ dysfunction defined by at least one of the 
following:
a) Cardiovascular Dysfunction defined as requiring both adequate fluid resuscitation and
vasopressors* to maintain Mean Arterial Pressure (MAP) greater than or equal to (>)
65 mmHg (implies fluid resuscitation alone does not raise MAP to  65 mmHg). 
Adequate fluid resuscitation is defined as:
o
Intravenous administration of at least 20 mL/kg crystalloid or 
10 mL/kg colloid infusion within 6 hours.
OR
o
Central Venous Pressure (CVP) greater than (>) 8 mmHg or 
Pulmonary Artery Wedge Pressure (PAWP) greater than (>)
12 mmHg.
* If dopamine is the only vasopressor used, the infusion rate must be greater 
than (>) 5 μg/kg/min (i.e., must be prescribed to support cardio-pulmonary 
perfusion). If vasopressin is used, it must be given in conjunction with another 
vasopressor.
b) Respiratory Dysfunction is defined as the acute need for mechanical ventilation and 
PaO2/FiO2 ratio of <250 (or < 200 when the lung is the site of infection). For the 


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purposes of this protocol, mechanical ventilation is defined as any type of ventilation 
administered via an endotracheal tube or nasotracheal intubation. A simple 
administration of supplemental oxygen is NOT considered to be mechanical 
ventilation for the purposes of this study.
4) Subjects with coagulopathy characterized by an INR >1.40 without other known etiology 
(e.g., anticoagulant therapy, chronic liver disease)
5) Subjects with coagulopathy characterized by platelet count in the range of greater than (>) 
30,000/mm3 to less than (<) 150,000/mm3 OR a greater than 30% decrease in platelets in 
24 hours 23, 24, 25, 26, 27, 28.
:LQGRZKRXUV
Organ dysfunction (Section 2.6.1) and coagulopathy (Section 2.6.1) criteria need to be present 
within 24 hours of each other. The 24 hour window begins when a patient with suspected or 
confirmed bacterial infection develops either 1) sepsis associated organ dysfunction 
(cardiovascular or respiratory) or 2) first qualifying platelet result or first qualifying INR. The 
qualifying time for organ dysfunction and coagulopathy is as follows:
1. Sepsis associated organ dysfunction
o
Cardiovascular dysfunction: the time that vasopressors are initiated (Section 
2.6.1, 3a).

For surgical patients having vasopressors initiated during surgery; if 
vasopressors are required post-surgery, the end time of the surgery is 
the qualifying time
o
Respiratory dysfunction: the time of intubation prior to the first qualifying 
PaO2/FiO2 ratio after intubation (Section 2.6.1, 3b).

For surgical patients that require mechanical ventilation for surgery: if  
the patient has a qualifying PaO2/FiO2 post-surgery due to sepsis 
associated respiratory dysfunction, the time the surgery ends is the 
qualifying time.
2. Coagulopathy


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o
Decreased platelets: a qualifying platelet count must occur within the 24 hour 
window (if more than one platelet is within the 24 hour window the time of the 
first qualifying platelet is to be used).

absolute value of > 30,000/ mm3 and < 150,000/ mm3.
OR

>30% decrease from one platelet count to another within 24 hours.
(Patients with a platelet count of  30,000/ mm3 are not eligible per 
Exclusion 10.)
o
INR: first qualifying INR > 1.40
:LQGRZKRXUV
Window 2 is a 12 hour period of time that starts when the last inclusion criteria is met for 
sepsis-associated organ dysfunction and coagulopathy. During this window, eligibility must be 
confirmed, informed consent obtained, authorization to randomize obtained from the CCC, and 
the subject randomized.  
Time windows and duration for the study are illustrated in Figure 1.
Figure 1
Enrollment Time Windows and Study Duration


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Please note: Infection criteria needs to be met prior to the start of window 2. Once informed 
consent has been obtained and the CCC confirms that all study eligibility criteria have been 
met and provides authorization to randomize, the subject should be randomized even if the 
subsequent laboratory values (platelets and INR) show that the subject no longer meets 
eligibility criteria, assuming no other study exclusion criteria have emerged during this time 
period that disqualify the subject from being dosed with the study product. If a subject is 
transferred from another facility, Window 1 starts from the time a patient with suspected or 
confirmed bacterial infection develops either 1) sepsis associated organ dysfunction or 2) 
coagulopathy regardless of the facility. Once informed consent has been obtained and the CCC 
confirms that all study eligibility criteria have been met and provides authorization to 
randomize, the subject should be randomized. The first dose of study drug must be 
administered as soon as possible and no later than 4 hours after randomization. (Refer to 
Section 13.2 Informed Consent for specific guidelines for Informed Consent). 
2.6.2
Exclusion Criteria
Candidates for the study will be excluded if ANY of the following criteria are present:
1. Subject or Authorized Representative is unable or unwilling to provide initial or 
ongoing informed consent (as applicable per local and country regulations)
2. Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of 
enrolling into the study
3. Subject is of childbearing potential and has a positive pregnancy test since admission 
to the hospital
4. Subject is < 18 years of age
5. Subject has a known allergy to ART-123 or any components of the drug product 
6. Subject is unwilling to allow transfusion of blood or blood products
7. Presence of an advance directive to withhold life-sustaining treatment (patients not 
wishing to receive Cardiopulmonary Resuscitation (CPR) may qualify provided they 
receive all other resuscitative measures e.g. mechanical ventilation, vasoactive agents, 
cardioversion)
8. Subject has had previous treatment with ART-123
9. %RG\ZHLJKWNJ


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10. Platelets < 30,000/ mm3 for any reason, PT prolongation or thrombocytopenia that is 
not due to sepsis (e.g. AML or ALL in induction therapy, acute leukemia of the M3 
type, myeloablative therapy within 4 weeks prior to enrollment, AIDS with persistent 
thrombocytopenia and/or bleeding disorder, ongoing pre-existing thrombocytopenia or 
coagulopathy).
11. Any surgery that is potentially hemorrhagic (e.g. intra-thoracic, intra-abdominal or 
non-traumatic orthopedic surgery of the femur or pelvis) that is completed within 
12 hours prior to the first dose of study drug, or ongoing impairment of hemostasis as 
a result of one of these procedures (Refer to Section 2.6.3.)
12. A history of head trauma, spinal trauma, or other acute trauma with an increased risk 
of bleeding within 3 months prior to consent (subjects with minor head trauma may be 
enrolled if there is a normal neurological examination and a normal CT scan of the 
head/spine post injury documented in the medical record)
13. Cerebral Vascular Accident (CVA) within 3 months prior to consent
14. Any history of Intracerebral Arteriovenous Malformation (AVM), cerebral aneurysm, 
or mass lesions of the central nervous system 
15. A history of congenital bleeding diatheses or anatomical anomaly that predisposes to 
hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia)
16. Significant gastrointestinal bleeding (e.g., melena, hematemesis) within 6 weeks prior 
to consent unless a corrective interventional procedure has been performed (i.e.,
therapeutic endoscopy)
17. Subject is diagnosed with a known medical condition associated with a 
hypercoagulable state, including:
a.   Resistance to activated protein C or known Factor V Leiden
b.   Hereditary deficiency of protein C or protein S
c. Presence of anticardiolipin antibody, antiphospholipid antibody, or prothrombin 
gene mutation
d. Deep-vein thrombosis or pulmonary embolism within 3 months prior to consent 
(if evaluation is in progress, this should be completed before consideration for 
this trial) 
e.
Any disorder with a requirement for full anticoagulation
18. History of cirrhosis or current Class C liver disease (Child-Pugh score of 10-15); (See 
Appendix E)


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19. Portosystemic hypertension or known history of bleeding esophageal varices
20. History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 
6 months prior to consent (uncomplicated kidney and autologous stem cell/bone 
marrow transplant subjects may be enrolled at any time after they have recovered from 
their transplant procedure)
21. Acute pancreatitis where infection has not been documented by a positive blood or 
abdominal fluid culture or gram stain consistent with bacterial infection. Also, in the 
opinion of the treating physician the subject is at an increased risk for developing 
hemorrhagic pancreatitis over the duration of the study
22. Subjects with renal dysfunction defined as:
a.
Chronic renal failure requiring renal replacement therapy (RRT), or
b. Acute renal failure with onset of oliguria (urine output < 0.3 ml/kg/hr) > 48 
hours prior to first dose of study drug whether receiving RRT or not.
23. Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 
72 hours prior to first dose of study drug with the exception of:
a.
Heparin locks/flushes
b. DVT Prophylaxis (see Appendix G) per prophylactic dosing on the package 
insert as approved in your country. 
c.
Up to 325 mg of aspirin daily for cardiac prophylaxis only
d. Anticoagulants for RRT: Regional citrate is preferred (see Appendix G). It is 
recommended that if unfractionated heparin or LMWH is used, that the 
systemic exposure be less than or equal to the DVT prophylaxis dose allowed. 
24. Life expectancy < 90 days due to underlying conditions such as, but not limited to, the 
following:
a.
Poorly controlled neoplasms 
b. New York Heart Association class IV or pulmonary vascular disease resulting 
in severe exercise restriction (i.e., unable to climb stairs or perform household 
duties), or chronic restrictive or obstructive pulmonary disease that also results 
in severe exercise restriction, or documented chronic hypoxia (needs 
continuous home oxygen treatment), hypercapnia, secondary polycythemia, 
severe pulmonary hypertension (Mean Arterial Pulmonary pressure level of 
> 40 mmHg) or respiratory dependency


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c.
Prior cardiac arrest requiring CPR without fully demonstrated neurological 
recovery, or subject with imminent death (in the next few hours)
d. End-stage neurological disorders (e.g., amyotrophic lateral sclerosis - Lou 
Gehrig's disease)
25. Current use of any chemotherapy agent likely to cause myeloablation (See 
Appendix H)
26. Participation in another research study involving an investigational agent within 
30 days prior to consent or projected study participation during the 28 days post study 
randomization
27. Confirmed or suspected endocarditis 
2.6.3
Post-surgical Subjects
For subjects that have had a potentially hemorrhagic surgery (e.g. intra-thoracic, intra-
abdominal, or non-traumatic orthopedic surgery of the femur or pelvis) the first dose of study 
drug must not be administered within 12 hours post completion of major surgery.
2.7
Criteria for Discontinuation from Study Drug or Study Participation 
2.7.1
Withdrawal from receiving study drug
A subject may remain in the study but discontinue the administration of study drug, at any time 
during treatment. Reasons may include:
1. Intolerable adverse event(s) such as Major Bleeding Event(s) (Section 7.1) or 
conditions that place the subject at high risk of bleeding.
2. Request by the subject or their AR / LAR.
3. Hospital discharge or transfer to another facility.
4. Investigator’s judgment (e.g. related SAE).
5. Administration of study drug is contraindicated if co-administration of an excluded 
concomitant medication (e.g. full heparinization, oral anticoagulant, anti-platelet 
drug) is required for subject treatment.
6. QTcB value of greater than 500 msec (provided that the baseline value was 
<500 msec) or the QTcB is >60 msec over baseline value and the subject is 
symptomatic.


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Subjects who terminate study treatment prior to receiving the protocol specified 6 days of 
dosing will have ETT assessments performed 24 hours (±2 hours) after the last dose of study 
drug administration. In such cases, the subject will continue ongoing protocol specified 
evaluations through Day 28 and will be contacted at 3, 6 and 12 months for survival status.
Approval for collection of this survival data will be provided at the time of the subject’s 
original Informed Consent.
If the subject is discharged from the admitting hospital or transferred to another outside facility 
during the treatment phase (Days 1-6), the administration of the study drug will be discontinued 
at the time of the discharge or transfer. The ETT visit is completed prior to discharge.
If the subject is transferred from the admitting hospital ICU to another unit within the hospital,
this is not considered as hospital discharge. Study drug administration, as well as all protocol 
specified study procedures, should continue uninterrupted.
2.7.2
Discontinuation from study participation
2.7.2.1
Discontinuation from study participation due to death
It is vital that all safety, concomitant medication(s), and health history data be collected and 
reported in accordance with all local and regional regulatory requirements as well as all Asahi 
Kasei Pharma America Corporation guidelines for any subject who expires while actively 
enrolled or during the follow up period after dosing is completed for this study. All study visit 
data from the time of informed consent to the time of death will be collected. 
If a subject dies while on study, efforts will be made to determine the cause of death and collect 
information about the subject’s status and treatments that he/she was receiving at the time of 
death. If available, a copy of the death certificate will be collected (in accordance with local 
regulations/statutes).  
2.7.2.2
Discontinuation from study participation due to withdrawal of consent
Subjects may voluntarily discontinue participation in the study at any time, for any reason. 
During the initial informed consent process, Investigators should advise potential study 
subjects of their right to withdraw consent, and provide education regarding alternate treatment 
options that are available to them. In situations where consent for participation is obtained by 
an Authorized or Legally Authorized Representative (AR/LAR respectively) or an independent 
physician (as defined in Section 13.2), provisions for ongoing participation are at the discretion 
of the AR/LAR or an independent physician who maintains the same rights as outlined herein 


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for the study subject; until such time that the subject is deemed able to do so.  Refer to Section 
13.2 Informed Consent for further guidelines.
If a subject indicates an interest in withdrawing from randomized treatment, Investigators 
should seek clarification about whether continued follow-up and survival status data collection
subsequent to the subject’s withdrawal is agreeable to the subject. This is covered when the 
initial Informed Consent is obtained. If such ongoing follow up is permissible, the subject 
should not be identified as having withdrawn consent.
At the time of withdrawal of consent, the subject should be reminded of their rights.  All study 
visit procedures, as well as the End of Study (EOS) visit assessments should be completed up 
to the time that consent was withdrawn.  The completion of all study visits up to the time that 
consent was withdrawn, as well as survival status at Day 28, 3 months, 6 months and 12 months 
post the first dose will be collected.
At the time of withdrawal of consent, final visit procedures and assessments will be performed
unless the subject is unwilling to comply. The subject will be directed to follow up with their 
primary care physician for ongoing medical treatment, informed of any known options for 
medical care and will be provided information regarding who to contact for any questions as 
well as information about the outcome of the study once completed. 
2.7.2.3
Discontinuation due to lost to follow up
Subjects who have not withdrawn consent, but have not returned for follow-up visits and no 
contact can be made to determine their status will be designated “Lost to Follow-up”. Site 
personnel will designate a subject as Lost to Follow-up for the primary endpoint at Day 28 
only after the subject or subject’s representative has not responded to two documented attempts 
at telephone contact and a registered letter sent to the subject’s last known mailing address. 
The Lost to Follow Up date will be recorded as the last date of contact with the subject. For all 
subjects who are lost to follow-up the investigator will report if, in the investigator’s judgment, 
the subject was improving and likely to be alive on Day 28.  
For subjects who have not withdrawn consent, site personnel are asked to make every attempt 
to collect long term survival status at the 3 month, 6 month and 12 month time points. Subjects 
are to be classified with a final status of “Lost to Follow Up” only if they are unable to be 
contacted at the 12 month survival status time point. 


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2.8
Data Monitoring Committee (DMC)
A DMC will monitor the progress of the study and review critical safety data.  Membership 
will consist of a biostatistician and 2 clinicians in the field.  The DMC will be independent of 
the study team and will have no direct involvement in other aspects of the trial.  The DMC will 
follow operating procedures provided in the DMC Charter. A biostatistician, independent of 
the project team, will perform the statistical analyses, including interim analysis, for the DMC.  
This independent biostatistician will not be a member of the DMC. The DMC will review 
unblinded efficacy and safety data, including quality of study conduct measures.  The DMC 
will provide recommendations to study leadership.  DMC monitoring guidelines have been 
outlined in Section 10.3 of this protocol.
The DMC will meet prior to study initiation and finalize the DMC Charter. Meetings may be 
held in-person or by teleconference.  Interim Analyses will be held at predefined milestones 
formally throughout the study.  In addition, the DMC can hold ad hoc meetings as deemed 
appropriate. Refer to Section 12.3.1 for further information regarding the DMC.
2.9
Clinical Coordinating Centers (CCCs)
Two CCCs, Ocean State Clinical Coordinating Center (OSCCC) and St. Luc Clinical 
Coordinating Center (SLCCC), will be providing clinical support for study sites. These CCCs 
are comprised of experts in critical care, infectious disease and pulmonary medicine. The CCCs
will work with the investigative sites to determine if subjects appropriately meet the study 
entry criteria and can be randomized into the study thereby ensuring an appropriate
homogenous study population.
3
TREATMENTS
Subjects will be randomized to receive either ART-123 or Placebo via 1:1 randomization.
After the subject is qualified for study entry, treatment assignment will be made via a Voice 
Activated or Web Access Automated Randomization System.  ART-123 and Placebo are both 
supplied in 1 mL glass ampules, which must be maintained at 2°C–8°C and kept away from 
light during storage.
ART-123 or Placebo will be administered at a dose of 0.06 mg/kg/day up to a maximum dose 
of 6 mg/day, every 24 hours (plus or minus 2 hours) for six (6) consecutive days.  When a 
subject requires a major surgery/intervention during the dosing period, if possible the 
surgery/intervention should be performed 12 hours after the last dose. If it is known ahead of 


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time that the subject will undergo major surgery/intervention, then the study drug dose that is
due prior to the surgery should be held if the surgery/intervention is planned within the next 
12 hours. Post procedure, the study drug is to be held for 12 hours and then may be resumed
unless otherwise contraindicated. The study drug dosing clock now restarts, using the time the 
post procedure dose was given, and all subsequent doses are to be administered using the new 
clock. Subjects whose body weight iVNJZLOOUHFHLYHWKHVWXG\GUXJDWDYROXPHRI
mL/kg/day (0.06 mg/kg/day) up to a volume of 1 mL/day (6mg). Subjects whose body weight 
in the range of 100-174 kg will receive 1 mL/day (6mg) of study drug regardless of body 
weight. A detailed rationale for the 0.06 mg/kg/day dose may be found in the Investigator’s 
Brochure.
ART-123 or Placebo will be administered as an IV bolus injection or diluted in 50 mL of NS, 
and infused over a period of 15 minutes. ART-123 or Placebo must be given in a dedicated 
line and must not be administered concurrently with any other medications. If the same IV 
line that is used for delivery of other medications must be used for administering ART-123 or 
placebo then the line must be flushed with at least 5 mL of 0.9% NS solution both prior 
to and following the administration of ART-123 or placebo. If a heparin flush is requested it 
may be administered following the 0.9% NS flush, in accordance with institutional standards. 
The study drug can be administered either via a central line or through a large bore (greater 
than or equal to 20-gauge) peripheral IV line. Heparin coated central lines are not allowed 
for the administration of ART-123 or Placebo.
After drawing up study drug from the ampule into the syringe, administration should occur as
soon as possible post removal from the ampule. 
3.1
Investigational Product, Dosage and Mode of Administration
3.1.1
ART-123 (thrombomodulin alpha)
ART-123 or Placebo, are administered at the equivalent dose of 0.06 mg/kg/day up to a 
maximum dose of 6.0 mg/day for six days.  ART-123 is given by intravenous bolus or rapid IV 
infusion, in which case 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day is diluted in 50 
mL of NS and given over a period of 15 minutes. ART-123 must not be administered 
concurrently with any other medications or in the same IV line that is used for administering 
other medications. If the same IV line that is used for delivery of other medications must be 
used for administering study drug or placebo then the line must be flushed with at least 5 mL 
of 0.9% Saline solution both prior to and following of administration of study drug or placebo. 


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ART-123 is supplied as individual glass ampules containing 6.0 mg of formulated drug in 1 mL 
of total volume; with an overfill of 0.1mL. The total volume of each ampule equals 1.1 mL.
Stability data show ART-123 is stable for up to 18 months when stored at 2°C–8°C. 
Photostability studies indicate that ART-123 is sensitive to light. The investigational drug 
product is kept in closed cartons and should be protected from sunlight at all times. 
3.2
Reference Therapy, Dosage and Mode of Administration
3.2.1
Placebo for ART-123
Placebo for this study is supplied as identically labeled, individual glass ampules in 1 mL of 
total volume; with an overfill of 0.1mL. The total volume of each ampule equals 1.1 mL.
Placebo will also be required to be maintained refrigerated at 2°C–8°C and protected from light 
during storage.  Placebo must be administered according to the same procedures and guidelines 
as ART-123, i.e., Placebo must not be administered concurrently with any other medications 
and the IV line that is used for administering placebo must be flushed with at least 5 mL of 
0.9% Saline solution both prior to and following administration of study drug or placebo.
3.3
Blinding
Study drug will be assigned and administered in a double blind fashion. In the event of a 
medical emergency where it is imperative to know which treatment arm the subject was 
randomized to in order to make future treatment decisions, the Investigator may break the blind 
for an individual subject.
Because there is no antidote for ART-123, and the treatment for subjects should be as per 
standard of care, there should be little reason for unblinding the treatment of an individual 
subject. If the Investigator needs to unblind an individual subject, the Medical Monitor or 
designee should be notified in advance whenever possible. In addition, the sponsor should also 
be notified prior to the blind being broken.
All adverse events causing the need for subject unblinding will be handled as a serious adverse 
event in accordance with the procedures outlined in this protocol. Any broken blind will need 
to be clearly justified, explained by a comment within the Electronic Case Report Form 
(eCRF), and captured on the Serious Adverse Event Form.
The treatment assignment for the subject can be determined by the Investigator only and only 
by calling into the automated system for randomization assignment via password protected 
access. The Investigator must record the date, time and the reason for the unblinding in the 
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4
LABORATORY SAMPLES
For this study there will be both local and central laboratory blood draw requirements.  The list 
below outlines which study specific laboratory blood draws are for central laboratory draws 
(using the provided central laboratory kit) and which are for local laboratory draws (using 
hospital stock supplies).  If Standard of Care (SOC) local labs for Organ Dysfunction (OD) are 
to be drawn on the days where study drug is administered, we suggest these be drawn within 1 
hour after the study drug is administered. On days where Standard of Care labs are drawn, use 
the PaO2/FiO2 (for ventilated subjects) results for the Organ Dysfunction assessments. If an 
ABG is not performed as SOC, a Pulse Oximetry O2 saturation may be used for calculating the 
PaO2/FiO2 (Refer to
. For centers that 
may be at an altitude of more than 1000 meters, an adjustment may be needed for purposes of 
calculating PaO2/FiO2.
To avoid contamination or clotting, all coagulation tests taken for the purposes of this study 
should be obtained from an original arterial stick or venipuncture. If it is not possible to obtain 
blood from an original stick or venipuncture, blood may be collected from an arterial line in 
which no Heparin is infused. The arterial line will be flushed with NS both prior to and after 
the blood draw. No coagulation samples can be obtained from a Heparin infused or Heparin 
coated central line. Heparin must not be used when flushing an arterial line for this purpose. 
The site staff should use proper collection technique as described in the Central Laboratory 
Manual.  If an original arterial stick or venipuncture is used then to avoid clotting, the 
coagulation test tubes should not be the first tube of blood filled. Any other non-coagulation 
blood tests unable to be obtained from the original arterial stick or venipuncture may be taken 
from an existing port or line. If a central line is used, exploratory laboratory tests should be the 
last to be collected.
4.1
Central Laboratory Tests:
x
Serum Chemistry profile (Sodium (Na),
Potassium (K), Chloride (Cl), 
bicarbonate, non-fasting glucose (Glu), Calcium (Ca), Blood Urea Nitrogen 
(BUN), Creatinine, ALT, AST, Alkaline Phosphatase and total bilirubin) 
x
D-dimer 
x
Arterial lactate concentration
x
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x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
4.2
Local Laboratory Tests:
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Serum Chemistry (Creatinine, Total bilirubin at Baseline Visit only)
x
Pregnancy test; Serum or Urine human Chorionic Gonadotropin (hCG) -
Pregnancy test only required for woman of childbearing potential 
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
x
Albumin and total bilirubin, if not performed as standard of care in the past 7 days 
(Screening), for Child-Pugh Score calculation in patients with severe liver disease.
5
VISIT SCHEDULE AND ASSESSMENTS
5.1
Screening Visit
Subjects must meet the 5 inclusion criteria (be in the ICU or acute care setting, infection, sepsis 
associated organ dysfunction, and coagulopathy) and have none of the exclusion criteria in 
order to be eligible for randomization in this study.  


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5.2
Consent and Randomization Process
Subjects who meet criteria for infection, sepsis-associated organ dysfunction and coagulopathy 
according to protocol parameters, are in an ICU or acute care setting, have none of the 
exclusion criteria, and have been consented, may be randomized after authorization to 
randomize has been provided by the CCC.
If in the opinion of the investigator the subject will require the administration of anticoagulants, 
antiplatelet agents, antithrombotics, or thrombolytics during any period of the study, that
subject is not eligible for this study. A list of prohibited medications is provided in
Appendix G. Subjects who discontinue dosing will follow the visit schedule and procedures as 
outlined in Section 2.7.1 of this protocol. If the subject is female and is of childbearing 
potential, a pregnancy test (serum or urine hCG) will be obtained if not previously performed 
as SOC during this hospitalization, and the results determined and documented prior to 
baseline visit.
Guidelines for the management of subjects that require an AR/LAR or other legal intervention 
due to their medical status, and are unable to provide consent for him/herself, may be found in 
Section 13.2.
In extreme and urgent circumstances when emergent action is required to mitigate the risk of 
death and where allowable per local laws, it is understood that the presumed will of the subject 
will be determined by a physician and documented based on his/her knowledge of the study 
subject. As appropriate, an independent physician, who is a qualified medical doctor with at 
least one year’s experience in intensive care medicine but must be from another department 
and/or hospital than the investigator, may sign the informed consent for the subject if the local 
laws, regulations and ethics committees approve this process. In countries where permissible, 
this independent physician may be from the same department. The study subject must be 
presented with the informed consent as soon as it is possible and reasonable, and informed 
consent obtained for continued study participation.  The AR/LAR or independent physician 
may act as an agent on the subject’s behalf once they are available to provide informed consent. 
The above guidelines apply to all areas of the protocol where Informed Consent is referenced 
or required.
5.3
Baseline Visit (prior to dosing)
Subjects who meet all eligibility criteria and have signed informed consent will be discussed 
with the CCC for authorization to randomize. After the CCC verifies eligibility of the subject 


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and authorizes randomization, the subject will be randomized by the site via an automated 
phone/internet system.
Once the subject is randomized, the automated system will provide the study staff with a unique 
randomization number for the subject and an assigned investigational product kit number. The 
assigned kit should be ordered or obtained by the PI or designee from the pharmacy or 
applicable investigational product storage location. 
For each study subject the following data/assessments are required to be collected:
The following data/assessments may have preceded the time of the last inclusion criteria 
and consent as the information is collected as part of the medical record. However, no 
data is collected until the subject has been consented.
x
Demographics, height and weight (actual baseline dry weight since hospital admission or 
if unavailable, usual body weight. If weight is unavailable, estimated body weight can be 
used).
x
Medical history (all known information regarding the subject’s health history/relevant 
surgeries/interventions).  
x
Acute Physiology and Chronic Health Evaluation (APACHE) II29,30 (timeframe for data 
collection is the 24 hours prior to the first dose, See Appendix K and Appendix L)
x
Concomitant medications administered within the 7 days prior to randomization (including
fluids for resuscitation and blood products).
x
Historical information regarding treatment for the current episode of sepsis.
x
Documentation of the infection (site of infection and, if available: positive culture results, 
prior antibiotics, sensitivity of cultured organism to antibiotics, nonmedical treatment such 
as surgery or drainage)
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
If Respiratory dysfunction: duration on mechanical ventilation, qualifying PaO2/FiO2 ratio
prior to randomization.
x
If Cardiovascular Dysfunction: fluid administration, CVP, and/or PAWP, duration on 
vasopressors, name of vasopressor currently administered. 
x
If the subject is receiving dopamine, dobutamine, or other inotropes for cardiac 
dysfunction, record the dose. 
x
Record Interventions/Surgeries 


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The following assessments are to be performed/collected after the consent has been 
obtained, last inclusion criteria is met, and authorization to randomize has been received
from the CCC:
x
Vital signs: Pulse – beats per minute (BPM), Blood Pressure (BP) mmHg, Respirations –
breaths per minute, Temperature 
x
Changes in concomitant medications
x
Blood Product administration
x
Physical Examination including the following: general appearance, Head, Eye, Ear Nose 
Throat (HEENT), neck, respiratory, cardiovascular, chest, abdomen, lymphatic, 
musculoskeletal and extremities, skin and neurologic examination 
x
12 lead ECG: to be read centrally
x
Adverse Events/Serious Adverse Events 
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
Interventions/Surgeries
x
Major Bleeding Events
Blood will be obtained for following local laboratory tests:
x
Serum Chemistry (Creatinine and Total bilirubin)
x
PaO2/FiO2 (only for respiratory dysfunction)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional labs will be drawn for analysis at the central laboratory:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)
x
D-dimer
x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII


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x
Inflammation: CRP, Microparticles, and C5a
x
Arterial lactate concentration
x
Anti-drug Antibodies to ART-123
For randomized subjects who do not receive any study drug all study tests completed prior to 
the point it was known the subject would not be dosed will be collected. All AEs, SAEs and 
survival status through Day 28 will be collected, but further study visits/procedures (including 
ETT) will not be performed.
5.4
Dosing Visit (Day 1)
The first dose of study drug must be administered as soon as possible and within 4 hours after 
randomization. For post-surgical subjects see Section 2.6.3. Follow the instructions in the Drug 
Accountability and Handling Manual for proper preparation and administration instructions.
Within one hour after the administration of the first dose record the following:
x
Vital signs 
x
Changes in concomitant medications
x
Blood Product administration
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization 
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
PaO2/FiO2 if available within one hour after IP administration (only if vented)
x
Interventions or Surgeries 
x
Major Bleeding Events
x
Assessment of the degree of burden and risk threshold, and assess continuation of treatment 
with ART-123/placebo (refer to Section 7.5)
5.5
Day 2 Visit 
On Day 2, administration of the second dose of study medication will begin 24 hours 
(±2 hours) after the first dose was given (dosing Day 1). Please refer to Section 3 if the subject 
has had an intervention/procedure since the first dose of study drug.


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Within one (1) hour after study drug administration, perform/record the following:
x
Vital signs  
x
Changes in concomitant medications
x
Blood product administration
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization 
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
Interventions/Surgeries 
x
Major Bleeding Events
x
Assessment of the degree of burden and risk threshold, and assess continuation of treatment 
with ART-123/placebo (refer to Section 7.5)
Blood will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and
WBC with differential count)
x
Platelet count
x
Coagulation Panel: Prothrombin time and INR
Additional blood samples will be drawn for analysis at the central lab:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)
x
D-dimer
5.6
Day 3 Visit (Pre-dose)
On Day 3, administration of the third dose of study medication will begin 48 hours (±2 hours) 
after the first dose of study medication was given (Dosing Day 1). Please refer to Section 3 if 
the subject has had an intervention/procedure since the first dose of study drug.
Within one (1) hour PRIOR to study drug administration, blood samples will be collected 
for the following central laboratory tests:
x
Plasma thrombomodulin concentration (PK)


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x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
5.7
Day 3 Visit (Post-dose)
Within one (1) hour after study drug administration, perform/record the following:
x
Vital signs
x
Changes in concomitant medications
x
Blood product administration
x
12 lead ECG: to be read centrally
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization 
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
Interventions/Surgeries 
x
Major Bleeding Events
x
Assessment of the degree of burden and risk threshold, and assess continuation of treatment 
with ART-123/placebo (refer to Section 7.5)
Blood will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional labs will be drawn for analysis at the central lab:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)
x
D-dimer
x
Plasma thrombomodulin concentration (PK)


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x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
5.8
Days 4-6 Visits
On Days 4, 5 and 6 administration of the fourth, fifth and sixth doses of study medication will 
begin 72, 96 and 120 hours (±2 hours) after the first dose of study drug was administered, 
respectively. Please refer to Section 3 if the subject has had an intervention/procedure since 
the first dose of study drug.
Within one (1) hour after the administration of study drug (doses 4-6), perform/record 
the following:
x
Vital Signs
x
Changes in concomitant medications
x
Blood product administration
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization 
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
Interventions/Surgeries
x
Major Bleeding Events
x
Assessment of the degree of burden and risk threshold, and assess continuation of 
treatment with ART-123/placebo (refer to Section 7.5)
Blood will be obtained for the following local laboratory tests on Days 4 and 6 only:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional labs on Days 4 and 6 only will be drawn for analysis at the central laboratory:


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x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)
x
D-dimer
On study Day 5 only, blood will be obtained for the following local laboratory test:
x
PaO2/FiO2 (only if vented and not collected as SOC)
On study Day 6 only, the following will be performed:
x
12 lead ECG: to be read centrally
x
Blood will be will be drawn for analysis at the central laboratory:
x
Plasma thrombomodulin concentration (PK) 
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
Days 4-6
If the QTcB is >500 msec or the QTcB is > 60 msec over the baseline value, continue to 
monitor ECGs once daily until the earlier of Day 14 or the time when such conditions are no 
longer met. In the event of hospital discharge at this time, the Investigator should carefully 
evaluate these parameters prior to hospital discharge. 
5.9
Day 7 Visit 
On Day 7, assessments will begin 144 hours (± 2 hours) after the first dose (dosing Day 1) of 
study drug was administered. If a subject is discharged on Day 7, the Day 7 Visit, not the 
Hospital Discharge Visit, is performed.
Perform/record the following:
x
Vital Signs
x
Changes in concomitant medications
x
Blood product administration
x
12 lead ECG: to be read centrally
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization 


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x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
Interventions/Surgeries
x
Major Bleeding Events
Blood will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional blood samples will be drawn for analysis at the central laboratory:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)
x
D-dimer
x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
x
Arterial lactate concentration
If the QTcB is >500 msec or the QTcB is > 60 msec over the baseline value, continue to 
monitor ECGs once daily until the earlier of Day 14 or the time when such conditions are no 
longer met. In the event of hospital discharge at this time, the Investigator should carefully 
evaluate these parameters prior to hospital discharge.
5.10 Early Treatment Termination (ETT) Visit
The ETT visit is for subjects who discontinue study drug treatment early and remain 
hospitalized or who are discharged from the hospital on Study Days 1-6. The ETT Visit 
assessments are to be done in place of the daily assessments required for the actual study visit 
day.


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x
For subjects who discontinue treatment early (prior to the 6th dose) and remain 
hospitalized: the ETT is performed 24 hours (±2 hours) after the last dose of study 
medication that was administered.
x
For subjects discharged from the hospital on Study Days 1-6: the ETT is performed
(not the Hospital Discharge Visit),
Note: Any subject who completes the ETT visit remains in the study. If the subject is still 
hospitalized, study visits must continue to be completed. All subjects discharged from the 
hospital before Day 14 must return for Day 14 and Day 28 visit procedures. Subjects 
discharged from the hospital after Day 14 but before Day 28 must return for Day 28 procedures.
All subjects must be contacted at 3, 6 and 12 months for survival status.
Record the following:
x
Vital Signs
x
Changes in concomitant medications
x
Blood product administration
x
12 lead ECG: to be read centrally
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization 
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis
x
Interventions/Surgeries
x
Major Bleeding Events
Blood samples will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional blood samples will be drawn for analysis at the central lab:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)


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x
D-dimer
x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
x
Arterial lactate concentration
If the QTcB is >500 msec or the QTcB is > 60 msec over the baseline value, continue to 
monitor ECGs once daily until the earlier of Day 14 or the time when such conditions are no 
longer met. In the event of hospital discharge at this time, the Investigator should carefully 
evaluate these parameters prior to hospital discharge.
5.11 Days 8-13
Beginning with Day 8 all prospective visits are based on calendar days. From this visit 
forward days are calendar days and are counted as follows: first dose on Day 1=1, D2=2, etc.
On study days 8-13, the following assessments will be completed as long as the subject remains 
in the hospital:
Perform/record the following:
x
Changes in concomitant medications
x
Blood product administration
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis and if 
the subject is vented, collect blood for PaO2/FiO2 (if not done as SOC)
x
Interventions/Surgeries
x
Major Bleeding Events
If the QTcB is >500 msec or the QTcB is > 60 msec over the baseline value, continue to 
monitor ECGs once daily until the earlier of Day 14 or the time when such conditions are no 
longer met. In the event of hospital discharge at this time, the Investigator should carefully 
evaluate these parameters prior to hospital discharge.


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5.12 Day 14 (+ 3 days) 
Subjects must return to the hospital for Day 14 procedures (+3 day deviation is acceptable).
For subjects who remain hospitalized, this visit’s procedures are performed on Day 14. If a 
subject is to be discharged on Day 13, the Day 14 Visit procedures must be performed in lieu 
of the procedures scheduled for Day 13. Subjects who are discharged from the hospital on the 
same day as the Day 14 Visit, complete the Day 14 Visit not the Hospital Discharge Visit.
Perform/record the following:
x
Vital signs
x
Changes in concomitant medications
x
Blood product administration
x
12 lead ECG: to be read centrally
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis 
x
Interventions/Surgeries
x
Major Bleeding Events
Blood will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and WBC 
with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional blood samples will be drawn for analysis at the central laboratory:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, AST, 
Alkaline Phosphatase and Total bilirubin)
x
D-dimer
x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII


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x
Inflammation: CRP, Microparticles, and C5a
x
Anti-drug antibodies to ART-123
5.13 Days 15-27
On study days 15-27, the following assessments will be completed as long as the subject 
remains in the hospital:
Perform/record the following:
x
Changes in concomitant medications
x
Blood product administration
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis and 
if the subject is vented, collect blood for PaO2/FiO2 (if not done as SOC)
x
Interventions/Surgeries
x
Major Bleeding Events
5.14 Hospital Discharge
This visit applies to subjects discharged from the hospital on Day 8 up to Day 28 except for 
Days 13 / 14 or Day 28 in which case please refer to the respective study visit for study 
procedures.
Perform/record the following prior to discharge:
x
Vital signs
x
Changes in concomitant medications
x
Blood product administration
x
12 lead ECG: to be read centrally 
Note: If the QTcB is >500 msec or the QTcB is > 60 msec over the baseline value, 
continue to monitor ECGs once daily until the earlier of Day 14 or the time when such 
conditions are no longer met. In the event of hospital discharge at this time, the 


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Investigator should carefully evaluate these parameters prior to hospital discharge.
Upon meeting this condition, the Hospital Discharge Visit is to be performed.
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis 
x
Interventions/Surgeries 
x
Major Bleeding Events
Blood will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and WBC 
with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
Additional labs will be drawn for analysis at the central lab:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, AST, 
Alkaline Phosphatase, and Total bilirubin)
x
D-dimer
x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
x
Anti-drug antibodies to ART-123
All subjects discharged from the hospital before Day 14 must return for Day 14 and Day 28 
visit procedures. Subjects discharged from the hospital after Day 14 but before Day 28 must 
return for Day 28 procedures.
All subjects must be contacted at 3, 6 and 12 months for survival status.


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5.15 Day 28 (+3 days) or End of Study Visit
For subjects who remain hospitalized, assessments will be performed on the 28th day using the 
first dosing day as Day 1. Subjects who were discharged must return to the hospital for this 
visit so safety assessments can be performed. For subjects who were discharged from the 
hospital prior to Day 28, there is a visit window of +3 days and the subject must return on Day 
28–31 for the completion of this visit. If a subject is unable or unwilling to return to the hospital 
for this visit, it may be conducted via telephone and any required assessments that cannot be 
done will be recorded as protocol deviations (i.e., laboratory draws). Telephone based 
assessments will document the date of the call, the name of the person initiating the call, the 
name and relationship to the subject of the person providing the information if the subject is 
unable to do so, and the survival status of the subject.  Additionally, the subject/person 
providing the information will be asked about any potential adverse events, significant 
bleeding inclusive of any major bleeding events, or re-hospitalizations that the subject may 
have had since their discharge date and any changes to medications they are taking.  
The End of Study Visit occurs whenever the subject discontinues study participation (as 
defined in Section 2.7.2.2) from the study prior to Day 28. 
Perform/record the following:
x
Changes in concomitant medications
x
Blood product administration
x
Adverse Events/Serious Adverse Events
x
Assessment of ICU stay and hospitalization
x
Complete the Organ Dysfunction (OD) assessments of Shock, Ventilator, Dialysis 
x
Interventions/Surgeries
x
Major Bleeding Events
Blood will be obtained for following local laboratory tests:
x
PaO2/FiO2 (only if vented and not collected as SOC)
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)


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Additional blood samples will be drawn for analysis at the central laboratory:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, 
AST, Alkaline Phosphatase and Total bilirubin)
x
Anti-drug antibodies to ART-123. Additionally, all subjects that develop anti-drug 
antibodies to ART-123 will be followed for blood draw and medical evaluation at 
3 months intervals until their serum antibody titer results become negative for a 
maximum duration of 18 months. Serum samples from subjects that have 
demonstrated the development of antidrug antibodies that are present on Day 28 
or End of Study Visit will be tested for the presence of neutralizing antibodies.
Note: Survival status for all subjects must be reflective of survival status on calendar Day 29.
5.16 Survival Status at Day 28 (+3 day) Visit
Please note that survival status must reflect subject status on or after the 29th calendar day,
which is 28 days after the administration of the first dose of the study drug. If subject has died, 
additional information required includes:

Date of Death

Cause of Death (including Death Certificate and autopsy results if available)
5.17 3 Month, 6 Month and 12 Month Follow-Up Visits  
Subjects will be contacted to obtain their survival status at 3 months (90 ± 3 Days), 6 months 
(180 ± 3 Days) and 12 months (360 ± 3 days) post the first dose of study drug.  This 
information can be obtained via telephone or in person.  All reasonable efforts must be made 
to obtain the actual survival status for the subject.  At a minimum, there must be 2 documented 
telephone calls to the subject’s last known telephone number and a certified letter sent to their 
last known address. If a subject cannot be located at 3 months, the same attempts must be made 
at 6 months and 12 months respectively.  Subjects will only be considered lost to follow up if 
they cannot be located at 12 months post study completion.
5.18 Follow-Up Visits for Subjects who have an anti-ART-123 antibody
Any subject with positive anti-ART-123 antibody results will return to the site at 3 month 
intervals for collection of a blood sample to be used for determination of presence or absence 


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of the antibody. Serum samples from subjects that have demonstrated the development of 
antidrug antibodies that are present on Day 28 or at the “End of Study” Visit will be tested for 
the presence of neutralizing antibodies.
This process will be continued every 3 months until antibody results are negative or until the 
subject’s 18 month Follow-Up Visit. Sites will be informed when subjects are antibody 
positive.
SAEs/thrombotic events information in these antibody positive subjects will be collected and
reported to the sponsor over a maximum of 18 months or subject becoming antibody negative, 
whichever is earlier.


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5.19 Schedule of Activities
Table 1:       Visit Schedule and Assessments
Assessment Period
Screen
-ing
Base-
line
Dosing
Post Treatment Follow-up
Long Term FU
VISIT
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
ETT/
LD24
V11
V12
V13
HD
V14
FU
3m
FU
6m
FU
12m
Study Day
0
13
23
Day 3 Pre
Day 3 Post3
43
53
63
76
ETT Last 
Dose 24 ± 2 
hrsb
8-131, 9
14
(+3d)1
15-279
Hospit-al
Discha-rge 
(HD) 12
28
(+3d)/
EOSa,8
3 m
(90±3 d)
6 m
(180±3 d)
12 m
(360±3 d)
Informed Consent
X
Inclusion/Exclusion Criteria
X
Pregnancy Test (serum/urine)
X
Platelet, WBC w/ diff and INR 
(LOCAL laboratory draw)
X
Verification of Eligibility (CCC)
X
Randomization 
X
Demographics, Height/Weight
X
Medical History and APACHE II
X
Vital Signs (Pulse, BP, 
Respirations, Temperature)
X
X
X
X
X
X
X
X
X
X
X
Record Con. Med. /Blood 
Product Admin.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Given for Current 
Episode of Sepsis
X
Documentation of Infection 
X
Physical Examination
X
12 Lead Central ECG9
X
X
Q5
Q5
X5
X5
X5
Q5
X5
X5
Assessment of AE/SAE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X10
X10
X10
ICU Stay and Hospitalization 
Assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Assessment Period
Screen
-ing
Base-
line
Dosing
Post Treatment Follow-up
Long Term FU
VISIT
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
ETT/
LD24
V11
V12
V13
HD
V14
FU
3m
FU
6m
FU
12m
Study Day
0
13
23
Day 3 Pre
Day 3 Post3
43
53
63
76
ETT Last 
Dose 24 ± 2 
hrsb
8-131, 9
14
(+3d)1
15-279
Hospit-al
Discha-rge 
(HD) 12
28
(+3d)/
EOSa,8
3 m
(90±3 d)
6 m
(180±3 d)
12 m
(360±3 d)
Organ Dysfunction Assessments 
(Shock, Ventilator, Dialysis)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LOCAL LABORATORY:
Organ Dysfunction 
Assessments,
total bilirubin & serum 
creatinine
X
Organ Dysfunction 
Assessments, PaO2/FiO2 if 
vented (use SOC laboratory, if 
available)
X
X7
X
X
X
X
X
X
X
X
X
X
X
X
CBC w/differential, Platelets, 
Coagulation (PT/INR)
X
X
X
X
X
X
X
X
X
X
CENTRAL LABORATORY
Serum Chemistry
X
X
X
X
X
X
X
X
X
X
D-dimer
X
X
X
X
X
X
X
X
X
Plasma PK, Exploratory Labs
X
X4
X
X
X
X
X
X
Arterial lactate
X
X
X
Anti-ART-123 Antibodies
X
X
X
X10
X10
X10
X10
Interventions / Surgeries
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Major Bleeding Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of the degree of 
burden and risk threshold, and 
assess continuation of treatment 
with ART-123/placebo
X
X
X
X
X
X
Dispense ART-123/Placebo2
X
X
X
X
X
X
Survival Status
X
X
X
X


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Table Footnotes:
a   EOS = End of Study – When a subject is discontinued from the study prior to Day 28 for any reason other than Death (i.e., withdrawal of consent as defined in Section 2.7.2). This 
does not include the subjects who discontinue study drug early, but remain in the study for all other assessments.
b  This visit is performed when a subject is discharged from the hospital on Study Days 1-6 or when a subject remains hospitalized and discontinues study drug administration prior to 
the 6th dose. The Early Treatment Termination Visit is performed 24 hours (± 2 hours) after the last dose of study medication if study drug administration was discontinued early or 
this window does not apply. This visit is done in place of the daily study visit.
1. If the subject is to be discharged from the hospital on Day 13 perform the Day 14 visit in place of Day 13 visit (Hospital Discharge visit is not performed). ONLY if subject has been 
discharged from the hospital is there a +3 day window for the subject to return for the Day 14 assessments and labs. Subjects who remain hospitalized for Day 14 must have the 
assessments performed on the 14th calendar day.
2. The first dose of study drug must be administered as soon as possible after randomization and within 4 hours. For post-surgical patients that had potentially hemorrhagic 
surgery the first dose of study drug must not be administered within 12 hours of major surgery. (See Section 2.6.3.) All dosing times are based on the first dose of drug. 
The windows are: Day 2: 24 hours (±2 hours), Day 3: 48 hours (±2 hours), Day 4: 72 (±2 hours), Day 5: 96 hours (±2 hours) and Day 6: 120 hours (±2 hours). If IP is held 
due to surgery refer to Section 3. Dosing is discontinued when a subject is discharged from the hospital. Administration of study drug is contraindicated if the co-administration of 
excluded concomitant medication (e.g. full heparinization, oral anticoagulant, anti-platelets drug) is required for subject treatment, or has an intolerable adverse event, such as 
bleeding events or conditions that place the subject at high risk of bleeding.
3. Assessments are made within one hour after IP administration on Dosing Days. If blood samples (central, local and Arterial Blood Gas if vented, and not performed as SOC) and
ECG are required these are to be completed within (1) hour AFTER study drug administration. 
4. Within one (1) hour PRIOR to study drug administration, blood samples will be collected.
5. “Q” ECGs If the QTcB is > 500 msec or the QTcB is >60 msec over the baseline value, the Investigator should evaluate the subject prior to hospital discharge. If the subject remains 
hospitalized, continue to monitor ECGs once daily until the earlier of Day 14 or the time when such conditions are no longer met. Use the QTcB from the ECG printout obtained 
during the study visit for these assessments.
6. On Day 7, assessments will begin 144 hours (± 2 hours) after the first dose (dosing Day 1) of study drug was administered.  If the subject is discharged on Day 7, complete the Day 7 
visit (not Hospital Discharge Visit).
7. On Day 1 record Arterial Blood Gas only if performed within one hour after IP administration.
8. The End of Study Visit occurs whenever the subject discontinues study participation (as defined in Section 2.7.2) prior to Day 28. ONLY if subject has been discharged is there a +3 
day window for the subject to return to the hospital for Day 28 assessments and labs. Subjects who remain hospitalized on Day 28 must have the assessments performed on the 28th 
calendar day. (Day 1 is the day of administration of the first dose of study drug.)  Survival Status is to reflect survival status on Day 29. If a subject is unable or unwilling to return to 
the hospital for this visit, information may be collected via telephone. Any required assessments that cannot be done will be recorded as protocol deviations (i.e., laboratory draws).
9. Beginning with Day 8 all prospective visits are based on calendar days. On study days 8-13 and 15-27, assessments are completed as long as the subject remains in the hospital.
10. Only subjects that develop anti-drug antibodies to ART-123 will be followed for blood draw and medical evaluation at 3 months intervals until their serum antibody titer results 
become negative for a maximum duration of 18 months. Subjects who return for testing will be queried for occurrence of any SAEs and clinical evidence of thrombosis.
11. 3 Month, 6 Month and 12 Month Follow up: Subjects will be contacted to obtain their survival status at 3 months (90+3 Days), 6 months (180+3 Days) and 12 months (360+3
days). If a subject cannot be located at 3 months, the same attempts must be made at 6 months and 12 months respectively.  Subjects will only be considered lost to follow up if they 
cannot be located at 12 months post study completion.
12. Hospital Discharge (HD) visit applies only to subjects who are discharged from the hospital on Study Day 8 onwards (except for subjects who are discharged on Days 13/14 or 
Day 28).


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6
EFFICACY ASSESSMENTS
Primary Efficacy Endpoint:
x
28 day all-cause mortality
Secondary Efficacy Endpoints:
x
Follow-up of all-cause mortality at 3 months
x
Resolution of organ dysfunction through Day 28 as measured by:
o
Shock free and alive days
o
Ventilator free and alive days
o
Dialysis free and alive days
Tertiary Efficacy Endpoints:
x
Follow-up of all-cause mortality at 6 and 12 months
x
Organ Dysfunction (Hepatic, Renal, Respiratory and Cardiac (Septic Shock) at Baseline, Day 
3, Day 7, Day 14 and Day 28; Hepatic Dysfunction and Renal Dysfunction will be assessed 
with central laboratory data (total bilirubin and serum creatinine, respectively)
x
ICU free and alive days through Day 28
x
Hospitalization free and alive days through Day 28
x
INR at Baseline, Day 3, Day 7, Day 14 and Day 28
7
SAFETY ASSESSMENTS AND REPORTING
7.1
Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment.  An 
AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product. A baseline event refers to medical history that is present prior to 
the last inclusion criteria being met and obtaining informed consent. Examples of adverse events 
include:
x
Increase in severity of a baseline event


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x
Clinically significant worsening of laboratory values post baseline (consolidate to a diagnosis if 
available)
x
A new event with an onset date post baseline
x
An event present at baseline where more aggressive treatment or an intervention/surgery is 
required post baseline (e.g. increase in total dosage per day, an invasive intervention such as chest 
tube insertion, debridement, etc.).
All local and systemic adverse events, whether volunteered by the subject, discovered by Investigator 
questioning, or detected through other means, will be collected and recorded on the Adverse Event 
form and followed as appropriate.
Once the patient is authorized to randomize SAEs will be collected through Day 28. Once 
randomization has occurred both AEs and SAEs are collected. The DAIDS Toxicity/Adverse Event 
Grading Table (Appendix I) will be used by the Investigators to grade the events in the Case Report 
Form. If Appendix I does not provide severity guidelines for certain events, please see Section 7.1.1
of the protocol.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology
by the data management group.
Medical conditions/diseases present before authorization to randomize are only considered AEs if 
they subsequently worsen in severity, require more aggressive treatment/intervention/surgery, or if 
they resolve then re-emerge. Whenever possible, a diagnosis will be used to describe the AE. If a 
diagnosis is not available, the event will be captured using signs and symptoms. Each sign or 
symptom is its own AE until a diagnosis that they can be collapsed under is known.
Clinically significant laboratory abnormalities (both from central or local laboratories), if not part of 
a diagnosis, are required to be captured as AEs.
As far as possible, each AE will also be described by:  
x
The duration (start and end dates)
x
The severity grade (Grade 1/mild, Grade 2/moderate, Grade 3/severe, Grade 4/Potentially life 
threatening as defined by the DAIDS Toxicity Table)
x
The relationship to the study drug (none, unlikely, related)
x
Whether the AE involved bleeding of any kind
x
The action(s) taken 
x
The outcome


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Major Bleeding Events
A Major Bleeding event is defined as:
x
any intracranial hemorrhage,
x
any life-threatening bleeding, 
x
any bleeding event classified as serious by the Investigator (e.g., resulting in permanent 
morbidity), 
x
the administration of at least 1440 mL (typically 6 units) of packed red cells over two consecutive 
days.6
Note: Should a major bleeding event occur, study product must be discontinued.
All major bleeding events must be collected, documented, and promptly reported as SAEs.
Blood product administration will be recorded in the eCRF.
7.1.1
Severity of Adverse Events
The Investigator is to classify the severity of an AE using the DAIDS Toxicity Table provided in 
Appendix I. If the toxicity table does not provide severity guidelines for certain events, the following 
definitions will be used:
Table 2: Guidelines for Grading AE Severity
Severity
Characteristic
Mild:
Symptoms causing no or minimal interference with usual social & 
functional activities
Moderate:
Symptoms causing greater than minimal interference with usual social & 
functional activities
Severe:
Symptoms causing inability to perform usual social & functional activities
Potentially Life-
Threatening
Symptoms causing inability to perform basic self-care functions OR 
Medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity
whereas seriousness is defined by the criteria in Section 7.2. An AE of severe intensity need not


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necessarily be considered serious. For example, nausea that persists for several hours may be
considered severe nausea, but not an SAE. On the other hand, a stroke that results in only a limited
degree of disability may be considered a mild stroke but would be an SAE.
If an adverse event changes in severity, the worst severity of the AE should be recorded. Should the 
AE become serious, the AE record will note an end date and a new entry for the SAE should be 
recorded with an onset date equal to the date the event met seriousness criteria.
7.1.2
Relationship of AE to Study Drug
The following table should be used as a guideline for assigning the relationship of the adverse event 
to the study drug. 
Table 3:  Guidelines for Grading Relationship of AE to Study Drug
Association
Definition
None (not related):
(1) The existence of a clear alternative explanation (e.g., mechanical 
bleeding at surgical site) or (2) non-plausibility, e.g., the subject is struck 
by an automobile or cancer developing a few days after drug 
administration.
Unlikely (remote):
A clinical event, including laboratory test abnormality (if applicable), 
with an improbable time sequence to drug administration and in which 
other drugs, chemicals, or underlying disease provide plausible 
explanations. 
Related:
A clinical event, including laboratory test abnormality (if applicable), 
occurring in a reasonable time relationship to drug administration and 
which cannot be explained by concurrent disease or other drugs or 
chemicals.  The response to withdrawal of the drug should be clinically 
plausible.
Adverse events judged as “Unlikely” or “Related” will be defined as “Adverse Drug Reaction”.
7.2
Serious Adverse Events
Information about all serious adverse events (SAEs) must be collected and recorded on the SAE 
Report form and faxed or emailed to the sponsor within 24 hours of learning of its occurrence. 


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If follow-up indicates a change in the SAE from serious to fatal or life-threatening, this information
needs to be reported within 24 hours. If a non-serious AE becomes serious, this and other relevant
follow-up information must also be reported within 24 hours as described above.
(Safety reporting contact information is provided in Appendix A). The site is to follow their local 
regulations related to the reporting of SAEs to their local IRB/REB/IEC.  An SAE is any undesirable 
sign, symptom, or medical condition which:
x
Is fatal or life-threatening (i.e., an event with an outcome of ‘Death’), or
x
Requires or prolongs inpatient hospitalization, or
x
Results in persistent or significant disability/incapacity, or
x
Constitutes a congenital anomaly or a birth defect; or
x
Is medically significant, as determined by a qualified health professional, may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the outcomes listed 
above
x
Major Bleeding Events must be reported as SAEs (See Section 7.1)
x
Any adverse event causing a need for unblinding must be reported as a serious adverse event
Events not considered to be SAEs are: 
x
Hospitalizations for treatment which is elective or pre-planned, for a pre-existing condition that 
did not worsen; or
x
Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
serious given above and not resulting in hospital admission.
All on-study deaths, including new fatal adverse events or adverse events that worsen post-
baseline resulting in death, must be reported as the outcome of an associated SAE. If the cause 
of death is not immediately known the event may be reported initially as “Death”, with the actual 
diagnostic event term provided as follow-up as soon as it is determined.
Pregnancies are not considered SAEs unless complications result which meet serious criteria.  
Pregnancy, although not in itself an SAE, must also be reported to the Sponsor within 24 hours of 
becoming aware on the Pregnancy Report Form, using the contact information provided in 
Appendix A. Pregnancies will be followed to term in order to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth defects 
or congenital abnormalities. 


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All SAEs which occur after the subject has been authorized for randomization will be reported. SAEs 
are collected through Day 28 and followed until resolution or final outcome. AEs will be collected 
after authorization for randomization through Day 28, for those subjects that are randomized.
Any subject with positive anti-ART-123 antibody results will have SAEs/thrombotic events captured 
beyond Day 28 until antibody results are negative or until the subject’s 18 month Follow-Up Visit.
Clinical evidence of thrombosis may include deep vein thrombosis (DVT), pulmonary embolism, 
post-thrombotic syndrome, superficial thrombophlebitis, stroke, and myocardial infarction. 
Sites will be informed when subjects are antibody positive, after which SAEs and thrombotic events 
occurring after Day 28 be collected and reported.
7.3
Expected Adverse Events
Expected Adverse Events are those that are consistent with the current version of the Investigator 
Brochure, including specificity or severity.
7.4
Expedited Reporting
All serious adverse events meeting the definition of reportable will be forwarded to the proper 
governing regulatory authority within the mandated timelines set forth by that agency.  
Once the safety report has been generated and forwarded to the proper agency, a letter will be written 
and forwarded to the study Investigators.  The Investigators will be instructed to submit this 
notification to their IRB/REB/IEC as soon as possible according to their local requirements. 
7.5 Assessment of Risk Burden
In acknowledgement of the need to provide added oversight for vulnerable populations, monitoring 
for the degree of burden and risk, and assessment of the appropriateness of continuation of treatment 
with ART-123/placebo during the dosing period of Days 1-6 will be performed. Since the sepsis 
subjects enrolled to this study have critically ill conditions at the entry, definitive thresholds based on 
laboratory assessments or physical examination cannot be defined, and the risk and burden for a 
subject should be monitored by referring to all the assessments and examinations required for this 
protocol as well as performed as a standard of care. Additionally, because of the inherent risk of 
bleeding with compounds such as ART-123, in addition to the assessments called for in the protocol 
(Sections 5.6 - 5.10) study drug must be discontinued in instances where a major bleeding event 


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(defined in Section 7.1) is observed. Additional conditions where study drug must be discontinued 
are detailed in protocol Section 2.7.1.
7.6 Clinical Laboratory Evaluations
For this study, there will be both Local and Central laboratory blood draw requirements.  The list 
below outlines which study specific laboratory blood draws are for central laboratory draws (using 
the provided central laboratory kit) and which are for local laboratory draws (using hospital stock 
supplies).  
To avoid contamination or clotting, all coagulation tests taken for the purposes of this study should 
be obtained from an original arterial stick or venipuncture. If it is not possible to obtain blood from 
an original stick or venipuncture, blood may be collected from an arterial line in which no Heparin is 
infused. The arterial line will be flushed with NS both prior to and after the blood draw. No 
coagulation samples can be obtained from a Heparin infused or Heparin coated central line. Heparin 
must not be used when flushing an arterial line for this purpose. The site staff should use proper 
collection technique as described in the Central Laboratory Manual.  If an original arterial stick or 
venipuncture is then used to avoid clotting, the coagulation test tubes should not be the first 
tube of blood filled. Any other blood tests unable to be obtained from the original arterial stick 
or venipuncture may be taken from an existing port or line. If a central line is used, exploratory 
laboratory tests should be the last samples to be collected.
7.6.1
Central Laboratory Tests:
The following laboratory assessments will be collected and sent to the central laboratory for analysis:
x
Serum Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, ALT, AST, 
Alkaline Phosphatase and Total bilirubin)
x
Arterial lactate concentration 
x
D-dimer
x
Anti-drug Antibodies to ART-123
x
Plasma thrombomodulin concentration (PK)
x
Exploratory Laboratory Tests 
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a


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7.6.2
Local Laboratory Tests:
The following laboratory assessments will be collected for analysis at the local laboratory:
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and 
WBC with differential count)
x
Serum Chemistry (Creatinine, Total bilirubin at Baseline Visit only; albumin and 
total bilirubin if not performed as SOC and necessary to calculate Child-Pugh in 
patients with severe liver disease at Screening)
x
Pregnancy test; Serum or Urine human chorionic gonadotropin (hCG)
x
Platelet count
x
Coagulation Panel (Prothrombin time and INR)
7.6.3
Laboratory Sample Categories
There are four types of clinical laboratory evaluations: Safety, Coagulation Panel, Organ 
Dysfunction, and Exploratory. 
Safety laboratory tests include the following:
x
Serum Chemistry: Chemistry (Na, K, Cl, Bicarbonate, Glucose, Ca, BUN, Creatinine, 
ALT, AST, Alkaline Phosphatase, Total bilirubin) 
x
Complete Blood Count with differential (RBC, Hemoglobin, Hematocrit, and WBC with 
differential count)
x
Pregnancy test: Serum or Urine hCG
x
Platelet count
x
Antibodies to ART-123.
Note: All subjects that develop positive antibodies to ART-123 at Day 28 will be followed at 3 month 
intervals until their serum antibody titer level returns back to baseline or for a maximum of 18 months. 
Coagulation Panel includes the following tests: 
x
Prothrombin time 


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x
INR
x
D-dimer
Organ Dysfunction labs include the following tests:
x
Serum creatinine
x
Total bilirubin
x
PaO2/FiO2 ratio
Exploratory labs include the following tests:
x
Coagulation: functional protein C, TAT, F1.2, PAI-1 and ATIII
x
Inflammation: CRP, Microparticles, and C5a
x
Plasma thrombomodulin concentration (PK)
x
Arterial lactate concentration
7.7 Physical Examination
Physical examination is performed at the Baseline Visit. The physical will include general 
appearance; HEENT; neck; respiratory; cardiovascular; chest; abdomen; lymphatic; musculoskeletal 
and extremities; skin; and neurologic examination. Routine physical examinations will not be 
recorded after baseline. Any findings on the baseline physical, that are not attributable to a medical 
condition present prior to obtaining informed consent and meeting the last inclusion criteria, are to 
be captured either under a medical diagnosis on the Adverse Event eCRF or as a sign or symptom on 
the Adverse Event eCRF if not part of an diagnosis. All changes in physical examination from the 
time the subject met the last inclusion criteria and signed informed consent must be documented and 
recorded as an adverse event (either under a medical diagnosis or as a sign or symptom if not part of 
a diagnosis) in the eCRF.
7.7.1
Vital Signs
Vital signs include: 
x
Blood Pressure
x
Respiratory rate 
x
Heart rate


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x
Temperature
7.8
Electrocardiogram (ECG)
A 12-lead ECG will be performed as outlined in the “Visit Schedule and Assessments” (beginning 
with Section 5) and the table outlining the “Schedule of Events” (Section 5.19).  Subject’s ECGs will 
be read centrally and the final read/interpretation of the ECG will be forwarded to the sites for filing 
in subject source records and documentation in subject’s eCRF. Clinically significant changes in the 
ECG findings vs. baseline will be evaluated by the Principal Investigator and recorded as AEs / SAEs 
as applicable. 
8
PROTOCOL AMENDMENTS
8.1
Protocol Amendments
Sponsor retains the responsibility for any protocol amendments. Any change or addition to this 
protocol requires a written protocol amendment that must be approved by the Regulatory Authorities
and the IRB/IEC, as applicable, before implementation.  
9
DATA MANAGEMENT 
9.1
Documentation
Electronic Case Report Forms (eCRFs) will identify each subject by subject number (compilation of 
site number and subject number) and subject's initials (per local regulatory guidelines). Originals or 
copies of all source documents, and correspondence will be kept on file at the investigational site. 
The data required by the protocol will be recorded in the appropriate eCRFs. All source data will be 
available to the study monitor who may perform a 100% data check (comparison of the data recorded 
in the eCRF with those in the source documents).  The source data will also be available for an audit 
by the Sponsor or the FDA (Food and Drug Administration) and all applicable regulatory agencies at 
any time.


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9.2
Data Collection
In addition to the eCRFs, individual subject files or subject medical records as well as Sponsor 
approved source data information will be maintained. Data will be entered into eCRFs. The eCRFs 
will be kept current, so that they reflect the latest observations on the subjects enrolled in the study. 
The eCRFs will include an audit trail to include changes made, reason for change, date of change, 
and person making changes. 
The original signed informed consent form will be available for review at each study visit. All records 
will be kept in conformance to applicable national laws and regulations.
Analytical data from the central laboratory will be received in an electronic data file format for 
incorporation into the study database.
9.3
Database Management 
When the subject specific database information has been declared to be complete and accurate the 
database will be locked. Any changes to the database after that time can only be made with written 
agreement of the Sponsor. 
10
STATISTICAL CONSIDERATIONS 
P-values will be reported as 2-sided p-values with the decision criteria discussed in Section 10.1.1
evaluated using these values.  Confidence intervals will be generally reported using traditional 95% 
two-sided intervals.  The primary analysis for this study will be conducted on the data up through 
Day 28.  Long-term survival status data will be analyzed once it becomes available following the 
analysis of the data through Day 28.  
Randomization will utilize permuted blocks with a 1 to 1 ratio and will be stratified by site.
10.1
Sample Size and Power Considerations
The primary analysis for this study will be based on a stratified Cochran-Mantel-Haenszel test. For 
sample size and power calculations an unstratified Cochran-Mantel-Haenszel (chi-squared) test has 
been used.  A sample size of 800 subjects provides 80% power if the following assumptions are made:
1. 5% two-sided Į level


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2. 8% treatment effect (24% placebo mortality rate vs. 16% ART-123 mortality rate)
3. 1 to 1 randomization 
The assumed treatment effect and mortality rates are based upon post-hoc results from study 2-001 
and assume the Day 28 mortality status will be known for all subjects.  
If the true treatment effect is 12% (24% vs. 12%) a sample size of 800 provides greater than 80% 
power when a 0.1% alpha level is used.
These sample size and power calculations were performed with Pass 2007.
10.1.1 Decision Guidelines
The primary analysis of this Phase 3 trial is formally based on a two-category decision guideline.  To 
be specific, the decision guideline for this trial is based on whether the observed two-sided p-value 
associated with comparison of the 28-day survival for the ART-123 arm vs. the placebo arm is, 
between 0.05 and 0.001 or less than 0.001.
1.
If the two-sided p-value is between 5% and 0.1% then the ART-123-based regimen will have met 
the generally accepted level of evidence (false positive error rate) required to demonstrate 
efficacy.
2.
If the two-sided p-value is less than 0.1% and supporting analyses corroborate this finding ART-
123-based regimen will have provided highly reliable and statistically strong mortality results in 
a disease with limited treatment options.  A second confirmatory study would then not be required. 
In this 800 subject study an observed treatment benefit of approximately 6% is expected to result in 
a two-sided p-value less than 5% and a difference of approximately 9% is expected to result in a two-
sided p-value less than 0.1%. A sample size of 800 subjects and these assumptions also provide 32% 
power for a 0.1% two-sided Įlevel.
10.2
Analysis Populations
The primary efficacy analysis population will be the Full Analysis Set, FAS. The Full Analysis Set 
will consist of all randomized subjects who receive study drug and will be used for efficacy
analyses. The Safety population will consist of all subjects who receive drug and will be used for 
safety analyses.


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10.3
Study Stopping Rules / Interim Analyses
The Data Monitoring Committee (DMC) will use the following stopping rules regarding stopping the 
study early for safety, efficacy or futility.
10.3.1
Stopping for Safety
Termination or modification of the study due to safety concerns will not be limited to a fixed set of 
analyses. The DMC will be provided with unblinded safety data, including unblinded SAE reports,
prior to scheduled data review meetings or upon request.
10.3.2
Stopping for Efficacy
Early termination of the study for efficacy will not be actively pursued unless it would be unethical 
to continue the study based upon the magnitude of benefit observed.  In this situation should the 
primary efficacy results surpass an O’Brien-Fleming type
boundary with Lan-DeMets 
implementation based upon a two-sided alpha level of 0.001 and the DMC believes the study results 
are extremely robust and so positive it is unethical to continue the study they may recommend 
termination for efficacy.  
10.3.3
Stopping Due to Lack of Clinically Meaningful Benefit/Futility
An analysis to rule out clinically meaningful benefit will also be performed. The goal of these 
analyses is to stop the study if sufficient evidence exists that there is not a clinically meaningful 
treatment benefit. The futility analyses will be conducted with the use of a lower O’Brien-Fleming 
type boundary.  This boundary will be constructed using a one-sided alpha level of 0.20 and the 
hypothesis: the 28-day mortality rate on ART-123 is reduced by 6%. Should interim analyses be 
performed after the 600 subjects time-point (75% information) the DMC will interpret the results of 
the futility calculations in context of the remaining enrollment.
10.4
Handling of Missing Data
Missing data will not be imputed for summarization; summary statistics will be reported based upon 
observed data.  
Exception: for testing of the primary endpoint, Day 28 mortality status, subjects with unknown 
mortality status will be imputed.  Investigators will be asked to assess if at the last point they had 


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contact with the subject, the subject’s health was such that it was unlikely they would be alive at Day 
28.   If so, it will be assumed the subject was dead at Day 28 otherwise they will be classified as alive 
for the primary analysis.
10.5
Efficacy Analysis
10.5.1 Primary Analysis
The primary analysis will test the difference in the 28-day all-cause mortality rates between treatment 
groups in the Full Analysis Set. This analysis will be based upon a Cochran-Mantel-Haenszel test 
controlling for the randomization strata, site.  Sites with low enrollment will be pooled.  Subjects with 
missing mortality status at Day 28 will have their mortality status imputed as outlined in Section
10.4.  To investigate the degree of variance reduction resulting from the stratification an unstratified 
test (chi-squared test) of the primary endpoint will be conducted. 
Summary measures of survival status at the end of treatment and Day 14 will also be produced. 
10.5.2 Secondary Analyses
Descriptive statistics will be used to summarize secondary endpoints.  The difference in alive and 
event free days will be tested using a stratified Wilcoxon test (van Elteren test).  Survival time will 
be summarized using Kaplan Meier methods and tested with a stratified log rank test. 
10.6
Safety Analysis
10.6.1 Extent of Exposure
Duration of treatment and amount of drug received will be summarized.
10.6.2 Concomitant Medications
Concomitant medications will be coded by the World Health Organization (WHO) Drug Dictionary 
and tabulated by treatment group. Medication taken prior to treatment will be summarized separately.


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10.6.3 Adverse Events
The incidence of adverse events (AEs), treatment-related AEs, AEs leading to discontinuation, 
serious adverse events (SAEs), fatal adverse events and AEs by severity will be tabulated by treatment 
received.  These AEs will be classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA).  For incidence reporting, if a subject reported more 
than one AE that was coded to the same system organ class or preferred term, the subject will be 
counted only once for that specific system organ class or preferred term. Once the patient is authorized 
to randomize, SAEs will be collected through Day 28. Once randomization has occurred both AEs 
and SAEs are collected.
10.6.4 Major Bleeding Events
The number of subjects with major bleeds, as defined in Appendix B, will be compared between 
treatment arms, as will the numbers of subjects with serious major bleeding events. The number of 
major bleeding events will be compared between groups at Days 3, 7, 14 and overall.
10.6.5 Clinical Laboratory Results
Summary statistics for actual values and for changes from baseline will be tabulated for laboratory 
results by scheduled visit.  Subjects with clinical laboratory values outside of the normal reference 
range will be summarized.  
10.6.6 Vital Signs and ECG
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics. 
11 PROCEDURES AND INSTRUCTIONS
11.1
Safety-Related Procedures 
11.1.1 Reporting Responsibility
Serious adverse events will be reported immediately, not more than 24 hours after the investigative 
personnel first become aware of the event (see Appendix A for contact information). 
The Investigator will report each SAE to the Sponsor within 24 hours of learning of its occurrence, 
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will also be reported to the Sponsor within 48 hours.  The site is to follow their local regulations 
related to the reporting of SAEs to their local IRB/REB/IEC.
11.1.2 Reporting Procedures
The Investigator must complete the SAE report form in English, assess the relationship to study 
treatment, and send the completed form by fax or email to the Sponsor.  Follow-up information should 
be submitted in the same manner as the original SAE form. The form and fax confirmation sheet or 
email will be retained in the site’s investigator binder. Safety contact information has been provided 
in Appendix A of this protocol.  
12 ADMINISTRATIVE PROCEDURES
12.1
Monitoring Procedures 
During the study, the Sponsor or their designee will visit the site regularly to check the completeness 
of subject records, the accuracy of entries on the eCRFs, the adherence to the protocol and to FDA 
regulations, ICH-GCP guidelines, and any local regulatory authority, the progress of enrollment, and 
also to ensure that study product is being stored, dispensed and accounted for according to 
specifications and applicable regulations.  Key trial personnel will be available to assist the field 
monitor during these visits.
The Investigator will give the monitor access to all relevant clinical records, to confirm their 
consistency with the eCRF entries.  No information in these records about the identity of the subjects 
will leave the study center.  Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
12.2
Recording of Data and Retention of Documents
The Investigator must complete the eCRFs and transmit the data, as instructed by the Sponsor and or 
designee.  All entries to the eCRFs must be made as instructed by appropriate study personnel prior 
to each monitoring visit.
During the study, data collected on eCRFs about the subjects will be documented in an anonymous 
fashion and the subject will only be identified by the subject number and by his/her initials (per local 
regulatory guidelines).  If, as an exception, it is necessary for safety or regulatory reasons to identify 
the subject, both the Sponsor and the Investigator are bound to keep this information confidential. 


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The Investigator must maintain any applicable source documents for each subject in the study, 
consisting of all demographic and medical information, and the signed informed consent form.  
The Investigator will retain study related documents for as long as needed to comply with national 
and international regulations. The Sponsor will notify the Investigator(s)/institution(s) when the 
study-related records are no longer required. 
12.3
Study Organization
12.3.1 Data Monitoring Committee
The Data Monitoring Committee (DMC) is responsible for the unblinded review of all Serious 
Adverse Events and overall safety data. The DMC will meet according to an agreed-upon schedule 
as detailed in the DMC Charter.
The DMC will consist of 3 members, one of whom shall be a biostatistician and the other two clinical 
experts. No DMC member may participate in the study. Unblinded reports to the DMC will be 
prepared by an unblinded independent statistician who will not participate in any study analysis.
Blinded presentations concerning study status will be made by Asahi Kasei Pharma America 
Corporation’s medical representative or designee.
12.3.2 Publication of Results  
Any formal presentation or publication of data from this study will require prior approval by the 
Sponsor, and may be considered as a joint publication by the Investigators and the Sponsor.  Primary 
authorship may be determined by the Sponsor.
Publication of subsets of data will be subject to review by the Sponsor. All data remain the property 
of the Sponsor, except, of course, copies maintained at each site in compliance with ICH GCP and 
other regulations. 
13 ETHICS AND GOOD CLINICAL PRACTICE
This study will be carried out in compliance with the protocol and in accordance with all applicable 
standard operating procedures (SOPs).  These will be designed to ensure adherence to GCP, as 
described in: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.  


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Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community.
US 21 Code of Federal Regulations (CFR) (312) dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations).
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it, and thereby to adhere to the principles of GCP to which it conforms.
13.1
Institutional Review Board/Research Ethics Board/ Independent Ethics 
Committee
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects will be reviewed by a properly constituted IRB/REB/IEC.  A signed and dated 
statement that the protocol and informed consent have been approved by the IRB/REB/IEC will be 
given to the Sponsor before study initiation.  The name and occupation of the chairman and the 
members of the IRB/REB/IEC will be supplied to the Sponsor.  This committee will approve any 
amendments to the protocol, other than administrative changes.
13.2
Informed Consent
Fully informed consent will be obtained before any study specific procedures are performed.  The 
content and process of obtaining informed consent must be in accordance with all applicable ethical 
and regulatory requirements.
It is anticipated, by the very nature of the study that many subjects who will be eligible for this 
protocol will not be able to give fully informed consent themselves due to various reasons including 
sedation, unconscious state, etc.  Therefore, in a situation where a subject is unable to provide consent 
for him/herself, informed consent will be obtained by using one of the following possible options, 
which must comply with an individual country’s local laws and ethics committees regulating the 
enrollment of incapacitated adults into clinical trials.
This process must be expedited to ensure that securing an authorized representative’s consent does 
not lead to delays that may result in increased risk to the subject.  Furthermore, at no time will medical 
treatment be delayed to secure authorized informed consent for study participation.
Therefore, the following will be applied as long as your local laws allow:
x
Consent from a LAR/AR / next of kin / legally appointed individual in person;


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x
Verbal consent from a LAR / AR / next of kin / legally appointed individual via telephone, 
confirmed by signed consent form sent by fax or email (at least 2 people from the study 
site are required, one to administer the informed consent and the second as a witness);
x
Consent from a judge or specifically appointed lawyer for this purpose– if required by 
local regulations;
x
In extreme and urgent circumstances when emergent action is required to mitigate the risk 
of death, it is understood that the presumed will of the subject will be determined by a 
physician and documented based on his/her knowledge of the study subject. As 
appropriate, an independent physician, who is a qualified medical doctor with at least one 
year’s experience in intensive care medicine but must be from another department and/or 
hospital than the investigator, may sign the informed consent for the subject if the local 
laws, regulations and ethics committees approve this process. In countries where 
permissible, this independent physician may be from the same department. The study 
subject must be presented with the informed consent as soon as it is possible and 
reasonable, and informed consent obtained for continued study participation.
The 
AR/LAR may act as an agent on the subject’s behalf once they are available to provide 
informed consent. 
When consent is obtained by fax via a LAR / AR / next of kin / authorized individual, an original 
signature must be obtained at the earliest opportunity.
Subjects enrolled in the study on the basis of consent by a LAR / AR / next of kin / legally appointed 
individual  / independent physician will be given the opportunity to provide written confirmatory 
consent when and if they become able to do so.  If the subject declines to confirm consent, they will 
be withdrawn from the study at the point where they decline consent.
In addition, where local regulatory and/or ethics committees allow, advance consent may be obtained 
prior to study entry in an attempt to obtain personal consent from the subject themselves. 
Should a subject who is enrolled in the study on the basis of advance consent subsequently become
unable to make medical decisions for him/herself, then the subject's legally acceptable next of kin / 
LAR should be informed of the subject's participation in the trial.
The above guidelines apply to all areas of the protocol where Informed Consent is referenced or 
required.


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14 REFERENCES
1.
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines 
for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference 
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1992;101:1644-55.
2.
Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International 
Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6.
3.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International 
guidelines for management of severe sepsis and septic shock,2012. Crit Care Med 
2013;41(2):580-637.
4.
Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient. High-dose antithrombin 
III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-78.
5.
Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue 
factor pathway inhibitor) in severe sepsis: a randomized controlled trial. Jama 2003;290:238-
47.
6.
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human 
activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
7.
ARDSNet. Ventilation with lower tidal volumes as compared with traditional tidal volumes
for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory 
Distress Syndrome Network. N Engl J Med 2000;342:1301-8.
8.
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe 
sepsis and septic shock. N Engl J Med 2001;345:1368-77.
9.
Corrigan JJ, Jr., Ray WL, May N. Changes in the blood coagulation system associated with 
septicemia. N Engl J Med 1968;279:851-6.
10.
Rice TW, Wheeler AP. Coagulopathy in critically ill patients: part 1: platelet disorders. Chest 
2009;136:1622-30.
11.
Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586-
92.
12.
Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation 
system. Cardiovasc Res 2003;60:26-39.


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13.
Esmon C. Do-all receptor takes on coagulation, inflammation. Nature medicine 2005;11:475-
7.
14.
Esmon CT, Fukudome K, Mather T, et al. Inflammation, sepsis, and coagulation. 
Haematologica 1999;84:254-9.
15.
Polderman KH, Girbes AR. Drug intervention trials in sepsis: divergent results. Lancet 
2004;363:1721-3.
16.
Kienast J, Juers M, Wiedermann CJ, et al. Treatment effects of high-dose antithrombin 
without concomitant heparin in patients with severe sepsis with or without disseminated 
intravascular coagulation. J Thromb Haemost 2006;4:90-7.
17.
Esmon CT. New mechanisms for vascular control of inflammation mediated by natural 
anticoagulant proteins. J Exp Med 2002; 196(5):561-564.
18.
Nagato M, Okamoto K, abe Y, Higure A, Yamaguchi K. Recombinant human soluble 
thrombomodulin decreases the plasma high mobility group box-1 protein levels, whereas 
improving the acute liver injury and survival rates in experimental endotoxemia. Crit Care 
Med 2009; 37(7):2181-2186.
19.
Faust SN, Heyderman RS, Levin M. Coagulation in severe sepsis: a central role for 
thrombomodulin and activated protein C. Crit Care Med 2001;29:S62-7; discussion S7-8.
20.
Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA scores to 
predict outcome in critically ill patients. Jama 2001;286:1754-8.
21.
Lawrence KR, Klee JA. Rifaximin for the Treatment of Hepatic Encephalopathy. 
Pharmacotherapy 2008; 28(8): 1019-1032.
22.
Bernard GR, Wheeler AP, Arons MM, et. al. A trial of antioxidants N-acetylcysteine and 
procysteine in ARDS. The antioxidant in ARDS study group. Chest 1997; 112: 164-172.
23.
Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of disseminated 
intravascular coagulation diagnostic criteria for critically ill patients: Comparing current 
criteria. Crit Care Med 2006; 34(3): 625-631.
24.
Gando S, Saitoh D, Ogura Y, et al. A multicenter, prospective validation study of the Japanese 
Association for Acute Medicine disseminated intravascular coagulation scoring system in 
patients with severe sepsis. Critical Care 2013: 17(R111).
25.
Moreau D, Timsit JF, Vesin A et al. Platelet count decline: An early prognostic marker in 
critically ill patients with prolonged ICU stays. Chest 2007; 131(6): 1735-1741.


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Greinacher A, Selleng Kathleen. Thrombocytopenia in the intensive care unit patient. 
Hematology Am Soc Hematol Educ Program 2010; 2010; 135-143.
27.
Kinasewitz, G, Zein J, Lee G, et al. Prognostic value of a simple evolving disseminated 
intravascular coagulation score in patients with severe sepsis. Crit Care Med 2005; 33(10): 
2214-2221.
28.
Strauss R, Wehler M, Mehler K, et al. Thrombocytopenia in patients in the medical intensive 
care unit: Bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 2002; 
30 (8): 1765-1771.
29.
Knaus W, Draper E, Wagner D, Zimmerman J. APACHE II: a severity of disease 
classification system. Critical Care Medicine 1985; 13(10): 818–29.
30.
Teasdale G, Murray G, Parker L, Jennett B. Adding up the Glasgow coma score. Acta 
Neurochir 1979; 28(suppl):13-16.
31.
Severinghaus, J. Simple, accurate equations for human blood O2 dissociation computations. J 
Appl Physiol: Respirat Environ Exercise Physiol. 46(3):599-602, 1979. revisions, 1999, 2002, 
2007.


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15 APPENDICES
15.1
Appendix A: Serious Adverse Events
All Serious Adverse Events as defined in the Serious Adverse Event section of this protocol will be 
reported to the Safety and Pharmacovigilance Department using the contact information provided 
below. The logistical aspects will be defined in the study specific safety plan.
Fax: North America: 781-419-5028
Other Countries: Refer to study –specific regional fax number lists
Email: SAE@om.asahi-kasei.com


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15.2
Appendix B: Key Study Definitions
Major Bleeding Events
A Major Bleeding event is defined as any intracranial hemorrhage, any life-threatening bleeding, 
any bleeding event classified as serious by the Investigator (e.g., resulting in permanent 
morbidity), or any bleeding that required the administration of at least 1440 mL (typically 6 units) 
of packed red cells over two consecutive days.6
All major bleeding events must be collected, documented, and promptly reported as SAEs.
Appropriateness of Initial Antibiotic Therapy
The Investigator will review all culture data from the time of infection onset to determine whether 
there is a definite identification of a causal organism (i.e., culture from a normally sterile site such 
as blood or pleural fluid), a likely identification of a causal organism (i.e., culture of suspected 
pathogen from another site with additional support [e.g., sputum culture where the sputum had 
< 10 epithelial cells and > 25 WBC per field]), or no causative organism identified. The 
Investigator will also review initial antibiotic therapy and organism MIC data, to determine 
whether it was appropriate for the known or suspected causative organism. Such review may 
include calculations of AUC/MIC relationships based on doses and anticipated clearances.
Mechanical Ventilation
Mechanical ventilation is described for the purposes of this protocol as any kind of ventilation 
administered via an endotracheal tube or nasotracheal intubation. This applies to all modes of 
ventilation (VA, VC and PC). Pressure Support Ventilation (PSV) is permissible. Simple 
administration of supplemental oxygen is NOT considered to be mechanical ventilation.


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15.3
Appendix C: Definitions of Infection in the ICU
Clinical objective evidence of bacterial infection and being treated with antimicrobial medication(s):
The evidence of bacterial infection would include but not be limited to the following:
x
Physical examination findings (i.e., cellulitis or abscesses)
x
Positive culture(s) from normally sterile areas**
x
Gram stain or other fluid/ tissue preparations (i.e., Direct Fluorescent Antibody, Nucleic Acid 
probes)
x
Antigen detection in urine (i.e., Legionella, Streptococcus pneumoniae)
x
Radiographic studies
x
Surgical pathology specimens
** Note: A positive culture is not required 
Infection is a pathological process caused by invasion of a host tissue or a normally sterile fluid or 
body cavity by pathogenic or potentially pathogenic bacteria that produce disease by multiplication, 
local tissue injury, and immune response/inhibition or toxin production.  
Examples of compelling clinical objective evidence of bacterial infection (temperature and/or WBC may 
be required) include: 
x
Radiographic evidence of pneumonia associated with production of purulent sputum and a positive 
Gram stain or urinary antigen
x
Radiographic evidence of perforated abdominal viscus (i.e., air under the diaphragm), except in cases 
of chemical peritonitis
x
Presence of white blood cells in a normally sterile body fluid (e.g., cerebrospinal fluid or CSF)
Examples of cases lacking compelling clinical objective evidence of bacterial infection (temperature and 
WBC may be required):
x
Bilateral basilar infiltrates without productive sputum and confirmation of bacterial infection with 
Gram stain, or urinary antigen
x
Urine sample with some bacteria and no WBC
x
Urine sample with a positive leukoesterase test or only a few WBC and no bacteria
x
Abdominal tenderness accompanied by peritoneal signs in the absence of other objective evidence 
(ultrasound, CT, or surgical findings)


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15.4
Appendix D: Organ Dysfunction Scale 22
The following organ dysfunction/failure assessment is based on the ARDSnet organ dysfunction
scale. The subject will be assessed, using this scale, daily from Baseline through Day 28. If the subject 
is discharged from the hospital, no further daily assessments are required after hospital discharge 
except on Day 14 and Day 28.
The presence of organ dysfunction will be determined based on laboratory or clinical parameters, as 
follows:
1. Hepatic: Any day with a bilirubin greater than or equal to 2.0 mg/dL will be counted as a 
hepatic insufficiency day, consistent with the ARDSnet criteria and a Sequential Organ 
Failure Assessment (SOFA) score greater than or equal to 2.7,20
2. Renal: Any day with a creatinine greater than or equal to 2.0 mg/dL is counted as a renal 
dysfunction day, consistent with the ARDSnet criteria and a SOFA score greater than or equal 
to 2.7,18 Assess hemofiltration or dialysis use.
3. Respiratory: Any day that mechanical ventilation was used (except during surgery) is counted 
as a respiratory failure day. Assess PaO2/FiO2 ratio.
4. Shock (cardiocirculatory): Any day when a vasopressor is used will be counted as a shock 
day. Vasopressors include any use of norepinephrine, epinephrine, phenylephrine or 
vasopressin, or any use of dopamine at a dose greater than (>) 5 μg/kg/min. If vasopressin is 
used, it must be given in conjunction with another vasopressor.


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15.5
Appendix E: Child-Pugh Scoring
Child-Pugh Score is a tool for classifying the severity of liver disease according to the degree of 
ascites, the plasma concentrations of bilirubin and albumin, the INR and the degree of encephalopathy.
ASSESSMENT
Measure
1 point
2 points
3 points
Units
Bilirubin
< 2
2–3
> 3
mg/100mL
Serum albumin
> 3.5
2.8–3.5
< 2.8
g/100mL
INR
< 1.7
1.7–2.3
> 2.3
no unit
Ascites*
Absent
Slight
Moderate
no unit
Hepatic encephalopathy None
Grade I–II 
Grade III–IV 
no unit
*As determined by physical examination alone
SCORING
Points
Class
5-6
A
7-9
B
10-15
C


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15.6
Appendix F: West Haven Criteria for Grading of Mental Status in Hepatic 
Encephalopathy 21
Grade
Criteria
I
Trivial lack of awareness
Shortened attention span
Impaired performance of addition 
Euphoria or anxiety
II
Lethargy or apathy
Minimal disorientation for time or place
Subtle personality change
Inappropriate behavior 
Impaired performance of subtraction
III
Somnolence to semi stupor, responsive to verbal stimuli
Confusion
Gross disorientation, bizarre behavior
IV
Coma (unresponsive to verbal or noxious stimuli)


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15.7
Appendix G: Prohibited Medications
The listing provided below includes medications that are most frequently given in the critical care setting. Please 
note that this list is not all-inclusive.  There may be other medications that fall into a protocol prohibited medication 
class.  The Sponsor should be contacted with any questions.
Antithrombotics* (thrombolytics, anticoagulants and antiplatelet drugs)
Vitamin K antagonists
Acenocoumarol • Clorindione • Coumatetralyl • Dicumarol (Dicoumarol) • Diphenadione • 
Ethyl biscoumacetate • Phenprocoumon • Phenindione • Tioclomarol • Warfarin
Heparin group
Danaparoid • Sulodexide
Glycoprotein IIb/IIIa 
inhibitors
Abciximab • Eptifibatide • Tirofiban
Other platelet
aggregation inhibitors
Aloxiprin • Ditazole • Carbasalate calcium • Cloricromen • Dipyridamole • Indobufen • 
Picotamide • Ticagrelor • Triflusal • ADP receptor inhibitors (Clopidogrel, Ticlopidine, 
Prasugrel) • prostaglandin analogue (Beraprost, Prostacyclin, Iloprost, Treprostinil), 
Acetylsalicylic acid/Aspirin
Enzymes
Plasminogen activators (Alteplase/Reteplase/Tenecteplase, Streptokinase, 
Urokinase/Saruplase, Anistreplase) • other serine endopeptidases (Ancrod, Fibrinolysin) • 
Brinase
Direct thrombin 
inhibitors
Direct Factor Xa 
Inhibitors
Argatroban • Bivalirudin • Dabigatran • Desirudin • Hirudin • Lepirudin • Melagatran • 
Ximelagatran
Rivaroxaban • Apixaban • Edoxaban
Other antithrombotics
Defibrotide • Dermatan sulfate • Fondaparinux* • Otamixaban • Rivaroxaban
Non-medicinal
EDTA • Oxalate
*All of the above antithrombotics are excluded with the exception of:
a. Heparin locks/flushes
b. Prophylaxis for DVT per prophylactic dosing on the package insert as approved in your country. Examples 
include:
1.
unfractionated heparin at total daily doses no higher than 15,000 U SQ  
2.
LMWH at a total daily dose no higher than 15000 U SQ
3.
rivaroxaban 10 mg p.o. qd or 20 mg p.o. qd for prevention of recurrent DVT
4.
enoxaparin 40 mg SQ qd
5.
fondaparinux 2.5 mg SQ qd
6.
danaparoid 750 units SQ q12h
7.
desirudin 15 mg SQ q12h
8.
apixabin 2.5 p.o. mg BID
c. Prophylaxis for cardiovascular disease:
1.
Up to 325 mg of aspirin daily  
d. Anticoagulants for RRT: 
1.
Regional citrate is preferred. It is recommended that if unfractionated heparin or LMWH is used, that 
the systemic exposure be less than or equal to the DVT prophylaxis dose allowed.


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15.8
Appendix H: Chemotherapeutic Agents Known to Cause Myeloablation
The listing provided below includes medications that have a known side effect of myelosuppression. 
The Sponsor should be contacted with any questions.
Alkylating Agents
Busulfan • Bendamustine • Carboplatin • Carmustine • Chlorambucil • 
Cisplatin • Cyclophosphamide • Dacarbazine • Ifosfamide • Lomustine • 
Mechlorethamine • Melphalan • Oxaliplatin • Streptozocin • 
Temozolomide 
Cytotoxic Agents
Azothiaprine • Bleomycin • Bortezomib • Busulfan • Capectabine • 
Carboplatin • Carmustine • Chlorambucil • Cisplatin • Cladribine, • 
Colaspase • Cyclophosphamide • Cytarabine • Dacarbazine • 
Dactinomycin • Daunorubicin • Docetaxel • Doxorubicin • Epirubicin • 
Etoposide • Fludarabine • Fluorouracil • Fotomusine • Ganciclovir
Anti-metabolites
Capecitabine • Hydroxyurea • Pemetrexed • Mercaptopurine •
Methotrexate • Gemcitabine • Nelarabine • Clofarabine 
Plant Alkaloids
Irinotecan • Topotecan • Etoposide • Paclitaxel
Topoisomerase 
Inhibitors
Hycamtin • Irinotecan • Novantrone


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15.9
Appendix I: Toxicity/Adverse Event Grading Table
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS 
AE Grading Table”) is a descriptive terminology which can be utilized for Adverse Event (AE) 
reporting. A grading (severity) scale is provided for each AE term.
This clarification of the DAIDS Table for Grading the Severity of Adult and Pediatric AE’s provides 
additional explanation of the DAIDS AE Grading Table and clarifies some of the parameters. 
I.
Instructions and Clarifications
Grading Adult and Pediatric AEs
The DAIDS AE Grading Table includes parameters for grading both Adult and Pediatric AEs.  When 
a single set of parameters is not appropriate for grading specific types of AEs for both Adult and 
Pediatric populations, separate sets of parameters for Adult and/or Pediatric populations (with 
specified respective age ranges) are given in the Table.  If there is no distinction in the Table between 
Adult and Pediatric values for a type of AE, then the single set of parameters listed is to be used for 
grading the severity of both Adult and Pediatric events of that type.  
Note: In the classification of adverse events, the term “severe” is not the same as “serious.” 
Severity is an indication of the intensity of a specific event (as in mild, moderate, or severe 
chest pain).  The term “serious” relates to a participant/event outcome or action criteria,
usually associated with events that pose a threat to a participant’s life or functioning. 
Addenda 1-3 Grading Tables for Microbicide Studies
For protocols involving topical application of products to the female genital tract, male genital area 
or rectum, strong consideration should be given to using Appendices I-III as the primary grading 
scales for these areas. The protocol would need to specifically state that one or more of the 
Appendices would be primary (and thus take precedence over the main Grading Table) for items that 
are listed in both the Appendix and the main Grading Table.
Addendum 1 - Female Genital Grading Table for Use in Microbicide Studies - PDF
Addendum 2 - Male Genital Grading Table for Use in Microbicide Studies - PDF
Addendum 3 - Rectal Grading Table for Use in Microbicide Studies - PDF
Grade 5
For any AE where the outcome is death, the severity of the AE is classified as Grade 5. 
Estimating Severity Grade for Parameters Not Identified in the Table
In order to grade a clinical AE that is not identified in the DAIDS AE grading table, use the 
category “Estimating Severity Grade” located on Page 3.


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Determining Severity Grade for Parameters “Between Grades”
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE 
could be either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a laboratory 
value that is graded as a multiple of the ULN or LLN falls between two grades, select the higher of 
the two grades for the AE. For example, Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x ULN for a 
parameter. If the laboratory value is 2.53 x ULN (which is between the two grades), the severity of 
this AE would be Grade 2, the higher of the two grades.
Values Below Grade 1
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded.
Determining Severity Grade when Local Laboratory Normal Values Overlap with Grade 1 Ranges 
In these situations, the severity grading is based on the ranges in the DAIDS AE Grading Table, even 
when there is a reference to the local laboratory LLN.
For example: Phosphate, Serum, Low, Adult and Pediatric > 14 years (Page 20) Grade 1 range is 
2.50 mg/dL - < LLN. A particular laboratory’s normal range for Phosphate is 2.1–3.8 mg/dL. A 
participant’s actual laboratory value is 2.5.   In this case, the value of 2.5 exceeds the LLN for the 
local lab, but will be graded as Grade 1 per DAIDS AE Grading Table.


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II.
Definitions of terms used in the Table:
Basic Self-care Functions
Adult
Activities such as bathing, dressing, toileting, 
transfer/movement, continence, and feeding.
Young Children
Activities that are age and culturally appropriate (e.g., feeding 
self with culturally appropriate eating implement).
LLN
Lower limit of normal
Medical Intervention
Use of pharmacologic or biologic agent(s) for treatment of an 
AE.
NA
Not Applicable
Operative Intervention
Surgical OR other invasive mechanical procedures.
ULN
Upper limit of normal
Usual Social & Functional 
Activities
Adult
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc.
Young Children
Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.).


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event 
NOT identified 
elsewhere in this 
DAIDS AE Grading 
Table 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
Symptoms causing 
inability to perform 
usual social & 
functional activities
Symptoms causing 
inability to perform 
basic self-care 
functions OR Medical 
or operative 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability, or death 
SYSTEMIC
Acute systemic 
allergic reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated
Generalized urticaria 
OR Angioedema with 
medical intervention 
indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
Symptoms causing 
inability to perform 
usual social & 
functional activities
Incapacitating fatigue/ 
malaise symptoms 
causing inability to 
perform basic self-care 
functions
Fever (non-axillary)
37.7% – 38.6qC
38.7% – 39.3qC
39.4% – 40.5qC
> 40.5qC


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pain (indicate body 
site)
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain)
See also Headache, 
Arthralgia, and 
Myalgia
Pain causing no or 
minimal interference 
with usual social & 
functional activities
Pain causing greater than 
minimal interference with 
usual social & functional 
activities
Pain causing inability 
to perform usual 
social & functional 
activities
Disabling pain causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization (other 
than emergency room 
visit) indicated
Unintentional weight 
loss
NA
5 – 9% loss in body 
weight from baseline
10 – 19% loss in body 
weight from baseline
t 20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated 
[e.g., tube feeding or 
total parenteral 
nutrition (TPN)]


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
INFECTION
Infection (any other 
than HIV infection)
Localized, no systemic 
antimicrobial treatment 
indicated AND 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
Systemic 
antimicrobial 
treatment indicated 
AND Symptoms 
causing inability to 
perform usual social 
& functional activities 
OR Operative 
intervention (other 
than simple incision 
and drainage) 
indicated
Life-threatening 
consequences (e.g., 
septic shock)
INJECTION SITE REACTIONS
Injection site pain 
(pain without 
touching)
Or
Tenderness (pain 
when area is 
touched) 
Pain/tenderness 
causing no or minimal 
limitation of use of limb
Pain/tenderness limiting 
use of limb OR 
Pain/tenderness causing 
greater than minimal 
interference with usual 
social & functional 
activities
Pain/tenderness 
causing inability to 
perform usual social 
& functional activities
Pain/tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness
Injection site reaction (localized)
Adult > 15 years
Erythema OR 
Induration
of 5x5 cm – 9x9 cm (or 
25 cm2 – 81cm2)
Erythema OR Induration 
OR Edema 
> 9 cm any diameter
(or > 81 cm2)
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving 
dermis and deeper 
tissue)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pediatric d 15 years
Erythema OR 
Induration OR Edema 
present but d 2.5 cm 
diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% 
surface area of the 
extremity segment (e.g., 
upper arm/thigh)
Erythema OR 
Induration OR Edema 
involving 
t 50% surface area of 
the extremity 
segment (e.g., upper 
arm/thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving 
dermis and deeper 
tissue)
Pruritis associated 
with injection 
See also Skin: Pruritis 
(itching - no skin 
lesions)
Itching localized to 
injection site AND 
Relieved 
spontaneously or with 
< 48 hours treatment 
Itching beyond the 
injection site but not 
generalized OR Itching 
localized to injection site 
requiring t 48 hours 
treatment 
Generalized itching 
causing inability to
perform usual social 
& functional activities
NA
SKIN – DERMATOLOGICAL
Alopecia
Thinning detectable by 
study participant (or by 
caregiver for young 
children and disabled 
adults)
Thinning or patchy hair 
loss detectable by health 
care provider
Complete hair loss
NA


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ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 93 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Cutaneous reaction –
rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations
of mucous membrane 
limited to one site
Extensive or 
generalized bullous 
lesions OR Stevens-
Johnson syndrome OR 
Ulceration of mucous 
membrane involving 
two or more distinct 
mucosal sites OR 
Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritus (itching – no
skin lesions) 
(See also Injection 
Site Reactions: 
Pruritus associated 
with injection)
Itching causing no or 
minimal interference 
with usual social & 
functional activities
Itching causing greater 
than minimal interference 
with usual social & 
functional activities
Itching causing 
inability to perform 
usual social & 
functional activities 
NA
CARDIOVASCULAR
Cardiac arrhythmia 
(general)
(By ECG or physical 
exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical 
intervention indicated
Symptomatic, non-
life-threatening AND 
Non-urgent medical 
intervention indicated 
Life-threatening 
arrhythmia OR Urgent
intervention indicated
Cardiac-
ischemia/infarction
NA
NA
Symptomatic 
ischemia (stable 
angina) OR Testing 
consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction


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ADULT AND PEDIATRIC ADVERSE EVENTS
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hemorrhage 
(significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of d
2 units packed RBCs 
(for children d
10 cc/kg) indicated 
Life-threatening 
hypotension OR 
Transfusion of >
2 units packed RBCs 
(for children > 10 
cc/kg) indicated
Hypertension
Adult > 17 years
(with repeat testing at 
same visit)
140 – 159 mmHg 
systolic
OR
90 – 99 mmHg 
diastolic
160 – 179 mmHg systolic
OR
100 – 109 mmHg diastolic
 180 mmHg systolic
OR
 110 mmHg diastolic
Life-threatening 
consequences (e.g., 
malignant 
hypertension) OR 
Hospitalization 
indicated (other than 
emergency room visit)
Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to t 100 -109 from > 100-109 (diastolic) and 
in Grade 3 to t 180 from > 180 (systolic) and to t 110 from > 110 (diastolic).
Pediatric d 17 years
(with repeat testing at 
same visit)
NA
91st – 94th percentile 
adjusted for age, height, 
and gender (systolic 
and/or diastolic)
th percentile 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic)
Life-threatening 
consequences (e.g., 
malignant 
hypertension) OR 
Hospitalization 
indicated (other than 
emergency room visit)
Hypotension
NA
Symptomatic, corrected 
with oral fluid replacement
Symptomatic, IV 
fluids indicated
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pericardial effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate 
or larger effusion requiring 
no intervention
Effusion with non-life 
threatening 
physiologic 
consequences OR 
Effusion with non-
urgent intervention 
indicated
Life-threatening 
consequences (e.g., 
tamponade) OR 
Urgent intervention 
indicated
Prolonged PR interval
Adult > 16 years
PR interval 
0.21 – 0.25 sec
PR interval
> 0.25 sec
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 sec
Complete AV block 
3HGLDWULF\HDUV
1st degree AV block
(PR > normal for age 
and rate)
Type I 2nd degree AV 
block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Adult > 16 years
Asymptomatic, QTc
interval 0.45 – 0.47 
sec OR Increase 
interval < 0.03 sec 
above baseline
Asymptomatic, QTc 
interval 0.48 – 0.49 sec 
OR Increase in interval 
0.03 – 0.05 sec above 
baseline
Asymptomatic, QTc 
interval t 0.50 sec 
OR Increase in 
interval 
t 0.06 sec above 
baseline
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated 
serious ventricular 
dysrhythmia
3HGLDWULF\HDUV
Asymptomatic, QTc 
interval 0.450 –
0.464 sec 
Asymptomatic, QTc 
interval 0.465 –
0.479 sec 
Asymptomatic, QTc 
interval t 0.480 sec 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated 
serious ventricular 
dysrhythmia


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ADULT AND PEDIATRIC ADVERSE EVENTS
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Thrombosis/embolism
NA
Deep vein thrombosis 
AND No intervention 
indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis 
AND Intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure) 
Embolic event (e.g., 
pulmonary embolism, 
life-threatening 
thrombus) 
Vasovagal episode 
(associated with a 
procedure of any 
kind)
Present without loss of 
consciousness 
Present with transient loss 
of consciousness
NA 
NA
Ventricular 
dysfunction 
(congestive heart 
failure)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with 
symptoms OR 
Worsening 
symptomatic 
congestive heart 
failure
Life-threatening 
congestive heart 
failure
GASTROINTESTINAL
Anorexia
Loss of appetite 
without decreased oral 
intake
Loss of appetite 
associated with decreased 
oral intake without 
significant weight loss
Loss of appetite 
associated with 
significant weight loss
Life-threatening 
consequences OR 
Aggressive 
intervention indicated 
[e.g., tube feeding or 
total parenteral 
nutrition (TPN)]
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when 
grading anorexia, this is not a requirement and should not be used as a substitute for clinical judgment. 
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Cholecystitis
NA
Symptomatic AND 
Medical intervention 
indicated
Radiologic, 
endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences (e.g., 
sepsis or perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated
Life-threatening 
consequences (e.g., 
obstruction)
Diarrhea
Adult and Pediatric 
t 1 year
Transient or 
intermittent episodes 
of unformed stools OR 
,QFUHDVHRIVWRROV
over baseline per 24-
hour period
Persistent episodes of 
unformed to watery stools 
OR Increase of 4 – 6
stools over baseline per 
24-hour period
Bloody diarrhea OR 
,QFUHDVHRIVWRROV
per 24-hour period
OR IV fluid 
replacement indicated
Life-threatening 
consequences (e.g., 
hypotensive shock)
Pediatric < 1 year
Liquid stools (more 
unformed than usual) 
but usual number of 
stools
Liquid stools with 
increased number of 
stools OR Mild 
dehydration
Liquid stools with 
moderate dehydration
Liquid stools resulting 
in severe dehydration 
with aggressive 
rehydration indicated 
OR Hypotensive shock
Dysphagia-
Odynophagia 
Symptomatic but able 
to eat usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing 
severely altered 
dietary intake with 
medical intervention 
indicated
Life-threatening 
reduction in oral intake


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VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Mucositis/stomatitis 
(clinical exam)
Indicate site (e.g., 
larynx, oral)
See Genitourinary for 
Vulvovaginitis 
See also Dysphagia-
Odynophagia and 
Proctitis
Erythema of the 
mucosa
Patchy 
pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences (e.g., 
aspiration, choking)
Nausea 
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake
Persistent nausea 
resulting in decreased oral 
intake for 24 – 48 hours
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR Aggressive 
rehydration indicated 
(e.g., IV fluids)
Life-threatening 
consequences (e.g., 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit)
Symptomatic AND 
Hospitalization 
indicated (other than 
emergency room 
visit)
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis)
Proctitis (functional-
symptomatic)
Also see 
Mucositis/stomatitis 
for clinical exam
Rectal discomfort AND 
No intervention 
indicated
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing 
inability to perform 
usual social &
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Vomiting
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids)
Life-threatening 
consequences (e.g., 
hypotensive shock)
NEUROLOGIC
Alteration in 
personality-behavior 
or in mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no 
or minimal interference 
with usual social & 
functional activities 
Alteration causing greater 
than minimal interference 
with usual social & 
functional activities 
Alteration causing 
inability to perform 
usual social & 
functional activities 
Behavior potentially 
harmful to self or 
others (e.g., suicidal 
and homicidal ideation 
or attempt, acute 
psychosis) OR 
Causing inability to 
perform basic self-care 
functions 
Altered Mental Status 
For Dementia, see 
Cognitive and 
behavioral/attention
disturbance (including 
dementia and 
attention deficit 
disorder)
Changes causing no or 
minimal interference 
with usual social & 
functional activities
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities
Delirium OR 
obtundation, OR coma
Ataxia 
Asymptomatic ataxia 
detectable on exam 
OR Minimal ataxia 
causing no or minimal 
interference with usual 
social & functional 
activities
Symptomatic ataxia 
causing greater than 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia 
causing inability to 
perform usual social
& functional activities 
Disabling ataxia 
causing inability to 
perform basic self-care 
functions


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ADULT AND PEDIATRIC ADVERSE EVENTS
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Cognitive and 
behavioral/attention
disturbance (including 
dementia and 
attention deficit 
disorder) 
Disability causing no or 
minimal interference 
with usual social & 
functional activities OR 
Specialized resources 
not indicated
Disability causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Specialized resources on 
part-time basis indicated
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated
CNS ischemia
(acute)
NA
NA
Transient ischemic 
attack
Cerebral vascular 
accident (CVA, stroke) 
with neurological 
deficit 
Developmental delay 
– Pediatric d 16
years
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate developmental 
delay,  either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting 
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either 
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Headache 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities
Symptoms causing 
inability to perform 
usual social & 
functional activities
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated (other than 
emergency room visit) 
OR Headache with 
significant impairment 
of alertness or other 
neurologic function 


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ADULT AND PEDIATRIC ADVERSE EVENTS
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social & functional
activities
Difficulty sleeping 
causing inability to 
perform usual social 
& functional activities
Disabling insomnia 
causing inability to 
perform basic self-care 
functions
Neuromuscular 
weakness 
(including myopathy 
& neuropathy) 
Asymptomatic with 
decreased strength on 
exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with usual 
social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual 
social & functional 
activities
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation
Neurosensory 
alteration (including 
paresthesia and 
painful neuropathy)
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing no 
or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities
Disabling sensory 
alteration or 
paresthesia causing 
inability to perform 
basic self-care 
functions
Seizure: (new onset)
– $GXOW\HDUV
See also Seizure: 
(known pre-existing 
seizure disorder)
NA
1 seizure 
2 – 4 seizures 
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy)


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VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Seizure: (known pre-
existing seizure 
disorder)
– $GXOW\HDUV
For worsening of 
existing epilepsy the 
grades should be 
based on an increase 
from previous level of 
control to any of 
these levels.
NA
Increased frequency of 
pre-existing seizures (non-
repetitive) without change 
in seizure character OR 
Infrequent break-through 
seizures while on stable 
medication in a previously 
controlled seizure disorder
Change in seizure 
character from 
baseline either in 
duration or quality 
(e.g., severity or 
focality) 
Seizures of any kind 
which are prolonged,
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy)
Seizure 
– Pediatric < 18 
years
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
< 5 minutes with 
< 24 hours post ictal 
state
Seizure, generalized 
onset with or without 
secondary generalization, 
lasting 5 – 20 minutes with 
< 24 hours post ictal state
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized 
onset with or without 
secondary 
generalization, 
requiring intubation 
and sedation
Syncope (not 
associated with a 
procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities
Vertigo causing greater 
than minimal interference 
with usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities
Disabling vertigo 
causing inability to 
perform basic self-care 
functions
RESPIRATORY
Bronchospasm 
(acute)
FEV1 or peak flow 
reduced to 
70% – 80%
FEV1 or peak flow 
50% – 69%
FEV1 or peak flow 
25% – 49% 
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation
Dyspnea or respiratory distress


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ADULT AND PEDIATRIC ADVERSE EVENTS
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
$GXOW\HDUV
Dyspnea on exertion 
with no or minimal 
interference with usual 
social & functional 
activities 
Dyspnea on exertion 
causing greater than 
minimal interference with 
usual social & functional 
activities 
Dyspnea at rest 
causing inability to 
perform usual social
& functional activities 
Respiratory failure with 
ventilatory support 
indicated
Pediatric < 14 years
Wheezing OR minimal 
increase in respiratory 
rate for age
Nasal flaring OR 
Intercostal retractions OR 
Pulse oximetry 90% –
95%
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90%
Respiratory failure with 
ventilatory support 
indicated
MUSCULOSKELETAL
Arthralgia
See also Arthritis
Joint pain causing no 
or minimal interference 
with usual social & 
functional activities
Joint pain causing greater 
than minimal interference 
with usual social & 
functional activities
Joint pain causing 
inability to perform 
usual social & 
functional activities
Disabling joint pain 
causing inability to 
perform basic self-care 
functions
Arthritis
See also Arthralgia
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities
Stiffness or joint swelling 
causing greater than 
minimal interference with 
usual social & functional
activities
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities
Disabling joint stiffness 
or swelling causing 
inability to perform 
basic self-care 
functions 
Bone Mineral Loss
$GXOW\HDUV
BMD t-score 
-2.5 to -1.0 
BMD t-score < -2.5
Pathological fracture 
(including loss of 
vertebral height)
Pathologic fracture 
causing life-
threatening 
consequences 
Pediatric < 21 years
BMD z-score 
-2.5 to -1.0
BMD z-score < -2.5
Pathological fracture 
(including loss of 
vertebral height)
Pathologic fracture 
causing life-
threatening 
consequences 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Myalgia
(non-injection site)
Muscle pain causing 
no or minimal 
interference with usual 
social & functional 
activities
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities
Muscle pain causing 
inability to perform 
usual social & 
functional activities
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings AND 
No operative intervention 
indicated
Symptomatic bone 
pain with radiographic 
findings OR 
Operative intervention 
indicated
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions
GENITOURINARY
Cervicitis 
(symptoms)
(For use in studies 
evaluating topical  
study agents) 
For other cervicitis 
see Infection: 
Infection (any other 
than HIV infection) 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions 
Cervicitis 
(clinical exam)
(For use in studies 
evaluating topical  
study agents) 
For other cervicitis 
see Infection: 
Infection (any other 
than HIV infection) 
Minimal cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial 
disruption 
< 25% of total surface
Moderate cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR Epithelial 
disruption of 25% – 49% 
total surface
Severe cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial 
disruption 
50% – 75% total 
surface
Epithelial disruption 
> 75% total surface


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Inter-menstrual 
bleeding (IMB)
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic 
examination
Inter-menstrual bleeding 
not greater in duration or 
amount than usual 
menstrual cycle
Inter-menstrual 
bleeding greater in 
duration or amount 
than usual menstrual 
cycle
Hemorrhage with life-
threatening 
hypotension OR 
Operative intervention 
indicated
Urinary tract 
obstruction (e.g., 
stone)
NA
Signs or symptoms of 
urinary tract obstruction 
without  hydronephrosis or 
renal dysfunction
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction
Obstruction causing 
life-threatening 
consequences
Vulvovaginitis 
(symptoms)
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection)
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions 
Vulvovaginitis 
(clinical exam)
(Use in studies 
evaluating topical 
study agents) 
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection)
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
< 25% of total surface
Moderate vaginal 
abnormalities on 
examination OR Epithelial 
disruption of 25% - 49% 
total surface
Severe vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
50% - 75% total 
surface
Vaginal perforation OR 
Epithelial disruption
> 75% total surface


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 106 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
OCULAR/VISUAL
Uveitis
Asymptomatic but 
detectable on exam
Symptomatic anterior 
uveitis OR Medical 
intervention indicated
Posterior or pan-
uveitis OR Operative 
intervention indicated
Disabling visual loss in 
affected eye(s) 
Visual changes (from 
baseline)
Visual changes 
causing no or minimal 
interference with usual 
social & functional 
activities
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities
Visual changes 
causing inability to 
perform usual social 
& functional activities
Disabling visual loss in 
affected eye(s)
ENDOCRINE/METABOLIC
Abnormal fat 
accumulation
(e.g., back of neck, 
breasts, abdomen)
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults)
Detectable on physical 
exam by health care 
provider
Disfiguring OR 
Obvious changes on 
casual visual 
inspection
NA
Diabetes mellitus
NA
New onset without need to 
initiate medication OR 
Modification of current 
medications to regain 
glucose control
New onset with 
initiation of 
medication indicated 
OR Diabetes 
uncontrolled despite 
treatment 
modification
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical 
exam by health care 
provider
Disfiguring OR 
Obvious on casual 
visual inspection
NA


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 107 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperthyroidism 
Asymptomatic
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma)
Lipoatrophy
(e.g., fat loss from the 
face, extremities, 
buttocks)
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults)
Detectable on physical 
exam by health care 
provider
Disfiguring OR 
Obvious on casual 
visual inspection
NA
LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Standard International Units are listed in italics


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 108 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Absolute CD4+ count
– Adult and 
Pediatric 
> 13 years
(HIV NEGATIVE
ONLY)
300 – 400/mm3
300 – 400/μL
200 – 299/mm3
200 – 299/μL
100 – 199/mm3
100 – 199/μL
< 100/mm3
< 100/μL
Absolute lymphocyte 
count 
– Adult and 
Pediatric
> 13 years
(HIV NEGATIVE
ONLY)
600 – 650/mm3
0.600 x 109 –
0.650 x 109/L
500 – 599/mm3
0.500 x 109 –
0.599 x 109/L
350 – 499/mm3
0.350 x 109 –
0.499 x 109/L
< 350/mm3
< 0.350 x 109/L
Comment: 9DOXHVLQFKLOGUHQ\HDUVDUHQRWJLYHQIRUWKHWZRSDUDPHWHUVDERYHEHFDXVHWKHDEVROXWHFRXQWVDUHYDULDEOH
Absolute neutrophil count (ANC)
Adult and Pediatric, 
> 7 days
1,000 – 1,300/mm3
1.000 x 109 –
1.300 x 109/L
750 – 999/mm3
0.750  x 109 –
0.999 x 109/L
500 – 749/mm3
0.500  x 109 –
0.749 x 109/L  
< 500/mm3
< 0.500 x 109/L
Infant†, 2 – d 7 days
1,250 – 1,500/mm3
1.250  x 109 –
1.500 x 109/L
1,000 – 1,249/mm3
1.000 x 109 –
1.249 x 109/L
750 – 999/mm3
0.750  x 109 –
0.999  x 109/L
< 750/mm3
< 0.750 x 109/L
Infant†, 1 day
4,000 – 5,000/mm3
4.000 x 109 –
5.000 x 109/L
3,000 – 3,999/mm3
3.000 x 109 –
3.999 x109/L
1,500 – 2,999/mm3
1.500 x 109 –
2.999 x 109/L
< 1,500/mm3
< 1.500 x 109/L
Comment: Parameter changed from “Infant, < 1 day” to “Infant, 1 day”


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 109 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Fibrinogen, 
decreased
100 – 200 mg/dL
1.00 – 2.00 g/L
OR
0.75 – 0.99 x LLN
75 – 99 mg/dL
0.75 – 0.99 g/L
OR
0.50 – 0.74 x LLN
50 – 74 mg/dL
0.50 – 0.74 g/L
OR
0.25 – 0.49 x LLN
< 50 mg/dL 
< 0.50 g/L
OR
< 0.25 x LLN
OR 
Associated with gross 
bleeding 
Hemoglobin (Hgb)
Comment:  The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been 
changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results obtained by an analytic 
method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor 
for that lab.
Adult and Pediatric
t 57 days
(HIV POSITIVE ONLY)
8.5 – 10.0 g/dL
5.24 – 6.23 mmol/L
7.5 – 8.4 g/dL
4.62–5.23 mmol/L
6.50 – 7.4 g/dL
4.03–4.61 mmol/L
< 6.5 g/dL
< 4.03 mmol/L
Adult and Pediatric 
t 57 days 
(HIV NEGATIVE
ONLY)
10.0 – 10.9 g/dL
6.18 – 6.79 mmol/L
OR
Any decrease 
2.5 – 3.4 g/dL
1.58 – 2.13 mmol/L
9.0 – 9.9 g/dL
5.55 - 6.17 mmol/L
OR
Any decrease 
3.5 – 4.4 g/dL
2.14 – 2.78 mmol/L
7.0 – 8.9 g/dL
4.34 - 5.54 mmol/L
OR
Any decrease 
t 4.5 g/dL
> 2.79 mmol/L
< 7.0 g/dL
< 4.34 mmol/L
Comment:  The decrease is a decrease from baseline
Infant†, 36 – 56
days
(HIV POSITIVE OR
NEGATIVE)
8.5 – 9.4 g/dL
5.24 – 5.86 mmol/L
7.0 – 8.4 g/dL
4.31 – 5.23 mmol/L
6.0 – 6.9 g/dL
3.72 – 4.30 mmol/L
< 6.00 g/dL
< 3.72 mmol/L


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 110 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Infant†, 22 – 35
days
(HIV POSITIVE OR
NEGATIVE)
9.5 – 10.5 g/dL
5.87 - 6.54 mmol/L
8.0 – 9.4 g/dL
4.93 – 5.86 mmol/L
7.0 – 7.9 g/dL
4.34 – 4.92 mmol/L
< 7.00 g/dL
< 4.34 mmol/L
Infant†,  21 days
(HIV POSITIVE OR
NEGATIVE)
12.0 – 13.0 g/dL
7.42 – 8.09 mmol/L
10.0 – 11.9 g/dL
6.18 – 7.41 mmol/L
9.0 – 9.9 g/dL
5.59- 6.17 mmol/L
< 9.0 g/dL
< 5.59 mmol/L
Correction:  Parameter changed from “Infant < 21 days” to “Infant GD\V´
International 
Normalized Ratio of 
prothrombin time 
(INR)
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0 – 10.0%
10.1 – 15.0%
15.1 – 20.0%
> 20.0%
Prothrombin Time 
(PT)
1.1 – 1.25 x ULN
1.26 – 1.50 x ULN
1.51 – 3.00 x ULN
> 3.00 x ULN
Partial 
Thromboplastin Time 
(PTT)
1.1 – 1.66 x ULN
1.67 – 2.33 x ULN
2.34 – 3.00 x ULN
> 3.00 x ULN
Platelets, decreased
100,000 –
124,999/mm3
100.000 x 109 –
124.999 x 109/L
50,000 –
99,999/mm3
50.000 x 109 –
99.999 x 109/L
25,000 –
49,999/mm3
25.000 x 109 –
49.999 x 109/L
< 25,000/mm3
< 25.000 x 109/L
WBC, decreased
2,000 – 2,500/mm3
2.000 x 109 –
2.500 x 109/L
1,500 – 1,999/mm3
1.500 x 109 –
1.999 x 109/L
1,000 – 1,499/mm3
1.000 x 109 –
1.499 x 109/L
< 1,000/mm3
< 1.000 x 109/L
CHEMISTRIES
Standard International Units are listed in italics
Acidosis
NA
pH < normal, but t 7.3
pH < 7.3 without life-
threatening 
consequences
pH < 7.3 with life-
threatening 
consequences


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 111 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Albumin, serum, low
3.0 g/dL – < LLN
30 g/L – < LLN
2.0 – 2.9 g/dL
20 – 29 g/L
< 2.0 g/dL
< 20 g/L
NA
Alkaline Phosphatase
1.25 – 2.5 x ULN†
2.6 – 5.0 x ULN†
5.1 – 10.0 x ULN†
> 10.0 x ULN†
Alkalosis
NA
pH > normal, but d 7.5
pH > 7.5 without life-
threatening 
consequences
pH > 7.5 with life-
threatening 
consequences 
ALT (SGPT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
AST (SGOT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
Bicarbonate, serum, 
low
16.0 mEq/L – < LLN
16.0 mmol/L – < LLN
11.0 – 15.9 mEq/L
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L
8.0 – 10.9 mmol/L
< 8.0 mEq/L
< 8.0 mmol/L
Comment: Some laboratories will report this value as bicarbonate (HCO3) and others as Total Carbon Dioxide (bicarbonate).  
These are the same tests; values should be graded according to the ranges for bicarbonate as listed above.
Bilirubin (Total)
Adult and Pediatric 
> 14 days
1.1 – 1.5 x ULN
1.6 – 2.5 x ULN
2.6 – 5.0 x ULN
> 5.0 x ULN
Infant†GD\V
(non-hemolytic)
NA
20.0 – 25.0 mg/dL
342 – 428 μmol/L
25.1 – 30.0 mg/dL
429 – 513 μmol/L
> 30.0 mg/dL
> 513.0 μmol/L
Infant†GD\V
(hemolytic)
NA
NA
20.0 – 25.0 mg/dL
342 – 428 μmol/L
> 25.0 mg/dL
> 428 μmol/L
Calcium, serum, high
Adult and Pediatric 
GD\V
10.6  – 11.5 mg/dL
2.65 – 2.88 mmol/L
11.6  – 12.5 mg/dL
2.89 – 3.13 mmol/L
12.6  – 13.5 mg/dL
3.14 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Infant†, < 7 days
11.5 – 12.4 mg/dL
2.88 – 3.10 mmol/L
12.5 – 12.9 mg/dL
3.11 – 3.23 mmol/L
13.0 – 13.5 mg/dL
3.245 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Calcium, serum, low 
Adult and Pediatric 
GD\V
7.8  – 8.4 mg/dL
1.95 – 2.10 mmol/L
7.0  – 7.7 mg/dL
1.75 – 1.94 mmol/L
6.1  – 6.9 mg/dL
1.53 – 1.74 mmol/L
< 6.1 mg/dL
< 1.53 mmol/L
Infant†, < 7 days
6.5 – 7.5 mg/dL
1.63 – 1.88 mmol/L
6.0 – 6.4 mg/dL
1.50 – 1.62 mmol/L
5.50 – 5.90 mg/dL
1.38 – 1.51 mmol/L
< 5.50 mg/dL
< 1.38 mmol/L


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 112 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Comment: Do not adjust Calcium, serum, low or Calcium, serum, high for albumin
Cardiac troponin I 
(cTnI)
NA
NA
NA
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer
Cardiac troponin T 
(cTnT)
NA
NA
NA
t 0.20 ng/mL
OR
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer
Cholesterol (fasting)
$GXOW\HDUV
200 – 239 mg/dL
5.18 – 6.19 mmol/L
240 – 300 mg/dL
6.20 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Pediatric < 18 years
170 – 199 mg/dL
4.40 – 5.15 mmol/L
200 – 300 mg/dL
5.16 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Creatinine Kinase
3.0 – 5.9 x ULN†
6.0 – 9.9 x ULN†
10.0 – 19.9 x ULN†
t 20.0 x ULN†
Creatinine
1.1 – 1.3 x ULN†
1.4 – 1.8 x ULN†
1.9 – 3.4 x ULN†
t 3.5 x ULN†
Glucose, serum, high 
Non-fasting
116 – 160 mg/dL
6.44 – 8.88 mmol/L
161 – 250 mg/dL
8.89 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Fasting
110 – 125 mg/dL
6.11 – 6.94 mmol/L
126 – 250 mg/dL
6.95 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Glucose, serum, low
Adult and Pediatric 
PRQWK
55 – 64 mg/dL
3.05 – 3.55 mmol/L
40 – 54 mg/dL
2.22 – 3.06 mmol/L
30 – 39 mg/dL
1.67 – 2.23 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Infant†, < 1 month
50 – 54 mg/dL
2.78 – 3.00 mmol/L
40 – 49 mg/dL
2.22 – 2.77 mmol/L
30 – 39 mg/dL
1.67 – 2.21 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Lactate
ULN - < 2.0 x ULN 
without acidosis
t 2.0 x ULN without 
acidosis
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences 
Comment: Added ULN to Grade 1 parameter 
LDL cholesterol (fasting)
$GXOW\HDUV
130 – 159 mg/dL
3.37 – 4.12 mmol/L
160 – 190 mg/dL
4.13 – 4.90 mmol/L
t 190 mg/dL
t 4.91 mmol/L
NA


DIVISON OF AIDS TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
Page 113 of 116
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pediatric > 2 - < 18 
years
110 – 129 mg/dL 
2.85 – 3.34 mmol/L
130 – 189 mg/dL
3.35 – 4.90 mmol/L
PJG/
PPRO/
NA
Lipase
1.1 – 1.5 x ULN
1.6 – 3.0 x ULN
3.1 – 5.0 x ULN
> 5.0 x ULN
Magnesium, serum,
low
1.2  – 1.4 me/L
0.60 – 0.70 mmol/L
0.9 – 1.1 mEq/L
0.45 – 0.59 mmol/L
0.6 – 0.8 mEq/L
0.30 – 0.44 mmol/L
< 0.60 me/L
< 0.30 mmol/L
Pancreatic amylase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
Phosphate, serum, low
Adult and Pediatric 
> 14 years
2.5 mg/dL – < LLN
0.81 mmol/L – < LLN
2.0 – 2.4 mg/dL
0.65 – 0.80 mmol/L
1.0 – 1.9 mg/dL
0.32 – 0.64 mmol/L
< 1.00 mg/dL
< 0.32 mmol/L
Pediatric 1 year – 14
years 
3.0 – 3.5 mg/dL
0.97 – 1.13 mmol/L
2.5 – 2.9 mg/dL
0.81 – 0.96 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Pediatric < 1 year
3.5 – 4.5 mg/dL
1.13 – 1.45 mmol/L
2.5 – 3.4 mg/dL
0.81 – 1.12 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Potassium, serum, 
high
5.6 – 6.0 me/L
5.6 – 6.0 mmol/L
6.1 – 6.5 me/L
6.1 – 6.5 mmol/L
6.6 – 7.0 me/L
6.6 – 7.0 mmol/L
> 7.0 me/L
> 7.0 mmol/L
Potassium, serum, 
low
3.0 – 3.4 me/L
3.0 – 3.4 mmol/L
2.5 – 2.9 me/L
2.5 – 2.9 mmol/L
2.0 – 2.4 me/L
2.0 – 2.4 mmol/L
< 2.0 me/L
< 2.0 mmol/L
Sodium, serum, high
146 – 150 me/L
146 – 150 mmol/L
151 – 154 me/L
151 – 154 mmol/L
155 – 159 me/L
155 – 159 mmol/L
t 160 me/L
t 160 mmol/L
Sodium, serum, low
130 – 135 me/L
130 – 135 mmol/L
125 – 129 me/L
125 – 129 mmol/L
121 – 124 me/L
121 – 124 mmol/L
d 120 me/L
d 120 mmol/L
Triglycerides (fasting)
NA
500 – 750 mg/dL
5.65 – 8.48 mmol/L
751 – 1,200 mg/dL
8.49 – 13.56 mmol/L
> 1,200 mg/dL
> 13.56 mmol/L
Uric acid
7.5 – 10.0 mg/dL
0.45 – 0.59 mmol/L
10.1 – 12.0 mg/dL
0.60 – 0.71 mmol/L
12.1 – 15.0 mg/dL
0.72 – 0.89 mmol/L
> 15.0 mg/dL
> 0.89 mmol/L
URINALYSIS
Standard International Units are listed in italics
Hematuria 
(microscopic)
6 – 10 RBC/HPF
> 10 RBC/HPF
Gross, with or without 
clots OR with RBC 
casts
Transfusion indicated
Proteinuria, random 
collection
1 +
2 – 3 +
4 +
NA
Proteinuria, 24 hour collection
Adult and Pediatric 
t 10 years
200 – 999 mg/24 h
0.200 – 0.999 g/d
1,000 – 1,999 mg/24 h
1.000 – 1.999 g/d
2,000 – 3,500 mg/24 
h
2.000 – 3.500 g/d
> 3,500 mg/24 h
> 3.500 g/d
Pediatric > 3 mo -
< 10 years
201 – 499 mg/m2/24 h
0.201 – 0.499 g/d
500 – 799 mg/m2/24 h
0.500 – 0.799 g/d
800 – 1,000 
mg/m2/24 h
0.800 – 1.000 g/d
> 1,000 mg/ m2/24 h
> 1.000 g/d


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Page 114 of 116
15.10 Appendix J: Conversions for PaO2/FiO2 calculations
Conversions for PaO2/FiO2 when the altitude is greater than 1000 m:
1) If your center uses Pb (Pb=barometric pressure in mmHg): Place the barometric pressure at 
your altitude into the equation PaO2/FiO2 x (Pb / 760 mm Hg)
2) If your center uses kPa: Place the atmospheric pressure at your altitude, into this equation 
PaO2/FiO2 x kPa/100 kPa.
Adapted from the equation developed by Severinghaus31: SO2 = (23,400 * (pO23 + 150 * pO2)-1 + 1)-1
O2 Saturation Conversion Table31
Pulse oximetry O2 saturation may be used for Calculating PaO2/FiO2 ratio when 
ABG is not available
SaO2 (%)
Calculated PaO2
80
44
81
45
82
46
83
47
84
49
85
50
86
52
87
53
88
55
89
57
90
60
91
62
92
65
93
69
94
73
95
79
96
86
97
96
98
112
99
145


Protocol 3-001    
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Version 4.1
Asahi Kasei Pharma America Corporation
Page 115 of 116
15.11 Appendix K: The APACHE II Severity of Disease Classification System29


Protocol 3-001    
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Page 116 of 116
15.12 Appendix L: Glasgow Coma Scale30
The scale consists of three separate responses: eye opening (E), verbal (V), and motor responses
(M), each classified by a series of grades of responsiveness.
Eye Opening 
Best Verbal Response
Best Motor Response
Spontaneous
4
Oriented
5
Obey commands
6
To Sound
3
Confused
4
Localize
5
To Pain
2
Inappropriate
3
Flexion: normal
4
Never
1
Incomprehensible
2
Flexion: abnormal
3
None
1
Extension
2
Nil
1

SAP_001.pdf: 
Asahi Kasei Pharma America Corporation 
 
ART-123
Protocol: 3-001
Clinical study report
16.1.9
Documentation of Statistical Methods
This section contains the following document: 
Statistical Analysis Plan (SAP) version 1.0 dated 18 Jun 2018 
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This document contains confidential information regarding above clinical study conducted by Asahi 
Kasei Pharma America Corporation. Upon acceptance of this document, the Investigator and Institution 
agrees to maintain the information as confidential and limit the access to any such information to only 
those persons who are under, the Investigator or Institution direct control and, will be engaged in 
employing such information for the purpose of conducting the study. At no time shall such information be 
available and employed for any other purposes without   prior written approval of Asahi Kasei Pharma 
America Corporation. This document is prepared in accordance with the ICH E6 Guidance for Good 
Clinical Practice. 
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